Rev. 1.0.3. Last updated 02/04/20.

The Q&A below was created by people with ME/CFS working with the project lead, Professor Chris Ponting of Edinburgh University and with science blogger and patient, Simon McGrath. It will be updated as the project progresses.

Topics are:

  • The science/research
  • Recruitment/taking part
  • Funding
  • The Partnership
  • Public and patient involvement
  • To view the answer, simply click on the question *

The science/research

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 guide drug development. This design has previously been 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 a similar number of non-ME/CFS matched controls. These would be people from a similar population who do not have ME/CFS, such as people drawn from the UK Biobank.

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

We take diagnosis very seriously. You will be diagnosed 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 are accurately diagnosed, and a GWAS does not need 100% diagnostic accuracy to produce valid results.

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 criteria, but not the 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 will help to ensure that findings are compatible with those from biomedical research around the world, which uses these criteria.

We undertook an online survey and the majority of people supported this. These criteria were also agreed at the MRC/NIHR Workshop with researchers, patients and carers.

Will you be asking patients to send in documentary evidence of their diagnosis along with the questionnaires?

No, we won’t be asking them to send in evidence: making a declaration that they have a clinical diagnosis and completing the questionnaire is sufficient. This does mean that someone could falsely claim to have an ME diagnosis and access the questionnaire part of the study. But: (1) we feel that the number of people who might do so will be too small to be significant, and (2) we would anyway prefer to keep the barriers to taking part to a minimum for patients.

How will you 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 patients’ 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 patients’ background and illness and we will link this survey data to their genetic data.

We may also ask patients 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 patients’ illness, progression and symptoms, but would be entirely optional and will not affect eligibility for the study.

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 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.

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, the triglyceride group, 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.
What can we learn from how the previous successful GWAS projects did?

We are looking to learn all the (good) lessons that previous projects can teach us. One good example that we are aware of is the UK GLAD study, which has used predominantly online recruitment. One year in, 79,000 people had registered online, 47,400 had given consent and 20,000 people had returned saliva samples to become study participants.

The GLAD study is recruiting from the 1 in 3 people aged 16+ who have ever had anxiety or depression (18 million), while we have the much more challenging task of recruiting from the approximately 1 in 250 people who have ME/CFS. Even so, the GLAD study’s recruitment is at least a proof of concept, and also gives examples of ways of engagement that will be useful to us in our study, though the disease focus of the research is very different.

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.

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 the 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.

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. StanfordHarvard 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.

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.

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 that 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.

Would it be useful to include relatives who have ME to see whether they have the same mutations associated with disease?

We welcome participation by all people with ME, whether or not others in their family are affected. Our project is not to identify such large effect, family-specific DNA variants, but smaller effect, general population DNA variants. To address the question of whether there is a single, large DNA change we would need a very large family with many members who have ME/CFS.

Will there be any attempt in this study to identify samples from patients who are related?

There will be no attempt at identifying related individuals, other than as a routine part of the statistical analyses.

Is the focus of this first study to identify gene associations to the disease first, and then once these are identified, to perhaps do separate studies to look at whether these track in relatives with ME?

Yes, genetic associations to ME/CFS will be looked at first. The next step is unlikely to be “tracking in families” because we expect there to be not one or two DNA differences, but rather dozens or hundreds of DNA differences that tilt the balance one way or another, changing someone’s risk of having ME/CFS. Having one DNA difference is unlikely to be sufficient to change that risk.

Instead, the second step – once the type of cell or metabolic process that is disrupted in ME/CFS has been identified – will be to chase down what immediate effect this “root cause” has on the body and then see whether it can be reversed.

Why have you dropped the plans to expand the UK ME/CFS Biobank?

When we approached the potential funders earlier this year, we presented an indicative budget. Unfortunately, when the full budget was calculated, we realised that there was limited space for any biobanking work. At a workshop organised by the funders, which people with ME and scientists attended, there was overall agreement that the GWAS should be prioritised and that a proposal to extend the CureME Biobank should be developed separately.

Additions made to the application for funding.

In the final weeks before the application for funding was submitted, we were able to identify a number of areas where we could make some savings.

Sadly these savings weren’t sufficient to re-implement our original plan of an expansion of the UK ME/CFS Biobank, but they did allow us to add the following items:

100 whole genome sequences

Whole genome sequencing (WGS) will allow us to assess the accuracy of our GWAS genotypes and would be a pilot for a future – much larger – WGS study. We can’t make reliable claims about genetic variants causing ME/CFS with only 100 genome sequences. There is a very small chance that ME/CFS-causing genetic variants are commonly present in one or two genes and if so we would observe this, but this is unlikely. The ME Biomedical Partnership study was always going to bank a DNA sample for future WGS and this pilot study will demonstrate to funders that this future WGS study is feasible. Eventually, we hope that all DNA samples, for which consent was given, will be subjected to WGS.

