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• Ethical Considerations in Research | Types & Examples

Ethical Considerations in Research | Types & Examples

Published on October 18, 2021 by Pritha Bhandari . Revised on June 22, 2023.

Ethical considerations in research are a set of principles that guide your research designs and practices. Scientists and researchers must always adhere to a certain code of conduct when collecting data from people.

The goals of human research often include understanding real-life phenomena, studying effective treatments, investigating behaviors, and improving lives in other ways. What you decide to research and how you conduct that research involve key ethical considerations.

These considerations work to

• protect the rights of research participants
• enhance research validity
• maintain scientific or academic integrity

Table of contents

Why do research ethics matter, getting ethical approval for your study, types of ethical issues, voluntary participation, informed consent, confidentiality, potential for harm, results communication, examples of ethical failures, other interesting articles, frequently asked questions about research ethics.

Research ethics matter for scientific integrity, human rights and dignity, and collaboration between science and society. These principles make sure that participation in studies is voluntary, informed, and safe for research subjects.

You’ll balance pursuing important research objectives with using ethical research methods and procedures. It’s always necessary to prevent permanent or excessive harm to participants, whether inadvertent or not.

Defying research ethics will also lower the credibility of your research because it’s hard for others to trust your data if your methods are morally questionable.

Even if a research idea is valuable to society, it doesn’t justify violating the human rights or dignity of your study participants.

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Before you start any study involving data collection with people, you’ll submit your research proposal to an institutional review board (IRB) .

An IRB is a committee that checks whether your research aims and research design are ethically acceptable and follow your institution’s code of conduct. They check that your research materials and procedures are up to code.

If successful, you’ll receive IRB approval, and you can begin collecting data according to the approved procedures. If you want to make any changes to your procedures or materials, you’ll need to submit a modification application to the IRB for approval.

If unsuccessful, you may be asked to re-submit with modifications or your research proposal may receive a rejection. To get IRB approval, it’s important to explicitly note how you’ll tackle each of the ethical issues that may arise in your study.

There are several ethical issues you should always pay attention to in your research design, and these issues can overlap with each other.

You’ll usually outline ways you’ll deal with each issue in your research proposal if you plan to collect data from participants.

Voluntary participation means that all research subjects are free to choose to participate without any pressure or coercion.

All participants are able to withdraw from, or leave, the study at any point without feeling an obligation to continue. Your participants don’t need to provide a reason for leaving the study.

It’s important to make it clear to participants that there are no negative consequences or repercussions to their refusal to participate. After all, they’re taking the time to help you in the research process , so you should respect their decisions without trying to change their minds.

Voluntary participation is an ethical principle protected by international law and many scientific codes of conduct.

Take special care to ensure there’s no pressure on participants when you’re working with vulnerable groups of people who may find it hard to stop the study even when they want to.

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Informed consent refers to a situation in which all potential participants receive and understand all the information they need to decide whether they want to participate. This includes information about the study’s benefits, risks, funding, and institutional approval.

You make sure to provide all potential participants with all the relevant information about

• what the study is about
• the risks and benefits of taking part
• how long the study will take
• your supervisor’s contact information and the institution’s approval number

Usually, you’ll provide participants with a text for them to read and ask them if they have any questions. If they agree to participate, they can sign or initial the consent form. Note that this may not be sufficient for informed consent when you work with particularly vulnerable groups of people.

If you’re collecting data from people with low literacy, make sure to verbally explain the consent form to them before they agree to participate.

For participants with very limited English proficiency, you should always translate the study materials or work with an interpreter so they have all the information in their first language.

In research with children, you’ll often need informed permission for their participation from their parents or guardians. Although children cannot give informed consent, it’s best to also ask for their assent (agreement) to participate, depending on their age and maturity level.

Anonymity means that you don’t know who the participants are and you can’t link any individual participant to their data.

You can only guarantee anonymity by not collecting any personally identifying information—for example, names, phone numbers, email addresses, IP addresses, physical characteristics, photos, and videos.

In many cases, it may be impossible to truly anonymize data collection . For example, data collected in person or by phone cannot be considered fully anonymous because some personal identifiers (demographic information or phone numbers) are impossible to hide.

You’ll also need to collect some identifying information if you give your participants the option to withdraw their data at a later stage.

Data pseudonymization is an alternative method where you replace identifying information about participants with pseudonymous, or fake, identifiers. The data can still be linked to participants but it’s harder to do so because you separate personal information from the study data.

Confidentiality means that you know who the participants are, but you remove all identifying information from your report.

All participants have a right to privacy, so you should protect their personal data for as long as you store or use it. Even when you can’t collect data anonymously, you should secure confidentiality whenever you can.

Some research designs aren’t conducive to confidentiality, but it’s important to make all attempts and inform participants of the risks involved.

As a researcher, you have to consider all possible sources of harm to participants. Harm can come in many different forms.

• Psychological harm: Sensitive questions or tasks may trigger negative emotions such as shame or anxiety.
• Social harm: Participation can involve social risks, public embarrassment, or stigma.
• Physical harm: Pain or injury can result from the study procedures.
• Legal harm: Reporting sensitive data could lead to legal risks or a breach of privacy.

It’s best to consider every possible source of harm in your study as well as concrete ways to mitigate them. Involve your supervisor to discuss steps for harm reduction.

Make sure to disclose all possible risks of harm to participants before the study to get informed consent. If there is a risk of harm, prepare to provide participants with resources or counseling or medical services if needed.

Some of these questions may bring up negative emotions, so you inform participants about the sensitive nature of the survey and assure them that their responses will be confidential.

The way you communicate your research results can sometimes involve ethical issues. Good science communication is honest, reliable, and credible. It’s best to make your results as transparent as possible.

Take steps to actively avoid plagiarism and research misconduct wherever possible.

Plagiarism means submitting others’ works as your own. Although it can be unintentional, copying someone else’s work without proper credit amounts to stealing. It’s an ethical problem in research communication because you may benefit by harming other researchers.

Self-plagiarism is when you republish or re-submit parts of your own papers or reports without properly citing your original work.

This is problematic because you may benefit from presenting your ideas as new and original even though they’ve already been published elsewhere in the past. You may also be infringing on your previous publisher’s copyright, violating an ethical code, or wasting time and resources by doing so.

In extreme cases of self-plagiarism, entire datasets or papers are sometimes duplicated. These are major ethical violations because they can skew research findings if taken as original data.

You notice that two published studies have similar characteristics even though they are from different years. Their sample sizes, locations, treatments, and results are highly similar, and the studies share one author in common.

Research misconduct

Research misconduct means making up or falsifying data, manipulating data analyses, or misrepresenting results in research reports. It’s a form of academic fraud.

These actions are committed intentionally and can have serious consequences; research misconduct is not a simple mistake or a point of disagreement about data analyses.

Research misconduct is a serious ethical issue because it can undermine academic integrity and institutional credibility. It leads to a waste of funding and resources that could have been used for alternative research.

Later investigations revealed that they fabricated and manipulated their data to show a nonexistent link between vaccines and autism. Wakefield also neglected to disclose important conflicts of interest, and his medical license was taken away.

This fraudulent work sparked vaccine hesitancy among parents and caregivers. The rate of MMR vaccinations in children fell sharply, and measles outbreaks became more common due to a lack of herd immunity.

Research scandals with ethical failures are littered throughout history, but some took place not that long ago.

Some scientists in positions of power have historically mistreated or even abused research participants to investigate research problems at any cost. These participants were prisoners, under their care, or otherwise trusted them to treat them with dignity.

To demonstrate the importance of research ethics, we’ll briefly review two research studies that violated human rights in modern history.

These experiments were inhumane and resulted in trauma, permanent disabilities, or death in many cases.

After some Nazi doctors were put on trial for their crimes, the Nuremberg Code of research ethics for human experimentation was developed in 1947 to establish a new standard for human experimentation in medical research.

In reality, the actual goal was to study the effects of the disease when left untreated, and the researchers never informed participants about their diagnoses or the research aims.

Although participants experienced severe health problems, including blindness and other complications, the researchers only pretended to provide medical care.

When treatment became possible in 1943, 11 years after the study began, none of the participants were offered it, despite their health conditions and high risk of death.

Ethical failures like these resulted in severe harm to participants, wasted resources, and lower trust in science and scientists. This is why all research institutions have strict ethical guidelines for performing research.

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

• Normal distribution
• Measures of central tendency
• Chi square tests
• Confidence interval
• Quartiles & Quantiles
• Cluster sampling
• Stratified sampling
• Thematic analysis
• Cohort study
• Peer review
• Ethnography

Research bias

• Implicit bias
• Cognitive bias
• Conformity bias
• Hawthorne effect
• Availability heuristic
• Attrition bias
• Social desirability bias

Ethical considerations in research are a set of principles that guide your research designs and practices. These principles include voluntary participation, informed consent, anonymity, confidentiality, potential for harm, and results communication.

Scientists and researchers must always adhere to a certain code of conduct when collecting data from others .

These considerations protect the rights of research participants, enhance research validity , and maintain scientific integrity.

Research ethics matter for scientific integrity, human rights and dignity, and collaboration between science and society. These principles make sure that participation in studies is voluntary, informed, and safe.

Anonymity means you don’t know who the participants are, while confidentiality means you know who they are but remove identifying information from your research report. Both are important ethical considerations .

You can only guarantee anonymity by not collecting any personally identifying information—for example, names, phone numbers, email addresses, IP addresses, physical characteristics, photos, or videos.

You can keep data confidential by using aggregate information in your research report, so that you only refer to groups of participants rather than individuals.

These actions are committed intentionally and can have serious consequences; research misconduct is not a simple mistake or a point of disagreement but a serious ethical failure.

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Understanding Scientific and Research Ethics

How to pass journal ethics checks to ensure a smooth submission and publication process

Reputable journals screen for ethics at submission—and inability to pass ethics checks is one of the most common reasons for rejection. Unfortunately, once a study has begun, it’s often too late to secure the requisite ethical reviews and clearances. Learn how to prepare for publication success by ensuring your study meets all ethical requirements before work begins.

The underlying principles of scientific and research ethics

Scientific and research ethics exist to safeguard human rights, ensure that we treat animals respectfully and humanely, and protect the natural environment.

The specific details may vary widely depending on the type of research you’re conducting, but there are clear themes running through all research and reporting ethical requirements:

Documented 3rd party oversight

• Consent and anonymity
• Full transparency

If you fulfill each of these broad requirements, your manuscript should sail through any journal’s ethics check.

If your research is 100% theoretical, you might be able to skip this one. But if you work with living organisms in any capacity—whether you’re administering a survey, collecting data from medical records, culturing cells, working with zebrafish, or counting plant species in a ring—oversight and approval by an ethics committee is a prerequisite for publication. This oversight can take many different forms:

For human studies and studies using human tissue or cells, obtain approval from your institutional review board (IRB). Register clinical trials with the World Health Organization (WHO) or International Committee of Medical Journal Editors (ICMJE). For animal research consult with your institutional animal care and use committee (IACUC). Note that there may be special requirements for non-human primates, cephalopods, and other specific species, as well as for wild animals. For field studies , anthropology and paleontology , the type of permission required will depend on many factors, like the location of the study, whether the site is publicly or privately owned, possible impacts on endangered or protected species, and local permit requirements. 

TIP: You’re not exempt until your committee tells you so

Even if you think your study probably doesn’t require approval, submit it to the review board anyway. Many journals won’t consider retrospective approvals. Obtaining formal approval or an exemption up front is worth it to ensure your research is eligible for publication in the future.

TIP: Keep your committee records close

Clearly label your IRB/IACUC paperwork, permit numbers, and any participant permission forms (including blank copies), and keep them in a safe place. You will need them when you submit to a journal. Providing these details proactively as part of your initial submission can minimize delays and get your manuscript through journal checks and into the hands of reviewers sooner.

Consent & anonymity

Obtaining consent from human subjects.

You may not conduct research on human beings unless the subjects understand what you are doing and agree to be a part of your study. If you work with human subjects, you must obtain informed written consent from the participants or their legal guardians. 

There are many circumstances where extra care may be required in order to obtain consent. The more vulnerable the population you are working with the stricter these guidelines will be. For example, your IRB may have special requirements for working with minors, the elderly, or developmentally delayed participants. Remember that these rules may vary from country to country. Providing a link to the relevant legal reference in your area can help speed the screening and approval process.

TIP: What if you are working with a population where reading and writing aren’t common?

Alternatives to written consent (such as verbal consent or a thumbprint) are acceptable in some cases, but consent still has to be clearly documented. To ensure eligibility for publication, be sure to:

• Get IRB approval for obtaining verbal rather than written consent
• Be prepared to explain why written consent could not be obtained
• Keep a copy of the script you used to obtain this consent, and record when consent was obtained for your own records

Consent and reporting for human tissue and cell lines

Consent from the participant or their next-of-kin is also required for the use of human tissue and cell lines. This includes discarded tissue, for example the by-products of surgery.  

When working with cell lines transparency and good record keeping are essential. Here are some basic guidelines to bear in mind:

• When working with established cell lines , cite the published article where the cell line was first described.
• If you’re using repository or commercial cell lines ,  explain exactly which ones, and provide the catalog or repository number. 
• If you received a cell line from a colleague , rather than directly from a repository or company, be sure to mention it. Explain who gifted the cells and when.
• For a new cell line obtained from a colleague there may not be a published article to cite yet, but the work to generate the cell line must meet the usual requirements of consent—even if it was carried out by another research group. You’ll need to provide a copy of your colleagues’ IRB approval and details about the consent procedures in order to publish the work.

Finally, you’re obliged to keep your human subjects anonymous and to protect any identifying information in photos and raw data. Remove all names, birth dates, detailed addresses, or job information from files you plan to share. Blur faces and tattoos in any images. Details such as geography (city/country), gender, age, or profession may be shared at a generalized level and in aggregate. Read more about standards for de-identifying datasets in The BMJ .

TIP: Anonymity can be important in field work too

Be careful about revealing geographic data in fieldwork. You don’t want to tip poachers off to the location of the endangered elephant population you studied, or expose petroglyphs to vandalism.

Full Transparency

No matter the discipline, transparent reporting of methods, results, data, software and code is essential to ethical research practice. Transparency is also key to the future reproducibility of your work.

When you submit your study to a journal, you’ll be asked to provide a variety of statements certifying that you’ve obtained the appropriate permissions and clearances, and explaining how you conducted the work. You may also be asked to provide supporting documentation, including field records and raw data. Provide as much detail as you can at this stage. Clear and complete disclosure statements will minimize back-and-forth with the journal, helping your submission to clear ethics checks and move on to the assessment stage sooner.

TIP: Save that data

As you work, be sure to clearly label and organize your data files in a way that will make sense to you later. As close as you are to the work as you conduct your study, remember that two years could easily pass between capturing your data and publishing an article reporting the results. You don’t want to be stuck piecing together confusing records in order to create figures and data files for repositories.

Read our full guide to preparing data for submission .

Keep in mind that scientific and research ethics are always evolving. As laws change and as we learn more about influence, implicit bias and animal sentience, the scientific community continues to strive to elevate our research practice.

A checklist to ensure you’re ethics-check ready

Before you begin your research

Obtain approval from your IRB, IACUC or other approving body

Obtain written informed consent from human participants, guardians or next-of-kin

Obtain permits or permission from property owners, or confirm that permits are not required

Label and save all of records

As you work

Adhere strictly to the protocols approved by your committee

Clearly label your data, and store it in a way that will make sense to your future self

As you write, submit and deposit your results

Be ready to cite specific approval organizations, permit numbers, cell lines, and other details in your ethics statement and in the methods section of your manuscript

Anonymize all participant data (including human and in some cases animal or geographic data)

If a figure does include identifying information (e.g. a participant’s face) obtain special consent

The contents of the Peer Review Center are also available as a live, interactive training session, complete with slides, talking points, and activities. …

The contents of the Writing Center are also available as a live, interactive training session, complete with slides, talking points, and activities. …

There’s a lot to consider when deciding where to submit your work. Learn how to choose a journal that will help your study reach its audience, while reflecting your values as a researcher…

A Roadmap to Successful Scientific Publishing pp 27–34 Cite as

Understanding Research Ethics

• Sarah Cuschieri 2  
• First Online: 22 April 2022

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As a researcher, whatever your career stage, you need to understand and practice good research ethics. Moral and ethical principles are requisite in research to ensure no deception or harm to participants, scientific community, and society occurs. Failure to follow such principles leads to research misconduct, in which case the researcher faces repercussions ranging from withdrawal of an article from publication to potential job loss. This chapter describes the various types of research misconduct that you should be aware of, i.e., data fabrication and falsification, plagiarism, research bias, data integrity, researcher and funder conflicts of interest. A sound comprehension of research ethics will take you a long way in your career.

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Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, Msida, Malta

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Introduction: What is Research Ethics?

Research Ethics is defined here to be the ethics of the planning, conduct, and reporting of research. This introduction covers what research ethics is, its ethical distinctions, approaches to teaching research ethics, and other resources on this topic.

What is Research Ethics

Why Teach Research Ethics

Animal Subjects

Biosecurity

Collaboration

Conflicts of Interest

Data Management

Human Subjects

Peer Review

Publication

Research Misconduct

Social Responsibility

Stem Cell Research

Whistleblowing

Descriptions of educational settings , including in the classroom, and in research contexts.

Case Studies

Other Discussion Tools

Information about the history and authors of the Resources for Research Ethics Collection

What is Research Ethics?

Research Ethics is defined here to be the ethics of the planning, conduct, and reporting of research. It is clear that research ethics should include:

• Protections of human and animal subjects

However, not all researchers use human or animal subjects, nor are the ethical dimensions of research confined solely to protections for research subjects. Other ethical challenges are rooted in many dimensions of research, including the:

• Collection, use, and interpretation of research data
• Methods for reporting and reviewing research plans or findings
• Relationships among researchers with one another
• Relationships between researchers and those that will be affected by their research
• Means for responding to misunderstandings, disputes, or misconduct
• Options for promoting ethical conduct in research

The domain of research ethics is intended to include nothing less than the fostering of research that protects the interests of the public, the subjects of research, and the researchers themselves.

Ethical Distinctions

In discussing or teaching research ethics, it is important to keep some basic distinctions in mind.

• It is important not to confuse moral claims about how people ought to behave with descriptive claims about how they in fact do behave. From the fact that gift authorship or signing off on un-reviewed data may be "common practice" in some contexts, it doesn't follow that they are morally or professionally justified. Nor is morality to be confused with the moral beliefs or ethical codes that a given group or society holds (how some group thinks people should live). A belief in segregation is not morally justified simply because it is widely held by a group of people or given society. Philosophers term this distinction between prescriptive and descriptive claims the 'is-ought distinction.'  
• A second important distinction is that between morality and the law. The law may or may not conform to the demands of ethics (Kagan, 1998). To take a contemporary example: many believe that the law prohibiting federally funded stem cell research is objectionable on moral (as well as scientific) grounds, i.e., that such research can save lives and prevent much human misery. History is full of examples of bad laws, that is laws now regarded as morally unjustifiable, e.g., the laws of apartheid, laws prohibiting women from voting or inter-racial couples from marrying.  
• It is also helpful to distinguish between two different levels of discussion (or two different kinds of ethical questions): first-order or "ground-level" questions and second-order questions.  
• First-order moral questions concern what we should do. Such questions may be very general or quite specific. One might ask whether the tradition of 'senior' authorship should be defended and preserved or, more generally, what are the principles that should go into deciding the issue of 'senior' authorship. Such questions and the substantive proposals regarding how to answer them belong to the domain of what moral philosophers call 'normative ethics.'  
• Second-order moral questions concern the nature and purpose of morality itself. When someone claims that falsifying data is wrong, what exactly is the standing of this claim? What exactly does the word 'wrong' mean in the conduct of scientific research? And what are we doing when we make claims about right and wrong, scientific integrity and research misconduct? These second-order questions are quite different from the ground-level questions about how to conduct one's private or professional life raised above. They concern the nature of morality rather than its content, i.e., what acts are required, permitted or prohibited. This is the domain of what moral philosophers call 'metaethics' (Kagan, 1998).

Ethical Approaches

Each of these approaches provides moral principles and ways of thinking about the responsibilities, duties and obligations of moral life. Individually and jointly, they can provide practical guidance in ethical decision-making.

• One of the most influential and familiar approaches to ethics is deontological ethics, associated with Immanuel Kant (1742-1804). Deontological ethics hold certain acts as right or wrong in themselves, e.g., promise breaking or lying. So, for example, in the context of research, fraud, plagiarism and misrepresentation are regarded as morally wrong in themselves, not simply because they (tend to) have bad consequences. The deontological approach is generally grounded in a single fundamental principle: Act as you would wish others to act towards you OR always treat persons as an end, never as a means to an end.  
• From such central principles are derived rules or guidelines for what is permitted, required and prohibited. Objections to principle-based or deontological ethics include the difficulty of applying highly general principles to specific cases, e.g.: Does treating persons as ends rule out physician-assisted suicide, or require it? Deontological ethics is generally contrasted to consequentialist ethics (Honderich, 1995).  
• According to consequentialist approaches, the rightness or wrongness of an action depends solely on its consequences. One should act in such a way as to bring about the best state of affairs, where the best state of affairs may be understood in various ways, e.g., as the greatest happiness for the greatest number of people, maximizing pleasure and minimizing pain or maximizing the satisfaction of preferences. A theory such as Utilitarianism (with its roots in the work of Jeremy Bentham and John Stuart Mill) is generally taken as the paradigm example of consequentialism. Objections to consequentialist ethics tend to focus on its willingness to regard individual rights and values as "negotiable." So, for example, most people would regard murder as wrong independently of the fact that killing one person might allow several others to be saved (the infamous sacrifice of an ailing patient to provide organs for several other needy patients). Similarly, widespread moral opinion holds certain values important (integrity, justice) not only because they generally lead to good outcomes, but in and of themselves.
• Virtue ethics focuses on moral character rather than action and behavior considered in isolation. Central to this approach is the question what ought we (as individuals, as scientists, as physicians) to be rather than simply what we ought to do. The emphasis here is on inner states, that is, moral dispositions and habits such as courage or a developed sense of personal integrity. Virtue ethics can be a useful approach in the context of RCR and professional ethics, emphasizing the importance of moral virtues such as compassion, honesty, and respect. This approach has also a great deal to offer in discussions of bioethical issues where a traditional emphasis on rights and abstract principles frequently results in polarized, stalled discussions (e.g., abortion debates contrasting the rights of the mother against the rights of the fetus).  
• The term 'an ethics of care' grows out of the work of Carol Gilligan, whose empirical work in moral psychology claimed to discover a "different voice," a mode of moral thinking distinct from principle-based moral thinking (e.g., the theories of Kant and Mill). An ethics of care stresses compassion and empathetic understanding, virtues Gilligan associated with traditional care-giving roles, especially those of women.  
• This approach differs from traditional moral theories in two important ways. First, it assumes that it is the connections between persons, e.g., lab teams, colleagues, parents and children, student and mentor, not merely the rights and obligations of discrete individuals that matter. The moral world, on this view, is best seen not as the interaction of discrete individuals, each with his or her own interests and rights, but as an interrelated web of obligations and commitment. We interact, much of the time, not as private individuals, but as members of families, couples, institutions, research groups, a given profession and so on. Second, these human relationships, including relationships of dependency, play a crucial role on this account in determining what our moral obligations and responsibilities are. So, for example, individuals have special responsibilities to care for their children, students, patients, and research subjects.  
• An ethics of care is thus particularly useful in discussing human and animal subjects research, issues of informed consent, and the treatment of vulnerable populations such as children, the infirm or the ill.  
• The case study approach begins from real or hypothetical cases. Its objective is to identify the intuitively plausible principles that should be taken into account in resolving the issues at hand. The case study approach then proceeds to critically evaluate those principles. In discussing whistle-blowing, for example, a good starting point is with recent cases of research misconduct, seeking to identify and evaluate principles such as a commitment to the integrity of science, protecting privacy, or avoiding false or unsubstantiated charges. In the context of RCR instruction, case studies provide one of the most interesting and effective approaches to developing sensitivity to ethical issues and to honing ethical decision-making skills.  
• Strictly speaking, casuistry is more properly understood as a method for doing ethics rather than as itself an ethical theory. However, casuistry is not wholly unconnected to ethical theory. The need for a basis upon which to evaluate competing principles, e.g., the importance of the well-being of an individual patient vs. a concern for just allocation of scarce medical resources, makes ethical theory relevant even with case study approaches.  
• Applied ethics is a branch of normative ethics. It deals with practical questions particularly in relation to the professions. Perhaps the best known area of applied ethics is bioethics, which deals with ethical questions arising in medicine and the biological sciences, e.g., questions concerning the application of new areas of technology (stem cells, cloning, genetic screening, nanotechnology, etc.), end of life issues, organ transplants, and just distribution of healthcare. Training in responsible conduct of research or "research ethics" is merely one among various forms of professional ethics that have come to prominence since the 1960s. Worth noting, however, is that concern with professional ethics is not new, as ancient codes such as the Hippocratic Oath and guild standards attest (Singer, 1986).
• Adams D, Pimple KD (2005): Research Misconduct and Crime: Lessons from Criminal Science on Preventing Misconduct and Promoting Integrity. Accountability in Research 12(3):225-240.
• Anderson MS, Horn AS, Risbey KR, Ronning EA, De Vries R, Martinson BC (2007): What Do Mentoring and Training in the Responsible Conduct of Research Have To Do with Scientists' Misbehavior? Findings from a National Survey of NIH-Funded Scientists . Academic Medicine 82(9):853-860.
• Bulger RE, Heitman E (2007): Expanding Responsible Conduct of Research Instruction across the University. Academic Medicine. 82(9):876-878.
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The Resources for Research Ethics Education site was originally developed and maintained by Dr. Michael Kalichman, Director of the Research Ethics Program at the University of California San Diego. The site was transferred to the Online Ethics Center in 2021 with the permission of the author.

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This material is based upon work supported by the National Science Foundation under Award No. 2055332. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.

• Original article
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• Published: 13 July 2021

Assisting you to advance with ethics in research: an introduction to ethical governance and application procedures

• Shivadas Sivasubramaniam 1 ,
• Dita Henek Dlabolová 2 ,
• Veronika Kralikova 3 &
• Zeenath Reza Khan 3  

International Journal for Educational Integrity volume  17 , Article number:  14 ( 2021 ) Cite this article

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Ethics and ethical behaviour are the fundamental pillars of a civilised society. The focus on ethical behaviour is indispensable in certain fields such as medicine, finance, or law. In fact, ethics gets precedence with anything that would include, affect, transform, or influence upon individuals, communities or any living creatures. Many institutions within Europe have set up their own committees to focus on or approve activities that have ethical impact. In contrast, lesser-developed countries (worldwide) are trying to set up these committees to govern their academia and research. As the first European consortium established to assist academic integrity, European Network for Academic Integrity (ENAI), we felt the importance of guiding those institutions and communities that are trying to conduct research with ethical principles. We have established an ethical advisory working group within ENAI with the aim to promote ethics within curriculum, research and institutional policies. We are constantly researching available data on this subject and committed to help the academia to convey and conduct ethical behaviour. Upon preliminary review and discussion, the group found a disparity in understanding, practice and teaching approaches to ethical applications of research projects among peers. Therefore, this short paper preliminarily aims to critically review the available information on ethics, the history behind establishing ethical principles and its international guidelines to govern research.

The paper is based on the workshop conducted in the 5th International conference Plagiarism across Europe and Beyond, in Mykolas Romeris University, Lithuania in 2019. During the workshop, we have detailed a) basic needs of an ethical committee within an institution; b) a typical ethical approval process (with examples from three different universities); and c) the ways to obtain informed consent with some examples. These are summarised in this paper with some example comparisons of ethical approval processes from different universities. We believe this paper will provide guidelines on preparing and training both researchers and research students in appropriately upholding ethical practices through ethical approval processes.

Introduction

Ethics and ethical behaviour (often linked to “responsible practice”) are the fundamental pillars of a civilised society. Ethical behaviour with integrity is important to maintain academic and research activities. It affects everything we do, and gets precedence with anything that would include/affect, transform, or impact upon individuals, communities or any living creatures. In other words, ethics would help us improve our living standards (LaFollette, 2007 ). The focus on ethical behaviour is indispensable in certain fields such as medicine, finance, or law, but is also gaining recognition in all disciplines engaged in research. Therefore, institutions are expected to develop ethical guidelines in research to maintain quality, initiate/own integrity and above all be transparent to be successful by limiting any allegation of misconduct (Flite and Harman, 2013 ). This is especially true for higher education organisations that promote research and scholarly activities. Many European institutions have developed their own regulations for ethics by incorporating international codes (Getz, 1990 ). The lesser developed countries are trying to set up these committees to govern their academia and research. World Health Organization has stated that adhering to “ ethical principles … [is central and important]... in order to protect the dignity, rights and welfare of research participants ” (WHO, 2021 ). Ethical guidelines taught to students can help develop ethical researchers and members of society who uphold values of ethical principles in practice.

As the first European-wide consortium established to assist academic integrity (European Network for Academic Integrity – ENAI), we felt the importance of guiding those institutions and communities that are trying to teach, research, and include ethical principles by providing overarching understanding of ethical guidelines that may influence policy. Therefore, we set up an advisory working group within ENAI in 2018 to support matters related to ethics, ethical committees and assisting on ethics related teaching activities.

Upon preliminary review and discussion, the group found a disparity in understanding, practice and teaching approaches to ethical applications among peers. This became the premise for this research paper. We first carried out a literature survey to review and summarise existing ethical governance (with historical perspectives) and procedures that are already in place to guide researchers in different discipline areas. By doing so, we attempted to consolidate, document and provide important steps in a typical ethical application process with example procedures from different universities. Finally, we attempted to provide insights and findings from practical workshops carried out at the 5th International Conference Plagiarism across Europe and Beyond, in Mykolas Romeris University, Lithuania in 2019, focussing on:

• highlighting the basic needs of an ethical committee within an institution,

• discussing and sharing examples of a typical ethical approval process,

• providing guidelines on the ways to teach research ethics with some examples.

