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UK: MRC and NIHR announce ME/CFS workshop, November 2019 & ME/CFS Biomedical Partnership FAQ

Discussion in 'BioMedical ME/CFS News' started by Andy, Nov 7, 2019.

  1. Andy

    Andy Committee Member & Outreach

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    An ME/CFS workshop has been announced by the MRC and NIHR.
    https://mrc.ukri.org/funding/scienc...our-science-and-contacts-psmb/cfsme/#workshop

    Statement from Stephen Holgate on behalf of the CMRC
    Statement from CureME Biobank Team
    FAQ from the ME/CFS Biobank Partnership in next post below.
     
  2. Andy

    Andy Committee Member & Outreach

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    The ME/CFS Biomedical Partnership: Genetics and Biomarkers

    Genome-wide association study: questions & answers

    What is the ME/CFS Biomedical Partnership?

    ME/CFS Biomedical Partnership: Genetics and Biomarkers is the working title for a partnership of researchers, including Professor Chris Ponting (pictured left) and the CureME UK ME/CFS Biobank (UKMEB) team headed up by Dr Luis Nacul (pictured right), and ME/CFS patients, carers and public. Early in 2020, the partnership will make a grant application to the Medical Research Council (MRC) and the National Institute for Health Research (NIHR) for a very large genetic study, a genome-wide association study, and a major expansion of the UKMEB.


    Below we provide questions put forward by members of the Science for ME online forum. Our answers were initially drafted by one of us (CPP) and Simon McGrath, a frequent blogger on ME/CFS biomedical research. Changes were then suggested by others in the Partnership and community. Issues raised often provoked further questions which we then also tried to answer. All contributions have hugely improved this set of Q&A and will improve the project itself, should it be funded.

    We think of this as a living document so hope to update it further in the future. One update we will do as soon as possible is to provide detail on the UK ME/CFS Biobank expansion.

    ________

    Summary

    • The Partnership will apply for funding for a large genetics study as well as an expansion of the UK/ME CFS Biobank
    • If funded, the genetics study will require saliva samples from 20,000 patients.
    • The study will look for the potential genetic cause(s) of ME/CFS.
    • Submitting a sample will be made as easy as possible in order to enable as many patients as possible to take part.
    • Patients, and their representatives, will form an important part of the Partnership.

    1. What is a genome-wide association study?

    A genome-wide association study (GWAS) is a very large genetic study that seeks to uncover some of the biological roots of ME/CFS. By probing small DNA differences among people, a GWAS can help to pinpoint the genetic causes of disease and then can help to guide drug development. This design has previously proved helpful in identifying genes together with molecular and cellular pathways that contribute to disease risk. Read more about the science of GWAS.


    To work well, the study needs to recruit around 20,000 patients whose DNA will be compared with that of similar numbers of non-ME/CFS matched controls (i.e. people from a similar population but who do not have ME/CFS).



    2. How will the study ensure that all participants recruited to the trial really do have ME/CFS?

    We take participant selection very seriously. We will be using the CureME patient questionnaire that has been in use for the UK ME/CFS Biobank for several years. This is additional to your report that you’ve been diagnosed with ME or CFS by a clinician.


    GWAS need to be very large to generate robust results and it wouldn’t be economically feasible to clinically assess every patient independently. However, as part of the study, some patients will have an assessment by a clinician with knowledge of ME/CFS to confirm the diagnosis is accurate. We anticipate this work will find a high proportion of patients who have been accurately diagnosed, and a GWAS does not need 100% diagnostic accuracy to produce valid results.


    3. What case definitions will be used (specifically, what about the Oxford and NICE criteria)?

    CureME will apply its diagnostic algorithm (a very specific set of rules) to assess people according to well accepted diagnostic criteria: the Institute of Medicine 2015 or the 2003 Canadian Consensus or Fukuda, but not Oxford or NICE, criteria. Post-exertional malaise (PEM) will be a mandatory symptom. This is because patients, patients’ organisations and ME/CFS biomedical researchers all regard it as a defining symptom of the disease. Using these definitions help to ensure that findings are compatible with those used in biomedical research around the world.


