Many of you have asked us questions about MEGA. We can’t yet answer some of the detailed questions as the Scientific Team and Patient Advisory Group are still in the early stages of applying for funding. This means that the details of the experimental design have yet to be discussed and agreed. However, below we have set out some Q&As that we hope you find useful. We will add to these as details of MEGA are developed.
Latest update: 29 March 2017
1. How does the funding process work?
We are applying for funding in 2017 for the first stage of the study, setting up the world’s largest Bioresource of data and samples from ME/CFS patients. Our aim is to create a resource that researchers all over the world can use.
When applying for funding, most mainstream funding bodies require researchers to submit an outline proposal. This sets out the scope of the project, and how much it will cost. If the outline is accepted, researchers are invited to submit a full proposal. This is much more detailed, and sets out the design of the study.
If the full application is accepted, and funding is awarded, the first phase of the study will begin. In the case of the MEGA project, the level of funding available for this first phase will be insufficient to include blood and urine samples from patients who cannot visit the clinic, although data and saliva samples can be collected online and by post. When the time is right, further funding will be applied for to ensure that patients who are house and/or bedbound can be visited at home. The MEGA team see inclusion of these patients as essential.
We would also like to do additional, more time-consuming and expensive tests on a sample of patients that will help us better understand the biology of M.E., and will apply for further funding for this, too.
2. Will MEGA include people with M.E. who are severely affected?
Yes. The Scientific Team agree that this it is absolutely essential to include those who are severely affected by M.E., which means those who are house and/or bedbound.
The funding bodies have very clear limits on how much money we can ask for. This means that we are not able to include home visits to house and/or bedbound patients, which are enormously expensive, in our initial application.
What we can do is apply for further funding to devote to the collection of data and samples from house and/or bedbound people with ME/CFS. By establishing the MEGA bioresource and proving to funders that we can collect data from patients in clinic, the chances of us successfully accessing further funding are hugely increased.
It’s also worth noting that we think there will be some severely affected patients who, despite our advice and the personal cost to their health, will come to clinic so that they can take part in this biological research.
Those whose samples are collected for the bioresource will have their diagnoses and severity of illness confirmed and recorded at point of collection. Several case definitions will be used to categorise patients and it will be clear which case definition any given patient fits into. When analysing results of tests undertaken on samples from the bioresource, the Scientific Team will be clear which subset of patients the results specifically relate to.
The Patient Advisory Group have highlighted that how we define mild, moderate, severe and very severe ME/CFS is very important, and the Scientific Team will work with them to do this, if our application is successful.
3. Will MEGA include people who don’t have post-exertional malaise?
No. Everyone whose data we collect will have post-exertional malaise. We will agree how to define this if we are asked to submit a full application from funders (see question 1).
For example, in their clinical work, one of the Scientific Team defines post-exertional malaise as an increase in symptoms after they have undertaken more activity than usual.
The Patient Advisory Group will decide how best to identify and define post-exertional malaise and work with the specialists on the Scientific Team to hone this definition.
4. Will this study use all the funds that are available for research into ME/CFS?
There isn’t a limited fund for research in ME/CFS. We want to increase research funding and access to the Bioresource will potentially help facilitate a greater level of research into the illness. The MEGA team will apply to a variety of funders for future studies once the resource is set up. We also hope that other researchers and consortia will be able to obtain additional funding for research once MEGA is set up. While significant funding will be required for this study, there will still funding available for other research through all mainstream funders.
5. What is the plan to address the clearance of the MEGA study by an NHS Ethics Board/Committee or similar independent body?
As with all studies involving human subjects, the appropriate ethical permissions will have to be sought. The funders will not permit a study to be funded or proceed unless they are in place.
6. Is the MEGA study achievable?
Yes – but only if everyone pulls together. Working with the NHS and the ME/CFS clinics across the country, and a network of health professionals interested in the condition (the British Association for CFS/ME), the researchers, charities and Patients Advisory Groups will aim to create the interconnectivity needed to deliver MEGA’s objectives.
The work will need to be carried out in stages, starting with the construction of a patient register and Bioresource. Only then can the multi-level -omics be conducted. We have sought the help of the Farr Institute to help with the data analyses which will be challenging and complex, but doable.