We believe this paper provides guidelines on preparing and training both researchers and research students in appropriately upholding ethical practices through ethical approval processes.

Background literature survey

Responsible research practice (RRP) is scrutinised by the aspects of ethical principles and professional standards (WHO’s Code of Conduct for responsible Research, 2017). The Singapore statement on research integrity (The Singapore Statement on Research integrity, 2010) has provided an internationally acceptable guidance for RRP. The statement is based on maintaining honesty, accountability, professional courtesy in all aspects of research and maintaining fairness during collaborations. In other words, it does not simply focus on the procedural part of the research, instead covers wider aspects of “integrity” beyond the operational aspects (Israel and Drenth, 2016 ).

Institutions should focus on providing ethical guidance based on principles and values reflecting upon all aspects/stages of research (from the funding application/project development stage upto or beyond project closing stage). Figure  1 summarizes the different aspects/stages of a typical research and highlights the needs of RRP in compliance with ethical governance at each stage with examples (the figure is based on Resnik, 2020 ; Žukauskas et al., 2018 ; Anderson, 2011 ; Fouka and Mantzorou, 2011 ).

Summary of the enabling ethical governance at different stages of research. Note that it is imperative for researchers to proactively consider the ethical implications before, during and after the actual research process. The summary shows that RRP should be in line with ethical considerations even long before the ethical approval stage

Individual responsibilities to enhance RRP

As explained in Fig.  1 , a successfully governed research should consider ethics at the planning stages prior to research. Many international guidance are compatible in enforcing/recommending 14 different “responsibilities” that were first highlighted in the Singapore Statement (2010) for researchers to follow and achieve competency in RRP. In order to understand the purpose and the expectation of these ethical guidelines, we have carried out an initial literature survey on expected individual responsibilities. These are summarised in Table  1 .

By following these directives, researchers can carry out accountable research by maximising ethical self-governance whilst minimising misconducts. In our own experiences of working with many researchers, their focus usually revolves around ethical “clearance” rather than behaviour. In other words, they perceive this as a paper exercise rather than trying to “own” ethical behaviour in everything they do. Although the ethical principles and responsibilities are explicitly highlighted in the majority of international guidelines [such as UK’s Research Governance Policy (NICE, 2018 ), Australian Government’s National Statement on Ethical Conduct in Human Research (Difn website a - National Statement on Ethical Conduct in Human Research (NSECHR), 2018 ), the Singapore Statement (2010) etc.]; and the importance of holistic approach has been argued in ethical decision making, many researchers and/or institutions only focus on ethics linked to the procedural aspects.

Studies in the past have also highlighted inconsistencies in institutional guidelines pointing to the fact that these inconsistencies may hinder the predicted research progress (Desmond & Dierickx 2021 ; Alba et al., 2020 ; Dellaportas et al., 2014 ; Speight 2016 ). It may also be possible that these were and still are linked to the institutional perceptions/expectations or the pre-empting contextual conditions that are imposed by individual countries. In fact, it is interesting to note many research organisations and HE institutions establish their own policies based on these directives.

Research governance - origins, expectations and practices

Ethical governance in clinical medicine helps us by providing a structure for analysis and decision-making. By providing workable definitions of benefits and risks as well as the guidance for evaluating/balancing benefits over risks, it supports the researchers to protect the participants and the general population.

According to the definition given by National Institute of Clinical care Excellence, UK (NICE 2018 ), “ research governance can be defined as the broad range of regulations, principles and standards of good practice that ensure high quality research ”. As stated above, our literature-based research survey showed that most of the ethical definitions are basically evolved from the medical field and other disciplines have utilised these principles to develop their own ethical guidance. Interestingly, historical data show that the medical research has been “self-governed” or in other words implicated by the moral behaviour of individual researchers (Fox 2017 ; Shaw et al., 2005 ; Getz, 1990 ). For example, early human vaccination trials conducted in 1700s used the immediate family members as test subjects (Fox, 2017 ). Here the moral justification might have been the fact that the subjects who would have been at risk were either the scientists themselves or their immediate families but those who would reap the benefits from the vaccination were the general public/wider communities. However, according to the current ethical principles, this assumption is entirely not acceptable.

Historically, ambiguous decision-making and resultant incidences of research misconduct have led to the need for ethical research governance in as early as the 1940’s. For instance, the importance of an international governance was realised only after the World War II, when people were astonished to note the unethical research practices carried out by Nazi scientists. As a result of this, in 1947 the Nuremberg code was published. The code mainly focussed on the following:

Informed consent and further insisted the research involving humans should be based on prior animal work,

The anticipated benefits should outweigh the risk,

Research should be carried out only by qualified scientists must conduct research,

Avoiding physical and mental suffering and.

Avoiding human research that would result in which death or disability.

(Weindling, 2001 ).

Unfortunately, it was reported that many researchers in the USA and elsewhere considered the Nuremberg code as a document condemning the Nazi atrocities, rather than a code for ethical governance and therefore ignored these directives (Ghooi, 2011 ). It was only in 1964 that the World Medical Association published the Helsinki Declaration, which set the stage for ethical governance and the implementation of the Institutional Review Board (IRB) process (Shamoo and Irving, 1993 ). This declaration was based on Nuremberg code. In addition, the declaration also paved the way for enforcing research being conducted in accordance with these guidelines.

Incidentally, the focus on research/ethical governance gained its momentum in 1974. As a result of this, a report on ethical principles and guidelines for the protection of human subjects of research was published in 1979 (The Belmont Report, 1979 ). This report paved the way to the current forms of ethical governance in biomedical and behavioural research by providing guidance.

Since 1994, the WHO itself has been providing several guidance to health care policy-makers, researchers and other stakeholders detailing the key concepts in medical ethics. These are specific to applying ethical principles in global public health.

Likewise, World Organization for Animal Health (WOAH), and International Convention for the Protection of Animals (ICPA) provide guidance on animal welfare in research. Due to this continuous guidance, together with accepted practices, there are internationally established ethical guidelines to carry out medical research. Our literature survey further identified freely available guidance from independent organisations such as COPE (Committee of Publication Ethics) and ALLEA (All European Academics) which provide support for maintaining research ethics in other fields such as education, sociology, psychology etc. In reality, ethical governance is practiced differently in different countries. In the UK, there is a clinical excellence research governance, which oversees all NHS related medical research (Mulholland and Bell, 2005 ). Although, the governance in other disciplines is not entirely centralised, many research funding councils and organisations [such as UKRI (UK-Research and Innovation; BBSC (Biotechnology and Biological Sciences Research Council; MRC (Medical Research Council); EPSRC (Economic and Social Research Council)] provide ethical governance and expect institutional adherence and monitoring. They expect local institutional (i.e. university/institutional) research governance for day-to-day monitoring of the research conducted within the organisation and report back to these funding bodies, monthly or annually (Department of Health, 2005). Likewise, there are nationally coordinated/regulated ethics governing bodies such as the US Office for Human Research Protections (US-OHRP), National Institute of Health (NIH) and the Canadian Institutes for Health Research (CIHR) in the USA and Canada respectively (Mulholland and Bell, 2005 ). The OHRP in the USA formally reviews all research activities involving human subjects. On the other hand, in Canada, CIHR works with the Natural Sciences and Engineering Research Council (NSERC), and the Social Sciences and Humanities Research Council (SSHRC). They together have produced a Tri-Council Policy Statement (TCPS) (Stephenson et al., 2020 ) as ethical governance. All Canadian institutions are expected to adhere to this policy for conducting research. As for Australia, the research is governed by the Australian code for the responsible conduct of research (2008). It identifies the responsibilities of institutions and researchers in all areas of research. The code has been jointly developed by the National Health and Medical Research Council (NHMRC), the Australian Research Council (ARC) and Universities Australia (UA). This information is summarized in Table  2 .

Basic structure of an institutional ethical advisory committee (EAC)

The WHO published an article defining the basic concepts of an ethical advisory committee in 2009 (WHO, 2009 - see above). According to this, many countries have established research governance and monitor the ethical practice in research via national and/or regional review committees. The main aims of research ethics committees include reviewing the study proposals, trying to understand the justifications for human/animal use, weighing the merits and demerits of the usage (linking to risks vs. potential benefits) and ensuring the local, ethical guidelines are followed Difn website b - Enago academy Importance of Ethics Committees in Scholarly Research, 2020 ; Guide for Research Ethics - Council of Europe, 2014 ). Once the research has started, the committee needs to carry out periodic surveillance to ensure the institutional ethical norms are followed during and beyond the study. They may also be involved in setting up and/or reviewing the institutional policies.

For these aspects, IRB (or institutional ethical advisory committee - IEAC) is essential for local governance to enhance best practices. The advantage of an IRB/EEAC is that they understand the institutional conditions and can closely monitor the ongoing research, including any changes in research directions. On the other hand, the IRB may be overly supportive to accept applications, influenced by the local agenda for achieving research excellence, disregarding ethical issues (Kotecha et al., 2011 ; Kayser-Jones, 2003 ) or, they may be influenced by the financial interests in attracting external funding. In this respect, regional and national ethics committees are advantageous to ensure ethical practice. Due to their impartiality, they would provide greater consistency and legitimacy to the research (WHO, 2009 ). However, the ethical approval process of regional and national ethics committees would be time consuming, as they do not have the local knowledge.

As for membership in the IRBs, most of the guidelines [WHO, NICE, Council of Europe, (2012), European Commission - Facilitating Research Excellence in FP7 ( 2013 ) and OHRP] insist on having a variety of representations including experts in different fields of research, and non-experts with the understanding of local, national/international conflicts of interest. The former would be able to understand/clarify the procedural elements of the research in different fields; whilst the latter would help to make neutral and impartial decisions. These non-experts are usually not affiliated to the institution and consist of individuals representing the broader community (particularly those related to social, legal or cultural considerations). IRBs consisting of these varieties of representation would not only be in a position to understand the study procedures and their potential direct or indirect consequences for participants, but also be able to identify any community, cultural or religious implications of the study.

Understanding the subtle differences between ethics and morals

Interestingly, many ethical guidelines are based on society’s moral “beliefs” in such a way that the words “ethics”‘and “morals” are reciprocally used to define each other. However, there are several subtle differences between them and we have attempted to compare and contrast them herein. In the past, many authors have interchangeably used the words “morals”‘and “ethics”‘(Warwick, 2003 ; Kant, 2018 ; Hazard, GC (Jr)., 1994 , Larry, 1982 ). However, ethics is linked to rules governed by an external source such as codes of conduct in workplaces (Kuyare et al., 2014 ). In contrast, morals refer to an individual’s own principles regarding right and wrong. Quinn ( 2011 ) defines morality as “ rules of conduct describing what people ought and ought not to do in various situations … ” while ethics is “... the philosophical study of morality, a rational examination into people’s moral beliefs and behaviours ”. For instance, in a case of parents demanding that schools overturn a ban on use of corporal punishment of children by schools and teachers (Children’s Rights Alliance for England, 2005 ), the parents believed that teachers should assume the role of parent in schools and use corporal or physical punishment for children who misbehaved. This stemmed from their beliefs and what they felt were motivated by “beliefs of individuals or groups”. For example, recent media highlights about some parents opposing LGBT (Lesbian, Gay, Bisexual, and Transgender) education to their children (BBC News, 2019 ). One parent argued, “Teaching young children about LGBT at a very early stage is ‘morally’ wrong”. She argued “let them learn by themselves as they grow”. This behaviour is linked to and governed by the morals of an ethnic community. Thus, morals are linked to the “beliefs of individuals or group”. However, when it comes to the LGBT rights these are based on ethical principles of that society and governed by law of the land. However, the rights of children to be protected from “inhuman and degrading” treatment is based on the ethical principles of the society and governed by law of the land. Individuals, especially those who are working in medical or judicial professions have to follow an ethical code laid down by their profession, regardless of their own feelings, time or preferences. For instance, a lawyer is expected to follow the professional ethics and represent a defendant, despite the fact that his morals indicate the defendant is guilty.

In fact, we as a group could not find many scholarly articles clearly comparing or contrasting ethics with morals. However, a table presented by Surbhi ( 2015 ) (Difn website c ) tries to differentiate these two terms (see Table  3 ).

Although Table 3 gives some insight on the differences between these two terms, in practice many use these terms as loosely as possible mainly because of their ambiguity. As a group focussed on the application of these principles, we would recommend to use the term “ethics” and avoid “morals” in research and academia.

Based on the literature survey carried out, we were able to identify the following gaps:

there is some disparity in existing literature on the importance of ethical guidelines in research

there is a lack of consensus on what code of conduct should be followed, where it should be derived from and how it should be implemented

The mission of ENAI’s ethical advisory working group

The Ethical Advisory Working Group of ENAI was established in 2018 to promote ethical code of conduct/practice amongst higher educational organisations within Europe and beyond (European Network for Academic Integrity, 2018 ). We aim to provide unbiased advice and consultancy on embedding ethical principles within all types of academic, research and public engagement activities. Our main objective is to promote ethical principles and share good practice in this field. This advisory group aims to standardise ethical norms and to offer strategic support to activities including (but not exclusive to):

● rendering advice and assistance to develop institutional ethical committees and their regulations in member institutions,

● sharing good practice in research and academic ethics,

● acting as a critical guide to institutional review processes, assisting them to maintain/achieve ethical standards,

● collaborating with similar bodies in establishing collegiate partnerships to enhance awareness and practice in this field,

● providing support within and outside ENAI to develop materials to enhance teaching activities in this field,

● organising training for students and early-career researchers about ethical behaviours in form of lectures, seminars, debates and webinars,

● enhancing research and dissemination of the findings in matters and topics related to ethics.

The following sections focus on our suggestions based on collective experiences, review of literature provided in earlier sections and workshop feedback collected:

a) basic needs of an ethical committee within an institution;

b) a typical ethical approval process (with examples from three different universities); and

c) the ways to obtain informed consent with some examples. This would give advice on preparing and training both researchers and research students in appropriately upholding ethical practices through ethical approval processes.

Setting up an institutional ethical committee (ECs)

Institutional Ethical Committees (ECs) are essential to govern every aspect of the activities undertaken by that institute. With regards to higher educational organisations, this is vital to establish ethical behaviour for students and staff to impart research, education and scholarly activities (or everything) they do. These committees should be knowledgeable about international laws relating to different fields of studies (such as science, medicine, business, finance, law, and social sciences). The advantages and disadvantages of institutional, subject specific or common (statutory) ECs are summarised in Fig.  2 . Some institutions have developed individual ECs linked to specific fields (or subject areas) whilst others have one institutional committee that overlooks the entire ethical behaviour and approval process. There is no clear preference between the two as both have their own advantages and disadvantages (see Fig. 2 ). Subject specific ECs are attractive to medical, law and business provisions, as it is perceived the members within respective committees would be able to understand the subject and therefore comprehend the need of the proposed research/activity (Kadam, 2012 ; Schnyder et al., 2018 ). However, others argue, due to this “ specificity ”, the committee would fail to forecast the wider implications of that application. On the other hand, university-wide ECs would look into the wider implications. Yet they find it difficult to understand the purpose and the specific applications of that research. Not everyone understands dynamics of all types of research methodologies, data collection, etc., and therefore there might be a chance of a proposal being rejected merely because the EC could not understand the research applications (Getz, 1990 ).

Summary of advantages and disadvantages of three different forms of ethical committees

[N/B for Fig. 2 : Examples of different types of ethical application procedures and forms used were discussed with the workshop attendees to enhance their understanding of the differences. GDPR = General Data Protection Regulation].

Although we recommend a designated EC with relevant professional, academic and ethical expertise to deal with particular types of applications, the membership (of any EC) should include some non-experts who would represent the wider community (see above). Having some non-experts in EC would not only help the researchers to consider explaining their research in layperson’s terms (by thinking outside the box) but also would ensure efficiency without compromising participants/animal safety. They may even help to address the common ethical issues outside research culture. Some UK universities usually offer this membership to a clergy, councillor or a parliamentarian who does not have any links to the institutions. Most importantly, it is vital for any EC members to undertake further training in addition to previous experience in the relevant field of research ethics.

Another issue that raises concerns is multi-centre research, involving several institutions, where institutionalised ethical approvals are needed from each partner. In some cases, such as clinical research within the UK, a common statutory EC called National Health Services (NHS) Research Ethics Committee (NREC) is in place to cover research ethics involving all partner institutions (NHS, 2018 ). The process of obtaining approval from this type of EC takes time, therefore advanced planning is needed.

Ethics approval forms and process

During the workshop, we discussed some anonymised application forms obtained from open-access sources for qualitative and quantitative research as examples. Considering research ethics, for the purpose of understanding, we arbitrarily divided this in two categories; research based on (a) quantitative and (b) qualitative methodologies. As their name suggests their research approach is extremely different from each other. The discussion elicited how ECs devise different types of ethical application form/questions. As for qualitative research, these are often conducted as “face-to-face” interviews, which would have implications on volunteer anonymity.

Furthermore, discussions posited when the interviews are replaced by on-line surveys, they have to be administered through registered university staff to maintain confidentiality. This becomes difficult when the research is a multi-centre study. These types of issues are also common in medical research regarding participants’ anonymity, confidentially, and above all their right to withdraw consent to be involved in research.

Storing and protecting data collected in the process of the study is also a point of consideration when applying for approval.

Finally, the ethical processes of invasive (involving human/animals) and non-invasive research (questionnaire based) may slightly differ from one another. Following research areas are considered as investigations that need ethical approval:

research that involves human participants (see below)

use of the ‘products’ of human participants (see below)

work that potentially impacts on humans (see below)

research that involves animals

In addition, it is important to provide a disclaimer even if an ethical approval is deemed unnecessary. Following word cloud (Fig.  3 ) shows the important variables that need to be considered at the brainstorming stage before an ethical application. It is worth noting the importance of proactive planning predicting the “unexpected” during different phases of a research project (such as planning, execution, publication, and future directions). Some applications (such as working with vulnerable individuals or children) will require safety protection clearance (such as DBS - Disclosure and Barring Service, commonly obtained from the local police). Please see section on Research involving Humans - Informed consents for further discussions.

Examples of important variables that need to be considered for an ethical approval

It is also imperative to report or re-apply for ethical approval for any minor or major post-approval changes to original proposals made. In case of methodological changes, evidence of risk assessments for changes and/or COSHH (Control of Substances Hazardous to Health Regulations) should also be given. Likewise, any new collaborative partners or removal of researchers should also be notified to the IEAC.

Other findings include:

in case of complete changes in the project, the research must be stopped and new approval should be seeked,

in case of noticing any adverse effects to project participants (human or non-human), these should also be notified to the committee for appropriate clearance to continue the work, and

the completion of the project must also be notified with the indication whether the researchers may restart the project at a later stage.

Research involving humans - informed consents

While discussing research involving humans and based on literature review, findings highlight the human subjects/volunteers must willingly participate in research after being adequately informed about the project. Therefore, research involving humans and animals takes precedence in obtaining ethical clearance and its strict adherence, one of which is providing a participant information sheet/leaflet. This sheet should contain a full explanation about the research that is being carried out and be given out in lay-person’s terms in writing (Manti and Licari 2018 ; Hardicre 2014 ). Measures should also be in place to explain and clarify any doubts from the participants. In addition, there should be a clear statement on how the participants’ anonymity is protected. We provide below some example questions below to help the researchers to write this participant information sheet:

What is the purpose of the study?

Why have they been chosen?

What will happen if they take part?

What do they have to do?

What happens when the research stops?

What if something goes wrong?

What will happen to the results of the research study?

Will taking part be kept confidential?

How to handle “vulnerable” participants?

How to mitigate risks to participants?

Many institutional ethics committees expect the researchers to produce a FAQ (frequently asked questions) in addition to the information about research. Most importantly, the researchers also need to provide an informed consent form, which should be signed by each human participant. The five elements identified that are needed to be considered for an informed consent statement are summarized in Fig.  4 below (slightly modified from the Federal Policy for the Protection of Human Subjects ( 2018 ) - Diffn website c ).

Five basic elements to consider for an informed consent [figure adapted from Diffn website c ]

The informed consent form should always contain a clause for the participant to withdraw their consent at any time. Should this happen all the data from that participant should be eliminated from the study without affecting their anonymity.

Typical research ethics approval process

In this section, we provide an example flow chart explaining how researchers may choose the appropriate application and process, as highlighted in Fig.  5 . However, it is imperative to note here that these are examples only and some institutions may have one unified application with separate sections to demarcate qualitative and quantitative research criteria.

Typical ethical approval processes for quantitative and qualitative research. [N/B for Fig. 5 - This simplified flow chart shows that fundamental process for invasive and non-invasive EC application is same, the routes and the requirements for additional information are slightly different]

Once the ethical application is submitted, the EC should ensure a clear approval procedure with distinctly defined timeline. An example flow chart showing the procedure for an ethical approval was obtained from University of Leicester as open-access. This is presented in Fig.  6 . Further examples of the ethical approval process and governance were discussed in the workshop.

An example ethical approval procedures conducted within University of Leicester (Figure obtained from the University of Leicester research pages - Difn website d - open access)

Strategies for ethics educations for students

Student education on the importance of ethics and ethical behaviour in research and scholarly activities is extremely essential. Literature posits in the area of medical research that many universities are incorporating ethics in post-graduate degrees but when it comes to undergraduate degrees, there is less appetite to deliver modules or even lectures focussing on research ethics (Seymour et al., 2004 ; Willison and O’Regan, 2007 ). This may be due to the fact that undergraduate degree structure does not really focus on research (DePasse et al., 2016 ). However, as Orr ( 2018 ) suggested, institutions should focus more on educating all students about ethics/ethical behaviour and their importance in research, than enforcing punitive measures for unethical behaviour. Therefore, as an advisory committee, and based on our preliminary literature survey and workshop results, we strongly recommend incorporating ethical education within undergraduate curriculum. Looking at those institutions which focus on ethical education for both under-and postgraduate courses, their approaches are either (a) a lecture-based delivery, (b) case study based approach or (c) a combined delivery starting with a lecture on basic principles of ethics followed by generating a debate based discussion using interesting case studies. The combined method seems much more effective than the other two as per our findings as explained next.

As many academics who have been involved in teaching ethics and/or research ethics agree, the underlying principles of ethics is often perceived as a boring subject. Therefore, lecture-based delivery may not be suitable. On the other hand, a debate based approach, though attractive and instantly generates student interest, cannot be effective without students understanding the underlying basic principles. In addition, when selecting case studies, it would be advisable to choose cases addressing all different types of ethical dilemmas. As an advisory group within ENAI, we are in the process of collating supporting materials to help to develop institutional policies, creating advisory documents to help in obtaining ethical approvals, and teaching materials to enhance debate-based lesson plans that can be used by the member and other institutions.

Concluding remarks

In summary, our literature survey and workshop findings highlight that researchers should accept that ethics underpins everything we do, especially in research. Although ethical approval is tedious, it is an imperative process in which proactive thinking is essential to identify ethical issues that might affect the project. Our findings further lead us to state that the ethical approval process differs from institution to institution and we strongly recommend the researchers to follow the institutional guidelines and their underlying ethical principles. The ENAI workshop in Vilnius highlighted the importance of ethical governance by establishing ECs, discussed different types of ECs and procedures with some examples and highlighted the importance of student education to impart ethical culture within research communities, an area that needs further study as future scope.

Declarations

The manuscript was entirely written by the corresponding author with contributions from co-authors who have also taken part in the delivery of the workshop. Authors confirm that the data supporting the findings of this study are available within the article. We can also confirm that there are no potential competing interests with other organisations.

Availability of data and materials

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Abbreviations

ALL European academics

Australian research council

Biotechnology and biological sciences research council

Canadian institutes for health research

Committee of publication ethics

Ethical committee

European network of academic integrity

Economic and social research council

International convention for the protection of animals

institutional ethical advisory committee

Institutional review board

Immaculata university of Pennsylvania

Lesbian, gay, bisexual, and transgender

Medical research council)

National health services

National health services nih national institute of health (NIH)

National institute of clinical care excellence

National health and medical research council

Natural sciences and engineering research council

National research ethics committee

National statement on ethical conduct in human research

Responsible research practice

Social sciences and humanities research council

Tri-council policy statement

World Organization for animal health

Universities Australia

UK-research and innovation

US office for human research protections

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Sivasubramaniam, S., Dlabolová, D.H., Kralikova, V. et al. Assisting you to advance with ethics in research: an introduction to ethical governance and application procedures. Int J Educ Integr 17 , 14 (2021). https://doi.org/10.1007/s40979-021-00078-6

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Ethical Issues in Research: Perceptions of Researchers, Research Ethics Board Members and Research Ethics Experts

Marie-josée drolet.

1 Department of Occupational Therapy (OT), Université du Québec à Trois-Rivières (UQTR), Trois-Rivières (Québec), Canada

Eugénie Rose-Derouin

2 Bachelor OT program, Université du Québec à Trois-Rivières (UQTR), Trois-Rivières (Québec), Canada

Julie-Claude Leblanc

Mélanie ruest, bryn williams-jones.

3 Department of Social and Preventive Medicine, School of Public Health, Université de Montréal, Montréal (Québec), Canada

In the context of academic research, a diversity of ethical issues, conditioned by the different roles of members within these institutions, arise. Previous studies on this topic addressed mainly the perceptions of researchers. However, to our knowledge, no studies have explored the transversal ethical issues from a wider spectrum, including other members of academic institutions as the research ethics board (REB) members, and the research ethics experts. The present study used a descriptive phenomenological approach to document the ethical issues experienced by a heterogeneous group of Canadian researchers, REB members, and research ethics experts. Data collection involved socio-demographic questionnaires and individual semi-structured interviews. Following the triangulation of different perspectives (researchers, REB members and ethics experts), emerging ethical issues were synthesized in ten units of meaning: (1) research integrity, (2) conflicts of interest, (3) respect for research participants, (4) lack of supervision and power imbalances, (5) individualism and performance, (6) inadequate ethical guidance, (7) social injustices, (8) distributive injustices, (9) epistemic injustices, and (10) ethical distress. This study highlighted several problematic elements that can support the identification of future solutions to resolve transversal ethical issues in research that affect the heterogeneous members of the academic community.

Introduction

Research includes a set of activities in which researchers use various structured methods to contribute to the development of knowledge, whether this knowledge is theoretical, fundamental, or applied (Drolet & Ruest, accepted ). University research is carried out in a highly competitive environment that is characterized by ever-increasing demands (i.e., on time, productivity), insufficient access to research funds, and within a market economy that values productivity and speed often to the detriment of quality or rigour – this research context creates a perfect recipe for breaches in research ethics, like research misbehaviour or misconduct (i.e., conduct that is ethically questionable or unacceptable because it contravenes the accepted norms of responsible conduct of research or compromises the respect of core ethical values that are widely held by the research community) (Drolet & Girard, 2020 ; Sieber, 2004 ). Problematic ethics and integrity issues – e.g., conflicts of interest, falsification of data, non-respect of participants’ rights, and plagiarism, to name but a few – have the potential to both undermine the credibility of research and lead to negative consequences for many stakeholders, including researchers, research assistants and personnel, research participants, academic institutions, and society as a whole (Drolet & Girard, 2020 ). It is thus evident that the academic community should be able to identify these different ethical issues in order to evaluate the nature of the risks that they pose (and for whom), and then work towards their prevention or management (i.e., education, enhanced policies and procedures, risk mitigation strategies).

In this article, we define an “ethical issue” as any situation that may compromise, in whole or in part, the respect of at least one moral value (Swisher et al., 2005 ) that is considered socially legitimate and should thus be respected. In general, ethical issues occur at three key moments or stages of the research process: (1) research design (i.e., conception, project planning), (2) research conduct (i.e., data collection, data analysis) and (3) knowledge translation or communication (e.g., publications of results, conferences, press releases) (Drolet & Ruest, accepted ). According to Sieber ( 2004 ), ethical issues in research can be classified into five categories, related to: (a) communication with participants and the community, (b) acquisition and use of research data, (c) external influence on research, (d) risks and benefits of the research, and (e) selection and use of research theories and methods. Many of these issues are related to breaches of research ethics norms, misbehaviour or research misconduct. Bruhn et al., ( 2002 ) developed a typology of misbehaviour and misconduct in academia that can be used to judge the seriousness of different cases. This typology takes into consideration two axes of reflection: (a) the origin of the situation (i.e., is it the researcher’s own fault or due to the organizational context?), and (b) the scope and severity (i.e., is this the first instance or a recurrent behaviour? What is the nature of the situation? What are the consequences, for whom, for how many people, and for which organizations?).

A previous detailed review of the international literature on ethical issues in research revealed several interesting findings (Beauchemin et al., 2021 ). Indeed, the current literature is dominated by descriptive ethics, i.e., the sharing by researchers from various disciplines of the ethical issues they have personally experienced. While such anecdotal documentation is relevant, it is insufficient because it does not provide a global view of the situation. Among the reviewed literature, empirical studies were in the minority (Table  1 ) – only about one fifth of the sample (n = 19) presented empirical research findings on ethical issues in research. The first of these studies was conducted almost 50 years ago (Hunt et al., 1984 ), with the remainder conducted in the 1990s. Eight studies were conducted in the United States (n = 8), five in Canada (n = 5), three in England (n = 3), two in Sweden (n = 2) and one in Ghana (n = 1).

Summary of Empirical Studies on Ethical Issues in Research by the year of publication

Further, the majority of studies in our sample (n = 12) collected the perceptions of a homogeneous group of participants, usually researchers (n = 14) and sometimes health professionals (n = 6). A minority of studies (n = 7) triangulated the perceptions of diverse research stakeholders (i.e., researchers and research participants, or students). To our knowledge, only one study has examined perceptions of ethical issues in research by research ethics board members (REB; Institutional Review Boards [IRB] in the USA), and none to date have documented the perceptions of research ethics experts. Finally, nine studies (n = 9) adopted a qualitative design, seven studies (n = 7) a quantitative design, and three (n = 3) a mixed-methods design.

