Trial By Error: UK Funds Genetics Project; My Letter to CODES Investigators

By David Tuller, DrPH

UK Funding for Major Genetics ME Study

Two of the UK’s largest public funding agencies announced this week that they would provide £3.2 million (around $4 million at current rates) for a study that will analyze genetic material from as many as 20,000 people to search for underlying causes of myalgic encephalomyelitis. The Medical Research Council and the National Institute for Health Research are providing, respectively, £1.8 million and £1.4 million to support the project, called DecodeME.

While this sum represents a significant investment, it is still much less than the £5 million that the MRC and other government agencies spent on the now-discredited PACE trial more than a decade ago. Contrary to the expectations—and claims—of the PACE investigators, that piece of crap documented pretty authoritatively that cognitive behavior therapy and graded exercise therapy are not effective treatments for ME (or chronic fatigue syndrome, the term they favored.)

The new study is what is called a genome-wide association study, or GWAS. Here’s how lead investigator Chris Ponting, a professor of genetics at the University of Edinburgh, described the approach in a press release from the research team:

“Our focus will be on DNA differences that increase a person’s risk of becoming ill with ME/CFS. We chose to study DNA because significant differences between people with, and without, ME/CFS must reflect a biological cause of the illness. It is our hope that this study, the world’s largest genetic analysis so far, will transform ME/CFS research by injecting much-needed robust evidence into the field.”

The project was developed, with significant patient input, by the UK CFS/ME Research Collaborative, which was established in 2013, and the CureME Biobank at the London School of Hygiene and Tropical Medicine. Professor Ponting became vice-chair of CMRC in 2018 after the previous vice-chair stepped down. Professor Ponting’s predecessor, the methodologically and ethically challenged Professor Esther Crawley of Bristol University, failed in her efforts to land two major grants–one from MRC and another from the Wellcome Trust. Her focus on psychological and behavioral interventions like cognitive behavior therapy and the Lightning Process also angered patients.

Andy Devereux-Cooke, a patient who has been involved in setting up the study, said this in a statement: “As someone living with ME/CFS, I’m well aware that the patient community has waited a long time for a study such as this one that has such a strong, genuine element of patient involvement. All of us involved with this research project hope that it can start to address the totally unwarranted stigma and lack of understanding that so many patients with ME/CFS face on a daily basis.”

The study is not scheduled to begin for some months, but anyone with ME/CFS who is 16 or older and might like to participate can register their interest in advance. The study will use both the 2003 Canadian Consensus Criteria for ME/CFS and the 2015 Institute of Medicine definition for what it called–unfortunately–systemic exertion intolerance disease, or SEID. *(Both of these were created as clinical case definitions, not research case definitions.) [This sentence has been corrected. See below.]

Some patients have criticized the GWAS study for not using another definition, the 2011 International Consensus Criteria for ME. Others still mistrust the CMRC after Professor Crawley’s rocky tenure. Under her leadership, the organization pursued a project called the ME/CFS Epidemiology and Genomics Alliance (MEGA), which bears superficial resemblance to DecodeME. At the time, patients feared that Professor Crawley would use the MEGA data to pursue her sub-par research into psychological and behavioral aspects rather than to seriously investigate pathophysiological processes.

That’s why I wasn’t surprised at the lively discussion among commenters when I wrote about this project in January. The patient advocacy group Opposing MEGA remains skeptical of the new study. In response to my previous post, a commenter on Opposing MEGA’s Facebook page wrote: “No way would I trust my data with this research group. This is a rerun of the MEGA proposal with revisions to overcome the failure first time round.”

I have more optimism about this project than that. But given the history of how people with this illness have been treated, I understand why others might have concerns.

*The sentence previously read: (The latter was meant to be a clinical case definition and not a research case definition, but the combination of the two sets of criteria has become fairly common among investigators.) It was not accurate to write that this combination is “fairly common.” As always, I apologize for the error.

**********

My Letter to the Investigators of the CODES Trial

Subject: Invitation to respond to my posts about CODES

Dear Professors Goldstein, Stone and Chalder–

I have recently posted some blogs about the CODES trial on Virology Blog, a well-read science site hosted by Professor Vincent Racaniello, a microbiologist at Columbia University. These posts are herehere and here

Given my critical assessment, I felt it was important to offer you a chance to respond directly to the concerns I have raised. If you send me your comments, at whatever length you choose, I will be happy to post them in full on Virology Blog, without editorial comment or interruption. If I decide to respond, I will do so in a separate post. (I have cc’d Professor Racaniello on this e-mail.)

Earlier this month, I also wrote to King’s College London to express concerns about the problematic press release for CODES. The press release failed to mention that the primary outcome had null results and that any reported benefits were from secondary outcomes. It is perplexing that KCL would omit such key details when communicating important scientific findings to the public.

Since I have not yet heard back from KCL, perhaps you could address this issue as well in your comments. Did you all read and approve the press release before it was disseminated? Do you stand by KCL’s decision to not distinguish between the results for the primary and secondary outcomes?

