hypothesis in qualitative research studies usually

Chapter 1. Introduction

“Science is in danger, and for that reason it is becoming dangerous” -Pierre Bourdieu, Science of Science and Reflexivity

Why an Open Access Textbook on Qualitative Research Methods?

I have been teaching qualitative research methods to both undergraduates and graduate students for many years.  Although there are some excellent textbooks out there, they are often costly, and none of them, to my mind, properly introduces qualitative research methods to the beginning student (whether undergraduate or graduate student).  In contrast, this open-access textbook is designed as a (free) true introduction to the subject, with helpful, practical pointers on how to conduct research and how to access more advanced instruction.  

Textbooks are typically arranged in one of two ways: (1) by technique (each chapter covers one method used in qualitative research); or (2) by process (chapters advance from research design through publication).  But both of these approaches are necessary for the beginner student.  This textbook will have sections dedicated to the process as well as the techniques of qualitative research.  This is a true “comprehensive” book for the beginning student.  In addition to covering techniques of data collection and data analysis, it provides a road map of how to get started and how to keep going and where to go for advanced instruction.  It covers aspects of research design and research communication as well as methods employed.  Along the way, it includes examples from many different disciplines in the social sciences.

The primary goal has been to create a useful, accessible, engaging textbook for use across many disciplines.  And, let’s face it.  Textbooks can be boring.  I hope readers find this to be a little different.  I have tried to write in a practical and forthright manner, with many lively examples and references to good and intellectually creative qualitative research.  Woven throughout the text are short textual asides (in colored textboxes) by professional (academic) qualitative researchers in various disciplines.  These short accounts by practitioners should help inspire students.  So, let’s begin!

What is Research?

When we use the word research , what exactly do we mean by that?  This is one of those words that everyone thinks they understand, but it is worth beginning this textbook with a short explanation.  We use the term to refer to “empirical research,” which is actually a historically specific approach to understanding the world around us.  Think about how you know things about the world. [1] You might know your mother loves you because she’s told you she does.  Or because that is what “mothers” do by tradition.  Or you might know because you’ve looked for evidence that she does, like taking care of you when you are sick or reading to you in bed or working two jobs so you can have the things you need to do OK in life.  Maybe it seems churlish to look for evidence; you just take it “on faith” that you are loved.

Only one of the above comes close to what we mean by research.  Empirical research is research (investigation) based on evidence.  Conclusions can then be drawn from observable data.  This observable data can also be “tested” or checked.  If the data cannot be tested, that is a good indication that we are not doing research.  Note that we can never “prove” conclusively, through observable data, that our mothers love us.  We might have some “disconfirming evidence” (that time she didn’t show up to your graduation, for example) that could push you to question an original hypothesis , but no amount of “confirming evidence” will ever allow us to say with 100% certainty, “my mother loves me.”  Faith and tradition and authority work differently.  Our knowledge can be 100% certain using each of those alternative methods of knowledge, but our certainty in those cases will not be based on facts or evidence.

For many periods of history, those in power have been nervous about “science” because it uses evidence and facts as the primary source of understanding the world, and facts can be at odds with what power or authority or tradition want you to believe.  That is why I say that scientific empirical research is a historically specific approach to understand the world.  You are in college or university now partly to learn how to engage in this historically specific approach.

In the sixteenth and seventeenth centuries in Europe, there was a newfound respect for empirical research, some of which was seriously challenging to the established church.  Using observations and testing them, scientists found that the earth was not at the center of the universe, for example, but rather that it was but one planet of many which circled the sun. [2]   For the next two centuries, the science of astronomy, physics, biology, and chemistry emerged and became disciplines taught in universities.  All used the scientific method of observation and testing to advance knowledge.  Knowledge about people , however, and social institutions, however, was still left to faith, tradition, and authority.  Historians and philosophers and poets wrote about the human condition, but none of them used research to do so. [3]

It was not until the nineteenth century that “social science” really emerged, using the scientific method (empirical observation) to understand people and social institutions.  New fields of sociology, economics, political science, and anthropology emerged.  The first sociologists, people like Auguste Comte and Karl Marx, sought specifically to apply the scientific method of research to understand society, Engels famously claiming that Marx had done for the social world what Darwin did for the natural world, tracings its laws of development.  Today we tend to take for granted the naturalness of science here, but it is actually a pretty recent and radical development.

To return to the question, “does your mother love you?”  Well, this is actually not really how a researcher would frame the question, as it is too specific to your case.  It doesn’t tell us much about the world at large, even if it does tell us something about you and your relationship with your mother.  A social science researcher might ask, “do mothers love their children?”  Or maybe they would be more interested in how this loving relationship might change over time (e.g., “do mothers love their children more now than they did in the 18th century when so many children died before reaching adulthood?”) or perhaps they might be interested in measuring quality of love across cultures or time periods, or even establishing “what love looks like” using the mother/child relationship as a site of exploration.  All of these make good research questions because we can use observable data to answer them.

What is Qualitative Research?

“All we know is how to learn. How to study, how to listen, how to talk, how to tell.  If we don’t tell the world, we don’t know the world.  We’re lost in it, we die.” -Ursula LeGuin, The Telling

At its simplest, qualitative research is research about the social world that does not use numbers in its analyses.  All those who fear statistics can breathe a sigh of relief – there are no mathematical formulae or regression models in this book! But this definition is less about what qualitative research can be and more about what it is not.  To be honest, any simple statement will fail to capture the power and depth of qualitative research.  One way of contrasting qualitative research to quantitative research is to note that the focus of qualitative research is less about explaining and predicting relationships between variables and more about understanding the social world.  To use our mother love example, the question about “what love looks like” is a good question for the qualitative researcher while all questions measuring love or comparing incidences of love (both of which require measurement) are good questions for quantitative researchers. Patton writes,

Qualitative data describe.  They take us, as readers, into the time and place of the observation so that we know what it was like to have been there.  They capture and communicate someone else’s experience of the world in his or her own words.  Qualitative data tell a story. ( Patton 2002:47 )

Qualitative researchers are asking different questions about the world than their quantitative colleagues.  Even when researchers are employed in “mixed methods” research ( both quantitative and qualitative), they are using different methods to address different questions of the study.  I do a lot of research about first-generation and working-college college students.  Where a quantitative researcher might ask, how many first-generation college students graduate from college within four years? Or does first-generation college status predict high student debt loads?  A qualitative researcher might ask, how does the college experience differ for first-generation college students?  What is it like to carry a lot of debt, and how does this impact the ability to complete college on time?  Both sets of questions are important, but they can only be answered using specific tools tailored to those questions.  For the former, you need large numbers to make adequate comparisons.  For the latter, you need to talk to people, find out what they are thinking and feeling, and try to inhabit their shoes for a little while so you can make sense of their experiences and beliefs.

Examples of Qualitative Research

You have probably seen examples of qualitative research before, but you might not have paid particular attention to how they were produced or realized that the accounts you were reading were the result of hours, months, even years of research “in the field.”  A good qualitative researcher will present the product of their hours of work in such a way that it seems natural, even obvious, to the reader.  Because we are trying to convey what it is like answers, qualitative research is often presented as stories – stories about how people live their lives, go to work, raise their children, interact with one another.  In some ways, this can seem like reading particularly insightful novels.  But, unlike novels, there are very specific rules and guidelines that qualitative researchers follow to ensure that the “story” they are telling is accurate , a truthful rendition of what life is like for the people being studied.  Most of this textbook will be spent conveying those rules and guidelines.  Let’s take a look, first, however, at three examples of what the end product looks like.  I have chosen these three examples to showcase very different approaches to qualitative research, and I will return to these five examples throughout the book.  They were all published as whole books (not chapters or articles), and they are worth the long read, if you have the time.  I will also provide some information on how these books came to be and the length of time it takes to get them into book version.  It is important you know about this process, and the rest of this textbook will help explain why it takes so long to conduct good qualitative research!

Example 1 : The End Game (ethnography + interviews)

Corey Abramson is a sociologist who teaches at the University of Arizona.   In 2015 he published The End Game: How Inequality Shapes our Final Years ( 2015 ). This book was based on the research he did for his dissertation at the University of California-Berkeley in 2012.  Actually, the dissertation was completed in 2012 but the work that was produced that took several years.  The dissertation was entitled, “This is How We Live, This is How We Die: Social Stratification, Aging, and Health in Urban America” ( 2012 ).  You can see how the book version, which was written for a more general audience, has a more engaging sound to it, but that the dissertation version, which is what academic faculty read and evaluate, has a more descriptive title.  You can read the title and know that this is a study about aging and health and that the focus is going to be inequality and that the context (place) is going to be “urban America.”  It’s a study about “how” people do something – in this case, how they deal with aging and death.  This is the very first sentence of the dissertation, “From our first breath in the hospital to the day we die, we live in a society characterized by unequal opportunities for maintaining health and taking care of ourselves when ill.  These disparities reflect persistent racial, socio-economic, and gender-based inequalities and contribute to their persistence over time” ( 1 ).  What follows is a truthful account of how that is so.

Cory Abramson spent three years conducting his research in four different urban neighborhoods.  We call the type of research he conducted “comparative ethnographic” because he designed his study to compare groups of seniors as they went about their everyday business.  It’s comparative because he is comparing different groups (based on race, class, gender) and ethnographic because he is studying the culture/way of life of a group. [4]   He had an educated guess, rooted in what previous research had shown and what social theory would suggest, that people’s experiences of aging differ by race, class, and gender.  So, he set up a research design that would allow him to observe differences.  He chose two primarily middle-class (one was racially diverse and the other was predominantly White) and two primarily poor neighborhoods (one was racially diverse and the other was predominantly African American).  He hung out in senior centers and other places seniors congregated, watched them as they took the bus to get prescriptions filled, sat in doctor’s offices with them, and listened to their conversations with each other.  He also conducted more formal conversations, what we call in-depth interviews, with sixty seniors from each of the four neighborhoods.  As with a lot of fieldwork , as he got closer to the people involved, he both expanded and deepened his reach –

By the end of the project, I expanded my pool of general observations to include various settings frequented by seniors: apartment building common rooms, doctors’ offices, emergency rooms, pharmacies, senior centers, bars, parks, corner stores, shopping centers, pool halls, hair salons, coffee shops, and discount stores. Over the course of the three years of fieldwork, I observed hundreds of elders, and developed close relationships with a number of them. ( 2012:10 )

When Abramson rewrote the dissertation for a general audience and published his book in 2015, it got a lot of attention.  It is a beautifully written book and it provided insight into a common human experience that we surprisingly know very little about.  It won the Outstanding Publication Award by the American Sociological Association Section on Aging and the Life Course and was featured in the New York Times .  The book was about aging, and specifically how inequality shapes the aging process, but it was also about much more than that.  It helped show how inequality affects people’s everyday lives.  For example, by observing the difficulties the poor had in setting up appointments and getting to them using public transportation and then being made to wait to see a doctor, sometimes in standing-room-only situations, when they are unwell, and then being treated dismissively by hospital staff, Abramson allowed readers to feel the material reality of being poor in the US.  Comparing these examples with seniors with adequate supplemental insurance who have the resources to hire car services or have others assist them in arranging care when they need it, jolts the reader to understand and appreciate the difference money makes in the lives and circumstances of us all, and in a way that is different than simply reading a statistic (“80% of the poor do not keep regular doctor’s appointments”) does.  Qualitative research can reach into spaces and places that often go unexamined and then reports back to the rest of us what it is like in those spaces and places.

Example 2: Racing for Innocence (Interviews + Content Analysis + Fictional Stories)

Jennifer Pierce is a Professor of American Studies at the University of Minnesota.  Trained as a sociologist, she has written a number of books about gender, race, and power.  Her very first book, Gender Trials: Emotional Lives in Contemporary Law Firms, published in 1995, is a brilliant look at gender dynamics within two law firms.  Pierce was a participant observer, working as a paralegal, and she observed how female lawyers and female paralegals struggled to obtain parity with their male colleagues.

Fifteen years later, she reexamined the context of the law firm to include an examination of racial dynamics, particularly how elite white men working in these spaces created and maintained a culture that made it difficult for both female attorneys and attorneys of color to thrive. Her book, Racing for Innocence: Whiteness, Gender, and the Backlash Against Affirmative Action , published in 2012, is an interesting and creative blending of interviews with attorneys, content analyses of popular films during this period, and fictional accounts of racial discrimination and sexual harassment.  The law firm she chose to study had come under an affirmative action order and was in the process of implementing equitable policies and programs.  She wanted to understand how recipients of white privilege (the elite white male attorneys) come to deny the role they play in reproducing inequality.  Through interviews with attorneys who were present both before and during the affirmative action order, she creates a historical record of the “bad behavior” that necessitated new policies and procedures, but also, and more importantly , probed the participants ’ understanding of this behavior.  It should come as no surprise that most (but not all) of the white male attorneys saw little need for change, and that almost everyone else had accounts that were different if not sometimes downright harrowing.

I’ve used Pierce’s book in my qualitative research methods courses as an example of an interesting blend of techniques and presentation styles.  My students often have a very difficult time with the fictional accounts she includes.  But they serve an important communicative purpose here.  They are her attempts at presenting “both sides” to an objective reality – something happens (Pierce writes this something so it is very clear what it is), and the two participants to the thing that happened have very different understandings of what this means.  By including these stories, Pierce presents one of her key findings – people remember things differently and these different memories tend to support their own ideological positions.  I wonder what Pierce would have written had she studied the murder of George Floyd or the storming of the US Capitol on January 6 or any number of other historic events whose observers and participants record very different happenings.

This is not to say that qualitative researchers write fictional accounts.  In fact, the use of fiction in our work remains controversial.  When used, it must be clearly identified as a presentation device, as Pierce did.  I include Racing for Innocence here as an example of the multiple uses of methods and techniques and the way that these work together to produce better understandings by us, the readers, of what Pierce studied.  We readers come away with a better grasp of how and why advantaged people understate their own involvement in situations and structures that advantage them.  This is normal human behavior , in other words.  This case may have been about elite white men in law firms, but the general insights here can be transposed to other settings.  Indeed, Pierce argues that more research needs to be done about the role elites play in the reproduction of inequality in the workplace in general.

Example 3: Amplified Advantage (Mixed Methods: Survey Interviews + Focus Groups + Archives)

The final example comes from my own work with college students, particularly the ways in which class background affects the experience of college and outcomes for graduates.  I include it here as an example of mixed methods, and for the use of supplementary archival research.  I’ve done a lot of research over the years on first-generation, low-income, and working-class college students.  I am curious (and skeptical) about the possibility of social mobility today, particularly with the rising cost of college and growing inequality in general.  As one of the few people in my family to go to college, I didn’t grow up with a lot of examples of what college was like or how to make the most of it.  And when I entered graduate school, I realized with dismay that there were very few people like me there.  I worried about becoming too different from my family and friends back home.  And I wasn’t at all sure that I would ever be able to pay back the huge load of debt I was taking on.  And so I wrote my dissertation and first two books about working-class college students.  These books focused on experiences in college and the difficulties of navigating between family and school ( Hurst 2010a, 2012 ).  But even after all that research, I kept coming back to wondering if working-class students who made it through college had an equal chance at finding good jobs and happy lives,

What happens to students after college?  Do working-class students fare as well as their peers?  I knew from my own experience that barriers continued through graduate school and beyond, and that my debtload was higher than that of my peers, constraining some of the choices I made when I graduated.  To answer these questions, I designed a study of students attending small liberal arts colleges, the type of college that tried to equalize the experience of students by requiring all students to live on campus and offering small classes with lots of interaction with faculty.  These private colleges tend to have more money and resources so they can provide financial aid to low-income students.  They also attract some very wealthy students.  Because they enroll students across the class spectrum, I would be able to draw comparisons.  I ended up spending about four years collecting data, both a survey of more than 2000 students (which formed the basis for quantitative analyses) and qualitative data collection (interviews, focus groups, archival research, and participant observation).  This is what we call a “mixed methods” approach because we use both quantitative and qualitative data.  The survey gave me a large enough number of students that I could make comparisons of the how many kind, and to be able to say with some authority that there were in fact significant differences in experience and outcome by class (e.g., wealthier students earned more money and had little debt; working-class students often found jobs that were not in their chosen careers and were very affected by debt, upper-middle-class students were more likely to go to graduate school).  But the survey analyses could not explain why these differences existed.  For that, I needed to talk to people and ask them about their motivations and aspirations.  I needed to understand their perceptions of the world, and it is very hard to do this through a survey.

By interviewing students and recent graduates, I was able to discern particular patterns and pathways through college and beyond.  Specifically, I identified three versions of gameplay.  Upper-middle-class students, whose parents were themselves professionals (academics, lawyers, managers of non-profits), saw college as the first stage of their education and took classes and declared majors that would prepare them for graduate school.  They also spent a lot of time building their resumes, taking advantage of opportunities to help professors with their research, or study abroad.  This helped them gain admission to highly-ranked graduate schools and interesting jobs in the public sector.  In contrast, upper-class students, whose parents were wealthy and more likely to be engaged in business (as CEOs or other high-level directors), prioritized building social capital.  They did this by joining fraternities and sororities and playing club sports.  This helped them when they graduated as they called on friends and parents of friends to find them well-paying jobs.  Finally, low-income, first-generation, and working-class students were often adrift.  They took the classes that were recommended to them but without the knowledge of how to connect them to life beyond college.  They spent time working and studying rather than partying or building their resumes.  All three sets of students thought they were “doing college” the right way, the way that one was supposed to do college.   But these three versions of gameplay led to distinct outcomes that advantaged some students over others.  I titled my work “Amplified Advantage” to highlight this process.

These three examples, Cory Abramson’s The End Game , Jennifer Peirce’s Racing for Innocence, and my own Amplified Advantage, demonstrate the range of approaches and tools available to the qualitative researcher.  They also help explain why qualitative research is so important.  Numbers can tell us some things about the world, but they cannot get at the hearts and minds, motivations and beliefs of the people who make up the social worlds we inhabit.  For that, we need tools that allow us to listen and make sense of what people tell us and show us.  That is what good qualitative research offers us.

How Is This Book Organized?

This textbook is organized as a comprehensive introduction to the use of qualitative research methods.  The first half covers general topics (e.g., approaches to qualitative research, ethics) and research design (necessary steps for building a successful qualitative research study).  The second half reviews various data collection and data analysis techniques.  Of course, building a successful qualitative research study requires some knowledge of data collection and data analysis so the chapters in the first half and the chapters in the second half should be read in conversation with each other.  That said, each chapter can be read on its own for assistance with a particular narrow topic.  In addition to the chapters, a helpful glossary can be found in the back of the book.  Rummage around in the text as needed.

Chapter Descriptions

Chapter 2 provides an overview of the Research Design Process.  How does one begin a study? What is an appropriate research question?  How is the study to be done – with what methods ?  Involving what people and sites?  Although qualitative research studies can and often do change and develop over the course of data collection, it is important to have a good idea of what the aims and goals of your study are at the outset and a good plan of how to achieve those aims and goals.  Chapter 2 provides a road map of the process.

Chapter 3 describes and explains various ways of knowing the (social) world.  What is it possible for us to know about how other people think or why they behave the way they do?  What does it mean to say something is a “fact” or that it is “well-known” and understood?  Qualitative researchers are particularly interested in these questions because of the types of research questions we are interested in answering (the how questions rather than the how many questions of quantitative research).  Qualitative researchers have adopted various epistemological approaches.  Chapter 3 will explore these approaches, highlighting interpretivist approaches that acknowledge the subjective aspect of reality – in other words, reality and knowledge are not objective but rather influenced by (interpreted through) people.

Chapter 4 focuses on the practical matter of developing a research question and finding the right approach to data collection.  In any given study (think of Cory Abramson’s study of aging, for example), there may be years of collected data, thousands of observations , hundreds of pages of notes to read and review and make sense of.  If all you had was a general interest area (“aging”), it would be very difficult, nearly impossible, to make sense of all of that data.  The research question provides a helpful lens to refine and clarify (and simplify) everything you find and collect.  For that reason, it is important to pull out that lens (articulate the research question) before you get started.  In the case of the aging study, Cory Abramson was interested in how inequalities affected understandings and responses to aging.  It is for this reason he designed a study that would allow him to compare different groups of seniors (some middle-class, some poor).  Inevitably, he saw much more in the three years in the field than what made it into his book (or dissertation), but he was able to narrow down the complexity of the social world to provide us with this rich account linked to the original research question.  Developing a good research question is thus crucial to effective design and a successful outcome.  Chapter 4 will provide pointers on how to do this.  Chapter 4 also provides an overview of general approaches taken to doing qualitative research and various “traditions of inquiry.”

Chapter 5 explores sampling .  After you have developed a research question and have a general idea of how you will collect data (Observations?  Interviews?), how do you go about actually finding people and sites to study?  Although there is no “correct number” of people to interview , the sample should follow the research question and research design.  Unlike quantitative research, qualitative research involves nonprobability sampling.  Chapter 5 explains why this is so and what qualities instead make a good sample for qualitative research.

Chapter 6 addresses the importance of reflexivity in qualitative research.  Related to epistemological issues of how we know anything about the social world, qualitative researchers understand that we the researchers can never be truly neutral or outside the study we are conducting.  As observers, we see things that make sense to us and may entirely miss what is either too obvious to note or too different to comprehend.  As interviewers, as much as we would like to ask questions neutrally and remain in the background, interviews are a form of conversation, and the persons we interview are responding to us .  Therefore, it is important to reflect upon our social positions and the knowledges and expectations we bring to our work and to work through any blind spots that we may have.  Chapter 6 provides some examples of reflexivity in practice and exercises for thinking through one’s own biases.

Chapter 7 is a very important chapter and should not be overlooked.  As a practical matter, it should also be read closely with chapters 6 and 8.  Because qualitative researchers deal with people and the social world, it is imperative they develop and adhere to a strong ethical code for conducting research in a way that does not harm.  There are legal requirements and guidelines for doing so (see chapter 8), but these requirements should not be considered synonymous with the ethical code required of us.   Each researcher must constantly interrogate every aspect of their research, from research question to design to sample through analysis and presentation, to ensure that a minimum of harm (ideally, zero harm) is caused.  Because each research project is unique, the standards of care for each study are unique.  Part of being a professional researcher is carrying this code in one’s heart, being constantly attentive to what is required under particular circumstances.  Chapter 7 provides various research scenarios and asks readers to weigh in on the suitability and appropriateness of the research.  If done in a class setting, it will become obvious fairly quickly that there are often no absolutely correct answers, as different people find different aspects of the scenarios of greatest importance.  Minimizing the harm in one area may require possible harm in another.  Being attentive to all the ethical aspects of one’s research and making the best judgments one can, clearly and consciously, is an integral part of being a good researcher.

Chapter 8 , best to be read in conjunction with chapter 7, explains the role and importance of Institutional Review Boards (IRBs) .  Under federal guidelines, an IRB is an appropriately constituted group that has been formally designated to review and monitor research involving human subjects .  Every institution that receives funding from the federal government has an IRB.  IRBs have the authority to approve, require modifications to (to secure approval), or disapprove research.  This group review serves an important role in the protection of the rights and welfare of human research subjects.  Chapter 8 reviews the history of IRBs and the work they do but also argues that IRBs’ review of qualitative research is often both over-inclusive and under-inclusive.  Some aspects of qualitative research are not well understood by IRBs, given that they were developed to prevent abuses in biomedical research.  Thus, it is important not to rely on IRBs to identify all the potential ethical issues that emerge in our research (see chapter 7).

Chapter 9 provides help for getting started on formulating a research question based on gaps in the pre-existing literature.  Research is conducted as part of a community, even if particular studies are done by single individuals (or small teams).  What any of us finds and reports back becomes part of a much larger body of knowledge.  Thus, it is important that we look at the larger body of knowledge before we actually start our bit to see how we can best contribute.  When I first began interviewing working-class college students, there was only one other similar study I could find, and it hadn’t been published (it was a dissertation of students from poor backgrounds).  But there had been a lot published by professors who had grown up working class and made it through college despite the odds.  These accounts by “working-class academics” became an important inspiration for my study and helped me frame the questions I asked the students I interviewed.  Chapter 9 will provide some pointers on how to search for relevant literature and how to use this to refine your research question.

Chapter 10 serves as a bridge between the two parts of the textbook, by introducing techniques of data collection.  Qualitative research is often characterized by the form of data collection – for example, an ethnographic study is one that employs primarily observational data collection for the purpose of documenting and presenting a particular culture or ethnos.  Techniques can be effectively combined, depending on the research question and the aims and goals of the study.   Chapter 10 provides a general overview of all the various techniques and how they can be combined.

The second part of the textbook moves into the doing part of qualitative research once the research question has been articulated and the study designed.  Chapters 11 through 17 cover various data collection techniques and approaches.  Chapters 18 and 19 provide a very simple overview of basic data analysis.  Chapter 20 covers communication of the data to various audiences, and in various formats.

Chapter 11 begins our overview of data collection techniques with a focus on interviewing , the true heart of qualitative research.  This technique can serve as the primary and exclusive form of data collection, or it can be used to supplement other forms (observation, archival).  An interview is distinct from a survey, where questions are asked in a specific order and often with a range of predetermined responses available.  Interviews can be conversational and unstructured or, more conventionally, semistructured , where a general set of interview questions “guides” the conversation.  Chapter 11 covers the basics of interviews: how to create interview guides, how many people to interview, where to conduct the interview, what to watch out for (how to prepare against things going wrong), and how to get the most out of your interviews.

Chapter 12 covers an important variant of interviewing, the focus group.  Focus groups are semistructured interviews with a group of people moderated by a facilitator (the researcher or researcher’s assistant).  Focus groups explicitly use group interaction to assist in the data collection.  They are best used to collect data on a specific topic that is non-personal and shared among the group.  For example, asking a group of college students about a common experience such as taking classes by remote delivery during the pandemic year of 2020.  Chapter 12 covers the basics of focus groups: when to use them, how to create interview guides for them, and how to run them effectively.

Chapter 13 moves away from interviewing to the second major form of data collection unique to qualitative researchers – observation .  Qualitative research that employs observation can best be understood as falling on a continuum of “fly on the wall” observation (e.g., observing how strangers interact in a doctor’s waiting room) to “participant” observation, where the researcher is also an active participant of the activity being observed.  For example, an activist in the Black Lives Matter movement might want to study the movement, using her inside position to gain access to observe key meetings and interactions.  Chapter  13 covers the basics of participant observation studies: advantages and disadvantages, gaining access, ethical concerns related to insider/outsider status and entanglement, and recording techniques.

Chapter 14 takes a closer look at “deep ethnography” – immersion in the field of a particularly long duration for the purpose of gaining a deeper understanding and appreciation of a particular culture or social world.  Clifford Geertz called this “deep hanging out.”  Whereas participant observation is often combined with semistructured interview techniques, deep ethnography’s commitment to “living the life” or experiencing the situation as it really is demands more conversational and natural interactions with people.  These interactions and conversations may take place over months or even years.  As can be expected, there are some costs to this technique, as well as some very large rewards when done competently.  Chapter 14 provides some examples of deep ethnographies that will inspire some beginning researchers and intimidate others.

Chapter 15 moves in the opposite direction of deep ethnography, a technique that is the least positivist of all those discussed here, to mixed methods , a set of techniques that is arguably the most positivist .  A mixed methods approach combines both qualitative data collection and quantitative data collection, commonly by combining a survey that is analyzed statistically (e.g., cross-tabs or regression analyses of large number probability samples) with semi-structured interviews.  Although it is somewhat unconventional to discuss mixed methods in textbooks on qualitative research, I think it is important to recognize this often-employed approach here.  There are several advantages and some disadvantages to taking this route.  Chapter 16 will describe those advantages and disadvantages and provide some particular guidance on how to design a mixed methods study for maximum effectiveness.

Chapter 16 covers data collection that does not involve live human subjects at all – archival and historical research (chapter 17 will also cover data that does not involve interacting with human subjects).  Sometimes people are unavailable to us, either because they do not wish to be interviewed or observed (as is the case with many “elites”) or because they are too far away, in both place and time.  Fortunately, humans leave many traces and we can often answer questions we have by examining those traces.  Special collections and archives can be goldmines for social science research.  This chapter will explain how to access these places, for what purposes, and how to begin to make sense of what you find.

Chapter 17 covers another data collection area that does not involve face-to-face interaction with humans: content analysis .  Although content analysis may be understood more properly as a data analysis technique, the term is often used for the entire approach, which will be the case here.  Content analysis involves interpreting meaning from a body of text.  This body of text might be something found in historical records (see chapter 16) or something collected by the researcher, as in the case of comment posts on a popular blog post.  I once used the stories told by student loan debtors on the website studentloanjustice.org as the content I analyzed.  Content analysis is particularly useful when attempting to define and understand prevalent stories or communication about a topic of interest.  In other words, when we are less interested in what particular people (our defined sample) are doing or believing and more interested in what general narratives exist about a particular topic or issue.  This chapter will explore different approaches to content analysis and provide helpful tips on how to collect data, how to turn that data into codes for analysis, and how to go about presenting what is found through analysis.

Where chapter 17 has pushed us towards data analysis, chapters 18 and 19 are all about what to do with the data collected, whether that data be in the form of interview transcripts or fieldnotes from observations.  Chapter 18 introduces the basics of coding , the iterative process of assigning meaning to the data in order to both simplify and identify patterns.  What is a code and how does it work?  What are the different ways of coding data, and when should you use them?  What is a codebook, and why do you need one?  What does the process of data analysis look like?

Chapter 19 goes further into detail on codes and how to use them, particularly the later stages of coding in which our codes are refined, simplified, combined, and organized.  These later rounds of coding are essential to getting the most out of the data we’ve collected.  As students are often overwhelmed with the amount of data (a corpus of interview transcripts typically runs into the hundreds of pages; fieldnotes can easily top that), this chapter will also address time management and provide suggestions for dealing with chaos and reminders that feeling overwhelmed at the analysis stage is part of the process.  By the end of the chapter, you should understand how “findings” are actually found.

The book concludes with a chapter dedicated to the effective presentation of data results.  Chapter 20 covers the many ways that researchers communicate their studies to various audiences (academic, personal, political), what elements must be included in these various publications, and the hallmarks of excellent qualitative research that various audiences will be expecting.  Because qualitative researchers are motivated by understanding and conveying meaning , effective communication is not only an essential skill but a fundamental facet of the entire research project.  Ethnographers must be able to convey a certain sense of verisimilitude , the appearance of true reality.  Those employing interviews must faithfully depict the key meanings of the people they interviewed in a way that rings true to those people, even if the end result surprises them.  And all researchers must strive for clarity in their publications so that various audiences can understand what was found and why it is important.

The book concludes with a short chapter ( chapter 21 ) discussing the value of qualitative research. At the very end of this book, you will find a glossary of terms. I recommend you make frequent use of the glossary and add to each entry as you find examples. Although the entries are meant to be simple and clear, you may also want to paraphrase the definition—make it “make sense” to you, in other words. In addition to the standard reference list (all works cited here), you will find various recommendations for further reading at the end of many chapters. Some of these recommendations will be examples of excellent qualitative research, indicated with an asterisk (*) at the end of the entry. As they say, a picture is worth a thousand words. A good example of qualitative research can teach you more about conducting research than any textbook can (this one included). I highly recommend you select one to three examples from these lists and read them along with the textbook.

A final note on the choice of examples – you will note that many of the examples used in the text come from research on college students.  This is for two reasons.  First, as most of my research falls in this area, I am most familiar with this literature and have contacts with those who do research here and can call upon them to share their stories with you.  Second, and more importantly, my hope is that this textbook reaches a wide audience of beginning researchers who study widely and deeply across the range of what can be known about the social world (from marine resources management to public policy to nursing to political science to sexuality studies and beyond).  It is sometimes difficult to find examples that speak to all those research interests, however. A focus on college students is something that all readers can understand and, hopefully, appreciate, as we are all now or have been at some point a college student.

Recommended Reading: Other Qualitative Research Textbooks

I’ve included a brief list of some of my favorite qualitative research textbooks and guidebooks if you need more than what you will find in this introductory text.  For each, I’ve also indicated if these are for “beginning” or “advanced” (graduate-level) readers.  Many of these books have several editions that do not significantly vary; the edition recommended is merely the edition I have used in teaching and to whose page numbers any specific references made in the text agree.

Barbour, Rosaline. 2014. Introducing Qualitative Research: A Student’s Guide. Thousand Oaks, CA: SAGE.  A good introduction to qualitative research, with abundant examples (often from the discipline of health care) and clear definitions.  Includes quick summaries at the ends of each chapter.  However, some US students might find the British context distracting and can be a bit advanced in some places.  Beginning .

Bloomberg, Linda Dale, and Marie F. Volpe. 2012. Completing Your Qualitative Dissertation . 2nd ed. Thousand Oaks, CA: SAGE.  Specifically designed to guide graduate students through the research process. Advanced .

Creswell, John W., and Cheryl Poth. 2018 Qualitative Inquiry and Research Design: Choosing among Five Traditions .  4th ed. Thousand Oaks, CA: SAGE.  This is a classic and one of the go-to books I used myself as a graduate student.  One of the best things about this text is its clear presentation of five distinct traditions in qualitative research.  Despite the title, this reasonably sized book is about more than research design, including both data analysis and how to write about qualitative research.  Advanced .

Lareau, Annette. 2021. Listening to People: A Practical Guide to Interviewing, Participant Observation, Data Analysis, and Writing It All Up .  Chicago: University of Chicago Press. A readable and personal account of conducting qualitative research by an eminent sociologist, with a heavy emphasis on the kinds of participant-observation research conducted by the author.  Despite its reader-friendliness, this is really a book targeted to graduate students learning the craft.  Advanced .

Lune, Howard, and Bruce L. Berg. 2018. 9th edition.  Qualitative Research Methods for the Social Sciences.  Pearson . Although a good introduction to qualitative methods, the authors favor symbolic interactionist and dramaturgical approaches, which limits the appeal primarily to sociologists.  Beginning .

Marshall, Catherine, and Gretchen B. Rossman. 2016. 6th edition. Designing Qualitative Research. Thousand Oaks, CA: SAGE.  Very readable and accessible guide to research design by two educational scholars.  Although the presentation is sometimes fairly dry, personal vignettes and illustrations enliven the text.  Beginning .

Maxwell, Joseph A. 2013. Qualitative Research Design: An Interactive Approach .  3rd ed. Thousand Oaks, CA: SAGE. A short and accessible introduction to qualitative research design, particularly helpful for graduate students contemplating theses and dissertations. This has been a standard textbook in my graduate-level courses for years.  Advanced .

Patton, Michael Quinn. 2002. Qualitative Research and Evaluation Methods . Thousand Oaks, CA: SAGE.  This is a comprehensive text that served as my “go-to” reference when I was a graduate student.  It is particularly helpful for those involved in program evaluation and other forms of evaluation studies and uses examples from a wide range of disciplines.  Advanced .

Rubin, Ashley T. 2021. Rocking Qualitative Social Science: An Irreverent Guide to Rigorous Research. Stanford : Stanford University Press.  A delightful and personal read.  Rubin uses rock climbing as an extended metaphor for learning how to conduct qualitative research.  A bit slanted toward ethnographic and archival methods of data collection, with frequent examples from her own studies in criminology. Beginning .

Weis, Lois, and Michelle Fine. 2000. Speed Bumps: A Student-Friendly Guide to Qualitative Research . New York: Teachers College Press.  Readable and accessibly written in a quasi-conversational style.  Particularly strong in its discussion of ethical issues throughout the qualitative research process.  Not comprehensive, however, and very much tied to ethnographic research.  Although designed for graduate students, this is a recommended read for students of all levels.  Beginning .

Patton’s Ten Suggestions for Doing Qualitative Research

The following ten suggestions were made by Michael Quinn Patton in his massive textbooks Qualitative Research and Evaluations Methods . This book is highly recommended for those of you who want more than an introduction to qualitative methods. It is the book I relied on heavily when I was a graduate student, although it is much easier to “dip into” when necessary than to read through as a whole. Patton is asked for “just one bit of advice” for a graduate student considering using qualitative research methods for their dissertation.  Here are his top ten responses, in short form, heavily paraphrased, and with additional comments and emphases from me:

• Make sure that a qualitative approach fits the research question. The following are the kinds of questions that call out for qualitative methods or where qualitative methods are particularly appropriate: questions about people’s experiences or how they make sense of those experiences; studying a person in their natural environment; researching a phenomenon so unknown that it would be impossible to study it with standardized instruments or other forms of quantitative data collection.
• Study qualitative research by going to the original sources for the design and analysis appropriate to the particular approach you want to take (e.g., read Glaser and Straus if you are using grounded theory )
• Find a dissertation adviser who understands or at least who will support your use of qualitative research methods. You are asking for trouble if your entire committee is populated by quantitative researchers, even if they are all very knowledgeable about the subject or focus of your study (maybe even more so if they are!)
• Really work on design. Doing qualitative research effectively takes a lot of planning.  Even if things are more flexible than in quantitative research, a good design is absolutely essential when starting out.
• Practice data collection techniques, particularly interviewing and observing. There is definitely a set of learned skills here!  Do not expect your first interview to be perfect.  You will continue to grow as a researcher the more interviews you conduct, and you will probably come to understand yourself a bit more in the process, too.  This is not easy, despite what others who don’t work with qualitative methods may assume (and tell you!)
• Have a plan for analysis before you begin data collection. This is often a requirement in IRB protocols , although you can get away with writing something fairly simple.  And even if you are taking an approach, such as grounded theory, that pushes you to remain fairly open-minded during the data collection process, you still want to know what you will be doing with all the data collected – creating a codebook? Writing analytical memos? Comparing cases?  Having a plan in hand will also help prevent you from collecting too much extraneous data.
• Be prepared to confront controversies both within the qualitative research community and between qualitative research and quantitative research. Don’t be naïve about this – qualitative research, particularly some approaches, will be derided by many more “positivist” researchers and audiences.  For example, is an “n” of 1 really sufficient?  Yes!  But not everyone will agree.
• Do not make the mistake of using qualitative research methods because someone told you it was easier, or because you are intimidated by the math required of statistical analyses. Qualitative research is difficult in its own way (and many would claim much more time-consuming than quantitative research).  Do it because you are convinced it is right for your goals, aims, and research questions.
• Find a good support network. This could be a research mentor, or it could be a group of friends or colleagues who are also using qualitative research, or it could be just someone who will listen to you work through all of the issues you will confront out in the field and during the writing process.  Even though qualitative research often involves human subjects, it can be pretty lonely.  A lot of times you will feel like you are working without a net.  You have to create one for yourself.  Take care of yourself.
• And, finally, in the words of Patton, “Prepare to be changed. Looking deeply at other people’s lives will force you to look deeply at yourself.”
• We will actually spend an entire chapter ( chapter 3 ) looking at this question in much more detail! ↵
• Note that this might have been news to Europeans at the time, but many other societies around the world had also come to this conclusion through observation.  There is often a tendency to equate “the scientific revolution” with the European world in which it took place, but this is somewhat misleading. ↵
• Historians are a special case here.  Historians have scrupulously and rigorously investigated the social world, but not for the purpose of understanding general laws about how things work, which is the point of scientific empirical research.  History is often referred to as an idiographic field of study, meaning that it studies things that happened or are happening in themselves and not for general observations or conclusions. ↵
• Don’t worry, we’ll spend more time later in this book unpacking the meaning of ethnography and other terms that are important here.  Note the available glossary ↵

An approach to research that is “multimethod in focus, involving an interpretative, naturalistic approach to its subject matter.  This means that qualitative researchers study things in their natural settings, attempting to make sense of, or interpret, phenomena in terms of the meanings people bring to them.  Qualitative research involves the studied use and collection of a variety of empirical materials – case study, personal experience, introspective, life story, interview, observational, historical, interactional, and visual texts – that describe routine and problematic moments and meanings in individuals’ lives." ( Denzin and Lincoln 2005:2 ). Contrast with quantitative research .

In contrast to methodology, methods are more simply the practices and tools used to collect and analyze data.  Examples of common methods in qualitative research are interviews , observations , and documentary analysis .  One’s methodology should connect to one’s choice of methods, of course, but they are distinguishable terms.  See also methodology .

A proposed explanation for an observation, phenomenon, or scientific problem that can be tested by further investigation.  The positing of a hypothesis is often the first step in quantitative research but not in qualitative research.  Even when qualitative researchers offer possible explanations in advance of conducting research, they will tend to not use the word “hypothesis” as it conjures up the kind of positivist research they are not conducting.

The foundational question to be addressed by the research study.  This will form the anchor of the research design, collection, and analysis.  Note that in qualitative research, the research question may, and probably will, alter or develop during the course of the research.

An approach to research that collects and analyzes numerical data for the purpose of finding patterns and averages, making predictions, testing causal relationships, and generalizing results to wider populations.  Contrast with qualitative research .

Data collection that takes place in real-world settings, referred to as “the field;” a key component of much Grounded Theory and ethnographic research.  Patton ( 2002 ) calls fieldwork “the central activity of qualitative inquiry” where “‘going into the field’ means having direct and personal contact with people under study in their own environments – getting close to people and situations being studied to personally understand the realities of minutiae of daily life” (48).

The people who are the subjects of a qualitative study.  In interview-based studies, they may be the respondents to the interviewer; for purposes of IRBs, they are often referred to as the human subjects of the research.

The branch of philosophy concerned with knowledge.  For researchers, it is important to recognize and adopt one of the many distinguishing epistemological perspectives as part of our understanding of what questions research can address or fully answer.  See, e.g., constructivism , subjectivism, and  objectivism .