    4. How can people with ME/CFS take part?

    We are working very hard to make taking part as easy as possible. Our plans are for just two steps: First, potential participants will register online or by returning a paper form sent to the CureME team. Second, accepted participants will be asked to post a saliva sample to the project using a collection kit which they will receive by mail (a "spit-and-post" sample). Some participants, e.g. those who are already part of other studies or the UKMEB and who have previously consented, may be contacted directly by the researchers.


    The GWAS is open to anyone who already has a diagnosis of ME or CFS from a clinician and who also meets the CureME research diagnostic criteria as assessed by questionnaire and in some cases complemented by a clinical assessment by the CureME clinical team. People who meet these criteria will receive a sample collection kit through the post so that they can return a saliva sample using the freepost envelope provided.


    When we receive it back, we will extract DNA and then look at nearly a million “variants”, places in the human genome where the DNA commonly differs from person to person. These DNA variants make people different from one another, and in some cases make people more or less likely to develop some diseases. They also play a role in determining many things about us, such as our height, weight and intelligence.


    All participants must meet the recruitment criteria, but not meeting the criteria does not mean that someone does not have ME/CFS.


    5. Can those who are severely affected take part?

    We have chosen online recruitment and the “spit-and-post” design. This makes it possible for people who are severely affected with ME/CFS to join the study. It may also be possible for family, friends and carers to assist in completing the questionnaire and sending back the saliva sample.


    6. To maximise recruitment, will the online questionnaire be short? And will there be a paper questionnaire alternative, for those who struggle to use the Internet because of their illness or another reason?

    We understand that questionnaires can be very tiring for people with ME/CFS, particularly for those who are severely affected. The questionnaire will be designed to balance the need to capture a person’s relevant information with the need for brevity.. We plan to offer a paper questionnaire as well as the online version. As these are completed at home, participants may complete the questionnaire in more than one go.


    7. How will we use the survey, biological and genetic information that people provide?

    Our goal is to identify causes of ME/CFS. For this we will first isolate and analyse your DNA from the saliva sample. We will then look at around a million common variants in DNA and see if any of the variants are more or less common in patients than seen in control individuals. Survey data such as age, type of onset and symptoms will be used to gain a better understanding of your background and illness and we will link this survey data to your genetic data.


    We may also ask people if they are willing to provide us access to their electronic health record, with personal clinical information kept by their GPs. This would help us to get a more detailed understanding of your illness, progression and symptoms, but would be entirely optional and would not affect eligibility for the study.


    8. How will samples and data of participants be kept secure and private?

    We take sample and data security, and your privacy, very seriously. All samples and data will be kept secure according to the UK’s and international highest standards overseen by ethical review. All institutions contributing to this project have adopted these standards and use them routinely, and comply with the Human Tissue Act 2004 and all other relevant regulations and legislation, including the General Data Protection Regulation (GDPR). The UKMEB has extensive experience in doing research in ME/CFS including the international distribution of samples to researchers worldwide, always ensuring the highest level of privacy from participants and full compliance with ethical standards and legislation.


    9. Will the target number of cases be big enough to generate meaningful findings, and to detect any subgroups?

    Until the first GWAS study for an illness is done it is just not possible to know how meaningful its findings will be. However, we’ve chosen to study 20,000 people with ME/CFS because other projects of this size commonly have found around five causal links between DNA and disease diagnosis.

    ME/CFS could have many independent genetic causes and a study of this size will have a chance of revealing part of this potential spectrum of genetic causes.


    10. How will the study ensure the support of the patient community?

    The study will only reach its participant target with the active support of people who have the disease. The Management Group of this study will include both researchers and public and patient/carer representatives. In addition, both the Patient Advisory Group of the CMRC and the Steering Committee of the CureME Biobank which includes patients and charities will be involved in all aspects of the project. The project will always adhere to the CMRC’s values, which include the following:

    • We are a collaborative community inviting all stakeholders to join our programmes and shape our activity.
    • We support and expect the highest quality research.
    • We encourage insightful questions and open and informed debate; we applaud and listen to those who have questions about research.

    We are working with a representative from the CureME Biobank Patient Group, Andy Devereux-Cooke who is also a co-founder of Science for ME forum, and one from the CMRC, Sonya Chowdhury, CEO of Action for M.E., to help set up a Patient and Public Involvement (PPI) Steering Group. Additional members will include:

    • Countess of Mar, on behalf of Forward M.E. and the patients/carers the member organisations represent
    • CMRC Patient Advisory Group representative
    • Charles Shepherd, on behalf of ME Association and as a Patient Charity representative on CMRC from its inception.