60 Smartwatches 

We will use these to measure wearers’ activity and skin temperature continuously over the period of one week. Once the smartwatch is returned and its data downloaded, then we can objectively compare any participant’s measured activity to anyone else’s, including individuals from the UK Biobank project. At no cost, we’ve recruited an expert (Dr Thanasis Tsanas) to help us with the data analysis.

Further development of the LSHTM CureME algorithm

We will also further develop the algorithm for identifying cases of ME/CFS, according to the CCC and IOM criteria, using electronic health records. This research will be based on clinical parameters which are available for both UK ME/CFS Biobank and UK Biobank participants, and will enable us to re-classify ME/CFS cases without a formal diagnosis according to those clinical criteria, with a good degree of certainty. 

Patients with potential ME/CFS and no exclusionary conditions will be placed into four groups – where Group 1 has the strongest indication of ME/CFS in line with clinical parameters and Group 4 has the weakest indication, i.e. having been misclassified, or having another condition such as general tiredness. A random sample of 125 patients in each group will be referred to an online platform for completing a questionnaire to validate their diagnosis. We will compare features of patients with a valid diagnosis to those without a diagnosis. This specific algorithm would be a valuable output that can be directly applied to the GWAS study, as well as to clinical practice and epidemiological research using big data.

What is the time frame to collect this number of samples?

If funded, we hope to launch very early in 2021. We plan for recruitment to take up to two or three years, but the sooner the better!

Could there be more than one genetic ME predisposition?

This is highly likely. The risk of having a complex disease such as an autoimmune condition is altered by many, many different DNA letters scattered around the human genome, and we think it is likely that it will be the same for ME/CFS. The genetic variants all could have the same effect (for example, muting the body’s immune system) but might have separate effects on different bodily processes.

Modern biomedical science tries not to compartmentalise. The body’s health is like a tune that can become discordant because of faults in any of the musical instruments, being played by many different parts of the body’s orchestra!

Who will be able to use my data and sample?

Your information and samples will only be used by researchers who have relevant scientific and ethical approval for research. This could include researchers working in other countries or with commercial companies who are looking for new treatments or lab tests.

What if my data or sample creates an invention?

You’re providing your sample as a gift. You won’t receive any payment for your contribution. The Partnership won’t sell your data or sample.  Samples and data may be made available to other research institutions, in the public and private sector, in the UK and overseas, to help researchers make an invention. If an invention is created from research on your data or sample, you won’t receive any compensation or payment.

Recruitment/taking part

How can people with ME/CFS take part?

You can register your interest to take part and keep updated while we are applying for funding. 

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. 

We have tried 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 sent a collection kit by mail and asked to post a saliva sample (a “spit-and-post” sample) via freepost to the project. Some participants who are already part of other studies or the UK ME/CFS Biobank may have given their consent to be contacted by other researchers. If so, we may contact them about this study.

When we receive the saliva sample back, we will extract the 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.

Is there anything I can do to help before the study goes live?

Please register your interest in the study. We will notify you if we get funding and when the study goes live, so that you can join straight away.

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 the patient in completing the questionnaire and sending back the saliva sample.

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.

What’s the minimum age for taking part?

You need to be over 16 years old to take part. Anyone reaching this age during the study can sign up then – the study will take place over four years.

Can people who have improved or recovered participate?

Those who pass the Canadian Consensus or Institute of Medicine criteria can participate. Following these criteria to the letter (as we will do) unfortunately means that those who are fully recovered will not be able to participate. This is an unfortunate but inevitable consequence of the need for us to fully comply with these criteria.

Can people from outside the UK participate? If not, why not? Would it be possible to develop an international ‘Plan B’ in parallel with planning UK recruitment efforts?

Our ‘Plan A’ is to recruit within the UK only, and that is how we will start the study. We do have a ‘Plan B’ which is to recruit other, non-UK participants.

It’s important to say, however, that our study needs data for a large set of “control” (non-ME/CFS) individuals, and in the UK, this will be the half-million-strong UK Biobank. The ancestry of these individuals should be matched to that of people with ME, and so this requirement for proper matching narrows down the sets of non-UK patients that we could recruit.

Will you be recruiting healthy controls?

No, we’d like to spend the project’s funds only on participants with ME, by taking advantage of existing data from the UK Biobank on controls (people who do not have ME/CFS).

Will the CureME Biobank contact its severely ill ME patients (or their carers) to ask them to participate?

Yes, wherever we can, we will be re-contacting people who have already been in contact with CureME. However, we will have to abide by any applicable privacy and/or ethical concerns, so where patients or their carers haven’t confirmed that the patients are happy to be contacted about other studies such as this, we will be unable to contact them.

Will the study recruit from fatigue clinics and, if so, 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 to ensure they meet the criteria being used for this research project). These recruits may include people attending fatigue and/or specialist ME/CFS clinics. We anticipate that a large number of participants will be recruited to the study through social and traditional media, and through our contacts with charities.

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.

How will participants’ samples and data be kept secure and private?

We take sample and data security, and patients’ 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 UK ME/CFS Biobank has extensive experience in doing research in ME/CFS, including the international distribution of samples to researchers worldwide. The Biobank always ensures the highest level of privacy for participants and full compliance with ethical standards and legislation.