An approach that refutes the possibility of neutrality in social science research.  All research is “guided by a set of beliefs and feelings about the world and how it should be understood and studied” (Denzin and Lincoln 2005: 13).  In contrast to positivism , interpretivism recognizes the social constructedness of reality, and researchers adopting this approach focus on capturing interpretations and understandings people have about the world rather than “the world” as it is (which is a chimera).

The cluster of data-collection tools and techniques that involve observing interactions between people, the behaviors, and practices of individuals (sometimes in contrast to what they say about how they act and behave), and cultures in context.  Observational methods are the key tools employed by ethnographers and Grounded Theory .

Research based on data collected and analyzed by the research (in contrast to secondary “library” research).

The process of selecting people or other units of analysis to represent a larger population. In quantitative research, this representation is taken quite literally, as statistically representative.  In qualitative research, in contrast, sample selection is often made based on potential to generate insight about a particular topic or phenomenon.

A method of data collection in which the researcher asks the participant questions; the answers to these questions are often recorded and transcribed verbatim. There are many different kinds of interviews - see also semistructured interview , structured interview , and unstructured interview .

The specific group of individuals that you will collect data from.  Contrast population.

The practice of being conscious of and reflective upon one’s own social location and presence when conducting research.  Because qualitative research often requires interaction with live humans, failing to take into account how one’s presence and prior expectations and social location affect the data collected and how analyzed may limit the reliability of the findings.  This remains true even when dealing with historical archives and other content.  Who we are matters when asking questions about how people experience the world because we, too, are a part of that world.

The science and practice of right conduct; in research, it is also the delineation of moral obligations towards research participants, communities to which we belong, and communities in which we conduct our research.

An administrative body established to protect the rights and welfare of human research subjects recruited to participate in research activities conducted under the auspices of the institution with which it is affiliated. The IRB is charged with the responsibility of reviewing all research involving human participants. The IRB is concerned with protecting the welfare, rights, and privacy of human subjects. The IRB has the authority to approve, disapprove, monitor, and require modifications in all research activities that fall within its jurisdiction as specified by both the federal regulations and institutional policy.

Research, according to US federal guidelines, that involves “a living individual about whom an investigator (whether professional or student) conducting research:  (1) Obtains information or biospecimens through intervention or interaction with the individual, and uses, studies, or analyzes the information or biospecimens; or  (2) Obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens.”

One of the primary methodological traditions of inquiry in qualitative research, ethnography is the study of a group or group culture, largely through observational fieldwork supplemented by interviews. It is a form of fieldwork that may include participant-observation data collection. See chapter 14 for a discussion of deep ethnography. 

A form of interview that follows a standard guide of questions asked, although the order of the questions may change to match the particular needs of each individual interview subject, and probing “follow-up” questions are often added during the course of the interview.  The semi-structured interview is the primary form of interviewing used by qualitative researchers in the social sciences.  It is sometimes referred to as an “in-depth” interview.  See also interview and  interview guide .

A method of observational data collection taking place in a natural setting; a form of fieldwork .  The term encompasses a continuum of relative participation by the researcher (from full participant to “fly-on-the-wall” observer).  This is also sometimes referred to as ethnography , although the latter is characterized by a greater focus on the culture under observation.

A research design that employs both quantitative and qualitative methods, as in the case of a survey supplemented by interviews.

An epistemological perspective that posits the existence of reality through sensory experience similar to empiricism but goes further in denying any non-sensory basis of thought or consciousness.  In the social sciences, the term has roots in the proto-sociologist August Comte, who believed he could discern “laws” of society similar to the laws of natural science (e.g., gravity).  The term has come to mean the kinds of measurable and verifiable science conducted by quantitative researchers and is thus used pejoratively by some qualitative researchers interested in interpretation, consciousness, and human understanding.  Calling someone a “positivist” is often intended as an insult.  See also empiricism and objectivism.

A place or collection containing records, documents, or other materials of historical interest; most universities have an archive of material related to the university’s history, as well as other “special collections” that may be of interest to members of the community.

A method of both data collection and data analysis in which a given content (textual, visual, graphic) is examined systematically and rigorously to identify meanings, themes, patterns and assumptions.  Qualitative content analysis (QCA) is concerned with gathering and interpreting an existing body of material.    

A word or short phrase that symbolically assigns a summative, salient, essence-capturing, and/or evocative attribute for a portion of language-based or visual data (Saldaña 2021:5).

Usually a verbatim written record of an interview or focus group discussion.

The primary form of data for fieldwork , participant observation , and ethnography .  These notes, taken by the researcher either during the course of fieldwork or at day’s end, should include as many details as possible on what was observed and what was said.  They should include clear identifiers of date, time, setting, and names (or identifying characteristics) of participants.

The process of labeling and organizing qualitative data to identify different themes and the relationships between them; a way of simplifying data to allow better management and retrieval of key themes and illustrative passages.  See coding frame and  codebook.

A methodological tradition of inquiry and approach to analyzing qualitative data in which theories emerge from a rigorous and systematic process of induction.  This approach was pioneered by the sociologists Glaser and Strauss (1967).  The elements of theory generated from comparative analysis of data are, first, conceptual categories and their properties and, second, hypotheses or generalized relations among the categories and their properties – “The constant comparing of many groups draws the [researcher’s] attention to their many similarities and differences.  Considering these leads [the researcher] to generate abstract categories and their properties, which, since they emerge from the data, will clearly be important to a theory explaining the kind of behavior under observation.” (36).

A detailed description of any proposed research that involves human subjects for review by IRB.  The protocol serves as the recipe for the conduct of the research activity.  It includes the scientific rationale to justify the conduct of the study, the information necessary to conduct the study, the plan for managing and analyzing the data, and a discussion of the research ethical issues relevant to the research.  Protocols for qualitative research often include interview guides, all documents related to recruitment, informed consent forms, very clear guidelines on the safekeeping of materials collected, and plans for de-identifying transcripts or other data that include personal identifying information.

Introduction to Qualitative Research Methods Copyright © 2023 by Allison Hurst is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License , except where otherwise noted.

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7.4 Qualitative Research

Learning objectives.

• List several ways in which qualitative research differs from quantitative research in psychology.
• Describe the strengths and weaknesses of qualitative research in psychology compared with quantitative research.
• Give examples of qualitative research in psychology.

What Is Qualitative Research?

This book is primarily about quantitative research . Quantitative researchers typically start with a focused research question or hypothesis, collect a small amount of data from each of a large number of individuals, describe the resulting data using statistical techniques, and draw general conclusions about some large population. Although this is by far the most common approach to conducting empirical research in psychology, there is an important alternative called qualitative research. Qualitative research originated in the disciplines of anthropology and sociology but is now used to study many psychological topics as well. Qualitative researchers generally begin with a less focused research question, collect large amounts of relatively “unfiltered” data from a relatively small number of individuals, and describe their data using nonstatistical techniques. They are usually less concerned with drawing general conclusions about human behavior than with understanding in detail the experience of their research participants.

Consider, for example, a study by researcher Per Lindqvist and his colleagues, who wanted to learn how the families of teenage suicide victims cope with their loss (Lindqvist, Johansson, & Karlsson, 2008). They did not have a specific research question or hypothesis, such as, What percentage of family members join suicide support groups? Instead, they wanted to understand the variety of reactions that families had, with a focus on what it is like from their perspectives. To do this, they interviewed the families of 10 teenage suicide victims in their homes in rural Sweden. The interviews were relatively unstructured, beginning with a general request for the families to talk about the victim and ending with an invitation to talk about anything else that they wanted to tell the interviewer. One of the most important themes that emerged from these interviews was that even as life returned to “normal,” the families continued to struggle with the question of why their loved one committed suicide. This struggle appeared to be especially difficult for families in which the suicide was most unexpected.

The Purpose of Qualitative Research

Again, this book is primarily about quantitative research in psychology. The strength of quantitative research is its ability to provide precise answers to specific research questions and to draw general conclusions about human behavior. This is how we know that people have a strong tendency to obey authority figures, for example, or that female college students are not substantially more talkative than male college students. But while quantitative research is good at providing precise answers to specific research questions, it is not nearly as good at generating novel and interesting research questions. Likewise, while quantitative research is good at drawing general conclusions about human behavior, it is not nearly as good at providing detailed descriptions of the behavior of particular groups in particular situations. And it is not very good at all at communicating what it is actually like to be a member of a particular group in a particular situation.

But the relative weaknesses of quantitative research are the relative strengths of qualitative research. Qualitative research can help researchers to generate new and interesting research questions and hypotheses. The research of Lindqvist and colleagues, for example, suggests that there may be a general relationship between how unexpected a suicide is and how consumed the family is with trying to understand why the teen committed suicide. This relationship can now be explored using quantitative research. But it is unclear whether this question would have arisen at all without the researchers sitting down with the families and listening to what they themselves wanted to say about their experience. Qualitative research can also provide rich and detailed descriptions of human behavior in the real-world contexts in which it occurs. Among qualitative researchers, this is often referred to as “thick description” (Geertz, 1973). Similarly, qualitative research can convey a sense of what it is actually like to be a member of a particular group or in a particular situation—what qualitative researchers often refer to as the “lived experience” of the research participants. Lindqvist and colleagues, for example, describe how all the families spontaneously offered to show the interviewer the victim’s bedroom or the place where the suicide occurred—revealing the importance of these physical locations to the families. It seems unlikely that a quantitative study would have discovered this.

Data Collection and Analysis in Qualitative Research

As with correlational research, data collection approaches in qualitative research are quite varied and can involve naturalistic observation, archival data, artwork, and many other things. But one of the most common approaches, especially for psychological research, is to conduct interviews . Interviews in qualitative research tend to be unstructured—consisting of a small number of general questions or prompts that allow participants to talk about what is of interest to them. The researcher can follow up by asking more detailed questions about the topics that do come up. Such interviews can be lengthy and detailed, but they are usually conducted with a relatively small sample. This was essentially the approach used by Lindqvist and colleagues in their research on the families of suicide survivors. Small groups of people who participate together in interviews focused on a particular topic or issue are often referred to as focus groups . The interaction among participants in a focus group can sometimes bring out more information than can be learned in a one-on-one interview. The use of focus groups has become a standard technique in business and industry among those who want to understand consumer tastes and preferences. The content of all focus group interviews is usually recorded and transcribed to facilitate later analyses.

Another approach to data collection in qualitative research is participant observation. In participant observation , researchers become active participants in the group or situation they are studying. The data they collect can include interviews (usually unstructured), their own notes based on their observations and interactions, documents, photographs, and other artifacts. The basic rationale for participant observation is that there may be important information that is only accessible to, or can be interpreted only by, someone who is an active participant in the group or situation. An example of participant observation comes from a study by sociologist Amy Wilkins (published in Social Psychology Quarterly ) on a college-based religious organization that emphasized how happy its members were (Wilkins, 2008). Wilkins spent 12 months attending and participating in the group’s meetings and social events, and she interviewed several group members. In her study, Wilkins identified several ways in which the group “enforced” happiness—for example, by continually talking about happiness, discouraging the expression of negative emotions, and using happiness as a way to distinguish themselves from other groups.

Data Analysis in Quantitative Research

Although quantitative and qualitative research generally differ along several important dimensions (e.g., the specificity of the research question, the type of data collected), it is the method of data analysis that distinguishes them more clearly than anything else. To illustrate this idea, imagine a team of researchers that conducts a series of unstructured interviews with recovering alcoholics to learn about the role of their religious faith in their recovery. Although this sounds like qualitative research, imagine further that once they collect the data, they code the data in terms of how often each participant mentions God (or a “higher power”), and they then use descriptive and inferential statistics to find out whether those who mention God more often are more successful in abstaining from alcohol. Now it sounds like quantitative research. In other words, the quantitative-qualitative distinction depends more on what researchers do with the data they have collected than with why or how they collected the data.

But what does qualitative data analysis look like? Just as there are many ways to collect data in qualitative research, there are many ways to analyze data. Here we focus on one general approach called grounded theory (Glaser & Strauss, 1967). This approach was developed within the field of sociology in the 1960s and has gradually gained popularity in psychology. Remember that in quantitative research, it is typical for the researcher to start with a theory, derive a hypothesis from that theory, and then collect data to test that specific hypothesis. In qualitative research using grounded theory, researchers start with the data and develop a theory or an interpretation that is “grounded in” those data. They do this in stages. First, they identify ideas that are repeated throughout the data. Then they organize these ideas into a smaller number of broader themes. Finally, they write a theoretical narrative —an interpretation—of the data in terms of the themes that they have identified. This theoretical narrative focuses on the subjective experience of the participants and is usually supported by many direct quotations from the participants themselves.

As an example, consider a study by researchers Laura Abrams and Laura Curran, who used the grounded theory approach to study the experience of postpartum depression symptoms among low-income mothers (Abrams & Curran, 2009). Their data were the result of unstructured interviews with 19 participants. Table 7.1 “Themes and Repeating Ideas in a Study of Postpartum Depression Among Low-Income Mothers” shows the five broad themes the researchers identified and the more specific repeating ideas that made up each of those themes. In their research report, they provide numerous quotations from their participants, such as this one from “Destiny:”

Well, just recently my apartment was broken into and the fact that his Medicaid for some reason was cancelled so a lot of things was happening within the last two weeks all at one time. So that in itself I don’t want to say almost drove me mad but it put me in a funk.…Like I really was depressed. (p. 357)

Their theoretical narrative focused on the participants’ experience of their symptoms not as an abstract “affective disorder” but as closely tied to the daily struggle of raising children alone under often difficult circumstances.

Table 7.1 Themes and Repeating Ideas in a Study of Postpartum Depression Among Low-Income Mothers

The Quantitative-Qualitative “Debate”

Given their differences, it may come as no surprise that quantitative and qualitative research in psychology and related fields do not coexist in complete harmony. Some quantitative researchers criticize qualitative methods on the grounds that they lack objectivity, are difficult to evaluate in terms of reliability and validity, and do not allow generalization to people or situations other than those actually studied. At the same time, some qualitative researchers criticize quantitative methods on the grounds that they overlook the richness of human behavior and experience and instead answer simple questions about easily quantifiable variables.

In general, however, qualitative researchers are well aware of the issues of objectivity, reliability, validity, and generalizability. In fact, they have developed a number of frameworks for addressing these issues (which are beyond the scope of our discussion). And in general, quantitative researchers are well aware of the issue of oversimplification. They do not believe that all human behavior and experience can be adequately described in terms of a small number of variables and the statistical relationships among them. Instead, they use simplification as a strategy for uncovering general principles of human behavior.

Many researchers from both the quantitative and qualitative camps now agree that the two approaches can and should be combined into what has come to be called mixed-methods research (Todd, Nerlich, McKeown, & Clarke, 2004). (In fact, the studies by Lindqvist and colleagues and by Abrams and Curran both combined quantitative and qualitative approaches.) One approach to combining quantitative and qualitative research is to use qualitative research for hypothesis generation and quantitative research for hypothesis testing. Again, while a qualitative study might suggest that families who experience an unexpected suicide have more difficulty resolving the question of why, a well-designed quantitative study could test a hypothesis by measuring these specific variables for a large sample. A second approach to combining quantitative and qualitative research is referred to as triangulation . The idea is to use both quantitative and qualitative methods simultaneously to study the same general questions and to compare the results. If the results of the quantitative and qualitative methods converge on the same general conclusion, they reinforce and enrich each other. If the results diverge, then they suggest an interesting new question: Why do the results diverge and how can they be reconciled?

Key Takeaways

• Qualitative research is an important alternative to quantitative research in psychology. It generally involves asking broader research questions, collecting more detailed data (e.g., interviews), and using nonstatistical analyses.
• Many researchers conceptualize quantitative and qualitative research as complementary and advocate combining them. For example, qualitative research can be used to generate hypotheses and quantitative research to test them.
• Discussion: What are some ways in which a qualitative study of girls who play youth baseball would be likely to differ from a quantitative study on the same topic?

Abrams, L. S., & Curran, L. (2009). “And you’re telling me not to stress?” A grounded theory study of postpartum depression symptoms among low-income mothers. Psychology of Women Quarterly, 33 , 351–362.

Geertz, C. (1973). The interpretation of cultures . New York, NY: Basic Books.

Glaser, B. G., & Strauss, A. L. (1967). The discovery of grounded theory: Strategies for qualitative research . Chicago, IL: Aldine.

Lindqvist, P., Johansson, L., & Karlsson, U. (2008). In the aftermath of teenage suicide: A qualitative study of the psychosocial consequences for the surviving family members. BMC Psychiatry, 8 , 26. Retrieved from http://www.biomedcentral.com/1471-244X/8/26 .

Todd, Z., Nerlich, B., McKeown, S., & Clarke, D. D. (2004) Mixing methods in psychology: The integration of qualitative and quantitative methods in theory and practice . London, UK: Psychology Press.

Wilkins, A. (2008). “Happier than Non-Christians”: Collective emotions and symbolic boundaries among evangelical Christians. Social Psychology Quarterly, 71 , 281–301.

Research Methods in Psychology Copyright © 2016 by University of Minnesota is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License , except where otherwise noted.

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• 1 University of Nebraska Medical Center
• 2 GDB Research and Statistical Consulting
• 3 GDB Research and Statistical Consulting/McLaren Macomb Hospital
• PMID: 29262162
• Bookshelf ID: NBK470395

Qualitative research is a type of research that explores and provides deeper insights into real-world problems. Instead of collecting numerical data points or intervening or introducing treatments just like in quantitative research, qualitative research helps generate hypothenar to further investigate and understand quantitative data. Qualitative research gathers participants' experiences, perceptions, and behavior. It answers the hows and whys instead of how many or how much. It could be structured as a standalone study, purely relying on qualitative data, or part of mixed-methods research that combines qualitative and quantitative data. This review introduces the readers to some basic concepts, definitions, terminology, and applications of qualitative research.

Qualitative research, at its core, asks open-ended questions whose answers are not easily put into numbers, such as "how" and "why." Due to the open-ended nature of the research questions, qualitative research design is often not linear like quantitative design. One of the strengths of qualitative research is its ability to explain processes and patterns of human behavior that can be difficult to quantify. Phenomena such as experiences, attitudes, and behaviors can be complex to capture accurately and quantitatively. In contrast, a qualitative approach allows participants themselves to explain how, why, or what they were thinking, feeling, and experiencing at a particular time or during an event of interest. Quantifying qualitative data certainly is possible, but at its core, qualitative data is looking for themes and patterns that can be difficult to quantify, and it is essential to ensure that the context and narrative of qualitative work are not lost by trying to quantify something that is not meant to be quantified.

However, while qualitative research is sometimes placed in opposition to quantitative research, where they are necessarily opposites and therefore "compete" against each other and the philosophical paradigms associated with each other, qualitative and quantitative work are neither necessarily opposites, nor are they incompatible. While qualitative and quantitative approaches are different, they are not necessarily opposites and certainly not mutually exclusive. For instance, qualitative research can help expand and deepen understanding of data or results obtained from quantitative analysis. For example, say a quantitative analysis has determined a correlation between length of stay and level of patient satisfaction, but why does this correlation exist? This dual-focus scenario shows one way in which qualitative and quantitative research could be integrated.

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• Introduction
• Issues of Concern
• Clinical Significance
• Enhancing Healthcare Team Outcomes
• Review Questions

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Qualitative Research: Model and Hypotheses Refinement

• First Online: 18 November 2021

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• Kerstin Kurzhals 2  

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Despite the active discussion of firms policies to foster innovation generation, few researchers have engaged in analysing RRs, their characteristics and key drivers, be it from a management or a research perspective. On the other hand, conceptual elaborations have been made within the DC literature, and “the dynamic capability framework is drawing support and increased validity by researchers, empirical studies of dynamic capabilities remain relatively rare”. Scattered research has emerged in recent years stating the increased relevance of DCs in firms and conceptually investigating the notion of DCs, hitherto “we have little theoretical or empirical evidence on which to base any suggestions as to how dynamic capabilities can be deliberately built”.

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noventum consulting GmbH is an international IT management consulting group, founded 1996 in Germany. The group is represented in Turkey, Luxembourg and Southafrica. The consulting approach combines strategic and procedural issues with technical solutions. The focus of noventum’s service offering lies in the definition, optimisation and implementation of commercial and IT processes, beside this noventum is active in the field of innovation and future management, where service offerings cover the development of future concepts, future management workshops, innovation and ideas management (source: www.noventum.de )

All interviewees were categorised based on their self-rated level of experience in RR activities, leading to an equal number of interviewees with a high and moderate level of experience in RR activities.

Note from the author: The quotes from the interviews display the original and transcribed outcome of the interviews, which is that often interviewees interrupted sentences, switched their thoughts within the same sentence, and used a rough wording. Nonetheless, to avoid any change of meaning, the quotes were included in its original wording without any grammatical or language corrections.

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Kurzhals, K. (2021). Qualitative Research: Model and Hypotheses Refinement. In: Resource Recombination in Firms from a Dynamic Capability Perspective. Gabler Theses. Springer Gabler, Wiesbaden. https://doi.org/10.1007/978-3-658-35666-8_4

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Visually hypothesising in scientific paper writing: confirming and refuting qualitative research hypotheses using diagrams.

1. Introduction

2. overview of visual communication and post-positivist research, visual communication in post-positivist qualitative research, 3. understanding qualitative research (and hypotheses): types, notions, contestations and epistemological underpinnings, 3.1. what is qualitative research, 3.2. types of qualitative research and their epistemological underpinnings, 3.3. what is a research hypothesis can it be used in qualitative research, 3.4. analogical arguments in support of using hypotheses in qualitative research, 3.5. can a hypothesis be “tested” in qualitative research, 4. the process of developing and using hypotheses in qualitative research.

“Begin a research study without having to test a hypothesis. Instead, it allows them to develop hypotheses by listening to what the research participants say. Because the method involves developing hypotheses after the data are collected, it is called hypothesis-generating research rather than hypothesis-testing research. The grounded theory method uses two basic principles: (1) questioning rather than measuring, and (2) generating hypotheses using theoretical coding.”

4.1. Formulating the Qualitative Research Hypothesis

• The qualitative hypothesis should be based on a research problem derived from the research questions.
• It should be supported by literature evidence (on the relationship or association between variables).
• It should be informed by past research and observations.
• It must be falsifiable or disprovable (see Popper [ 77 ]).
• It should be analysable using data collected from the field or literature.
• It has to be testable or verifiable, provable, nullifiable, refutable, confirmable or disprovable based on the results of analysing data collected from the field or literature.

4.2. Refuting or Verifying a Qualitative Research Hypothesis Diagrammatically (with Illustration)

“A core development concern in Nigeria is the magnitude of challenges rural people face. Inefficient infrastructures, lack of employment opportunities and poor social amenities are some of these challenges. These challenges persist mainly due to ineffective approaches used in tackling them. This research argues that an approach based on territorial development would produce better outcomes. The reason is that territorial development adopts integrated policies and actions with a focus on places as opposed to sectoral approaches. The research objectives were to evaluate rural development approaches and identify a specific approach capable of activating poverty reduction. It addressed questions bordering on past rural development approaches and how to improve urban-rural linkages in rural areas. It also addressed questions relating to ways that rural areas can reduce poverty through territorial development…” [ 16 ], p. 1

“Nigeria has legal and institutional opportunities for comprehensive improvement of rural areas through territorial development. However, due to the absence of a concrete rural development plan and area-based rural development strategies, this has not been materialized”.

• Proposition 1: Legal and institutional opportunities that can lead to comprehensive improvement of rural areas through territorial development exist in Nigeria .
• Proposition 2: However, due to the absence of a concrete rural development plan and area-based rural development strategies, this has not been materialized .
• Independent variables: legal and institutional opportunities; incessant structural changes in its political history; and policy negligence.
• Dependent variable: comprehensive rural improvements through territorial development.

5. Discussion and Conclusion

Acknowledgments, conflicts of interest.

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Chigbu, U.E. Visually Hypothesising in Scientific Paper Writing: Confirming and Refuting Qualitative Research Hypotheses Using Diagrams. Publications 2019 , 7 , 22. https://doi.org/10.3390/publications7010022

Chigbu UE. Visually Hypothesising in Scientific Paper Writing: Confirming and Refuting Qualitative Research Hypotheses Using Diagrams. Publications . 2019; 7(1):22. https://doi.org/10.3390/publications7010022

Chigbu, Uchendu Eugene. 2019. "Visually Hypothesising in Scientific Paper Writing: Confirming and Refuting Qualitative Research Hypotheses Using Diagrams" Publications 7, no. 1: 22. https://doi.org/10.3390/publications7010022

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Methodology

• How to Write a Strong Hypothesis | Steps & Examples

How to Write a Strong Hypothesis | Steps & Examples

Published on May 6, 2022 by Shona McCombes . Revised on November 20, 2023.

A hypothesis is a statement that can be tested by scientific research. If you want to test a relationship between two or more variables, you need to write hypotheses before you start your experiment or data collection .

Example: Hypothesis

Daily apple consumption leads to fewer doctor’s visits.

Table of contents

What is a hypothesis, developing a hypothesis (with example), hypothesis examples, other interesting articles, frequently asked questions about writing hypotheses.

A hypothesis states your predictions about what your research will find. It is a tentative answer to your research question that has not yet been tested. For some research projects, you might have to write several hypotheses that address different aspects of your research question.

A hypothesis is not just a guess – it should be based on existing theories and knowledge. It also has to be testable, which means you can support or refute it through scientific research methods (such as experiments, observations and statistical analysis of data).

Variables in hypotheses

Hypotheses propose a relationship between two or more types of variables .

• An independent variable is something the researcher changes or controls.
• A dependent variable is something the researcher observes and measures.

If there are any control variables , extraneous variables , or confounding variables , be sure to jot those down as you go to minimize the chances that research bias  will affect your results.

In this example, the independent variable is exposure to the sun – the assumed cause . The dependent variable is the level of happiness – the assumed effect .

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Step 1. Ask a question

Writing a hypothesis begins with a research question that you want to answer. The question should be focused, specific, and researchable within the constraints of your project.

Step 2. Do some preliminary research

Your initial answer to the question should be based on what is already known about the topic. Look for theories and previous studies to help you form educated assumptions about what your research will find.

At this stage, you might construct a conceptual framework to ensure that you’re embarking on a relevant topic . This can also help you identify which variables you will study and what you think the relationships are between them. Sometimes, you’ll have to operationalize more complex constructs.

Step 3. Formulate your hypothesis

Now you should have some idea of what you expect to find. Write your initial answer to the question in a clear, concise sentence.

4. Refine your hypothesis

You need to make sure your hypothesis is specific and testable. There are various ways of phrasing a hypothesis, but all the terms you use should have clear definitions, and the hypothesis should contain:

• The relevant variables
• The specific group being studied
• The predicted outcome of the experiment or analysis

5. Phrase your hypothesis in three ways

To identify the variables, you can write a simple prediction in  if…then form. The first part of the sentence states the independent variable and the second part states the dependent variable.

In academic research, hypotheses are more commonly phrased in terms of correlations or effects, where you directly state the predicted relationship between variables.

If you are comparing two groups, the hypothesis can state what difference you expect to find between them.

6. Write a null hypothesis

If your research involves statistical hypothesis testing , you will also have to write a null hypothesis . The null hypothesis is the default position that there is no association between the variables. The null hypothesis is written as H 0 , while the alternative hypothesis is H 1 or H a .

• H 0 : The number of lectures attended by first-year students has no effect on their final exam scores.
• H 1 : The number of lectures attended by first-year students has a positive effect on their final exam scores.

If you want to know more about the research process , methodology , research bias , or statistics , make sure to check out some of our other articles with explanations and examples.

• Sampling methods
• Simple random sampling
• Stratified sampling
• Cluster sampling
• Likert scales
• Reproducibility

 Statistics

• Null hypothesis
• Statistical power
• Probability distribution
• Effect size
• Poisson distribution

Research bias

• Optimism bias
• Cognitive bias
• Implicit bias
• Hawthorne effect
• Anchoring bias
• Explicit bias

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A hypothesis is not just a guess — it should be based on existing theories and knowledge. It also has to be testable, which means you can support or refute it through scientific research methods (such as experiments, observations and statistical analysis of data).

Null and alternative hypotheses are used in statistical hypothesis testing . The null hypothesis of a test always predicts no effect or no relationship between variables, while the alternative hypothesis states your research prediction of an effect or relationship.

Hypothesis testing is a formal procedure for investigating our ideas about the world using statistics. It is used by scientists to test specific predictions, called hypotheses , by calculating how likely it is that a pattern or relationship between variables could have arisen by chance.

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Chapter 7: Nonexperimental Research

Qualitative research, learning objectives.

• List several ways in which qualitative research differs from quantitative research in psychology.
• Describe the strengths and weaknesses of qualitative research in psychology compared with quantitative research.
• Give examples of qualitative research in psychology.

What Is Qualitative Research?

This textbook is primarily about  quantitative research . Quantitative researchers typically start with a focused research question or hypothesis, collect a small amount of data from each of a large number of individuals, describe the resulting data using statistical techniques, and draw general conclusions about some large population. Although this method is by far the most common approach to conducting empirical research in psychology, there is an important alternative called qualitative research. Qualitative research originated in the disciplines of anthropology and sociology but is now used to study many psychological topics as well. Qualitative researchers generally begin with a less focused research question, collect large amounts of relatively “unfiltered” data from a relatively small number of individuals, and describe their data using nonstatistical techniques. They are usually less concerned with drawing general conclusions about human behaviour than with understanding in detail the  experience  of their research participants.

Consider, for example, a study by researcher Per Lindqvist and his colleagues, who wanted to learn how the families of teenage suicide victims cope with their loss (Lindqvist, Johansson, & Karlsson, 2008) [1] . They did not have a specific research question or hypothesis, such as, What percentage of family members join suicide support groups? Instead, they wanted to understand the variety of reactions that families had, with a focus on what it is like from  their  perspectives. To address this question, they interviewed the families of 10 teenage suicide victims in their homes in rural Sweden. The interviews were relatively unstructured, beginning with a general request for the families to talk about the victim and ending with an invitation to talk about anything else that they wanted to tell the interviewer. One of the most important themes that emerged from these interviews was that even as life returned to “normal,” the families continued to struggle with the question of why their loved one committed suicide. This struggle appeared to be especially difficult for families in which the suicide was most unexpected.

The Purpose of Qualitative Research

Again, this textbook is primarily about quantitative research in psychology. The strength of quantitative research is its ability to provide precise answers to specific research questions and to draw general conclusions about human behaviour. This method is how we know that people have a strong tendency to obey authority figures, for example, or that female undergraduate students are not substantially more talkative than male undergraduate students. But while quantitative research is good at providing precise answers to specific research questions, it is not nearly as good at  generating  novel and interesting research questions. Likewise, while quantitative research is good at drawing general conclusions about human behaviour, it is not nearly as good at providing detailed descriptions of the behaviour of particular groups in particular situations. And it is not very good at all at communicating what it is actually like to be a member of a particular group in a particular situation.

But the relative weaknesses of quantitative research are the relative strengths of qualitative research. Qualitative research can help researchers to generate new and interesting research questions and hypotheses. The research of Lindqvist and colleagues, for example, suggests that there may be a general relationship between how unexpected a suicide is and how consumed the family is with trying to understand why the teen committed suicide. This relationship can now be explored using quantitative research. But it is unclear whether this question would have arisen at all without the researchers sitting down with the families and listening to what they themselves wanted to say about their experience. Qualitative research can also provide rich and detailed descriptions of human behaviour in the real-world contexts in which it occurs. Among qualitative researchers, this depth is often referred to as “thick description” (Geertz, 1973) [2] . Similarly, qualitative research can convey a sense of what it is actually like to be a member of a particular group or in a particular situation—what qualitative researchers often refer to as the “lived experience” of the research participants. Lindqvist and colleagues, for example, describe how all the families spontaneously offered to show the interviewer the victim’s bedroom or the place where the suicide occurred—revealing the importance of these physical locations to the families. It seems unlikely that a quantitative study would have discovered this detail.

Data Collection and Analysis in Qualitative Research

As with correlational research, data collection approaches in qualitative research are quite varied and can involve naturalistic observation, archival data, artwork, and many other things. But one of the most common approaches, especially for psychological research, is to conduct  interviews . Interviews in qualitative research can be unstructured—consisting of a small number of general questions or prompts that allow participants to talk about what is of interest to them–or structured, where there is a strict script that the interviewer does not deviate from. Most interviews are in between the two and are called semi-structured interviews, where the researcher has a few consistent questions and can follow up by asking more detailed questions about the topics that do come up. Such interviews can be lengthy and detailed, but they are usually conducted with a relatively small sample. The unstructured interview was the approach used by Lindqvist and colleagues in their research on the families of suicide survivors because the researchers were aware that how much was disclosed about such a sensitive topic should be led by the families not by the researchers. Small groups of people who participate together in interviews focused on a particular topic or issue are often referred to as  focus groups . The interaction among participants in a focus group can sometimes bring out more information than can be learned in a one-on-one interview. The use of focus groups has become a standard technique in business and industry among those who want to understand consumer tastes and preferences. The content of all focus group interviews is usually recorded and transcribed to facilitate later analyses. However, we know from social psychology that group dynamics are often at play in any group, including focus groups, and it is useful to be aware of those possibilities.

Another approach to data collection in qualitative research is participant observation. In  participant observation , researchers become active participants in the group or situation they are studying. The data they collect can include interviews (usually unstructured), their own notes based on their observations and interactions, documents, photographs, and other artifacts. The basic rationale for participant observation is that there may be important information that is only accessible to, or can be interpreted only by, someone who is an active participant in the group or situation. An example of participant observation comes from a study by sociologist Amy Wilkins (published in  Social Psychology Quarterly ) on a university-based religious organization that emphasized how happy its members were (Wilkins, 2008) [3] . Wilkins spent 12 months attending and participating in the group’s meetings and social events, and she interviewed several group members. In her study, Wilkins identified several ways in which the group “enforced” happiness—for example, by continually talking about happiness, discouraging the expression of negative emotions, and using happiness as a way to distinguish themselves from other groups.

Data Analysis in Quantitative Research

Although quantitative and qualitative research generally differ along several important dimensions (e.g., the specificity of the research question, the type of data collected), it is the method of data  analysis  that distinguishes them more clearly than anything else. To illustrate this idea, imagine a team of researchers that conducts a series of unstructured interviews with recovering alcoholics to learn about the role of their religious faith in their recovery. Although this project sounds like qualitative research, imagine further that once they collect the data, they code the data in terms of how often each participant mentions God (or a “higher power”), and they then use descriptive and inferential statistics to find out whether those who mention God more often are more successful in abstaining from alcohol. Now it sounds like quantitative research. In other words, the quantitative-qualitative distinction depends more on what researchers  do  with the data they have collected than with why or how they collected the data.

But what does qualitative data analysis look like? Just as there are many ways to collect data in qualitative research, there are many ways to analyze data. Here we focus on one general approach called  grounded theory  (Glaser & Strauss, 1967) [4] . This approach was developed within the field of sociology in the 1960s and has gradually gained popularity in psychology. Remember that in quantitative research, it is typical for the researcher to start with a theory, derive a hypothesis from that theory, and then collect data to test that specific hypothesis. In qualitative research using grounded theory, researchers start with the data and develop a theory or an interpretation that is “grounded in” those data. They do this analysis in stages. First, they identify ideas that are repeated throughout the data. Then they organize these ideas into a smaller number of broader themes. Finally, they write a  theoretical narrative —an interpretation—of the data in terms of the themes that they have identified. This theoretical narrative focuses on the subjective experience of the participants and is usually supported by many direct quotations from the participants themselves.

As an example, consider a study by researchers Laura Abrams and Laura Curran, who used the grounded theory approach to study the experience of postpartum depression symptoms among low-income mothers (Abrams & Curran, 2009) [5] . Their data were the result of unstructured interviews with 19 participants.  Table 7.1  shows the five broad themes the researchers identified and the more specific repeating ideas that made up each of those themes. In their research report, they provide numerous quotations from their participants, such as this one from “Destiny:”

Well, just recently my apartment was broken into and the fact that his Medicaid for some reason was cancelled so a lot of things was happening within the last two weeks all at one time. So that in itself I don’t want to say almost drove me mad but it put me in a funk.…Like I really was depressed. (p. 357)

Their theoretical narrative focused on the participants’ experience of their symptoms not as an abstract “affective disorder” but as closely tied to the daily struggle of raising children alone under often difficult circumstances.

The Quantitative-Qualitative “Debate”

Given their differences, it may come as no surprise that quantitative and qualitative research in psychology and related fields do not coexist in complete harmony. Some quantitative researchers criticize qualitative methods on the grounds that they lack objectivity, are difficult to evaluate in terms of reliability and validity, and do not allow generalization to people or situations other than those actually studied. At the same time, some qualitative researchers criticize quantitative methods on the grounds that they overlook the richness of human behaviour and experience and instead answer simple questions about easily quantifiable variables.

In general, however, qualitative researchers are well aware of the issues of objectivity, reliability, validity, and generalizability. In fact, they have developed a number of frameworks for addressing these issues (which are beyond the scope of our discussion). And in general, quantitative researchers are well aware of the issue of oversimplification. They do not believe that all human behaviour and experience can be adequately described in terms of a small number of variables and the statistical relationships among them. Instead, they use simplification as a strategy for uncovering general principles of human behaviour.

Many researchers from both the quantitative and qualitative camps now agree that the two approaches can and should be combined into what has come to be called  mixed-methods research  (Todd, Nerlich, McKeown, & Clarke, 2004) [6] . (In fact, the studies by Lindqvist and colleagues and by Abrams and Curran both combined quantitative and qualitative approaches.) One approach to combining quantitative and qualitative research is to use qualitative research for hypothesis generation and quantitative research for hypothesis testing. Again, while a qualitative study might suggest that families who experience an unexpected suicide have more difficulty resolving the question of why, a well-designed quantitative study could test a hypothesis by measuring these specific variables for a large sample. A second approach to combining quantitative and qualitative research is referred to as  triangulation . The idea is to use both quantitative and qualitative methods simultaneously to study the same general questions and to compare the results. If the results of the quantitative and qualitative methods converge on the same general conclusion, they reinforce and enrich each other. If the results diverge, then they suggest an interesting new question: Why do the results diverge and how can they be reconciled?

Using qualitative research can often help clarify quantitative results in triangulation. Trenor, Yu, Waight, Zerda, and Sha (2008) [7] investigated the experience of female engineering students at university. In the first phase, female engineering students were asked to complete a survey, where they rated a number of their perceptions, including their sense of belonging.  Their results were compared by the student ethnicities, and statistically, the various ethnic groups showed no differences in their ratings of sense of belonging.  One might look at that result and conclude that ethnicity does not have anything to do with sense of belonging.  However, in the second phase, the authors also conducted interviews with the students, and in those interviews, many minority students reported how the diversity of cultures at the university enhanced their sense of belonging. Without the qualitative component, we might have drawn the wrong conclusion about the quantitative results.

This example shows how qualitative and quantitative research work together to help us understand human behaviour. Some researchers have characterized quantitative research as best for identifying behaviours or the phenomenon whereas qualitative research is best for understanding meaning or identifying the mechanism. However, Bryman (2012) [8] argues for breaking down the divide between these arbitrarily different ways of investigating the same questions.

Key Takeaways

• Qualitative research is an important alternative to quantitative research in psychology. It generally involves asking broader research questions, collecting more detailed data (e.g., interviews), and using nonstatistical analyses.
• Many researchers conceptualize quantitative and qualitative research as complementary and advocate combining them. For example, qualitative research can be used to generate hypotheses and quantitative research to test them.
• Discussion: What are some ways in which a qualitative study of girls who play youth baseball would be likely to differ from a quantitative study on the same topic? What kind of different data would be generated by interviewing girls one-on-one rather than conducting focus groups?
• Lindqvist, P., Johansson, L., & Karlsson, U. (2008). In the aftermath of teenage suicide: A qualitative study of the psychosocial consequences for the surviving family members. BMC Psychiatry, 8 , 26. Retrieved from http://www.biomedcentral.com/1471-244X/8/26 ↵
• Geertz, C. (1973). The interpretation of cultures . New York, NY: Basic Books. ↵
• Wilkins, A. (2008). “Happier than Non-Christians”: Collective emotions and symbolic boundaries among evangelical Christians. Social Psychology Quarterly, 71 , 281–301. ↵
• Glaser, B. G., & Strauss, A. L. (1967). The discovery of grounded theory: Strategies for qualitative research . Chicago, IL: Aldine. ↵
• Abrams, L. S., & Curran, L. (2009). “And you’re telling me not to stress?” A grounded theory study of postpartum depression symptoms among low-income mothers. Psychology of Women Quarterly, 33 , 351–362. ↵
• Todd, Z., Nerlich, B., McKeown, S., & Clarke, D. D. (2004) Mixing methods in psychology: The integration of qualitative and quantitative methods in theory and practice . London, UK: Psychology Press. ↵
• Trenor, J.M., Yu, S.L., Waight, C.L., Zerda. K.S & Sha T.-L. (2008). The relations of ethnicity to female engineering students’ educational experiences and college and career plans in an ethnically diverse learning environment. Journal of Engineering Education, 97 (4), 449-465. ↵
• Bryman, A. (2012). Social Research Methods , 4th ed. Oxford: OUP. ↵
• Research Methods in Psychology. Authored by : Paul C. Price, Rajiv S. Jhangiani, and I-Chant A. Chiang. Provided by : BCCampus. Located at : https://opentextbc.ca/researchmethods/ . License : CC BY-NC-SA: Attribution-NonCommercial-ShareAlike

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• Published: 27 August 2024

Facilitators and barriers to interprofessional collaboration among health professionals in primary healthcare centers in Qatar: a qualitative exploration using the “Gears” model

• Alla El-Awaisi 1 ,
• Ola Hasan Yakti 2 ,
• Abier Mohamed Elboshra 1 ,
• Kawthar Hasan Jasim 1 ,
• Alzahraa Fathi AboAlward 1 ,
• Raghad Walid Shalfawi 3 ,
• Ahmed Awaisu 1 ,
• Daniel Rainkie 4 ,
• Noora Al Mutawa 3 , 5 &
• Stella Major 6  

BMC Primary Care volume  25 , Article number:  316 ( 2024 ) Cite this article

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The number of patients seeking medical care is increasing, necessitating more access to primary healthcare services. As several of these patients usually present with complex medical conditions, the need for interprofessional collaboration (IPC) among health professionals in primary care is necessary. IPC is essential for facing the increasing and challenging healthcare demands. Therefore, the facilitators of and the barriers to IPC should be studied in the hope that the results will be used to promote such endeavors.