    The Group met for the first time on 4 November 2019 and agreed how it will work together. It will ensure that its terms of reference are made available, alongside other key documents and minutes from meetings. There will be other mechanisms for people not represented through the organisations represented on the Steering Group, to engage with the project; more information will be available as soon as possible on this.


    Patients will always be at the heart of the study.

    cont..
     
  3. Andy

    Andy Committee Member & Outreach

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    11. How will the study manage to recruit so many patients?

    Recruiting so many people with ME/CFS will be a huge challenge, particularly as it is not as common as, for example, diabetes (around one in 250 people have ME/CFS, compared to 1 in every 16 for diabetes). It is also the case that many people do not have a clinical diagnosis. So it is clear that the support of people with ME/CFS and their carers, as well as the different ME/CFS charities, will be critical to the successful recruitment of 20,000 with ME/CFS.


    With guidance from patients, carers and professionals, we will put together a recruitment campaign.

    The proposal is being backed by all the charities within Forward ME: the ME Association, ME Research UK, Action for M.E., #MEAction, the ME Trust, the 25% M.E. Group, the Young ME Sufferers Trust, reMEmber, Blue Ribbon for Awareness of ME and the Neurological Alliance.


    12. Will this be an international study, recruiting patients in multiple countries, and collaborating with researchers beyond the UK?

    We are considering recruiting patients diagnosed with ME/CFS who live outside the UK. This would need to meet the appropriate high ethical standards to protect the privacy of individuals from other countries in the same way as people who are in the UK.


    13. Will the study recruit from fatigue clinics and might that affect diagnostic accuracy?

    We will be looking to recruit people with a clinical diagnosis of ME/CFS (and who pass the Cure ME diagnostic algorithm). These may include people attending fatigue clinics although many attendees of these clinics will not have ME/CFS. We anticipate that the bulk of participants will be recruited to the study through social and traditional media, and through our contacts with charities.


    14. Can you give examples of how genome-wide association studies have helped progress understanding or treatment of other diseases?

    Findings from such studies have helped to:

    • establish the identity of numerous genes involved in Type II diabetes, such as those affecting the action of insulin on fat cells and liver cells. These studies have also helped to identify an unsuspected role in Type II diabetes for a protein that transports zinc into cells, and scientists are developing drugs that target this protein.
    • reveal that microglia, the immune cells of the brain, play a key role in Alzheimer’s disease.
    • demonstrate that thermogenesis, where “brown fat” cells burn off fat to produce heat, is an important pathway impacting on obesity.
    • show that high levels of "good" HDL-cholesterol is simply associated with lower levels of heart disease — but is not actually protective. This explains why the pharmaceutical industry's $5 billion investment in drugs that increase HDL-cholesterol came to nothing. Instead, GWAS helped to show that a different type of fat, triglycerides, does increase the risk of heart disease.
    • establish that many different diseases often share some common biological mechanisms. An immune-regulating molecule called IL-23 plays a significant role in numerous autoimmune diseases. As a result of this insight, existing drugs that are used to inhibit the IL-23 pathway in other diseases have become a mainstay treatment for several autoimmune conditions, including psoriasis and ankylosing spondylitis.

    15. Why this particular approach over others?

    A GWAS has the major advantage that its results indicate root causes of illness, because DNA doesn’t change with ME onset, so GWAS findings reflect causes rather than effects of illness. With most other approaches, it is not usually possible to know if findings indicate the effects of illness, or the cause. For example, people who are unable to exercise are likely to show molecular changes that are solely due to being sedentary, rather than highlighting the root causes of their disease.


    GWAS have been successfully applied to many different diseases (asthma, schizophrenia, diabetes, pulmonary disease etc – see a comprehensive list here) and traits. We believe that it is time that ME/CFS science took full advantage of this cutting-edge genetics approach which is entirely complementary to approaches taken by other ME/CFS researchers.



    16. Why don't researchers just do the analysis on all the existing ME/CFS Biobank samples to see what it reveals first?

    Existing samples from UK ME/CFS Biobank will be used. However, we need a very large number of people for a GWAS study, typically at least 10,000–20,000 patients. This will require a significant expansion of the UKMEB, and collaboration with the NIHR Biosample Centre in Milton Keynes.