More studies using empirical research methods are needed to better identify broader trends, to enrich discussions on the values that should govern responsible conduct of research in the academic community, and to evaluate the means by which these values can be supported in practice (Bahn, 2012 ; Beauchemin et al., 2021 ; Bruhn et al., 2002 ; Henderson et al., 2013 ; Resnik & Elliot, 2016; Sieber 2004 ). To this end, we conducted an empirical qualitative study to document the perceptions and experiences of a heterogeneous group of Canadian researchers, REB members, and research ethics experts, to answer the following broad question: What are the ethical issues in research?

Research Methods

Research design.

A qualitative research approach involving individual semi-structured interviews was used to systematically document ethical issues (De Poy & Gitlin, 2010 ; Hammell et al., 2000 ). Specifically, a descriptive phenomenological approach inspired by the philosophy of Husserl was used (Husserl, 1970 , 1999 ), as it is recommended for documenting the perceptions of ethical issues raised by various practices (Hunt & Carnavale, 2011 ).

Ethical considerations

The principal investigator obtained ethics approval for this project from the Research Ethics Board of the Université du Québec à Trois-Rivières (UQTR). All members of the research team signed a confidentiality agreement, and research participants signed the consent form after reading an information letter explaining the nature of the research project.

Sampling and recruitment

As indicated above, three types of participants were sought: (1) researchers from different academic disciplines conducting research (i.e., theoretical, fundamental or empirical) in Canadian universities; (2) REB members working in Canadian organizations responsible for the ethical review, oversight or regulation of research; and (3) research ethics experts, i.e., academics or ethicists who teach research ethics, conduct research in research ethics, or are scholars who have acquired a specialization in research ethics. To be included in the study, participants had to work in Canada, speak and understand English or French, and be willing to participate in the study. Following Thomas and Polio’s (2002) recommendation to recruit between six and twelve participants (for a homogeneous sample) to ensure data saturation, for our heterogeneous sample, we aimed to recruit approximately twelve participants in order to obtain data saturation. Having used this method several times in related projects in professional ethics, data saturation is usually achieved with 10 to 15 participants (Drolet & Goulet, 2018 ; Drolet & Girard, 2020 ; Drolet et al., 2020 ). From experience, larger samples only serve to increase the degree of data saturation, especially in heterogeneous samples (Drolet et al., 2017 , 2019 ; Drolet & Maclure, 2016 ).

Purposive sampling facilitated the identification of participants relevant to documenting the phenomenon in question (Fortin, 2010 ). To ensure a rich and most complete representation of perceptions, we sought participants with varied and complementary characteristics with regards to the social roles they occupy in research practice (Drolet & Girard, 2020 ). A triangulation of sources was used for the recruitment (Bogdan & Biklen, 2006 ). The websites of Canadian universities and Canadian health institution REBs, as well as those of major Canadian granting agencies (i.e., the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, and the Social Sciences and Humanities Research Council of Canada, Fonds de recherche du Quebec), were searched to identify individuals who might be interested in participating in the study. Further, people known by the research team for their knowledge and sensitivity to ethical issues in research were asked to participate. Research participants were also asked to suggest other individuals who met the study criteria.

Data Collection

Two tools were used for data collecton: (a) a socio-demographic questionnaire, and (b) a semi-structured individual interview guide. English and French versions of these two documents were used and made available, depending on participant preferences. In addition, although the interview guide contained the same questions, they were adapted to participants’ specific roles (i.e., researcher, REB member, research ethics expert). When contacted by email by the research assistant, participants were asked to confirm under which role they wished to participate (because some participants might have multiple, overlapping responsibilities) and they were sent the appropriate interview guide.

The interview guides each had two parts: an introduction and a section on ethical issues. The introduction consisted of general questions to put the participant at ease (i.e., “Tell me what a typical day at work is like for you”). The section on ethical issues was designed to capture the participant’s perceptions through questions such as: “Tell me three stories you have experienced at work that involve an ethical issue?” and “Do you feel that your organization is doing enough to address, manage, and resolve ethical issues in your work?”. Although some interviews were conducted in person, the majority were conducted by videoconference to promote accessibility and because of the COVID-19 pandemic. Interviews were digitally recorded so that the verbatim could be transcribed in full, and varied between 40 and 120 min in duration, with an average of 90 min. Research assistants conducted the interviews and transcribed the verbatim.

Data Analysis

The socio-demographic questionnaires were subjected to simple descriptive statistical analyses (i.e., means and totals), and the semi-structured interviews were subjected to qualitative analysis. The steps proposed by Giorgi ( 1997 ) for a Husserlian phenomenological reduction of the data were used. After collecting, recording, and transcribing the interviews, all verbatim were analyzed by at least two analysts: a research assistant (2nd author of this article) and the principal investigator (1st author) or a postdoctoral fellow (3rd author). The repeated reading of the verbatim allowed the first analyst to write a synopsis, i.e., an initial extraction of units of meaning. The second analyst then read the synopses, which were commented and improved if necessary. Agreement between analysts allowed the final drafting of the interview synopses, which were then analyzed by three analysts to generate and organize the units of meaning that emerged from the qualitative data.

Participants

Sixteen individuals (n = 16) participated in the study, of whom nine (9) identified as female and seven (7) as male (Table  2 ). Participants ranged in age from 22 to 72 years, with a mean age of 47.5 years. Participants had between one (1) and 26 years of experience in the research setting, with an average of 14.3 years of experience. Participants held a variety of roles, including: REB members (n = 11), researchers (n = 10), research ethics experts (n = 4), and research assistant (n = 1). As mentioned previously, seven (7) participants held more than one role, i.e., REB member, research ethics expert, and researcher. The majority (87.5%) of participants were working in Quebec, with the remaining working in other Canadian provinces. Although all participants considered themselves to be francophone, one quarter (n = 4) identified themselves as belonging to a cultural minority group.

Description of Participants

With respect to their academic background, most participants (n = 9) had a PhD, three (3) had a post-doctorate, two (2) had a master’s degree, and two (2) had a bachelor’s degree. Participants came from a variety of disciplines: nine (9) had a specialty in the humanities or social sciences, four (4) in the health sciences and three (3) in the natural sciences. In terms of their knowledge of ethics, five (5) participants reported having taken one university course entirely dedicated to ethics, four (4) reported having taken several university courses entirely dedicated to ethics, three (3) had a university degree dedicated to ethics, while two (2) only had a few hours or days of training in ethics and two (2) reported having no knowledge of ethics.

Ethical issues

As Fig.  1 illustrates, ten units of meaning emerge from the data analysis, namely: (1) research integrity, (2) conflicts of interest, (3) respect for research participants, (4) lack of supervision and power imbalances, (5) individualism and performance, (6) inadequate ethical guidance, (7) social injustices, (8) distributive injustices, (9) epistemic injustices, and (10) ethical distress. To illustrate the results, excerpts from verbatim interviews are presented in the following sub-sections. Most of the excerpts have been translated into English as the majority of interviews were conducted with French-speaking participants.

Ethical issues in research according to the participants

Research Integrity

The research environment is highly competitive and performance-based. Several participants, in particular researchers and research ethics experts, felt that this environment can lead both researchers and research teams to engage in unethical behaviour that reflects a lack of research integrity. For example, as some participants indicated, competition for grants and scientific publications is sometimes so intense that researchers falsify research results or plagiarize from colleagues to achieve their goals.

Some people will lie or exaggerate their research findings in order to get funding. Then, you see it afterwards, you realize: “ah well, it didn’t work, but they exaggerated what they found and what they did” (participant 14). Another problem in research is the identification of authors when there is a publication. Very often, there are authors who don’t even know what the publication is about and that their name is on it. (…) The time that it surprised me the most was just a few months ago when I saw someone I knew who applied for a teaching position. He got it I was super happy for him. Then I looked at his publications and … there was one that caught my attention much more than the others, because I was in it and I didn’t know what that publication was. I was the second author of a publication that I had never read (participant 14). I saw a colleague who had plagiarized another colleague. [When the colleague] found out about it, he complained. So, plagiarism is a serious [ethical breach]. I would also say that there is a certain amount of competition in the university faculties, especially for grants (…). There are people who want to win at all costs or get as much as possible. They are not necessarily going to consider their colleagues. They don’t have much of a collegial spirit (participant 10).

These examples of research misbehaviour or misconduct are sometimes due to or associated with situations of conflicts of interest, which may be poorly managed by certain researchers or research teams, as noted by many participants.

Conflict of interest

The actors and institutions involved in research have diverse interests, like all humans and institutions. As noted in Chap. 7 of the Canadian Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS2, 2018),

“researchers and research students hold trust relationships, either directly or indirectly, with participants, research sponsors, institutions, their professional bodies and society. These trust relationships can be put at risk by conflicts of interest that may compromise independence, objectivity or ethical duties of loyalty. Although the potential for such conflicts has always existed, pressures on researchers (i.e., to delay or withhold dissemination of research outcomes or to use inappropriate recruitment strategies) heighten concerns that conflicts of interest may affect ethical behaviour” (p. 92).

The sources of these conflicts are varied and can include interpersonal conflicts, financial partnerships, third-party pressures, academic or economic interests, a researcher holding multiple roles within an institution, or any other incentive that may compromise a researcher’s independence, integrity, and neutrality (TCPS2, 2018). While it is not possible to eliminate all conflicts of interest, it is important to manage them properly and to avoid temptations to behave unethically.

Ethical temptations correspond to situations in which people are tempted to prioritize their own interests to the detriment of the ethical goods that should, in their own context, govern their actions (Swisher et al., 2005 ). In the case of researchers, this refers to situations that undermine independence, integrity, neutrality, or even the set of principles that govern research ethics (TCPS2, 2018) or the responsible conduct of research. According to study participants, these types of ethical issues frequently occur in research. Many participants, especially researchers and REB members, reported that conflicts of interest can arise when members of an organization make decisions to obtain large financial rewards or to increase their academic profile, often at the expense of the interests of members of their research team, research participants, or even the populations affected by their research.

A company that puts money into making its drug work wants its drug to work. So, homeopathy is a good example, because there are not really any consequences of homeopathy, there are not very many side effects, because there are no effects at all. So, it’s not dangerous, but it’s not a good treatment either. But some people will want to make it work. And that’s a big issue when you’re sitting at a table and there are eight researchers, and there are two or three who are like that, and then there are four others who are neutral, and I say to myself, this is not science. I think that this is a very big ethical issue (participant 14). There are also times in some research where there will be more links with pharmaceutical companies. Obviously, there are then large amounts of money that will be very interesting for the health-care institutions because they still receive money for clinical trials. They’re still getting some compensation because its time consuming for the people involved and all that. The pharmaceutical companies have money, so they will compensate, and that is sometimes interesting for the institutions, and since we are a bit caught up in this, in the sense that we have no choice but to accept it. (…) It may not be the best research in the world, there may be a lot of side effects due to the drugs, but it’s good to accept it, we’re going to be part of the clinical trial (participant 3). It is integrity, what we believe should be done or said. Often by the pressure of the environment, integrity is in tension with the pressures of the environment, so it takes resistance, it takes courage in research. (…) There were all the debates there about the problems of research that was funded and then the companies kept control over what was written. That was really troubling for a lot of researchers (participant 5).

Further, these situations sometimes have negative consequences for research participants as reported by some participants.

Respect for research participants

Many research projects, whether they are psychosocial or biomedical in nature, involve human participants. Relationships between the members of research teams and their research participants raise ethical issues that can be complex. Research projects must always be designed to respect the rights and interests of research participants, and not just those of researchers. However, participants in our study – i.e., REB members, researchers, and research ethics experts – noted that some research teams seem to put their own interests ahead of those of research participants. They also emphasized the importance of ensuring the respect, well-being, and safety of research participants. The ethical issues related to this unit of meaning are: respect for free, informed and ongoing consent of research participants; respect for and the well-being of participants; data protection and confidentiality; over-solicitation of participants; ownership of the data collected on participants; the sometimes high cost of scientific innovations and their accessibility; balance between the social benefits of research and the risks to participants (particularly in terms of safety); balance between collective well-being (development of knowledge) and the individual rights of participants; exploitation of participants; paternalism when working with populations in vulnerable situations; and the social acceptability of certain types of research. The following excerpts present some of these issues.

Where it disturbs me ethically is in the medical field – because it’s more in the medical field that we’re going to see this – when consent forms are presented to patients to solicit them as participants, and then [these forms] have an average of 40 pages. That annoys me. When they say that it has to be easy to understand and all that, adapted to the language, and then the hyper-technical language plus there are 40 pages to read, I don’t understand how you’re going to get informed consent after reading 40 pages. (…) For me, it doesn’t work. I read them to evaluate them and I have a certain level of education and experience in ethics, and there are times when I don’t understand anything (participant 2). There is a lot of pressure from researchers who want to recruit research participants (…). The idea that when you enter a health care institution, you become a potential research participant, when you say “yes to a research, you check yes to all research”, then everyone can ask you. I think that researchers really have this fantasy of saying to themselves: “as soon as people walk through the door of our institution, they become potential participants with whom we can communicate and get them involved in all projects”. There’s a kind of idea that, yes, it can be done, but it has to be somewhat supervised to avoid over-solicitation (…). Researchers are very interested in facilitating recruitment and making it more fluid, but perhaps to the detriment of confidentiality, privacy, and respect; sometimes that’s what it is, to think about what type of data you’re going to have in your bank of potential participants? Is it just name and phone number or are you getting into more sensitive information? (participant 9).

In addition, one participant reported that their university does not provide the resources required to respect the confidentiality of research participants.

The issue is as follows: researchers, of course, commit to protecting data with passwords and all that, but we realize that in practice, it is more difficult. It is not always as protected as one might think, because professor-researchers will run out of space. Will the universities make rooms available to researchers, places where they can store these things, especially when they have paper documentation, and is there indeed a guarantee of confidentiality? Some researchers have told me: “Listen; there are even filing cabinets in the corridors”. So, that certainly poses a concrete challenge. How do we go about challenging the administrative authorities? Tell them it’s all very well to have an ethics committee, but you have to help us, you also have to make sure that the necessary infrastructures are in place so that what we are proposing is really put into practice (participant 4).

If the relationships with research participants are likely to raise ethical issues, so too are the relationships with students, notably research assistants. On this topic, several participants discussed the lack of supervision or recognition offered to research assistants by researchers as well as the power imbalances between members of the research team.

Lack of Supervision and Power Imbalances

Many research teams are composed not only of researchers, but also of students who work as research assistants. The relationship between research assistants and other members of research teams can sometimes be problematic and raise ethical issues, particularly because of the inevitable power asymmetries. In the context of this study, several participants – including a research assistant, REB members, and researchers – discussed the lack of supervision or recognition of the work carried out by students, psychological pressure, and the more or less well-founded promises that are sometimes made to students. Participants also mentioned the exploitation of students by certain research teams, which manifest when students are inadequately paid, i.e., not reflective of the number of hours actually worked, not a fair wage, or even a wage at all.

[As a research assistant], it was more of a feeling of distress that I felt then because I didn’t know what to do. (…) I was supposed to get coaching or be supported, but I didn’t get anything in the end. It was like, “fix it by yourself”. (…) All research assistants were supposed to be supervised, but in practice they were not (participant 1). Very often, we have a master’s or doctoral student that we put on a subject and we consider that the project will be well done, while the student is learning. So, it happens that the student will do a lot of work and then we realize that the work is poorly done, and it is not necessarily the student’s fault. He wasn’t necessarily well supervised. There are directors who have 25 students, and they just don’t supervise them (participant 14). I think it’s really the power relationship. I thought to myself, how I saw my doctorate, the beginning of my research career, I really wanted to be in that laboratory, but they are the ones who are going to accept me or not, so what do I do to be accepted? I finally accept their conditions [which was to work for free]. If these are the conditions that are required to enter this lab, I want to go there. So, what do I do, well I accepted. It doesn’t make sense, but I tell myself that I’m still privileged, because I don’t have so many financial worries, one more reason to work for free, even though it doesn’t make sense (participant 1). In research, we have research assistants. (…). The fact of using people… so that’s it, you have to take into account where they are, respect them, but at the same time they have to show that they are there for the research. In English, we say “carry” or take care of people. With research assistants, this is often a problem that I have observed: for grant machines, the person is the last to be found there. Researchers, who will take, use student data, without giving them the recognition for it (participant 5). The problem at our university is that they reserve funding for Canadian students. The doctoral clientele in my field is mostly foreign students. So, our students are poorly funded. I saw one student end up in the shelter, in a situation of poverty. It ended very badly for him because he lacked financial resources. Once you get into that dynamic, it’s very hard to get out. I was made aware of it because the director at the time had taken him under her wing and wanted to try to find a way to get him out of it. So, most of my students didn’t get funded (participant 16). There I wrote “manipulation”, but it’s kind of all promises all the time. I, for example, was promised a lot of advancement, like when I got into the lab as a graduate student, it was said that I had an interest in [this particular area of research]. I think there are a lot of graduate students who must have gone through that, but it is like, “Well, your CV has to be really good, if you want to do a lot of things and big things. If you do this, if you do this research contract, the next year you could be the coordinator of this part of the lab and supervise this person, get more contracts, be paid more. Let’s say: you’ll be invited to go to this conference, this big event”. They were always dangling something, but you have to do that first to get there. But now, when you’ve done that, you have to do this business. It’s like a bit of manipulation, I think. That was very hard to know who is telling the truth and who is not (participant 1).

These ethical issues have significant negative consequences for students. Indeed, they sometimes find themselves at the mercy of researchers, for whom they work, struggling to be recognized and included as authors of an article, for example, or to receive the salary that they are due. For their part, researchers also sometimes find themselves trapped in research structures that can negatively affect their well-being. As many participants reported, researchers work in organizations that set very high productivity standards and in highly competitive contexts, all within a general culture characterized by individualism.

Individualism and performance

Participants, especially researchers, discussed the culture of individualism and performance that characterizes the academic environment. In glorifying excellence, some universities value performance and productivity, often at the expense of psychological well-being and work-life balance (i.e., work overload and burnout). Participants noted that there are ethical silences in their organizations on this issue, and that the culture of individualism and performance is not challenged for fear of retribution or simply to survive, i.e., to perform as expected. Participants felt that this culture can have a significant negative impact on the quality of the research conducted, as research teams try to maximize the quantity of their work (instead of quality) in a highly competitive context, which is then exacerbated by a lack of resources and support, and where everything must be done too quickly.

The work-life balance with the professional ethics related to work in a context where you have too much and you have to do a lot, it is difficult to balance all that and there is a lot of pressure to perform. If you don’t produce enough, that’s it; after that, you can’t get any more funds, so that puts pressure on you to do more and more and more (participant 3). There is a culture, I don’t know where it comes from, and that is extremely bureaucratic. If you dare to raise something, you’re going to have many, many problems. They’re going to make you understand it. So, I don’t talk. It is better: your life will be easier. I think there are times when you have to talk (…) because there are going to be irreparable consequences. (…) I’m not talking about a climate of terror, because that’s exaggerated, it’s not true, people are not afraid. But people close their office door and say nothing because it’s going to make their work impossible and they’re not going to lose their job, they’re not going to lose money, but researchers need time to be focused, so they close their office door and say nothing (participant 16).

Researchers must produce more and more, and they feel little support in terms of how to do such production, ethically, and how much exactly they are expected to produce. As this participant reports, the expectation is an unspoken rule: more is always better.

It’s sometimes the lack of a clear line on what the expectations are as a researcher, like, “ah, we don’t have any specific expectations, but produce, produce, produce, produce.” So, in that context, it’s hard to be able to put the line precisely: “have I done enough for my work?” (participant 3).

Inadequate ethical Guidance

While the productivity expectation is not clear, some participants – including researchers, research ethics experts, and REB members – also felt that the ethical expectations of some REBs were unclear. The issue of the inadequate ethical guidance of research includes the administrative mechanisms to ensure that research projects respect the principles of research ethics. According to those participants, the forms required for both researchers and REB members are increasingly long and numerous, and one participant noted that the standards to be met are sometimes outdated and disconnected from the reality of the field. Multicentre ethics review (by several REBs) was also critiqued by a participant as an inefficient method that encumbers the processes for reviewing research projects. Bureaucratization imposes an ever-increasing number of forms and ethics guidelines that actually hinder researchers’ ethical reflection on the issues at stake, leading the ethics review process to be perceived as purely bureaucratic in nature.

The ethical dimension and the ethical review of projects have become increasingly bureaucratized. (…) When I first started working (…) it was less bureaucratic, less strict then. I would say [there are now] tons of forms to fill out. Of course, we can’t do without it, it’s one of the ways of marking out ethics and ensuring that there are ethical considerations in research, but I wonder if it hasn’t become too bureaucratized, so that it’s become a kind of technical reflex to fill out these forms, and I don’t know if people really do ethical reflection as such anymore (participant 10). The fundamental structural issue, I would say, is the mismatch between the normative requirements and the real risks posed by the research, i.e., we have many, many requirements to meet; we have very long forms to fill out but the research projects we evaluate often pose few risks (participant 8). People [in vulnerable situations] were previously unable to participate because of overly strict research ethics rules that were to protect them, but in the end [these rules] did not protect them. There was a perverse effect, because in the end there was very little research done with these people and that’s why we have very few results, very little evidence [to support practices with these populations] so it didn’t improve the quality of services. (…) We all understand that we have to be careful with that, but when the research is not too risky, we say to ourselves that it would be good because for once a researcher who is interested in that population, because it is not a very popular population, it would be interesting to have results, but often we are blocked by the norms, and then we can’t accept [the project] (participant 2).

Moreover, as one participant noted, accessing ethics training can be a challenge.

There is no course on research ethics. […] Then, I find that it’s boring because you go through university and you come to do your research and you know how to do quantitative and qualitative research, but all the research ethics, where do you get this? I don’t really know (participant 13).

Yet, such training could provide relevant tools to resolve, to some extent, the ethical issues that commonly arise in research. That said, and as noted by many participants, many ethical issues in research are related to social injustices over which research actors have little influence.

Social Injustices

For many participants, notably researchers, the issues that concern social injustices are those related to power asymmetries, stigma, or issues of equity, diversity, and inclusion, i.e., social injustices related to people’s identities (Blais & Drolet, 2022 ). Participants reported experiencing or witnessing discrimination from peers, administration, or lab managers. Such oppression is sometimes cross-sectional and related to a person’s age, cultural background, gender or social status.

I have my African colleague who was quite successful when he arrived but had a backlash from colleagues in the department. I think it’s unconscious, nobody is overtly racist. But I have a young person right now who is the same, who has the same success, who got exactly the same early career award and I don’t see the same backlash. He’s just as happy with what he’s doing. It’s normal, they’re young and they have a lot of success starting out. So, I think there is discrimination. Is it because he is African? Is it because he is black? I think it’s on a subconscious level (participant 16).

Social injustices were experienced or reported by many participants, and included issues related to difficulties in obtaining grants or disseminating research results in one’s native language (i.e., even when there is official bilingualism) or being considered credible and fundable in research when one researcher is a woman.

If you do international research, there are things you can’t talk about (…). It is really a barrier to research to not be able to (…) address this question [i.e. the question of inequalities between men and women]. Women’s inequality is going to be addressed [but not within the country where the research takes place as if this inequality exists elsewhere but not here]. There are a lot of women working on inequality issues, doing work and it’s funny because I was talking to a young woman who works at Cairo University and she said to me: “Listen, I saw what you had written, you’re right. I’m willing to work on this but guarantee me a position at your university with a ticket to go”. So yes, there are still many barriers [for women in research] (participant 16).

Because of the varied contextual characteristics that intervene in their occurrence, these social injustices are also related to distributive injustices, as discussed by many participants.

Distributive Injustices

Although there are several views of distributive justice, a classical definition such as that of Aristotle ( 2012 ), describes distributive justice as consisting in distributing honours, wealth, and other social resources or benefits among the members of a community in proportion to their alleged merit. Justice, then, is about determining an equitable distribution of common goods. Contemporary theories of distributive justice are numerous and varied. Indeed, many authors (e.g., Fraser 2011 ; Mills, 2017 ; Sen, 2011 ; Young, 2011 ) have, since Rawls ( 1971 ), proposed different visions of how social burdens and benefits should be shared within a community to ensure equal respect, fairness, and distribution. In our study, what emerges from participants’ narratives is a definite concern for this type of justice. Women researchers, francophone researchers, early career researchers or researchers belonging to racialized groups all discussed inequities in the distribution of research grants and awards, and the extra work they need to do to somehow prove their worth. These inequities are related to how granting agencies determine which projects will be funded.

These situations make me work 2–3 times harder to prove myself and to show people in power that I have a place as a woman in research (participant 12). Number one: it’s conservative thinking. The older ones control what comes in. So, the younger people have to adapt or they don’t get funded (participant 14).

Whether it is discrimination against stigmatized or marginalized populations or interest in certain hot topics, granting agencies judge research projects according to criteria that are sometimes questionable, according to those participants. Faced with difficulties in obtaining funding for their projects, several strategies – some of which are unethical – are used by researchers in order to cope with these situations.

Sometimes there are subjects that everyone goes to, such as nanotechnology (…), artificial intelligence or (…) the therapeutic use of cannabis, which are very fashionable, and this is sometimes to the detriment of other research that is just as relevant, but which is (…), less sexy, less in the spirit of the time. (…) Sometimes this can lead to inequities in the funding of certain research sectors (participant 9). When we use our funds, we get them given to us, we pretty much say what we think we’re going to do with them, but things change… So, when these things change, sometimes it’s an ethical decision, but by force of circumstances I’m obliged to change the project a little bit (…). Is it ethical to make these changes or should I just let the money go because I couldn’t use it the way I said I would? (participant 3).

Moreover, these distributional injustices are not only linked to social injustices, but also epistemic injustices. Indeed, the way in which research honours and grants are distributed within the academic community depends on the epistemic authority of the researchers, which seems to vary notably according to their language of use, their age or their gender, but also to the research design used (inductive versus deductive), their decision to use (or not use) animals in research, or to conduct activist research.

Epistemic injustices

The philosopher Fricker ( 2007 ) conceptualized the notions of epistemic justice and injustice. Epistemic injustice refers to a form of social inequality that manifests itself in the access, recognition, and production of knowledge as well as the various forms of ignorance that arise (Godrie & Dos Santos, 2017 ). Addressing epistemic injustice necessitates acknowledging the iniquitous wrongs suffered by certain groups of socially stigmatized individuals who have been excluded from knowledge, thus limiting their abilities to interpret, understand, or be heard and account for their experiences. In this study, epistemic injustices were experienced or reported by some participants, notably those related to difficulties in obtaining grants or disseminating research results in one’s native language (i.e., even when there is official bilingualism) or being considered credible and fundable in research when a researcher is a woman or an early career researcher.

I have never sent a grant application to the federal government in English. I have always done it in French, even though I know that when you receive the review, you can see that reviewers didn’t understand anything because they are English-speaking. I didn’t want to get in the boat. It’s not my job to translate, because let’s be honest, I’m not as good in English as I am in French. So, I do them in my first language, which is the language I’m most used to. Then, technically at the administrative level, they are supposed to be able to do it, but they are not good in French. (…) Then, it’s a very big Canadian ethical issue, because basically there are technically two official languages, but Canada is not a bilingual country, it’s a country with two languages, either one or the other. (…) So I was not funded (participant 14).

Researchers who use inductive (or qualitative) methods observed that their projects are sometimes less well reviewed or understood, while research that adopts a hypothetical-deductive (or quantitative) or mixed methods design is better perceived, considered more credible and therefore more easily funded. Of course, regardless of whether a research project adopts an inductive, deductive or mixed-methods scientific design, or whether it deals with qualitative or quantitative data, it must respect a set of scientific criteria. A research project should achieve its objectives by using proven methods that, in the case of inductive research, are credible, reliable, and transferable or, in the case of deductive research, generalizable, objective, representative, and valid (Drolet & Ruest, accepted ). Participants discussing these issues noted that researchers who adopt a qualitative design or those who question the relevance of animal experimentation or are not militant have sometimes been unfairly devalued in their epistemic authority.

There is a mini war between quantitative versus qualitative methods, which I think is silly because science is a method. If you apply the method well, it doesn’t matter what the field is, it’s done well and it’s perfect ” (participant 14). There is also the issue of the place of animals in our lives, because for me, ethics is human ethics, but also animal ethics. Then, there is a great evolution in society on the role of the animal… with the new law that came out in Quebec on the fact that animals are sensitive beings. Then, with the rise of the vegan movement, [we must ask ourselves]: “Do animals still have a place in research?” That’s a big question and it also means that there are practices that need to evolve, but sometimes there’s a disconnection between what’s expected by research ethics boards versus what’s expected in the field (participant 15). In research today, we have more and more research that is militant from an ideological point of view. And so, we have researchers, because they defend values that seem important to them, we’ll talk for example about the fight for equality and social justice. They have pressure to defend a form of moral truth and have the impression that everyone thinks like them or should do so, because they are defending a moral truth. This is something that we see more and more, namely the lack of distance between ideology and science (participant 8).

The combination or intersectionality of these inequities, which seems to be characterized by a lack of ethical support and guidance, is experienced in the highly competitive and individualistic context of research; it provides therefore the perfect recipe for researchers to experience ethical distress.