This study aimed to explore the perspectives of different health professionals regarding the facilitators of and the barriers to IPC in the primary healthcare settings in Qatar.

A qualitative study using focus groups was conducted within the Primary Health Care Corporation (PHCC) in Qatar. Several health professionals were invited to participate in the focus groups. The focus groups were uniprofessional for general practitioners (GPs), nurses, and dentists, while they were interprofessional for the other health professionals. Focus groups were audio-recorded and transcribed verbatim and validated by the research team. The data were analyzed by deductive thematic analysis using the “Gears” Conceptual Model as a coding framework.

Fourteen focus groups were conducted involving 58 participants (including 17 GPs, 12 nurses, 15 pharmacists, 3 dentists, and 11 allied health professionals) working in PHCC in Qatar. The findings revealed a spectrum of factors influencing IPC, categorized into four main domains: Macro, Meso, Micro, and individual levels, with each accompanied by relevant barriers and facilitators. Key challenges identified included a lack of communication skills, insufficient professional competencies, and power imbalances, among others. To address these challenges, recommendations were made to implement dedicated training sessions on IPC, reduce hierarchical barriers among different health professionals, and enhance the effectiveness of existing systems. Conversely, it was emphasized that projects and campaigns focused on IPC, alongside the development of enhanced communication skills and the presence of supportive leadership, as essential for facilitating effective IPC in PHCCs.

The interplay between the meso, macro, micro, and individual levels highlight the significance of a multifaceted approach to interventions, aiming to enhance the successes of IPC. While initiatives like interprofessional education training are underway, numerous challenges persist before achieving improved collaboration and more efficient integration of IPC in the PHCC setting.

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Introduction

The World Health Organization (WHO) projects a global deficit of health professionals in comparison to the needs, expected to exceed 18 million by 2030, which will impede the provision of optimal healthcare services. In their “Global strategy on human resources for health: Workforce 2030”, they highlighted the need to equip health professionals with the skills needed to practice collaboratively in interprofessional teams [ 1 ]. One of the best solutions to face this strain on the healthcare system and to provide better management of the complex health challenges is to implement and promote the concept of interprofessional collaboration (IPC) as these demands often are beyond the expertise of any single profession [ 2 , 3 , 4 ]. According to the WHO, IPC occurs when “multiple healthcare workers from different professional backgrounds provide comprehensive services by working with patients, their families, caregivers, and communities to deliver the highest quality of care across settings” [ 2 ]. IPC recently has become one of the core demands of accreditors, funding institutions, policymakers, and practicing health professionals, recognizing its potential to improve the quality of care and address the increasing demand for healthcare services [ 5 , 6 , 7 , 8 ].

Research has consistently highlighted the positive impact of IPC on healthcare work processes, patient safety, and patient outcomes across various disease states such as diabetes, heart failure and asthma, which were treated in hospital, primary care, and community settings [ 9 , 10 , 11 ]. Research has concluded that a high degree of IPC has led to better subjective outcomes, including overall satisfaction, treatment success, and willingness to recommend the healthcare institution to others. Additionally, objective outcomes such as reduced mortality rate, readmissions, and hospital length of stay have been noted. Furthermore, collaboration has been associated with improved decision-making and increased innovation [ 12 , 13 ]. It has also been demonstrated that as the relationship and level of connectedness between physicians and other health professionals increase; hospitalization costs and readmission rates decrease [ 14 ].

Primary healthcare is the foundation of any country’s healthcare system. It is not only considered the primary point of contact with the healthcare system, but it also serves as the vehicle for ensuring continuity of care across settings. The increase in the number of people with multiple chronic diseases that are associated with considerable social, functional, and emotional impairment and an increase in the healthcare demand, leading to an increase in the needed services [ 15 , 16 , 17 , 18 ]. Consequently, policymakers on an international scale have persistently advocated for the greater integration of interprofessional team-based care in primary healthcare settings and the development of influencing factors that explicitly acknowledge the value of this collaborative approach [ 19 , 20 ]. Several studies in the literature have highlighted the positive outcomes associated with effective collaboration within primary healthcare settings [ 21 , 22 , 23 ]. This has led to an internationally movement towards team-based primary healthcare, to enhance the integration of services and to emphasize health promotion and chronic disease management [ 19 ]. Ineffective collaboration leads to an increased risk of preventable errors, lack of efficiency, and loss of motivation, resulting in suboptimal patient care based on nurses’ opinions [ 24 ].

While IPC efforts are usually initiated by policymakers, research have demonstrated that health professionals’ play a vital role in providing high-quality IPC. Therefore, it is of crucial importance to consider the perspectives of health professionals working in primary healthcare settings regarding IPC when designing and implementing IPC projects [ 25 ]. Numerous studies have examined IPC across various countries. For example, a systematic review was conducted to explore facilitators and barriers to IPC implementation in primary healthcare settings. This review included studies conducted in Great Britain, the United States, the Netherlands, Australia, Spain, Brazil, Canada, and New Zealand. The findings of this review indicated that allied health professionals generally hold positive perceptions of IPC within primary healthcare contexts [ 26 , 27 ]. However, limited research has been conducted to investigate healthcare IPC practice in Qatar, particularly in primary healthcare settings. Given the recent expansion of scope of practice in primary care in Qatar [ 28 ], it is essential to explore the current practices in primary healthcare in Qatar in terms of IPC facilitators and barriers, and determining the necessary steps to achieve optimal collaboration within the Qatari healthcare system.

This study is a continuation of a previous study that explored the perspective of 1415 health professionals in primary healthcare settings through a self-administered questionnaire [ 28 ]. Results of the study showed that health professionals generally have a positive attitude and readiness toward IPC. Interprofessional differences were noted regarding their readiness to be involved in IPC, where physicians had slightly more positive readiness towards understanding their professional identity compared to other health professionals. Health professionals with previous IPC or interprofessional education (IPE) experiences revealed greater, but non-significant positive attitudes toward IPC compared to those without previous experiences. Participants suggested that facilitators and barriers for IPC in primary healthcare settings are conceptual rather than physical. Facilitators included personal belief in IPC benefit, higher professional satisfaction, interprofessional respect, appreciation of other health professionals’ role, institutional support, and leadership. Barriers identified included lack of time, leadership, support, and limited resources.

In an effort to understand the health professionals’ perception of the facilitators and barriers for IPC in primary healthcare in Qatar, the current study will explore the factors affecting the IPC in primary healthcare in Qatar using the “Gears” conceptual model [ 7 ]. The Gears model offers a taxonomy of factors influencing IPC within Interprofessional Primary Care Teams (IPCTs). These factors are categorized into levels: policymakers (macro gear), organizational managers (meso gear), healthcare teams (micro gear), and health professionals (individual gear). Most of the factors identified by the “Gears model” are within the micro gear, or those affecting the individual. These involve formal processes such as quality audits and group problem-solving; social processes pertained to open communication and supportive colleagues; team attitudes such as feeling part of the team; and team structure such as team size and having a collaboration champion or facilitator. Macro gears/policy factors are those that change less frequently and are pertained to regulations regarding the general scope of practice, funding, etc. Meso gears/ organizational factors are those that change more often and affect more than one team in the organization, those are concerned with the information systems, organizational culture, etc. Individual factors include the individual health professional characteristics such as belief in IPC care and personal flexibility.

The aim of this study is to identify factors facilitating or impeding IPC in primary healthcare in Qatar by exploring the perspectives of health professionals working in primary healthcare qualitatively. These include GPs, nurses, pharmacists, dentists, and allied health professionals (lab technicians, physiotherapists, dieticians, and radiographers). Findings from this study will be used to find ways to enhance and promote collaborative practice in primary healthcare in Qatar.

Study design

In this qualitative study design, data were collected through semi-structured focus groups. A qualitative approach was used to explore comprehensively the lived experiences of health professional’s perspective as it allows for investigating a phenomenon from the people who have experienced it. It gives a deeper insight and answers to what, how, and why questions [ 12 ].

Study setting

The study was conducted among health professionals working in the Primary Health Care Corporation (PHCC) in Qatar. PHCC was established in 1978 to provide comprehensive primary healthcare services and became an independent body in 2012 with full administrative and financial autonomy. At the present time, the PHCC provides PHC through 27 PHC centers distributed across the country. Each center is staffed with health professionals who provide a broad range of services, focusing on health promotion and disease prevention. PHCC has adopted and implemented family medicine model of care and offers a wide range of services, including general medicine, dentistry, ophthalmology, optometry, ENT, dermatology, mental health, preventive and lifestyle services such as wellness, premarital care, cancer screening, gym and geriatric, physiotherapy and radiology services [ 29 ]. In February 2018, a local continuous professional development (CPD) program was initiated by PHCC Workforce Training Department (WFTD) for implementing learning activities across the 27 PHCC health centers using interprofessional and collaborative approaches.

Study participants and sampling

The study comprised 58 participants, including 17 general practitioners, 12 nurses, 3 dentists, 15 pharmacists, and 11 allied health professionals (e.g., laboratory technologists, radiologists, optometrists, and audiologists) working in PHCC in Qatar. A purposive sampling strategy was employed to select health professionals with experience or understanding of IPC, aiming to maximize participant recruitment and ensure representation of the study population’s views [ 16 ]. Sampling continued until thematic saturation was reached, indicating no further emergent ideas from discussions [ 17 ].

Participants’ recruitment

Emails were sent to the health professionals working at PHCC in Qatar inviting them to participate in the study focus groups that were planned to be conducted at Qatar University or PHCC headquarters. Recruitment of participants was facilitated through WFTD which took the responsibility of recruiting and arranging appropriate focus group schedule that can suit study participants. An invitation email was sent with consent form and participant information sheet to participants prior to the focus groups.

Data collection

The topic guide was developed through discussions with the research team, a review of previous literature, and based on phase 1 quantitative results [ 28 ] (please see supplementary file). A pilot interview was conducted with minor adjustments and included a few health professionals working in PHCC. Because no significant changes were made it was included in the final analysis. The focus group were uniprofessional (i.e. homogenous groups) for GPs, nurses and dentist and interprofessional (i.e. heterogeneous groups) for the remaining health professionals and varied in duration between 90 and 120 min. The discussions were audio-recorded and transcribed verbatim.

Data analysis

A deductive thematic analysis was conducted of data, which is an analytical method in which authors use existing themes, categories, or domains to categorize new data under such categories [ 30 ]. Participants’ ideas were categorized under four main domains adapted from the “Gears model” [ 7 ]. The gears model outlines the factors affecting IPC within IPCTs under four main factor domains: macro, meso, micro, and individual factors. AME, AA, KJ, RS reviewed and validated the transcripts. They then independently reviewed couple of transcripts to generate codes in discussion with the lead author (AE). Coding for the rest of the transcripts was validated by one faculty member from the research team. A final discussion took place with all authors to agree on themes and subthemes.

Reflexivity

During the data collection and analysis process, the research team engaged in reflexive practices to mitigate potential biases. The team consisted of various individuals with diverse backgrounds, including faculty members with pharmacy, nursing and medical backgrounds, three of whom were practicing health professionals, along with four pharmacy students and one alumna. The team offered a broad spectrum of perspectives and insights for data generation and analysis. These faculty members had an understanding of IPE and had previously conducted workshops on interprofessional collaboration for health professionals at PHCC. With a background in IPC, participants’ ideas were more easily understood, facilitating deeper engagement, and enabling the comprehension of their perspectives more readily, thus ensuring a comprehensive interpretation of the data. Throughout the research process, attention was paid to the potential influence of professional backgrounds, with reflexive practices employed to mitigate biases and ensure the integrity of the findings.

Data collection were mostly led by the principal investigator, with support from students adhering to a pre-defined topic guide to minimize personal biases. To further enhance trustworthiness of the study, students independently coded the data, which was validated by a faculty member of the research team. The team met several times to review and compare codes and themes, refining the analysis iteratively until consensus was reached. Each stage of the research process was overseen by the principal investigator, ensuring the rigor and robustness of the study.

Fourteen focus groups were conducted between September 2019 and February 2020, involving 58 health professionals working in primary healthcare centers in Qatar (17 general practitioners, 12 nurses 15 pharmacists, 3 dentists, and 11 allied health professionals). The baseline characteristics of the participants are summarized in Table  1 . Four domains, 10 themes, and 14 sub-themes were identified from the focus groups. The domains, themes, and sub-themes are summarized in Table  2 .

Gears domain 1: macro factors

Facilitators, theme 1: the influence of organizational policies on ipc.

Several factors were identified by health professionals pertaining to the policies that can affect IPC. These factors were mainly related to the rules and regulations set by the organization’s managers or government bodies, which typically influence the general scopes of practice, funding mechanisms, and remuneration of providers. Consensus was reached that these regulations play a significant role in fostering IPC among health professionals.

“Actually , we have very well prepared and organized policies. Policies related to teamwork , which align with best-practices and international guidelines. The policies at our PHCC facilitate collaboration… but how to use it? Is everybody aware of its use?” [Laboratory technologist 1].

No major barriers were identified under the macro factors.

Gear’s domain 2: meso factors

Theme 2.1: leveraging technology for enhanced communication.

Participants unanimously agreed that the current health information system, specifically CERNER, serve as a strong facilitator for enhancing communication among health professionals. It enables seamless sharing of patients’ details documented by other health professionals.

“I find the CERNER system software amazing , because you can get to see the history of the patients and previous appointments records. Everything is well documented” [Dentist 3].

Theme 2.2: communication hindered by limitations in healthcare information system utilization

Several participants noted that current system (CERNER) is not fully utilized for documenting and reporting of medical or medication errors which can serve as a barrier. As an example, one participant expressed reluctance to utilize the system and filing an OVA (incidental report) for fear of retaliation in case the reporter is identified.

“If I were to write OVA (incidental report) for him/her , he/she will get angry at me. So , there’s no use. Actually , the purpose is to report in order for others to learn from them , but there is no clear pathway that there will be no consequences for us reporters” [Nurse 2].

Furthermore, another HCP mentioned that the current information system might be a barrier, as not all health professionals have equal access to the system.

“The pharmacist is not allowed to enter a recommendation into the system; they have their own system” [GP 5].

Theme 2.3: barriers in organizational dynamics hindering IPC

Sub-theme 2.3.1: hierarchy hinders collaborative spirit.

One of the primary obstacles to collaboration within the institution is perceived to be the presence of a hierarchical structure. This perception is based not only in the observable existence of a grading system that categorizes health professionals according to their profession and seniority, but also in the benefits associated with higher hierarchical positions.

“The hierarchy is influenced by salary differences” [GP 4].

Participants in the study observed that this hierarchical system leads to disparities, which undermine their willingness to collaborate. As an example, pharmacists expressed feeling of being treated differently compared to GPs, who are routinely offered opportunities to attend international conferences. The lack of such opportunities for pharmacists and other health professionals further reinforces the perception of hierarchy within the institution.

“I have tried to attend a conference; I have a right to enhance my education. Why does this apply to the GP and not to the pharmacist?” [Pharmacist 8]. “He -the GP- thinks that the pharmacist as being of lower status , and he is the only one to have the authority to write and make decisions” [Pharmacist 9].

Sub-theme 2.3.2: blame culture instils apprehension among health professionals

Another significant factor that had a considerable impact on collaborative efforts was the existence of a culture of blame within the PHCC organization. This culture of blame surfaced frequently during discussions among health professionals and was found to hinder effective collaboration among team members. Some perceived the level of blame not to be equitable.

“What if I did a mistake? And what if the mistake was done by the GP? The blame wouldn’t be equal. We would receive more blame” [Nurse 3]. “I still believe that some of us should refrain from perpetuating a blame culture or name-calling. After all , all of us are human beings. We are prone to making errors” [GP 10]. “We need to promote a culture of no blame. When things go wrong or mistakes occur , we should view them as collective challenges rather than assigning fault to individuals and subjecting them to humiliation. This approach will significantly transform the overall attitude within the environment” [GP 2].

Sub-theme 2.3.3: Lack of feedback contributes to the perception that health professionals’ efforts are undervalued

Some health professionals have expressed concerns regarding the lack of feedback on their performance, interventions, and error reports, particularly within Datix, a patient safety software utilized for healthcare risk reporting. This absence of feedback is perceived as a significant impediment to IPC, as it fosters the perception that the efforts of health professionals are not adequately acknowledged or valued.

“The risk management team should gather data and determine the significance of incidents reported through Datix , which is serious or recurring. If a mistake is repeated , they will ask or make an investigation about this issue. However , aside from these instances , no action is taken. No feedback is provided” [Pharmacist 1].

Gears domain 3: micro factor

Theme 3.1: expanding the scope of practice of team members enhances collaboration.

Given that IPC heavily relies on teamwork, the topic of collaborative efforts and teamwork surfaced frequently during focus groups.

“ The most important thing in primary healthcare practice is the teamwork. We underscore its importance , as it permeates our daily operations” [GP 6].

Expanding the scope of practice of healthcare team members has the potential to foster enhanced collaboration between team members. For example, pharmacists who participated in the discussions expressed that the inclusion of a clinical pharmacist within PHCC would enhance collaboration. This is attributed to the direct involvement of the clinical pharmacist with the interprofessional team, which obviates the need for external prompting to initiate collaborative efforts.

Theme 3.2: effective communication channels foster collaboration

Effective collaboration among participants was found to significantly hinge on the establishment of robust communication channels. This encompasses both formal features and tools, ranging from cordial and conversational telephonic exchanges to more structured modes of communication, such as the sharing of electronic patient records. Several participants cited instances of proficient communication that had led to successful collaboration outcomes.

“Every colleague should be encouraged to express their concerns , whether in written form or verbally , as it facilitates communication” [Dentist 3]. “Many doctors respect our opinion and express gratitude , acknowledging that we draw their attention to certain points“ [Pharmacist 9].

The majority of participants highlighted the importance of communication tools provided by the institution, including telephones, the CERNER system, and email platforms. Participants expressed their appreciation for these communication channels, noting that they effectively save time and enable seamless collaboration, even when they are attending to patients in different locations.

“It’s not difficult because we have our colleagues , whom we can contact directly by phone” [Dentist 1].

Theme 3.3: formal team processes have a significant role in facilitating collaboration

Sub-theme 3.3.1: supportive leaders empower team members to collaborate.

Leaders who demonstrate appreciation and dedication play a crucial role in fostering positive experiences of IPC. Regular interprofessional meetings organized by these leaders ensure that the environment is conducive to collaboration, and support empowering health professionals to initiate and engage in collaborative endeavor.

“So , if we have any issues , we talk to our supervisor , who then reports it to the health center manager. She is really supportive” [Pharmacist 3].

Sub-theme 3.3.2: engagement in interprofessional initiatives enhances collaboration among team members

Participants emphasized that their involvement in workplace initiatives, such as projects, campaigns, seminars, and workshops, played a crucial role in promoting IPC. According to health professionals, these initiatives were beneficial as they provided them with diverse professional perspectives, opinions, and ideas, which in turn enhanced their chances of success in their collaborative efforts.

“In our health center , we initiated a project to improve the practice of antibiotic prescribing. We were collaborating with GPs to know from them how to write and put a protocol to lessen the misuse of antibiotic” [Pharmacist 2].

Participants also recognized that engaging in collaborative research activities involving multiple team members was an effective facilitator for enhancing patient safety.

“I conducted research on medication use reviews , actively engaging with general practitioners’ clinics. I would regularly visit these clinics to share information about the study. During these interactions , I explained my criteria , encouraging them to refer eligible patients to the pharmacy” [Pharmacist 6].

Furthermore, vaccination campaigns were considered essential by several pharmacists as they provided opportunities for collaboration with other disciplines including educational outreach events. Several pharmacists reported on their involvement in these campaigns and the subsequent positive impact on collaboration dynamics. Specifically, one pharmacist highlighted a reduction in the uptake of pneumococcal vaccine among eligible patients and assumed a proactive role by gathering information from various GPs regarding the decreased prescription of such vaccines.

“We did a project in collaboration with GPs , regarding vaccinating high risk patients with pneumococcal vaccine” [Pharmacist 4]. “During the immunization week , I held a seminar about immunization. I taught them -nurses- individually how to use each vaccine properly and why we are using it” [Pharmacist 2].

Moreover, participants found case-based discussions and interprofessional training sessions with other health professionals valuable for collaboration. These sessions allowed discussion of each profession’s role and facilitated idea exchange.

“ As part of our interprofessional education efforts , we conduct weekly lectures and brief discussions for an hour… sometimes , new nurses and physiotherapists attend these lectures…… We discuss how we can help promote the collaboration between all of us for better care for the patients” [GP 9].

Sub-theme 3.3.3: optimizing accessible healthcare environments

Experiences related to the impact of the environment on collaboration were generally positively perceived. For instance, the close proximity of a nurse diabetic educator to the pharmacy facilitated direct communication between pharmacists and educators, enabling them to address any concerns more efficiently. Moreover, having practitioners co-located in a single setting, rather than dispersed in various locations within the center, was deemed more advantageous.

“We have it , diabetic educator , clinical pharmacist , and GP all in one place , so they all work together for assessment of patient and education , particularly high-risk patient” [Pharmacist 4].

Theme 3.4: time constraints impede collaboration and affect patient outcomes

Participants identified time constraints as a significant challenge to collaboration, with health professionals struggling to allocate sufficient time for documentation, communication, and knowledge-sharing, potentially impacting patient outcomes.

“We can’t afford the luxury of opening CERNER each time since we are already occupied with other tasks” [Pharmacist 5]. “Even when there is an issue …. we should learn from it. We are not learning. We just want to finish this issue and just move on because there is no time. There is too much work” [Laboratory technologist 1].

Theme: 3.5: lack of clarity in scope of practice leads to misunderstandings and hinders collaboration

A number of health professionals expressed concerns regarding the potential misunderstanding of their scope of practice, leading to requests to perform tasks beyond their designated role which impact the collaborative culture leading to frustration.

“Nurses are responsible for taking vital signs , following the patient’s care plan , and managing medications , but cleaning is not part of their role although some doctors mistakenly believe it to be so” [Nurse 3]. “At times , we notice that some GPs are unaware of the difference between a technician and a radiologist” [Laboratory technologist 1].

Gears domain 4: individual factors

Theme 4.1: prior exposure to ipe enhances appreciation for ipc.

The study observed that health professionals who had prior experience with IPE exhibited a greater appreciation towards collaborative work.

“We learned and practiced IPE during our education. However , in practical settings , there is still a need for a comprehensive understanding of IPE and its implementation. While there are individual efforts to apply it , full implementation has not been achieved yet” [Pharmacist 3].

Theme 4.2: health professionals’ factors

Subtheme 4.2.1: effective communication skills drive enhanced collaboration among health professionals.

Effective communication was deemed crucial by participants in healthcare settings. Nurses felt valued and integral to the team when equipped with proper communication skills, while GPs found direct communication with other health professionals to be advantageous, enhancing their practice.

“Quite a few times , I’ve reached out to the on-site ophthalmologist by phone. When there’s a concern about a patient , whether its suspected cornea issues or the need to rule out certain conditions , a simple phone call often results in them accommodating the patient. The ophthalmologist has consistently been responsive and helpful in these interactions” [GP 6].

Subtheme 4.2.2: positive interpersonal qualities among health professionals enhance collaboration

The collaboration within the team is influenced by health professionals’ interpersonal qualities which was identified as a significant factor, with approachability and friendliness being crucial in facilitating collaboration.

“The difference here is that I find everybody to be approachable and friendly [GP 6]. Very friendly environment. You can approach the nurses , the doctors—everyone is accessible” [GP 10].

Furthermore, respect and trust were highly valued facilitators of IPC and were discussed in conjunction with other facilitators.

“Mutual respect among all health professionals will facilitate smoother and more effective collaboration” [Nurse 3]. “We must respect each other. Just because I am a GP , it doesn’t mean my opinion is the only opinion or the correct one” [GP 3].

Theme 4.3: patient perceptions impact IPC

Patient perceptions were found to exert a considerable impact on the dynamics of collaboration between nurses, GPs, and other health professionals. Participants reported that patients tended to perceive nurses as occupying a subordinate position relative to GPs, and consequently, were less forthcoming in discussing healthcare concerns with them.

“ You are the nurse; you know less than the doctor” [Nurse 4]. “ Patients typically highly value recommendations from physicians. However , when they seek advice or education from nurses or pharmacists , they sometimes may not value it as much as they would if it came from a physician ” [Pharmacist 7].

Additionally, participants believe patients regard GPs as the key health professionals, and preferred to communicate exclusively with them. This perception placed an additional workload on GPs, leading to potential consequences on their capacity to collaborate effectively with other health professionals.

“We need to educate patients more about the roles each team member plays and how we all work together as a team. When a patient comes in , they often see the doctor as the leader but it’s important for them to understand the contributions of all team members” [GP 5].

Theme 4.4: impact of of perceived approachability and ego on IPC

On the other hand, encountered challenges in communicating with GPs, including when they perceived a sense of ego, or if they were less approachable. Nurses expressed reluctancy to approach pharmacists or GPs whom they felt would not respect them.

“ Being approachable is one of the most important things especially when it comes to the team. For example , some of the nurses would know a lot of information about the patient but if you’re not an approachable GP , they will not come and voluntarily divulge the information” [GP 6]. “Ego. When you are dealing with people these things are barriers and the best solution is always communication” [Nurse 6].

Similarly, GPs encountered similar challenges in communicating with other health professionals if they perceived them as unfriendly or unapproachable. However, they differed from the nurses in that they seemed to encounter these challenges within their own field of practice rather than in interactions with other health professionals.

Theme 5: enhancing IPC through equity, training, and support

The study participants put forth several proposals to enhance IPC in their workplace. A key recommendation was to ensure equity among health professionals, such that all members had full and equal access to patient files. This would enable effective IPC by keeping all team members abreast of the patient’s evolving health status and treatment plan. Participants recognized that institutional and leadership support would be necessary to achieve this equity. Additionally, due to the acknowledged limitations posed by workload and time constraints, many participants suggested that the recruitment of additional staff could facilitate IPC processes. Further, the participants proposed the need for more frequent training sessions to improve communication skills, enhance system and documentation writing, and provide IPC disease management, role clarification, and professional competencies education.

“When they send you for training you will be empowered” [Nurse 2].

Finally, health professionals emphasized the importance of a supportive system that offers constructive feedback to identify weaknesses and facilitate continuous improvement of practice. In addition, health professionals remarked on the impact of managerial support on collaboration and performance.

“When we receive support from the health center manager during our practice , we find that collaboration improves , leading to better outcomes” [Pharmacist 2].

This qualitative focus group study explored facilitators of and barriers to IPC as perceived by health professionals (including GPs, nurses, pharmacists, dentists, and allied health professionals) from various backgrounds in primary healthcare in Qatar using the “Gears” conceptual model. Overall, the majority of health professionals who participated in this study have acknowledged and appreciated the importance of IPC work within their institutions, which is consistent with other published studies [ 27 , 31 , 32 ].

Facilitators under the micro-gear domain focused on healthcare teams. Participants agreed that the diversity of health professionals within the same PHCC is a major facilitator for better collaboration. They also agreed that the presence of different communication channels (e.g. telephones, CERNER, etc.) is another facilitator. Supportive leaders in the team were acknowledged to have a positive influence on attitudes toward IPC. IPE activities were identified as positively influencing attitudes towards toward IPE and IPC. These findings are consistent with those of other studies. There was an agreement among several studies regarding the importance of open communication and various communication strategies and tools in facilitating IPC [ 33 , 34 ]. For example, Müller et al. [ 33 ], in their study where authors interviewed several clinical executive managers, found that participants agreed that multilateral communication is one of the enablers for effective IPC. Facilitators within the individual-gear, includes Individual contextual factors contributing to IPC such as previous exposure to IPC, patient related factors, and characteristics of health professionals. Previous exposure to IPC emerged as a significant facilitator for both health professionals and patients. Communication skills were identified as crucial in supporting exposure to IPC. Participants highlighted the importance of accessible communication methods, such as availability by phone or in person conversations, eliminating roadblocks to IPC. Furthermore, the approachability of health professionals, characterized by their openness to information sharing and their trust and respect for the competency, knowledge, and skills of other health professionals was a key facilitator to IPC.

Regarding the meso-gear facilitators, participants valued the importance of receiving ongoing, and timely feedback based on practice experiences to consolidate learning and minimize recurrence of errors. They advocated for utilizing data from platforms such as Datix; an Incident Reporting System (IRS), which is a valuable resource among all team members involved in patient care. Participants recommend a wider use of such data for learning, in interprofessional team meetings. This aligns with evidence from the literature which suggests that critical to the success of any IRS is the quality of the feedback given to reporters to enable learning, encourage reporting, and give reporters evidence that the information they are providing is being used appropriately [ 35 , 36 ]. Space and proximity are reported as excellent opportunity for teams to work together and share perspectives in the care for the patient [ 37 ]. As new PHCC centers are created to serve the growing needs of Qatar’s population, leaders can benefit from including members of the care teams, in the final design discussions, so that space and proximity can continue to remain optimal and facilitate interprofessional practice and team centered patient care.

The least number of factors were identified under the macro-gears. These relate to governance and regulations, which were considered as a major facilitator for better IPC in the primary healthcare setting in Qatar. The participants in this study had reflected on the existing policy and regulatory facilitators that foster collaborative practice in PHC setting in Qatar, but did not discuss barriers to policies and regulations. The study findings reaffirm the potential role and influence of government policies and regulations in facilitating IPC in primary care settings from the perspective of the health professionals. Additionally, organizational-level policies were also perceived as key facilitators. This aligns with the macro-level factors of the Gears conceptual model, which allows the conceptualization of the intricate relationships between this and the other domains of the model from the perspective of the health professionals. Previous studies have documented the influence of policy and regulation in promoting collaborative practice and IPE. One international review has summarized the global policies and legal factors influencing the behaviors of health professionals towards successful implementation of collaborative practice [ 38 ]. These factors largely influence the scope of practice of various health professions and how the different professions work collaboratively, funding mechanisms, and reimbursement systems for health services.

In Qatar, health professions and practices are regulated by the Department of Healthcare Professions under the Ministry of Public Health (MoPH) [ 39 ], which is considered a key aspect of professional practice [ 38 ]. Although there are no umbrella laws to regulate multiple health professions under a single statute, which is a major drawback to an effective and conducive implementation of collaborative practice in various settings, having a unified regulatory and legal structure has been shown to foster a culture of equity among different health professionals [ 40 ]. An important aspect of policy and professional regulation is the scope of practice, which should typically clarify roles and represent specific areas of competence for each particular health profession. Participants indicated the presence of scope of practice for various professions in the State of Qatar. Previous studies and reports have highlighted the importance of restructuring the scope of practice of health professions towards effective IPC and to remove barriers to healthcare provision. This will allow health professionals to practice within the scope of their practices and to the full extent of their professional competence without encroaching other professions’ scope of practice, which will ultimately lead to effective collaborative practice [ 41 , 42 ]. In addition, funding and reimbursement are macro-level aspects that can significantly impact IPC [ 40 , 43 ]. In the present study, there was a consensus that these regulatory factors play a key role in facilitating the IPC among the health professionals in primary care settings in Qatar.

Barriers pertaining to the healthcare teams, or the micro-gear, are the lack of understanding of other professionals’ scope of practice, and the lack of time. This is not different from what is reported in the literature, where lack of time and poor understanding of other health professionals ' roles were considered, besides other barriers, major hinderers for IPC in one review paper that collected multiple articles that studied the enablers and hinderers of IPC [ 34 ]. For the individual-gear barriers, health professionals identified that the hierarchy entrenched within the healthcare system contributed a major barrier to collaboration. Within the studied context, GPs are seen as the pinnacle health professional by patients. Therefore, patients are reluctant to provide information to health professionals other than the GP. This ultimately reduces the effectiveness of the healthcare system as the scope of practice of the remainder of the interprofessional team are constrained to meet patient needs. This might limit other health professionals’ roles, and hence they might be less able to exchange care. This idea might go with the concept of the “patient-doctor dyad” that has been reported in the literature, where authors described that one of the hinderers of IPC is the patient’s desire to be mainly seen and examined by GPs, which is often prioritized over collaborative care [ 44 , 45 , 46 ]. Pharmacists, in this study, described that patients also might ignore pharmacists’ recommendations if it was not aligned with the GPs’ recommendations. While IPC may beget IPC, participants remarked that there was difficulty bringing IPC to life in their PHCC context. Knowledge of IPC must be accompanied by a shift in organizational culture, supported by policies and performance review, led by champions, and guided by exemplars of IPC.

Two subthemes were considered under the meso-factors, which are mainly regarding the information system and the organizational culture. Our results indicate that although a health information system (HIS) is operating within the primary healthcare center (PHCC) system, however, not all members of the team use nor rely on it, to complete their duties in patient care. This fragmentation of data systems poses a threat to team unity and excludes some team members (in this context the pharmacists) from being on the same page as the rest. Efforts to merge all data subunits and enable all team members to access the HIS, can enhance work time efficiency (a micro challenge) that participants reported for pharmacists to require in order to be on the same page as the other care providers in the team and is supported by research which stresses the benefits of a health information system which enables the participation of all staff who are directly concerned with patient care in that setting [ 47 , 48 ].

In the interest of optimizing patient safety, whilst participants in this study valued the opportunity for a shared HIS to serve as a platform where errors could be recorded, our data indicates that health care team members did not feel safe enough to do so. According to Smiley and colleagues [ 49 ] the fear of being fired and subjected to judicial inquiry and prosecution make many nurses conceal errors. This aligns with our participants’ reported concerns about the prevalence of “blame culture” and how this results in individuals feeling personally and professionally vulnerable. Blame culture in health care organizations is mainly associated with the approach used by management when dealing with medical errors and accidents [ 50 , 51 ]. Efforts to embrace a culture that promotes transparency and accountability, and management approach which as described by Catino [ 52 ] relates the causal factors of a given event to the whole organization rather than the individual, are priorities for the PHCC organizational leadership to consider.

Furthermore, hierarchy in privileges, such as varied levels of access to professional development opportunities, threatens team unity, and in turn generates a sense where some professions feel less valued for working in their roles. Educators postulate that if individuals from different professions learn together, they will be able to more effectively work together in teams to achieve desired outcomes [ 53 ]. Integrating CPD in interprofessional decision support with quality improvement and patient safety initiatives will likely enhance the uptake and ability to sustain these educational initiatives [ 54 ]. For instance, the “Schwartz Center Rounds” in the US and UK provide a forum in which professional and nonprofessional staff across healthcare disciplines can discuss challenging psychosocial and emotional aspects of a patient’s care and the impact of these challenges on the care team. These rounds do not focus solely on decision-making, but attendees report significantly enhanced appreciation of colleagues’ roles and contributions, communication, and teamwork [ 55 ]. In this way, the professional learning needs can meet not only the individual profession, but also translate into opportunities for teams to problem solve together and in turn improve safer patient care.

In general, the current study results on facilitators and barriers to IPC align well with those identified by a review study by [ 34 ] that summarized the facilitators and barriers for interprofessional care in primary healthcare. Common facilitators in both studies are the lack of time and training for the health professionals, lack of understanding of others’ roles, and poor communication. It is interesting to note that fears relating to professional identity were identified as a hinderer in the review; however, it was not mentioned by any HCP in the current study. This could be due to the proper understanding of the self-role of the HCP in this study. IPC enablers identified by the review were all reported in this study (i.e. communication tools, co-location of HCP, and recognition of other professionals’ roles and contributions).

Strengths and limitations

One strength of this study is the use of the “Gears model” to understand facilitators and barriers at each level within the IPCTs. Identifying the facilitators and barriers at each level of the work environment makes it easier for decision-makers to identify the gaps and the points that need improvement specific for each level, and hence will help implement appropriate, and probably more efficient, interventions suitable for each level to improve IPC within the PHCC settings. The current study included a high diversity of health professionals and did not focus on certain professions, which aligns with what interprofessional work is all about. This study, as mentioned before, is a continuation of a previous quantitative study done on more than 1400 health professionals to assess their attitude toward IPC. Although the previous study showed that health professionals have a positive attitude toward IPC, which was evident by the survey, the current study examined these quantitative findings from a qualitative lens. This provided a clearer insight to ensure a comprehensive understanding of what shapes these perspectives.

Limitations of the study might include the lack of anonymity in focus groups, which might increase the social desirability. Second, although the study included multiple professions, most participants were GPs, pharmacists, or nurses. Moreover, some HCP were not present (e.g. pharmacy technicians, and physiotherapists), which could limit the generalizability of the current study to these professions.

The interplay between the meso, macro, micro, and individual gears showcases the importance of a multifaceted approach to interventions to amplify the successes of IPC. Policies such as data sharing and collaborative key performance indicators support the interaction between the meso and individual gears. The individual assists the macro and meso gears through communication and trust in the scope of practice of the other team members. Simultaneously, health professionals must advocate for their colleagues to patients. Patients have a direct connection to the micro and individual gears which ultimately affect the care being provided to them.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

Thanks to Dr. Jessie Johnson from the University of Calgary-Qatar for her initial support with this project. Also, we would like to thank all health professionals from primary health care who volunteered to participate in this study.

This publication was supported by Qatar University Student Grant [QUST-1-CPH-2020-25]/ [QUST-2-CPH-2019-3]. The findings achieved herein are solely the responsibility of the author[s].

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AE contributed to the conception of this research idea, study design, data collection, data analysis, and including supporting all stages of this paper. AME, KJ, AAZ, RS accompanied AE in the focus groups. AME, KJ, AAZ, RS, AA, DR, NA, SM supported with the study design, study conceptualization, analysis, and interpretation of findings. OY supported with the data validation, analysis, and interpretation of findings. All authors contributed to drafting the manuscript and reviewed and approved the final version of the manuscript.

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El-Awaisi, A., Yakti, O.H., Elboshra, A.M. et al. Facilitators and barriers to interprofessional collaboration among health professionals in primary healthcare centers in Qatar: a qualitative exploration using the “Gears” model. BMC Prim. Care 25 , 316 (2024). https://doi.org/10.1186/s12875-024-02537-8

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Day Two: Placebo Workshop: Translational Research Domains and Key Questions

July 11, 2024

July 12, 2024

Day 1 Recap and Day 2 Overview

ERIN KING: All right. It is 12:01 so we'll go ahead and get started. And so on behalf of the Co-Chairs and the NIMH Planning Committee, I'd like to welcome you back to day two of the NIMH Placebo Workshop, Translational Research Domains and Key Questions. Before we begin, I will just go over our housekeeping items again. So attendees have been entered into the workshop in listen-only mode with cameras disabled. You can submit your questions via the Q&A box at any time during the presentation. And be sure to address your question to the speaker that you would like to respond.

For more information on today's speakers, their biographies can be found on the event registration website. If you have technical difficulties hearing or viewing the workshop, please note these in the Q&A box and our technicians will work to fix the problem. And you can also send an e-mail to [email protected]. And we'll put that e-mail address in the chat box for you. This workshop will be recorded and posted to the NIMH event web page for later viewing.

Now I would like to turn it over to our workshop Co-Chair, Dr. Cristina Cusin, for today's introduction.

CRISTINA CUSIN: Thank you so much, Erin. Welcome, everybody. It's very exciting to be here for this event.

My job is to provide you a brief recap of day one and to introduce you to the speakers of day two. Let me share my slides.

Again, thank you to the amazing Planning Committee. Thanks to their effort, we think this is going to be a success. I learned a lot of new information and a lot of ideas for research proposals and research projects from day one. Very briefly, please go and watch the videos. They are going to be uploaded in a couple of weeks if you missed them.

But we had an introduction from Tor, my Co-Chair. We had an historic perspective on clinical trials from the industry regulatory perspective. We had the current state from the FDA on placebo.

We had an overview of how hard it is to sham, to provide the right sham for device-based trials, and the challenges for TMS. We have seen some new data on the current state of placebo in psychosocial trials and what is the equivalent of a placebo pill for psychosocial trials. And some social neuroscience approach to placebo analgesia. We have come a long way from snake oil and we are trying to figure out what is placebo.

Tor, my Co-Chair, presented some data on the neurocircuitry underlying placebo effect and the questions that how placebo is a mixture of different elements including regression to the mean, sampling bias, selective attrition for human studies, the natural history of illness, the placebo effect per se that can be related to expectations, context, learning, interpretation.