    17. Wouldn't it be better to back research to find a reliable biomarker first, to ensure participants in this kind of study actually have ME/CFS?

    As yet, there is no such biomarker and despite some promising research, there is still no test that can reliably separate people with ME/CFS from people with other, similar diseases. We know that others around the world (e.g. Stanford, Harvard and Uppsala) are actively pursuing biomarker research, and we hope they are successful. But there is no guarantee of success and the timescale to development is uncertain. So, it is our view that we should press ahead with our complementary approach.


    18. Will the study have a serious, scientific-sounding name? Acronyms for medical studies can sometimes sound forced and trivialising.

    The working title for this project is ME/CFS Biomedical Partnership: Genetics and Biomarkers. We have not reduced this to an acronym.


    The study will need a short and memorable name to use in promotion which means something to the majority of people with ME, who may not have the energy to follow the research. We will consult with patients before finalising the name which will be serious, will not trivialise the illness and will not be an acronym.


    19. Will the project be requesting a budget to fund recruitment activity?

    Yes, Patient and Public Involvement (PPI) will be essential to the scientific success of this project. We plan to request funding from the MRC and NIHR for the recruitment of participants, data and sample collection and analysis of results.


    20. Will the study team provide supporting materials to patients, such as posters for GP surgeries?

    The aim is to provide patients with good materials to support recruitment. We will engage with people with ME/CFS at every stage of the process on what is appropriate, but materials might include videos for social media, posters for GP surgeries and template letters for writing to local papers.


    21. What happens if, after all this effort and money, the study finds nothing? Will the MRC say, "That's it, we're not funding any more research into ME/CFS"?

    As with all research studies, there is no guarantee that this GWAS will make significant findings. However, the GWAS is only one aspect of this project, the other being the expansion of the UK ME/CFS Biobank so that it will contain samples from about 1,000 people with ME/CFS. Funders would support expansion of the Biobank in the expectation that it will continue to facilitate numerous and diverse studies into the biomedical causes of ME/CFS.


    22. Will psychosocial researchers be involved?

    No — the lead investigators are a specialist in human genetics (Chris Ponting, Professor for Medical Bioinformatics at the MRC Human Genetics Unit), and a clinician (Dr Luis Nacul, who heads up the CureME team and the UK ME/CFS Biobank). All researchers in this project are focused on biomedical research.


    23. How long will the GWAS study take to complete?

    In total, four years but we will release preliminary results as soon as we can, prior to publication. The sooner we can recruit participants, the sooner the results will be released.


    24. How likely do you think it is that the MRC will fund the proposal?

    In general, there is a 20% chance that any grant proposal is funded. Nevertheless, we believe that there is a good scientific and impactful argument for funding, and we will make this as strongly as we can.


    25. Will participants have the chance to take part in future studies as well?

    When people sign up to this study, we will ask them if they are willing to be contacted about taking part (directly, or by agreeing to share samples and data from this study) in new studies, either related to this one or unrelated. This will make it much easier for researchers to recruit participants for studies, speeding up the pace of research.



    We'd like to thank everyone who asked questions about the GWAS idea on the Science for ME forum, as well as the many people with ME or their carers who made helpful suggestions and comments on the various drafts of the Q&A. They have helped to improve the Q&A and importantly to improve the project itself.

    ETA: Attached a PDF version of the above FAQ.
     

    Attached Files:

    Last edited: Nov 7, 2019
  4. Andy

    Andy Committee Member & Outreach

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    Personal note.

    I have been involved in the ME/CFS Biomedical Partnership for just over two weeks now, so obviously the other members have done the vast majority of the work to get it to this stage. Having said that, I definitely feel that I am accepted as a vital member of the team, able to bring important insight from my own patient experience and through contact with the patient community.

    I'm not there however as a representative of the forum. I am there, currently, in my personal capacity and as a representative for the CureME Steering Committee.

    I'm also really tired with all the work we have been putting in to this, so while I intended a more comprehensive statement about this project, this is all I've got at the moment. I'll be here to answer the questions that I can for this afternoon, and those I think are most useful, especially related to my involvement, I will edit into this post.