Ethical distress

The concept of “ethical distress” refers to situations in which people know what they should do to act ethically, but encounter barriers, generally of an organizational or systemic nature, limiting their power to act according to their moral or ethical values (Drolet & Ruest, 2021 ; Jameton, 1984 ; Swisher et al., 2005 ). People then run the risk of finding themselves in a situation where they do not act as their ethical conscience dictates, which in the long term has the potential for exhaustion and distress. The examples reported by participants in this study point to the fact that researchers in particular may be experiencing significant ethical distress. This distress takes place in a context of extreme competition, constant injunctions to perform, and where administrative demands are increasingly numerous and complex to complete, while paradoxically, they lack the time to accomplish all their tasks and responsibilities. Added to these demands are a lack of resources (human, ethical, and financial), a lack of support and recognition, and interpersonal conflicts.

We are in an environment, an elite one, you are part of it, you know what it is: “publish or perish” is the motto. Grants, there is a high level of performance required, to do a lot, to publish, to supervise students, to supervise them well, so yes, it is clear that we are in an environment that is conducive to distress. (…). Overwork, definitely, can lead to distress and eventually to exhaustion. When you know that you should take the time to read the projects before sharing them, but you don’t have the time to do that because you have eight that came in the same day, and then you have others waiting… Then someone rings a bell and says: “ah but there, the protocol is a bit incomplete”. Oh yes, look at that, you’re right. You make up for it, but at the same time it’s a bit because we’re in a hurry, we don’t necessarily have the resources or are able to take the time to do things well from the start, we have to make up for it later. So yes, it can cause distress (participant 9). My organization wanted me to apply in English, and I said no, and everyone in the administration wanted me to apply in English, and I always said no. Some people said: “Listen, I give you the choice”, then some people said: “Listen, I agree with you, but if you’re not [submitting] in English, you won’t be funded”. Then the fact that I am young too, because very often they will look at the CV, they will not look at the project: “ah, his CV is not impressive, we will not finance him”. This is complete nonsense. The person is capable of doing the project, the project is fabulous: we fund the project. So, that happened, organizational barriers: that happened a lot. I was not eligible for Quebec research funds (…). I had big organizational barriers unfortunately (participant 14). At the time of my promotion, some colleagues were not happy with the type of research I was conducting. I learned – you learn this over time when you become friends with people after you enter the university – that someone was against me. He had another candidate in mind, and he was angry about the selection. I was under pressure for the first three years until my contract was renewed. I almost quit at one point, but another colleague told me, “No, stay, nothing will happen”. Nothing happened, but these issues kept me awake at night (participant 16).

This difficult context for many researchers affects not only the conduct of their own research, but also their participation in research. We faced this problem in our study, despite the use of multiple recruitment methods, including more than 200 emails – of which 191 were individual solicitations – sent to potential participants by the two research assistants. REB members and organizations overseeing or supporting research (n = 17) were also approached to see if some of their employees would consider participating. While it was relatively easy to recruit REB members and research ethics experts, our team received a high number of non-responses to emails (n = 175) and some refusals (n = 5), especially by researchers. The reasons given by those who replied were threefold: (a) fear of being easily identified should they take part in the research, (b) being overloaded and lacking time, and (c) the intrusive aspect of certain questions (i.e., “Have you experienced a burnout episode? If so, have you been followed up medically or psychologically?”). In light of these difficulties and concerns, some questions in the socio-demographic questionnaire were removed or modified. Talking about burnout in research remains a taboo for many researchers, which paradoxically can only contribute to the unresolved problem of unhealthy research environments.

Returning to the research question and objective

The question that prompted this research was: What are the ethical issues in research? The purpose of the study was to describe these issues from the perspective of researchers (from different disciplines), research ethics board (REB) members, and research ethics experts. The previous section provided a detailed portrait of the ethical issues experienced by different research stakeholders: these issues are numerous, diverse and were recounted by a range of stakeholders.

The results of the study are generally consistent with the literature. For example, as in our study, the literature discusses the lack of research integrity on the part of some researchers (Al-Hidabi et al., 2018 ; Swazey et al., 1993 ), the numerous conflicts of interest experienced in research (Williams-Jones et al., 2013 ), the issues of recruiting and obtaining the free and informed consent of research participants (Provencher et al., 2014 ; Keogh & Daly, 2009 ), the sometimes difficult relations between researchers and REBs (Drolet & Girard, 2020 ), the epistemological issues experienced in research (Drolet & Ruest, accepted; Sieber 2004 ), as well as the harmful academic context in which researchers evolve, insofar as this is linked to a culture of performance, an overload of work in a context of accountability (Berg & Seeber, 2016 ; FQPPU; 2019 ) that is conducive to ethical distress and even burnout.

If the results of the study are generally in line with those of previous publications on the subject, our findings also bring new elements to the discussion while complementing those already documented. In particular, our results highlight the role of systemic injustices – be they social, distributive or epistemic – within the environments in which research is carried out, at least in Canada. To summarize, the results of our study point to the fact that the relationships between researchers and research participants are likely still to raise worrying ethical issues, despite widely accepted research ethics norms and institutionalized review processes. Further, the context in which research is carried out is not only conducive to breaches of ethical norms and instances of misbehaviour or misconduct, but also likely to be significantly detrimental to the health and well-being of researchers, as well as research assistants. Another element that our research also highlighted is the instrumentalization and even exploitation of students and research assistants, which is another important and worrying social injustice given the inevitable power imbalances between students and researchers.

Moreover, in a context in which ethical issues are often discussed from a micro perspective, our study helps shed light on both the micro- and macro-level ethical dimensions of research (Bronfenbrenner, 1979 ; Glaser 1994 ). However, given that ethical issues in research are not only diverse, but also and above all complex, a broader perspective that encompasses the interplay between the micro and macro dimensions can enable a better understanding of these issues and thereby support the identification of the multiple factors that may be at their origin. Triangulating the perspectives of researchers with those of REB members and research ethics experts enabled us to bring these elements to light, and thus to step back from and critique the way that research is currently conducted. To this end, attention to socio-political elements such as the performance culture in academia or how research funds are distributed, and according to what explicit and implicit criteria, can contribute to identifying the sources of the ethical issues described above.

Contemporary culture characterized by the social acceleration

The German sociologist and philosopher Rosa (2010) argues that late modernity – that is, the period between the 1980s and today – is characterized by a phenomenon of social acceleration that causes various forms of alienation in our relationship to time, space, actions, things, others and ourselves. Rosa distinguishes three types of acceleration: technical acceleration , the acceleration of social changes and the acceleration of the rhythm of life . According to Rosa, social acceleration is the main problem of late modernity, in that the invisible social norm of doing more and faster to supposedly save time operates unchallenged at all levels of individual and collective life, as well as organizational and social life. Although we all, researchers and non-researchers alike, perceive this unspoken pressure to be ever more productive, the process of social acceleration as a new invisible social norm is our blind spot, a kind of tyrant over which we have little control. This conceptualization of the contemporary culture can help us to understand the context in which research is conducted (like other professional practices). To this end, Berg & Seeber ( 2016 ) invite faculty researchers to slow down in order to better reflect and, in the process, take care of their health and their relationships with their colleagues and students. Many women professors encourage their fellow researchers, especially young women researchers, to learn to “say No” in order to protect their mental and physical health and to remain in their academic careers (Allaire & Descheneux, 2022 ). These authors also remind us of the relevance of Kahneman’s ( 2012 ) work which demonstrates that it takes time to think analytically, thoroughly, and logically. Conversely, thinking quickly exposes humans to cognitive and implicit biases that then lead to errors in thinking (e.g., in the analysis of one’s own research data or in the evaluation of grant applications or student curriculum vitae). The phenomenon of social acceleration, which pushes the researcher to think faster and faster, is likely to lead to unethical bad science that can potentially harm humankind. In sum, Rosa’s invitation to contemporary critical theorists to seriously consider the problem of social acceleration is particularly insightful to better understand the ethical issues of research. It provides a lens through which to view the toxic context in which research is conducted today, and one that was shared by the participants in our study.

Clark & Sousa ( 2022 ) note, it is important that other criteria than the volume of researchers’ contributions be valued in research, notably quality. Ultimately, it is the value of the knowledge produced and its influence on the concrete lives of humans and other living beings that matters, not the quantity of publications. An interesting articulation of this view in research governance is seen in a change in practice by Australia’s national health research funder: they now restrict researchers to listing on their curriculum vitae only the top ten publications from the past ten years (rather than all of their publications), in order to evaluate the quality of contributions rather than their quantity. To create environments conducive to the development of quality research, it is important to challenge the phenomenon of social acceleration, which insidiously imposes a quantitative normativity that is both alienating and detrimental to the quality and ethical conduct of research. Based on our experience, we observe that the social norm of acceleration actively disfavours the conduct of empirical research on ethics in research. The fact is that researchers are so busy that it is almost impossible for them to find time to participate in such studies. Further, operating in highly competitive environments, while trying to respect the values and ethical principles of research, creates ethical paradoxes for members of the research community. According to Malherbe ( 1999 ), an ethical paradox is a situation where an individual is confronted by contradictory injunctions (i.e., do more, faster, and better). And eventually, ethical paradoxes lead individuals to situations of distress and burnout, or even to ethical failures (i.e., misbehaviour or misconduct) in the face of the impossibility of responding to contradictory injunctions.

Strengths and Limitations of the study

The triangulation of perceptions and experiences of different actors involved in research is a strength of our study. While there are many studies on the experiences of researchers, rarely are members of REBs and experts in research ethics given the space to discuss their views of what are ethical issues. Giving each of these stakeholders a voice and comparing their different points of view helped shed a different and complementary light on the ethical issues that occur in research. That said, it would have been helpful to also give more space to issues experienced by students or research assistants, as the relationships between researchers and research assistants are at times very worrying, as noted by a participant, and much work still needs to be done to eliminate the exploitative situations that seem to prevail in certain research settings. In addition, no Indigenous or gender diverse researchers participated in the study. Given the ethical issues and systemic injustices that many people from these groups face in Canada (Drolet & Goulet, 2018 ; Nicole & Drolet, in press ), research that gives voice to these researchers would be relevant and contribute to knowledge development, and hopefully also to change in research culture.

Further, although most of the ethical issues discussed in this article may be transferable to the realities experienced by researchers in other countries, the epistemic injustice reported by Francophone researchers who persist in doing research in French in Canada – which is an officially bilingual country but in practice is predominantly English – is likely specific to the Canadian reality. In addition, and as mentioned above, recruitment proved exceedingly difficult, particularly amongst researchers. Despite this difficulty, we obtained data saturation for all but two themes – i.e., exploitation of students and ethical issues of research that uses animals. It follows that further empirical research is needed to improve our understanding of these specific issues, as they may diverge to some extent from those documented here and will likely vary across countries and academic research contexts.

Conclusions

This study, which gave voice to researchers, REB members, and ethics experts, reveals that the ethical issues in research are related to several problematic elements as power imbalances and authority relations. Researchers and research assistants are subject to external pressures that give rise to integrity issues, among others ethical issues. Moreover, the current context of social acceleration influences the definition of the performance indicators valued in academic institutions and has led their members to face several ethical issues, including social, distributive, and epistemic injustices, at different steps of the research process. In this study, ten categories of ethical issues were identified, described and illustrated: (1) research integrity, (2) conflicts of interest, (3) respect for research participants, (4) lack of supervision and power imbalances, (5) individualism and performance, (6) inadequate ethical guidance, (7) social injustices, (8) distributive injustices, (9) epistemic injustices, and (10) ethical distress. The triangulation of the perspectives of different members (i.e., researchers from different disciplines, REB members, research ethics experts, and one research assistant) involved in the research process made it possible to lift the veil on some of these ethical issues. Further, it enabled the identification of additional ethical issues, especially systemic injustices experienced in research. To our knowledge, this is the first time that these injustices (social, distributive, and epistemic injustices) have been clearly identified.

Finally, this study brought to the fore several problematic elements that are important to address if the research community is to develop and implement the solutions needed to resolve the diverse and transversal ethical issues that arise in research institutions. A good starting point is the rejection of the corollary norms of “publish or perish” and “do more, faster, and better” and their replacement with “publish quality instead of quantity”, which necessarily entails “do less, slower, and better”. It is also important to pay more attention to the systemic injustices within which researchers work, because these have the potential to significantly harm the academic careers of many researchers, including women researchers, early career researchers, and those belonging to racialized groups as well as the health, well-being, and respect of students and research participants.

Acknowledgements

The team warmly thanks the participants who took part in the research and who made this study possible. Marie-Josée Drolet thanks the five research assistants who participated in the data collection and analysis: Julie-Claude Leblanc, Élie Beauchemin, Pénéloppe Bernier, Louis-Pierre Côté, and Eugénie Rose-Derouin, all students at the Université du Québec à Trois-Rivières (UQTR), two of whom were active in the writing of this article. MJ Drolet and Bryn Williams-Jones also acknowledge the financial contribution of the Social Sciences and Humanities Research Council of Canada (SSHRC), which supported this research through a grant. We would also like to thank the reviewers of this article who helped us improve it, especially by clarifying and refining our ideas.

Competing Interests and Funding

As noted in the Acknowledgements, this research was supported financially by the Social Sciences and Humanities Research Council of Canada (SSHRC).

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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The Belmont Report: the Ethics of Human Research

This essay about the Belmont Report illuminates its critical role in guiding ethical research involving human subjects. Drafted in the late 1970s, the document sets forth three foundational principles: Respect for Persons, Beneficence, and Justice. These principles advocate for the autonomy of participants, the maximization of benefits while minimizing harms, and fairness in the distribution of research’s burdens and benefits, respectively. The report’s influence extends into the regulatory realm, shaping policies that oversee research conduct, notably through Institutional Review Boards (IRBs). These boards ensure research proposals align with the ethical standards championed by the Belmont Report, emphasizing the protection and dignity of participants. Ultimately, the essay portrays the Belmont Report as a cornerstone of ethical research, essential for maintaining integrity and humanity in the pursuit of scientific knowledge.

How it works

In the world of research, where the quest for knowledge often treads a fine line between breakthrough and breach of trust, the Belmont Report stands as a beacon of ethical guidance. Crafted in the late 1970s, this pivotal document outlines three bedrock principles essential to ethical research involving human subjects: Respect for Persons, Beneficence, and Justice. These principles have since become the moral compass for researchers navigating the complex interplay of innovation and integrity.

At the heart of the Belmont Report is the principle of Respect for Persons, a declaration that individuals are more than just means to an end.

This principle champions the autonomy of participants, advocating for their right to make informed decisions about their involvement in research. It’s a call to honor each person’s capacity to choose, underscored by a commitment to protect those who might not fully wield this autonomy, such as children or those with cognitive impairments. It’s about ensuring that everyone gets a fair say, and those who can’t speak for themselves are given the consideration they deserve.

Then there’s Beneficence, a principle that pushes the ethical envelope beyond merely avoiding harm to actively seeking good. It’s not enough for researchers to dodge the pitfalls of damage; they are tasked with creating scenarios where the scales tip decidedly toward benefit. This is where the meticulous balance of risk and reward comes into play, requiring a delicate dance to ensure that the pursuit of knowledge doesn’t come at an unacceptable cost to participants.

Justice, the third pillar, addresses the equitable distribution of the research’s burdens and benefits. It’s a principle steeped in fairness, challenging researchers to scrutinize who reaps the rewards of research and who bears its weight. This isn’t just academic musing; it’s a practical guide to ensuring that research doesn’t exploit or overlook any group, aiming for a level playing field where everyone has equal opportunity to benefit from scientific advances.

The influence of the Belmont Report transcends its pages, breathing ethical life into the entire research process. Its principles underpin the rules and regulations that govern research today, including the oversight by Institutional Review Boards (IRBs). These bodies, charged with the review and approval of research proposals, are the guardians of the ethical standards set forth in the Belmont Report, ensuring that research doesn’t just push boundaries but also respects them.

In essence, the Belmont Report is more than a document; it’s a declaration of our collective commitment to conducting research with conscience. It’s a reminder that in the rush toward the next big discovery, we must pause to consider the human element. As research methodologies evolve and new ethical challenges arise, the Belmont Report remains a touchstone, reminding us that at the intersection of science and humanity, ethics must always have the right of way.

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• Open access
• Published: 08 April 2024

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

• Felicity Liew 1   na1 ,
• Claudia Efstathiou   ORCID: orcid.org/0000-0001-6125-8126 1   na1 ,
• Sara Fontanella 1 ,
• Matthew Richardson 2 ,
• Ruth Saunders 2 ,
• Dawid Swieboda 1 ,
• Jasmin K. Sidhu 1 ,
• Stephanie Ascough 1 ,
• Shona C. Moore   ORCID: orcid.org/0000-0001-8610-2806 3 ,
• Noura Mohamed 4 ,
• Jose Nunag   ORCID: orcid.org/0000-0002-4218-0500 5 ,
• Clara King 5 ,
• Olivia C. Leavy 2 , 6 ,
• Omer Elneima 2 ,
• Hamish J. C. McAuley 2 ,
• Aarti Shikotra 7 ,
• Amisha Singapuri   ORCID: orcid.org/0009-0002-4711-7516 2 ,
• Marco Sereno   ORCID: orcid.org/0000-0003-4573-9303 2 ,
• Victoria C. Harris 2 ,
• Linzy Houchen-Wolloff   ORCID: orcid.org/0000-0003-4940-8835 8 ,
• Neil J. Greening   ORCID: orcid.org/0000-0003-0453-7529 2 ,
• Nazir I. Lone   ORCID: orcid.org/0000-0003-2707-2779 9 ,
• Matthew Thorpe 10 ,
• A. A. Roger Thompson   ORCID: orcid.org/0000-0002-0717-4551 11 ,
• Sarah L. Rowland-Jones 11 ,
• Annemarie B. Docherty   ORCID: orcid.org/0000-0001-8277-420X 10 ,
• James D. Chalmers 12 ,
• Ling-Pei Ho   ORCID: orcid.org/0000-0001-8319-301X 13 ,
• Alexander Horsley   ORCID: orcid.org/0000-0003-1828-0058 14 ,
• Betty Raman 15 ,
• Krisnah Poinasamy 16 ,
• Michael Marks 17 , 18 , 19 ,
• Onn Min Kon 1 ,
• Luke S. Howard   ORCID: orcid.org/0000-0003-2822-210X 1 ,
• Daniel G. Wootton 3 ,
• Jennifer K. Quint 1 ,
• Thushan I. de Silva   ORCID: orcid.org/0000-0002-6498-9212 11 ,
• Antonia Ho 20 ,
• Christopher Chiu   ORCID: orcid.org/0000-0003-0914-920X 1 ,
• Ewen M. Harrison   ORCID: orcid.org/0000-0002-5018-3066 10 ,
• William Greenhalf 21 ,
• J. Kenneth Baillie   ORCID: orcid.org/0000-0001-5258-793X 10 , 22 , 23 ,
• Malcolm G. Semple   ORCID: orcid.org/0000-0001-9700-0418 3 , 24 ,
• Lance Turtle 3 , 24 ,
• Rachael A. Evans   ORCID: orcid.org/0000-0002-1667-868X 2 ,
• Louise V. Wain 2 , 6 ,
• Christopher Brightling 2 ,
• Ryan S. Thwaites   ORCID: orcid.org/0000-0003-3052-2793 1   na1 ,
• Peter J. M. Openshaw   ORCID: orcid.org/0000-0002-7220-2555 1   na1 ,
• PHOSP-COVID collaborative group &

ISARIC investigators

Nature Immunology volume  25 ,  pages 607–621 ( 2024 ) Cite this article

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• Inflammasome
• Inflammation
• Innate immunity

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood 1 . Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.

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Epidemiology, clinical presentation, pathophysiology, and management of long COVID: an update

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One in ten severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections results in post-acute sequelae of coronavirus disease 2019 (PASC) or long coronavirus disease (COVID), which affects 65 million people worldwide 1 . Long COVID (LC) remains common, even after mild acute infection with recent variants 2 , and it is likely LC will continue to cause substantial long-term ill health, requiring targeted management based on an understanding of how disease phenotypes relate to underlying mechanisms. Persistent inflammation has been reported in adults with LC 1 , 3 , but studies have been limited in size, timing of samples or breadth of immune mediators measured, leading to inconsistent or absent associations with symptoms. Markers of oxidative stress, metabolic disturbance, vasculoproliferative processes and IFN-, NF-κB- or monocyte-related inflammation have been suggested 3 , 4 , 5 , 6 .

The PHOSP-COVID study, a multicenter United Kingdom study of patients previously hospitalized with COVID-19, has reported inflammatory profiles in 626 adults with health impairment after COVID-19, identified through clustering. Elevated IL-6 and markers of mucosal inflammation were observed in those with severe impairment compared with individuals with milder impairment 7 . However, LC is a heterogeneous condition that may be a distinct form of health impairment after COVID-19, and it remains unclear whether there are inflammatory changes specific to LC symptom subtypes. Determining whether activated inflammatory pathways underlie all cases of LC or if mechanisms differ according to clinical presentation is essential for developing effective therapies and has been highlighted as a top research priority by patients and clinicians 8 .

In this Letter, in a prospective multicenter study, we measured 368 plasma proteins in 657 adults previously hospitalized for COVID-19 (Fig. 1a and Table 1 ). Individuals in our cohort experienced a range of acute COVID-19 severities based on World Health Organization (WHO) progression scores 9 ; WHO 3–4 (no oxygen support, n  = 133 and median age of 55 years), WHO 5–6 (oxygen support, n  = 353 and median age of 59 years) and WHO 7–9 (critical care, n  = 171 and median age of 57 years). Participants were hospitalized for COVID-19 ≥3 months before sample collection (median 6.1 months, interquartile range (IQR) 5.1–6.8 months and range 3.0–8.3 months) and confirmed clinically ( n  = 36/657) or by PCR ( n  = 621/657). Symptom data indicated 233/657 (35%) felt fully recovered at 6 months (hereafter ‘recovered’) and the remaining 424 (65%) reported symptoms consistent with the WHO definition for LC (symptoms ≥3 months post infection 10 ). Given the diversity of LC presentations, patients were grouped according to symptom type (Fig. 1b ). Groups were defined using symptoms and health deficits that have been commonly reported in the literature 1 ( Methods ). A multivariate penalized logistic regression model (PLR) was used to explore associations of clinical covariates and immune mediators at 6 months between recovered patients ( n  = 233) and each LC group (cardiorespiratory symptoms, cardioresp, n  = 398, Fig. 1c ; fatigue, n  = 384, Fig. 1d ; affective symptoms, anxiety/depression, n  = 202, Fig. 1e ; gastrointestinal symptoms, GI, n  = 132, Fig. 1f ; and cognitive impairment, cognitive, n  = 61, Fig. 1g ). Women ( n  = 239) were more likely to experience CardioResp (odds ratio (OR 1.14), Fatigue (OR 1.22), GI (OR 1.13) and Cognitive (OR 1.03) outcomes (Fig. 1c,d,f,g ). Repeated cross-validation was used to optimize and assess model performance ( Methods and Extended Data Fig. 1 ). Pre-existing conditions, such as chronic lung disease, neurological disease and cardiovascular disease (Supplementary Table 1 ), were associated with all LC groups (Fig. 1c–g ). Age, C-reactive protein (CRP) and acute disease severity were not associated with any LC group (Table 1 ).

a , Distribution of time from COVID-19 hospitalization at sample collection. All samples were cross-sectional. The vertical red line indicates the 3 month cutoff used to define our final cohort and samples collected before 3 months were excluded. b , An UpSet plot describing pooled LC groups. The horizontal colored bars represent the number of patients in each symptom group: cardiorespiratory (Cardio_Resp), fatigue, cognitive, GI and anxiety/depression (Anx_Dep). Vertical black bars represent the number of patients in each symptom combination group. To prevent patient identification, where less than five patients belong to a combination group, this has been represented as ‘<5’. The recovered group ( n  = 233) were used as controls. c – g , Forest plots of Olink protein concentrations (NPX) associated with Cardio_Resp ( n  = 365) ( c ), fatigue (n = 314) ( d ), Anx_Dep ( n  = 202) ( e ), GI ( n  = 124) ( f ) and cognitive ( n  = 60) ( g ). Neuro_Psych, neuropsychiatric. The error bars represent the median accuracy of the model. h , i , Distribution of Olink values (NPX) for IL-1R2 ( h ) and MATN2, neurofascin and sCD58 ( i ) measured between symptomatic and recovered individuals in recovered ( n  = 233), Cardio_Resp ( n  = 365), fatigue ( n  = 314) and Anx_Dep ( n  = 202) groups ( h ) and MATN2 in GI ( n  = 124), neurofascin in cognitive ( n  = 60) and sCD58 in Cardio_Resp and recovered groups ( i ). The box plot center line represents the median, the boundaries represent IQR and the whisker length represents 1.5× IQR. The median values were compared between groups using two-sided Wilcoxon signed-rank test, * P  < 0.05, ** P  < 0.01, *** P  < 0.001 and **** P  < 0.0001.

To study the association of peripheral inflammation with symptoms, we analyzed cross-sectional data collected approximately 6 months after hospitalizations. We measured 368 immune mediators from plasma collected contemporaneously with symptom data. Mediators suggestive of myeloid inflammation were associated with all symptoms (Fig. 1c–h ). Elevated IL-1R2, an IL-1 receptor expressed by monocytes and macrophages modulating inflammation 11 and MATN2, an extracellular matrix protein that modulates tissue inflammation through recruitment of innate immune cells 12 , were associated with cardioresp (IL-1R2 OR 1.14, Fig. 1c,h ), fatigue (IL-1R2 OR 1.45, Fig. 1d,h ), anxiety/depression (IL-1R2 OR 1.34. Fig. 1e,h ) and GI (MATN2 OR 1.08, Fig. 1f ). IL-3RA, an IL-3 receptor, was associated with cardioresp (OR 1.07, Fig. 1c ), fatigue (OR 1.21, Fig. 1d ), anxiety/depression (OR 1.12, Fig. 1e ) and GI (OR 1.06, Fig. 1f ) groups, while CSF3, a cytokine promoting neutrophilic inflammation 13 , was elevated in cardioresp (OR 1.06, Fig. 1c ), fatigue (OR 1.12, Fig. 1d ) and GI (OR 1.08, Fig. 1f ).

Elevated COLEC12, which initiates inflammation in tissues by activating the alternative complement pathway 14 , associated with cardioresp (OR 1.09, Fig. 1c ), fatigue (OR 1.19, Fig. 1d ) and anxiety/depression (OR 1.11, Fig. 1e ), but not with GI (Fig. 1f ) and only weakly with cognitive (OR 1.02, Fig. 1g ). C1QA, a degradation product released by complement activation 15 was associated with GI (OR 1.08, Fig. 1f ) and cognitive (OR 1.03, Fig. 1g ). C1QA, which is known to mediate dementia-related neuroinflammation 16 , had the third strongest association with cognitive (Fig. 1g ). These observations indicated that myeloid inflammation and complement activation were associated with LC.

Increased expression of DPP10 and SCG3 was observed in the GI group compared with recovered (DPP10 OR 1.07 and SCG3 OR 1.08, Fig. 1f ). DPP10 is a membrane protein that modulates tissue inflammation, and increased DPP10 expression is associated with inflammatory bowel disease 17 , 18 , suggesting that GI symptoms may result from enteric inflammation. Elevated SCG3, a multifunctional protein that has been associated with irritable bowel syndrome 19 , suggested that noninflammatory disturbance of the brain–gut axis or dysbiosis, may occur in the GI group. The cognitive group was associated with elevated CTSO (OR 1.04), NFASC (OR 1.03) and SPON-1 (OR 1.02, Fig. 1g,i ). NFASC and SPON-1 regulate neural growth 20 , 21 , while CTSO is a cysteine proteinase supporting tissue turnover 22 . The increased expression of these three proteins as well as C1QA and DPP10 in the cognitive group (Fig. 1g ) suggested neuroinflammation and alterations in nerve tissue repair, possibly resulting in neurodegeneration. Together, our findings indicated that complement activation and myeloid inflammation were common to all LC groups, but subtle differences were observed in the GI and cognitive groups, which may have mechanistic importance. Acutely elevated fibrinogen during hospitalization has been reported to be predictive of LC cognitive deficits 23 . We found elevated fibrinogen in LC relative to recovered (Extended Data Fig. 2a ; P  = 0.0077), although this was not significant when restricted to the cognitive group ( P  = 0.074), supporting our observation of complement pathway activation in LC and in keeping with reports that complement dysregulation and thrombosis drive severe COVID-19 (ref. 24 ).

Elevated sCD58 was associated with lower odds of all LC symptoms and was most pronounced in cardioresp (OR 0.85, Fig. 1c,i ), fatigue (OR 0.80, Fig. 1d ) and anxiety/depression (OR 0.83, Fig. 1e ). IL-2 was negatively associated with the cardioresp (Fig. 1c , OR 0.87), fatigue (Fig. 1d , OR 0.80), anxiety/depression (Fig. 1e , OR 0.84) and cognitive (Fig. 1g , OR 0.96) groups. Both IL-2 and sCD58 have immunoregulatory functions 25 , 26 . Specifically, sCD58 suppresses IL-1- or IL-6-dependent interactions between CD2 + monocytes and CD58 + T or natural killer cells 26 . The association of sCD58 with recovered suggests a central role of dysregulated myeloid inflammation in LC. Elevated markers of tissue repair, IDS and DNER 27 , 28 , were also associated with recovered relative to all LC groups (Fig. 1c–g ). Taken together, our data suggest that suppression of myeloid inflammation and enhanced tissue repair were associated with recovered, supporting the use of immunomodulatory agents in therapeutic trials 29 (Supplementary Table 2 ).