We have seen a little bit of how is the impact on clinical trial design and how do we know that something, it really works. Or whatever this "it" is. And why do even placebo effect exists? It's fascinating idea that placebo exists as a predictive control to anticipate threats and the opportunity to respond in advance and to provide causal inference, a construct perception to infer the underlying state of body and of world.

We have seen historical perspective. And Ni Aye Khin and Mike Detke provided some overview of 25 years of randomized control trials from the data mining in major depressive disorders, schizophrenia trials and the lessons we have learned.

We have seen some strategies, both historical strategies and novel strategies to decrease placebo response in clinical trials and the results. Start from trial design, SPCD, lead-in, placebo phase and flexible dosing. Use of different scales. The use of statistical approaches like last observation carried forward or MMRM. Centralized ratings, self-rating, computer rating for different assessments. And more issues in clinical trials related to patient selection and professional patients.

Last, but not least, the dream of finding biomarkers for psychiatric conditions and tying response, clinical response to biomarkers. And we have seen how difficult it is to compare more recent studies with studies that were started in the '90s.

We have the FDA perspective with Tiffany Farchione in this placebo being a huge issue from the FDA. Especially the discussion towards the end of the day was on how to blind psychedelics.

We have seen an increasing placebo response rate in randomized controlled trials, also in adolescents, that is. And the considerations from the FDA of novel design models in collaboration with industry. We had examples of drugs approved for other disorders, not psychiatric condition, and realized -- made me realize how little we know about the true pathophysiology of psychiatric disorders, likely also heterogeneous conditions.

It made me very jealous of other fields because they have objective measures. They have biology, they have histology, they have imaging, they have lab values. While we are -- we are far behind, and we are not really able to explain to our patients why our mitigations are supposed to work or how they really work.

We heard from Holly Lisanby and Zhi-De Deng. The sham, the difficulty in producing the right sham for each type of device because most of them have auxiliary effects that are separate from the clinical effect like the noise or the scalp stimulation for TMS.

And it's critical to obtain a true blinding and separating sham from verum. We have seen how in clinical trials for devices expectancy from the patient, high tech environment and prolonged contact with clinicians and staff may play a role. And we have seen how difficult it is to develop the best possible sham for TMS studies in tDCS. It's really complicated and it's so difficult also to compare published studies in meta-analysis because they've used very different type of sham. Not all sham are created equal. And some of them could have been biologically active, so therefore invalidating the result or making the study uninformative.

Then we moved on to another fascinating topic with Dr. Rief and Dr. Atlas. What is the impact of psychological factors when you're studying a psychological intervention. Expectations, specific or nonspecific factors in clinical trials and what is interaction between those factors.

More, we learned about the potential nocebo effect of standard medical care or being on a wait list versus being in the active arm of a psychotherapy trial. And the fact that we are not accurately measuring the side effect of psychotherapy trial itself. And we heard more a fascinating talk about the neurocircuitry mediating placebo effect -- salience, affective value, cognitive control. And how perception of provider, perception of his or her warmth and competence and other social factors can affect response and placebo response, induce bias in evaluation of acute pain of others. Another very interesting field of study.

From a clinician perspective, this is -- and from someone who conduct clinical trials, all this was extremely informative because in many case in our patient situation no matter how good the treatment is, they have severe psychosocial stressors. They have difficulties to accessing food, to access treatment, transportation, or they live in an extremely stressful environment. So to disentangle other psychosocial factors from the treatment, from the biology is going to be critical to figure out how to treat best our patients.

And there is so much more work to do. Each of us approach the placebo topic for research from a different perspective. And like the blind man trying to understand what is an elephant, we have to endure it, we have to talk to each other, we have to collaborate and understand better the underlying biology, understand different aspect of the placebo phenomena.

And this lead us to the overview for day two. We are going to hear more about other topic that are so exciting. The placebo, the nocebo effect and other predictive factors in laboratory setting. We are going to hear about genetic of the placebo response to clinical trials. More physiological and psychological and neuromechanism for analgesia. And after a brief break around 1:30, we are going to hear about novel biological and behavioral approaches for the placebo effect.

We are going to hear about brain mapping. We are going to hear about other findings from imaging. And we're going to hear about preclinical modeling. There were some questions yesterday about animal models of placebo. And last, but not least, please stay around because in the panel discussion, we are going to tackle some of your questions. And we are going to have two wonderful moderators, Ted Kaptchuk and Matthew Rudorfer. So please stay with us and ask questions. We love to see more challenges for our speakers. And we're going to be all of the panelists from yesterday, from today are going to be present. Thank you so much.

Now we're going to move on to our first speaker of the day. If I am correct according to the last -- Luana.

Measuring & Mitigating the Placebo Effect

LUANA COLLOCA: Thank you very much, Cristina. First, I would love to thank the organizer. This is a very exciting opportunity to place our awareness about this important phenomenon for clinical trials and the clinical practice.

And today, I wish to give you a very brief overview of the psychoneurobiological mechanism of a placebo and nocebo, the description of some pharmacological studies, and a little bit of information on social learning. That is a topic that has been mentioned a little bit yesterday. And finally, the translational part. Can we translate what we learn from mechanistic approach to placebo and nocebo in terms of a disease and symptomatology and eventually predictors is the bigger question.

So we learned yesterday that placebo effects are generated by verbal suggestion, this medication has strong antidepressant effects. Therapeutic prior experience, merely taking a medication weeks, days before being substitute with a simulation of placebo sham treatment. Observation of a benefit in other people, contextual and treatment cue, and interpersonal interactions.

Especially in the fields of pain where we can simulate nociception, painful experience in laboratory setting, we learn a lot about the modulation related to placebo. In particular, expectation can provide a reaction and activation of parts of the brain like frontal area, nucleus accumbens, ventral striatum. And this kind of mechanism can generate a descending stimulation to make the painful nociceptive stimulus less intense.

The experience of analgesia at the level of a pain mechanism translate into a modulation reduction of a pain intensity. But most important, pain unpleasantness and the effective components of the pain. I will show today some information about the psychological factor, the demographic factor as well as genetic factors that can be predictive of placebo effects in the context of a pain.

On the other hand, a growing interest is related to nocebo effects, the negative counter sides of this phenomenon. When we talk about nocebo effects, we refer to increase in worsening of outcome in symptoms related to negative expectation, prior negative therapeutic experience, observing a negative outcome in others, or even mass psychogenic modeling such as some nocebo-related response during the pandemic. Treatment leaflets, the description of all side effects related to a medication. Patient-clinician communication. The informed consent where we list all of the side effects of a procedure or medication as well as contextual cues in clinical encounters.

And importantly, internal factor like emotion, mood, maladaptive cognitive appraisal, negative valence, personality traits, somatosensory features and omics can be predictive of negative worsening of symptom and outcome related to placebo and nocebo effects. In terms of a nocebo very briefly, there is a lot of attention again related to brain imaging with beautiful data show that the brainstem, the spinal cord, the hippocampus play a critical role during nocebo hyperalgesic effects.

And importantly, we learn that about placebo and nocebo through different approach including brain imaging, as we saw yesterday, but also pharmacological approach. We start from realizing that placebo effects are really neurobiological effects with the use of agonist or antagonist.

In other words, we can use a drug to mimic the action of that drug when we replace the drug with a saline solution, for example. In the cartoon here, you can see a brief pharmacological conditioning with apomorphine. Apomorphine is a dopamine agonist. And after three days of administration, apomorphine was replaced with saline solution in the intraoperative room to allow us to understand if we can mimic at the level of neuronal response the effects of apomorphine.

So in brief these are patients undergoing subthalamic EEG installation of deep brain stimulation. You can see here reaching the subthalamic nucleus. So after crossing the thalamus, the zona incerta, the STN, and the substantia nigra, the surgeon localized the area of stimulation. Because we have two subthalamic nuclei, we can use one as control and the other one as target to study in this case the effects of saline solution given after three days of apomorphine.

What we found was in those people who respond, there was consistency in reduction of clinical symptoms. As you can see here, the UPDRS, a common scale to measure rigidity in Parkinson, the frequency of a discharge at the level of neurons and the self-perception, patients with sentences like I feel like after Levodopa, I feel good. This feeling good translate in less rigidity, less tremor in the surgical room.

On the other hand, some participants didn't respond. Consistently we found no clinical improvement, no difference in preference over this drug at the level of a single unit and no set perception of a benefit. This kind of effects started to trigger the questions what is the reason why some people who responded to placebo and pharmacological conditioning and some other people don't. I will try to address this question in the second part of my talk.

On the other hand, we learn a lot about the endogenous modulation of pain and true placebo effects by using in this case an antagonist. The goal in this experiment was to create a painful sensation through a tourniquet. Week one with no treatment. Week two we pre-inject healthy participant with morphine. Week three the same morphine. And week four we replace morphine with placebo.

And you can see that a placebo increase the pain tolerance in terms of imminent. And this was not carryover effects. In fact, the control at week five showed no differences. Part of the participants were pre-injected with an antagonist Naloxone that when we use Naloxone at high dose, we can block the opioids delta and K receptors. You can see that by pre-injecting Naloxone there is a blockage of placebo analgesia, and I would say this morphine-like effects related to placebo given after morphine.

We start to then consider this phenomenon. Is this a way for tapering opioids. And we called this sort of drug-like effects as dose-extending placebo. The idea is that if we use a pharmacological treatment, morphine, apomorphine, as I showed to you, and then we replace the treatment with a placebo, we can create a pharmacological memory, and this can translate into a clinical benefit. Therefore, the dose-extending placebo can be used to extend the benefit of the drug, but also to reduce side effects related to the active drug.

In particular for placebo given after morphine, you can see on this graph, the effects is similarly strong if we do the repetition of a morphine one day apart or one week apart. Interestingly, this is the best model to be used in animal research.

Here at University of Maryland in collaboration with Todd Degotte, we create a model of anhedonia in mice and we condition animals with Ketamine. The goal was to replace Ketamine with a placebo. There are several control as you can see. But what is important for us, we condition animal with Ketamine week one, three and five. And then we substitute Ketamine with saline along with the CS. The condition of the stimulus was a light, a low light. And we want to compare this with an injection of Ketamine given at week seven.

So as you can see here, of course Ketamine was inducing a benefit as compared to saline and the Ketamine. But what is seen testing when we compare Ketamine week seven with saline replacing the Ketamine, we found no difference; suggesting that even in animals, in mice we were able to create drug-related effects. In this case, a Ketamine antidepressant-like placebo effects. These effects also add dimorphic effects in the sense that we observed this is in males but not in females.

So another approach to use agonist, like I mentioned for apomorphine in Parkinson patient, was to use vasopressin and oxytocin to increase placebo effects. In this case, we used verbal suggestion that in our experience especially with healthy participants tended to create very small sample size in terms of placebo analgesic effects. So we knew that from the literature that there is a dimorphic effects for this hormone. So we inject people with intranasal vasopressin, saline, oxytocin in low dose and no treatment. You can see there was a drug effects in women whereby vasopressin boost placebo analgesic effects, but not in men where yet we found many effects of manipulation but not drug effects.

Importantly, vasopressin affect dispositional anxiety as well as cortisol. And there is a negative correlation between anxiety and cortisol in relationship to vasopressin-induced placebo analgesia.

Another was, can we use medication to study placebo in laboratory setting or can we study placebo and nocebo without any medication? One example is to use a manipulation of the intensity of the painful stimulations. We use a thermal stimulation tailored at three different levels. 80 out of 100 with a visual analog scale, 50 or 20, as you can see from the thermometer.

We also combined the level of pain with a face. So first to emphasize there is three level of pain, participants will see an anticipatory cue just before the thermal stimulation. Ten seconds of the thermal stimulation to provide the experience of analgesia with the green and the hyperalgesia with the red as compared to the control, the yellow condition.

Therefore, the next day we move in the fMRI. And the goal was to try to understand to what extent expectation is relevant in placebo and nocebo effects. We mismatch what they anticipate, and they learn the day before. But also you can see we tailored the intensity at the same identical level. 50 for each participant.

We found that when expectation matched the level of the cues, anticipatory cue and face, we found a strong nocebo effects and placebo effects. You can see in red that despite the level of pain were identical, the perceived red-related stimuli as higher in terms of intensity, and the green related the stimuli as lower when compared to the control. By mismatching what they expect with what they saw, we blocked completely placebo effects and still nocebo persist.

So then I showed to you that we can use conditioning in animals and in humans to create placebo effects. But also by suggestion, the example of vasopressin. Another important model to study placebo effects in laboratory setting is social observation. We see something in other people, we are not told what we are seeing and we don't experience the thermal stimulation. That is the setting. A demonstrator receiving painful or no painful stimulation and someone observing this stimulation.

When we tested the observers, you can see the level of pain were tailored at the same identical intensity. And these were the effects. In 2009, when we first launched this line of research, this was quite surprising. We didn't anticipate that merely observing someone else could boost the expectations and probably creating this long-lasting analgesic effect. This drove our attention to the brain mechanism of what is so important during this transfer of placebo analgesia.

So we scanned participants when they were observing a video this time. And a demonstrator receiving control and placebo cream. We counterbalance the color. We controlled for many variables. So during the observation of another person when they were not stimulated, they didn't receive the cream, there is an activation of the left and right temporoparietal junction and a different activation of the amygdala with the two creams. And importantly, an activation of the periaqueductal gray that I show to you is critical in modulating placebo analgesia.

Afterwards we put both the placebo creams with the two different color. We tailored the level of pain at the identical level of intensity. And we saw how placebo effects through observation are generated. They create strong different expectation and anxiety. And importantly, we found that the functional connectivity between the dorsolateral prefrontal cortex and temporoparietal junction that was active during the observation mediate the behavior results. Suggesting that there is some mechanism here that may be relevant to exploit in clinical trials and clinical practice.

From this, I wish to switch to a more translational approach. Can we replicate these results observed in health participant for nociception in people suffering from chronic pain. So we chose as population of facial pain that is an orphan disease that has no consensus on how to treat it, but also it affects the youngest including children.

So participants were coming to the lab. And thus you can see we used the same identical thermal stimulation, the same electrodes, the same conditioning that I showed to you. We measured expectation before and after the manipulation. The very first question was can we achieve similar monitored distribution of placebo analgesia in people suffering chronically from pain and comorbidities. You can see that we found no difference between temporo parenthala, between TMD and controls. Also, we observed that some people responded to the placebo manipulation with hyperalgesia. We call this nocebo effect.

Importantly, these affects are less relevant than the benefit that sometime can be extremely strong show that both health control and TMD. Because we run experiment in a very beautiful ecological environment where we are diverse, the lab, the experimenters as well as the population we recruit in the lab has a very good distribution of race, ethnicity.

So the very first question was we need to control for this factor. And this turned out to be a beautiful model to study race, ethnicity in the lab. So when chronic pain patient were studied by same experimenter race, dark blue, we observe a larger placebo effect. And this tell us about the disparity in medicine. In fact, we didn't see these effects in our controls.

In chronic pain patient, we also saw a sex concordance influence. But in the opposite sense in women studied by a man experimenter placebo effects are larger. Such an effect was not seen in men.

The other question that we had was what about the contribution of psychological factors. At that stage, there were many different survey used by different labs. Some are based on the different area of, you know, the states of the world, there were trends where in some people in some study they observe an effects of neurodisease, more positive and negative set, that refer to the words. Instead of progressing on single survey, and now we have a beautiful meta-analysis today that is not worth in the sense that it is not predictive of placebo effects.

We use the rogue model suggested by the NIMH. And by doing a sophisticated approach we were able to combine this into four balances. Emotional distress, reward-seeking, pain related fear catastrophizing, empathy and openness. These four valences then were interrelated to predict placebo effects. And you can see that emotional distress is associated with lower magnitude of placebo effects extinguishing over time and lower proportion of placebo responsivity.

Also people who tend to catastrophizing display lower magnitude of placebo effects. In terms of expectation, it is also interesting patients expect to benefit, they have this desire for a reward. But also those people who are more open and characterized by empathy tend for the larger expectations. But this doesn't translate necessarily in larger placebo effects, somehow hinting that the two phenomenon can be not necessarily linked.

Because we study chronic pain patients they come with their own baggage of disease comorbidities. And Dr. Wang in his department look at insomnia. Those people suffering from insomnia tends to have lower placebo analgesic effects along with those who have a poor pattern of sleep, suggesting that clinical factor can be relevant when we wish to predict placebo effects.

Another question that we address how simple SNPs, single nucleotide polymorphism variants in three regions that have been published can be predictive of placebo effects. In particular, I'm referring to OPRM1 that is linked to the gene for endogenous opioids. COMT linked to endogenous dopamine. And FAAH linked to endogenous cannabinoids. And we will learn about that more with the next talk.

And you can see that there is a prediction. These are rogue codes that can be interesting. We model all participants with verbal suggestion alone, the conditioning. There isn't really a huge difference between using one SNP versus two or three. What is truly impact and was stronger in terms of prediction was accounting for the procedure we used to study placebo. Whether by suggestion alone versus condition. When we added the manipulation, the prediction becomes stronger.

More recently, we started gene expression transcriptomic profile associated with placebo effects. We select from the 402 participants randomly 54. And we extract their transcriptomic profiles. Also we select a validation cohort to see if we can't replicate what we discover in terms of mRNA sequencing. But we found over 600 genes associated with the discovered cohort. In blue are the genes downregulated and in red upregulated.

We chose the top 20 genes and did the PCA to validate the top 20. And we found that six of them were replicated and they include all these genes that you see here. The Selenom for us was particularly interesting, as well as the PI3, the CCDC85B, FBXL15, HAGHL and the TNFRSF4. So with this --

LUANA COLLOCA: Yes, I'm done. With this, that is the goal probably one day with AI and other approach to combine clinical psychological brain imaging and so on, characteristic and behavior to predict a level of transitory response to placebo. That may guide us in clinical trials and clinical path to tailor the treatment. Therefore, the placebo and nocebo biological response can be to some extent predicted. And identify those who responded to placebo can help tailoring drug development and symptom management.

Thank you to my lab. All of you, the funding agencies. And finally, for those who like to read more about placebo, this book is available for free to be downloaded. And they include many of the speakers from this two-day event as contributors to this book. Thank you very much.

CRISTINA CUSIN: Thank you so much, Luana. It was a wonderful presentation. We have one question in the Q&A.

Elegant studies demonstrating powerful phenomena. Two questions. Is it possible to extend or sustain placebo-boosting effect? And what is the dose response relationship with placebo or nocebo?

LUANA COLLOCA: Great questions. The goal is to boost a placebo effects. And one way, as I showed was, for example, using intranasal vasopressin. But also extending relationship with placebo we know that we need the minimum of a three or four other administration before boosting this sort of pharmacological memory. And the longer is the administration of the active drug before we replace with placebo, the larger the placebo effects.

For nocebo, we show similar relationship with the collaborators. So again, the longer we condition, the stronger the placebo or nocebo effects. Thank you so much.

CRISTINA CUSIN: I wanted to ask, do you have any theory or interpretation about the potential for transmit to person a placebo response between the observer or such, do you have any interpretation of this phenomenon?

LUANA COLLOCA: It is not completely new in the literature. There is a lot of studies show that we can transfer pain in both animal models and humans.

So transfer analgesia is a natural continuation of that line of research. And the fact that we mimic things that we see in some other people, this is the very most basic form of learning when we grow up. But also from a revolutionary point of view protect us from predators and animals and us as human beings observing is a very good mechanism to boost behaviors and in this case placebo effects. Thank you.

CRISTINA CUSIN: Okay. We will have more time to ask questions.

We are going to move on to the next speaker. Dr. Kathryn Hall.

KATHRYN HALL: Thank you. Can you see my screen okay? Great.

So I'm going to build on Dr. Colloca's talk to really kind of give us a deeper dive into the genetics of the placebo response in clinical trials.

So I have no disclosures. So as we heard and as we have been hearing over the last two days, there is -- there are physiological drivers of placebo effects, whether they are opioid signaling or dopamine signaling. And these are potentiated by the administration or can be potentiated by saline pills, saline injections, sugar pills. And what's really interesting here, I think, is this discussion about how drugs impact the drivers of placebo response. In particular we heard about Naloxone yesterday and proglumide.

What I really want to do today is think about the next layer. Like how do the genes that shape our biology and really drive or influence that -- those physiological drivers of placebo response, how do the genes, A, modify our placebo response? But also, how are they modifying the effect of the drugs and the placebos on this basic -- this network?

And if you think about it, we really don't know much about all of the many interactions that are happening here. And I would actually argue that it goes even beyond genetic variation to other factors that lead to heterogeneity in clinical trials. Today I'm going to really focus on genes and variations in the genome.

So let's go back so we have the same terminology. I'm going to be talking about placebo-responsing trials. And so we saw this graph or a version of this graph yesterday where in clinical trials when we want to assess the effect of a drug, we subtract the outcomes in the placebo arm from the outcomes in the drug treatment arm. And there is a basic assumption here that the placebo response is additive to the drug response.

And what I want to do today is to really challenge that assumption. I want to challenge that expectation. Because I think we have enough literature and enough studies that have already been done that demonstrate that things are not as simple as that and that we might be missing a lot from this basic averaging and subtracting that we are doing.

So the placebo response is that -- is the bold lines there which includes placebo effects which we have been focusing on here. But it also includes a natural history of the disease or the condition, phenomenon such as statistical regression not mean, blinding and bias and Hawthorn effects. So we lump all of those together in the placebo arm of the trial and subtract the placebo response from the drug response to really understand the drug effect.

So one way to ask about, well, how do genes affect this is to look at candidate genes. And as Dr. Colloca pointed out and has done some very elegant studies in this area, genes like COMT, opioid receptors, genes like OPRM1, the FAAH endocannabinoid signaling genes are all candidate genes that we can look at in clinical trials and ask did these genes modify what we see in the placebo arm of trials?

We did some studies in COMT. And I want to just show you those to get a -- so you can get a sense of how genes can influence placebo outcomes. So COMT is catacholamethyl transferase. And it's a protein, an enzyme that metabolizes dopamine which as you saw is important in mediating the placebo response. COMT also metabolizes epinephrin, norepinephrine and catecholest estrogen. So the fact that COMT might be involved in placebo response is really interesting because it might be doing more than just metabolizing dopamine.

So we asked the question what happens if we look at COMT genetic variation in clinical trials of irritable bowel syndrome? And working with Ted Kaptchuk and Tony Lembo at Beth Israel Deaconess Medical Center, we did just that. We looked at COMT effects in a randomized clinical trial of irritable bowel syndrome. And what we did see was that for the gene polymorphism RS46AD we saw that people who had the weak version of the COMT enzyme actually had more placebo response. These are the met/met people here shown on this, in this -- by this arrow. And that the people who had less dopamine because that enzyme didn't work as well for this polymorphism, they had less of a placebo response in one of the treatment arms. And we would later replicate this study in another clinical trial that was recently concluded in 2021.

So to get a sense, as you can see, we are somewhat -- we started off being somewhat limited by what was available in the literature. And so we wanted to expand on that to say more about genes that might be associated with placebo response. So we went back, and we found 48 studies in the literature where there was a gene that was looked at that modified the placebo response.

And when we mapped those to the interactome, which is this constellation of all gene products and their interactions, their physical interactions, we saw that the placebome or the placebo module had certain very interesting characteristics. Two of those characteristics that I think are relevant here today are that they overlapped with the targets of drugs, whether they were analgesics, antidepressive drugs, anti-Parkinson's agents, placebo genes putatively overlapped with drug treatment genes or targets.

They also overlapped with disease-related genes. And so what that suggests is that when we were looking at the outcomes of clinical trial there might be a lot more going on that we are missing.

And let's just think about that for a minute. On the left is what we expect. We expect that we are going to see an effect in the drug, it's going to be greater than the effect of the placebo and that difference is what we want, that drug effect. But what we often see is on the right here where there is really no difference between drug and placebo. And so we are left to scratch our heads. Many companies go out of business. Many sections of companies close. And, quite frankly, patients are left in need. Money is left on the table because we can't discern between drug and placebo.

And I think what is interesting is that's been a theme that's kind of arisen since yesterday where oh, if only we had better physiological markers or better genes that targeted physiology then maybe we could see a difference and we can, you know, move forward with our clinical trials.

But what I'm going to argue today is actually what we need to do is to think about what is happening in the placebo arm, what is contributing to the heterogeneity in the placebo arm, and I'm going to argue that when we start to look at that compared to what is happening in the drug treatment arm, oftentimes -- and I'm going to give you demonstration after demonstration. And believe me, this is just the tip of the iceberg.

What we are seeing is there are differential effects by genotype in the drug treatment arm and the placebo treatment arm such that if you average out what's happening in these -- in these drug and placebo arms, you would basically see that there is no difference. But actually there's some people that are benefiting from the drug but not placebo. And conversely, benefiting from placebo but not drug. Average out to no difference.

Let me give you some examples. We had this hypothesis and we started to look around to see if we could get partners who had already done clinical trials that had happened to have genotyped COMT. And what we saw in this clinical trial for chronic fatigue syndrome where adolescents were treated with clonidine was that when we looked in the placebo arm, we saw that the val/val patients, so this is the COMT genotype. The low activity -- sorry, that is high activity genotype. They had the largest number increase in the number of steps they were taking per week. In contrast, the met/met people, the people with the weaker COMT had fewer, almost no change in the number of steps they were taking per week.

So you would look at this and you would say, oh, the val/val people were the placebo responders and the met/met people didn't respond to placebo. But what we saw when we looked into the drug treatment arm was very surprising. We saw that clonidine literally erased the effect that we were seeing in placebo for the val/val participants in this trial. And clonidine basically was having no effect on the heterozygotes, the val/mets or on the met/mets. And so this trial rightly concluded that there was no benefit for clonidine.

But if they hadn't taken this deeper look at what was happening, they would have missed that clonidine may potentially be harmful to people with chronic fatigue in this particular situation. What we really need to do I think is look not just in the placebo or not just in the drug treatment arm but in both arms to understand what is happening there.

And I'm going to give you another example. And, like I said, the literature is replete with these examples. On the left is an example from a drug that was used to test cognitive -- in cognitive scales, Tolcupone, which actually targets COMT. And what you can see here again on the left is differential outcomes in the placebo arm and in the drug treatment arm that if you were to just average these two you would not see the differences.

On the right is a really interesting study looking at alcohol among people with alcohol disorder, number of percent drinking days. And they looked at both COMT and OPRM1. And this is what Dr. Colloca was just talking about there seemed to be not just gene-placebo drug interactions but gene-gene drug placebo interactions. This is a complicated space. And I know we like things to be very simple. But I think what these data are showing is we need to pay more attention.

So let me give you another example because these -- you know, you could argue, okay, those are objective outcomes -- sorry, subjective outcomes. Let's take a look at the Women's Health Study. Arguably, one of the largest studies on aspirin versus placebo in history. 30,000 women were randomized to aspirin or placebo. And lo and behold, after 10 years of following them the p value was nonsignificant. There was no difference between drug and placebo.

So we went to this team, and we asked them, could we look at COMT because we had a hypothesis that COMT might modify the outcomes in the placebo arm and potentially differentially modify the treatments in the drug treatment arm. You might be saying that can't have anything to do with the placebo effect and we completely agree. This if we did find it would suggest that there might be something to do with the placebo response that is related to natural history. And I'm going to show you the data that -- what we found.

So when we compared the outcomes in the placebo arm to the aspirin arm, what we found was the met/met women randomized to placebo had the highest of everybody rates of cardiovascular disease. Which means the highest rates of myocardial infarction, stroke, revascularization and death from a cardiovascular disease cause. In contrast, the met/met women on aspirin had benefit, had a statistically significant reduction in these rates.

Conversely, the val/val women on placebo did the best, but the val/val women on aspirin had the highest rates, had significantly higher rates than the val/val women on placebo. What does this tell us? Well, we can't argue that this is a placebo effect because we don't have the control for placebo effects, which is a no treatment control.

But we can say that these are striking differences that, like I said before, if you don't pay attention to them, you miss the point that there are subpopulations for benefit or harm because of differential outcomes in the drug and placebo arms of the trial.

And so I'm going to keep going. There are other examples of this. We also partnered with a group at Brigham and Women's Hospital that had done the CAMP study, the Childhood Asthma Management Study. And in this study, they randomized patients to placebo, Budesonide or Nedocromil for five years and study asthma outcomes.

Now what I was showing you previously was candidate gene analyses. What this was, was a GWAS. We wanted to be agnostic and ask are there genes that modify the placebo outcomes and are these outcomes different in the -- when we look in the drug treatment arm. And so that little inset is a picture of all of the genes that were looked at in the GWAS. And we had a borderline genome Y significant hit called BBS9. And when we looked at BBS9 in the placebo arm, those white boxes at the top are the baseline levels of coughing and wheezing among these children. And in the gray are at the end of the treatment their level of coughing and wheezing.

And what you can see here is that participants with the AA genotype were the ones that benefited from the Bedenoside -- from placebo, whereas the GG, the patients with the GG genotype really there was no significant change.

Now, when we looked in the drug treatment arms, we were surprised to see that the outcomes were the same, of course, at baseline. There is no -- everybody is kind of the same. But you can see the differential responses depending on the genotype. And so, again, not paying attention to these gene drug/placebo interactions we miss another story that is happening here among our patients.

Now, I just want to -- I added this one because it is important just to realize that this is not just about gene-drug placebo. But these are also about epigenetic effects. And so here is the same study that I showed earlier on alcohol use disorder. They didn't just stop at looking at the polymorphisms or the genetic variants. This team also went so far as to look at methylation of OPRM1 and COMT.

So methylation is basically when the promoter region of a gene is basically blocked because it has a methyl group. It has methylation on some of the nucleotides in that region. So you can't make the protein as efficiently. And if you look on the right, what you can see in the three models that they looked at, they looked at other genes. They also looked at SLC6A3 that's involved in dopamine transport. And what you can see here is that there is significant gene by group by time interactions for all these three genes, these are candidate genes that they looked at.

And even more fascinating is their gene-by-gene interactions. Basically it is saying that you cannot say what the outcome is going to be unless you know the patient's or the participant's COMT or OPRM genotype A and also how methylated the promoter region of that -- of these genes are. So this makes for a very complicated story. And I know we like very simple stories.

But I want to say that I'm just adding to that picture that we had before to say that it's not just in terms of the gene's polymorphisms, but as Dr. Colloca just elegantly showed it is transcription as well as methylation that might be modifying what is happening in the drug treatment arm and the placebo treatment arm. And to add to this it might also be about the natural history of the condition.

So BBS9 is actually a gene that is involved in the cilia, the activity of the formation of the cilia which is really important in breathing in the nasal canal. And so, you can see that it is not just about what's happening in the moment when you are doing the placebo or drug or the clinical trial, it also might -- the genes might also be modifying where the patient starts out and how the patient might develop over time. So, in essence, we have a very complicated playground here.

But I think I have shown you that genetic variation, whether it is polymorphisms in the gene, gene-gene interactions or epigenetics or all of the above can modify the outcomes in placebo arms of clinical trials. And that this might be due to the genetic effects on placebo effects or the genetic effects on natural history. And this is something I think we need to understand and really pay attention to.

And I also think I've showed you, and these are just a few examples, there are many more. But genetic variation can differentially modify drugs and placebos and that these potential interactive effects really challenge this basic assumption of additivity that I would argue we have had for far too long and we really need to rethink.

TED KAPTCHUK: (Laughing) Very cool.

KATHRYN HALL: Hi, Ted.

TED KAPTCHUK: Oh, I didn't know I was on.

KATHRYN HALL: Yeah, that was great. That's great.

So in summary, can we use these gene-placebo drug interactions to improve clinical trials. Can we change our expectations about what is happening. And perhaps as we have been saying for the last two days, we don't need new drugs with clear physiological effects, what we need is to understand drug and placebo interactions and how they impact subpopulations and can reveal who benefits or is harmed by therapies.

And finally, as we started to talk about in the last talk, can we use drugs to boost placebo responses? Perhaps some drugs already do. Conversely, can we use drugs to block placebo responses? And perhaps some drugs already do.

So I just want to thank my collaborators. There was Ted Kaptchuk, one of my very close mentors and collaborators. And really, thank you for your time.

CRISTINA CUSIN: Thank you so much. It was a terrific presentation. And definitely Ted's captured laugh, it was just one of the best spontaneous laughs.

We have a couple of questions coming through the chat. One is about the heterogeneity of response in placebo arms. It is not uncommon to see quite a dispersion of responses at trials. Was that thought experiment, if one looks at the fraction of high responders in the placebo arms, would one expect to see, enrich for some of the genetic marker for and as placebo response?

KATHRYN HALL: I absolutely think so. We haven't done that. And I would argue that, you know, we have been having kind of quiet conversation here about Naloxone because I think as Lauren said yesterday that the findings of Naloxone is variable. Sometimes it looks like Naloxone is blocking placebo response and sometimes it isn't.

We need to know more about who is in that trial, right? Is this -- I could have gone on and showed you that there is differences by gender, right. And so this heterogeneity that is coming into clinical trials is not just coming from the genetics. It's coming from race, ethnicity, gender, population. Like are you in Russia or are you in China or are you in the U.S. when you're conducting your clinical trial? We really need to start unpacking this and paying attention to it. I think because we are not paying attention to it, we are wasting a lot of money.

CRISTINA CUSIN: And epigenetic is another way to consider traumatic experiences, adverse event learning. There is another component that we are not tracking accurately in clinical trials. I don't think this is a one of the elements routinely collected. Especially in antidepressant clinical trials it is just now coming to the surface.

KATHRYN HALL: Thank you.

CRISTINA CUSIN: Another question comes, it says the different approaches, one is GWAS versus candidate gene approach.

How do you start to think about genes that have a potential implication in neurophysiological pathways and choosing candidates to test versus a more agnostic U.S. approach?

KATHRYN HALL: I believe you have to do both because you don't know what you're going to find if you do a GWAS and it's important to know what is there.

At the same time, I think it's also good to test our assumptions and to replicate our findings, right? So once you do the GWAS and you have a finding -- for instance, our BBS9 finding would be amazing to replicate or to try and test in another cohort. But, of course, it is really difficult to do a whole clinical trial again. These are very expensive, and they last many years.

And so, you know, I think replication is something that is tough to do in this space, but it is really important. And I would do both.

CRISTINA CUSIN: Thank you. We got a little short on time. We are going to move on to the next speaker. Thank you so much.

FADEL ZEIDAN: Good morning. It's me, I imagine. Or good afternoon.

Let me share my screen. Yeah, so good morning. This is going to be a tough act to follow. Dr. Colloca and Dr. Hall's presentations were really elegant. So manage your expectations for mine. And, Ted, please feel free to unmute yourself because I think your laugh is incredibly contagious, and I think we were all were laughing as well.

So my name is Fadel Zeidan, I'm at UC San Diego. And I'll be discussing mostly unpublished data that we have that's under review examining if and how mindfulness meditation assuages pain and if the mechanism supporting mindfulness meditation-based analgesia are distinct from placebo.

And so, you know, this is kind of like a household slide that we all are here because we all appreciate how much of an epidemic chronic pain is and, you know, how significant it is, how much it impacts our society and the world. And it is considered a silent epidemic because of the catastrophic and staggering cost to our society. And that is largely due to the fact that the subjective experience of pain is modulated and constructed by a constellation of interactions between sensory, cognitive, emotional dimensions, genetics, I mean I can -- the list can go on.

And so what we've been really focused on for the last 20 years or so is to appreciate if there is a non-pharmacological approach, a self-regulated approach that can be used to directly assuage the experience of pain to acutely modify exacerbated pain.

And to that extent, we've been studying meditation, mindfulness-based meditation. And mindfulness is a very nebulous construct. If you go from one lab to another lab to another lab, you are going to get a different definition of what it is. But obviously my lab's definition is the correct one. And so the way that we define it is awareness of arising sensory events without reaction, without judgment.

And we could develop this construct, this disposition by practicing mindfulness-based meditation, which I'll talk about here in a minute. And we've seen a lot of -- and this is an old slide -- a lot of new evidence, converging evidence demonstrating that eight weeks of manualized mindfulness-based interventions can produce pretty robust improvements in chronic pain and opiate misuse. These are mindfulness-based stress reduction programs, mindfulness-oriented recovery enhancement, mindfulness-based cognitive therapy which are about eight weeks long, two hours of formalized didactics a week, 45 minutes a day of homework.

There is yoga, there is mental imagery, breathing meditation, walking meditation, a silent retreat and about a $600 tab. Which may not be -- I mean although they are incredibly effective, may not be targeting demographics and folks that may not have the time and resources to participate in such an intense program.

And to that extent and, you know, as an immigrant to this country I've noticed that we are kind of like this drive-thru society where, you know, we have a tendency to eat our lunches and our dinners in our cars. We're attracted to really brief interventions for exercise or anything really, pharmaceuticals, like ":08 Abs" and "Buns of Steel." And we even have things called like the military diet that promise that you'll lose ten pounds in three days without dying.

So we seemingly are attracted to these fast-acting interventions. And so to this extent we've worked for quite some time to develop a very user friendly, very brief mindfulness-based intervention. So this is an intervention that is about four sessions, 20 minutes each session. And participants are -- we remove all religious aspects, all spiritual aspects. And we really don't even call it meditation, we call it mindfulness-based mental training.

And our participants are taught to sit in a straight posture, close their eyes, and to focus on the changing sensations of the breath as they arise. And what we've seen is this repetitive practice enhances cognitive flexibility and the ability to -- flexibility and the ability to sustain attention. And when individual's minds drift away from focusing on the breath, they are taught to acknowledge distractive thoughts, feelings, emotions without judging themselves or the experience. Doing so by returning their attention back to the breath.

So there is really a one-two punch here where, A, you're focusing on the breath and enhancing cognitive flexibility; and, B, you're training yourself to not judge discursive events. And that we believe enhances emotion regulation. So quite malleable to physical training we would say mental training. Now that we have the advent of imaging, we can actually see that there are changes in the brain related to this.

But as many of you know, mindfulness is kind of like a household term now. It's all over our mainstream media. You know, we have, you know, Lebron meditating courtside. Oprah meditating with her Oprah blanket. Anderson Cooper is meditating on TV. And Time Magazine puts, you know, people on the cover meditating. And it's just all over the place.

And so these types of images and these types of, I guess, insinuations could elicit nonspecific effects related to meditation. And for quite some time I've been trying to really appreciate not is meditation more effective than placebo, although that's interesting, but does mindfulness meditation engage mechanisms that also are shared by placebo? So beliefs that you are meditating could elicit analgesic responses.

The majority of the manualized interventions in their manuals they use terms like the power of meditation, which I guarantee you is analgesic. To focus on the breath, we need to slow the breath down. Not implicit -- not explicitly, but it just happens naturally. And slow breathing can also reduce pain. Facilitator attention, social support, conditioning, all factors that are shared with other therapies and interventions but in particular are also part of meditation training.

So the question is because of all this, is mindfulness meditation merely -- or not merely after these two rich days of dialogue -- but is mindfulness meditation engaging processes that are also shared by placebo.

So if I apply a placebo cream to someone's calf and then throw them in the scanner versus asking someone to meditate, the chances are very high that the brain processes are going to be distinct. So we wanted to create a -- and validate an operationally matched mindfulness meditation intervention that we coined as sham mindfulness meditation. It's not sham meditation because it is meditation. It's a type of meditative practice called Pranayama.

But here in this intervention we randomize folks, we tell folks that they've been randomized to a genuine mindfulness meditation intervention. Straight posture, eyes closed. And every two to three minutes they are instructed to, quote-unquote, take a deep breath as we sit here in mindfulness meditation. We even match the time giving instructions between the genuine and the sham mindfulness meditation intervention.

So the only difference between the sham mindfulness and the genuine mindfulness is that the genuine mindfulness is taught to explicitly focus on the changing sensations of the breath without judgment. The sham mindfulness group is just taking repetitive deep, slow breaths. So if the magic part of mindfulness, if the active component of mindfulness is this nonjudgmental awareness, then we should be able to see disparate mechanisms between these.

And we also use a third arm, a book listening control group called the "Natural History of Selborne" where it's a very boring, arguably emotionally pain-evocating book for four days. And this is meant to control for facilitator time and -- sorry, facilitator attention and the time elapsed in the other group's interventions.

So we use a very high level of noxious heat to the back of the calf. And we do so because imaging is quite expensive, and we want to ensure that we can see pain-related processing within the brain. Here and across all of our studies, we use ten 12-second plateaus of 49 degrees to the calf, which is pretty painful.

And then we assess pain intensity and pain unpleasantness using a visual analog scale, where here the participants just see red the more they pull on the algometer the more in pain they are. But on the back, the numbers fluoresce where 0 is no pain and 10 is the worst pain imaginable.

So pain intensity can be considered like sensory dimension of pain, and pain unpleasantness could be more like I don't want to say pain affect but more like the bothersome component of pain, pain unpleasantness. So what we did was we combined all of our studies that have used the mindfulness, sham mindfulness in this book listing control, to see does mindfulness meditation engage is mindfulness meditation more effective than sham mindfulness meditation at reducing pain.

We also combined two different fMRI techniques: Blood oxygen dependent level signalling, bold, which allows us a higher temporal resolution and signal to noise ratio than, say, perfusion imaging technique and allows us to look at connectivity. However, meditation is also predicated on changes in respiration rate which could elicit pretty dramatic artifacts in the brain, breathing related artifacts explicitly related to CO2 output.

So using the perfusion based fMRI technique like arterial spin labeling is really advantageous as well, although it's not as temporally resolute as bold, it provides us a direct quantifiable measurement of cerebral blood flow.