    ETA:
    Action for ME article on this news here, https://www.actionforme.org.uk/news/me/cfs-biomedical-partnership-to-apply-for-funding/

    CureME article, https://cureme.lshtm.ac.uk/a-collaborative-research-proposal-with-the-cmrc/

    ME Association article here, https://www.meassociation.org.uk/20...hip-genetics-and-biomarkers-07-november-2019/
     
    Last edited: Nov 9, 2019
  5. Simon M

    Simon M Senior Member (Voting Rights)

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    This seems important to me. The project has to go through peer review - and on average only 20% of proposals are funded - but the MRC is taking an active interest by organising a workshop to improve the research proposal. Fingers crossed.

    Having a huge genetic study (GWAS) and a major expansion of the CureME mecfs biobank ,would represent a massive increase in biomedical research in the UK.

    Perhaps as important is the central role that patients have. Congrats (and thanks) to @Andy for his role as a co-investigator on the project.

    I helped draft the Q&A, and organise the first few rounds of feedback, and I am very impressed by how willing @Chris Ponting and others have been to listen to pwME. This isn't Q&A as a way to disseminate information. It's been a process to capture patient concerns and to try to respond to them - as a way to make the project better. The plan to offer the option of paper questionnaires is just one example of this.

    And of course, patients and patient support will be critical to getting 20,000 samples for the GWAS.

    All this, of course, depends on funding.
    Note the Q&A focuses on the GWAS, not the biobank expansion.
     
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  6. InitialConditions

    InitialConditions Senior Member (Voting Rights)

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    Thanks for your involvement and work Andy. I didn't realise this announcement was being made today. I've just seen some social media stuff from Action for ME. I hope even at this early stage there will be a collaborative effort to promote this project to the furthest reaches of our community, and not just those active on forums and social media. This will be one of the biggest challenges for the team if the proposal is funded. I know there are people working on this already.
     
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  7. NelliePledge

    NelliePledge Senior Member (Voting Rights)

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    Good to see positive developments I haven’t absorbed any of the details but MRC working with the biobank has to be a step forward from the position 2 years ago.

    thanks to @Andy and @Simon M for your contributions on behalf of PWME
     
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  8. Andy

    Andy Committee Member & Outreach

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    Yes, we are aware that reaching as many patients as possible is one of our biggest challenges. As you say, we, collectively, are working on this already and hopefully the workshop will be of use in this regard as well.
     
  9. strategist

    strategist Senior Member (Voting Rights)

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    It would be good to know this sooner rather than later as I imagine that collaborators in other countries also need time to prepare.

    The European ME Alliance could be a good collaborator.
     
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  10. Trish

    Trish Moderator Staff Member

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    I guess that would depend whether samples can be posted from other countries to the UK, or whether the lab work needs to be done in the participant's home region. If the former, then all the organisations in other countries would need to do would be to publicise it.
     
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  11. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    I shall be involved as an advisor. My view would be that it would be a serious mistake to try to extend recruitment beyond the UK at least for an initial definitive GWAS cohort. The biggest problem with the study is going to be recruitment bias. There is likely to be bias associated with all sorts of social factors - which may well knock on to racial imbalance and so on. That would immediately throw up genes like MHC, associated with race, which would be spurious.

    If the sample is 20,000 of the maybe 120,000 in the UK then at least there are some constraints on how bad the bis may be. If the recruitment is extended outside the UK then bias is likely to go haywire. Populations from there countries might be useful as further comparators but a dilute sample from all over the place is likely to be the most misleading.
     
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  12. MEMarge

    MEMarge Senior Member (Voting Rights)

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    I think it is a little optimistic to think that most GPs will have much idea about this!

    "We may also ask people if they are willing to provide us access to their electronic health record, with personal clinical information kept by their GPs. This would help us to get a more detailed understanding of your illness, progression and symptoms, but would be entirely optional and would not affect eligibility for the study."

    This is not a criticism, just a comment. It may help GPs realise that there is an organic problem.