Thanks much. I hope to hear back and have the opportunity to post your full response on Virology Blog. Please consider this a standing invitation.

Best–David

David Tuller, DrPH
Senior Fellow in Public Health and Journalism
Center for Global Public Health
School of Public Health
University of California, Berkeley

{ 23 comments… add one }
  • CT 25 June 2020, 3:35 am

    With respect to the DecodeME genetics project, it’s a shame that the funders (the MRC and NIHR), rather than the scientists, chose the definition to be in line with the NIH. Political interests still win out when it comes to ME research, it seems. When you’re looking for a needle in a haystack, and you can choose a smaller haystack, why wouldn’t you ?

    With respect to the CODES trial nonsense, I doubt these people will ever get past their false illness beliefs and their baseless conviction that such trials provide evidence for the use of CBT -https://sites.reading.ac.uk/charlie-waller-institute/event/chronic-fatigue-syndrome-a-cognitive-behavioural-approach/ , so I wouldn’t expect a sensible reply from them any time soon.

  • Sasha 25 June 2020, 4:33 am

    CT (above) comments, “With respect to the DecodeME genetics project, it’s a shame that the funders (the MRC and NIHR), rather than the scientists, chose the [case] definition to be in line with the NIH.”

    But this wasn’t the case, according to the DecodeME FAQs page (https://www.decodeme.org.uk/faqs/):

    “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.”

  • CT 25 June 2020, 4:55 am

    Sasha – can’t both be true? This sentence – “Using these definitions will help to ensure that findings are compatible with those from biomedical research around the world, which uses these criteria” kind of lends support to what I said, doesn’t it?

  • Sasha 25 June 2020, 5:10 am

    Hi CT, thanks for responding. You said, ‘the funders (the MRC and NIHR), rather than the scientists, chose the definition to be in line with the NIH’. Have you seen any evidence that the funders did so?

  • Sasha 25 June 2020, 5:15 am

    Just to clarify – I see no evidence that the funders chose the case definition at all, and the norm would be for the researchers to do so before submitting their research proposal to the funders.

  • CT 25 June 2020, 5:36 am

    I believe that there is good evidence. I’d suggest that someone asks the researchers if it’s true.

  • Sasha 25 June 2020, 5:41 am

    But what evidence, CT? I can’t see that you’ve presented any.

  • CT 25 June 2020, 5:49 am

    It’s not for me to present the evidence Sasha, but I wouldn’t have made the original comment if I didn’t believe it to be true. I’m not in the business of making mischief.

  • Lady Shambles 25 June 2020, 6:17 am

    Wrt to the MRC and NIHR (funders): yes there is indisputable evidence that it was their choice to pursue criteria based on the NIH model and David Tuller has seen evidence of this.

    CT said “When you’re looking for a needle in a haystack, and you can choose a smaller haystack, why wouldn’t you ?”
    I quite agree: why wouldn’t you? I do find it odd that the ICC is regularly overlooked in favour of CCC. CCC had its merits back when it was first born…not least because it drew a picture much closer to what ME should look like than any previous exercise since Ramsay described the disease in the last century… but preferring it to ICC is akin, imo, to choosing to use Windows 7 over Windows 10. It seems to make no sense. The only thing I can ponder wrt that choice is that ICC is an ‘ME ‘ definition (if one reads the paper which David has kindly linked to above it’s clear that the authors want to relinquish the ‘CFS’ moniker) whereas the CCC definition is referred to as being for a patient population with ‘ME/CFS’. Did we have to accept the earlier and less accurate version to placate whomever might be lurking in the BPS-hued shadows maybe? It’s a thought.
    Or was it because the IOM definition is so inclusive that, whilst it draws in people with ME, it has such big holes in its net that it also draws in people who have all sorts of other maladies which aren’t ME and therefore cannot be used alongside the ICC definition as the two definitions ‘fight’ each other? After all Jason observed when comparing SEID (IOM/NAM) with the almost universally derided Fukuda: ” “The findings indicate that many individuals from major depressive disorder illness groups as well as other medical illnesses were categorized as having SEID. The past CFS Fukuda et al. prevalence rate in a community based sample of 0.42 increased by 2.8 times with the new SEID criteria.” So IOM was worse than Fukuda in this respect.
    Now I can see why a project that was formerly conceived and headed by either members of the BPS or those predisposed to their views, might still want to ensure a large proportion of the cohort for the Decode ME project as having a psychiatric disease.. because it fits their model doesn’t it? But that’s only a consideration if indeed those members are still wielding some influence. Can we rely on the words of others when they tell us that Crawley, White and Holgate (for example, but not elusively) have no authority over this at all?
    But to come back to your question CT: why wouldn’t we and the Decode ME team want a smaller haystack? I’m still none the wiser! They should want one..that makes logical sense ..but they’ve opted for the bigger haystack. When science doesn’t seem to progress logically, when the protocol snags haven’t been ironed out in the planning process, well that doesn’t sit easily with me. Clearly it doesn’t with you too, CT?