We next sought to validate the experimental and analytical approaches used. Although Olink has been validated against other immunoassay platforms, showing superior sensitivity and specificity 30 , 31 , we confirmed the performance of Olink against chemiluminescent immunoassays within our cohort. We performed chemiluminescent immunoassays on plasma from a subgroup of 58 participants (recovered n  = 13 and LC n  = 45). There were good correlations between results from Olink (normalized protein expression (NPX)) and chemiluminescent immunoassays (pg ml −1 ) for CSF3, IL-1R2, IL-3RA, TNF and TFF2 (Extended Data Fig. 3 ). Most samples did not have concentrations of IL-2 detectable using a mesoscale discovery chemiluminescent assay, limiting this analysis to 14 samples (recovered n  = 4, LC n  = 10, R  = 0.55 and P  = 0.053, Extended Data Fig. 3 ). We next repeated our analysis using alternative definitions of LC. The Centers for Disease Control and Prevention and National Institute for Health and Care Excellence definitions for LC include symptoms occurring 1 month post infection 32 , 33 . Using the 1 month post-infection definition included 62 additional participants to our analysis (recovered n  = 21, 3 females and median age 61 years and LC n  = 41, 15 females and median age 60 years, Extended Data Fig. 2c ) and found that inflammatory associations with each LC group were consistent with our analysis based on the WHO definition (Extended Data Fig. 2d–h ). Finally, to validate the analytical approach (PLR) we examined the distribution of data, prioritizing proteins that were most strongly associated with each LC/recovered group (IL-1R2, MATN2, NFASC and sCD58). Each protein was significantly elevated in the LC group compared with recovered (Fig. 1h,i and Extended Data Fig. 4 ), consistent with the PLR. Alternative regression approaches (unadjusted regression models and partial least squares, PLS) reported results consistent with the original analysis of protein associations and LC outcome in the WHO-defined cohort (Fig. 1c–g , Supplementary Table 3 and Extended Data Figs. 5 and 6 ). The standard errors of PLS estimates were wide (Extended Data Fig. 6 ), consistent with previous demonstrations that PLR is the optimal method to analyze high-dimensional data where variables may have combined effects 34 . As inflammatory proteins are often colinear, working in-tandem to mediate effects, we prioritized PLR results to draw conclusions.

To explore the relationship between inflammatory mediators associated with different LC symptoms, we performed a network analysis of Olink mediators highlighted by PLR within each LC group. COLEC12 and markers of endothelial and mucosal inflammation (MATN2, PCDH1, ROBO1, ISM1, ANGPTL2, TGF-α and TFF2) were highly correlated within the cardioresp, fatigue and anxiety/depression groups (Fig. 2 and Extended Data Fig. 7 ). Elevated PCDH1, an adhesion protein modulating airway inflammation 35 , was highly correlated with other inflammatory proteins associated with the cardioresp group (Fig. 2 ), suggesting that systemic inflammation may arise from the lung in these individuals. This was supported by increased expression of IL-3RA, which regulates innate immune responses in the lung through interactions with circulating IL-3 (ref. 36 ), in fatigue (Figs. 1d and 2 ), which correlated with markers of tissue inflammation, including PCDH1 (Fig. 2 ). MATN2 and ISM1, mucosal proteins that enhance inflammation 37 , 38 , were highly correlated in the GI group (Fig. 2 ), highlighting the role of tissue-specific inflammation in different LC groups. SCG3 correlated less closely with mediators in the GI group (Fig. 2 ), suggesting that the brain–gut axis may contribute separately to some GI symptoms. SPON-1, which regulates neural growth 21 , was the most highly correlated mediator in the cognitive group (Fig. 2 and Extended Data Fig. 7 ), highlighting that processes within nerve tissue may underlie this group. These observations suggested that inflammation might arise from mucosal tissues and that additional mechanisms may contribute to pathophysiology underlying the GI and cognitive groups.

Network analysis of Olink mediators associated with cardioresp ( n  = 365), fatigue ( n  = 314), anxiety/depression ( n  = 202), GI ( n  = 124) and cognitive groups ( n  = 60). Each node corresponds to a protein mediator identified by PLR. The edges (blue lines) were weighted according to the size of Spearman’s rank correlation coefficient between proteins. All edges represent positive and significant correlations ( P  < 0.05) after FDR adjustment.

Women were more likely to experience LC (Table 1 ), as found in previous studies 1 . As estrogen can influence immunological responses 39 , we investigated whether hormonal differences between men and women with LC in our cohort explained this trend. We grouped men and women with LC symptoms into two age groups (those younger than 50 years and those 50 years and older, using age as a proxy for menopause status in women) and compared mediator levels between men and women in each age group, prioritizing those identified by PLR to be higher in LC compared with recovered. As we aimed to understand whether women with LC had stronger inflammatory responses than men with LC, we did not assess differences in men and women in the recovered group. IL-1R2 and MATN2 were significantly higher in women ≥50 years than men ≥50 years in the cardioresp group (Fig. 3a , IL-1R2 and MATN2) and the fatigue group (Fig. 3b ). In the GI group, CSF3 was higher in women ≥50 years compared with men ≥50 years (Fig. 3c ), indicating that the inflammatory markers observed in women were not likely to be estrogen-dependent. Women have been reported to have stronger innate immune responses to infection and to be at greater risk of autoimmunity 39 , possibly explaining why some women in the ≥50 years group had higher inflammatory proteins than men the same group. Proteins associated with the anxiety/depression (IL-1R2 P  = 0.11 and MATN2 P  = 0.61, Extended Data Fig. 8a ) and cognitive groups (CTSO P  = 0.64 and NFASC P  = 0.41, Extended Data Fig. 8b ) were not different between men and women in either age group, consistent with the absent/weak association between sex and these outcomes identified by PLR (Fig. 1e,g ). Though our findings suggested that nonhormonal differences in inflammatory responses may explain why some women are more likely to have LC, they require confirmation in adequately powered studies.

a – c , Olink-measured plasma protein levels (NPX) of IL-1R2 and MATN2 ( a and b ) and CSF3 ( c ) between LC men and LC women divided by age (<50 or ≥50 years) in the cardiorespiratory group (<50 years n  = 8 and ≥50 years n  = 270) ( a ), fatigue group (<50 years n  = 81 and ≥50 years n  = 227) ( b ) and GI group (<50 years n  = 34 and ≥50 years n  = 82) ( c ). the median values were compared between men and women using two-sided Wilcoxon signed-rank test, * P  < 0.05, ** P  < 0.01, *** P  < 0.001 and **** P  < 0.0001. The box plot center line represents the median, the boundaries represent IQR and the whisker length represents 1.5× IQR.

To test whether local respiratory tract inflammation persisted after COVID-19, we compared nasosorption samples from 89 participants (recovered, n  = 31; LC, n  = 33; and healthy SARS-CoV-2 naive controls, n  = 25, Supplementary Tables 4 and 5 ). Several inflammatory markers were elevated in the upper respiratory tract post COVID (including IL-1α, CXCL10, CXCL11, TNF, VEGF and TFF2) when compared with naive controls, but similar between recovered and LC (Fig. 4a ). In the cardioresp group ( n  = 29), inflammatory mediators elevated in plasma (for example, IL-6, APO-2, TGF-α and TFF2) were not elevated in the upper respiratory tract (Extended Data Fig. 9a ) and there was no correlation between plasma and nasal mediator levels (Extended Data Fig. 9b ). This exploratory analysis suggested upper respiratory tract inflammation post COVID was not specifically associated with cardiorespiratory symptoms.

a , Nasal cytokines measured by immunoassay in post-COVID participants ( n  = 64) compared with healthy SARS-CoV-2 naive controls ( n  = 25), and between the the cardioresp group ( n  = 29) and the recovered group ( n  = 31). The red values indicate significantly increased cytokine levels after FDR adjustment ( P  < 0.05) using two-tailed Wilcoxon signed-rank test. b , SARS-CoV-2 N antigen measured in sputum by electrochemiluminescence from recovered ( n  = 17) and pooled LC ( n  = 23) groups, compared with BALF from SARS-CoV-2 naive controls ( n  = 9). The horizontal dashed line indicates the lower limit of detection of the assay. c , Plasma S- and N-specific IgG responses measured by electrochemiluminescence in the LC ( n  = 35) and recovered ( n  = 19) groups. The median values were compared using two-sided Wilcoxon signed-rank tests, NS P  > 0.05, * P  < 0.05, ** P  < 0.01, *** P  < 0.001 and **** P  < 0.0001. The box plot center lines represent the median, the boundaries represent IQR and the whisker length represents 1.5× IQR.

To explore whether SARS-CoV-2 persistence might explain the inflammatory profiles observed in the cardioresp group, we measured SARS-CoV-2 nucleocapsid (N) antigen in sputum from 40 participants (recovered n  = 17 and LC n  = 23) collected approximately 6 months post hospitalization (Supplementary Table 6 ). All samples were compared with prepandemic bronchoalveolar lavage fluid ( n  = 9, Supplementary Table 4 ). Only four samples (recovered n  = 2 and LC n  = 2) had N antigen above the assay’s lower limit of detection, and there was no difference in N antigen concentrations between LC and recovered (Fig. 4b , P  = 0.78). These observations did not exclude viral persistence, which might require tissues samples for detection 40 , 41 . On the basis of the hypothesis that persistent viral antigen might prevent a decline in antibody levels over time, we examined the titers of SARS-CoV-2-specific antibodies in unvaccinated individuals (recovered n  = 19 and LC n  = 35). SARS-CoV-2 N-specific ( P  = 0.023) and spike (S)-specific ( P  = 0.0040) immunoglobulin G (IgG) levels were elevated in LC compared with recovered (Fig. 4c ).

Overall, we identified myeloid inflammation and complement activation in the cardioresp, fatigue, anxiety/depression, cognitive and GI groups 6 months after hospitalization (Extended Data Fig. 10 ). Our findings build on results of smaller studies 5 , 6 , 42 and are consistent with a genome-wide association study that identified an independent association between LC and FOXP4 , which modulates neutrophilic inflammation and immune cell function 43 , 44 . In addition, we identified tissue-specific inflammatory elements, indicating that myeloid disturbance in different tissues may result in distinct symptoms. Multiple mechanisms for LC have been suggested, including autoimmunity, thrombosis, vascular dysfunction, SARS-CoV-2 persistence and latent virus reactivation 1 . All these processes involve myeloid inflammation and complement activation 45 . Complement activation in LC has been suggested in a proteomic study in 97 mostly nonhospitalized COVID-19 cases 42 and a study of 48 LC patients, of which one-third experienced severe acute disease 46 . As components of the complement system are known to have a short half-life 47 , ongoing complement activation suggests active inflammation rather than past tissue damage from acute infection.

Despite the heterogeneity of LC and the likelihood of coexisting or multiple etiologies, our work suggests some common pathways that might be targeted therapeutically and supports the rationale for several drugs currently under trial. Our finding of increased sCD58 levels (associated with suppression of monocyte–lymphocyte interactions 26 ) in the recovered group, strengthens our conclusion that myeloid inflammation is central to the biology of LC and that trials of steroids, IL-1 antagonists, JAK inhibitors, naltrexone and colchicine are justified. Although anticoagulants such as apixaban might prevent thrombosis downstream of complement dysregulation, they can also increase the risk of serious bleeding when given after COVID-19 hospitalization 48 . Thus, clinical trials, already underway, need to carefully assess the risks and benefits of anticoagulants (Supplementary Table 2 ).

Our finding of elevated S- and N-specific IgG in LC could suggest viral persistence, as found in other studies 6 , 42 , 49 . Our network analysis indicated that inflammatory proteins in the cardioresp group interacted strongly with ISM1 and ROBO1, which are expressed during respiratory tract infection and regulate lung inflammation 50 , 51 . Although we were unable to find SARS-CoV-2 antigen in sputum from our LC cases, we did not test for viral persistence in GI tract and lung tissue 40 , 41 or in plasma 52 . Evidence of SARS-CoV-2 persistence would justify trials of antiviral drugs (singly or in combination) in LC. It is also possible that autoimmune processes could result in an innate inflammatory profile in LC. Autoreactive B cells have been identified in LC patients with higher SARS-CoV-2-specific antibody titers in a study of mostly mild acute COVID cases (59% WHO 2–3) 42 , a different population from our study of hospitalized cases.

Our observations of distinct protein profiles in GI and cognitive groups support previous reports on distinct associations between Epstein–Barr virus reactivation and neurological symptoms, or autoantibodies and GI symptoms relative to other forms of LC 49 , 53 . We did not assess autoantibody induction but found evidence of brain–gut axis disturbance (SCG3) in the GI group, which occurs in many autoimmune diseases 54 . We found signatures suggestive of neuroinflammation (C1QA) in the cognitive group, consistent with findings of brain abnormalities on magnetic resonance imaging after COVID-19 hospitalization 55 , as well as findings of microglial activation in mice after COVID-19 (ref. 56 ). Proinflammatory signatures dominated in the cardioresp, fatigue and anxiety/depression groups and were consistent with those seen in non-COVID depression, suggesting shared mechanisms 57 . The association between markers of myeloid inflammation, including IL-3RA, and symptoms was greatest for fatigue. Whilst membrane-bound IL-3RA facilitates IL-3 signaling upstream of myelopoesis 36 its soluble form (measured in plasma) can bind IL-3 and can act as a decoy receptor, preventing monocyte maturation and enhancing immunopathology 58 . Monocytes from individuals with post-COVID fatigue are reported to have abnormal expression profiles (including reduced CXCR2), suggestive of altered maturation and migration 5 , 59 . Lung-specific inflammation was suggested by the association between PCDH1 (an airway epithelial adhesion molecule 35 ) and cardioresp symptoms.

Our observations do not align with all published observations on LC. One proteomic study of 55 LC cases after generally mild (WHO 2–3) acute disease found that TNF and IFN signatures were elevated in LC 3 . Vasculoproliferative processes and metabolic disturbance have been reported in LC 4 , 60 , but these studies used uninfected healthy individuals for comparison and cannot distinguish between LC-specific phenomena and residual post-COVID inflammation. A study of 63 adults (LC, n  = 50 and recovered, n  = 13) reported no association between immune cell activation and LC 3 months after infection 61 , though myeloid inflammation was not directly measured, and 3 months post infection may be too early to detect subtle differences between LC and recovered cases due to residual acute inflammation.

Our study has limitations. We designed the study to identify inflammatory markers identifying pathways underlying LC subgroups rather than diagnostic biomarkers. The ORs we report are small, but associations were consistent across alternative methods of analysis and when using different LC definitions. Small effect sizes can be expected when using PLR, which shrinks correlated mediator coefficients to reflect combined effects and prevent colinear inflation 62 , and could also result from measurement of plasma mediators that may underestimate tissue inflammation. Although our LC cohort is large compared with most other published studies, some of our subgroups are small (only 60 cases were designated cognitive). Though the performance of the cognitive PLR model was adequate, our findings should be validated in larger studies. It should be noted that our cohort of hospitalized cases may not represent all types of LC, especially those occurring after mild infection. We looked for an effect of acute disease severity within our study and did not find it, and are reassured that the inflammatory profiles we observed were consistent with those seen in smaller studies including nonhospitalized cases 42 , 46 . Studies of posthospital LC may be confounded by ‘posthospital syndrome’, which encompasses general and nonspecific effects of hospitalization (particularly intensive care) 63 .

In conclusion, we found markers of myeloid inflammation and complement activation in our large prospective posthospital cohort of patients with LC, in addition to distinct inflammatory patterns in patients with cognitive impairment or gastrointestinal symptoms. These findings show the need to consider subphenotypes in managing patients with LC and support the use of antiviral or immunomodulatory agents in controlled therapeutic trials.

Study design and ethics

After hospitalization for COVID-19, adults who had no comorbidity resulting in a prognosis of less than 6 months were recruited to the PHOSP-COVID study ( n  = 719). Patients hospitalized between February 2020 and January 2021 were recruited. Both sexes were recruited and gender was self-reported (female, n  = 257 and male, n  = 462). Written informed consent was obtained from all patients. Ethical approvals for the PHOSP-COVID study were given by Leeds West Research Ethics Committee (20/YH/0225).

Symptom data and samples were prospectively collected from individuals approximately 6 months (IQR 5.1–6.8 months and range 3.0–8.3 months) post hospitalization (Fig. 1a ), via the PHOSP-COVID multicenter United Kingdom study 64 . Data relating to patient demographics and acute admission were collected via the International Severe Acute Respiratory and Emerging Infection Consortium World Health Organization Clinical Characterisation Protocol United Kingdom (ISARIC4C study; IRAS260007/IRAS126600) (ref. 65 ). Adults hospitalized during the SARS-CoV-2 pandemic were systematically recruited into ISARIC4C. Written informed consent was obtained from all patients. Ethical approval was given by the South Central–Oxford C Research Ethics Committee in England (reference 13:/SC/0149), Scotland A Research Ethics Committee (20/SS/0028) and WHO Ethics Review Committee (RPC571 and RPC572l, 25 April 2013).

Data were collected to account for variables affecting symptom outcome, via hospital records and self-reporting. Acute disease severity was classified according to the WHO clinical progression score: WHO class 3–4: no oxygen therapy; class 5: oxygen therapy; class 6: noninvasive ventilation or high-flow nasal oxygen; and class 7–9: managed in critical care 9 . Clinical data were used to place patients into six categories: ‘recovered’, ‘GI’, ‘cardiorespiratory’, ‘fatigue’, ‘cognitive impairment’ and ‘anxiety/depression’ (Supplementary Table 7 ). Patient-reported symptoms and validated clinical scores were used when feasible, including Medical Research Council (MRC) breathlessness score, dyspnea-12 score, Functional Assessment of Chronic Illness Therapy (FACIT) score, Patient Health Questionnaire (PHQ)-9 and Generalized Anxiety Disorder (GAD)-7. Cognitive impairment was defined as a Montreal Cognitive Assessment score <26. GI symptoms were defined as answering ‘Yes’ to the presence of at least two of the listed symptoms. ‘Recovered’ was defined by self-reporting. Patients were placed in multiple groups if they experienced a combination of symptoms.

Matched nasal fluid and sputum samples were prospectively collected from a subgroup of convalescent patients approximately 6 months after hospitalization via the PHOSP-COVID study. Nasal and bronchoalveolar lavage fluid (BALF) collected from healthy volunteers before the COVID-19 pandemic were used as controls (Supplementary Table 4 ). Written consent was obtained for all individuals and ethical approvals were given by London–Harrow Research Ethics Committee (13/LO/1899) for the collection of nasal samples and the Health Research Authority London–Fulham Research Ethics Committee (IRAS project ID 154109; references 14/LO/1023, 10/H0711/94 and 11/LO/1826) for BALF samples.

Ethylenediaminetetraacetic acid plasma was collected from whole blood taken by venepuncture and frozen at −80 °C as previously described 7 , 66 . Nasal fluid was collected using a NasosorptionTM FX·I device (Hunt Developments), which uses a synthetic absorptive matrix to collect concentrated nasal fluid. Samples were eluted and stored as previously described 67 . Sputum samples were collected via passive expectoration and frozen at −80 °C without the addition of buffers. Sputum samples from convalescent individuals were compared with BALF from healthy SARS-CoV-2-naive controls, collected before the pandemic. BALF samples were used to act as a comparison for lower respiratory tract samples since passively expectorated sputum from healthy SARS-CoV-2-naive individuals was not available. BALF samples were obtained by instillation and recovery of up to 240 ml of normal saline via a fiberoptic bronchoscope. BALF was filtered through 100 µM strainers into sterile 50 ml Falcon tubes, then centrifuged for 10 min at 400  g at 4 °C. The resulting supernatant was transferred into sterile 50 ml Falcon tubes and frozen at −80 °C until use. The full methods for BALF collection and processing have been described previously 68 , 69 .

Immunoassays

To determine inflammatory signatures that associated with symptom outcomes, plasma samples were analyzed on an Olink Explore 384 Inflammation panel 70 . Supplementary Table 8 (Appendix 1 ) lists all the analytes measured. To ensure the validity of results, samples were run in a single batch with the use of negative controls, plate controls in triplicate and repeated measurement of patient samples between plates in duplicate. Samples were randomized between plates according to site and sample collection date. Randomization between plates was blind to LC/recovered outcome. Data were first normalized to an internal extension control that was included in each sample well. Plates were standardized by normalizing to interplate controls, run in triplicate on each plate. Each plate contained a minimum of four patient samples, which were duplicates on another plate; these duplicate pairs allowed any plate to be linked to any other through the duplicates. Data were then intensity normalized across all cohort samples. Finally, Olink results underwent quality control processing and samples or analytes that did not reach quality control standards were excluded. Final normalized relative protein quantities were reported as log 2 NPX values.

To further validate our findings, we performed conventional electrochemiluminescence (ECL) assays and enzyme-linked immunosorbent assay for Olink mediators that were associated with symptom outcome ( Supplementary Methods ). Contemporaneously collected plasma samples were available from 58 individuals. Like most omics platforms, Olink measures relative quantities, so perfect agreement with conventional assays that measure absolute concentrations is not expected.

Sputum samples were thawed before analysis and sputum plugs were extracted with the addition of 0.1% dithiothreitol creating a one in two sample dilution, as previously described 71 . SARS-CoV-2 S and N proteins were measured by ECL S-plex assay at a fixed dilution of one in two (Mesoscale Diagnostics), as per the manufacturers protocol 72 . Control BALF samples were thawed and measured on the same plate, neat. The S-plex assay is highly sensitive in detecting viral antigen in respiratory tract samples 73 .

Nasal cytokines were measured by ECL (mesoscale discovery) and Luminex bead multiplex assays (Biotechne). The full methods and list of analytes are detailed in Supplementary Methods .

Statistics and reproducibility

Clinical data was collected via the PHOSP REDCap database, to which access is available under reasonable request as per the data sharing statement in the manuscript. All analyses were performed within the Outbreak Data Analysis Platform (ODAP). All data and code can be accessed using information in the ‘Data sharing’ and ‘Code sharing’ statements at the end of the manuscript. No statistical method was used to predetermine sample size. Data distribution was assumed to be normal but this was not formally tested. Olink assays and immunoassays were randomized and investigators were blinded to outcomes.

To determine protein signatures that associated with each symptom outcome, a ridge PLR was used. PLR shrinks coefficients to account for combined effects within high-dimensional data, preventing false discovery while managing multicollinearity 34 . Thus, PLR was chosen a priori as the most appropriate model to assess associations between a large number of explanatory variables (that may work together to mediate effects) and symptom outcome 34 , 62 , 70 , 74 . In keeping with our aim to perform an unbiased exploration of inflammatory process, the model alpha was set to zero, facilitating regularization without complete penalization of any mediator. This enabled review of all possible mediators that might associate with LC 62 .

A 50 repeats tenfold nested cross-validation was used to select the optimal lambda for each model and assess its accuracy (Extended Data Fig. 1 ). The performance of the cognitive impairment model was influenced by the imbalance in size of the symptom group ( n  = 60) relative to recovered ( n  = 250). The model was weighted to account for this imbalance resulting in a sensitivity of 0.98, indicating its validity. We have expanded on the model performance and validation approaches in Supplementary Information .

Age, sex, acute disease severity and preexisting comorbidities were included as covariates in the PLR analysis (Supplementary Tables 1 and 3 ). Covariates were selected a priori using features reported to influence the risk of LC and inflammatory responses 1 , 39 , 64 , 75 . Ethnicity was not included since it has been shown not to predict symptom outcome in this cohort 64 . Individuals with missing data were excluded from the regression analysis. Each symptom group was compared with the ‘recovered’ group. The model coefficients of each covariate were converted into ORs for each outcome and visualized in a forest plot, after removing variables associated with regularized OR between 0.98 and 1.02 or in cases where most variables fell outside of this range, using mediators associated with the highest decile of coefficients either side of this range. This enabled exclusion of mediators with effect sizes that were unlikely to have clinical or mechanistic importance since the ridge PLR shrinks and orders coefficients according to their relative importance rather than making estimates with standard error. Thus, confidence intervals cannot be appropriately derived from PLR, and forest plot error bars were calculated using the median accuracy of the model generated by the nested cross-validation. To verify observations made through PLR analysis, we also performed an unadjusted PLR, an unadjusted logistic regression and a PLS analysis. Univariate analyses using Wilcoxon signed-rank test was also performed (Supplementary Table 8 , Appendix 1 ). Analyses were performed in R version 4.2.0 using ‘data.table v1.14.2’, ‘EnvStats v2.7.0’ ‘tidyverse v1.3.2’, ‘lme4 v1.1-32’, ‘caret v6.0-93’, ‘glmnet v4.1-6’, ‘mdatools v0.14.0’, ‘ggpubbr v0.4.0’ and ‘ggplot2 v3.3.6’ packages.

To further investigate the relationship between proteins elevated in each symptom group, we performed a correlation network analysis using Spearman’s rank correlation coefficient and false discovery rate (FDR) thresholding. The mediators visualized in the PLR forest plots, which were associated with cardiorespiratory symptoms, fatigue, anxiety/depression GI symptoms and cognitive impairment were used, respectively. Analyses were performed in R version 4.2.0 using ‘bootnet v1.5.6 ’ and ‘qgraph v1.9.8 ’ packages.

To determine whether differences in protein levels between men and women related to hormonal differences, we divided each symptom group into premenopausal and postmenopausal groups using an age cutoff of 50 years old. Differences between sexes in each group were determined using the Wilcoxon signed-rank test. To understand whether antigen persistence contributed to inflammation in adults with LC, the median viral antigen concentration from sputum/BALF samples and cytokine concentrations from nasal samples were compared using the Wilcoxon signed-rank test. All tests were two-tailed and statistical significance was defined as a P value < 0.05 after adjustment for FDR ( q -value of 0.05). Analyses were performed in R version 4.2.0 using ‘bootnet v1.5.6’ and ‘qgraph v1.9.8’ packages.

Extended Data Fig. 10 was made using Biorender, accessed at www.biorender.com .

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

Data availability

This is an open access article under the CC BY 4.0 license.

The PHOSP-COVID protocol, consent form, definition and derivation of clinical characteristics and outcomes, training materials, regulatory documents, information about requests for data access, and other relevant study materials are available online at ref. 76 . Access to these materials can be granted by contacting [email protected] and [email protected].

The ISARIC4C protocol, data sharing and publication policy are available at https://isaric4c.net . ISARIC4C’s Independent Data and Material Access Committee welcomes applications for access to data and materials ( https://isaric4c.net ).

The datasets used in the study contain extensive clinical information at an individual level that prevent them from being deposited in an public depository due to data protection policies of the study. Study data can only be accessed via the ODAP, a protected research environment. All data used in this study are available within ODAP and accessible under reasonable request. Data access criteria and information about how to request access is available online at ref. 76 . If criteria are met and a request is made, access can be gained by signing the eDRIS user agreement.

Code availability

Code was written within the ODAP, using R v4.2.0 and publicly available packages (‘data.table v1.14.2’, ‘EnvStats v2.7.0’, ‘tidyverse v1.3.2’, ‘lme4 v1.1-32’, ‘caret v6.0-93’, ‘glmnet v4.1-6’, ‘mdatools v0.14.0’, ‘ggpubbr v0.4.0’, ‘ggplot2 v3.3.6’, ‘bootnet v1.5.6’ and ‘qgraph v1.9.8’ packages). No new algorithms or functions were created and code used in-built functions in listed packages available on CRAN. The code used to generate data and to analyze data is publicly available at https://github.com/isaric4c/wiki/wiki/ISARIC ; https://github.com/SurgicalInformatics/cocin_cc and https://github.com/ClaudiaEfstath/PHOSP_Olink_NatImm .

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Acknowledgements

This research used data assets made available by ODAP as part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref. MC_PC_20058). This work is supported by the following grants: the PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research (NIHR; grant references MR/V027859/1 and COV0319). ISARIC4C is supported by grants from the National Institute for Health and Care Research (award CO-CIN-01) and the MRC (grant MC_PC_19059) Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research (grant reference C18616/A25153). Other grants that have supported this work include the UK Coronavirus Immunology Consortium (funder reference 1257927), the Imperial Biomedical Research Centre (NIHR Imperial BRC, grant IS-BRC-1215-20013), the Health Protection Research Unit in Respiratory Infections at Imperial College London and NIHR Health Protection Research Unit in Emerging and Zoonotic Infections at University of Liverpool, both in partnership with Public Health England, (NIHR award 200907), Wellcome Trust and Department for International Development (215091/Z/18/Z), Health Data Research UK (grant code 2021.0155), MRC (grant code MC_UU_12014/12) and NIHR Clinical Research Network for providing infrastructure support for this research. We also acknowledge the support of the MRC EMINENT Network (MR/R502121/1), which is cofunded by GSK, the Comprehensive Local Research Networks, the MRC HIC-Vac network (MR/R005982/1) and the RSV Consortium in Europe Horizon 2020 Framework Grant 116019. F.L. is supported by an MRC clinical training fellowship (award MR/W000970/1). C.E. is funded by NIHR (grant P91258-4). L.-P.H. is supported by Oxford NIHR Biomedical Research Centre. A.A.R.T. is supported by a British Heart Foundation (BHF) Intermediate Clinical Fellowship (FS/18/13/33281). S.L.R.-J. receives support from UK Research and Innovation (UKRI), Global Challenges Research Fund (GCRF), Rosetrees Trust, British HIV association (BHIVA), European & Developing Countries Clinical Trials Partnership (EDCTP) and Globvac. J.D.C. has grants from AstraZeneca, Boehringer Ingelheim, GSK, Gilead Sciences, Grifols, Novartis and Insmed. R.A.E. holds a NIHR Clinician Scientist Fellowship (CS-2016-16-020). A. Horsley is currently supported by UK Research and Innovation, NIHR and NIHR Manchester BRC. B.R. receives support from BHF Oxford Centre of Research Excellence, NIHR Oxford BRC and MRC. D.G.W. is supported by an NIHR Advanced Fellowship. A. Ho has received support from MRC and for the Coronavirus Immunology Consortium (MR/V028448/1). L.T. is supported by the US Food and Drug Administration Medical Countermeasures Initiative contract 75F40120C00085 and the National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections (NIHR200907) at the University of Liverpool in partnership with UK Health Security Agency (UK-HSA), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford. L.V.W. has received support from UKRI, GSK/Asthma and Lung UK and NIHR for this study. M.G.S. has received support from NIHR UK, MRC UK and Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool. J.K.B. is supported by the Wellcome Trust (223164/Z/21/Z) and UKRI (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1 and MC_PC_20029). The funders were not involved in the study design, interpretation of data or writing of this manuscript. The views expressed are those of the authors and not necessarily those of the Department of Health and Social Care (DHSC), the Department for International Development (DID), NIHR, MRC, the Wellcome Trust, UK-HSA, the National Health Service or the Department of Health. P.J.M.O. is supported by a NIHR Senior Investigator Award (award 201385). We thank all the participants and their families. We thank the many research administrators, health-care and social-care professionals who contributed to setting up and delivering the PHOSP-COVID study at all of the 65 NHS trusts/health boards and 25 research institutions across the United Kingdom, as well as those who contributed to setting up and delivering the ISARIC4C study at 305 NHS trusts/health boards. We also thank all the supporting staff at the NIHR Clinical Research Network, Health Research Authority, Research Ethics Committee, Department of Health and Social Care, Public Health Scotland and Public Health England. We thank K. Holmes at the NIHR Office for Clinical Research Infrastructure for her support in coordinating the charities group. The PHOSP-COVID industry framework was formed to provide advice and support in commercial discussions, and we thank the Association of the British Pharmaceutical Industry as well the NIHR Office for Clinical Research Infrastructure for coordinating this. We are very grateful to all the charities that have provided insight to the study: Action Pulmonary Fibrosis, Alzheimer’s Research UK, Asthma and Lung UK, British Heart Foundation, Diabetes UK, Cystic Fibrosis Trust, Kidney Research UK, MQ Mental Health, Muscular Dystrophy UK, Stroke Association Blood Cancer UK, McPin Foundations and Versus Arthritis. We thank the NIHR Leicester Biomedical Research Centre patient and public involvement group and Long Covid Support. We also thank G. Khandaker and D. C. Newcomb who provided valuable feedback on this work. Extended Data Fig. 10 was created using Biorender.