So straight to the results. On the Y axis we have the pain ratings, and on the X axis are book listening controls sham mindfulness meditation, mindfulness meditation. Here are large sample sizes. Blue is intensity and red is unpleasantness. This is the post intervention fMRI scans where we see the first half of the scan to the second half of the scan our controlled participants are simply resting and pain just increases because of pain sensitization and being in a claustrophobic MRI environment.

And you can see here that sham mindfulness meditation does produce pretty significant reduction in pain intensity and unpleasantness, more than the control book. But mindfulness meditation is more effective than sham mindfulness and the controls at reducing pain intensity and pain unpleasantness.

There does seem to be some kind of additive component to the genuine intervention, although this is a really easy practice, the sham techniques.

So for folks that have maybe fatigue or cognitive deficits or just aren't into doing mindfulness technique, I highly recommend this technique, which is just a slow breathing approach, and it's dead easy to do.

Anyone that's practiced mindfulness for the first time or a few times can state that it can be quite difficult and what's the word? -- involving, right?

So what happened in the brain? These are our CBF maps from two studies that we replicated in 2011 and '15 where we found that higher activity, higher CBF in the right anterior insula, which is ipsilateral to the stimulation site and higher rostral anterior cingulate cortex subgenual ACC was associated with greater pain relief, pain intensity, and in the context of pain unpleasantness, higher over the frontal cortical activity was associated with lower pain, and this is very reproducible where we see greater thalamic deactivation predicts greater analgesia on the unpleasantness side.

These areas, obviously right entry insula in conjunction with other areas is associated with interoceptive processing awareness of somatic sensations. And then the ACC and the OFC are associated with higher order cognitive flexibility, emotional regulation processes. And the thalamus is really the gatekeeper from the brain -- I'm sorry, from the body to the brain. Nothing can enter the brain except unless it goes through the thalamus, except if it's the sense of smell.

So it's really like this gatekeeper of arising nociceptive information.

So the takehome here is that mindfulness is engaging multiple neural processes to assuage pain. It's not just one singular pathway.

Our gold studies were also pretty insightful. Here we ran a PPI analysis, psychophysiologic interaction analysis and this was whole brain to see what brain regions are associated with pain relief on the context of using the bold technique, and we find that greater ventral medial prefrontal cortical activity deactivation I'm sorry is associated with lower pain, and the vmPFC is a super evolved area that's associated with, like, higher order processes relating to self. It's one of the central nodes of the so called default mode network, a network supporting self referential processing. But in the context of the vmPFC, I like the way that Tor and Mathieu reflect the vmPFC as being more related to affective meaning and has a really nice paper showing that vmPFC is uniquely involved in, quote/unquote, self ownership or subjective value, which is particularly interesting for the context of pain because pain is a very personal experience that's directly related to the interpretation of arising sensations and what they mean to us.

And seemingly -- I apologize for the reverse inferencing here -- but seemingly mindfulness meditation based on our qualitative assessments as well is reducing the ownership or the intrinsic value, the contextual value of those painful sensations, i.e., they don't feel like they bother -- that pain is there but it doesn't bother our participants as much, which is quite interesting as a manipulation.

We also ran our connectivity analysis between the contralateral thalamus and the whole brain, and we found that greater decoupling between the contralateral thalamus and the precuneus, another central node of the default mode network predicted greater analgesia.

This is a really cool, I think, together mechanism showing that two separate analyses are indicating that the default mode network could be an analgesic system which we haven't seen before. We have seen the DMN involved in chronic pain and pain related exacerbations, but I don't think we've seen it as being a part of an analgesic, like being a pain relieving mechanism. Interestingly, the thalamus and precuneus together are the first two nodes to go offline when we lose consciousness, and they're the first two nodes to come back online when we recover from consciousness, suggesting that these two -- that the thalamus and precuneus are involved in self referential awareness, consciousness of self, things of this nature.

Again, multiple processes involved in meditation based pain relief which maybe gives rise to why we are seeing consistently that meditation could elicit long lasting improvements in pain unpleasantness, in particular, as compared to sensory pain. Although it does that as well.

And also the data gods were quite kind on this because these mechanisms are also quite consistent with the primary premises of Buddhist and contemplative scriptures saying that the primary principle is that your experiences are not you.

Not that there is no self, but that the processes that arise in our moment to moment experience are merely reflections and interpretations in judgments, and that may not be the true inherent nature of mind.

And so before I get into more philosophical discourse, I'm going to keep going for the sake of time. Okay.

So what happened with the sham mindfulness meditation intervention?

We did not find any neural processes predicted analgesia significantly and during sham mindfulness meditation. What did predict analgesia during sham mindfulness was slower breathing rate, which we've never seen before with mindfulness. We've never seen a significant or even close to significant relationship between mindfulness based meditation analgesia and slow breathing. But over and over we see that sham mindfulness based analgesia is related to slower breathing which provides us this really cool distinct process where kind of this perspective where mindfulness is engaging higher order top down type processes to assuage pain while sham mindfulness may be engaging this more bottom up type response to assuage pain.

I'm going to move on to some other new work, and this is in great collaboration with the lovely Tor Wager, and he's developed, with Marta and Woo, these wonderful signatures, these machine learned multivariate pattern signatures that are remarkably accurate at predicting pain over I think like 98, 99 percent.

His seminal paper, the Neurological Pain Signature, was published in the New England Journal of Medicine that showed that these signatures can predict nociceptive specific, in particular, for this particular, thermal heat pain with incredible accuracy.

And it's not modulated by placebo or affective components, per se. And then the SIIPS is a machine learned signature that is, as they put it, associated with cerebral contributions to pain. But if you look at it closely, these are markers that are highly responsive to the placebo response.

So the SIIPS can be used -- he has this beautiful pre print out, showing that it does respond with incredible accuracy to placebo, varieties of placebo.

So we used this MVPA to see if meditation engages signature supporting placebo responses.

And then Marta Ceko's latest paper with Tor published in Nature and Neuro found that the negative affect of signature predicts pain responses above and beyond nociceptive related processes. So this is pain related to negative affect, which again contributes to the multimodal processing of pain and how now we could use these elegant signatures to kind of disentangle which components of pain meditation and other techniques assuage. Here's the design.

We had 40 -- we combined two studies. One with bold and one with ASL. So this would be the first ASL study with signatures, with these MVPA signatures.

And we had the mindfulness interventions that I described before, the book listing interventions I described before and a placebo cream intervention which I'll describe now, all in response to 49 degrees thermal stimuli.

So across again all of our studies we use the same methods. And the placebo group -- I'll try to be quick about this -- this is kind of a combination of Luana Colloca, Don Price and Tor's placebo conditioning interventions where we administer 49 degrees -- we tell our participants that we're testing a new form of lidocaine, and the reason that it's new is that the more applications of this cream, the stronger the analgesia.

And so in the conditioning sessions, they come in, administer 49 degrees, apply and remove this cream, which is just petroleum jelly after 10 minutes, and then we covertly reduce the temperature to 48.

And then they come back in in session two and three, after 49 degrees and removing the cream, we lower the temperature to 47. And then on the last conditioning session, after we remove the cream, we lower the temperature to 46.5, which is a qualitatively completely different experience than 49.

And we do this to lead our participants to believe that the cream is actually working.

And then in a post intervention MRI session, after we remove the cream, we don't modulate the temperature, we just keep it at 49, and that's how we measured placebo in these studies. And then so here, again -- oops -- John Dean and Gabe are coleading this project.

Here, pain intensity on this axis, pain unpleasantness on that axis, controls from the beginning of the scan to the end of the scan significantly go up in pain.

Placebo cream was effective at reducing intensity and unpleasantness, but we see mindfulness meditation was more effective than all the conditions at reducing pain. The signatures, we see that the nociceptive specific signature, the controls go up in pain here.

No change in the placebo and mindfulness meditation you can see here produces a pretty dramatic reduction in the nociceptive specific signature.

The same is true for the negative affective pain signature. Mindfulness meditation uniquely modifies this signature as well which I believe this is one of the first studies to show something like this.

But it does not modulate the placebo signature. What does modulate the placebo signature is our placebo cream, which is a really nice manipulation check for these signatures.

So here, taken together, we show that mindfulness meditation, again, is engaging multiple processes and is reducing pain by directly assuaging nociceptive specific markers as well as markers supporting negative affect but not modulating placebo related signatures, providing further credence that it's not a placebo type response, and we're also demonstrating this granularity between a placebo mechanism that's not being shared by another active mechanism. While we all assume that active therapies and techniques are using a shared subset of mechanisms or processes with placebo, here we're providing accruing evidence that mindfulness is separate from a placebo.

I'll try to be very quick on this last part. This is all not technically related placebo, but I would love to hear everyone's thoughts on these new data we have.

So as we've seen elegantly that pain relief by placebo, distraction, acupuncture, transcranial magnetic stimulation, prayer, are largely driven by endogenous opioidergic release. And, yes, there are other systems. A prime other system is the (indiscernible) system, serotonergic system, dopamine. The list can go on. But it's considered by most of us that the endogenous opioidergic system is this central pain modulatory system.

And the way we do this is by antagonizing endogenous opioids by employing incredibly high administration dosage of naloxone.

And I think this wonderful paper by Ciril Etnes's (phonetic) group provides a nice primer on the appropriate dosages for naloxone to antagonize opiates. And I think a lot of the discussions here where we see differences in naloxone responses are really actually reflective of differences in dosages of naloxone.

It metabolizes so quickly that I would highly recommend a super large bolus with a maintenance infusion IV.

And we've seen this to be a quite effective way to block endogenous opioids. And across four studies now, we've seen that mindfulness based pain relief is not mediated by endogenous opioids. It's something else. We don't know what that something else is but we don't think it's endogenous opioids. But what if it's sex differences that could be driving these opioidergic versus non opioid opioidergic differences?

We've seen that females require -- exhibit higher rates of chronic pain than males. They are prescribed opiates at a higher rate than men. And when you control for weight, they require higher dosages than men. Why?

Well, there's excellent literature in rodent models and preclinical models that demonstrate that male rodents versus female -- male rodents engage endogenous opioids to reduce pain but female rodents do not.

And this is a wonderful study by Ann Murphy that basically shows that males, in response to morphine, have a greater latency and paw withdrawal when coupled with morphine and not so much with females.

But when you add naloxone to the picture, with morphine, the latency goes down. It basically blocks the analgesia in male rodents but enhances analgesia in female rodents.

We basically asked -- we basically -- Michaela, an undergraduate student doing an odyssey thesis asked this question: Are males and females in humans engaging in distinct systems to assuage pain?

She really took off with this and here's the design. We had heat, noxious heat in the baseline.

CRISTINA CUSIN: Doctor, you have one minute left. Can you wrap up?

FADEL ZEIDAN: Yep. Basically we asked, are there sex differences between males and females during meditation in response to noxious heat? And there are.

Baseline, just change in pain. Green is saline. Red is naloxone. You can see that with naloxone onboard, there's greater analgesia in females, and we reversed the analgesia. Largely, there's no differences between baseline in naloxone in males, and the males are reducing pain during saline.

We believe this is the first study to show something like this in humans. Super exciting. It also blocked the stress reduction response in males but not so much in females. Let me just acknowledge our funders. Some of our team. And I apologize for the fast presentation. Thank you.

CRISTINA CUSIN: Thank you so much. That was awesome.

We're a little bit on short on time.

I suggest we go into a short break, ten minute, until 1:40. Please continue to add your questions in Q&A. Our speakers are going to answer or we'll bring some of those questions directly to the discussion panel at the end of the session today. Thank you so much.

Measuring & Mitigating the Placebo Effect (continued)

CRISTINA CUSIN: Hello, welcome back. I'm really honored to introduce our next speaker, Dr. Marta Pecina. And she's going to talk about mapping expectancy-mood interactions in antidepressant placebo effects. Thank you so much.

MARTA PECINA: Thank you, Cristina. It is my great pleasure to be here. And just I'm going to switch gears a little bit to talk about antidepressant placebo effects. And in particular, I'm going to talk about the relationship between acute expectancy-mood neural dynamics and long-term antidepressant placebo effects.

So while we all know that depression is a very prevalent disorder, and just in 2020, Major Depressive Disorder affected 21 million adults in the U.S. and 280 million adults worldwide. And current projections indicate that by the year 2030 it will be the leading cause of disease burden globally.

Now, response rates to first-line treatments, antidepressant treatments are approximately 50%. And complete remission is only achieved in 30 to 35% of individuals. Also, depression tends to be a chronic disorder with 50% of those recovering from a first episode having an additional episode. And 80% of those with two or more episodes having another recurrence.

And so for patients who are nonresponsive to two intervention, remission rates with subsequent therapy drop significantly to 10 to 25%. And so, in summary, we're facing a disorder that is very resistant or becomes resistant very easily. And in this context, one would expect that antidepressant placebo effects would actually be low. But we all know that this is not the case. The response rate to placebos is approximately 40% compared to 50% response rates to antidepressants. And obviously this varies across studies.

But what we do know and learned yesterday as well is that response rates to placebos have increased approximately 7% over the last 40 years. And so these high prevalence of placebo response in depressions have significantly contributed to the current psychopharmacology crisis where large pharma companies have reduced at least in half the number of clinical trials devoted to CNS disorders.

Now, antidepressant placebo response rates among individuals with depression are higher than in any other psychiatric condition. And this was recently published again in this meta-analysis of approximately 10,000 psychiatric patients. Now, other disorders where placebo response rates are also prevalent are generalized anxiety disorder, panic disorders, HDHC or PTSD. And maybe less frequent, although still there, in schizophrenia or OCD.

Now, importantly, placebo effects appear not only in response to pills but also surgical interventions or devices, as it was also mentioned yesterday. And this is particularly important today where there is a very large development of device-based interventions for psychiatric conditions. So, for example, in this study that also was mentioned yesterday of deep brain stimulation, patients with resistant depression were assigned to six months of either active or some pseudo level DBS. And this was followed by open level DBS.

As you can see here in this table, patients from both groups improved significantly compared to baseline, but there were no significant differences between the two groups. And for this reason, DBS has not yet been approved by the FDA for depression, even though it's been approved for OCD or Parkinson's disease as we all know.

Now what is a placebo effect, that's one of the main questions of this workshop, and how does it work from a clinical neuroscience perspective? Well, as it's been mentioned already, most of what we know about the placebo effect comes from the field of placebo analgesia. And in summary, classical theories of the placebo effect have consistently argued that placebo effects results from either positive expectancies regarding the potential beneficial effects of a drug or classical conditioning where the pairing of a neutral stimulus, in this case the placebo pill, with an unconditioned stimulus, in this case the active drug, results in a conditioned response.

Now more recently, theories of the placebo effect have used computational models to predict placebo effects. And these theories posit that individuals update their expectancies as new sensory evidence is accumulated by signaling the response between what is expected and what is perceived. And this information is then used to refine future expectancies. Now these conceptual models have been incorporated into a trial-by-trial manipulation of both expectancies of pain relief and pain sensory experience. And this has rapidly advanced our understanding of the neural and molecular mechanisms of placebo analgesia.

And so, for example, in these meta analytic studies using these experiments they have revealed really two patterns of distinct activations with decreases in brain activity in regions involving brain processing such as the dorsal medial prefrontal cortex, the amygdala and the thalamus; and increases in brain activity in regions involving effective appraisal, such as the vmDFC, the nucleus accumbens, and the PAG.

Now what happens in depression? Well, in the field of antidepressant placebo effects, the long-term dynamics of mood and antidepressant responses have not allowed us to have such trial-by-trial manipulation of expectancies. And so instead researchers have used broad brain changes in the context of a randomized control trial or a placebo lead-in phase which has, to some extent, limited the progress of the field.

Now despite these methodological limitations of these studies, they provide important insights about the neural correlates of antidepressant placebo effects. In particular, from studies -- two early on studies we can see the placebo was associated with increased activations broadly in cortical regions and decreased activations in subcortical regions. And these deactivations in subcortical regions were actually larger in patients who were assigned to an SSRI drug treatment.

We also demonstrated that there is similar to pain, antidepressant placebo effects were associated with enhanced endogenous opiate release during placebo administration, predicting the response to open label treatment after ten weeks. And we have also -- we and others have demonstrated that increased connectivity between the salience network and the rostral anterior cingulate during antidepressant placebo effects can actually predict short-term and long-term placebo effects.

Now an important limitation, and as I already mentioned, is that this study is basically the delay mechanism of action of common antidepressant and this low dynamics of mood which really limit the possibility of actively manipulating antidepressant expectancies.

So to address this important gap, we develop a trial-by-trial manipulation of antidepressant expectancies to be used inside of the scanner. And the purpose was really to be able to further disassociate expectancy and mood dynamics during antidepressant placebo effects.

And so the basic structure of this test involved an expectancy condition where subjects are presented with a four-second infusion cue followed by an expectancy rating cue, and a reinforcement condition which consist of 20 seconds of some neurofeedback followed by a mood rating cue. Now the expectancy and the reinforcement condition map onto the classical theories of the placebo effect that I explained earlier.

During the expectancy condition, the antidepressant infusions are compared to periods of calibration where no drug is administered. And during the reinforcement condition, on the other hand, some neurofeedback of positive sign 80% of the time as compared to some neurofeedback of baseline sign 80% of the time. And so this two-by-two study design results in four different conditions. The antidepressant reinforced, the antidepressant not reinforced, the calibration reinforced, and the calibration not reinforced.

And so the cover story is that we tell participants that we are testing the effects of a new fast-acting antidepressant compared to a conventional antidepressant, but in reality, they are both saline. And then we tell them that they will receive multiple infusions of these drugs inside of the scanner while we record their brain activity which we call neurofeedback. So then patients learn that positive neurofeedback compared to baseline is more likely to cause mood improvement. But they are not told that the neurofeedback is simulated.

Then we place an intravenous line for the administration of the saline infusion, and we bring them inside of the scanner. For these kind of experiments we recruit individuals who are 18 through 55 with or without anxiety disorders and have a HAMD depression rating scale greater than 16, consistent with moderate depression. They're antidepressant medication free for at least 25 -- 21 days and then we use consenting procedures that involve authorized deception.

Now, as suspected, behavioral results during this test consistently show that antidepressant expectancies are higher during the antidepressant infusions compared to the calibration, especially when they are reinforced by positive sham neurofeedback. Now mood responses also are significantly higher during positive sham neurofeedback compared to baseline. But this is also enhanced during the administration of the antidepressant infusions.

Now interestingly, these effects are moderated by the present severity such that the effects of the test conditions and the expectancies and mood ratings are weaker in more severe depression even though their overall expectancies are higher, and their overall mood are lower.

Now at a neuron level, what we see is that the presentation of the infusion cue is associated with an increased activation in the occipital cortex and the dorsal attention network suggesting greater attention processing engaged during the presentation of the treatment cue. And similarly, the reinforcement condition revealed increased activations in the dorsal attention network with additional responses in the ventral striatum suggesting that individuals processed the sham positive neurofeedback cue as rewarding.

Now an important question for us was now that we can manipulate acute placebo -- antidepressant placebo responses, can we use this experiment to understand the mechanisms implicated in short-term and long-term antidepressant placebo effects. And so as I mentioned earlier, there was emerging evidence suggesting that placebo analgesic could be explained by computational models, in particular reinforcement learning.

And so we tested the hypothesis that antidepressant placebo effects could be explained by similar models. So as you know, under these theories, learning occurs when an experienced outcome differs from what is expected. And this is called the prediction error. And then the expected value of the next possible outcome is updated with a portion of this prediction error as reflected in this cue learning rule.

Now in the context of our experiment, model predicted expectancies for each of the four trial conditions would be updated every time the antidepressant or the calibration infusion cue is presented and an outcome, whether positive or baseline neurofeedback, is observed based on a similar learning rule.

Now this basic model was then compared against two alternative models. One which included differential learning rates to account for the possibility that learning would depend on whether participants were updating expectancies for the placebo or the calibration. And then an additional model to account for the possibility that subjects were incorporating positive mood responses as mood rewards.

And then finally, we constructed this additional model to allow the possibility of the combination of models two and three. And so using patient model comparison, we found that the model -- the fourth model, model four which included a placebo bias learning in our reinforcement by mood dominated all the other alternatives after correction for patient omnibus risk.

Now we then map the expected value and reward predictions error signals from our reinforcement learning models into our raw data. And what we found was that expected value signals map into the salience network raw responses; whereas reward prediction errors map onto the dorsal attention network raw responses. And so all together, the combination of our model-free and model-based results reveal that the processing of the antidepressant in patient cue increase activation in the dorsal attention network; whereas, the encoding of the expectancies took place in the salience network once salience had been attributed to the cue.

And then furthermore, we demonstrated that the reinforcement learning model predicted expectancies in coding the salience network triggered mood changes that are perceived as reward signals. And then these mood reward signals further reinforce antidepressant expectancies through the information of expectancy mood dynamics defined by models of reinforcement learning, an idea that could possibly contribute to the formation of long-lasting antidepressant placebo effects.

And so the second aim was really -- was going to look at these in particular how to use behavioral neuroresponses of placebo effects to predict long-term placebo effects in the context of a clinical trial. And so our hypothesis was that during placebo administration greater salient attribution to the contextual cue in the salience network would transfer to regions involved in mood regulation to induce mood changes. So in particular we hypothesized that the DMN would play a key role in belief-induced mood regulation.

And why the DMN? Well, we knew that activity in the rostral anterior cingulate, which is a key node of the DMN, is a robust predictor of mood responses to both active antidepressant and placebos, implying its involvement in nonspecific treatment response mechanisms. We also knew that the rostral anterior cingulate is a robust predicter of placebo analgesia consistent with its role in cognitive appraisals, predictions and evaluation. And we also had evidence that the SN to DMN functional connectivity appears to be a predictor of placebo and antidepressant responses over ten weeks of treatment.

And so in our clinical trial, which you can see the cartoon diagram here, we randomized six individuals to placebo or escitalopram 20 milligrams. And this table is just to say there were no significant differences between the two groups in regard to the gender, race, age, or depression severity. But what we found interesting is that there were also no significant differences in the correct belief assignment with 60% of subjects in each group approximately guessing that they were receiving escitalopram.

Now as you can see here, participants showed lower MADR scores at eight weeks in both groups. But there was no significant differences between the two groups. However, when split in the two groups by the last drug assignment belief, subjects with the drug assignment belief improved significantly compared to those with a placebo assignment belief.

And so the next question was can we use neuroimaging to predict these responses? And what we found was at a neural level during expectancy process the salience network had an increased pattern of functional connectivity with the DMN as well as with other regions of the brainstem including the thalamus. Now at the end -- we also found that increased SN to DMN functional connectivity predicted expectancy ratings during the antidepressant placebo fMRI task such that higher connectivity was associated with greater modulation of the task conditions on expectancy ratings.

Now we also found that enhanced functional connectivity between the SN and the DMN predicted the response to eight weeks of treatment, especially on individuals who believed that they were of the antidepressant group. Now this data supports that during placebo administration, greater salient attributions to the contextual cue is encoded in the salience network; whereas belief-induced mood regulation is associated with an increased functional connectivity between the SN and DMN and altogether this data suggest that enhancements to DMN connectivity enables the switch from greater salient attribution to the treatment cue to DMN-mediated mood regulation.

And so finally, and this is going to be brief, but the next question for us was can we modulate these networks to actually enhance placebo-related activity. And in particular, we decided to use theta burst stimulation which can potentiate or depotentiate brain activity in response to brief periods of stimulation. And so in this study participants undergo three counterbalance sessions of TBS with either continuous, intermittent, or sham known to depotentiate, potentiate, and have no effect.

So each TBS is followed by an fMRI session during the antidepressant placebo effect task which happens approximately an hour after stimulation. The inclusive criteria are very similar to all of our other studies. And our pattern of stimulation is pretty straightforward. We do two blocks of TBS. And during the first block stimulation intensity is gradually escalated in 5% increments in order to enhance tolerability. And during the second session the stimulation is maintained constant at 80% of the moderate threshold.

Then we use the modified cTBS session consisting of three stimuli applied at intervals of 30 hertz. We first repeat it at 6 hertz for a total of 600 stimuli in a continuous train of 33.3 seconds. Then we did the iTBS session consist of a burst of three stimuli applied at intervals of 50 hertz with bursts repeated at 5 hertz for a total of 600 stimulus during 192 seconds. We also use a sham condition where 50% of subjects are assigned to sham TBS simulating the iTBS stimulus pattern, and 50% are assigned to sham TBS simulating the cTBS pattern.

Now our target is the DMN which is the cortical target for the dorsal medial -- the cortical target for the DMN -- sorry, the dmPFC which is the cortical target for the DMN. And this corresponds to the -- and we found these effects based on the results from the antidepressant placebo fMRI task.

And so this target corresponds to our neurosynth scalp which is located 30% of the distance from the nasion-to-inion forward from the vertex and 5% left which corresponds to an EEG location of F1. And the connectivity map of these regions actually result in activation of the DMN. Now we can also show here the E-Field map of this target which basically demonstrates supports a nice coverage of the DMN.

And so what we found here is that the iTBS compared to sham and cTBS enhances the effect of the reinforcement condition of mood responses. And we also found that at a neural level iTBS compared to cTBS shows significant greater bold responses during expectancy processing within the DMN with sham responses in the middle but really not significantly different from iTBS. Now, increased bold responses in the ventral medial prefrontal cortex were associated with a greater effect of the task conditions of mood responses.

And so all together our results suggest that first trial-by-trial modulation of antidepressant expectancies effectively disassociates expectancy mood dynamics. Antidepressant expectancies are predicted by models of reinforcement learning and they're encoded in the salience network. We also showed that enhanced SN to DMN connectivity enables the switch from greater salient attribution to treatment cues to DMN-mediated mood regulation, contributing to the formation of acute expectancy-mood interactions and long-term antidepressant placebo effects. And iTBS potentiation of the DMN enhances placebo-induced mood responses and expectancy processing.

With this, I would just like to thank my collaborators that started this work with me at the University of Michigan and mostly the people in my lab and collaborators at the University of Pittsburgh as well as the funding agencies.

CRISTINA CUSIN: Wonderful presentation. Really terrific way of trying to untangle different mechanism in placebo response in depression, which is not an easy feat.

There are no specific questions in the Q&A. I would encourage everybody attending the workshop to please post your question to the Q&A. Every panelist can answer in writing. And then we will answer more questions during the discussion, but please don't hesitate.

I think I will move on to the next speaker. We have only a couple of minutes so we're just going to move on to Dr. Schmidt. Thank you so much. We can see your slides. We cannot hear you.

LIANE SCHMIDT: Can you hear me now?

CRISTINA CUSIN: Yes, thank you.

LIANE SCHMIDT: Thank you. So I'm Liane Schmidt. I'm an INSERM researcher and team leader at the Paris Brain Institute. And I'm working on placebo effects but understanding the appetitive side of placebo effects. And what I mean by that I will try to explain to you in the next couple of slides.

NIMH Staff: Can you turn on your video?

LIANE SCHMIDT: Sorry?

NIMH Staff: Can you please turn on your video, Dr. Schmidt?

LIANE SCHMIDT: Yeah, yes, yes, sorry about that.

So it's about the appetitive side of placebo effects because actually placebo effects on cognitive processes such as motivation and biases and belief updating because these processes actually play also a role when patients respond to treatment. And when we measure placebo effects, basically when placebo effects matter in the clinical setting.

And this is done at the Paris Brain Institute. And I'm working also in collaboration with the Pitie-Salpetriere Hospital Psychiatry department to get access to patients with depression, for example.

So my talk will be organized around three parts. On the first part, I will show you some data about appetitive placebo effects on taste pleasantness, hunger sensations and reward learning. And this will make the bridge to the second part where I will show you some evidence for asymmetrical learning biases that are more tied to reward learning and that could contribute actually or can emerge after fast-acting antidepressant treatment effects in depression.

And why is this important? I will try to link these two different parts, the first and second part, in the third part to elaborate some perspectives on the synergies between expectations, expectation updating through learning mechanisms, motivational mechanisms, motivational processes and drug experiences and which we can -- might harness actually by using computational models such as, for example, risk-reward Wagner models as Marta just showed you all the evidence for this in her work.

The appetitive side of placebo effects is actually known very well from the field of research in consumer psychology and marketing research where price labels, for example, or quality labels can affect decision-making processes and also experiences like taste pleasantness experience. And since we are in France, one of the most salient examples for these kind of effects comes from wine tasting. And many people have shown -- many studies have shown that basically the price of wine can influence how pleasant it tastes.

And we and other people have shown that this is mediated by activation in what is called the brain valuation systems or regions that encode expected and experienced reward. And one of the most prominent hubs in this brain valuation system is the ventral medial prefrontal cortex, what you see here on the SPM on the slide. That can explain, that basically translates these price label effects on taste pleasantness liking. And what is interesting is also that its sensitivity to monetary reward, for example, obtaining by surprise a monetary reward. It activates, basically the vmPFC activates when you obtain such a reward surprisingly.

And the more in participants who activate the vmPFC more in these kind of positive surprises, these are also the participants in which the vmPFC encoded more strongly the difference between expensive and cheap wines, which makes a nice parallel to what we know from placebo hyperalgesia where it has also been shown that the sensitivity of the reward system in the brain can moderate placebo analgesia with participants with higher reward sensitivity in the ventral striatum, for example, another region showing stronger placebo analgesia.

So this is to basically hope to let you appreciate that these effects parallel nicely what we know from placebo effects in the pain and also in disease. So we went further beyond actually, so beyond just taste liking which is basically experiencing rewards such as wine. But what could be -- could placebos also affect motivational processes per se? So when we, for example, want something more.

And one way to study is to study basic motivation such as, for example, hunger. It is long thought, for instance, eating behavior that is conceptualized to be driven by homeostatic markers, hormone markers such as Ghrelin and Leptin that signal satiety and energy stores. And as a function of these different hormonal markers in our blood, we're going to go and look for food and eat food. But we also know from the placebo effects on taste pleasantness that there is a possibility that our higher order beliefs about our internal states not our hormones can influence whether we want to eat food, whether we engage in these types of very basic motivations. And that we tested that, and other people also, that's a replication.

In the study where we gave healthy participants who came into the lab in a fasted state a glass of water. And we told them well, water sometimes can stimulate hunger by stimulating the receptors in your mouth. And sometimes you can also drink a glass of water to kill your hunger. And a third group, a control group was given a glass of water and told it's just water; it does nothing to hunger. And then we asked them to rate how hungry they feel over the course of the experiment. And it's a three-hour experiment. Everybody has fasted. And they have to do this food choice task in an fMRI scanner so they get -- everybody gets hungry over this three hours.

But what was interesting and what you see here on this rain cloud plot is that participants who believed or drank the water suggested to be a hunger killer increased in their hunger rating less than participants who believed the water will enhance their hunger. So this is a nice replication what we already know from the field; other people have shown this, too.

And the interesting thing is that it also affected this food wanting, this motivational process how much you want to eat food. So when people laid there in the fMRI scanner, they saw different food items, and they were asked whether they want to eat it or not for real at the end of the experiment. So it's incentive compatible. And what you see here is basically what we call stimulus value. So how much do you want to eat this food.

And the hunger sensation ratings that I just showed you before parallel what we find here. The people in the decreased hunger suggestion group wanted to eat the food less than in the increased hunger suggestion group, showing that it is not only an effect on subjective self-reports or how you feel your body signals about hunger. It's also about what you would actually prefer, what your subjective preference of food that is influenced by the placebo manipulation. And it's also influencing how your brain valuation system again encodes the value for your food preference. And that's what you see on this slide.

Slide two, you see the ventral medial prefrontal cortex. The yellow boxes that the more yellow they are, the stronger they correlate to your food wanting. And you see on the right side with the temporal time courses of the vmPFC that that food wanting encoding is stronger when people were on the increased hunger suggestion group than in the decreased hunger suggestion group.

So basically what I've showed you here is three placebo effects. Placebo effects on subjective hunger ratings, placebo effects on food choices, and placebo effects on how the brain encodes food preference and food choices. And you could wonder -- these are readouts. So these are behavioral readouts, neural readouts. But you could wonder what is the mechanism behind? Basically what is in between the placebo intervention here and basically the behavior feed and neural readout of this effect.

And one snippet of the answer to this question is when you look at the expectation ratings. For example, expectations have long been shown to be one of the mediators, the cognitive mediators of placebo effects across domains. And that's what we see here, too. Especially in the hunger killer suggestion group. The participants who believed that the hunger -- that the drug will kill their hunger more strongly were also those whose hunger increased less over the course of the experiment experience.

And this moderated activity in the region that you see here, which is called the medial prefrontal cortex, that basically activated when people saw food on the screen and thought about whether they want to eat it or not. And this region activated by that activity was positively moderated by the strength of the expectancy about the glass of water to decrease their hunger. So the more you expect that the water will decrease your hunger, the more the mPFC activates when you see food on the screen.

It's an interesting brain region because it's right between the ventral medial prefrontal cortex that encodes the value, the food preference, and the dorsal lateral prefrontal cortex. And it has been shown by past research to connect to the vmPFC when participants self-control, especially during food decision-making paradigms.

But another mechanism or another way to answer the question about the mechanism of how the placebo intervention can affect this behavior in neural effects is to use computational modelings to better understand the preference formation -- the preference formation basically. And one way is that -- is drift diffusion modeling. So these drift diffusion models come from perceptual research for understanding perception. And they are recently also used to better understand preference formation. And they assume that your preference for a yes or no food choice, for example, is a noisy accumulation of evidence.

And there are two types of evidence you accumulate in these two -- in these decision-making paradigms is basically how tasty and how healthy food is. How much you like the taste, how much you consider the health. And this could influence this loop of your evidence accumulation how rapidly basically you reach a threshold towards yes or no.

It could also be that the placebo and the placebo manipulation could influence this loop. But the model loops test several other hypotheses. It could be that the placebo intervention basically affected also just the threshold like that reflects how carefully you made the decision towards a yes or no choice. It could be your initial bias; that is, basically initially you were biased towards a yes or a no response. Or it could be the nondecision time which reflects more sensory motor integration.

And the answer to this question is basically that three parameters were influenced by the placebo manipulation. Basically how much you integrated healthiness and tastiness in your initial starting bias. So you paid more attention to the healthiness when you believed that you were on a hunger killer. And more the tastiness when you believed that you were on a hunger enhancer. And similarly, you were initially biased towards accepting food more when participants believed they were on a hunger enhancer than on a hunger killer.

Interestingly, so this basically shows that this decision-making process is biased by the placebo intervention and basically also how much you filter information that is most relevant. When you are hungry, basically taste is very relevant for your choices. When you are believing you are less hungry, then you have more actually space or you pay less attention to taste, but you can also pay attention more to healthiness of food.

And so the example that shows that this might be a filtering of expectation-relevant information is to use psychophysiologic interaction analyzers that look basically at the brain activity in the vmPFC, that's our seed region. Where in the brain does it connect when people, when participants see food on a computer screen and have to think about whether they want to eat this food or not?

And what we observed there that's connected to the dlPFC, the dorsal lateral prefrontal cortex region. And it's a region of interest that we localized first to be sure it is actually a region that is inter -- activating through an interference resolution basically when we filter -- have to filter information that is most relevant to a task in a separate Stroop localizer task.

So the vmPFC connects stronger to this dlPFC interference resolution region and this is moderated especially in the decreased hunger suggestion group by how much participants considered the healthiness against the tastiness of food.

To wrap this part up, it's basically that we replicated findings from previous studies about appetitive placebo effects by showing that expectancies about efficiency of a drink can affect hunger sensations. How participants make -- form their food preferences, make food choices. And value encoding in the ventral medial prefrontal cortex.

But we also provided evidence for underlying neurocognitive mechanisms that involve the medial prefrontal cortex that is moderated by the strengths of the hunger expectation. That the food choice formation is biased in the form of attention-filtering mechanism toward expectancy congruent information that is taste for an increased hunger suggestion group, and healthiness for a decreased hunger suggestion group. And this is implemented by regions that are linked to interference resolution but also to valuation preference encoding.

And so why should we care? In the real world, it is not very relevant to provide people with deceptive information about hunger-influencing ingredients of drinks. But studies like this one provide insights into cognitive mechanisms of beliefs about internal states and how these beliefs can affect the interoceptive sensations and also associated motivations such as economic choices, for example.

And this can actually also give us insights into the synergy between drug experiences and outcome expectations. And that could be harnessed via motivational processes. So translated basically via motivational processes. And then through it maybe lead us to better understand active treatment susceptibility.

And I'm going to elaborate on this in the next part of the talk by -- I'm going a little bit far, coming a little bit far, I'm not talking about or showing evidence about placebo effects. But yes -- before that, yes, so basically it is.

Links to these motivational processes have long been suggested actually to be also part of placebo effects or mechanisms of placebo effect. And that is called the placebo-reward hypothesis. And that's based on findings in Parkinson's disease that has shown that when you give Parkinson's patients a placebo but tell them it's a dopaminergic drug, then you can measure dopamine in the brain. And the dopamine -- especially the marker for dopamine, its binding potential decreases. That is what you see here on this PET screen -- PET scan results.

And that suggests that the brain must have released endogenous dopamine. And dopamine is very important for expectations and learning. Basically learning from reward. And clinical benefit is the kind of reward that patients expect. So it might -- it is possible that basically when a patient expects reward clinical benefit, its brain -- their brain releases dopamine in remodulating that region such as the vmPFC or the ventral striatum.

And we have shown this in the past that the behavioral consequence of such a nucleus dopamine release under placebo could be linked to reward learning, indeed. And what we know is that, for example, that Parkinson patients have a deficit in learning from reward when they are off dopaminergic medication. But this normalizes when they are under active dopaminergic medication.

So we wondered if based on these PET studies under placebo, the brain releases dopamine, does this also have behavior consequences on their reward learning ability. And that is what you see here on the screen on the right side on the screen is that the Parkinson patients basically tested on placebo shows similar reward learning abilities as under active drug.

And this again was also underpinned by increased correlation of the ventral medial prefrontal cortex. Again, this hub of the brain valuation system to the learned reward value. That was stronger in the placebo and active drug condition compared to baseline of drug condition.

And I want to make now this -- a link to another type of disease where also the motivation is deficitary, and which is depression. And depression is known to be maintained or is sympathized to be maintained by this triad of very negative beliefs about the world, the future and one's self. Which is very insensitive to belief disconfirming information, especially if the belief disconfirming information is positive, so favorable. And this has been shown by cognitive neuroscience studies to be reflected by a thought of like of good news/bad news bias or optimism biases and belief updating in depression. And this good news/bad news bias is basically a bias healthy people have to consider favorable information that contradicts initial negative beliefs more than negative information.

And this is healthy because it avoids reversing of beliefs. And it also includes a form of motivational process because good news have motivational salience. So it should be more motivating to update beliefs about the future, especially if these beliefs are negative, then when we learn that our beliefs are way too negative and get information about that disconfirms this initial belief. But depressed patients, they like this good news/bad news bias. So we wonder what happens when patients respond to antidepressant treatments that give immediate sensory evidence about being on an antidepressant.

And these new fast-acting antidepressants such as Ketamine, these types of antidepressants that patients know right away whether they got the treatment through dissociative experiences. And so could it be that this effect or is it a cognitive model of depression. So this was the main question of the study. And then we wondered again what is the computational mechanism. And is it linked again also, as shown in the previous studies, to reward learning mechanisms, so biased updating of beliefs. And is it linked to clinical antidepressant effects and also potentially outcome expectations makes the link to placebo effects.

So patients were given the -- were performing a belief updating task three times before receiving Ketamine infusions. And then after first infusion and then one week after the third infusion, each time, testing time we measured the depression with the Montgomery-Asberg Depression Rating Scale. And patients performed this belief updating task where they were presented with different negative life events like, for example, getting a disease, losing a wallet here, for example.

And they were asked to estimate their probability of experiencing this life event in the near future. And they were presented with evidence about the contingencies of this event in the general population, what we call the base rate. And then they had the possibility to update their belief knowing now the base rate.

And this is, for example, a good news trial where participants initially overestimated the chance for losing a wallet and then learn it's much less frequent than they initially thought. Updates, for example, 15%. And in a bad news trial, it's you initially underestimated your probability of experiencing this adverse life event. And if you have a good news/bad news bias, well, you're going to consider this information to a lesser degree than in a good news trial.

And that's what -- exactly what happens in the healthy controls that you see on the left most part of the screen. I don't know whether you can see the models, but basically we have the belief updating Y axis. And this is healthy age-matched controls to patients. And you can see updating of the good news. Updating of the bad news. We tested the participants more than two times within a week. You can see the bias. There is a bias that decreases a little bit with more sequential testing in the healthy controls. But importantly, in the patients the bias is there although before Ketamine treatment.

But it becomes much more stronger after Ketamine treatment. It emerged basically. So patients become more optimistically biased after Ketamine treatment. And this correlates to the MADRS scores. Patients who improve more with treatment are also those who show a stronger good news/bad news bias after one week of treatment.

And we wondered again about the computational mechanisms. So one way to get at this using a Rescoria-Wagner model reward reinforcement learning model that basically assumes that updating is proportional to your surprise which is called the estimation error.

The difference between the initial estimate and the base rate. And this is weighted by learning rate. And the important thing here is the learning rate has got two components, a scaling parameter and an asymmetry parameter. And the asymmetry parameter basically weighs in how much the learning rate varies after good news, after positive estimation error, than after negative estimation errors.