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.

How will the study manage to recruit so many patients?

Recruiting so many people with ME/CFS will be a huge challenge, particularly as the disease is not as common as, for example, diabetes (around 1 in 250 people have ME/CFS, compared to 1 in 16 for diabetes). Also, 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 people 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, namely: 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.

We plan to have:

  1. a ‘big splash’ PR campaign at launch with press releases and TV and radio interviews;
  2. a patient-led social media campaign on Facebook, Instagram, Twitter etc.;
  3. digital advertising;
  4. a participant-gets-participant campaign;
  5. engagement with advocacy groups, patient groups, charities and the NHS;
  6. word of mouth.

We actually will need more than 20,000 people to take part, because not everyone will pass the criteria, complete the online questionnaire or return a saliva sample. We need as many patients as possible!

People can express an interest in taking part, if funding is secured.

I have some ideas for recruitment, who do I contact?

Let us know your ideas for recruitment, and tell us whether you would be willing to volunteer for the project (if it succeeds in being funded). If the project is funded, we will need everyone to spread the word to help recruit more people. The sooner the project has 20,000 participants who fit the clinical criteria, have filled in the questionnaires and provided a saliva sample, the sooner the final genetic analysis can be done.

Funding

Have you got any funding yet?

No. We are in the process of submitting an invited application to the Medical Research Council and National Institute of Health Research.

How likely is it that the Medical Research Council and National Institute of Health Research 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 impact-related argument for funding, and we will make this point as strongly as we can.

Will the project request 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 Medical Research Council and National Institute for Health Research for the recruitment of participants, data and sample collection and analysis of results.

Will there be a budget for marketing and for PR?

Yes, absolutely, there will be a significant budget held by the Patient Public Involvement group. We will need this to help promote the study and help with recruitment.

What happens if, after all this effort and money, the study finds nothing? Will the Medical Research Council 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.

The Partnership

What is the ME/CFS Biomedical Partnership?

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

Who is managing the project?

A Management Team makes decisions and comprises:

  • Professor Chris Ponting, Chair of Medical Bioinformatics, University of Edinburgh, Principal Investigator, Management Group Chair;
  • Sonya Chowdhury, on behalf of Action for M.E. (founding charity member of the CFS/ME Research Collaborative) and the Collaborative, and as Patient and Public Involvement Steering Group Chair;
  • Andy Devereux-Cooke on behalf of the CureME Biobank Steering Group and as part of the PPI Steering Group;
  • Dr Eliana Lacerda, Assistant Professor and Clinical Lead, CureME Biobank, London School of Hygiene & Tropical Medicine.

The Management Team is chaired by Sonya.

What changes have been made to the Management Team and why?

We’ve worked out a better way of working together, taking advantage of every individual’s strengths. For example, Sonya’s experience means that she is a great choice as Chair, allowing Chris and others in the team to focus more on the science. Having Eliana on the team allows her day-to-day experience in cohort building and biobanking to be brought into the project more effectively, and takes account of the fact that Luis spends a lot of his time working in Canada.

Will biopsychosocial 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.

Public and Patient Involvement

What have you done already in response to ideas from the community?

Patient and public involvement (PPI) is very important to the development of the proposal, via our PPI Steering Group. We have also incorporated feedback and ideas from the wider community into the funding proposal. Some examples:

  1. We consulted on the criteria for inclusion in the study and decided to use the Canadian Consensus or  Institute of Medicine and not Fukuda criteria as a result.
  2. We gained lots of ideas to help recruit 20,000+ participants.
  3. We used discussion on the Science for ME forum to inform our plans about recruiting from anywhere in the world, and what impact this might have.
  4. We recognised the need for a paper-based questionnaire, as well as an online one, for people wanting to participate.
  5. We’ve used the expertise of people with ME/CFS to develop our marketing strategy and budget.
How will you ensure that you have the support of the patient community for this project?

We’ll do this by continuing our outreach to, and engagement with the patient community. Gaining the support of the patient community will be a crucial challenge for the study, and is one that we do not take for granted.

As we began work on the proposal, we listened to previous issues raised by patients and consulted on the Science for ME online forum. We set up a Public and Patient Involvement Steering Group that involves patients, expert clinicians, a House of Lords expert representative, and representatives from most UK charities (directly or through Forward-ME). Our project has almost unprecedented levels of patient involvement compared to similar research projects on other diseases.

We have engaged with almost all of the UK’s ME charities/groups already. Hopefully all will spread the word, as we need to reach as much of the UK patient population as possible. We also plan to have members of the PPI team, including a paid PPI coordinator (to be recruited), who will visit patient groups who meet up offline to talk about the study. We will also provide updates to the community during the study.

We hope to gain public support from individuals whose views are well respected within the ME/CFS community to encourage people with ME/CFS to also support the project.

We have been working hard to engage with the community to win its trust, and will continue to do so. We are relying on the support of the community to spread the word, to enhance our chances of recruiting the number of participants that the science needs.