Author information

These authors contributed equally: Felicity Liew, Claudia Efstathiou, Ryan S. Thwaites, Peter J. M. Openshaw.

Authors and Affiliations

National Heart and Lung Institute, Imperial College London, London, UK

Felicity Liew, Claudia Efstathiou, Sara Fontanella, Dawid Swieboda, Jasmin K. Sidhu, Stephanie Ascough, Onn Min Kon, Luke S. Howard, Jennifer K. Quint, Christopher Chiu, Ryan S. Thwaites, Peter J. M. Openshaw, Jake Dunning & Peter J. M. Openshaw

Institute for Lung Health, Leicester NIHR Biomedical Research Centre, University of Leicester, Leicester, UK

Matthew Richardson, Ruth Saunders, Olivia C. Leavy, Omer Elneima, Hamish J. C. McAuley, Amisha Singapuri, Marco Sereno, Victoria C. Harris, Neil J. Greening, Rachael A. Evans, Louise V. Wain, Christopher Brightling & Ananga Singapuri

NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK

Shona C. Moore, Daniel G. Wootton, Malcolm G. Semple, Lance Turtle, William A. Paxton & Georgios Pollakis

The Imperial Clinical Respiratory Research Unit, Imperial College NHS Trust, London, UK

Noura Mohamed

Cardiovascular Research Team, Imperial College Healthcare NHS Trust, London, UK

Jose Nunag & Clara King

Department of Population Health Sciences, University of Leicester, Leicester, UK

Olivia C. Leavy, Louise V. Wain & Beatriz Guillen-Guio

NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK

Aarti Shikotra

Centre for Exercise and Rehabilitation Science, NIHR Leicester Biomedical Research Centre-Respiratory, University of Leicester, Leicester, UK

Linzy Houchen-Wolloff

Usher Institute, University of Edinburgh, Edinburgh, UK

Nazir I. Lone, Luke Daines, Annemarie B. Docherty, Nazir I. Lone, Matthew Thorpe, Annemarie B. Docherty, Thomas M. Drake, Cameron J. Fairfield, Ewen M. Harrison, Stephen R. Knight, Kenneth A. Mclean, Derek Murphy, Lisa Norman, Riinu Pius & Catherine A. Shaw

Centre for Medical Informatics, The Usher Institute, University of Edinburgh, Edinburgh, UK

Matthew Thorpe, Annemarie B. Docherty, Ewen M. Harrison, J. Kenneth Baillie, Sarah L. Rowland-Jones, A. A. Roger Thompson & Thushan de Silva

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK

A. A. Roger Thompson, Sarah L. Rowland-Jones, Thushan I. de Silva & James D. Chalmers

University of Dundee, Ninewells Hospital and Medical School, Dundee, UK

James D. Chalmers & Ling-Pei Ho

MRC Human Immunology Unit, University of Oxford, Oxford, UK

Ling-Pei Ho & Alexander Horsley

Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

Alexander Horsley & Betty Raman

Radcliffe Department of Medicine, University of Oxford, Oxford, UK

Betty Raman & Krisnah Poinasamy

Asthma + Lung UK, London, UK

Krisnah Poinasamy & Michael Marks

Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK

Michael Marks

Hospital for Tropical Diseases, University College London Hospital, London, UK

Division of Infection and Immunity, University College London, London, UK

Michael Marks & Mahdad Noursadeghi

MRC Centre for Virus Research, School of Infection and Immunity, University of Glasgow, Glasgow, UK

Antonia Ho & William Greenhalf

Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK

William Greenhalf & J. Kenneth Baillie

The Roslin Institute, University of Edinburgh, Edinburgh, UK

J. Kenneth Baillie, J. Kenneth Baillie, Sara Clohisey, Fiona Griffiths, Ross Hendry, Andrew Law & Wilna Oosthuyzen

Pandemic Science Hub, University of Edinburgh, Edinburgh, UK

J. Kenneth Baillie

The Pandemic Institute, University of Liverpool, Liverpool, UK

Malcolm G. Semple & Lance Turtle

University of Manchester, Manchester, UK

Kathryn Abel, Perdita Barran, H. Chinoy, Bill Deakin, M. Harvie, C. A. Miller, Stefan Stanel & Drupad Trivedi

Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK

Kathryn Abel & J. Kenneth Baillie

North Bristol NHS Trust and University of Bristol, Bristol, UK

H. Adamali, David Arnold, Shaney Barratt, A. Dipper, Sarah Dunn, Nick Maskell, Anna Morley, Leigh Morrison, Louise Stadon, Samuel Waterson & H. Welch

University of Edinburgh, Manchester, UK

Davies Adeloye, D. E. Newby, Riinu Pius, Igor Rudan, Manu Shankar-Hari, Catherine Sudlow, Sarah Walmsley & Bang Zheng

King’s College Hospital NHS Foundation Trust and King’s College London, London, UK

Oluwaseun Adeyemi, Rita Adrego, Hosanna Assefa-Kebede, Jonathon Breeze, S. Byrne, Pearl Dulawan, Amy Hoare, Caroline Jolley, Abigail Knighton, M. Malim, Sheetal Patale, Ida Peralta, Natassia Powell, Albert Ramos, K. Shevket, Fabio Speranza & Amelie Te

Guy’s and St Thomas’ NHS Foundation Trust, London, UK

Laura Aguilar Jimenez, Gill Arbane, Sarah Betts, Karen Bisnauthsing, A. Dewar, Nicholas Hart, G. Kaltsakas, Helen Kerslake, Murphy Magtoto, Philip Marino, L. M. Martinez, Marlies Ostermann, Jennifer Rossdale & Teresa Solano

Royal Free London NHS Foundation Trust, London, UK

Shanaz Ahmad, Simon Brill, John Hurst, Hannah Jarvis, C. Laing, Lai Lim, S. Mandal, Darwin Matila, Olaoluwa Olaosebikan & Claire Singh

University Hospital Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK

N. Ahmad Haider, Catherine Atkin, Rhiannon Baggott, Michelle Bates, A. Botkai, Anna Casey, B. Cooper, Joanne Dasgin, Camilla Dawson, Katharine Draxlbauer, N. Gautam, J. Hazeldine, T. Hiwot, Sophie Holden, Karen Isaacs, T. Jackson, Vicky Kamwa, D. Lewis, Janet Lord, S. Madathil, C. McGee, K. Mcgee, Aoife Neal, Alex Newton-Cox, Joseph Nyaboko, Dhruv Parekh, Z. Peterkin, H. Qureshi, Liz Ratcliffe, Elizabeth Sapey, J. Short, Tracy Soulsby, J. Stockley, Zehra Suleiman, Tamika Thompson, Maximina Ventura, Sinead Walder, Carly Welch, Daisy Wilson, S. Yasmin & Kay Por Yip

Stroke Association, London, UK

Rubina Ahmed & Richard Francis

University College London Hospital and University College London, London, UK

Nyarko Ahwireng, Dongchun Bang, Donna Basire, Jeremy Brown, Rachel Chambers, A. Checkley, R. Evans, M. Heightman, T. Hillman, Joseph Jacob, Roman Jastrub, M. Lipman, S. Logan, D. Lomas, Marta Merida Morillas, Hannah Plant, Joanna Porter, K. Roy & E. Wall

Oxford University Hospitals NHS Foundation Trust and University of Oxford, Oxford, UK

Mark Ainsworth, Asma Alamoudi, Angela Bloss, Penny Carter, M. Cassar, Jin Chen, Florence Conneh, T. Dong, Ranuromanana Evans, V. Ferreira, Emily Fraser, John Geddes, F. Gleeson, Paul Harrison, May Havinden-Williams, P. Jezzard, Ivan Koychev, Prathiba Kurupati, H. McShane, Clare Megson, Stefan Neubauer, Debby Nicoll, C. Nikolaidou, G. Ogg, Edmund Pacpaco, M. Pavlides, Yanchun Peng, Nayia Petousi, John Pimm, Najib Rahman, M. J. Rowland, Kathryn Saunders, Michael Sharpe, Nick Talbot, E. M. Tunnicliffe & C. Xie

St George’s University Hospitals NHS Foundation Trust, London, UK

Mariam Ali, Raminder Aul, A. Dunleavy, D. Forton, Mark Mencias, N. Msimanga, T. Samakomva, Sulman Siddique, Vera Tavoukjian & J. Teixeira

University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK

M. Aljaroof, Natalie Armstrong, H. Arnold, Hnin Aung, Majda Bakali, M. Bakau, E. Baldry, Molly Baldwin, Charlotte Bourne, Michelle Bourne, Nigel Brunskill, P. Cairns, Liesel Carr, Amanda Charalambou, C. Christie, Melanie Davies, Enya Daynes, Sarah Diver, Rachael Dowling, Sarah Edwards, C. Edwardson, H. Evans, J. Finch, Sarah Glover, Nicola Goodman, Bibek Gooptu, Kate Hadley, Pranab Haldar, Beverley Hargadon, W. Ibrahim, L. Ingram, Kamlesh Khunti, A. Lea, D. Lee, Gerry McCann, P. McCourt, Teresa Mcnally, George Mills, Will Monteiro, Manish Pareek, S. Parker, Anne Prickett, I. N. Qureshi, A. Rowland, Richard Russell, Salman Siddiqui, Sally Singh, J. Skeemer, M. Soares, E. Stringer, T. Thornton, Martin Tobin, T. J. C. Ward, F. Woodhead, Tom Yates & A. J. Yousuf

University of Exeter, Exeter, UK

Louise Allan, Clive Ballard & Andrew McGovern

University of Leicester, Leicester, UK

Richard Allen, Michelle Bingham, Terry Brugha, Selina Finney, Rob Free, Don Jones, Claire Lawson, Daniel Lozano-Rojas, Gardiner Lucy, Alistair Moss, Elizabeta Mukaetova-Ladinska, Petr Novotny, Kimon Ntotsis, Charlotte Overton, John Pearl, Tatiana Plekhanova, M. Richardson, Nilesh Samani, Jack Sargant, Ruth Saunders, M. Sharma, Mike Steiner, Chris Taylor, Sarah Terry, C. Tong, E. Turner, J. Wormleighton & Bang Zhao

Liverpool University Hospitals NHS Foundation Trust and University of Liverpool, Liverpool, UK

Lisa Allerton, Ann Marie Allt, M. Beadsworth, Anthony Berridge, Jo Brown, Shirley Cooper, Andy Cross, Sylviane Defres, S. L. Dobson, Joanne Earley, N. French, Kera Hainey, Hayley Hardwick, Jenny Hawkes, Victoria Highett, Sabina Kaprowska, Angela Key, Lara Lavelle-Langham, N. Lewis-Burke, Gladys Madzamba, Flora Malein, Sophie Marsh, Chloe Mears, Lucy Melling, Matthew Noonan, L. Poll, James Pratt, Emma Richardson, Anna Rowe, Victoria Shaw, K. A. Tripp, Lilian Wajero, S. A. Williams-Howard, Dan Wootton & J. Wyles

Sherwood Forest Hospitals NHS Foundation Trust, Nottingham, UK

Lynne Allsop, Kaytie Bennett, Phil Buckley, Margaret Flynn, Mandy Gill, Camelia Goodwin, M. Greatorex, Heidi Gregory, Cheryl Heeley, Leah Holloway, Megan Holmes, John Hutchinson, Jill Kirk, Wayne Lovegrove, Terri Ann Sewell, Sarah Shelton, D. Sissons, Katie Slack, Susan Smith, D. Sowter, Sarah Turner, V. Whitworth & Inez Wynter

Nottingham University Hospitals NHS Trust and University of Nottingham, London, UK

Paula Almeida, Akram Hosseini, Robert Needham & Karen Shaw

Manchester University NHS Foundation Trust and University of Manchester, London, UK

Bashar Al-Sheklly, Cristina Avram, John Blaikely, M. Buch, N. Choudhury, David Faluyi, T. Felton, T. Gorsuch, Neil Hanley, Tracy Hussell, Zunaira Kausar, Natasha Odell, Rebecca Osbourne, Karen Piper Hanley, K. Radhakrishnan & Sue Stockdale

Imperial College London, London, UK

Danny Altmann, Anew Frankel, Luke S. Howard, Desmond Johnston, Liz Lightstone, Anne Lingford-Hughes, William Man, Steve McAdoo, Jane Mitchell, Philip Molyneaux, Christos Nicolaou, D. P. O’Regan, L. Price, Jennifer K. Quint, David Smith, Jonathon Valabhji, Simon Walsh, Martin Wilkins & Michelle Willicombe

Hampshire Hospitals NHS Foundation Trust, Basingstoke, UK

Maria Alvarez Corral, Ava Maria Arias, Emily Bevan, Denise Griffin, Jane Martin, J. Owen, Sheila Payne, A. Prabhu, Annabel Reed, Will Storrar, Nick Williams & Caroline Wrey Brown

British Heart Foundation, Birmingham, UK

Shannon Amoils

NHS Greater Glasgow and Clyde Health Board and University of Glasgow, Glasgow, UK

David Anderson, Neil Basu, Hannah Bayes, Colin Berry, Ammani Brown, Andrew Dougherty, K. Fallon, L. Gilmour, D. Grieve, K. Mangion, I. B. McInnes, A. Morrow, Kathryn Scott & R. Sykes

University of Oxford, Oxford, UK

Charalambos Antoniades, A. Bates, M. Beggs, Kamaldeep Bhui, Katie Breeze, K. M. Channon, David Clark, X. Fu, Masud Husain, Lucy Kingham, Paul Klenerman, Hanan Lamlum, X. Li, E. Lukaschuk, Celeste McCracken, K. McGlynn, R. Menke, K. Motohashi, T. E. Nichols, Godwin Ogbole, S. Piechnik, I. Propescu, J. Propescu, A. A. Samat, Z. B. Sanders, Louise Sigfrid & M. Webster

Belfast Health and Social Care Trust and Queen’s University Belfast, Belfast, UK

Cherie Armour, Vanessa Brown, John Busby, Bronwen Connolly, Thelma Craig, Stephen Drain, Liam Heaney, Bernie King, Nick Magee, E. Major, Danny McAulay, Lorcan McGarvey, Jade McGinness, Tunde Peto & Roisin Stone

Airedale NHS Foundation Trust, Keighley, UK

Lisa Armstrong, Brigid Hairsine, Helen Henson, Claire Kurasz, Alison Shaw & Liz Shenton

Wrightington Wigan and Leigh NHS Trust, Wigan, UK

A. Ashish, Josh Cooper & Emma Robinson

Leeds Teaching Hospitals and University of Leeds, Leeds, UK

Andrew Ashworth, Paul Beirne, Jude Clarke, C. Coupland, Matthhew Dalton, Clair Favager, Jodie Glossop, John Greenwood, Lucy Hall, Tim Hardy, Amy Humphries, Jennifer Murira, Dan Peckham, S. Plein, Jade Rangeley, Gwen Saalmink, Ai Lyn Tan, Elaine Wade, Beverley Whittam, Nicola Window & Janet Woods

University of Liverpool, Liverpool, UK

M. Ashworth, D. Cuthbertson, G. Kemp, Anne McArdle, Benedict Michael, Will Reynolds, Lisa Spencer, Ben Vinson, Katie A. Ahmed, Jane A. Armstrong, Milton Ashworth, Innocent G. Asiimwe, Siddharth Bakshi, Samantha L. Barlow, Laura Booth, Benjamin Brennan, Katie Bullock, Nicola Carlucci, Emily Cass, Benjamin W. A. Catterall, Jordan J. Clark, Emily A. Clarke, Sarah Cole, Louise Cooper, Helen Cox, Christopher Davis, Oslem Dincarslan, Alejandra Doce Carracedo, Chris Dunn, Philip Dyer, Angela Elliott, Anthony Evans, Lorna Finch, Lewis W. S. Fisher, Lisa Flaherty, Terry Foster, Isabel Garcia-Dorival, Philip Gunning, Catherine Hartley, Karl Holden, Anthony Holmes, Rebecca L. Jensen, Christopher B. Jones, Trevor R. Jones, Shadia Khandaker, Katharine King, Robyn T. Kiy, Chrysa Koukorava, Annette Lake, Suzannah Lant, Diane Latawiec, Lara Lavelle-Langham, Daniella Lefteri, Lauren Lett, Lucia A. Livoti, Maria Mancini, Hannah Massey, Nicole Maziere, Sarah McDonald, Laurence McEvoy, John McLauchlan, Soeren Metelmann, Nahida S. Miah, Joanna Middleton, Joyce Mitchell, Ellen G. Murphy, Rebekah Penrice-Randal, Jack Pilgrim, Tessa Prince, P. Matthew Ridley, Debby Sales, Rebecca K. Shears, Benjamin Small, Krishanthi S. Subramaniam, Agnieska Szemiel, Aislynn Taggart, Jolanta Tanianis-Hughes, Jordan Thomas, Erwan Trochu, Libby van Tonder, Eve Wilcock & J. Eunice Zhang

University College London, London, UK

Shahab Aslani, Amita Banerjee, R. Batterham, Gabrielle Baxter, Robert Bell, Anthony David, Emma Denneny, Alun Hughes, W. Lilaonitkul, P. Mehta, Ashkan Pakzad, Bojidar Rangelov, B. Williams, James Willoughby & Moucheng Xu

Hull University Teaching Hospitals NHS Trust and University of Hull, Hull, UK

Paul Atkin, K. Brindle, Michael Crooks, Katie Drury, Nicholas Easom, Rachel Flockton, L. Holdsworth, A. Richards, D. L. Sykes, Susannah Thackray-Nocera & C. Wright

East Kent Hospitals University NHS Foundation Trust, Canterbury, UK

Liam Austin, Eva Beranova, Tracey Cosier, Joanne Deery, Tracy Hazelton, Carly Price, Hazel Ramos, Reanne Solly, Sharon Turney & Heather Weston

Baillie Gifford Pandemic Science Hub, Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK

Nikos Avramidis, J. Kenneth Baillie, Erola Pairo-Castineira & Konrad Rawlik

Roslin Institute, University of Edinburgh, Edinburgh, UK

Nikos Avramidis, J. Kenneth Baillie & Erola Pairo-Castineira

Newcastle upon Tyne Hospitals NHS Foundation Trust and University of Newcastle, Newcastle upon Tyne, UK

A. Ayoub, J. Brown, G. Burns, Gareth Davies, Anthony De Soyza, Carlos Echevarria, Helen Fisher, C. Francis, Alan Greenhalgh, Philip Hogarth, Joan Hughes, Kasim Jiwa, G. Jones, G. MacGowan, D. Price, Avan Sayer, John Simpson, H. Tedd, S. Thomas, Sophie West, M. Witham, S. Wright & A. Young

East Cheshire NHS Trust, Macclesfield, UK

Marta Babores, Maureen Holland, Natalie Keenan, Sharlene Shashaa & Helen Wassall

Sheffield Teaching NHS Foundation Trust and University of Sheffield, Sheffield, UK

J. Bagshaw, M. Begum, K. Birchall, Robyn Butcher, H. Carborn, Flora Chan, Kerry Chapman, Yutung Cheng, Luke Chetham, Cameron Clark, Zach Coburn, Joby Cole, Myles Dixon, Alexandra Fairman, J. Finnigan, H. Foot, David Foote, Amber Ford, Rebecca Gregory, Kate Harrington, L. Haslam, L. Hesselden, J. Hockridge, Ailsa Holbourn, B. Holroyd-Hind, L. Holt, Alice Howell, E. Hurditch, F. Ilyas, Claire Jarman, Allan Lawrie, Ju Hee Lee, Elvina Lee, Rebecca Lenagh, Alison Lye, Irene Macharia, M. Marshall, Angeline Mbuyisa, J. McNeill, Sharon Megson, J. Meiring, L. Milner, S. Misra, Helen Newell, Tom Newman, C. Norman, Lorenza Nwafor, Dibya Pattenadk, Megan Plowright, Julie Porter, Phillip Ravencroft, C. Roddis, J. Rodger, Peter Saunders, J. Sidebottom, Jacqui Smith, Laurie Smith, N. Steele, G. Stephens, R. Stimpson, B. Thamu, N. Tinker, Kim Turner, Helena Turton, Phillip Wade, S. Walker, James Watson, Imogen Wilson & Amira Zawia

University of Nottingham, Nottingham, UK

David Baguley, Chris Coleman, E. Cox, Laura Fabbri, Susan Francis, Ian Hall, E. Hufton, Simon Johnson, Fasih Khan, Paaig Kitterick, Richard Morriss, Nick Selby, Iain Stewart & Louise Wright

Wirral University Teaching Hospital, Wirral, UK

Elisabeth Bailey, Anne Reddington & Andrew Wight

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK

University of Swansea, Swansea, UK

University of Southampton, London, UK

David Baldwin, P. C. Calder, Nathan Huneke & Gemma Simons

Royal Brompton and Harefield Clinical Group, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

R. E. Barker, Daniele Cristiano, N. Dormand, P. George, Mahitha Gummadi, S. Kon, Kamal Liyanage, C. M. Nolan, B. Patel, Suhani Patel, Oliver Polgar, L. Price, P. Shah, Suver Singh & J. A. Walsh

York and Scarborough NHS Foundation Trust, York, UK

Laura Barman, Claire Brookes, K. Elliott, L. Griffiths, Zoe Guy, Kate Howard, Diana Ionita, Heidi Redfearn, Carol Sarginson & Alison Turnbull

NHS Highland, Inverness, UK

Fiona Barrett, A. Donaldson & Beth Sage

Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK

Helen Baxendale, Lucie Garner, C. Johnson, J. Mackie, Alice Michael, J. Newman, Jamie Pack, K. Paques, H. Parfrey, J. Parmar & A. Reddy

University Hospitals of Derby and Burton, Derby, UK

Paul Beckett, Caroline Dickens & Uttam Nanda

NHS Lanarkshire, Hamilton, UK

Murdina Bell, Angela Brown, M. Brown, R. Hamil, Karen Leitch, L. Macliver, Manish Patel, Jackie Quigley, Andrew Smith & B. Welsh

Cambridge University Hospitals NHS Foundation Trust, NIHR Cambridge Clinical Research Facility and University of Cambridge, Cambridge, UK

Areti Bermperi, Isabel Cruz, K. Dempsey, Anne Elmer, Jonathon Fuld, H. Jones, Sherly Jose, Stefan Marciniak, M. Parkes, Carla Ribeiro, Jessica Taylor, Mark Toshner, L. Watson & J. Worsley

Loughborough University, Loughborough, UK

Lettie Bishop & David Stensel

Betsi Cadwallader University Health Board, Bangor, UK

Annette Bolger, Ffyon Davies, Ahmed Haggar, Joanne Lewis, Arwel Lloyd, R. Manley, Emma McIvor, Daniel Menzies, K. Roberts, W. Saxon, David Southern, Christian Subbe & Victoria Whitehead

Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK

Charlotte Bolton, J. Bonnington, Melanie Chrystal, Catherine Dupont, Paul Greenhaff, Ayushman Gupta, W. Jang, S. Linford, Laura Matthews, Athanasios Nikolaidis, Sabrina Prosper & Andrew Thomas

King’s College London, London, UK

Kate Bramham, M. Brown, Khalida Ismail, Tim Nicholson, Carmen Pariante, Claire Sharpe, Simon Wessely & J. Whitney

Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK

Lucy Brear, Karen Regan, Dinesh Saralaya & Kim Storton

South London and Maudsley NHS Foundation Trust and King’s College London, London, UK

G. Breen & M. Hotopf

London School of Hygiene and Tropical Medicine, London, UK

Andrew Briggs

Whittington Health NHS Trust, London, UK

E. Bright, P. Crisp, Ruvini Dharmagunawardena & M. Stern

Cardiff and Vale University Health Board, Cardiff, UK

Lauren Broad, Teriann Evans, Matthew Haynes, L. Jones, Lucy Knibbs, Alison McQueen, Catherine Oliver, Kerry Paradowski, Ramsey Sabit & Jenny Williams

Yeovil District Hospital NHS Foundation Trust, Yeovil, UK

Andrew Broadley

University of Birmingham, Birmingham, UK

Mattew Broome, Paul McArdle, Paul Moss, David Thickett, Rachel Upthegrove, Dan Wilkinson, David Wraith & Erin L. Aldera

BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK

Anda Bularga

University of Cambridge, Cambridge, UK

Ed Bullmore, Jonathon Heeney, Claudia Langenberg, William Schwaeble, Charlotte Summers & J. Weir McCall

NIHR Leicester Biomedical Research Centre–Respiratory Patient and Public Involvement Group, Leicester, UK

Jenny Bunker, Rhyan Gill & Rashmita Nathu

Imperial College Healthcare NHS Trust and Imperial College London, London, UK

L. Burden, Ellen Calvelo, Bethany Card, Caitlin Carr, Edwin Chilvers, Donna Copeland, P. Cullinan, Patrick Daly, Lynsey Evison, Tamanah Fayzan, Hussain Gordon, Sulaimaan Haq, Gisli Jenkins, Clara King, Onn Min Kon, Katherine March, Myril Mariveles, Laura McLeavey, Silvia Moriera, Unber Munawar, Uchechi Nwanguma, Lorna Orriss-Dib, Alexandra Ross, Maura Roy, Emily Russell, Katherine Samuel, J. Schronce, Neil Simpson, Lawrence Tarusan, David Thomas, Chloe Wood & Najira Yasmin

Harrogate and District NHD Foundation Trust, Harrogate, UK

Tracy Burdett, James Featherstone, Cathy Lawson, Alison Layton, Clare Mills & Lorraine Stephenson

Newcastle University/Chair of NIHR Dementia TRC, Newcastle, UK

Oxford University Hospitals NHS Foundation Trust, Oxford, UK

A. Burns & N. Kanellakis

Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton-under-Lyne, UK

Al-Tahoor Butt, Martina Coulding, Heather Jones, Susan Kilroy, Jacqueline McCormick, Jerome McIntosh, Heather Savill, Victoria Turner & Joanne Vere

University of Oxford, Nuffield Department of Medicine, Oxford, UK

University of Glasgow, Glasgow, UK

Jonathon Cavanagh, S. MacDonald, Kate O’Donnell, John Petrie, Naveed Sattar & Mark Spears

United Lincolnshire Hospitals NHS Trust, Grantham, UK

Manish Chablani & Lynn Osborne

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

Trudie Chalder

University Hospital of South Manchester NHS Foundation Trust, Manchester, UK

N. Chaudhuri

University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK

Caroline Childs, R. Djukanovic, S. Fletcher, Matt Harvey, Mark Jones, Elizabeth Marouzet, B. Marshall, Reena Samuel, T. Sass, Tim Wallis & Helen Wheeler

King’s College Hospital/Guy’s and St Thomas’ NHS FT, London, UK

A. Chiribiri & C. O’Brien

Barts Health NHS Trust, London, UK

K. Chong-James, C. David, W. Y. James, Paul Pfeffer & O. Zongo

NHS Lothian and University of Edinburgh, Edinburgh, UK

Gaunab Choudhury, S. Clohisey, Andrew Deans, J. Furniss, Ewen Harrison, S. Kelly & Aziz Sheikh

School of Cardiovascular Medicine and Sciences. King’s College London, London, UK

Phillip Chowienczyk

Lewisham and Greenwich NHS Trust, London, UK

Hywel Dda University Health Board, Haverfordwest, UK

S. Coetzee, Kim Davies, Rachel Ann Hughes, Ronda Loosley, Heather McGuinness, Abdelrahman Mohamed, Linda O’Brien, Zohra Omar, Emma Perkins, Janet Phipps, Gavin Ross, Abigail Taylor, Helen Tench & Rebecca Wolf-Roberts

NHS Tayside and University of Dundee, Dundee, UK

David Connell, C. Deas, Anne Elliott, J. George, S. Mohammed, J. Rowland, A. R. Solstice, Debbie Sutherland & Caroline Tee