And what we can see that in healthy controls, there is a stronger learning rate for positive estimation errors and less stronger for negative estimation errors translating this good news/bad news bias. It's basically an asymmetrical learning mechanism. And in the patients, the asymmetrical learning is non-asymmetrical before Ketamine treatment. And it becomes asymmetrical as reflected in the learning rates after Ketamine treatment.

So what we take from that is basically that Ketamine induced an optimism bias. But an interesting question is whether -- basically what comes first. Is it basically the improvement in the depression that we measured with the Montgomery-Asberg Depression Rating Scale, or is it the optimism bias that emerged and that triggered basically. Since it's a correlation, we don't know what comes first.

And an interesting side effect or aside we put in the supplement was that in 16 patients, it's a very low sample size, the expectancy about getting better also correlated to the clinical improvement after Ketamine treatment. We have two expectancy ratings here about the efficiency about Ketamine and also what patients expect their intensity of depression will be after Ketamine treatment.

And so that suggested the clinical benefit is kind of in part or synergistically seems to interact with the drug experience that emerges that generates an optimism bias. And to test this more, we continued data collection just on the expectancy ratings. And basically wondered how the clinical improvement after first infusion links to the clinical improvement after third infusion.

And we know from here that patients improve after first infusion are also those that improved after a third infusion. But is it mediated by their expectancy about the Ketamine treatment? And that's what we indeed found is that basically the more patients expected to get better, the more they got better after one week of treatment. But it mediated this link between the first drug experience and the later drug experiences and suggested there might not be an additive effect as other panelist members today already put forward today, it might be synergetic link.

And one way to get at these synergies is basically again use computational models. And this idea has been around although yesterday that basically there could be self-fulfilling prophesies that could contribute to the treatment responsiveness and treatment adherence. And these self-fulfilling prophesies are biased symmetrically learning mechanisms that are more biased when you have positive treatment experiences, initial positive treatment experiences, and then might contribute how you adhere to the treatment in the long term and also how much you benefit from it in the long term. So it's both drug experience and an expectancy.

And so this is nonpublished work where we played with this idea basically using a reinforcement learning model. This is also very inspired by we know from placebo analgesia. Tor and Luana Kuven, they have a paper on showing that self-fulfilling prophecies can be harnessed with biased patient and reinforcement learning models. And the idea of these models is that there are two learning rates, alpha plus and alpha minus. And these learning rates rate differently into the updating of your expectation after drug experience.

LIANE SCHMIDT: Okay, yeah, I'm almost done.

So rate differently on these drug experiences and expectations as a function of whether the initial experience was congruent to your expectations. So a positive experience, then a negative one. And here are some simulations of this model. I'm showing this basically that your expectation is getting more updated the more bias, positively biased you are. Then when you are negatively biased. And these are some predictions of the model concerning depression improvement.

To wrap this up, the conclusion about this is that there seems to be asymmetrical learning that can capture self-fulfilling prophesies and could be a mechanism that translates expectations and drug experiences potentially across domains from placebo hypoalgesia to antidepressant treatment responsiveness. And the open question is obviously to challenge these predictions of these models more with empirical data in pain but also in mood disorders as Marta does and as we do also currently at Cypitria where we test the mechanisms of belief updating biases in depression with fMRI and these mathematical models.

And this has a direct link implication because it could help us to better understand how these fast-acting antidepressants work and what makes patients adhere to them and get responses to them. Thank you for your attention. We are the control-interoception-attention team. And thank you to all the funders.

CRISTINA CUSIN: Fantastic presentation. Thank you so much. Without further ado, let's move on to the next speaker. Dr. Greg Corder.

GREG CORDER: Did that work? Is it showing?

GREG CORDER: Awesome, all right. One second. Let me just move this other screen. Perfect. All right.

Hi, everyone. My name is Greg Corder. I'm an Assistant Professor at the University of Pennsylvania. I guess I get to be the final scientific speaker in this session over what has been an amazing two-day event. So thank you to the organizers for also having me get the honor of representing the entire field of preclinical placebo research as well.

And so I'm going to give a bit of an overview, some of my friends and colleagues over the last few years and then tell you a bit about how we're leveraging a lot of current neuroscience technologies to really identify the cell types and circuits building from, you know, the human fMRI literature that's really honed in on these key circuits for expectations, belief systems as well as endogenous antinociceptive symptoms, in particular opioid cell types.

So the work I'm going to show from my lab has really been driven by these two amazing scientists. Dr. Blake Kimmey, an amazing post-doc in the lab. As well as Lindsay Ejoh, who recently last week just received her D-SPAN F99/K00 on placebo circuitry. And we think this might be one of the first NIH-funded animal projects on placebo. So congratulations, Lindsay, if you are listening.

Okay. So why use animals, right? We've heard an amazing set of stories really nailing down the specific circuits in humans leveraging MRI, fMRI, EEG and PET imaging that give us this really nice roadmap and idea of how beliefs in analgesia might be encoded within different brain circuits and how those might change over times with different types of patient modeling or updating of different experiences.

And we love this literature. We -- in the lab we read it in depth as best as we can. And we use this as a roadmap in our animal studies because we can take advantage of animal models that really allow us to dive deep into the very specific circuits using techniques like that on the screen here from RNA sequencing, electrophysiology really showing that those functional measurements in fMRI are truly existent with the axons projecting from one region to another.

And then we can manipulate those connections and projections using things like optogenetics and chemogenetics that allow us really tight temporal coupling to turn cells on and off. And we can see the effects of that intervention in real time on animal behavior. And that's really the tricky part is we don't get to ask the animals do you feel pain? Do you feel less pain? It's hard to give verbal suggestions to animals.

And so we have to rely on a lot of different tricks and really get into the heads of what it's like to be a small prey animal existing in a world with a lot of large monster human beings around them. So we really have to be very careful about how we design our experiments. And it's hard. Placebo in animals is not an easy subject to get into. And this is reflected in the fact that as far as we can tell, there is only 24 published studies to date on placebo analgesia in animal models.

However, I think this is an excellent opportunity now to really take advantage of what has been the golden age of neuroscience technologies exploding in the last 10-15 years to revisit a lot of these open questions about when are opioids released, are they released? Can animals have expectations? Can they have something like a belief structure and violations of those expectations that lead to different types of predictions errors that can be encoded in different neural circuits. So we have a chance to really do that.

But I think the most critical first thing is how do we begin to behaviorally model placebo in these preclinical models. So I want to touch on a couple of things from some of my colleagues. So on the left here, this is a graph that has been shown on several different presentations over the past two days from Benedetti using these tourniquet pain models where you can provide pharmacological conditioning with an analgesic drug like morphine to increase this pain tolerance.

And then if it is covertly switched out for saline, you can see that there is an elevation in that pain tolerance reflective of something like a placebo analgesic response overall. And this is sensitive to Naloxone, the new opioid receptor antagonist, suggesting endogenous opioids are indeed involved in this type of a placebo-like response.

And my colleague, Dr. Matt Banghart, at UCSD has basically done a fantastic job of recapitulating this exact model in mice where you can basically use morphine and other analgesics to condition them. And so if I just kind of dive in a little bit into Matt's model here.

You can have a mouse that will sit on a noxious hot plate. You know, it's an environment that's unpleasant. You can have contextual cues like different types of patterns on the wall. And you can test the pain behavior responses like how much does the animal flick and flinch and lick and bite and protect itself to the noxious hot plate.

And then you can switch the contextual cues, provide an analgesic drug like morphine, see reductions in those pain behaviors. And then do the same thing in the Benedetti studies, you switch out the morphine for saline, but you keep the contextual cues. So the animal has effectively created a belief that when I am in this environment, when I'm in this doctor's office, I'm going to receive something that is going to reduce my perceptions of pain.

And, indeed, Matt sees a quite robust effect here where this sort of placebo response is -- shows this elevated paw withdrawal latency indicating that there is endogenous nociception occurring with this protocol. And it happens, again, pretty robustly. I mean most of the animals going through this conditioning protocol demonstrate this type of antinociceptive behavioral response. This is a perfect example of how we can leverage what we learn from human studies into rodent studies for acute pain.

And this is also really great to probe the effects of placebo in chronic neuropathic pain models. And so here this is Dr. Damien Boorman who was with Professor Kevin Key in Australia, now with Lauren Martin in Toronto.

And here Damien really amped up the contextual cues here. So this is an animal who has had an injury to the sciatic nerve with this chronic constriction injury. So now this animal is experiencing something like a tonic chronic neuropathic pain state. And then once you let the pain develop, you can have the animals enter into this sort of placebo pharmacological conditioning paradigm where animals will go onto these thermal plates, either hot or cool, in these rooms that have a large amount of visual tactile as well as odorant cues. And they are paired with either morphine or a controlled saline.

Again, the morphine is switched for saline on that last day. And what Damien has observed is that in a subset of the animals, about 30%, you can have these responder populations that show decreased pain behavior which we interpret as something like analgesia overall. So overall you can use these types of pharmacological conditionings for both acute and chronic pain.

So now what we're going to do in our lab is a bit different. And I'm really curious to hear the field's thoughts because all -- everything I'm about to show is completely unpublished. Here we're going to use an experimenter-free, drug-free paradigm of instrumental conditioning to instill something like a placebo effect.

And so this is what Blake and Lindsay have been working on since about 2020. And this is our setup in one of our behavior rooms here. Our apparatus is this tiny little device down here. And everything else are all the computers and optogenetics and calcium imaging techniques that we use to record the activity of what's going on inside the mouse's brain.

But simply, this is just two hot plates that we can control the temperature of. And we allow a mouse to freely explore this apparatus. And we can with a series of cameras and tracking devices plot the place preference of an animal within the apparatus. And we can also record with high speed videography these highly conserved sort of protective recuperative pain-like behaviors that we think are indicative of the negative affect of pain.

So let me walk you through our little model here real quick. Okay. So we call this the placebo analgesia conditioning assay or PAC assay. So here is our two-plate apparatus here. So plate number one, plate number two. And the animal can always explore whichever plate it wants. It's never restricted to one side. And so we have a habituation day, let the animal familiarize itself. Like oh, this is a nice office, I don't know what's about to happen.

And then we have a pretest. And in this pretest, importantly, we make both of these plates, both environments a noxious 45-degree centigrade. So this will allow the animal to form an initial expectation that the entire environment is noxious and it's going to hurt. So both sides are noxious. Then for our conditioning, this is where we actually make one side of the chamber non-noxious. So it's just room temperature. But we keep one side noxious. So now there is a new expectation for the animal that it learns that it can instrumentally move its body from one side to the other side to avoid and escape feeling pain.

And so we'll do this over three days, twice per day. And then on our post tester placebo day we make both environments hot again. So now we'll start the animal off over here and the animals will get to freely choose do they want to go to the side that they expect should be non-noxious? Or what happens? So what happens?

Actually, if you just look at the place preference for this, over the course of conditioning we can see that the animals will, unsurprisingly, choose the environment that is non-noxious. And they spend 100% of their time there basically. But when we flip the plates or flip the conditions such that everything is noxious on the post test day, the animals will still spend a significant amount of time on the expected analgesia side. So I'm going to show you some videos here now and you are all going to become mouse pain behavior experts by the end of this.

So what I'm going to show you are both side by side examples of conditioned and unconditioned animals. And try to follow along with me as you can see what the effect looks like. So on this post test day. Oh, gosh, let's see if this is going to -- here we go. All right. So on the top we have the control animal running back and forth. The bottom is our conditioned animal.

And you'll notice we start the animal over here and it's going to go to the side that it expects it to not hurt. Notice the posture of the animals. This animal is sitting very calm. It's putting its entire body down on the hot plate. This animal, posture up, tail up. It's running around a little bit frantically. You'll notice it start to lick and bite and shake its paws. This animal down here might have a couple of flinches so it's letting you know that some nociception is getting into the nervous system overall.

But over the course of this three-minute test, the animals will rightly choose to spend more time over here. And if we start to quantify these types of behaviors that the animals are doing in both conditions, what we find is that there is actually a pretty significant reduction in these nociceptive behaviors. But it's not across the entire duration of this placebo day or post test day.

So this trial is three minutes long. And what we see is that this antinociceptive and preference choice only exists for about the first 90 seconds of this assay. So this is when the video I just showed, the animal goes to the placebo side, it spends a lot of its time there, does not seem to be displaying pain-like behaviors.

And then around 90 seconds, the animal -- it's like -- it's almost like the belief or the expectation breaks. And at some point, the animal realizes oh, no, this is actually quite hot. It starts to then run around and starts to show some of the more typical nociceptive-like behaviors. And we really like this design because this is really, really amenable to doing different types of calcium imaging, electrophysiology, optogenetics because now we have a really tight timeline that we can observe the changing of neural dynamics at speeds that we can correlate with some type of behavior.

Okay. So what are those circuits that we're interested in overall that could be related to this form of placebo? Again, we like to use the human findings as a wonderful roadmap. And Tor has demonstrated, and many other people have demonstrated this interconnected distributed network involving prefrontal cortex, nucleus accumbens, insula, thalamus, as well as the periaqueductal gray.

And so today I'm going to talk about just the periaqueductal gray. Because there is evidence that there is also release of endogenous opioids within this system here. And so we tend to think that the placebo process and the encoding, whatever that is, the placebo itself is likely not encoded in the PAG. The PAG is kind of the end of the road. It's the thing that gets turned on during placebo and we think is driving the antinociceptive or analgesic effects of the placebo itself.

So the PAG, for anyone who's not as familiar, we like it because it's conserved across species. We look at in a mouse. There's one in a human. So potentially it's really good for translational studies as well. It has a very storied past where it's been demonstrated that the PAG subarchitecture has these beautiful anterior to posterior columns that if you electrically stimulate different parts of PAG, you can produce active versus passive coping mechanisms as well as analgesia that's dependent on opioids as well as endocannabinoids.

And then the PAG is highly connected. Both from ascending nociception from the spinal cord as well as descending control systems from prefrontal cortex as well as the amygdala. So with regard to opioid analgesia. If you micro infuse morphine into the posterior part of the PAG, you can produce an analgesic effect in rodents that is across the entire body. So it's super robust analgesia from this very specific part of the PAG.

If you look at the PAG back there and you do some of these techniques to look for histological indications that the mu opioid receptor is there, it is indeed there. There is a large amount of mu opioid receptors, it's OPRM1. And it's largely on glutamatergic neurons. So the excitatory cells, not the inhibitory cells. They are on some of them.

And as far as E-phys data goes as well, we can see that the mu opioid receptor is there. So DAMGOs and opioid agonist. We can see activation of inhibitory GIRK currents in those cells. So the system is wired up for placebo analgesia to happen in that location. Okay. So how are we actually going to start to tease this out? By finding these cells where they go throughout the brain and then understanding their dynamics during placebo analgesia.

So last year we teamed up with Karl Deisseroth's lab at Stanford to develop a new toolkit that leverages the genetics of the opioid system, in particular the promoter for the mu opioid receptor. And we were able to take the genetic sequence for this promoter and package it into adeno associated viruses along with a range of different tools that allow us to turn on or turn off cells or record their activity. And so we can use this mu opioid receptor promoter to gain genetic access throughout the brain or the nervous system for where the mu opioid receptors are. And we can do so with high fidelity.

This is just an example of our mu opioid virus in the central amygdala which is a highly mu opioid specific area. But so Blake used this tool using the promoter to drive a range of different trans genes within the periaqueductal gray. And right here, this is the G camp. So this is a calcium indicator that allows us to in real time assess the calcium activity of PAG mu opioid cells.

And so what Blake did was he took a mouse, and he recorded the nociceptive responses within that cell type and found that the mu opioid cell types are actually nociceptive. They respond to pain, and they do so with increasing activity to stronger and stronger and more salient and intense noxious stimuli. So these cells are actually nociceptive.

And if we look at a ramping hot plate, we can see that those same mu opioid cell types in the PAG increase the activity as this temperature on this hot plate increases. Those cells can decrease that activity if we infuse morphine.

Unsurprisingly, they express the mu opioid receptor and they're indeed sensitive to morphine. If we give naltrexone to block the mu opioid receptors, we can see greater activity to the noxious stimuli, suggesting that there could be an opioid tone or some type of an endogenous opioid system that's keeping this system in check, that it's repressing its activity. So when we block it, we actually enhance that activity. So it's going to be really important here. The activity of these mu opioid PAG cells correlates with affective measures of pain.

When animals are licking, shaking, biting, when it wants to escape away from noxious stimuli, that's when we see activity within those cells. So this is just correlating different types of behavior when we see peak amplitudes within those cell types. So let me skip that real quick.

Okay. So we have this ability to look and peek into the activity of mu opioid cell types. Let's go back to that placebo assay, our PAC assay I mentioned before. If we record from the PAG on that post test day in an animal that has not undergone conditioning, when the plates are super hot, we see a lot of nocioceptive activity in these cells here. They're bouncing up and down.

But if we look at the activity of the nociception in an animal undergoing placebo, what we see is there's a suppression of neural activity within that first 90 seconds. And this actually does seem to extinguish within the lighter 90 seconds. So kind of tracks along with the behavior of those animals. When they're showing anti nocioceptive behavior, that's when those cells are quiet.

When the pain behavior comes back, that's when those cell types are ramping up. But what about the opioids too? Mu opioid receptor cell type's decreasing activity. What about the opioids themselves here? The way to do this in animals has been to use microdialysis, fantastic technique but it's got some limitations to it. This is a way of sampling peptides in real time and then using liquid chromatography to tell if the protein was present. However, the sampling rate is about 10 minutes.

And in terms of the brain processing, 10 minutes might as well be an eternity. If we're talking about milliseconds here. But we want to know what these cells here and these red dots are doing. These are the enkephaliner cells in the PAG. We needed revolution in technologies. One of those came several years ago from Dr. Lin Tian, who developed some of the first sensors for dopamine. Some of you may have heard of it. It's called D-Light.

This is a version of D-Light. But it's actually an enkephalin opioid sensor. What Lin did to genetically engineer this is to take the delta opioid receptor, highly select it for enkephalin, and then link it with this GFP molecule here such that when enkephalin binds to the sensor it will fluoresce.

We can capture that florescence with microscopes that we implant over the PAG and we can see when enkephalin is being released with subsecond resolution. And so what we did for that is we want to see if enkephalin is indeed being released onto those mu opioid receptor expressing pain encoding neurons in the PAG. What I showed you before is that those PAG neurons, they ramp up their activity as the nociception increases, a mouse standing on a hot plate. We see nociception ramp up. What do you all think happened with the opoids?

It wasn't what we expected. It actually drops. So what we can tell is that there's a basal opioid tone within the PAG, but that as nociception increases, acute nociception, we see a decrease suppression of opioid peptide release.

We think this has to do with stuff that Tor has published on previously that the PAG is more likely involved in updating prediction errors. And this acute pain phenomenon we think is reflective of the need to experience pain to update your priors about feeling pain and to bias the selection of the appropriate behaviors, like affect related things to avoid pain. However, what happens in our placebo assay?

We actually see the opposite. So if we condition animals to expect pain relief within that PAC assay, we actually see an increase from the deltoid sensor suggesting that there is an increase in enkephalin release post conditioning. So there can be differential control of the opioid system within this brain region. So this next part is the fun thing you can do with animals. What if we just bypassed the need to do the placebo assay?

If we know that we just need to cause release of enkephalin within the PAG to produce pain relief, we could just directly do that with optigenetics. So we tried to us this animal that allows us to put a red light sensitive opsin protein into the enkephalinergic interneurons into the PAG.

When we shine red light on top of these cells, they turn on and they start to release their neurotransmitters. These are GABAergic and enkephalinergic. So they're dumping out GABA and now dumping out enkephalin into the ERG. We can visualize that using the Delta Light sensor from Lin Tien.

So here is an example of optogenetically released enkephalin within the PAG over 10 minutes. The weird thing that we still don't fully understand is that this signal continues after the optogenetic stimulation. So can we harness the placebo effect in mice? At least it seems we can. So if we turn on these cells strongly, cause them to release enkephalin and put animals back on these ramping hot plate tests we don't see any changes in the latency to detect pain, but we see specific ablation or reductions in these affective motivational pain like behaviors overall. Moderator: You have one minute remaining.

GREGORY CORDER: Cool. In this last minutes, people are skeptical. Can we actually test these higher order cognitive processes in animals? And for anyone who is not a behavioral preclinical neural scientist, you might not be aware there's an absolute revolution happening in behavior with the use of deep learning modules that can precisely and accurately quantify animal behavior. So this is an example of a deep learning tracking system.

We've built the Light Automated Pain Evaluator that can capture a range of different pain related behaviors fully automated without human intervention whatsoever that can be paired with brain reporting techniques like calcium imaging, that allow us to fit a lot of different computational models to understand what the activity of single neurons might be doing, let's say, in the cingulate cortex that might be driving that placebo response.

We can really start to tie now in at single cell resolution the activity of prefrontal cortex to drive these placebo effects and see if that alters anti nocioceptive behavior endogenously. I'll stop there and thank all the amazing people, Blake, Greg, and Lindsay, who did this work, as well as all of our funders and the numerous collaborators who have helped us do this. So thank you.

CRISTINA CUSIN: Terrific talk. Thank you so much. We're blown away. I'll leave the discussion to our two moderators. They're going to gather some of the questions from the chat and some of their own questions for all the presenters from today and from yesterday as well.

TED KAPTCHUK: Matt, you start gathering questions. I got permission to say a few moments of comments. I wanted to say this is fantastic. I actually learned an amazing amount of things. The amount of light that was brought forward about what we know about placebos and how we can possibly control placebo effects, how we can possibly harness placebo effects.

There was so much light and new information. What I want to do in my four minutes of comments is look to the future. What I mean by that is -- I want to give my comments and you can take them or leave them but I've got a few minutes.

What I want to say is we got the light, but we didn't put them together. There's no way we could have. We needed to be more in the same room. How does this fit in with your model? It's hard to do. What I mean by putting things together is I'll give you an example. In terms of how do we control placebo effects in clinical trials. I not infrequently get asked by the pharmaceutical industry, when you look at our placebo data -- we just blew it. Placebo was good as or always as good as the drug.

And the first thing I say is I want to talk to experts in that disease. I want to know the natural history. I want to know how you made your entry criteria so I can understand regression to the mean.

I want to know what's the relationship of the objective markers and subjective markers so I can begin to think about how much is the placebo response. I always tell them I don't know. If I knew how to reduce -- increase the difference between drug and placebo I'd be a rich man, I wouldn't be an academic. What I usually wind up saying is, get a new drug. And they pay me pretty well for that. And the reason is that they don't know anything about natural history. We're trying to harness something, and I just want to say -- I've done a lot of natural history controls, and that's more interesting than the rest of the experiments because they're unbelievable, the amount of improvement people show entering the trial without any treatment.

I just want to say we need to look at other things besides the placebo effect. We want to control the placebo response in a randomized control trial. I want to say that going forward. But I also want to say that we need a little bit of darkness. We need to be able to say, you know, I disagree with you. I think this other data, and one of the things I've learned doing placebo reach there's a paper that contradicts your paper real quickly and there's lots of contradictory information. It's very easy to say you're wrong, and we don't say it enough.

I want to take one example -- please forgive me -- I know that my research could be said that, Ted, you're wrong. But I just want to say something. Consistently in the two days of talk everyone talks about the increase of the placebo response over time. No one refers to the article published in 2022 in BMJ, first author was Mark Stone and senior author was Irving Kirsch. And they analyzed all FDA Mark Stone is in the Division of Psychiatry at CDER at the FDA. They analyzed all data of placebo controlled trials in major depressive disorder. They had over 230 trials, way more than 70,000 patients, and they analyzed the trend over time, in 1979 to the present, the publication. There was no increase in the placebo effect.

Are they right or are other people right? Nothing is one hundred percent clear right now and we need to be able to contradict each other when we get together personally and say, I don't think that's right, maybe that's right. I think that would help us. And the last thing I want to say is that some things were missing from the conference that we need to include in the future. We need to have ethics. Placebo is about ethics. If you're a placebo researcher in placebo controlled trials, that's an important question:

What are we talking about in terms of compromising ethics? There's no discussion that we didn't have time but in the future, let's do that.

And the last thing I would say is, we need to ask patients what their experience is. I've got to say I've been around for a long time. But the first time I started asking patients what their experiences were, they were in double blind placebo or open label placebo, I did it way after they finished the trial, the trial was over, and I actually took notes and went back and talked to people. They told me things I didn't even know about. And we need to have that in conferences. What I want to say, along those lines, is I feel so much healthier because I'm an older person, and I feel with this younger crowd here is significantly younger than me.

Maybe Matt and I are the same age, I don't know, but I think this is really one of the best conferences I ever went to. It was real clear data. We need to do lots of other things in the future. So with that, Matt, feed me some questions.

MATTHEW RUDORFER: Okay. Thanks. I didn't realize you were also 35. But okay. [LAUGHTER].

MATTHEW RUDORFER: I'll start off with a question of mine. The recent emergence of intravenous ketamine for resistant depression has introduced an interesting methodologic approach that we have not seen in a long time and that is the active placebo. So where the early trials just used saline, more recently we have seen benzodiazapine midazolam, while not mimicking really the full dissociative effect that many people get from ketamine, but the idea is for people to feel something, some kind of buzz so that they might believe that they're on some active compound and not just saline. And I wonder if the panel has any thoughts about the merits of using an active placebo and is that something that the field should be looking into more?

TED KAPTCHUK: I'm going to say something. Irving Kirsch published a meta analysis of H studies that used atropine as a control in depression studies. He felt that it made it difficult to detect a placebo drug difference. But in other meta analysis said that was not true. That was common in the '80s. People started thinking about that. But I have no idea how to answer your question.

MICHAEL DETKE: I think that's a great question. And I think in the presentations yesterday about devices, Dr. Lisanby was talking about the ideal sham. And I think it's very similar, the ideal active placebo would have none of the axia of the drug, of the drug in question, but would have, you know, exactly the same side effects and all other features, and of course that's attractive, but of course we probably would never have a drug that's exactly like that. I think midazolam was a great thing to try with ketamine. It's still not exactly the same. But I'd also add that it's not black and white. It's not like we need to do this with ketamine and ignore it for all of our other drugs. All of our drugs have side effects.

Arguably, if you do really big chunks, like classes of relatively modern antidepressants, antipsychotics and the psychostimulants, those are in order of bigger effect sizes in clinical trials, psychostimulants versus anti psychotics, versus -- and they're also in the order of roughly, I would argue, of unblinding, of functional unblinding. And in terms of more magnitude, Zyprexa will make you hungry. And also speed of onset of some of the adverse effects, stimulants and some of the Type II -- the second generation and beyond -- anti psychotics, they have pretty noticeable side effects for many subjects and relatively rapidly. So I think those are all important features to consider.

CRISTINA CUSIN: Dr. Schmidt?

LIANE SCHMIDT: I think using midazolam could give, like, some sensory sensations so the patients actually can say there's some effect on the body like immediately. But this raises actually a question whether these dissociations we observe in some patients of ketamine infusions we know have, will play a role for the antidepressant response. It's still an open question. So I don't have the answer to that question. And I think with midazolam doesn't really induce dissociations. I don't know, maybe you can isolate the dissociations you get on ketamine. But maybe even patients might be educated, expecting scientific reaction experiences and basically when they don't have -- so they make the midazolam experience something negative. So yeah, just self fulfilling prophesies might come into play.

CRISTINA CUSIN: I want to add for five seconds. Because I ran a large ketamine clinic. We know very little about cyto placebo maintaining an antidepressant response while the dissociation often wears off over time. It's completely separate from the anti depressant effect. We don't have long term placebo studies. The studies are extremely short lived and we study the acute effect. But we don't know how to sustain or how to maintain, what's the role of placebo effect in long term treatments. So that's another field that really is open to investigations. Dr. Rief.

WINFRIED RIEF: Following up on the issue of active placebos. I just want to mention that we did a study comparing active placebos to passive placebos and showing that active placebos are really more powerful. And I think the really disappointing part of this news is that it questions the blinding of our typical RCTs comparing antidepressants versus placebos because many patients who are in the active group or the tracked group, they perceive these onset effects and this will further boost the placebo mechanisms in the track group that are not existing in the passive placebo group. This is a challenge that further questions the validity of our typical RCTs.

CRISTINA CUSIN: Marta.

MARTA PECINA : Just a quick follow up to what Cristina was saying, too, that we need to clarify whether we want to find an active control for the dissociative effects or for the antidepressive effects. I think the approach will be very different. And this applies to ketamine but also psychodelics because we're having this discussion as well. So when thinking about how to control for or how to blind or how we just -- these treatments are very complicated. They have multiple effects. We just need to have the discussion of what are we trying to blind because the mechanism of action of the blinding drug will be very different.

TED KAPTCHUK: Can I say something about blinding? Robertson, who is the author of the 1970 -- no -- 1993 New England Journal paper saying that there's no that the placebo effect is a myth.

In 2022, published in BMJ, the largest -- he called it a mega meta analysis on blinding. And he took 144 randomized control trials that included nonblinded evidence on the drug versus blinded evidence of the drug. I'm not going to tell you the conclusion because it's unbelievable. But you should read it because it really influences -- it would influence what we think about blinding. That study was just recently replicated on a different set of patients with procedures in JAMA Surgery three months ago. And blinding like placebo is more complicated than we think. That's what I wanted to say.

MATTHEW RUDORFER: Another clinical factor that's come up during our discussion has been the relationship of the patient to the provider that we saw data showing that a warm relationship seemed to enhance therapeutic response, I believe, to most interventions. And I wonder what the panel thinks about the rise on the one hand of shortened clinical visits now that, for example, antidepressants are mostly given by busy primary care physicians and not specialists and the so called med check is a really, kind of, quickie visit, and especially since the pandemic, the rise of telehealth where a person might not ever even meet their provider in person, and is it possible we're on our way to where a clinical trial could involve, say, mailing medication every week to a patient, having them do their weekly ratings online and eliminating a provider altogether and just looking at the pharmacologic effect?

I mean, that probably isn't how we want to actually treat people clinically, but in terms of research, say, early phase efficacy, is there merit to that kind of approach?

LUANA COLLOCA: I'll comment on this, Dr. Rudorfer. We're very interested to see how the telemedicine or virtual reality can affect placebo effects, and we're modeling in the lab placebo effects induced via, you know, in person interaction.

There's an Avatar and virtual reality. And actually we found placebo effects with both the settings. Or whether, when we look at empathy, the Avatar doesn't elicit any empathy in the relationship. We truly need the in person connection to have empathy. So that suggests that our outcome that are affected by having in person versus telemedicine/para remote interactions, but yet the placebo effects persist in both the settings. The empathy is differently modulated and the empathy mediated, interestingly in our data, placebo effects only in the in person interactions. There is still a value in telemedicine. Effects that bypass empathy completely in competence.

MATTHEW RUDORFER: Dr. Hall.

KATHRYN HALL: Several of the large studies, like the Women's Health Study, Physicians' Health Study and, more recently, Vital, they did exactly that, where they mail these pill packs. And I mean, the population, obviously, is clinicians. So they are very well trained and well behaved. And they follow them for years but there's very little contact with the providers, and you still have these giant -- I don't know if you can call them placebo effects -- but certainly many of these trials have not proven to be more effective, the drugs they're studying, than placebo.

MATTHEW RUDORFER: Dr. Atlas.

LAUREN ATLAS: I wanted to chime in briefly on this important question. I think that the data that was presented yesterday in terms of first impressions of providers is relevant for this because it suggests that even when we use things like soft dot (phonetic) to select physicians and we have head shots (phonetic), that really we're making these decisions about who to see based on these kinds of just first impressions and facial features and having the actual interactions by providers is critical for sort of getting beyond that kind of factor that may drive selection. So I think if we have situations where there's reduced chances to interact, first of all, people are bringing expectations to the table based on what they know about the provider and then you don't really have the chance to build on that without the actual kind of therapeutic alliance. That's why I think, even though our study was done in an artificial setting, it really does show how we make these choices when there are bios for physicians and things available for patients to select from. I think there's a really important expectation being brought to the table before the treatment even occurs.

MATTHEW RUDORFER: Thanks. Dr. Lisanby.

SARAH “HOLLY” LISANBY: Thanks for raising this great question, Matt. I have a little bit of a different take on it. Equity in access to mental health care is a challenge. And the more that we can leverage technology to provide and extend the reach of mental health care the better. And so telemedicine and telepsychiatry, we've been thrust into this era by the pandemic but it existed before the pandemic as well. And it's not just about telepsychotherapy or teleprescription from monitoring pharmacotherapy, but digital remote neuromodulation is also a thing now. There are neuromodulation interventions that can be done at home that are being studied, and so there have been trials on transcranial direct current stimulation at home with remote monitoring. There are challenges in those studies differentiating between active and sham. But I think you're right in that we may have to rethink how do we control remote studies when the intensity of the clinician contact is very different, but I do think that we should explore these technologies so that we can extend the reach and extend access to research and to care for people who are not able to come into the research lab setting.

TED KAPTCHUK: May I add something on this? It's also criticizing myself. In 2008, I did this very nice study showing you could increase the doctor/patient relationship. And as you increase it, the placebo effect got bigger and bigger, like a dose response. A team in Korea that I worked with replicated that. I just published that replication.

The replication came out with the exact opposite results. The less doctor/patient relationship, the less intrusive, the less empathy got better effects. We're dealing with very complicated culturally constructed issues, and I just want to put it out there, the sand is soft. I'm really glad that somebody contradicted a major study that I did.

LUANA COLLOCA: Exactly. The central conference is so critical, what we observed in one context in one country, but even within the same in group or out group can be completely different in Japan, China or somewhere else. So the Americas, South Africa. So we need larger studies and more across country collaborations.

MATTHEW RUDORFER: Dr. Schmidt.

LIANE SCHMIDT: I just wanted to raise a point not really like -- it's more like a comment, like there's also very interesting research going on in the interactions between humans and robots, and usually humans treat robots very badly. And so I wonder what could be like -- here we focus on very human traits, like empathy, competence, what we look at. But when it comes to artificial intelligence, for example, and when we have to interact with algorithms, basically, like all these social interactions might completely turn out completely different, actually, and all have different effects on placebo effects. Just a thought.

MATTHEW RUDORFER: Dr. Rief.

WINFRIED RIEF: Yesterday, I expressed a belief for showing more warmth and competence, but I'll modify it a little bit today because I think the real truth became quite visible today, and that is that there is an interaction between these non specific effect placebo effects and the track effect. In many cases, at least. We don't know whether there are exceptions from this rule, but in many cases we have an interaction. And to learn about the interaction, we instead need study designs that modulate track intake versus placebo intake, but they also modulate the placebo mechanisms, the expectation mechanisms, the context of the treatment. And only if we have these 2 by 2 designs, modulating track intake and modulating context and psychological factors, then we learn about the interaction. You cannot learn about the interaction if you modulate only one factor.

And, therefore, I think what Luana and others have said that interact can be quite powerful and effective in one context but maybe even misleading in another context. I think this is proven. We have to learn more about that. And all the studies that have been shown from basic science to application that there could be an interaction, they're all indicating this line and to this necessity that we use more complex designs to learn about the interaction.

MATTHEW RUDORFER: Yes. And the rodent studies we've seen, I think, have a powerful message for us just in terms of being able to control a lot of variables that are just totally beyond our control in our usual human studies. It always seemed to me, for example, if you're doing just an antidepressant versus placebo trial in patients, well, for some people going into the clinic once a week to get ratings, that might be the only day of the week that they get up and take a shower, get dressed, have somebody ask them how they're doing, have some human interaction. And so showing up for your Hamilton rating could be a therapeutic intervention that, of course, we usually don't account for in the pharmacotherapy trial. And the number of variables really can escalate in a hurry when we look at our trials closely.

TED KAPTCHUK: Tor wants to say something.

TOR WAGER: Thanks, Ted.

I wanted to add on to the interaction issue, which came up yesterday, which Winfried and others just commented on, because it seems like it's really a crux issue. If the psychosocial or expectation effects and other things like that are entangled with specific effects so that one can influence the other and they might interact, then, yeah, we need more studies that independently manipulate specific drug or device effects and other kinds of psychological effects independently. And I wanted to bring this back up again because this is an idea that's been out here for a long time. I think the first review on this was in the '70s, like '76 or something, and it hasn't really been picked up for a couple of reasons. One, it's hard to do the studies. But second, when I talk to people who are in industry and pharma, they are very concerned about changing the study designs at all for FDA approval.

And since we had some, you know, FDA and regulatory perspectives here yesterday, I wanted to bring that up and see what people think, because I think that's been a big obstacle. And if it is, then that may be something that would be great for NIH to fund instead of pharma companies because then there's a whole space of drugs, psychological or neurostimulation psychological interactions, that can be explored.

MATTHEW RUDORFER: We also had a question. Yesterday there was discussion in a naloxone trial in sex differences in placebo response. And wonder if there's any further thoughts on studies of sex differences or diversity in general in placebo trials. Yes.

LUANA COLLOCA: We definitely see sex differences in placebo effect, and I show also, for example, women responded to arginine vasopressin in a way that we don't observe in men.

But also you asked about diversity. Currently actually in our paper just accepted today where we look at where people are living, the Maryland states, and even the location where they are based make a difference in placebo effects. So people who live in the most distressed, either the greatest Baltimore area, tended to have lower placebo effects as compared to a not distressful location. And we define that the radius of the criteria and immediately it's a race but we take into account the education, the income and so on. So it is interesting because across studies consistently we see an impact of diversity. And in that sense, I echo, listen to the comment that we need to find a way to reach out to these people and truly improve access and the opportunity for diversity. Thank you for asking.

MATTHEW RUDORFER: Thank you. Another issue that came up yesterday had to do with the pharmacogenomics. And there was a question or a question/comment about using candidate approaches and are they problematic.

KATHRYN HALL: What approaches.

MATTHEW RUDORFER: Candidate genes.

KATHRYN HALL: I think we have to start where we are. I think that the psychiatric field has had a really tough time with genetics. They've invested a lot and, sadly, don't have as much to show for it as they would like to. And I think that that has really tainted this quest for genetic markers of placebo and related studies, these interaction factors. But it's really important to not, I think, to use that to stop us from looking forward and identifying what's there. Because when you start to scratch the surface, there are interactions. You can see them. They're replete in the literature. And what's really fascinating is everybody who finds them, they don't see them when they report their study. And even some of these vasopressin studies, not obviously, Tor, yours, but I was reading one the other day where they had seen tremendous differences by genetics in response to arginine vasopressin. And they totally ignored what they were seeing in placebo and talked about who responds to drug. And so I think that not only do we need to start looking for what's happening, we need to start being more open minded and paying attention to what we're seeing in the placebo arm and accounting for that, taking that into account to understand what we're seeing across a trial in total.

CRISTINA CUSIN: I'll take a second to comment on sufficient selection and trying to figure out, depending on the site who are the patients who went there, treatment and depression clinical trial. If we eliminate from the discussion professional patient and we think about the patients who are more desperate, patients who don't have access to care, patients who are more likely to have psychosocial stressors or the other extreme, there are patients who are highly educated. The trials above and they search out, but they're certainly not representative of the general populations we see in the clinical setting.

They are somewhat different. And then if you think about the psychedelics trial, they go from 5,000 patients applying for a study and the study ends up recruiting 20, 30. So absolutely not representative of the general population we see in terms of diversity, in terms of comorbidities, in terms of psychosocial situations. So that's another factor that adds to the complexity of differentiating what happens in the clinical setting versus artificial setting like a research study. Tor.

MATTHEW RUDORFER: The question of who enters trials and I think the larger issue of diagnosis in general has, I think, really been a challenge to the field for many years. Ted and I go back a ways, and just looking at depression, of course, has dominated a lot of our discussion these last couple of days, with good reason. Now I realize the good database, my understanding is that the good database of placebo controlled trials go back to the late '90s, is what we heard yesterday. And if you go back further, the tricyclic era not only dealt with different medications, which we don't want to go back to, but if you think about practice patterns then, on the one hand, the tricyclics, most nonspecialists steered clear of, they required a lot of hands on. They required titration slowly up. They had some concerning toxicities, and so it was typical that psychiatrists would prescribe them but family docs would not. And that also had the effect of a naturalistic screening, that is, people would have to reach a certain level of severity before they were referred to a psychiatrist to get a prescription for medication.

More mildly ill people either wound up, probably inappropriately, on tranquilizers or no treatment at all and moderately to severely ill people wound up on tricyclics, and of course inpatient stays were common in those days, which again was another kind of screening. So it was the sort of thing, I mean, in the old days I heard of people talk about, well, you could, if you go to the inpatient board, you could easily collect people to be in clinical trial and you kind of knew that they were vetted already. That they had severe depression, the general sense was that the placebo response would be low. Though there's no real evidence for that. But the thing is, once we had the SSRIs on the one hand, the market vastly expanded because they're considered more broad spectrum. People with milder illness and anxiety disorders now are appropriate candidates and they're easier to dispense. The concern about overdose is much less, and so they're mostly prescribed by nonspecialists. So it's the sort of thing where we've seen a lot of large clinical trials where it doesn't take much to reach the threshold for entry, being if I go way back and this is just one of my personal concerns over many years the finer criteria, which I think were the first good set of diagnostic criteria based on data, based on literature, those were published in 1972 to have a diagnosis of major depression, called for four weeks of symptoms. Actually, literally, I think it said one month.

