Frequently Asked Questions
The Q&A below was created by people with ME/CFS working with the project team and science blogger and patient, Simon McGrath. It will be updated as the project progresses.
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 between 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 people with an ME/CFS diagnosis whose DNA will be compared with that of a similar number of non-ME/CFS matched controls. These will be people from a similar population who do not have ME/CFS drawn from the half-million-strong UK Biobank.
We take diagnosis very seriously. Participants will be diagnosed using the CureME questionnaire that has been in use for the UK ME/CFS Biobank for several years. This is additional to participants reporting that they have been diagnosed with ME or CFS by a clinician.
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.
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 (see previous question). 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.
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.
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.
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.
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.
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.
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 Biobank, and collaboration with the NIHR Biosample Centre in Milton Keynes.
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.
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.
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.
There will be no attempt at identifying related individuals, other than as a routine part of the statistical analyses.
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.
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 UK ME/CFS Biobank should be developed separately.
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!
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!
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.
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.
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.
Recruitment and taking part
You can register your interest to take part and keep updated on our homepage. We will notify all who have registered their interest once our participant selection process is open.
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.
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.
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.
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/CFS, and so this requirement for proper matching narrows down the sets of non-UK patients that we could recruit.
No, we’d like to spend the project’s funds only on participants with ME/CFS, by taking advantage of existing data from the UK Biobank on controls (people who do not have ME/CFS).
Yes, wherever we can, we will be re-contacting people who have already been in contact with the UK ME/CFS Biobank. 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.
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.
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.
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 UK ME/CFS Biobank always ensures the highest level of privacy for participants and full compliance with ethical standards and legislation.
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.
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 with ME/CFS do not have a clinical diagnosis.
We plan to have:
- a ‘big splash’ PR campaign when we launch in early 2021, with press releases and TV and radio interviews;
- a patient-led social media campaign on Facebook, Instagram, Twitter and so on;
- digital advertising;
- a campaign that encourages people with ME/CFS, their supporters and carers to reach out to every patient they know to recruit them to the study;
- engagement with advocacy groups, groups of people with ME/CFS, charities and the NHS;
- 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 participants as possible!
If you’d like to take part or help find patients, please indicate your interest via our homepage.
Public and patient involvement
Patient and public involvement (PPI) has been central to the development of the study, via our PPI Steering Group. We also incorporated feedback and ideas from the wider community into the study design. Some examples:
- 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.
- We gained lots of ideas to help recruit 20,000+ participants.
- 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.
- We recognised the need for a paper-based questionnaire, as well as an online one, for people wanting to participate.
- We’ve used the expertise of people with ME/CFS to develop our marketing strategy and budget.
We’ll do this by continuing our outreach to, and engagement with, the community of people with ME/CFS. Gaining the support of the 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 study design, 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 are also working to the National Standards for Public Involvement.
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.
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