Swansea Bay University Health Board, Port Talbot, UK

Lynda Connor, Amanda Cook, Gwyneth Davies, Tabitha Rees, Favas Thaivalappil & Caradog Thomas

Faculty of Medicine, Nursing and Health Sciences, School of Biomedical Sciences, Monash University, Melbourne, Victoria, Australia

Eamon Coughlan

Rotherham NHS Foundation Trust, Rotherham, UK

Alison Daniels, Anil Hormis, Julie Ingham & Lisa Zeidan

Salford Royal NHS Foundation Trust, Salford, UK

P. Dark, Nawar Diar-Bakerly, D. Evans, E. Hardy, Alice Harvey, D. Holgate, Sean Knight, N. Mairs, N. Majeed, L. McMorrow, J. Oxton, Jessica Pendlebury, C. Summersgill, R. Ugwuoke & S. Whittaker

Cwm Taf Morgannwg University Health Board, Mountain Ash, UK

Ellie Davies, Cerys Evenden, Alyson Hancock, Kia Hancock, Ceri Lynch, Meryl Rees, Lisa Roche, Natalie Stroud & T. Thomas-Woods

Borders General Hospital, NHS Borders, Melrose, UK

Joy Dawson, Hosni El-Taweel & Leanne Robinson

Aneurin Bevan University Health Board, Caerleon, UK

Amanda Dell, Sara Fairbairn, Nancy Hawkings, Jill Haworth, Michaela Hoare, Victoria Lewis, Alice Lucey, Georgia Mallison, Heeah Nassa, Chris Pennington, Andrea Price, Claire Price, Andrew Storrie, Gemma Willis & Susan Young

University of Exeter Medical School, Exeter, UK

London North West University Healthcare NHS Trust, London, UK

Shalin Diwanji, Sambasivarao Gurram, Padmasayee Papineni, Sheena Quaid, Gerlynn Tiongson & Ekaterina Watson

Alzheimer’s Research UK, Cambridge, UK

Hannah Dobson

Health and Care Research Wales, Cardiff, UK

Yvette Ellis

University of Bristol, Bristol, UK

Jonathon Evans

University of Sheffield, Sheffield, UK

L. Finnigan, Laura Saunders & James Wild

Great Western Hospital Foundation Trust, Swindon, UK

Eva Fraile & Jacinta Ugoji

Royal Devon and Exeter NHS Trust, Barnstaple, UK

Michael Gibbons

Kettering General Hospital NHS Trust, Kettering, UK

Anne-Marie Guerdette, Melanie Hewitt, R. Reddy, Katie Warwick & Sonia White

NIHR Leicester Biomedical Research Centre, Leicester, UK

Beatriz Guillen-Guio

University of Leeds, Leeds, UK

Elspeth Guthrie & Max Henderson

Royal Surrey NHS Foundation Trust, Cranleigh, UK

Mark Halling-Brown & Katherine McCullough

Chesterfield Royal Hospital NHS Trust, Calow, UK

Edward Harris & Claire Sampson

Long Covid Support, London, UK

Claire Hastie, Natalie Rogers & Nikki Smith

King’s College Hospital, NHS Foundation Trust and King’s College London, London, UK

Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK

Simon Heller

NIHR Office for Clinical Research Infrastructure, London, UK

Katie Holmes

Asthma UK and British Lung Foundation Partnership, London, UK

Ian Jarrold & Samantha Walker

North Middlesex University Hospital NHS Trust, London, UK

Bhagy Jayaraman & Tessa Light

Action for Pulmonary Fibrosis, Peterborough, UK

Cardiff University, National Centre for Mental Health, Cardiff, UK

McPin Foundation, London, UK

Thomas Kabir

Roslin Institute, The University of Edinburgh, Edinburgh, UK

Steven Kerr

The Hillingdon Hospitals NHS Foundation Trust, London, UK

Samantha Kon, G. Landers, Harpreet Lota, Mariam Nasseri & Sofiya Portukhay

Queen Mary University of London, London, UK

Ania Korszun

Swansea University, Swansea Welsh Network, Hywel Dda University Health Board, Swansea, UK

Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, UK

Nazir I. Lone

Barts Heart Centre, London, UK

Barts Health NHS Trust and Queen Mary University of London, London, UK

Adrian Martineau

Salisbury NHS Foundation Trust, Salisbury, UK

Wadzanai Matimba-Mupaya & Sophia Strong-Sheldrake

University of Newcastle, Newcastle, UK

Hamish McAllister-Williams, Stella-Maria Paddick, Anthony Rostron & John Paul Taylor

Gateshead NHS Trust, Gateshead, UK

W. McCormick, Lorraine Pearce, S. Pugmire, Wendy Stoker & Ann Wilson

Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Manchester, UK

Katherine McIvor

Kidney Research UK, Peterborough, UK

Aisling McMahon

NHS Dumfries and Galloway, Dumfries, UK

Michael McMahon & Paula Neill

Swansea University, Swansea, UK

MQ Mental Health Research, London, UK

Lea Milligan

BHF Centre for Cardiovascular Science, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK

Nicholas Mills

Shropshire Community Health NHS Trust, Shropshire, UK

Sharon Painter, Johanne Tomlinson & Louise Warburton

Somerset NHS Foundation Trust, Taunton, UK

Sue Palmer, Dawn Redwood, Jo Tilley, Carinna Vickers & Tania Wainwright

Francis Crick Institute, London, UK

Markus Ralser

Manchester University NHD Foundation Trust, Manchester, UK

Pilar Rivera-Ortega

Diabetes UK, University of Glasgow, Glasgow, UK

Elizabeth Robertson

Barnsley Hospital NHS Foundation Trust, Barnsley, UK

Amy Sanderson

MRC–University of Glasgow Centre for Virus Research, Glasgow, UK

Janet Scott

Diabetes UK, London, UK

Kamini Shah

British Heart Foundation Centre, King’s College London, London, UK

King’s College Hospital NHS Foundation Trust, London, UK

University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK

Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK

University College London NHS Foundation Trust, London and Barts Health NHS Trust, London, UK

Northumbria University, Newcastle upon Tyne, UK

Ioannis Vogiatzis

Swansea University and Swansea Welsh Network, Swansea, UK

N. Williams

DUK | NHS Digital, Salford Royal Foundation Trust, Salford, UK

Queen Alexandra Hospital, Portsmouth, UK

• Kayode Adeniji

Princess Royal Hospital, Haywards Heath, UK

Daniel Agranoff & Chi Eziefula

Bassetlaw Hospital, Bassetlaw, UK

Darent Valley Hospital, Dartford, UK

Queen Elizabeth the Queen Mother Hospital, Margate, UK

Ana Alegria

School of Informatics, University of Edinburgh, Edinburgh, UK

Beatrice Alex, Benjamin Bach & James Scott-Brown

North East and North Cumbria Ingerated, Newcastle upon Tyne, UK

Section of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

Petros Andrikopoulos, Kanta Chechi, Marc-Emmanuel Dumas, Julian Griffin, Sonia Liggi & Zoltan Takats

Section of Genomic and Environmental Medicine, Respiratory Division, National Heart and Lung Institute, Imperial College London, London, UK

Petros Andrikopoulos, Marc-Emmanuel Dumas, Michael Olanipekun & Anthonia Osagie

John Radcliffe Hospital, Oxford, UK

Brian Angus

Royal Albert Edward Infirmary, Wigan, UK

Abdul Ashish

Manchester Royal Infirmary, Manchester, UK

Dougal Atkinson

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, UK

Section of Molecular Virology, Imperial College London, London, UK

Wendy S. Barclay

Furness General Hospital, Barrow-in-Furness, UK

Shahedal Bari

Hull University Teaching Hospital Trust, Kingston upon Hull, UK

Gavin Barlow

Hillingdon Hospital, Hillingdon, UK

Stella Barnass

St Thomas’ Hospital, London, UK

Nicholas Barrett

Coventry and Warwickshire, Coventry, UK

Christopher Bassford

St Michael’s Hospital, Bristol, UK

Sneha Basude

Stepping Hill Hospital, Stockport, UK

David Baxter

Royal Liverpool University Hospital, Liverpool, UK

Michael Beadsworth

Bristol Royal Hospital Children’s, Bristol, UK

Jolanta Bernatoniene

Scarborough Hospital, Scarborough, UK

John Berridge

Golden Jubilee National Hospital, Clydebank, UK

Colin Berry

Liverpool Heart and Chest Hospital, Liverpool, UK

Nicola Best

Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK

Debby Bogaert & Clark D. Russell

James Paget University Hospital, Great Yarmouth, UK

Pieter Bothma & Darell Tupper-Carey

Aberdeen Royal Infirmary, Aberdeen, UK

Robin Brittain-Long

Adamson Hospital, Cupar, UK

Naomi Bulteel

Royal Devon and Exeter Hospital, Exeter, UK

Worcestershire Royal Hospital, Worcester, UK

Andrew Burtenshaw

ISARIC Global Support Centre, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK

Gail Carson, Laura Merson & Louise Sigfrid

Conquest Hospital, Hastings, UK

Vikki Caruth

The James Cook University Hospital, Middlesbrough, UK

David Chadwick

Dorset County Hospital, Dorchester, UK

Duncan Chambler

Antimicrobial Resistance and Hospital Acquired Infection Department, Public Health England, London, UK

Meera Chand

Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK

Kanta Chechi

Royal Bournemouth General Hospital, Bournemouth, UK

Harrogate Hospital, Harrogate, UK

Jenny Child

Royal Blackburn Teaching Hospital, Blackburn, UK

Srikanth Chukkambotla

Edinburgh Clinical Research Facility, University of Edinburgh, Edinburgh, UK

Richard Clark, Audrey Coutts, Lorna Donelly, Angie Fawkes, Tammy Gilchrist, Katarzyna Hafezi, Louise MacGillivray, Alan Maclean, Sarah McCafferty, Kirstie Morrice, Lee Murphy & Nicola Wrobel

Torbay Hospital, Torquay, UK

Northern General Hospital, Sheffield, UK

Paul Collini, Cariad Evans & Gary Mills

Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, UK

Marie Connor, Jo Dalton, Chloe Donohue, Carrol Gamble, Michelle Girvan, Sophie Halpin, Janet Harrison, Clare Jackson, Laura Marsh, Stephanie Roberts & Egle Saviciute

Department of Infectious Disease, Imperial College London, London, UK

Graham S. Cooke & Shiranee Sriskandan

St Georges Hospital (Tooting), London, UK

Catherine Cosgrove

Blackpool Victoria Hospital, Blackpool, UK

Jason Cupitt & Joanne Howard

The Royal London Hospital, London, UK

Maria-Teresa Cutino-Moguel

MRC-University of Glasgow Centre for Virus Research, Glasgow, UK

Ana da Silva Filipe, Antonia Y. W. Ho, Sarah E. McDonald, Massimo Palmarini, David L. Robertson, Janet T. Scott & Emma C. Thomson

Salford Royal Hospital, Salford, UK

University Hospital of North Durham, Durham, UK

Chris Dawson

Norfolk and Norwich University Hospital, Norwich, UK

Samir Dervisevic

Intensive Care Unit, Royal Infirmary Edinburgh, Edinburgh, UK

Annemarie B. Docherty & Seán Keating

Institute of Infection, Veterinary and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK

Cara Donegan & Rebecca G. Spencer

Salisbury District Hospital, Salisbury, UK

Phil Donnison

National Phenome Centre, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

Gonçalo dos Santos Correia, Matthew Lewis, Lynn Maslen, Caroline Sands, Zoltan Takats & Panteleimon Takis

Section of Bioanalytical Chemistry, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

Gonçalo dos Santos Correia, Matthew Lewis, Lynn Maslen, Caroline Sands & Panteleimon Takis

Guy’s and St Thomas’, NHS Foundation Trust, London, UK

Sam Douthwaite, Michael MacMahon, Marlies Ostermann & Manu Shankar-Hari

The Royal Oldham Hospital, Oldham, UK

Andrew Drummond

European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille University Hospital, University of Lille, Lille, France

Marc-Emmanuel Dumas

McGill University and Genome Quebec Innovation Centre, Montreal, Qeubec, Canada

National Infection Service, Public Health England, London, UK

Jake Dunning & Maria Zambon

Hereford Count Hospital, Hereford, UK

Ingrid DuRand

Southampton General Hospital, Southampton, UK

Ahilanadan Dushianthan

Northampton General Hospital, Northampton, UK

Tristan Dyer

University Hospital of Wales, Cardiff, UK

Chrisopher Fegan

University Hospitals Bristol NHS Foundation Trust, Bristol, UK

Liverpool School of Tropical Medicine, Liverpool, UK

Tom Fletcher

Leighton Hospital, Crewe, UK

Duncan Fullerton & Elijah Matovu

Manor Hospital, Walsall, UK

Scunthorpe Hospital, Scunthorpe, UK

Sanjeev Garg

Cambridge University Hospital, Cambridge, UK

Effrossyni Gkrania-Klotsas

West Suffolk NHS Foundation Trust, Bury St Edmunds, UK

Basingstoke and North Hampshire Hospital, Basingstoke, UK

Arthur Goldsmith

North Cumberland Infirmary, Carlisle, UK

Clive Graham

Paediatric Liver, GI and Nutrition Centre and MowatLabs, King’s College Hospital, London, UK

Tassos Grammatikopoulos

Institute of Liver Studies, King’s College London, London, UK

Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK

Christopher A. Green

Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK

William Greenhalf

Institute for Global Health, University College London, London, UK

Rishi K. Gupta

NIHR Health Protection Research Unit, Institute of Infection, Veterinary and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK

Hayley Hardwick, Malcolm G. Semple, Tom Solomon & Lance C. W. Turtle

Warwick Hospital, Warwick, UK

Elaine Hardy

Birmingham Children’s Hospital, Birmingham, UK

Stuart Hartshorn

Nottingham City Hospital, Nottingham, UK

Daniel Harvey

Glangwili Hospital Child Health Section, Carmarthen, UK

Peter Havalda

Alder Hey Children’s Hospital, Liverpool, UK

Daniel B. Hawcutt

Department of Infectious Diseases, Queen Elizabeth University Hospital, Glasgow, UK

Antonia Y. W. Ho

Bronglais General Hospital, Aberystwyth, UK

Maria Hobrok

Worthing Hospital, Worthing, UK

Luke Hodgson

Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK

Peter W. Horby

Rotheram District General Hospital, Rotheram, UK

Anil Hormis

Virology Reference Department, National Infection Service, Public Health England, Colindale Avenue, London, UK

Samreen Ijaz

Royal Free Hospital, London, UK

Michael Jacobs & Padmasayee Papineni

Homerton Hospital, London, UK

Airedale Hospital, Airedale, UK

Paul Jennings

Basildon Hospital, Basildon, UK

Agilan Kaliappan

The Christie NHS Foundation Trust, Manchester, UK

Vidya Kasipandian

University Hospital Lewisham, London, UK

Stephen Kegg

The Whittington Hospital, London, UK

Michael Kelsey

Southmead Hospital, Bristol, UK

Jason Kendall

Sheffield Childrens Hospital, Sheffield, UK

Caroline Kerrison

Royal United Hospital, Bath, UK

Ian Kerslake

Department of Pharmacology, University of Liverpool, Liverpool, UK

Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK

Paul Klenerman

Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK

Public Health Scotland, Edinburgh, UK

Susan Knight, Eva Lahnsteiner & Sarah Tait

Western General Hospital, Edinburgh, UK

Oliver Koch

Southend University Hospital NHS Foundation Trust, Southend-on-Sea, UK

Gouri Koduri

Hinchingbrooke Hospital, Huntingdon, UK

George Koshy & Tamas Leiner

Royal Preston Hospital, Fulwood, UK

Shondipon Laha

University Hospital (Coventry), Coventry, UK

Steven Laird

The Walton Centre, Liverpool, UK

Susan Larkin

ISARIC, Global Support Centre, COVID-19 Clinical Research Resources, Epidemic diseases Research Group, Oxford (ERGO), University of Oxford, Oxford, UK

James Lee & Daniel Plotkin

Centre for Health Informatics, Division of Informatics, Imaging and Data Science, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK

Gary Leeming

Hull Royal Infirmary, Hull, UK

Patrick Lillie

Nottingham University Hospitals NHS Trust:, Nottingham, UK

Wei Shen Lim

Darlington Memorial Hospital, Darlington, UK

Queen Elizabeth Hospital (Gateshead), Gateshead, UK

Vanessa Linnett

Warrington Hospital, Warrington, UK

Jeff Little

Bristol Royal Hospital for Children, Bristol, UK

Mark Lyttle

St Mary’s Hospital (Isle of Wight), Isle of Wight, UK

Emily MacNaughton

The Tunbridge Wells Hospital, Royal Tunbridge Wells, UK

Ravish Mankregod

Huddersfield Royal, Huddersfield, UK

Countess of Chester Hospital, Liverpool, UK

Ruth McEwen & Lawrence Wilson

Frimley Park Hospital, Frimley, UK

Manjula Meda

Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK

Alexander J. Mentzer

Department of Microbiology/Infectious Diseases, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

Alison M. Meynert & Murray Wham

St James University Hospital, Leeds, UK

Jane Minton

Arrowe Park Hospital, Birkenhead, UK

Kavya Mohandas

Great Ormond Street Hospital, London, UK

Royal Shrewsbury Hospital, Shrewsbury, UK

Addenbrookes Hospital, Cambridge, UK

Elinoor Moore

Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK

Shona C. Moore, William A. Paxton & Georgios Pollakis

East Surrey Hospital (Redhill), Redhill, UK

Patrick Morgan

Burton Hospital, Burton, UK

Craig Morris & Tim Reynolds

Peterborough City Hospital, Peterborough, UK

Katherine Mortimore

Kent and Canterbury Hospital, Canterbury, UK

Samuel Moses

Weston Area General Trust, Bristol, UK

Mbiye Mpenge

Bedfordshire Hospital, Bedfordshire, UK

Rohinton Mulla

Glasgow Royal Infirmary, Glasgow, UK

Michael Murphy

Macclesfield General Hospital, Macclesfield, UK

Thapas Nagarajan

Derbyshire Healthcare, Derbyshire, UK

Megan Nagel

Chelsea and Westminster Hospital, London, UK

Mark Nelson & Matthew K. O’Shea

Watford General Hospital, Watford, UK

Lillian Norris & Tom Stambach

EPCC, University of Edinburgh, Edinburgh, UK

Lucy Norris

Section of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, London, UK

Michael Olanipekun

Imperial College Healthcare NHS Trust: London, London, UK

Peter J. M. Openshaw

Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

Anthonia Osagie

Prince Philip Hospital, Llanelli, UK

Igor Otahal & Andrew Workman

George Eliot Hospital – Acute Services, Nuneaton, UK

Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK

Carlo Palmieri

Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK

Kettering General Hospital, Kettering, UK

Selva Panchatsharam

University Hospitals of North Midlands NHS Trust, North Midlands, UK

Danai Papakonstantinou

Russells Hall Hospital, Dudley, UK

Hassan Paraiso

Harefield Hospital, Harefield, UK

Lister Hospital, Lister, UK

Natalie Pattison

Musgrove Park Hospital, Taunton, UK

Justin Pepperell

Kingston Hospital, Kingston, UK

Mark Peters

Queen’s Hospital, Romford, UK

Mandeep Phull

Southport and Formby District General Hospital, Southport, UK

Stefania Pintus

St George’s University of London, London, UK

Tim Planche

King’s College Hospital (Denmark Hill), London, UK

Centre for Clinical Infection and Diagnostics Research, Department of Infectious Diseases, School of Immunology and Microbial Sciences, King’s College London, London, UK

Nicholas Price

Department of Infectious Diseases, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

The Clatterbridge Cancer Centre NHS Foundation, Bebington, UK

David Price

The Great Western Hospital, Swindon, UK

Rachel Prout

Ninewells Hospital, Dundee, UK

Nikolas Rae

Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK

Andrew Rambaut

Poole Hospital NHS Trust, Poole, UK

Henrik Reschreiter

William Harvey Hospital, Ashford, UK

Neil Richardson

King’s Mill Hospital, Sutton-in-Ashfield, UK

Mark Roberts

Liverpool Women’s Hospital, Liverpool, UK

Devender Roberts

Pinderfields Hospital, Wakefield, UK

Alistair Rose

North Devon District Hospital, Barnstaple, UK

Guy Rousseau

Queen Elizabeth Hospital, Birmingham, UK

Tameside General Hospital, Ashton-under-Lyne, UK

Brendan Ryan

City Hospital (Birmingham), Birmingham, UK

Taranprit Saluja

Department of Pediatrics and Virology, St Mary’s Medical School Bldg, Imperial College London, London, UK

Vanessa Sancho-Shimizu

The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK

Matthias Schmid

NHS Greater Glasgow and Clyde, Glasgow, UK

Janet T. Scott

Respiratory Medicine, Institute in The Park, University of Liverpool, Alder Hey Children’s Hospital, Liverpool, UK

Malcolm G. Semple

Broomfield Hospital, Broomfield, UK

Stoke Mandeville, UK

Prad Shanmuga

University Hospital of North Tees, Stockton-on-Tees, UK

Anil Sharma

Institute of Translational Medicine, University of, Liverpool, Merseyside, UK

Victoria E. Shaw

Royal Manchester Children’s Hospital, Manchester, UK

Anna Shawcross

New Cross Hospital, Wolverhampton, UK

Jagtur Singh Pooni

Bedford Hospital, Bedford, UK

Jeremy Sizer

Colchester General Hospital, Colchester, UK

Richard Smith

University Hospital Birmingham NHS Foundation Trust, Birmingham, UK

Catherine Snelson & Tony Whitehouse

Walton Centre NHS Foundation Trust, Liverpool, UK

Tom Solomon

Chesterfield Royal Hospital, Calow, UK

Nick Spittle

MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK

Shiranee Sriskandan

Princess Alexandra Hospital, Harlow, UK

Nikki Staines & Shico Visuvanathan

Milton Keynes Hospital, Eaglestone, UK

Richard Stewart

Division of Structural Biology, The Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK

David Stuart

Royal Bolton Hopital, Farnworth, UK

Pradeep Subudhi

Department of Medicine, University of Cambridge, Cambridge, UK

Charlotte Summers

Department of Child Life and Health, University of Edinburgh, Edinburgh, UK

Olivia V. Swann

Royal Gwent (Newport), Newport, UK

Tamas Szakmany

The Royal Marsden Hospital (London), London, UK

Kate Tatham

Blood Borne Virus Unit, Virus Reference Department, National Infection Service, Public Health England, London, UK

Richard S. Tedder

Transfusion Microbiology, National Health Service Blood and Transplant, London, UK

Department of Medicine, Imperial College London, London, UK

Queen Victoria Hospital (East Grinstead), East Grinstead, UK

Leeds Teaching Hospitals NHS Trust, Leeds, UK

Robert Thompson

Royal Stoke University Hospital, Stoke-on-Trent, UK

Chris Thompson

Whiston Hospital, Rainhill, UK

Ascanio Tridente

Tropical and Infectious Disease Unit, Royal Liverpool University Hospital, Liverpool, UK

Lance C. W. Turtle

Croydon University Hospital, Thornton Heath, UK

Mary Twagira

Gloucester Royal, Gloucester, UK

Nick Vallotton

West Hertfordshire Teaching Hospitals NHS Trust, Hertfordshire, UK

Rama Vancheeswaran

North Middlesex Hospital, London, UK

Rachel Vincent

Medway Maritime Hospital, Gillingham, UK

Lisa Vincent-Smith

Royal Papworth Hospital Everard, Cambridge, UK

Alan Vuylsteke

Derriford (Plymouth), Plymouth, UK

St Helier Hospital, Sutton, UK

Rachel Wake

Royal Berkshire Hospital, Reading, UK

Andrew Walden

Royal Liverpool Hospital, Liverpool, UK

Ingeborg Welters

Bradford Royal infirmary, Bradford, UK

Paul Whittaker

Central Middlesex, London, UK

Ashley Whittington

Royal Cornwall Hospital (Tresliske), Truro, UK

Meme Wijesinghe

North Bristol NHS Trust, Bristol, UK

Martin Williams

St. Peter’s Hospital, Runnymede, UK

Stephen Winchester

Leicester Royal Infirmary, Leicester, UK

Martin Wiselka

Grantham and District Hospital, Grantham, UK

Adam Wolverson

Aintree University Hospital, Liverpool, UK

Daniel G. Wootton

North Tyneside General Hospital, North Shields, UK

Bryan Yates

Queen Elizabeth Hospital, King’s Lynn, UK

Peter Young

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PHOSP-COVID collaborative group