DSM III came out in 1980 and it called for two weeks of symptoms. I don't know -- I've not been able to find any documentation of how the one month went to two weeks, except that the DSM, of course, is the manual that's used in clinical practice. And you can understand, well, you might not want to have too high a bar to treat people who are seeking help. But I think one of the challenges of DSM, it was not meant as a research manual. Though that's often how it's used. So ever since that time, those two weeks have gotten reified, and so my point is it doesn't take much to reach diagnostic criteria for DSM, now, 5TR, major depression. So if someone is doing a clinical trial of an antidepressant, it is tempting to enroll people who meet, honestly meet those criteria but the criteria are not very strict. So I wonder whether that contributes to the larger placebo effect that we see today.

End of soapbox. The question -- I'd like to revisit an excellent point that Dr. Lisanby raised yesterday which has to do with the research domain criteria, the RDOC criteria. I don't know if anyone on the panel has had experience in using that in any trials and whether you see any merit there. Could RDOC criteria essentially enrich the usual DSM type clinical criteria in terms of trying to more finely differentiate subtypes of depression, might respond differently to different treatments.

MODERATOR: I think Tor has been patient on the hand off. Maybe next question, Tor, I'm not sure if you had comments on previous discussion.

TOR WAGER: Sure, thanks. I wanted to make a comment on the candidate gene issue. And I think it links to what you were just saying as well, doctor, in a sense. I think it relates to the issue of predicting individual differences in placebo effects and using that to enhance clinical trials, which has been really sort of a difficult issue. And in genetics, I think what's happened, as many of us know, is that there were many findings on particular candidate genes, especially comped and other particular set of genes in Science and Nature, and none of those really replicated when larger GWA studies started being done. And the field of genetics really focused in on reproducibility and replicability in one of our sample sizes. So I think my genetics colleagues tell me something like 5,000 is a minimum for even making it into their database of genetic associations. And so that makes it really difficult to study placebo effects in sample sizes like that. And at the same time, there's been this trend in psychology and in science, really, in general, towards reproducibility and replicability that probably in part are sort of evoked by John Ioannidis's provocative claims that most findings are false, but there's something really there.

There's been many teams of people who have tried to pull together, like Brian Nosek's work with Open Science Foundation, and many lab studies to replicate effects in psychology with much higher power. So there's this sort of increasing effort to pull together consortia to really test these things vigorously. And I wonder if -- we might not have a GWA study of placebo effects in 100,000 people or something, which is what would convince a geneticist that there's some kind of association. I'm wondering what the ways forward are, and I think one way is to increasingly come together to pull studies or do larger studies that are pre registered and even registered reports which are reviewed before they're published so that we can test some of these associations that have emerged in these what we call early studies of placebo effects.

And I think if we preregister and found something in sufficiently large and diverse samples, that might make a dent in convincing the wider world that essentially there is something that we can use going forward in clinical trials. And pharma might be interested in, for example, as well. That's my take on that. And wondering what people think.

KATHRYN HALL: My two cents. I completely agree with you. I think the way forward is to pull our resources to look at this and not simply stop -- I think when things don't replicate, I think we need to understand why they don't replicate. I think there's a taboo on looking beyond, if you prespecified it and you don't see it, then it should be over. I think in at least this early stage, when we're trying to understand what's happening, I think we need to allow ourselves deeper dives not for action but for understanding.

So I agree with you. Let's pull our resources and start looking at this. The other thing I would like to point out that's interesting is when we've looked at some of these clinical trials at the placebo arm, we actually learn a lot about natural history. We just did one in Alzheimer's disease and in the placebo arm the genome wide significant hit was CETP, which is now a clinical target in Alzheimer's disease. You can learn a lot by looking at the placebo arms of these studies not just about whether or not the drug is working or how the drug is working, but what's happening in the natural history of these patients that might change the effect of the drug.

TED KAPTCHUK: Marta, did you have something to say; you had your hand up.

MARTA PECINA: Just a follow up to what everybody is saying. I do think the issue of individualability is important. I think that one thing that maybe kind of explains some of the things that was also saying at the beginning that there's a little bit of lack of consistency or a way to put all of these findings together. The fact that we think about it as a one single placebo effect and we do know that there's not one single placebo effect, but even within differing clinical conditions is the newer value placebo effect the same in depression as it is in pain?

Or are there aspects that are the same, for example, expectancy processing, but there's some other things that are very specific to the clinical condition, whether it's pain processing, mood or some others. So I think we face the reality of use from a neurobiology perspective that a lot of the research has been done in pain and still there's very little being done at least in psychiatry across many other clinical conditions that we just don't know. And we don't really even know if the placebo how does the placebo effect look when you have both pain and depression, for example?

And so those are still very open questions that kind of reflect our state, right, that we're making progress but there's a lot to do.

TED KAPTCHUK: Winfried, did you want to say something? You have your hand up.

WINFRIED RIEF: I wanted to come back to the question of whether we really understand this increase of placebo effects. I don't know whether you have (indiscernible) for that. But I'm more like a scientist I can't believe that people are nowadays more reacting to placebos than they did 20 years ago. So there might be other explanations for this effect, like we changed the trial designs. We have more control visits maybe nowadays compared to 30 years ago, but there could be also other factors like publication bias which was maybe more frequent, more often 30 years ago than it is nowadays with the need for greater registration. So there are a lot of methodological issues that could explain this increase of placebo effects or of responses in the placebo groups. I would be interested whether you think that this increase is well explained or what your explanations are for this increase.

TED KAPTCHUK: Winfried, I want to give my opinion. I did think about this issue. I remember the first time it was reported in scientists in Cleveland, 40, 50 patients, and I said, oh, my God, okay, and the newspapers had it all over: The placebo effect is increasing. There's this boogie man around, and everyone started believing it. I've been consistently finding as many papers saying there's no -- I've been collecting them. There's no change over time there are changes over time. When I read the original article, I said, of course there's differences. The patients that got recruited in 1980 were different than the patients in 1990 or 2010. They were either more chronic, less chronic.

They were recruited in different ways, and that's really an easy explanation of why things change. Natural history changes. People's health problems are different, and I actually think that the Stone's meta analysis with 70,033 patients says it very clearly. It's a flat line from 1979. And the more data you have, the more you have to believe it. That's all. That's my personal opinion. And I think we actually are very deeply influenced by the media. I mean, I can't believe this:

The mystery of the placebo. We know more about placebo effects at least compared to many drugs on the market. Thanks my opinion. Thanks, Winfried, for letting me say it.

MATTHEW RUDORFER: Thanks, Ted.

We have a question for Greg. The question is, I wonder what the magic of 90 seconds is? Is there a physiologic basis to the turning point when the mouse changes behavior?

GREGORY CORDER: I think I addressed it in a written post somewhere. We don't know. We see a lot of variability in those animals. So like in this putative placebo phase, some mice will remain on that condition side for 40 seconds, 45 seconds, 60 seconds. Or they'll stay there the entire three minutes of the test. We're not exactly sure what's driving the difference in those different animals. These are both male and females. We see the effect in both male and female C57 black six mice, a genetically inbred animal. We always try to restrict the time of day of testing. We do reverse light testing. This is the animal wake cycle.

And there are things like dominance hierarchies within the cages, alpha versus betas. They may have different levels of pain thresholds. But the breaking of whatever the anti nocioceptive effect is they're standing on a hot plate for quite a long time. At some point those nociceptors in the periphery are going to become sensitized and signal. And to some point it's to the animal's advantage to pay attention to pain. You don't want to necessarily go around not paying attention to something that's potentially very dangerous or harmful to you. We would have to scale up the number of animals substantially I think, to really start parse out what the difference is that would account for that. But that's an excellent point, though.

MATTHEW RUDORFER: Carolyn.

CAROLYN RODRIGUEZ: I want to thank all today's speakers and wonderful presentations today. I just wanted to just go back for a second to Dr. Pecina's point about thinking about a placebo effect is not a monolith and also thinking about individual disorders.

And so I'm a clinical trialist and do research in obsessive compulsive disorder, and a lot of the things that are written in the literature meta analysis is that OCD has one of the lowest placebo rates. And so, you know, from what we gathered today, I guess to turn the question on its head is, is why is that, is that the case, why is that the case, and does that say something about OCD pathology, and what about it? Right? How can we really get more refined in terms of different domains and really thinking about the placebo effect.

So just want to say thank you again and to really having a lot of food for thought.

MATTHEW RUDORFER: Thanks. As we're winding down, one of the looming questions on the table remains what are research gaps and where do you think the next set of studies should go. And I think if anyone wants to put some ideas on the table, they'd be welcome.

MICHAEL DETKE: One of the areas that I mentioned in my talk that is hard for industry to study, or there's a big incentive, which is I talked about having third party reviewers review source documents and videos or audios of the HAM D, MADRS, whatever, and that there's not much controlled evidence.

And, you know, it's a fairly simple design, you know, within our largest controlled trial, do this with half the sites and don't do it with the other half.

Blinding isn't perfect. I haven't thought about this, and it can probably be improved upon a lot, but imagine you're the sponsor who's paying the $20 million in three years to run this clinical trial. You want to test your drug as fast as you possibly can. You don't want to really be paying for this methodology.

So that might be -- earlier on Tor or someone mentioned there might be some specific areas where this might be something for NIH to consider picking up. Because that methodology is being used in hundreds of trials, I think, today, the third party remote reviewer. So there's an area to think about.

MATTHEW RUDORFER: Thanks. Holly.

SARAH “HOLLY” LISANBY: Yeah. Carolyn just mentioned one of the gap areas, really trying to understand why some disorders are more amenable to the placebo response than others and what can that teach us. That sounds like a research gap area to me.

Also, throughout these two days we've heard a number of research gap areas having to do with methodology, how to do placebos or shams, how to assess outcome, how to protect the blind, how do you select what your outcome measures should be.

And then also today my mind was going very much towards what can preclinical models teach us and the genetics, the biology of a placebo response, the biogender line, individual differences in placebo response.

There may be clues there. Carolyn, to your point to placebo response being lower in OCD, and yet there are some OCD patients who respond, what's different about them that makes them responders?

And so studies that just look at within a placebo response versus nonresponse or gradation response or durability response and the mechanisms behind that.

These are questions that I think may ultimately facilitate getting drugs and devices to market, but certainly are questions that might be helpful to answer at the research stage, particularly at the translational research stage, in order to inform the design of pivotal trials that you would ultimately do to get things to market.

So it seems like there are many stages before getting to the ideal pivotal trial. So I really appreciate everyone's input. Let me stop talking because I really want to hear what Dr. Hall has to say.

KATHRYN HALL: I wanted to just come back for one of my favorite gaps to this question increasing the placebo effect. I think it's an important one because so many trials are failing these days. And I think it's not all trials are the same.

And what's really fascinating to me is that you see in Phase II clinical trials really great results, and then what's the first thing you do as a pharma company when you got a good result? You get to put out a press release.

And what's the first thing you're going to go do when you enroll in a clinical trial? You're going to read a press release. You're going to read as much as you can about the drug or the trial you're enrolling in. And how placebo boosting is it going to be to see that this trial had amazing effects on this condition you're struggling with.

If lo and behold we go to Phase III, and you can -- we're actually writing a paper on this, how many times we see the words "unexpected results," and I think we saw them here today, today or yesterday. Like, this should not be unexpected. When your Phase III trial fails, you should not be surprised because this is what's happening time and time again.

And I think some of the -- yeah, I agree, Ted, it's like this is a modern time, but there's so much information out there, so much information to sway us towards placebo responses that I think that's a piece of the problem. And finding out what the problem is I think is a really critical gap.

MATTHEW RUDORFER: Winfried.

WINFRIED RIEF: Yeah. May I follow up in that I think it fits quite nicely to what has been said before, and I want to direct I want to answer directly to Michael Detke.

On first glance, it seems less expensive to do the trials the way we do it with one placebo group and one drug arm, and we try to keep the context constant. But this is the problem. We have a constant context without any variation, so we don't learn under which context conditions is this drug really effective and what are the context conditions the drug might not be effective at all.

And therefore I think the current strategy is more like a lottery. It's really by chance it can happen that you are in this little window where the drug can show the most positive effectivity, but it can also be that you are in this little window or the big window where the drug is not able to show its effectivity.

And therefore I think, on second glance, it's a very expensive strategy only to use one single context to evaluate a drug.

MATTHEW RUDORFER: If I have time for--

TED KAPTCHUK: Marta speak, and then Liane should speak.

MARTA PECINA: I just wanted to add kind of a minor comment here, which is this idea that we're going to have to move on from the idea that giving someone a placebo is enough to induce positive expectancies and the fact that expectancies evolve over time.

So at least in some of the data that we've shown, and it's a small sample, but still we see that 50% of those subjects who are given a placebo don't have drug assignment beliefs. And so that is a very large amount of variability there that we are getting confused with everything else.

And so I do think that it is really important, whether in clinical trials, in research, to really come up with very and really develop new ways of measuring expectancies and allow expectancies to be measured over time. Because they do change. We have some prior expectancies, and then we have some expectancies that are learned based on experience. And I do think that this is an area of improvement that the field could improve relatively easily, you know, assess expectancies better, measure expectancies better.

TED KAPTCHUK: Liane, why don't you say something, and Luana, and then Cristina.

LIANE SCHMIDT: So I wanted to -- maybe one -- another open gap is like about the cognition, like what studying placebo, how can it help us to better understand human reasoning, like, and vice versa, actually, all the biases we have, these cognitive processes like motivation, for example, or memory, and yet all the good news about optimism biases, how do they contribute to placebo effects on the patient side but also on the clinician side when the clinicians have to make diagnosis or judge, actually, treatment efficiency based on some clinical scale.

So basically using like tools from cognition, like psychology or cognitive neuroscience, to better understand the processes, the cognitive processes that intervene when we have an expectation and behavior reach out, a symptom or neural activation, what comes in between, like how is it translated, basically, from cognitive predictability.

LUANA COLLOCA: I think we tended to consider expectation as static measurement when in reality we know that what we expect at the beginning of this workshop is slightly different by the end of what we are hearing and, you know, learning.

So expectation is a dynamic phenomenon, and the assumption that we can predict placebo effects with our measurement of expectation can be very limiting in terms of, you know, applications. Rather, it is important to measure expectation over time and also realize that there are so many nuance, like Liane just mentioned, of expectations, you know.

There are people who say I don't expect anything, I try everything, or people who say, oh, I truly want, I will be I truly want to feel better. And these also problematic patients because having an unrealistic expectation can often destroy, as I show, with a violation of expectancies of placebo effects.

TED KAPTCHUK: Are we getting close? Do you want to summarize? Or who's supposed to do that? I don't know.

CRISTINA CUSIN: I think I have a couple of minutes for remarks. There's so much going on, and more questions than answers, of course.

That has been a fantastic symposium, and I was trying to pitch some idea about possibly organizing a summit with all the panelists, all the presenters, and everyone else who wants to join us, because I think that with a coffee or a tea in our hands and talking not through a Zoom video, we could actually come up with some great idea and some collaboration projects.

Anyone who wants to email us, we'll be happy to answer. And we're always open to collaborating and starting a new study, bouncing off each other new ideas. This is what we do for a living. So we're very enthusiastic about people asking difficult questions.

And some of the questions that are ongoing and I think would be future areas is what we were talking a few minutes ago, we don't know if a placebo responder in a migraine study, for example, would be a placebo responder of depression study or IBS study. We don't know if this person is going to be universal placebo responder or is the context include the type of disease they're suffering from so it's going to be fairly different, and why some disorders have lower placebo response rate overall compared to others. Is that a chronicity, a relaxing, remitting disorder, has higher chance of placebo because the system can be modulated, versus a disorder that is considered more chronic and stable? A lot of this information is not known in the natural history.

Also comes to mind the exact trial it is because we almost never have a threshold for number of prior episodes of depression to enter a trial or how chronic has it been or years of depression or other factors that can clearly change our probability of responding to a treatment.

We heard about methodology for clinical trial design and how patients could be responsive to placebo responses or sham, responsive to drug. How about patients who could respond to both? We have no idea how many of those patients are undergoing a trial, universal responders, unless we do a crossover. And we know that crossover is not a popular design for drug trials.

So we need to figure out also aspects of methodology, how to assess outcome, what's the best way to assess the outcome that we want, is it clinically relevant, how to protect the blind aspect, assess expectations and how expectations change over time.

We didn't hear much during the discussion about the role of mindfulness in pain management, and I would like to hear much more about how we're doing in identifying the areas and can we actually intervene on those areas with devices to help with pain management. That's one of the biggest problems we have in terms of clinical care.

In the eating disorder aspect, creating computational models to influence food choices. And, again, with devices or treatments specifically changing the balance about making healthier food choices, I can see an entire field developing. Because most of the medications we prescribe for psychiatric disorders affect food choices and there's weight gain, potentially leading to obesity and cardiovascular complications. So there's an entire field of research we have not touched on.

And the role of animal models in translational results, I don't know if animal researchers, like Greg, talk much with clinical trialists. I think that would be a cross fertilization that is much needed, and we can definitely learn from each other.

And just fantastic. I thank all the panelists for their willingness to work with us and their time, dedication, and just so many meetings to discuss to agree on the program and to divide and conquer different topics. Has been a phenomenal experience, and I'm very, very grateful.

And the NIMH staff has been also amazing, having to collaborate with all of them, and they were so organized. And just a fantastic panel. Thank you, everybody.

MATTHEW RUDORFER: Thank you.

TOR WAGER: Thank you.

NIMH TEAM: Thanks from the NIMH team to all of our participants here.

(Meeting adjourned)

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Conducting and Writing Quantitative and Qualitative Research

Edward barroga.

1 Department of Medical Education, Showa University School of Medicine, Tokyo, Japan.

Glafera Janet Matanguihan

2 Department of Biological Sciences, Messiah University, Mechanicsburg, PA, USA.

Atsuko Furuta

Makiko arima, shizuma tsuchiya, chikako kawahara, yusuke takamiya.

Comprehensive knowledge of quantitative and qualitative research systematizes scholarly research and enhances the quality of research output. Scientific researchers must be familiar with them and skilled to conduct their investigation within the frames of their chosen research type. When conducting quantitative research, scientific researchers should describe an existing theory, generate a hypothesis from the theory, test their hypothesis in novel research, and re-evaluate the theory. Thereafter, they should take a deductive approach in writing the testing of the established theory based on experiments. When conducting qualitative research, scientific researchers raise a question, answer the question by performing a novel study, and propose a new theory to clarify and interpret the obtained results. After which, they should take an inductive approach to writing the formulation of concepts based on collected data. When scientific researchers combine the whole spectrum of inductive and deductive research approaches using both quantitative and qualitative research methodologies, they apply mixed-method research. Familiarity and proficiency with these research aspects facilitate the construction of novel hypotheses, development of theories, or refinement of concepts.

Graphical Abstract

INTRODUCTION

Novel research studies are conceptualized by scientific researchers first by asking excellent research questions and developing hypotheses, then answering these questions by testing their hypotheses in ethical research. 1 , 2 , 3 Before they conduct novel research studies, scientific researchers must possess considerable knowledge of both quantitative and qualitative research. 2

In quantitative research, researchers describe existing theories, generate and test a hypothesis in novel research, and re-evaluate existing theories deductively based on their experimental results. 1 , 4 , 5 In qualitative research, scientific researchers raise and answer research questions by performing a novel study, then propose new theories by clarifying their results inductively. 1 , 6

RATIONALE OF THIS ARTICLE

When researchers have a limited knowledge of both research types and how to conduct them, this can result in substandard investigation. Researchers must be familiar with both types of research and skilled to conduct their investigations within the frames of their chosen type of research. Thus, meticulous care is needed when planning quantitative and qualitative research studies to avoid unethical research and poor outcomes.

Understanding the methodological and writing assumptions 7 , 8 underpinning quantitative and qualitative research, especially by non-Anglophone researchers, is essential for their successful conduct. Scientific researchers, especially in the academe, face pressure to publish in international journals 9 where English is the language of scientific communication. 10 , 11 In particular, non-Anglophone researchers face challenges related to linguistic, stylistic, and discourse differences. 11 , 12 Knowing the assumptions of the different types of research will help clarify research questions and methodologies, easing the challenge and help.

SEARCH FOR RELEVANT ARTICLES

To identify articles relevant to this topic, we adhered to the search strategy recommended by Gasparyan et al. 7 We searched through PubMed, Scopus, Directory of Open Access Journals, and Google Scholar databases using the following keywords: quantitative research, qualitative research, mixed-method research, deductive reasoning, inductive reasoning, study design, descriptive research, correlational research, experimental research, causal-comparative research, quasi-experimental research, historical research, ethnographic research, meta-analysis, narrative research, grounded theory, phenomenology, case study, and field research.

AIMS OF THIS ARTICLE

This article aims to provide a comparative appraisal of qualitative and quantitative research for scientific researchers. At present, there is still a need to define the scope of qualitative research, especially its essential elements. 13 Consensus on the critical appraisal tools to assess the methodological quality of qualitative research remains lacking. 14 Framing and testing research questions can be challenging in qualitative research. 2 In the healthcare system, it is essential that research questions address increasingly complex situations. Therefore, research has to be driven by the kinds of questions asked and the corresponding methodologies to answer these questions. 15 The mixed-method approach also needs to be clarified as this would appear to arise from different philosophical underpinnings. 16

This article also aims to discuss how particular types of research should be conducted and how they should be written in adherence to international standards. In the US, Europe, and other countries, responsible research and innovation was conceptualized and promoted with six key action points: engagement, gender equality, science education, open access, ethics and governance. 17 , 18 International ethics standards in research 19 as well as academic integrity during doctoral trainings are now integral to the research process. 20

POTENTIAL BENEFITS FROM THIS ARTICLE

This article would be beneficial for researchers in further enhancing their understanding of the theoretical, methodological, and writing aspects of qualitative and quantitative research, and their combination.

Moreover, this article reviews the basic features of both research types and overviews the rationale for their conduct. It imparts information on the most common forms of quantitative and qualitative research, and how they are carried out. These aspects would be helpful for selecting the optimal methodology to use for research based on the researcher’s objectives and topic.

This article also provides information on the strengths and weaknesses of quantitative and qualitative research. Such information would help researchers appreciate the roles and applications of both research types and how to gain from each or their combination. As different research questions require different types of research and analyses, this article is anticipated to assist researchers better recognize the questions answered by quantitative and qualitative research.

Finally, this article would help researchers to have a balanced perspective of qualitative and quantitative research without considering one as superior to the other.

TYPES OF RESEARCH

Research can be classified into two general types, quantitative and qualitative. 21 Both types of research entail writing a research question and developing a hypothesis. 22 Quantitative research involves a deductive approach to prove or disprove the hypothesis that was developed, whereas qualitative research involves an inductive approach to create a hypothesis. 23 , 24 , 25 , 26

In quantitative research, the hypothesis is stated before testing. In qualitative research, the hypothesis is developed through inductive reasoning based on the data collected. 27 , 28 For types of data and their analysis, qualitative research usually includes data in the form of words instead of numbers more commonly used in quantitative research. 29

Quantitative research usually includes descriptive, correlational, causal-comparative / quasi-experimental, and experimental research. 21 On the other hand, qualitative research usually encompasses historical, ethnographic, meta-analysis, narrative, grounded theory, phenomenology, case study, and field research. 23 , 25 , 28 , 30 A summary of the features, writing approach, and examples of published articles for each type of qualitative and quantitative research is shown in Table 1 . 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43

QUANTITATIVE RESEARCH

Deductive approach.

The deductive approach is used to prove or disprove the hypothesis in quantitative research. 21 , 25 Using this approach, researchers 1) make observations about an unclear or new phenomenon, 2) investigate the current theory surrounding the phenomenon, and 3) hypothesize an explanation for the observations. Afterwards, researchers will 4) predict outcomes based on the hypotheses, 5) formulate a plan to test the prediction, and 6) collect and process the data (or revise the hypothesis if the original hypothesis was false). Finally, researchers will then 7) verify the results, 8) make the final conclusions, and 9) present and disseminate their findings ( Fig. 1A ).

Types of quantitative research

The common types of quantitative research include (a) descriptive, (b) correlational, c) experimental research, and (d) causal-comparative/quasi-experimental. 21

Descriptive research is conducted and written by describing the status of an identified variable to provide systematic information about a phenomenon. A hypothesis is developed and tested after data collection, analysis, and synthesis. This type of research attempts to factually present comparisons and interpretations of findings based on analyses of the characteristics, progression, or relationships of a certain phenomenon by manipulating the employed variables or controlling the involved conditions. 44 Here, the researcher examines, observes, and describes a situation, sample, or variable as it occurs without investigator interference. 31 , 45 To be meaningful, the systematic collection of information requires careful selection of study units by precise measurement of individual variables 21 often expressed as ranges, means, frequencies, and/or percentages. 31 , 45 Descriptive statistical analysis using ANOVA, Student’s t -test, or the Pearson coefficient method has been used to analyze descriptive research data. 46

Correlational research is performed by determining and interpreting the extent of a relationship between two or more variables using statistical data. This involves recognizing data trends and patterns without necessarily proving their causes. The researcher studies only the data, relationships, and distributions of variables in a natural setting, but does not manipulate them. 21 , 45 Afterwards, the researcher establishes reliability and validity, provides converging evidence, describes relationship, and makes predictions. 47

Experimental research is usually referred to as true experimentation. The researcher establishes the cause-effect relationship among a group of variables making up a study using the scientific method or process. This type of research attempts to identify the causal relationships between variables through experiments by arbitrarily controlling the conditions or manipulating the variables used. 44 The scientific manuscript would include an explanation of how the independent variable was manipulated to determine its effects on the dependent variables. The write-up would also describe the random assignments of subjects to experimental treatments. 21

Causal-comparative/quasi-experimental research closely resembles true experimentation but is conducted by establishing the cause-effect relationships among variables. It may also be conducted to establish the cause or consequences of differences that already exist between, or among groups of individuals. 48 This type of research compares outcomes between the intervention groups in which participants are not randomized to their respective interventions because of ethics- or feasibility-related reasons. 49 As in true experiments, the researcher identifies and measures the effects of the independent variable on the dependent variable. However, unlike true experiments, the researchers do not manipulate the independent variable.

In quasi-experimental research, naturally formed or pre-existing groups that are not randomly assigned are used, particularly when an ethical, randomized controlled trial is not feasible or logical. 50 The researcher identifies control groups as those which have been exposed to the treatment variable, and then compares these with the unexposed groups. The causes are determined and described after data analysis, after which conclusions are made. The known and unknown variables that could still affect the outcome are also included. 7

QUALITATIVE RESEARCH

Inductive approach.

Qualitative research involves an inductive approach to develop a hypothesis. 21 , 25 Using this approach, researchers answer research questions and develop new theories, but they do not test hypotheses or previous theories. The researcher seldom examines the effectiveness of an intervention, but rather explores the perceptions, actions, and feelings of participants using interviews, content analysis, observations, or focus groups. 25 , 45 , 51

Distinctive features of qualitative research

Qualitative research seeks to elucidate about the lives of people, including their lived experiences, behaviors, attitudes, beliefs, personality characteristics, emotions, and feelings. 27 , 30 It also explores societal, organizational, and cultural issues. 30 This type of research provides a good story mimicking an adventure which results in a “thick” description that puts readers in the research setting. 52

The qualitative research questions are open-ended, evolving, and non-directional. 26 The research design is usually flexible and iterative, commonly employing purposive sampling. The sample size depends on theoretical saturation, and data is collected using in-depth interviews, focus groups, and observations. 27

In various instances, excellent qualitative research may offer insights that quantitative research cannot. Moreover, qualitative research approaches can describe the ‘lived experience’ perspectives of patients, practitioners, and the public. 53 Interestingly, recent developments have looked into the use of technology in shaping qualitative research protocol development, data collection, and analysis phases. 54

Qualitative research employs various techniques, including conversational and discourse analysis, biographies, interviews, case-studies, oral history, surveys, documentary and archival research, audiovisual analysis, and participant observations. 26

Conducting qualitative research

To conduct qualitative research, investigators 1) identify a general research question, 2) choose the main methods, sites, and subjects, and 3) determine methods of data documentation access to subjects. Researchers also 4) decide on the various aspects for collecting data (e.g., questions, behaviors to observe, issues to look for in documents, how much (number of questions, interviews, or observations), 5) clarify researchers’ roles, and 6) evaluate the study’s ethical implications in terms of confidentiality and sensitivity. Afterwards, researchers 7) collect data until saturation, 8) interpret data by identifying concepts and theories, and 9) revise the research question if necessary and form hypotheses. In the final stages of the research, investigators 10) collect and verify data to address revisions, 11) complete the conceptual and theoretical framework to finalize their findings, and 12) present and disseminate findings ( Fig. 1B ).

Types of qualitative research

The different types of qualitative research include (a) historical research, (b) ethnographic research, (c) meta-analysis, (d) narrative research, (e) grounded theory, (f) phenomenology, (g) case study, and (h) field research. 23 , 25 , 28 , 30

Historical research is conducted by describing past events, problems, issues, and facts. The researcher gathers data from written or oral descriptions of past events and attempts to recreate the past without interpreting the events and their influence on the present. 6 Data is collected using documents, interviews, and surveys. 55 The researcher analyzes these data by describing the development of events and writes the research based on historical reports. 2

Ethnographic research is performed by observing everyday life details as they naturally unfold. 2 It can also be conducted by developing in-depth analytical descriptions of current systems, processes, and phenomena or by understanding the shared beliefs and practices of a particular group or culture. 21 The researcher collects extensive narrative non-numerical data based on many variables over an extended period, in a natural setting within a specific context. To do this, the researcher uses interviews, observations, and active participation. These data are analyzed by describing and interpreting them and developing themes. A detailed report of the interpreted data is then provided. 2 The researcher immerses himself/herself into the study population and describes the actions, behaviors, and events from the perspective of someone involved in the population. 23 As examples of its application, ethnographic research has helped to understand a cultural model of family and community nursing during the coronavirus disease 2019 outbreak. 56 It has also been used to observe the organization of people’s environment in relation to cardiovascular disease management in order to clarify people’s real expectations during follow-up consultations, possibly contributing to the development of innovative solutions in care practices. 57

Meta-analysis is carried out by accumulating experimental and correlational results across independent studies using a statistical method. 21 The report is written by specifying the topic and meta-analysis type. In the write-up, reporting guidelines are followed, which include description of inclusion criteria and key variables, explanation of the systematic search of databases, and details of data extraction. Meta-analysis offers in-depth data gathering and analysis to achieve deeper inner reflection and phenomenon examination. 58

Narrative research is performed by collecting stories for constructing a narrative about an individual’s experiences and the meanings attributed to them by the individual. 9 It aims to hear the voice of individuals through their account or experiences. 17 The researcher usually conducts interviews and analyzes data by storytelling, content review, and theme development. The report is written as an in-depth narration of events or situations focused on the participants. 2 , 59 Narrative research weaves together sequential events from one or two individuals to create a “thick” description of a cohesive story or narrative. 23 It facilitates understanding of individuals’ lives based on their own actions and interpretations. 60

Grounded theory is conducted by engaging in an inductive ground-up or bottom-up strategy of generating a theory from data. 24 The researcher incorporates deductive reasoning when using constant comparisons. Patterns are detected in observations and then a working hypothesis is created which directs the progression of inquiry. The researcher collects data using interviews and questionnaires. These data are analyzed by coding the data, categorizing themes, and describing implications. The research is written as a theory and theoretical models. 2 In the write-up, the researcher describes the data analysis procedure (i.e., theoretical coding used) for developing hypotheses based on what the participants say. 61 As an example, a qualitative approach has been used to understand the process of skill development of a nurse preceptor in clinical teaching. 62 A researcher can also develop a theory using the grounded theory approach to explain the phenomena of interest by observing a population. 23

Phenomenology is carried out by attempting to understand the subjects’ perspectives. This approach is pertinent in social work research where empathy and perspective are keys to success. 21 Phenomenology studies an individual’s lived experience in the world. 63 The researcher collects data by interviews, observations, and surveys. 16 These data are analyzed by describing experiences, examining meanings, and developing themes. The researcher writes the report by contextualizing and reporting the subjects’ experience. This research approach describes and explains an event or phenomenon from the perspective of those who have experienced it. 23 Phenomenology understands the participants’ experiences as conditioned by their worldviews. 52 It is suitable for a deeper understanding of non-measurable aspects related to the meanings and senses attributed by individuals’ lived experiences. 60

Case study is conducted by collecting data through interviews, observations, document content examination, and physical inspections. The researcher analyzes the data through a detailed identification of themes and the development of narratives. The report is written as an in-depth study of possible lessons learned from the case. 2

Field research is performed using a group of methodologies for undertaking qualitative inquiries. The researcher goes directly to the social phenomenon being studied and observes it extensively. In the write-up, the researcher describes the phenomenon under the natural environment over time with no implantation of controls or experimental conditions. 45

DIFFERENCES BETWEEN QUANTITATIVE AND QUALITATIVE RESEARCH

Scientific researchers must be aware of the differences between quantitative and qualitative research in terms of their working mechanisms to better understand their specific applications. This knowledge will be of significant benefit to researchers, especially during the planning process, to ensure that the appropriate type of research is undertaken to fulfill the research aims.

In terms of quantitative research data evaluation, four well-established criteria are used: internal validity, external validity, reliability, and objectivity. 23 The respective correlating concepts in qualitative research data evaluation are credibility, transferability, dependability, and confirmability. 30 Regarding write-up, quantitative research papers are usually shorter than their qualitative counterparts, which allows the latter to pursue a deeper understanding and thus producing the so-called “thick” description. 29

Interestingly, a major characteristic of qualitative research is that the research process is reversible and the research methods can be modified. This is in contrast to quantitative research in which hypothesis setting and testing take place unidirectionally. This means that in qualitative research, the research topic and question may change during literature analysis, and that the theoretical and analytical methods could be altered during data collection. 44

Quantitative research focuses on natural, quantitative, and objective phenomena, whereas qualitative research focuses on social, qualitative, and subjective phenomena. 26 Quantitative research answers the questions “what?” and “when?,” whereas qualitative research answers the questions “why?,” “how?,” and “how come?.” 64

Perhaps the most important distinction between quantitative and qualitative research lies in the nature of the data being investigated and analyzed. Quantitative research focuses on statistical, numerical, and quantitative aspects of phenomena, and employ the same data collection and analysis, whereas qualitative research focuses on the humanistic, descriptive, and qualitative aspects of phenomena. 26 , 28

Structured versus unstructured processes

The aims and types of inquiries determine the difference between quantitative and qualitative research. In quantitative research, statistical data and a structured process are usually employed by the researcher. Quantitative research usually suggests quantities (i.e., numbers). 65 On the other hand, researchers typically use opinions, reasons, verbal statements, and an unstructured process in qualitative research. 63 Qualitative research is more related to quality or kind. 65

In quantitative research, the researcher employs a structured process for collecting quantifiable data. Often, a close-ended questionnaire is used wherein the response categories for each question are designed in which values can be assigned and analyzed quantitatively using a common scale. 66 Quantitative research data is processed consecutively from data management, then data analysis, and finally to data interpretation. Data should be free from errors and missing values. In data management, variables are defined and coded. In data analysis, statistics (e.g., descriptive, inferential) as well as central tendency (i.e., mean, median, mode), spread (standard deviation), and parameter estimation (confidence intervals) measures are used. 67

In qualitative research, the researcher uses an unstructured process for collecting data. These non-statistical data may be in the form of statements, stories, or long explanations. Various responses according to respondents may not be easily quantified using a common scale. 66

Composing a qualitative research paper resembles writing a quantitative research paper. Both papers consist of a title, an abstract, an introduction, objectives, methods, findings, and discussion. However, a qualitative research paper is less regimented than a quantitative research paper. 27

Quantitative research as a deductive hypothesis-testing design

Quantitative research can be considered as a hypothesis-testing design as it involves quantification, statistics, and explanations. It flows from theory to data (i.e., deductive), focuses on objective data, and applies theories to address problems. 45 , 68 It collects numerical or statistical data; answers questions such as how many, how often, how much; uses questionnaires, structured interview schedules, or surveys 55 as data collection tools; analyzes quantitative data in terms of percentages, frequencies, statistical comparisons, graphs, and tables showing statistical values; and reports the final findings in the form of statistical information. 66 It uses variable-based models from individual cases and findings are stated in quantified sentences derived by deductive reasoning. 24

In quantitative research, a phenomenon is investigated in terms of the relationship between an independent variable and a dependent variable which are numerically measurable. The research objective is to statistically test whether the hypothesized relationship is true. 68 Here, the researcher studies what others have performed, examines current theories of the phenomenon being investigated, and then tests hypotheses that emerge from those theories. 4

Quantitative hypothesis-testing research has certain limitations. These limitations include (a) problems with selection of meaningful independent and dependent variables, (b) the inability to reflect subjective experiences as variables since variables are usually defined numerically, and (c) the need to state a hypothesis before the investigation starts. 61

Qualitative research as an inductive hypothesis-generating design

Qualitative research can be considered as a hypothesis-generating design since it involves understanding and descriptions in terms of context. It flows from data to theory (i.e., inductive), focuses on observation, and examines what happens in specific situations with the aim of developing new theories based on the situation. 45 , 68 This type of research (a) collects qualitative data (e.g., ideas, statements, reasons, characteristics, qualities), (b) answers questions such as what, why, and how, (c) uses interviews, observations, or focused-group discussions as data collection tools, (d) analyzes data by discovering patterns of changes, causal relationships, or themes in the data; and (e) reports the final findings as descriptive information. 61 Qualitative research favors case-based models from individual characteristics, and findings are stated using context-dependent existential sentences that are justifiable by inductive reasoning. 24

In qualitative research, texts and interviews are analyzed and interpreted to discover meaningful patterns characteristic of a particular phenomenon. 61 Here, the researcher starts with a set of observations and then moves from particular experiences to a more general set of propositions about those experiences. 4

Qualitative hypothesis-generating research involves collecting interview data from study participants regarding a phenomenon of interest, and then using what they say to develop hypotheses. It involves the process of questioning more than obtaining measurements; it generates hypotheses using theoretical coding. 61 When using large interview teams, the key to promoting high-level qualitative research and cohesion in large team methods and successful research outcomes is the balance between autonomy and collaboration. 69

Qualitative data may also include observed behavior, participant observation, media accounts, and cultural artifacts. 61 Focus group interviews are usually conducted, audiotaped or videotaped, and transcribed. Afterwards, the transcript is analyzed by several researchers.

Qualitative research also involves scientific narratives and the analysis and interpretation of textual or numerical data (or both), mostly from conversations and discussions. Such approach uncovers meaningful patterns that describe a particular phenomenon. 2 Thus, qualitative research requires skills in grasping and contextualizing data, as well as communicating data analysis and results in a scientific manner. The reflective process of the inquiry underscores the strengths of a qualitative research approach. 2

Combination of quantitative and qualitative research

When both quantitative and qualitative research methods are used in the same research, mixed-method research is applied. 25 This combination provides a complete view of the research problem and achieves triangulation to corroborate findings, complementarity to clarify results, expansion to extend the study’s breadth, and explanation to elucidate unexpected results. 29

Moreover, quantitative and qualitative findings are integrated to address the weakness of both research methods 29 , 66 and to have a more comprehensive understanding of the phenomenon spectrum. 66

For data analysis in mixed-method research, real non-quantitized qualitative data and quantitative data must both be analyzed. 70 The data obtained from quantitative analysis can be further expanded and deepened by qualitative analysis. 23

In terms of assessment criteria, Hammersley 71 opined that qualitative and quantitative findings should be judged using the same standards of validity and value-relevance. Both approaches can be mutually supportive. 52

Quantitative and qualitative research must be carefully studied and conducted by scientific researchers to avoid unethical research and inadequate outcomes. Quantitative research involves a deductive process wherein a research question is answered with a hypothesis that describes the relationship between independent and dependent variables, and the testing of the hypothesis. This investigation can be aptly termed as hypothesis-testing research involving the analysis of hypothesis-driven experimental studies resulting in a test of significance. Qualitative research involves an inductive process wherein a research question is explored to generate a hypothesis, which then leads to the development of a theory. This investigation can be aptly termed as hypothesis-generating research. When the whole spectrum of inductive and deductive research approaches is combined using both quantitative and qualitative research methodologies, mixed-method research is applied, and this can facilitate the construction of novel hypotheses, development of theories, or refinement of concepts.

Disclosure: The authors have no potential conflicts of interest to disclose.

Author Contributions:

• Conceptualization: Barroga E, Matanguihan GJ.
• Data curation: Barroga E, Matanguihan GJ, Furuta A, Arima M, Tsuchiya S, Kawahara C, Takamiya Y, Izumi M.
• Formal analysis: Barroga E, Matanguihan GJ, Furuta A, Arima M, Tsuchiya S, Kawahara C.
• Investigation: Barroga E, Matanguihan GJ, Takamiya Y, Izumi M.
• Methodology: Barroga E, Matanguihan GJ, Furuta A, Arima M, Tsuchiya S, Kawahara C, Takamiya Y, Izumi M.
• Project administration: Barroga E, Matanguihan GJ.
• Resources: Barroga E, Matanguihan GJ, Furuta A, Arima M, Tsuchiya S, Kawahara C, Takamiya Y, Izumi M.
• Supervision: Barroga E.
• Validation: Barroga E, Matanguihan GJ, Furuta A, Arima M, Tsuchiya S, Kawahara C, Takamiya Y, Izumi M.
• Visualization: Barroga E, Matanguihan GJ.
• Writing - original draft: Barroga E, Matanguihan GJ.
• Writing - review & editing: Barroga E, Matanguihan GJ, Furuta A, Arima M, Tsuchiya S, Kawahara C, Takamiya Y, Izumi M.