Already studies on small patient groups using -omic technologies such as metabolomics are identifying novel pathways (eg. Naviaux, RK et al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci USA. 2016 Sep 13; 113(37): E5472-80).
It will be important that MEGA links with similar efforts across the world to replicate findings and to maximise synergies between our concerted efforts. If successful, MEGA will be the largest and most impactful study of the mechanisms of ME/CFS ever conducted and as such holds considerable promise for transforming the field.
7. Many people with ME/CFS do not have contact with specialist NHS ME/CFS clinics. So only using the clinics to recruit is likely to give an unrepresentative sample. How will the researchers address this?
For this application we need to be as sure as possible, with limited funds, that those who are included, using post-exertional malaise as an essential criterion, have ME/CFS. We know that up to 50% of those referred to specialist ME/CFS services do not have ME/CFS. If we accepted patients from other clinics into MEGA, we would need to pay for them to be seen by a specialist ME/CFS doctor if they were to be included in this application. We will not have the funds to do this at this early stage. Recruiting from the NHS Specialist services does not stop patients from other clinics being referred in to the specialist services.
In the future, we would like to apply for additional funding to collect samples from patients who are not part of the NHS clinics. We can either apply for funding for them to be seen by a ME/CFS specialist or we may look at using these samples without specialist review in studies, for example, in replication studies.
8. I have recovered enough from ME/CFS to work full-time and be physically active – would my data be of use, and if so how can I be included in the study?
This will be decided later. It is possible that we will use patients who have recovered for the genetic studies (as genes don’t change). However, we would want to be sure that they had ME/CFS.
9. What case definition will you use for MEGA?
To do the Genome Wide Association Studies (GWAS) that we want to do as part of MEGA, we think we need to recruit at least 10,000 adults and 2,000 children. The only way to do this is to recruit patients through NHS clinics throughout England. England is the only place in the world that can collect this large number of patients in a short time frame.
Patients with ME/CFS will be identified by clinicians in the NHS clinics which use NICE guidance to determine if patients have ME/CFS. This means patients with other causes of fatigue will not be recruited including, for example, those with thyroid disease, diabetes or depression that is sufficiently severe to explain their fatigue. Patients will have been examined, a full history taken and they will have had screening blood tests (to ensure other causes of fatigue have been excluded).
We will collect sufficient information on each patient to be able to say whether they have ME/CFS using other research criteria, for example, the CDC [Fukuda 1994] diagnostic criteria, Canadian Consensus Criteria , the International Consensus Criteria  and so on. We will also consider other tools such as the De Paul Symptom Questionnaire for capturing data as well as samples. We will listen to our Patient Advisory Groups in terms of how much data we can collect on different diagnostic criteria. Our advisory groups may recommend collecting less data as patients are so ill.
10. Have GWAS been useful in other diseases or would the money be better spent on other projects?
GWAS have been useful in helping us understand the biology of many illnesses including schizophrenia, multiple sclerosis and inflammatory bowel disease.
11. Profs George Davey Smith and Chris Ponting have explained the need for a large sample size of 10,000 in order to produce statistically significant results for studies of this type. However, it also seems possible – indeed probable – that people diagnosed with ME/CFS may include those suffering from a number of different illnesses. If, say, people who are severely affected and do not get better were suffering from a different illness to others with the same diagnosis, how many of those people would it be necessary to include in the study in order for that illness to be accurately differentiated using the methods you propose?
The study is powered on investigating the association of genes with ME/CFS. It will not be powered to investigate the association of genes with other conditions. However, as we are collecting samples that will allow us to look at all the -omics from genes to metabolites, we will be able to investigate different biological pathways in sub-groups of ME/CFS as well as different illnesses. All of this will require additional funding in the future and is a long way away. The number required will depend on the investigation planned and the strength of the genetic association.
12. Why use broad criteria?
As the symptoms and genetics of ME/CFS are highly heterogeneous we think it makes sense to build a Bioresource of samples from all people with ME/CFS. All patients will need to have post-exertional malaise to be present. We will take great care to exclude other causes of fatigue. Afterwards, when we do the analyses, we will separate out various subsets of people with ME/CFS according to different diagnostic criteria to see if this changes the results.