• Kathryn Abel
• , H. Adamali
• , Davies Adeloye
• , Oluwaseun Adeyemi
• , Rita Adrego
• , Laura Aguilar Jimenez
• , Shanaz Ahmad
• , N. Ahmad Haider
• , Rubina Ahmed
• , Nyarko Ahwireng
• , Mark Ainsworth
• , Asma Alamoudi
• , Mariam Ali
• , M. Aljaroof
• , Louise Allan
• , Richard Allen
• , Lisa Allerton
• , Lynne Allsop
• , Ann Marie Allt
• , Paula Almeida
• , Bashar Al-Sheklly
• , Danny Altmann
• , Maria Alvarez Corral
• , Shannon Amoils
• , David Anderson
• , Charalambos Antoniades
• , Gill Arbane
• , Ava Maria Arias
• , Cherie Armour
• , Lisa Armstrong
• , Natalie Armstrong
• , David Arnold
• , H. Arnold
• , A. Ashish
• , Andrew Ashworth
• , M. Ashworth
• , Shahab Aslani
• , Hosanna Assefa-Kebede
• , Paul Atkin
• , Catherine Atkin
• , Raminder Aul
• , Hnin Aung
• , Liam Austin
• , Cristina Avram
• , Nikos Avramidis
• , Marta Babores
• , Rhiannon Baggott
• , J. Bagshaw
• , David Baguley
• , Elisabeth Bailey
• , J. Kenneth Baillie
• , Steve Bain
• , Majda Bakali
• , E. Baldry
• , Molly Baldwin
• , David Baldwin
• , Clive Ballard
• , Amita Banerjee
• , Dongchun Bang
• , R. E. Barker
• , Laura Barman
• , Perdita Barran
• , Shaney Barratt
• , Fiona Barrett
• , Donna Basire
• , Neil Basu
• , Michelle Bates
• , R. Batterham
• , Helen Baxendale
• , Gabrielle Baxter
• , Hannah Bayes
• , M. Beadsworth
• , Paul Beckett
• , Paul Beirne
• , Murdina Bell
• , Robert Bell
• , Kaytie Bennett
• , Eva Beranova
• , Areti Bermperi
• , Anthony Berridge
• , Colin Berry
• , Sarah Betts
• , Emily Bevan
• , Kamaldeep Bhui
• , Michelle Bingham
• , K. Birchall
• , Lettie Bishop
• , Karen Bisnauthsing
• , John Blaikely
• , Angela Bloss
• , Annette Bolger
• , Charlotte Bolton
• , J. Bonnington
• , A. Botkai
• , Charlotte Bourne
• , Michelle Bourne
• , Kate Bramham
• , Lucy Brear
• , Jonathon Breeze
• , Katie Breeze
• , Andrew Briggs
• , E. Bright
• , Christopher Brightling
• , Simon Brill
• , K. Brindle
• , Lauren Broad
• , Andrew Broadley
• , Claire Brookes
• , Mattew Broome
• , Vanessa Brown
• , Ammani Brown
• , Angela Brown
• , Jeremy Brown
• , Terry Brugha
• , Nigel Brunskill
• , Phil Buckley
• , Anda Bularga
• , Ed Bullmore
• , Jenny Bunker
• , L. Burden
• , Tracy Burdett
• , David Burn
• , John Busby
• , Robyn Butcher
• , Al-Tahoor Butt
• , P. Cairns
• , P. C. Calder
• , Ellen Calvelo
• , H. Carborn
• , Bethany Card
• , Caitlin Carr
• , Liesel Carr
• , G. Carson
• , Penny Carter
• , Anna Casey
• , M. Cassar
• , Jonathon Cavanagh
• , Manish Chablani
• , Trudie Chalder
• , James D. Chalmers
• , Rachel Chambers
• , Flora Chan
• , K. M. Channon
• , Kerry Chapman
• , Amanda Charalambou
• , N. Chaudhuri
• , A. Checkley
• , Yutung Cheng
• , Luke Chetham
• , Caroline Childs
• , Edwin Chilvers
• , H. Chinoy
• , A. Chiribiri
• , K. Chong-James
• , N. Choudhury
• , Gaunab Choudhury
• , Phillip Chowienczyk
• , C. Christie
• , Melanie Chrystal
• , Cameron Clark
• , David Clark
• , Jude Clarke
• , S. Clohisey
• , G. Coakley
• , Zach Coburn
• , S. Coetzee
• , Joby Cole
• , Chris Coleman
• , Florence Conneh
• , David Connell
• , Bronwen Connolly
• , Lynda Connor
• , Amanda Cook
• , Shirley Cooper
• , B. Cooper
• , Josh Cooper
• , Donna Copeland
• , Tracey Cosier
• , Eamon Coughlan
• , Martina Coulding
• , C. Coupland
• , Thelma Craig
• , Daniele Cristiano
• , Michael Crooks
• , Andy Cross
• , Isabel Cruz
• , P. Cullinan
• , D. Cuthbertson
• , Luke Daines
• , Matthhew Dalton
• , Patrick Daly
• , Alison Daniels
• , Joanne Dasgin
• , Anthony David
• , Ffyon Davies
• , Ellie Davies
• , Kim Davies
• , Gareth Davies
• , Gwyneth Davies
• , Melanie Davies
• , Joy Dawson
• , Camilla Dawson
• , Enya Daynes
• , Anthony De Soyza
• , Bill Deakin
• , Andrew Deans
• , Joanne Deery
• , Sylviane Defres
• , Amanda Dell
• , K. Dempsey
• , Emma Denneny
• , J. Dennis
• , Ruvini Dharmagunawardena
• , Nawar Diar-Bakerly
• , Caroline Dickens
• , A. Dipper
• , Sarah Diver
• , Shalin Diwanji
• , Myles Dixon
• , R. Djukanovic
• , Hannah Dobson
• , S. L. Dobson
• , Annemarie B. Docherty
• , A. Donaldson
• , N. Dormand
• , Andrew Dougherty
• , Rachael Dowling
• , Stephen Drain
• , Katharine Draxlbauer
• , Katie Drury
• , Pearl Dulawan
• , A. Dunleavy
• , Sarah Dunn
• , Catherine Dupont
• , Joanne Earley
• , Nicholas Easom
• , Carlos Echevarria
• , Sarah Edwards
• , C. Edwardson
• , Claudia Efstathiou
• , Anne Elliott
• , K. Elliott
• , Yvette Ellis
• , Anne Elmer
• , Omer Elneima
• , Hosni El-Taweel
• , Teriann Evans
• , Ranuromanana Evans
• , Rachael A. Evans
• , Jonathon Evans
• , Cerys Evenden
• , Lynsey Evison
• , Laura Fabbri
• , Sara Fairbairn
• , Alexandra Fairman
• , K. Fallon
• , David Faluyi
• , Clair Favager
• , Tamanah Fayzan
• , James Featherstone
• , T. Felton
• , V. Ferreira
• , Selina Finney
• , J. Finnigan
• , L. Finnigan
• , Helen Fisher
• , S. Fletcher
• , Rachel Flockton
• , Margaret Flynn
• , David Foote
• , Amber Ford
• , D. Forton
• , Eva Fraile
• , C. Francis
• , Richard Francis
• , Susan Francis
• , Anew Frankel
• , Emily Fraser
• , N. French
• , Jonathon Fuld
• , J. Furniss
• , Lucie Garner
• , N. Gautam
• , John Geddes
• , J. George
• , P. George
• , Michael Gibbons
• , Rhyan Gill
• , Mandy Gill
• , L. Gilmour
• , F. Gleeson
• , Jodie Glossop
• , Sarah Glover
• , Nicola Goodman
• , Camelia Goodwin
• , Bibek Gooptu
• , Hussain Gordon
• , T. Gorsuch
• , M. Greatorex
• , Paul Greenhaff
• , William Greenhalf
• , Alan Greenhalgh
• , Neil J. Greening
• , John Greenwood
• , Rebecca Gregory
• , Heidi Gregory
• , D. Grieve
• , Denise Griffin
• , L. Griffiths
• , Anne-Marie Guerdette
• , Beatriz Guillen-Guio
• , Mahitha Gummadi
• , Ayushman Gupta
• , Sambasivarao Gurram
• , Elspeth Guthrie
• , Kate Hadley
• , Ahmed Haggar
• , Kera Hainey
• , Brigid Hairsine
• , Pranab Haldar
• , Lucy Hall
• , Mark Halling-Brown
• , Alyson Hancock
• , Kia Hancock
• , Neil Hanley
• , Sulaimaan Haq
• , Hayley Hardwick
• , Tim Hardy
• , Beverley Hargadon
• , Kate Harrington
• , Edward Harris
• , Victoria C. Harris
• , Ewen Harrison
• , Paul Harrison
• , Nicholas Hart
• , Alice Harvey
• , Matt Harvey
• , M. Harvie
• , L. Haslam
• , Claire Hastie
• , May Havinden-Williams
• , Jenny Hawkes
• , Nancy Hawkings
• , Jill Haworth
• , A. Hayday
• , Matthew Haynes
• , J. Hazeldine
• , Tracy Hazelton
• , Liam Heaney
• , Cheryl Heeley
• , Jonathon Heeney
• , M. Heightman
• , Simon Heller
• , Max Henderson
• , Helen Henson
• , L. Hesselden
• , Melanie Hewitt
• , Victoria Highett
• , T. Hillman
• , Ling-Pei Ho
• , Michaela Hoare
• , Amy Hoare
• , J. Hockridge
• , Philip Hogarth
• , Ailsa Holbourn
• , Sophie Holden
• , L. Holdsworth
• , D. Holgate
• , Maureen Holland
• , Leah Holloway
• , Katie Holmes
• , Megan Holmes
• , B. Holroyd-Hind
• , Anil Hormis
• , Alexander Horsley
• , Akram Hosseini
• , M. Hotopf
• , Linzy Houchen-Wolloff
• , Luke S. Howard
• , Kate Howard
• , Alice Howell
• , E. Hufton
• , Rachel Ann Hughes
• , Joan Hughes
• , Alun Hughes
• , Amy Humphries
• , Nathan Huneke
• , E. Hurditch
• , John Hurst
• , Masud Husain
• , Tracy Hussell
• , John Hutchinson
• , W. Ibrahim
• , Julie Ingham
• , L. Ingram
• , Diana Ionita
• , Karen Isaacs
• , Khalida Ismail
• , T. Jackson
• , Joseph Jacob
• , W. Y. James
• , Claire Jarman
• , Ian Jarrold
• , Hannah Jarvis
• , Roman Jastrub
• , Bhagy Jayaraman
• , Gisli Jenkins
• , P. Jezzard
• , Kasim Jiwa
• , C. Johnson
• , Simon Johnson
• , Desmond Johnston
• , Caroline Jolley
• , Ian Jones
• , Heather Jones
• , Mark Jones
• , Don Jones
• , Sherly Jose
• , Thomas Kabir
• , G. Kaltsakas
• , Vicky Kamwa
• , N. Kanellakis
• , Sabina Kaprowska
• , Zunaira Kausar
• , Natalie Keenan
• , Steven Kerr
• , Helen Kerslake
• , Angela Key
• , Fasih Khan
• , Kamlesh Khunti
• , Susan Kilroy
• , Bernie King
• , Clara King
• , Lucy Kingham
• , Jill Kirk
• , Paaig Kitterick
• , Paul Klenerman
• , Lucy Knibbs
• , Sean Knight
• , Abigail Knighton
• , Onn Min Kon
• , Samantha Kon
• , Ania Korszun
• , Ivan Koychev
• , Claire Kurasz
• , Prathiba Kurupati
• , Hanan Lamlum
• , G. Landers
• , Claudia Langenberg
• , Lara Lavelle-Langham
• , Allan Lawrie
• , Cathy Lawson
• , Claire Lawson
• , Alison Layton
• , Olivia C. Leavy
• , Ju Hee Lee
• , Elvina Lee
• , Karen Leitch
• , Rebecca Lenagh
• , Victoria Lewis
• , Joanne Lewis
• , Keir Lewis
• , N. Lewis-Burke
• , Felicity Liew
• , Tessa Light
• , Liz Lightstone
• , W. Lilaonitkul
• , S. Linford
• , Anne Lingford-Hughes
• , M. Lipman
• , Kamal Liyanage
• , Arwel Lloyd
• , Nazir I. Lone
• , Ronda Loosley
• , Janet Lord
• , Harpreet Lota
• , Wayne Lovegrove
• , Daniel Lozano-Rojas
• , Alice Lucey
• , Gardiner Lucy
• , E. Lukaschuk
• , Alison Lye
• , Ceri Lynch
• , S. MacDonald
• , G. MacGowan
• , Irene Macharia
• , J. Mackie
• , L. Macliver
• , S. Madathil
• , Gladys Madzamba
• , Nick Magee
• , Murphy Magtoto
• , N. Majeed
• , Flora Malein
• , Georgia Mallison
• , William Man
• , S. Mandal
• , K. Mangion
• , C. Manisty
• , R. Manley
• , Katherine March
• , Stefan Marciniak
• , Philip Marino
• , Myril Mariveles
• , Michael Marks
• , Elizabeth Marouzet
• , Sophie Marsh
• , M. Marshall
• , B. Marshall
• , Jane Martin
• , Adrian Martineau
• , L. M. Martinez
• , Nick Maskell
• , Darwin Matila
• , Wadzanai Matimba-Mupaya
• , Laura Matthews
• , Angeline Mbuyisa
• , Steve McAdoo
• , Hamish McAllister-Williams
• , Paul McArdle
• , Anne McArdle
• , Danny McAulay
• , Hamish J. C. McAuley
• , Gerry McCann
• , W. McCormick
• , Jacqueline McCormick
• , P. McCourt
• , Celeste McCracken
• , Lorcan McGarvey
• , Jade McGinness
• , K. McGlynn
• , Andrew McGovern
• , Heather McGuinness
• , I. B. McInnes
• , Jerome McIntosh
• , Emma McIvor
• , Katherine McIvor
• , Laura McLeavey
• , Aisling McMahon
• , Michael McMahon
• , L. McMorrow
• , Teresa Mcnally
• , M. McNarry
• , J. McNeill
• , Alison McQueen
• , H. McShane
• , Chloe Mears
• , Clare Megson
• , Sharon Megson
• , J. Meiring
• , Lucy Melling
• , Mark Mencias
• , Daniel Menzies
• , Marta Merida Morillas
• , Alice Michael
• , Benedict Michael
• , C. A. Miller
• , Lea Milligan
• , Nicholas Mills
• , Clare Mills
• , George Mills
• , L. Milner
• , Jane Mitchell
• , Abdelrahman Mohamed
• , Noura Mohamed
• , S. Mohammed
• , Philip Molyneaux
• , Will Monteiro
• , Silvia Moriera
• , Anna Morley
• , Leigh Morrison
• , Richard Morriss
• , A. Morrow
• , Paul Moss
• , Alistair Moss
• , K. Motohashi
• , N. Msimanga
• , Elizabeta Mukaetova-Ladinska
• , Unber Munawar
• , Jennifer Murira
• , Uttam Nanda
• , Heeah Nassa
• , Mariam Nasseri
• , Rashmita Nathu
• , Aoife Neal
• , Robert Needham
• , Paula Neill
• , Stefan Neubauer
• , D. E. Newby
• , Helen Newell
• , J. Newman
• , Tom Newman
• , Alex Newton-Cox
• , T. E. Nichols
• , Tim Nicholson
• , Christos Nicolaou
• , Debby Nicoll
• , Athanasios Nikolaidis
• , C. Nikolaidou
• , C. M. Nolan
• , Matthew Noonan
• , C. Norman
• , Petr Novotny
• , Kimon Ntotsis
• , Jose Nunag
• , Lorenza Nwafor
• , Uchechi Nwanguma
• , Joseph Nyaboko
• , Linda O’Brien
• , C. O’Brien
• , Natasha Odell
• , Kate O’Donnell
• , Godwin Ogbole
• , Olaoluwa Olaosebikan
• , Catherine Oliver
• , Zohra Omar
• , Peter J. M. Openshaw
• , D. P. O’Regan
• , Lorna Orriss-Dib
• , Lynn Osborne
• , Rebecca Osbourne
• , Marlies Ostermann
• , Charlotte Overton
• , Jamie Pack
• , Edmund Pacpaco
• , Stella-Maria Paddick
• , Sharon Painter
• , Erola Pairo-Castineira
• , Ashkan Pakzad
• , Sue Palmer
• , Padmasayee Papineni
• , K. Paques
• , Kerry Paradowski
• , Manish Pareek
• , Dhruv Parekh
• , H. Parfrey
• , Carmen Pariante
• , S. Parker
• , M. Parkes
• , J. Parmar
• , Sheetal Patale
• , Manish Patel
• , Suhani Patel
• , Dibya Pattenadk
• , M. Pavlides
• , Sheila Payne
• , Lorraine Pearce
• , John Pearl
• , Dan Peckham
• , Jessica Pendlebury
• , Yanchun Peng
• , Chris Pennington
• , Ida Peralta
• , Emma Perkins
• , Z. Peterkin
• , Tunde Peto
• , Nayia Petousi
• , John Petrie
• , Paul Pfeffer
• , Janet Phipps
• , S. Piechnik
• , John Pimm
• , Karen Piper Hanley
• , Riinu Pius
• , Hannah Plant
• , Tatiana Plekhanova
• , Megan Plowright
• , Krisnah Poinasamy
• , Oliver Polgar
• , Julie Porter
• , Joanna Porter
• , Sofiya Portukhay
• , Natassia Powell
• , A. Prabhu
• , James Pratt
• , Andrea Price
• , Claire Price
• , Carly Price
• , Anne Prickett
• , I. Propescu
• , J. Propescu
• , Sabrina Prosper
• , S. Pugmire
• , Sheena Quaid
• , Jackie Quigley
• , Jennifer K. Quint
• , H. Qureshi
• , I. N. Qureshi
• , K. Radhakrishnan
• , Najib Rahman
• , Markus Ralser
• , Betty Raman
• , Hazel Ramos
• , Albert Ramos
• , Jade Rangeley
• , Bojidar Rangelov
• , Liz Ratcliffe
• , Phillip Ravencroft
• , Konrad Rawlik
• , Anne Reddington
• , Heidi Redfearn
• , Dawn Redwood
• , Annabel Reed
• , Meryl Rees
• , Tabitha Rees
• , Karen Regan
• , Will Reynolds
• , Carla Ribeiro
• , A. Richards
• , Emma Richardson
• , M. Richardson
• , Pilar Rivera-Ortega
• , K. Roberts
• , Elizabeth Robertson
• , Leanne Robinson
• , Emma Robinson
• , Lisa Roche
• , C. Roddis
• , J. Rodger
• , Natalie Rogers
• , Gavin Ross
• , Alexandra Ross
• , Jennifer Rossdale
• , Anthony Rostron
• , Anna Rowe
• , J. Rowland
• , M. J. Rowland
• , A. Rowland
• , Sarah L. Rowland-Jones
• , Maura Roy
• , Igor Rudan
• , Richard Russell
• , Emily Russell
• , Gwen Saalmink
• , Ramsey Sabit
• , Beth Sage
• , T. Samakomva
• , Nilesh Samani
• , A. A. Samat
• , Claire Sampson
• , Katherine Samuel
• , Reena Samuel
• , Z. B. Sanders
• , Amy Sanderson
• , Elizabeth Sapey
• , Dinesh Saralaya
• , Jack Sargant
• , Carol Sarginson
• , Naveed Sattar
• , Kathryn Saunders
• , Peter Saunders
• , Ruth Saunders
• , Laura Saunders
• , Heather Savill
• , Avan Sayer
• , J. Schronce
• , William Schwaeble
• , Janet Scott
• , Kathryn Scott
• , Nick Selby
• , Malcolm G. Semple
• , Marco Sereno
• , Terri Ann Sewell
• , Kamini Shah
• , Ajay Shah
• , Manu Shankar-Hari
• , M. Sharma
• , Claire Sharpe
• , Michael Sharpe
• , Sharlene Shashaa
• , Alison Shaw
• , Victoria Shaw
• , Karen Shaw
• , Aziz Sheikh
• , Sarah Shelton
• , Liz Shenton
• , K. Shevket
• , Aarti Shikotra
• , Sulman Siddique
• , Salman Siddiqui
• , J. Sidebottom
• , Louise Sigfrid
• , Gemma Simons
• , Neil Simpson
• , John Simpson
• , Ananga Singapuri
• , Suver Singh
• , Claire Singh
• , Sally Singh
• , D. Sissons
• , J. Skeemer
• , Katie Slack
• , David Smith
• , Nikki Smith
• , Andrew Smith
• , Jacqui Smith
• , Laurie Smith
• , Susan Smith
• , M. Soares
• , Teresa Solano
• , Reanne Solly
• , A. R. Solstice
• , Tracy Soulsby
• , David Southern
• , D. Sowter
• , Mark Spears
• , Lisa Spencer
• , Fabio Speranza
• , Louise Stadon
• , Stefan Stanel
• , R. Steeds
• , N. Steele
• , Mike Steiner
• , David Stensel
• , G. Stephens
• , Lorraine Stephenson
• , Iain Stewart
• , R. Stimpson
• , Sue Stockdale
• , J. Stockley
• , Wendy Stoker
• , Roisin Stone
• , Will Storrar
• , Andrew Storrie
• , Kim Storton
• , E. Stringer
• , Sophia Strong-Sheldrake
• , Natalie Stroud
• , Christian Subbe
• , Catherine Sudlow
• , Zehra Suleiman
• , Charlotte Summers
• , C. Summersgill
• , Debbie Sutherland
• , D. L. Sykes
• , Nick Talbot
• , Ai Lyn Tan
• , Lawrence Tarusan
• , Vera Tavoukjian
• , Jessica Taylor
• , Abigail Taylor
• , Chris Taylor
• , John Paul Taylor
• , Amelie Te
• , Caroline Tee
• , J. Teixeira
• , Helen Tench
• , Sarah Terry
• , Susannah Thackray-Nocera
• , Favas Thaivalappil
• , David Thickett
• , David Thomas
• , S. Thomas
• , Caradog Thomas
• , Andrew Thomas
• , T. Thomas-Woods
• , A. A. Roger Thompson
• , Tamika Thompson
• , T. Thornton
• , Matthew Thorpe
• , Ryan S. Thwaites
• , Jo Tilley
• , N. Tinker
• , Gerlynn Tiongson
• , Martin Tobin
• , Johanne Tomlinson
• , Mark Toshner
• , T. Treibel
• , K. A. Tripp
• , Drupad Trivedi
• , E. M. Tunnicliffe
• , Alison Turnbull
• , Kim Turner
• , Sarah Turner
• , Victoria Turner
• , E. Turner
• , Sharon Turney
• , Lance Turtle
• , Helena Turton
• , Jacinta Ugoji
• , R. Ugwuoke
• , Rachel Upthegrove
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Contributions

F.L. recruited participants, acquired clinical samples, analyzed and interpreted data and cowrote the manuscript, including all drafting and revisions. C.E. analyzed and interpreted data and cowrote this manuscript, including all drafting and revisions. S.F. and M.R. supported the analysis and interpretation of data as well as drafting and revisions. D.S., J.K.S., S.C.M., S.A., N.M., J.N., C.K., O.C.L., O.E., H.J.C.M., A. Shikotra, A. Singapuri, M.S., V.C.H., M.T., N.J.G., N.I.L. and C.C. contributed to acquisition of data underlying this study. L.H.-W., A.A.R.T., S.L.R.-J., L.S.H., O.M.K., D.G.W., T.I.d.S. and A. Ho made substantial contributions to conception/design and implementation of this work and/or acquisition of clinical samples for this work. They have supported drafting and revisions of the manuscript. E.M.H., J.K.Q. and A.B.D. made substantial contributions to the study design as well as data access, linkage and analysis. They have supported drafting and revisions of this work. J.D.C., L.-P.H., A. Horsley, B.R., K.P., M.M. and W.G. made substantial contributions to the conception and design of this work and have supported drafting and revisions of this work. J.K.B. obtained funding for ISARIC4C, is ISARIC4C consortium co-lead, has made substantial contributions to conception and design of this work and has supported drafting and revisions of this work. M.G.S. obtained funding for ISARIC4C, is ISARIC4C consortium co-lead, sponsor/protocol chief investigator, has made substantial contributions to conception and design of this work and has supported drafting and revisions of this work. R.A.E. and L.V.W. are co-leads of PHOSP-COVID, made substantial contributions to conception and design of this work, the acquisition and analysis of data, and have supported drafting and revisions of this work. C.B. is the chief investigator of PHOSP-COVID and has made substantial contributions to conception and design of this work. R.S.T. and L.T. made substantial contributions to the acquisition, analysis and interpretation of the data underlying this study and have contributed to drafting and revisions of this work. P.J.M.O. obtained funding for ISARIC4C, is ISARIC4C consortium co-lead, sponsor/protocol chief investigator and has made substantial contributions to conception and design of this work. R.S.T. and P.J.M.O. have also made key contributions to interpretation of data and have co-written this manuscript. All authors have read and approve the final version to be published. All authors agree to accountability for all aspects of this work. All investigators within ISARIC4C and the PHOSP-COVID consortia have made substantial contributions to the conception or design of this study and/or acquisition of data for this study. The full list of authors within these groups is available in Supplementary Information .

Corresponding authors

Correspondence to Ryan S. Thwaites or Peter J. M. Openshaw .

Ethics declarations

Competing interests.

F.L., C.E., D.S., J.K.S., S.C.M., C.D., C.K., N.M., L.N., E.M.H., A.B.D., J.K.Q., L.-P.H., K.P., L.S.H., O.M.K., S.F., T.I.d.S., D.G.W., R.S.T. and J.K.B. have no conflicts of interest. A.A.R.T. receives speaker fees and support to attend meetings from Janssen Pharmaceuticals. S.L.R.-J. is on the data safety monitoring board for Bexero trial in HIV+ adults in Kenya. J.D.C. is the deputy chief editor of the European Respiratory Journal and receives consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Insmed, Janssen, Novartis, Pfizer and Zambon. A. Horsley is deputy chair of NIHR Translational Research Collaboration (unpaid role). B.R. receives honoraria from Axcella therapeutics. R.A.E. is co-lead of PHOSP-COVID and receives fees from AstraZenaca/Evidera for consultancy on LC and from AstraZenaca for consultancy on digital health. R.A.E. has received speaker fees from Boehringer in June 2021 and has held a role as European Respiratory Society Assembly 01.02 Pulmonary Rehabilitation secretary. R.A.E. is on the American Thoracic Society Pulmonary Rehabilitation Assembly program committee. L.V.W. also receives funding from Orion pharma and GSK and holds contracts with Genentech and AstraZenaca. L.V.W. has received consulting fees from Galapagos and Boehringer, is on the data advisory board for Galapagos and is Associate Editor for the European Respiratory Journal . A. Ho is a member of NIHR Urgent Public Health Group (June 2020–March 2021). M.M. is an applicant on the PHOSP study funded by NIHR/DHSC. M.G.S. acts as an independent external and nonremunerated member of Pfizer’s External Data Monitoring Committee for their mRNA vaccine program(s), is Chair of Infectious Disease Scientific Advisory Board of Integrum Scientific LLC, and is director of MedEx Solutions Ltd. and majority owner of MedEx Solutions Ltd. and minority owner of Integrum Scientific LLC. M.G.S.’s institution has been in receipt of gifts from Chiesi Farmaceutici S.p.A. of Clinical Trial Investigational Medicinal Product without encumbrance and distribution of same to trial sites. M.G.S. is a nonrenumerated member of HMG UK New Emerging Respiratory Virus Threats Advisory Group and has previously been a nonrenumerated member of the Scientific Advisory Group for Emergencies (SAGE). C.B. has received consulting fees and/or grants from GSK, AstraZeneca, Genentech, Roche, Novartis, Sanofi, Regeneron, Chiesi, Mologic and 4DPharma. L.T. has received consulting fees from MHRA, AstraZeneca and Synairgen and speakers’ fees from Eisai Ltd., and support for conference attendance from AstraZeneca. L.T. has a patent pending with ZikaVac. P.J.M.O. reports grants from the EU Innovative Medicines Initiative 2 Joint Undertaking during the submitted work; grants from UK Medical Research Council, GSK, Wellcome Trust, EU Innovative Medicines Initiative, UK National Institute for Health Research and UK Research and Innovation–Department for Business, Energy and Industrial Strategy; and personal fees from Pfizer, Janssen and Seqirus, outside the submitted work.

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Extended data

Extended data fig. 1 penalized logistic regression performance..

Graphs show classification error and Area under curve (AUC) from the 50 repeats tenfold nested cross-validation used to optimise and assess the performance of PLR testing associations with each LC outcome relative to Recovered (n = 233): Cardio_Resp (n = 398), Fatigue (n = 384), Anxiety/Depression (n = 202), GI (n = 132), ( e ) Cognitive (n = 6). The distributions of classification error and area under curve (AUC) from the nested cross-validation are shown. Box plot centre line represents the Median and boundaries of the box represent interquartile range (IQR), the whisker length represent 1.5xIQR.

Extended Data Fig. 2 Associations with long COVID symptoms in full study cohort.

( a ) Fibrinogen levels at 6 months were compared between pooled LC cases (n = 295) and Recovered (n = 233) and between the Cognitive group (n = 41) and Recovered (n = 233). Box plot centre line represent the Median and boundaries of the box represent interquartile range (IQR), the whisker length represents 1.5xIQR, any outliers beyond the whisker range are shown as individual dots. Median differences were compared using two-sided Wilcoxon signed-rank test *= p  < 0·05, **= p  < 0·01, ***= p  < 0·001, ****= p  < 0·0001. Unadjusted p-values are reported. b ) Distribution of time from COVID-19 hospitalisation at sample collection applying CDC and NICE definitions of LC (n = 719) ( c ) Upset plot of symptom groups. Horizontal coloured bars represent the number of patients in each symptom group: Cardiorespiratory (Cardio_Resp), Fatigue, Cognitive, Gastrointestinal (GI) and Anxiety/Depression (Anx_Dep). Vertical black bars represent the number of patients in each symptom combination group. To prevent patient identification, where less than 5 patients belong to a combination group, this has been represented as ‘<5’. The Recovered group (n = 250) were used as controls. Forest plots show Olink protein concentrations (NPX) associated with ( d ) Cardio_Resp (n = 398), ( e ) Fatigue (n = 342), ( f ) Anx_Dep (n = 219), ( g ) GI (n = 134), and ( h ) Cognitive (n = 65). Error bars represent the median accuracy of the model.

Extended Data Fig. 3 Validation of olink measurements using conventional assays in plasma.

Olink measured protein (NPX) were compared to chemiluminescence assays (ECL or ELISA, log2[pg/mL]) to validate our findings, where contemporaneously collected plasma samples were available (n = 58). Results from key mediators associated with LC groups were validated: CSF3, IL1R2, IL2, IL3RA, TNFa, TFF2. R = spearman rank correlation coefficient and shaded areas indicated the 95% confidence interval. Samples that fell below the lower limit of detection for a given assay were excluded and the ‘n’ value on each panel indicates the number of samples above this limit.

Extended Data Fig. 4 Univariate analysis of proteins associated with each symptom.

Olink measured plasma protein levels (NPX) compared between LC groups (Cardio_Resp, n = 398, Fatigue n = 384, Anxiety/Depression, n = 202, GI, n = 132 and Cognitive, n = 60) and Recovered (n = 233). Proteins identified by PLR were compared between groups. Median differences were compared using two-sided Wilcoxon signed-rank test. * = p < 0·05, ** = p < 0·01, *** = p < 0·001, ****= p < 0·0001 after FDR adjustment. Box plot centre line represent the Median and boundaries of the box represent interquartile range (IQR), the whisker length represents 1.5xIQR, any outliers beyond the whisker range are shown as individual dots.

Extended Data Fig. 5 Unadjusted Penalised Logistic Regression.

Olink measured proteins (NPX) and their association with Cardio_Resp (n = 398), Fatigue (n = 342), Anx_Dep (n = 219), GI (n = 134), and Cognitive (n = 65). Forest plots show odds of each LC outcome vs Recovered (n = 233), using PLR without adjusting for clinical co-variates. Error bars represent the median accuracy of the model.

Extended Data Fig. 6 Partial Least Squares analysis.

Olink measured proteins (NPX) and their association with Cardio_Resp (n = 398), Fatigue (n = 342), Anx_Dep (n = 219), GI (n = 134), and Cognitive (n = 65) groups. Forest plots show odds of LC outcome vs Recovered (n = 233), using PLS analysis. Error bars represent the standard error of the coefficient estimate.

Extended Data Fig. 7 Network analysis centrality.

Each graph shows the centrality score for each Olink measured protein (NPX) found to have significant associations with other proteins that were elevated in the Cardio_Resp (n = 398), Fatigue (n = 342), Anx_Dep (n = 219), GI (n = 134), and Cognitive (n = 65) groups relative to Recovered (n = 233).

Extended Data Fig. 8 Inflammation in men and women with long COVID.

Olink measured plasma protein levels (NPX) between men and women with symptoms, divided by age (<50 or >=50years): (a) shows IL1R2 and MATN2 in the Anxiety/Depression group (<50 n = 55, >=50 n = 133), (b) shows CTSO and NFASC in the Cognitive group (<50 n = 11, >=50 n = 50). Median values were compared between men and women using two-sided Wilcoxon signed-rank test. Box plot centre line represent the Median and boundaries represent interquartile range (IQR), the whisker length represents 1.5xIQR.

Extended Data Fig. 9 Inflammation in the upper respiratory tract.

Nasal cytokines measured by immunoassay in the CardioResp Group (n = 29) and Recovered (n = 31): ( a ) shows IL1a, IL1b, IL-6, APO-2, TGFa, TFF2. Median differences were compared using two-sided Wilcoxon signed-rank test. Box plot centre line represents the Median and boundaries of the box represent interquartile range (IQR), the whisker length represent 1.5xIQR. ( b ) Shows cytokines measured by immunoassay in paired plasma and nasal (n = 70). Correlations between IL1a, IL1b, IL-6, APO-2, TGFa and TFF2 in nasal and plasma samples were compared using Spearman’s rank correlation coefficient ( R ). Shaded areas indicated the 95% confidence interval of R.

Extended Data Fig. 10 Graphical abstract.

Summary of interpretation of key findings from Olink measured proteins and their association with CardioResp (n = 398), Fatigue (n = 342), Anx/Dep (n = 219), GI (n = 134), and Cognitive (n = 65) groups relative to Recovered (n = 233).

Supplementary information

Supplementary information.

Supplementary Methods, Statistics and reproducibility statement, Supplementary Results, Supplementary Tables 1–7, Extended data figure legends, Appendix 1 (Supplementary Table 8), Appendix 2 (PHOSP-COVID author list) and Appendix 3 (ISARIC4C author list).

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Liew, F., Efstathiou, C., Fontanella, S. et al. Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease. Nat Immunol 25 , 607–621 (2024). https://doi.org/10.1038/s41590-024-01778-0

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Received : 11 August 2023

Accepted : 06 February 2024

Published : 08 April 2024

Issue Date : April 2024

DOI : https://doi.org/10.1038/s41590-024-01778-0

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