• Open access
• Published: 28 August 2024

How does online postal self-sampling (OPSS) shape access to testing for sexually transmitted infections (STIs)? A qualitative study of service users

• Tommer Spence 1 ,
• Alison Howarth 2 ,
• David Reid 2 ,
• Jessica Sheringham 1 ,
• Vanessa Apea 3 ,
• David Crundwell 4 ,
• Sara Day 5 ,
• Claire Dewsnap 6 ,
• Louise Jackson 7 ,
• Catherine H. Mercer 2 ,
• Hamish Mohammed 8 ,
• Jonathan D. C. Ross 9 ,
• Ann Sullivan 5 ,
• Andy Williams 3 ,
• Andrew Winter 10 ,
• Geoff Wong 11 ,
• Fiona Burns 2   na1 &
• Jo Gibbs 2   na1  

BMC Public Health volume  24 , Article number:  2339 ( 2024 ) Cite this article

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Sexually transmitted infections (STIs) are a serious public health issue in many countries. Online postal self-sampling (OPSS) is increasingly used to test for STIs, a trend accelerated by the COVID-19 pandemic. There remains limited understanding of how service users experience OPSS and what leads them to access it over clinic-based services, or vice versa. This research seeks to address these gaps, by undertaking a large qualitative study which sits within the ASSIST study, a mixed-methods, realist evaluation of OPSS.

Participants were recruited via clinic-based and online sexual health services in three case study areas in England. Purposive sampling was used to over-represent populations disproportionately affected by poor sexual health: young people; people of colour; men who have sex with men; and trans and non-binary people. Semi-structured interviews were analysed using Levesque’s conceptual framework of access to healthcare.

We interviewed 100 service users. Participants typically became aware of OPSS from sexual health services, the internet or word of mouth. Acceptability of OPSS was facilitated by the perceived privacy it offered over clinic-based services, which some participants found embarrassing to access. OPSS also enabled participants to overcome barriers to reaching clinic-based services, such as a lack of appointment availability, although difficulty obtaining OPSS kits in some areas undermined this. As all services in our case study areas were free to use, affordability did not significantly shape access, although OPSS enabled some participants to avoid costs associated with travelling to clinic-based services. Participants were usually able to engage with OPSS, finding it easy to use and reliable, although blood self-sampling was challenging for most. Participants valued the support offered by clinic-based services beyond STI testing, including the opportunity to access contraception or ask staff questions, and felt this was more appropriate when they had specific concerns about their sexual health, such as STI symptoms.

Conclusions

Our findings constitute one of the largest qualitative studies to have explored OPSS and offer valuable insights to providers. OPSS shapes access to STI testing in a number of ways, including facilitating access in many circumstances, but users also want to retain access to clinic-based services, particularly for when they believe they need support beyond STI testing.

Peer Review reports

Sexually transmitted infections (STIs) are a serious public health issue in many countries [ 1 ]. In England, diagnoses of chlamydia – the most common STI – are now stable, but syphilis and gonorrhoea diagnoses reached record levels in 2023 [ 2 ]. STIs in England are distributed inequitably across the population, with men who have sex with men (MSM), black ethnic minorities and young people aged 15–24 being disproportionately affected [ 2 ].

STI testing is crucial to enabling treatment and limiting onward infection [ 3 ]. Over the past decade, online postal self-sampling (OPSS) has emerged as an alternative to testing in sexual health clinics and other clinic-based settings. OPSS allows users to order a kit online, collect their own samples, post them to a laboratory for testing and receive results remotely [ 4 ]. Accelerated by the COVID-19 pandemic, when access to clinic-based services was restricted, usage of OPSS for chlamydia testing by young women aged 15–24 in England increased from 16% in 2018 to 43% in 2023 [ 2 , 5 ]. This transition has occurred in the context of a wider effort to digitise healthcare, which has included a national recommendation that sexual health services in England provide OPSS [ 6 ]. OPSS services have also been introduced, and demonstrated strong uptake, in other high-income countries [ 7 , 8 , 9 ].

Despite this increase in usage, there remains limited understanding of what leads service users to access OPSS over clinic-based services, or vice versa. Uptake of OPSS has been found to be significantly higher among some population groups – such as heterosexual women, white people, MSM and those living in less deprived areas – than others [ 4 ]. Populations with lower uptake include black ethnic minorities and teenagers, both of whom experience high incidence of STIs. If populations which have lower uptake of OPSS also face barriers to accessing clinic-based services, then this could be leading to widening of health inequalities and increasing unmet need. Poor return rates for OPSS kits are also a cause for concern, with 52% of kits ordered from some services not being returned [ 10 ]. This is socially patterned, with heterosexual men and those living in deprived areas the least likely to use kits they have received [ 11 ]. There is wider evidence of certain populations being excluded by the shift towards digital healthcare, including some people with disabilities and those with fewer socioeconomic resources [ 12 , 13 ].

Access to healthcare is viewed by Levesque et al. [ 14 ] as “the possibility to identify healthcare needs , to seek healthcare services , to reach the healthcare resources , to obtain or use health care services , and to actually be offered services appropriate to the needs for care” . As set out in Fig.  1 , they theorise that the ability of service users to progress through these stages of access is influenced by five dimensions of healthcare services: approachability; acceptability; availability; affordability; and appropriateness. Each of these dimensions corresponds with a parallel dimension of service user ability: ability to perceive; ability to seek; ability to reach; ability to pay; and ability to engage. This widely-used framework – which informed the design of our research – centres the perceptions and experiences of service users and allows facilitators and barriers to be explored, with a focus on socioeconomic determinants [ 15 ].

Conceptual framework of access to healthcare by Levesque et al. [ 14 ]

Existing research on access to STI testing within the context of OPSS is limited, with much of the literature exploring OPSS focusing exclusively on uptake [ 4 ]. Although several surveys have found high levels of acceptability of OPSS, these typically explore only the views of users who have successfully completed an OPSS pathway and are therefore affected by responder bias [ 7 , 16 , 17 , 18 , 19 ]. They are also limited in how far they explore nuances in experiences. Qualitative research, which is well positioned to explore those nuances, has found that OPSS is acceptable to many people, in large part due to its perceived convenience and anonymity, but that many also have concerns around test accuracy, a lack of support when receiving results and inferior care compared to clinic-based testing [ 20 ]. Very few studies, however, have explored the experiences of users and those that have typically have small samples, or focus on a specific population or component of the OPSS pathway [ 20 , 21 , 22 ]. It is therefore challenging to know the applicability of these findings to other contexts and to understand divergent views.

This study seeks to address this gap by qualitatively exploring experiences of OPSS, alongside other sexual health services, and how this influences service users’ decisions on how they access STI testing. Unlike previous research, it explores OPSS in three case study areas, with large samples in each, allowing comparison of perceptions and experiences in different contexts. It also explores users’ previous experiences of sexual health services in considerable depth, giving insight into their routes to different services, and their experiences of the entire OPSS pathway. This includes access to care in clinic-based services, when participants were directed to these following the completion of STI testing.

This research formed part of the ASSIST study, a mixed-methods, realist evaluation of the implementation and impact of OPSS [ 23 ]. One of the study’s objectives was to understand the impact of OPSS on access to care and the service user experience.

ASSIST evaluated OPSS in three case study areas, labelled CSA1, CSA2 and CSA3 for anonymity. Although distinct in many ways, all three areas are urban and were selected in part because of their highly diverse populations, in terms of socioeconomic status, ethnicity, age and LGBTQ + identity. Each has a unique delivery model for sexual health services, including OPSS, which was launched at different times in each area. CSA1 operates OPSS, alongside a number of clinics, as part of an integrated sexual health service, which in England describes services set up to address most sexual health needs, including contraception, HIV pre-exposure prophylaxis (PrEP) and STI testing and treatment [ 6 ]. CSA2 operates OPSS as a standalone service, outsourced to a private sector partner. It is commissioned separately from, but works in partnership with, clinic-based integrated sexual health services across the city; two of these clinic-based services were selected as sites for this research, due to their high representation of populations of interest to this study. CSA3 delivers STI testing as part of a non-integrated sexual health service, with most contraceptive services in the area delivered separately and OPSS outsourced to a private sector partner. An overview of service provision in each area is provided in Table  1 . OPSS and other STI testing is available free at the point of use to residents in all three areas.

Sampling and recruitment

We aimed to recruit 30–45 participants per case study area and used a purposive sampling strategy to ensure participant demographics over-represented populations which disproportionately experience poor sexual health. Our quotas for each case study area were: 3–5 MSM; 7–10 people from ethnic minority backgrounds; 14–20 people under the age of 25; and 3–5 trans or non-binary people. We sought to include equal numbers of men and women, irrespective of whether they identified as trans. We also purposively sampled people who had used either one or both of OPSS and clinic-based services, as well as those who had received an STI diagnosis from OPSS, in order to gain insight into this aspect of the user journey. All participants were required to be 16 years or over, to speak English and to have accessed online or clinic-based sexual health services within the past 12 months, in the three case study areas.

Participants were recruited via OPSS or in sexual health clinics between December 2021 and February 2023. OPSS users saw a link on the landing page of the service website or at the end of the OPSS kit request form, which invited them to express interest in the research. Clinic users saw recruitment posters or were approached by clinic staff. Potential participants were screened according to their age; gender; ethnicity; sexual orientation; and previous use of sexual health services. Potential participants who fulfilled quota requirements were contacted by TS or DR, who explained the study and arranged a time for interview if they were interested in participating. Participants completed an online consent form ahead of the interview and consent was confirmed again verbally at the start.

Data collection

Data were collected via semi-structured interviews which explored participants’ use of the internet and online health services, their previous experiences of sexual health services (including, but not limited to, STI testing), their perceptions or experiences of the entire OPSS pathway (including ordering a kit, receiving and using it, returning it, receiving results and accessing treatment) and their perspectives on the appropriateness of different STI testing services in various contexts. The interview topic guide is provided as Supplementary Material 1. Participants had the choice of conducting their interview by phone, MS Teams or in person. They all received a £30 shopping voucher for participating. Interviews were conducted by TS, DR and AH, all of whom are professional researchers.

Data analysis

Interviews were audio recorded and transcribed verbatim. The transcripts were reviewed for accuracy and to gain familiarity, before being pseudonymised, uploaded to NVivo software and coded using an inductive-deductive approach. This began with TS developing codes from the initial programme theory (IPT), developed by the research team as part of the wider realist evaluation, which hypothesised how service users would access and experience OPSS based on prior literature and clinician perspectives [ 23 ]. The IPT was developed from an initial logic model postulated by the research team before the study began (Supplementary Material 2), which set out to explain the introduction and impact of OPSS. It assumed that service users would perceive OPSS as: easy to find and access; convenient; easy to use and fitting in with 21st century life; providing privacy and minimising embarrassment or judgement by others; as ‘good’ a service as clinic-based services; and providing test results they could believe [ 23 ]. Additional codes were added inductively by TS from an initial sample of transcripts. Coding of the remaining transcripts was then undertaken by TS, DR and AH, who double-coded a selection of transcripts initially to check for consistency and codebook clarity. As analysis progressed, codes were continuously modified and added inductively. There were periodic meetings between TS, DR and AH to discuss new codes and their organisation into categories; meetings were also held with other members of the research team to discuss the analysis. The final code categories were organised into the dimensions of the Levesque et al. [ 14 ] conceptual framework of access, as it equipped us to understand the relationship between service users’ experiences of sexual health services and the determinants of using OPSS.

Participants

We interviewed 100 participants. All participants chose to be interviewed by phone, aside from one who interviewed in person. Full demographic information is set out in Table  2 .

Our findings are organised according to the Levesque et al. [ 14 ]. conceptual framework of access. The framework’s corresponding service and service user dimensions are presented together, giving five overarching determinants of access. For each, we have articulated a question that illustrates how we have applied the framework to OPSS.

Approachability and ability to perceive: Could service users identify clinic-based and online sexual health services and what prompted them to recognise a need to access them?

All participants were aware of clinic-based services, often viewing them as the default option for STI testing before becoming aware of OPSS. However, participants were also overwhelmingly aware of OPSS, in large part due to the efforts of services to promote it. They often discovered it while searching for STI testing services online, with OPSS often featuring prominently on search engine results, in social media adverts or on the websites of sexual health services:

“I went onto the [sexual health service] website trying to get an appointment and they told me I could order a home kit instead. So , I just went with that option […] I think that’s where the first time I saw it [was].” (Participant 17 , Black cis heterosexual woman , aged 25–34) .

Staff in services raised awareness of OPSS, for example by directing participants to use it instead of attending a clinic, particularly when access to clinics was restricted during COVID-19 lockdowns:

“I called the clinic up and thought I need to make an appointment , but the lady said oh , you can register for a self test online , and it will be out this week.” (Participant 62 , White cis lesbian woman , aged 20–24) .

Participants also reported being recommended OPSS as a test of cure, following treatment for an STI:

“I went in to get tested , it did come back positive , so they said to test again to make sure it has gone before you see other sexual partners […] which you can do through an online testing kit , so that’s what I did.” (Participant 45 , White cis gay man , aged under 20) .

Alongside proactive efforts by services to increase awareness of OPSS, many participants reported learning about it via word of mouth, often from friends or new sexual partners:

“I was talking to a best friend about it really because he’d done it before and he recommended how easier it was and stuff like that.” (Participant 53 , White cis heterosexual man , aged 20–24) .

The corresponding demand-side dimension of Levesque’s et al. [ 12 ] framework addresses service users’ ability to perceive services, which is shaped by factors such as health literacy and beliefs. Participants expressed a range of reasons that motivated them to access STI testing, many of which indicated a high level of sexual health literacy. New sexual partners were a trigger for many participants to get tested, usually because they had had a condomless sexual encounter – and were concerned about having contracted an STI – or because they wanted to transition to having regular sex without condoms. Some participants had tested due to a sexual partner notifying them that they had been diagnosed with an STI. Many also attempted to test regularly if they were sexually active, regardless of the status of their relationships:

“I’ve had multiple friends in relationships that their partner has cheated on them and they’ve had chlamydia without knowing for a really long time. So , I’m a little bit of a hypochondriac where I’m like- I want kids eventually. […] So , if I get tested every three months , if I’ve had chlamydia for three months , it’s less likely to have a long term effect.” (Participant 28 , White cis heterosexual woman , aged 20–24) .

Participants were also aware that genitourinary symptoms were a reason to access testing and many had done so for this reason, either in their most recent testing experience or in an earlier one. However, they often believed that symptoms would mean it was more appropriate to get tested in sexual health clinics:

“I think if I knew I had symptoms I would go to the clinic […] but I think if I just , if I’d just had a new partner , or just had unprotected sex or whatever , I’d probably get the self-testing kit. Particularly as you can still get the blood test for the HIV in the self-testing kit as well , so I feel like unless I was experiencing at the minute , symptoms , or there was […] another thing that was going on , I probably would get the self-test kit.” (Participant 48 , White cis heterosexual woman , aged 25–34) .

There were also participants who had less awareness of when or where to get tested, however, which was sometimes shaped by their cultural background. One participant, for example, only considered testing after her GP recommended that she do so:

“I’m not really from the UK , I live in [country] and I’ve moved here recently and STI is not really a test people do unless you have to , like it’s not very common to do STI tests so I didn’t think about it.” (Participant 33 , Asian cis heterosexual woman , aged 25–34) .

Acceptability and ability to seek: Did service users feel able to access clinic-based or online services within wider cultural and social norms?

OPSS appealed to many due to the privacy they felt it offered over clinic-based services, and there were specific elements of the OPSS pathway which participants focused on as underpinning the privacy of the service, such as the discreet packaging kits were delivered in:

“I thought it was very well packaged. So it comes in a brown box , it’s quite discreet. So I think if anyone was worried about , if they are living with friends or whatever their circumstances , as to oh someone is going to see that I am getting STD tested , it’s quite a discreet box.” (Participant 4 , Asian cis gay man , aged 25–34) .

Similarly, the opportunity to self-sample rather than have samples collected by a clinician appealed to many participants:

“I’m quite a squeamish kind of person and I don’t like to be prodded and poked as everybody doesn’t. So , for me I was like oh yes , that sounds really good because you do it in privacy , do it myself and just send it off.” (Participant 73 , Asian cis heterosexual woman , aged 25–34) .

The option in some case study areas to collect OPSS kits, rather than having them posted, enhanced the perceived privacy of the service to some participants whose living situations meant that they felt they could not have a kit posted to their home:

“My dad’s a bit nosy at times. So a box probably comes through the letterbox he’d probably most likely open it to see what it is. And then if he does do that , that will be difficult for me explaining to him what it is.” (Participant 76 , Asian cis bisexual man , aged 35–44) .

The perceived privacy of OPSS contrasted strongly with many participants’ perceptions of sexual health clinics, which they often felt required uncomfortable waits among other service users, or awkward interactions with staff. Concerns about stigma were raised by a number of participants, even some who had had positive, non-stigmatising interactions with staff in clinics:

“I have got to say , the staff that I’ve come across at the NHS for sexual health specifically , have been absolutely wonderful. But I think with STI testing there is still societally such a stigma against it that I think when you are going for testing it’s invariable to have some of these […] anxieties.” (Participant 5 , White cis heterosexual woman , aged under 20) .

These concerns were also held about other clinic-based services, such as general practitioners (GPs). Although a number of participants had accessed STI testing opportunistically via their GP – and they did not feel the same concern about being seen in a GP practice, as no one in the waiting room would know their reason for being there – some still felt uncomfortable discussing sexual health with their GP:

“There are times when I’ve been to the GP for stuff like that , you almost get the talk of like what you should be doing and what you shouldn’t be doing and that sort of thing. And whereas like they don’t do that at the sexual health clinics , which I think is , is what you’d want , like […] you are there for a reason , you don’t want to be like told off at the same time.” (Participant 48 , White cis heterosexual woman , aged 25–34) .

There were also concerns from some younger users that a GP they shared with their family may be less confidential, for example if test results were routinely sent to a parent’s mobile phone. There were participants, however, who felt a GP was the most familiar and confidential option, at least in circumstances when they felt they need to be examined by a clinician:

“I go to the doctor’s for my contraception and […] smear tests and all of those things. So for some people if the clinic is somewhere where they already go to do all those other things , they might not have so much of a problem with going to the clinic whereas I don’t. I go to my doctor’s for those things. If I had symptoms , I would go to my doctor.” (Participant 52 , White cis heterosexual woman , aged 45–54) .

The communication of results was a component of STI testing which some participants felt compromised the acceptability of the service, particularly in the case study area which used SMS for this. Although participants were typically satisfied with results delivery, some had concerns that an SMS containing test results could be seen by others – a scenario which one participant had experienced:

“I was sitting at dinner with friends and my phone was face up on the table. Everyone at the table had known that I was waiting on results so it wasn’t a big deal but had I been with others who weren’t , then they would have seen the results of my sexual health screening.” (Participant 10 , Mixed ethnicity cis man , aged 20–24) .

This concern was not expressed in relation to the two OPSS services which required users to log into an online portal in order to see their results.

The corresponding service user dimension of Levesque’s et al. [ 14 ] framework focuses on the ability to seek healthcare, within the context of societal norms and rights. As all of our participants had successfully accessed STI testing, this was not a strong feature of our data and there were contrasting views between participants about the role their identities played in access. There were many who felt their identities had no impact on which services they might use:

“I’ve never felt like me being the skin colour I am or whatever is going to affect me wanting to go to a sex clinic or anything really. No , I’ve never felt that way.” (Participant 9 , Black cis heterosexual man , aged 35–44) .

There were a number of MSM, however, who felt that they were more easily able to access all STI testing services with less risk of stigmatisation due to cultural norms within their community and efforts by services to ensure they were inclusive:

“Being Indian not really , I don’t think that has impacted anything. I think the one thing about being gay is that I think you are just more aware of the importance of sexual health and regular testing. I think it’s drilled into you quite early in your sexual experience , when you come out.” (Participant 4 , Asian cis gay man , aged 25–34) .

Trans and non-binary participants also often felt that sexual health services – whether OPSS or clinics – were more inclusive than more generic services offering STI testing, such as pharmacies:

“Doing it through a pharmacy did mean that even though I was , my partner was a woman at the time , I was still being pushed contraceptives , which was not a pleasant experience […] I do think that if I was someone who was more sensitive to those issues it might have caused me distress. So, but like I have mentioned , I did really appreciate that [sexual health service] seems to be quite mindful about the gendered language that they are using.” (Participant 90 , White bisexual non-binary , aged 25–34) .

Although many appreciated that sexual health clinics were more trans-inclusive than other health services, trans and non-binary participants tended to prefer to test using OPSS, in part because it removed the risk of being misgendered or the burden of having to explain their gender identity.

Younger participants often felt they faced barriers accessing STI testing, although this led to different preferences in terms of service usage. There were some who were concerned about OPSS usage being identified, due to it arriving to their family home in the post, while others were more reluctant to use clinic-based services:

“At that age , because it’s your first time approaching the topic of contraception […] it was a bit daunting. You go on your own , because you are a little bit shy , so it’s a bit daunting , going in person.” (Participant 85 , Black cis woman , aged 25–34) .

Availability and ability to reach: How did the design , location and opening hours of sexual health services influence whether participants were able to access them?

This was another clear and strong influence for our participants. Almost all perceived OPSS as relatively convenient, particularly in terms of time saved and reduction in travel compared to attending clinic-based testing services, such as sexual health clinics:

“I am usually very , very limited for time , so […] I’ve missed maybe once or twice some appointments. So just the convenience of having a test kit come to your house , and you being able to test yourself , that’s […] very , very convenient. And then having to send it back , that’s pretty convenient.” (Participant 21 , Black cis heterosexual man , aged 25–34) .

Convenience also shaped how some participants chose to use OPSS, for example by posting their kit back for testing rather than dropping it off at a designated location:

“[Posting is] the easiest way I think. I think anything else would require me to get in the car and drive somewhere or interact with someone or , you know , to a post office and have to queue up or whatever. Whereas that’s just straight there , dropped off , straight back.” (Participant 51 , White cis heterosexual man , aged 25–34) .

The perceived convenience of OPSS stands in stark contrast to most participants’ perceptions of sexual health clinics. There was a widely-held view, often based on personal experience, that getting an appointment at a sexual health clinic was extremely challenging or time-consuming:

“I’ve not tried for a while but trying to get an appointment with [the sexual health clinic] was a little bit like trying to buy Glastonbury tickets. You have to be online at the exact right moment and you have to get lucky on top of that.” (Participant 26 , White bisexual non-binary , aged 35–44) .

Similarly, many participants spoke about the long waits which they expected or had experienced in clinics, even in circumstances where they had managed to get an appointment:

“The wait was a lot longer than I thought it was going to be […] I had to wait for like three hours which was really kind of , inconvenient. And annoying.” (Participant 49 , White non-binary , aged 20–24) .

The time and costs associated with travelling to attend clinics were another inconvenience for some participants:

“I was working and I’d have to take time out of work. I’d have to travel to the hospital. I’d have to have paid for parking. I’d have had to get there […] If I’d gone to a clinic , it would have easily took me maybe three , four hours to travel there and back , wait there.” (Participant 57 , Mixed ethnicity cis gay man , aged 25–34) .

There were participants who had experiences in clinics they felt were quick, however, for example in clinics which implemented effective processes to minimise waiting times:

“After the first visit I seen [sic] one particular nurse and then he gave me a number , it might have even been a direct number to book into upstairs and the real good thing about that was there was no waiting times at all. So , if your appointment was at four you would get seen at four , so that I really , really liked.” (Participant 11 , White cis gay man , aged 35–44) .

There were also issues around the availability of OPSS in some circumstances, which presented a barrier to access. For example, one case study area saw delivery and processing times increase considerably during the COVID-19 pandemic:

“I think the first time I got it , it did take a little while to get to my house. So , I was a bit annoyed , I wish I’d got it sooner in the post than I did […] I could have been seen to quicker if I’d just made an appointment.” (Participant 17 , Black cis heterosexual woman , aged 25–34) . “I’ve ordered the kit online and I think it took three months for the kit to arrive and it’s been three or four weeks since I’ve done the test and I’ve still not had the results.” (Participant 78 , White cis heterosexual woman , aged 25–34) .

Another case study area introduced a cap on daily OPSS orders during our data collection, which made it challenging for some participants to access this option:

“The only issue I have is this time it said all the packs had been ordered but it came up like that for five times a day for three days on a roll , so I think they’d maxed out.” (Participant 54 , White bisexual non-binary , aged 25–34) .

Similarly, some OPSS services restricted how often users could order a kit. This was frustrating for some participants, who felt they were doing the right thing for their sexual – and for public – health but being impeded by the service provider:

“The only bad thing about it is the fact that they don’t let you have more than a certain amount. Like the quota. And it makes you feel bad about yourself. It’s like , why won’t you just let me have a test? […] Because you’re trying to be responsible and get checked out.” (Participant 58 , White cis heterosexual woman , aged 25–34) .

Affordability and ability to pay: What was the cost of accessing sexual health services and can users afford this?

As all of the services included in this research were free to access, these dimensions were not strongly present in our data. However, many participants explicitly praised the fact that STI testing was available for free to them, particularly OPSS. This view was expressed particularly strongly by a number of people who were migrants to the UK when comparing sexual health services here to their countries of origin:

“I was a bit shocked that they were free and they would pay for delivery then pay for the delivery back and also do all this stuff and it’s all like written out and it’s just a lot of effort. I was pleasantly surprised because we definitely don’t have those in [my country of origin].” (Participant 92 , White cis heterosexual man , aged under 20) .

There were also a number of participants who had used, or considered using, private OPSS services and valued that this was available to them for free:

I did click on the [high street pharmacy] one first and I did look at all the different tests and the test for everything was like £120 […] If those tests had been cheaper and they’ve been like £15 , I might have only got to that point and just gone , oh , well , for £15 I don’t have to go to a clinic. I don’t have to take time off work. I’ll just pay for that and just do it because that would feel like not that much money. (Participant 52 , White cis heterosexual woman , aged 25–54)

As noted earlier, some participants chose to access OPSS due in part to costs associated with attending clinic-based services, such as parking.

Although it did not necessarily shape their own access, some participants expressed a perception of limited NHS resources. This led a number to accept service standards which were below their desired levels:

“Okay so I’d say that the walk-in clinics […] it’s a good and a bad. Like you’d wait for hours sometimes […] which obviously is not ideal. But at the end of the day I see it as , it’s a free service. And if there was more medical like staff to do it then yes , that would be the ideal world but we all know that we’re short staffed.” (Participant 14 , White cis heterosexual woman , aged 20–24) .

Some participants also expressed this view when discussing the wait for OPSS kits to be delivered in the case study area which experienced service disruption during the COVID-19 pandemic, although others were more critical of the delays.

There were also participants who chose OPSS over attending a clinic to preserve NHS resources for others they felt had greater need than them:

“It frees up appointments for people that need them , because I know they only do a certain amount a day, which I completely respect , because you can only do so much in one day , and there’s people that will need in-person appointments a lot more than just me.” (Participant 80 , White cis heterosexual woman , aged under 20) .

Appropriateness and ability to engage: Did services meet users’ health needs and did users have the capacity to do what services require of them?

Participants typically felt that OPSS was appropriate to meet their needs, with many sharing that they felt it was able to provide results quickly and accurately:

“I usually get those back within a week , week and a half , so it’s quicker to find out the results online which is [why] I use them […] I tested positive before so I know they’re obviously picking stuff up.” (Participant 55 , White cis gay man , 25–34) .

However, there was also a strong consensus among most participants that they should be seen in clinic-based in circumstances where they deemed themselves to be at higher likelihood of having an STI, such as when they were presenting with symptoms. This appealed to some participants as they felt it would enable them to be examined by a medical professional, to discuss their concerns with a clinician, receive quicker results and treatment, particularly in the case study area which experience delays in processing OPSS kits following the COVID-19 pandemic. Another appeal was the opportunity clinics offered to be tested for a wider range of STIs:

“Postal testing is very limited […] if you go somewhere like [sexual health clinic] […] they search for a range of things. So trichomoniasis you can get tested for , BV because they have the laboratory , they test for thrush if it may be thrush.” (Participant 7 , Black cis heterosexual woman , 25–34) .

There were a number of participants who valued these qualities of clinic-based testing, irrespective of whether they were concerned they had an STI, although for many the convenience of OPSS superseded these positive aspects. There were also participants who felt that clinics enabled better access to further care, such as contraception, PrEP or vaccines for conditions like hepatitis B:

“They talked about PrEP and were like , ‘Do you want to get on that? Go online and we can set up an appointment for you next week.’ So I’m actually going in next week to have my first PrEP appointment which is great. They were telling me about all the tests that they were doing and how I would get results back via text and that was great. I think the thing that surprised me the most was that I was able to get the vaccinations done right there and then.” (Participant 10 , Mixed ethnicity cis man , aged 20–24) .

Participants who had received a positive result via OPSS, however, often stated that they saw little difference in the pathway they subsequently followed. There were also some who had accessed additional care as a result of using OPSS:

“I got the testing kit […] and it was great that it actually showed that I’m not hep B immune , which actually prompted me to get my vaccination this year.” (Participant 2 , White cis gay man , aged 35–44) .

There were also a small number of participants who shared that they had deliberately given false responses to order an OPSS kit, in order to avoid attending a clinic, even when they thought that it might be more appropriate for their health needs:

“If you do have symptoms which ordinarily would require you to go to a [clinic] but […] there are no slots of , you know , convenient , in terms of time , you are more likely to say ‘Right well okay then , I will answer the questions in such a way that it does enable me to get this kit.’” (Participant 9 , Mixed ethnicity cis gay man , aged 55–64) .

The corresponding demand-side dimension of the framework addresses whether users have the ability to engage with a service. Most participants found OPSS easy to use, particularly in terms of ordering kits and – thanks to clear instructions – collecting urine, vaginal, oropharyngeal and rectal samples:

“So for me [self-swabbing has] always been fine , really easy. Like no problems , like the instructions are there , it tells you what to do.” (Participant 58 , White cis heterosexual woman , aged 25–34) .

Participants were typically confident with their self-swabs and urine samples, although some said they would be more confident if they had been obtained by a clinician.

There was a widespread view, however, that blood self-sampling was prohibitively difficult and unpleasant. Lots of participants had difficulty obtaining enough blood, despite following the instructions in the kit closely. This meant some received invalid HIV and syphilis test results, leading them to attend a clinic for repeat testing:

“It was very hard to get the blood out of. So I just ended up binning it because it was a nightmare […] It was painful […] I would have needed to literally slice my finger open and have the blood dripping in it for it to fill up.” (Participant 19 , White cis gay man , aged 35–44) .

There were a small number of participants who refused to use OPSS again following difficulties self-sampling blood, although others stated that it got easier with repeat usage and some had no difficulty at all. There were also a number of participants who accessed OPSS with a friend or partner, in some cases to get support with blood self-sampling:

“One person I’ve helped do them quite a lot. We would find that her blood taking is really difficult. It takes ages. Whereas , for me it was really quick , my blood just came out straightaway. But for her it takes so long.” (Participant 35 , Asian cis heterosexual woman , aged under 20) .

Other participants spoke about previously attending sexual health clinics with friends, to overcome barriers such as embarrassment and anxiety, with one saying that OPSS enabled them to get tested when a companion was not available to attend a clinic:

Interviewer: Okay. But previously , you’d always gone into the clinic. I guess , why did you choose to look for online services then? Participant: Just because- I didn’t really go into the clinic all that often because I didn’t get tested previously. But […] I have anxiety , so I don’t really like going places on my own , and that. And obviously , I couldn’t always have someone with me. (Participant 60 , Mixed ethnicity cis heterosexual woman , aged 20–24)

We found that service users’ experiences of OPSS and other sexual health services shaped their future access to STI testing in a number of ways, as identified by the Levesque et al. [ 14 ] conceptual framework of access. Service users usually had a longstanding awareness of clinic-based services, while their awareness of OPSS typically came from being directed towards it by sexual health services, discovering it online or receiving an informal recommendation from a friend or partner. The acceptability of, and ability to seek, OPSS was facilitated by the perceived privacy it offers over clinic-based services, with many participants reporting that they felt embarrassed or uncomfortable when attending a sexual health clinic. However, MSM and trans participants often felt that specialist sexual health services – including OPSS – were inclusive towards them. The availability and ability to reach OPSS was predominantly influenced by its perceived convenience, as it enabled participants to avoid travel to clinics and waiting for an appointment, although difficulty obtaining OPSS kits in some areas undermined this. Affordability and ability to pay did not demonstrably shape access, as OPSS and clinic-based services were all free at the point of use, although some associated costs were a barrier to clinic-based testing, such as parking. In respect to appropriateness and ability to engage, participants generally found OPSS easy to use, aside from blood self-sampling, and were confident in its reliability, but felt that the holistic support offered by clinic-based services would be more appropriate in situations where they were particularly concerned about having an STI or another sexual or reproductive health issue.

Our findings are consistent with previous qualitative studies on OPSS, which have also identified convenience and privacy as strong facilitators to access [ 16 , 18 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. As most previous studies had explored OPSS as a hypothetical scenario and did not include the perspectives of people who had experienced using OPSS, our findings add significant weight to the evidence indicating that these qualities facilitate access in practice. However, we also found that the ways in which OPSS is delivered can affect the impact of convenience and privacy as facilitators. Services which heavily restricted the availability of OPSS, for example, or which had long processing times for kits, were more likely to have users who felt clinic-based testing was a more convenient option.

Existing research has also identified concerns among some prospective users about self-sampling, such as worries about discomfort or samples being inaccurate. However, these were partially refuted by our data, highlighting the value of exploring the views of people who have used services [ 28 , 31 ]. We found that participants overwhelmingly consider OPSS easy to use, including the vaginal, oropharyngeal and rectal swabs, and have confidence that these samples are sufficiently accurate. However, most participants struggled considerably with blood self-sampling, which offers insight to studies which have identified poor return rates for the blood component of OPSS kits [ 32 ]. Studies of prospective users have also found mixed views on the acceptability of blood self-sampling [ 27 , 28 , 30 ]. This research also identified facilitators to blood self-sampling, such as repeat usage, having access to multiple lancets and taking a sample with the support of another person. Our findings on participant satisfaction with self-swabbing and/or urine sampling highlight a limitation of our study: our sample’s relatively high health literacy. Research by Middleton et al. [ 21 ]. found that people with a mild intellectual disability saw the prospect of self-swabbing as overwhelming and challenging, something which we did not identify frequently in our data. However, to date there have been no studies exploring the experiences of people with mild intellectual disabilities who have accessed, or attempted to access, OPSS.

Our findings offer insight into how people enter and leave the OPSS pathway, a topic which has not previously been explored. As with previous research, exploring access to clinic-based sexual health services, we found that new sexual partners and symptoms were common prompts for participants to access testing [ 33 ]. However, we also found that sexual health services and social networks both played a significant role in enabling many of our participants to access OPSS, with some even doing so with friends or partners. This contrasts with some previous research which found that people often attempt to keep their use of sexual health services secret, even from friends, although some studies have also found social networks to be a route into accessing other sexual health services, such as PrEP [ 34 , 35 ].

Access to further or more comprehensive care was part of the reason many participants valued the care on offer at clinics, at least in cases of high need, and there is some existing evidence supporting this perception. Bosó Pérez et al. [ 36 ]. found that people using remote sexual health services during the COVID-19 pandemic were less satisfied during more sensitive and emotional consultations, even though many recognised its value in other circumstances. Day et al. [ 37 ]. also reported challenges in identifying OPSS users who had experienced sexual assault, and providing them with adequate support. However, another study by the same research team found that OPSS operating procedures are effective at identifying and actioning safeguarding concerns with teenage users [ 38 ]. It is noteworthy that many of our participants who had tested positive for chlamydia or gonorrhoea using OPSS did not feel their treatment and care beyond this point was compromised or differed from what they would have experienced if they had tested at a sexual health clinic.

The communication of results is a key component of any STI testing pathway and there have been inconsistent findings from previous studies about service user preferences for how results are delivered. Research exploring the views of prospective users of OPSS had identified a range of preferred media for results communication, including SMS, email and phone, although with concerns among some about confidentiality and the lack of support from a healthcare professional [ 16 , 24 , 26 , 30 ]. Studies which have explored users’ experiences of OPSS results have found high satisfaction with both online portals and SMS [ 22 , 39 ]. Our findings corroborate this, with users of both methods typically expressing satisfaction. Although some users did have privacy concerns about SMS, it was not clear that this played a significant role in access.

Strengths and limitations

This study is, to our knowledge, the largest qualitative exploration of OPSS, as well as the first to include users of different OPSS services. This allowed us to capture a wide range of perceptions and experiences, while also comparing and contrasting between different methods of delivering OPSS, in different contexts. The use of the Levesque et al. [ 14 ] conceptual framework of access enabled us to explore a wide range of facilitators and barriers to accessing both OPSS and clinic-based STI testing, including a number – such as participants’ awareness of, and ability to seek, OPSS alongside other testing options – which have received limited attention in prior research. The study sample was also highly diverse, as a result of our efforts to include populations of interest, such as young people, people of colour, MSM and trans people.

The study was limited by the fact that we found it difficult to recruit participants who had no experience of OPSS, despite this population being a key demographic in our sampling strategy. This was partially a consequence of the COVID-19 pandemic and its after-effects, which were ongoing during our data collection and had restricted access to clinic-based services. Staff in clinics also had limited capacity to support recruitment of service users who may not have accessed OPSS. We also found it challenging to recruit service users with low digital literacy, and did not analyse the impact of participants’ socioeconomic status, meaning we could not draw conclusions on these as barriers to access. As previously discussed, our sample typically had reasonably high sexual health literacy, as having tested for STIs was one of our inclusion criteria, and all participants were inherently comfortable discussing sexual health, having volunteered for the research. This made it challenging to explore these factors as barriers.

Access to STI testing in the context of OPSS was shaped by a range of factors, including privacy, convenience, self-perceived risk, ability to self-sample and the opportunities users have to learn about OPSS. Commissioners and service providers seeking to improve access to STI testing should consider how the way services are delivered can reinforce facilitators to access, for example by minimising OPSS processing times and enabling kits to be collected as an alternative to home delivery, while also maintaining access to clinic-based testing for those who face barriers accessing OPSS. There would be value in further, targeted research exploring very marginalised populations whose perspectives have been insufficiently explored in the literature to date, such as those who are digitally excluded or who have never accessed OPSS, alongside populations which demonstrate persistently lower uptake of OPSS, including black ethnic groups, heterosexual men and people living in deprived areas.

Data availability

The data that support the findings of this study are not publicly available, as participants did not consent to this. Questions about the data can be directed to JG, Co-Chief Investigator, on [email protected].

Abbreviations

General practitioner

Initial programme theory

Men who have sex with men

Online postal self-sampling

Sexually transmitted infection(s)

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Acknowledgements

We thank the participants for sharing their time and experiences with us. We also thank the staff in our research sites who supported participant recruitment. We dedicate this paper to the memories of Prof Elizabeth Murray and Dr Naomi Fisher, who were co-applicants on ASSIST and made invaluable contributions to the study design.

This study is funded by the NIHR Health and Social Care Delivery Research Programme (NIHR129157). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

Author information

Fiona Burns and Jo Gibbs are joint senior authors.

Authors and Affiliations

Institute of Epidemiology and Health Care, University College London, London, UK

Tommer Spence & Jessica Sheringham

Institute for Global Health, University College London, London, UK

Alison Howarth, David Reid, Catherine H. Mercer, Fiona Burns & Jo Gibbs

Barts Health NHS Trust, London, UK

Vanessa Apea & Andy Williams

Lay representative, London, UK

David Crundwell

Chelsea and Westminster Hospital NHS Foundation Trust, London, UK

Sara Day & Ann Sullivan

Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

Claire Dewsnap

Institute of Applied Health Research, University of Birmingham, Birmingham, UK

Louise Jackson

STIs and HIV Division, Blood Safety, Health Security Agency, Hepatitis, London, UK

Hamish Mohammed

University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

Jonathan D. C. Ross

NHS Greater Glasgow and Clyde, Glasgow, UK

Andrew Winter

Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK

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Contributions

The study was conceived by FB and JG and designed by FB, JG, JS, LJ, GW and AH. Data were collected by TS, DR and AH. Data were analysed by TS, DR and AH, with input from JG, FB and JS. The manuscript was drafted by TS and revised by JG, FB, JS, AH and DR. VA, DC, SD, CD, LJ, CHM, HM, JDCR, AS, AW, AW and GW contributed to the interpretation of findings and critically reviewed the manuscript. All authors have read and approved the final version.

Corresponding author

Correspondence to Tommer Spence .

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This study was approved by the NHS South Central – Berkshire B Research Ethics Committee (21/SC/0223). All participants provided written informed consent.

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Not applicable.

Competing interests

VA is a Medical Director of Preventx; FB has received speaker fees and an institutional grant from Gilead Sciences Ltd. The authors declare no other competing interests.

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Spence, T., Howarth, A., Reid, D. et al. How does online postal self-sampling (OPSS) shape access to testing for sexually transmitted infections (STIs)? A qualitative study of service users. BMC Public Health 24 , 2339 (2024). https://doi.org/10.1186/s12889-024-19741-x

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Received : 11 June 2024

Accepted : 09 August 2024

Published : 28 August 2024

DOI : https://doi.org/10.1186/s12889-024-19741-x

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