13. It is good to see that you propose for all participants to have post-exertional malaise – how do you define post-exertional malaise?
This will be defined at a later stage.
14. Will people who meet the NICE criteria for ME/CFS but who have additional related problems (eg. POTs, hypotension, fibromyalgia, IBS) will be included in the MEGA study?
These people will be included.
15. What data will you collect?
We will collect symptom data on all patients to allow us to identify which patients will be identified as having ME/CFS using different diagnoses. We will also include data on fatigue, disability and co-morbid anxiety/depression. We would like to collect detailed data on pain. How much data we collect will depend on what our Patient Advisory Groups say will be acceptable to consenting patients and how much funding we get. We are concerned about placing demands on patients by asking too many questions so the Patient Advisory Group will be asked to monitor and advise on the limits for patient assessment by questions and other assays.
16. Will you be doing additional tests?
We would like to do additional, more time-consuming and expensive tests on a sample of patients that will help us more finely phenotype (describe ME/CFS more carefully) those recruited into the study. We don’t think we will have the money to do this for everybody or for everything. We would like to do additional studies to collect more data on pain, post-exertional malaise and sleep studies and possibly some imaging. We also want to be as sure as we can that we have carefully excluded other diagnoses such as depression and anxiety as a cause of fatigue. We haven’t worked on the details for this but will be asking our Patient Advisory Groups about what they think would be feasible and acceptable given the funding limits and compatibility with the demands on patients.
17. Will you be measuring orthostatic intolerance?
We would like to but this depends on whether the additional costs are perceived by the funders as being justified.
18. Will you use the Bell Disability Scale?
We haven’t decided yet. This will be decided at a later stage and will depend in part on whether this is perceived by the funders as being justified.
19. Are you quantifying the physical functional capacity of donors?
How we define physical function will be decided at a later stage.
20. What samples will you be taking?
We will take blood and urine samples that allow us to look at the genetics, the epigenetics (how genes are modified chemically), transcriptomics (identifying which genes are turned on and which are turned off), proteomics (the proteins in the blood), and the metabolomics (what small molecules are made by our enzymes and other proteins). We will use standard procedures for collection of these samples developed previously for many other studies.
21. Will the collected data be open access?
Yes. Subject to individuals’ consent, the data will be available for researchers to use. We want to rapidly increase effective research (by us, by anyone) to understand the biology, causes and different types of ME/CFS.
22. Will you ensure that only people with post-exertional malaise are included to ensure this is not a study about people who have unexplained fatigue, many of whom might have had an incorrect diagnosis of ME/CFS?
We agree it is very important that we check that the diagnosis of ME/CFS is correct and will check the diagnosis at several stages during recruitment.
23. Will you define the sample of patients and tests before the study starts or wait till data starts rolling in and then cherry pick the patients and data to best support your hypothesis?
Once we have created the Bioresource, we will apply for funding to do the research. We agree that it is very important that analyses are defined before it is done. It will be a requirement that all scientists who use the MEGA Bioresource will submit an analysis plan prior to using the data or samples.
24. How will you collaborate with other potentially overlapping research? Will the samples collected be done so in a manner that makes them suitable for replicating work of other scientists?
We are keen to collaborate as widely as possible. The MEGA Bioresource will be set up so that other researchers can use both the data and the samples. We agree it is very important to be able to replicate the work of others and will work to ensure that the samples (and data) are collected in such a manner to make this possible.
25. How will this study work with/use the existing UK ME/CFS Biobank of tissue samples?
The existing biobank does not have enough patients to answer the questions that we want to answer. In addition, we need all the patients to be recruited using the same criteria in the first instance. We also need additional biobanks to replicate the work. Researchers should have access to multiple biobanks.
We believe that collaboration is very important, particularly in terms of replication. The MEGA data and samples will be available to other researchers to use. We hope we will be able to test whether results from MEGA are replicated in other studies.
26. How will the MEGA team make decisions about aspects such as recruitment of study participants and which diagnostic criteria to use?
Decisions about the aims of the study, its design, and the samples, data and information collected, will be taken by the MEGA team, which includes the Patient Advisory Groups along with the scientists and charities. Following costing of the study, we will probably need to review these decisions to match the budget available, or to identify different phases for which we will need to seek additional funding.