    I am just reminded that last time my daughter went to the GP (about a non ME problem), he said "....and what was it you came in about originally, a bit of fatigue wasn't it?" :banghead::banghead::banghead::banghead::banghead:
     
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  13. wigglethemouse

    wigglethemouse Senior Member (Voting Rights)

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    Makes me very happy to hear of pwME involvement so thanks @Andy and @Simon M

    One point I'd like to bring up is on the expansion of the UK ME/CFS Biobank as part of this project proposal. Two things stick in my mind
    * Ron Davis said a couple of years ago that they looked at using Biobank samples (not sure where from) but they were not suitable. I understand his team has a specific time of day for sample collection, with fasting required for a certain period beforehand, and samples must be processed immediately upon collection.
    * Karl Morten in the recent s4me Q&A said he was very interested in how the different collecting, storage, and sample handling methods, can affect what they can measure, and repeatability.
    * I think for projects measuring metabolites which have varying half-lifes this could be critical to obtain meaningful results. And for mitochondrial function testing you will want to have the raw fuel in the sample not be used up, something Karl Morten highlighted in his recent work.

    If the Biobank expansion portion of the project is successful it would be great to see some pilot work done to determine if the collection and storage procedures can be optimised. Since you have a good relationship with Karl Morten @Andy, and are involved with the CureME team, when you get some energy this may be an area where you could bring people together to discuss this topic. Or perhaps this might already be a topic they are looking into.......
     
  14. rvallee

    rvallee Senior Member (Voting Rights)

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    A spit-and-post is basically how 23andme and others do it and they have international reach but it gets sent to their US locations. DNA seems stable enough for the couple of weeks it would take.

    I don't know whether the rates of participation will justify it but I would definitely take part if international samples are accepted. Probably much easier within the EU, especially as there are EU-wide collaborators that already certainly know the people at the biobank. But sending the requests through the various researchers around the world would definitely speed up reaching 20K samples.
     
  15. Sarah94

    Sarah94 Senior Member (Voting Rights)

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    Yeah lmao they don't record your "illness, progression and symptoms" accurately
     
  16. Sarah94

    Sarah94 Senior Member (Voting Rights)

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    If the Biobank's ME patient questionnaire is to be used for participant selection. It would be good to have a consultation about the questionnaire. When I filled it out, I had some concerns about the way that at least one of the questions was phrased.

    @Chris Ponting
     
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  17. wigglethemouse

    wigglethemouse Senior Member (Voting Rights)

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    I guess the problem is that the population stratification of the control group needs to match that of the patient group. This was @Simon M comment on this thread covering a blog he wrote on the topic of a GWAS study in ME
    Researchers propose deep trawl of DNA to help uncover the causes of ME/CFS (Simon McG blog)
    If you want to widen the geographic location for collection, then you would need a control group with the same population stratification. For example, if you can get all your samples from the UK population, then you can leverage existing data from the large UK Biobank GWAS studies as a control group, assuming the sequencing technology used is similar.

    But if you can't get 20,000 tubes of spit from the UK and you have to widen the collection area, then a compromise may have to be made, or alternatively accept the use of a smaller patient sample size.
     
    Last edited: Nov 7, 2019
  18. strategist

    strategist Senior Member (Voting Rights)

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    I'm sad that I won't be able to participate if recruitment is limited to the UK. The argument that recruiting from other countries could introduce a lot of bias is compelling. Shouldn't the very large sample size make this less of an issue though?

    Each country probably sees ME/CFS in its own particular way. Even within a country there are probably substantial variations between the various recruitment channels (eg. hospital, gps, patient organizations).
     
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  19. wigglethemouse

    wigglethemouse Senior Member (Voting Rights)

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    I think it may also be important to map out what happens after the initial findings from this study appear.

    For example will there be a budget earmarked to follow up say the top 5 findings - e.g. take a small sample of blood from patients who have the variants highlighted and perform proteomics and WGS/Sangar sequencing to determine if in fact the genetic marker has an effect on the resultant protein that the gene has a relationship with? Or at least a path to get that budget if there are positive findings.

    Otherwise we will have data, but then have to wait years for funding to follow-up on it, and all the momentum will be lost.

    There is obviously an awful lot of effort being put into preparing this proposal, which is not usual. Would be nice to make the most of it.
     
    Last edited: Nov 7, 2019
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  20. Sarah94

    Sarah94 Senior Member (Voting Rights)

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    Will people be able to participate as healthy controls if they are the relative of a person with ME?

    If not, it will be more challenging to recruit healthy controls.

    But if yes, could it make the study biased as relatives of PWME are likely to share genes, and there would be likely to be selection bias towards relatives of PWME since it will be easier to persuade them to participate?

    But if you exclude relatives of PWME from participation, then the sample of healthy controls wouldn't be fully representative of the population of healthy people?
     

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