27. How did you recruit the adult Patient Advisory Group?
We are committed to meaningful engagement and communication with members of the ME/CFS community. As part of this, we openly invited people to apply for one of 12 to 15 places in our Patient Advisory Group. We worked with Action for ME, the Association of Young People with ME, the ME Association and ME Research UK to promote this recruitment and received more than 40 applications. The group will need to be virtual and we would expect to agree any draft terms of reference with the group once it is established. The children and young people’s group is an existing group working with University of Bristol.
28. Why is a new patient advisory group for the children’s arm of MEGA not being recruited is the same way as the adults Patient Advisory Group?
Recruiting a children and young people’s Patient Advisory Group presents considerable challenges, as this patient group and their parents and carers frequently do not have the capacity and/or time to be part of such a group. So the MEGA team have decided to use an existing group, funded by the National Institute for Health Research as part of work being done at the University of Bristol. The group has been running for three years, with new participants recruited each year. Members are children, young people, parents, carers and young adults who had ME/CFS as a child, all of whom have expressed an interest in helping research, and they have contributed to and advised on a wide variety of projects including qualitative and epidemiological studies.
29. Why has the recruitment of the Patient Advisory Group been done on such a short time scale?
We wanted people with M.E. to have input into the application from the very beginning. The first draft of an application will be submitted in January. This has very little detail on the science, but we need to get the costs right. We want to involve people with M.E. in those decisions. The Patient Advisory Group will not be expected to make decisions on every detail of the application at this stage because we are only seeking feedback on whether the funders are interested in an application of this nature.
30. Can you provide assurances that all applications will be passed on to the selection process?
Action for M.E. is administering the MEGA Patient Advisory Group application process and as such will pass on all applications received by the deadline to the recruitment panel. No-one at Action for M.E. is involved in decision-making about who will and will not be recruited, and the applications will be anonymised before being sent to the decision-making panel, comprising representatives from the ME Association and ME Research UK and a scientist from the MEGA team, Prof Paul Little.
31. Does the MEGA Team intend to publish the names of those who have accepted a seat on the Patient Advisory Group and by what date does MEGA anticipate publishing the confirmed membership list?
The Patient Advisory Group discussed this at their first teleconference meeting in December 2016, and as a result made individual decisions about whether they wished to be named. Please see our Patient Advisory Group page for more information.
32. Please explain why different members are part of the MEGA team?
You can read about each of the MEGA team members and why they are involved on the MEGA TEAM page. We have recruited a team covering all the different research areas critical for a study of this kind and each member will make a shared contribution to the study.
33. Does MEGA project have a Steering Group overseeing the project?
A Steering or Oversight Group has not been established as there is as yet no project to oversee. If MEGA is funded, this will be established in due course.
34. Why are psychiatrists involved?
This is a biological study, but the MEGA consortium has brought together many experts from a wide range of different disciplines across genetics, genomics, metabolomics, pain research, proteomics, psychiatry, sleep research and transcriptomics. Psychiatry is one aspect. We will be doing psychiatric screening tests to ensure that we do not include people with a primary psychiatric disorder; we will carefully exclude primary depression and characterise secondary depression.
The MEGA study will be setting out to discover the genes that are involved in ME/CFS. The proteins expressed from these genes, as with many proteins, will likely be found in several different organs or systems in the body. As MEGA gathers momentum in the years ahead, it will be important to involve researchers from diverse disciplines to help interpret the data but at present we have to draw on the pool of researchers that are interested in the condition.
This does not mean that MEGA is an immunological study, a musculoskeletal study, a neurological or psychiatric study – it is an -omics study. As explained above, a GWAS needs to recruit large numbers of patients, and gather patient samples of DNA, because the effect of any single gene change may be small. Looking far ahead one may hope that the changes in particular genes, added together in different combinations in different patients, will help to explain both the underlying diseases mechanisms and also the spectrum of symptoms experienced by patients.
35. How is this study related to PACE?
PACE was a large trial investigating treatment in adults with ME/CFS. MEGA is not a trial and is not related to PACE – it is a basic science study into the aetiology of ME/CFS.