    Having said all that I will, of course, sign up to this. I want to see from the point of view of being a ‘patient’ what goes on inside the process. That will be interesting!

  • CT 25 June 2020, 7:32 am

    Lady Shambles said: “When science doesn’t seem to progress logically, when the protocol snags haven’t been ironed out in the planning process, well that doesn’t sit easily with me. Clearly it doesn’t with you too, CT? ”

    No, it doesn’t really, and I don’t trust the MRC and NIHR who seem to have a very biased agenda at present. I suspect that no definitions are watertight in that they will always be open to interpretation, so even if ICC was used patients could be included who don’t have the same disease as the rest. But from what I’ve seen of the different criteria, ICC does look like the best bet and would be the logical choice to my mind. But it’s too late now, the opportunity has been missed, so joining the study to see what happens seems sensible. The 20,000 cohort size approximately matches the size of Crawley’s NOD database. I hope that’s just a coincidence.

  • Wendy 25 June 2020, 7:58 am

    The IOM/SEID Criteria is not meant for Research and it does not include #PWME-ICC, Ramsay or Hyde

    The CCC itself states that it is a clinical diagnosis criteria and not to be used for research.

    ME-ICC is the only research criteria that can produce proof of Encephalomyelitis. If people prefer to use the CCC or the IOM/SEID then change the name of the Study to CFS. Including the title of ME and only selecting participants who have CFS is cherry picking bias.

  • Anton Mayer 25 June 2020, 4:11 pm

    I’m not impressed by baseless claims that the ICC criteria are somehow the best and/or the only true criteria. This idea is populism that appeals to some patients but not to those with a serious interest in the matter. The ICC is not so popular among scientists and clinicians because it is complex and makes claims that aren’t well supported by evidence.

    In my opinion the DecodeME team have made the right choices with the CCC and IOM criteria.

  • CT 26 June 2020, 2:19 am

    Anton – There may be a difference of opinion here but ‘baseless claims’, ‘populism’, and ‘not to those with a serious interest in the matter’? OUCH. Why don’t you ask the researchers if it’s true that the funders (the MRC and NIHR), rather than the scientists, chose the definition to be in line with the NIH? Perhaps the ICC isn’t popular among the scientists for that very reason – if they opt for ICC they don’t get funded.

  • @MECFSNews 26 June 2020, 4:13 am

    Just because some organizations don’t share your enthusiasm for the ICC and don’t believe it is the only true and best criteria does not mean they are conspiring to suppress the truth.

  • CT 26 June 2020, 4:52 am

    @MECFSNews – if you’re answering my comment, then I never said that ICC was the ‘only true’ criteria so don’t put words in my mouth. And ‘conspiring to suppress the truth’? Where did I say that? All I said was “that the funders (the MRC and NIHR), rather than the scientists, chose the definition to be in line with the NIH.” Ask the researchers. Why are people getting so irate about this? If you support the CCC and IOM definitions then you got your way, didn’t you?

  • Lady Shambles 26 June 2020, 5:23 am

    “The ICC is not so popular among scientists and clinicians because it is complex and makes claims that aren’t well supported by evidence.”

    These scientists evidently don’t agree with that: -https://www.me-international.org/published-me-icc-studies.html?fbclid=IwAR2LeBaDWiHFg15xSTmykOBJCY_P8qsveOYToS7NIPvz3tv9jd4TJ5V22zs

  • CT 26 June 2020, 5:55 am

    Dare I ask another genuine question? How are they managing to do this project for just £160 per person?

  • Guido den Broeder 26 June 2020, 10:50 am

    At least te authors of PACE didn’t pretend it was about ME. This is very poor science. It shouts: ‘Look at me! I’m so great, I have 20k participants!!’
    But it is exactly this unrealistically large number that makes certain even a concerted effort to include ME patients would fail to make them stand out in the crowd. And there is no such effort. Instead, the registry form requires that participants have ‘ME/CFS’, a misnomer for SEID. Only about 2% of people satisfying SEID have ME.

  • Martin 26 June 2020, 4:55 pm

    I disagree

    If you are diagnosed with CFS (and no one is diagnosed with ME anyway that I know)
    then that is what you have if other reasons for fatigue and mental cognition problems and light headedness/OI are excluded. That is what CFS is at the moment. An exclusion illness. I think they should analyse sudden onset ME/CFS as a primary outcome and other ways of getting it as a secondary one.

  • Wendy 26 June 2020, 5:41 pm

    Absolutely no one has stated that the ICC is the best criteria for all but it certainly is the most important criteria for those of us who have definitive proof of Encephalomyelitis by using SPECT Scans and Viral testing. The ICPrimer 2012 is invaluable. The CCC was written as a clinical diagnostic tool however, the IOM Panel refused to adopt the CCC that thousands lobbied for by petition with signatures delivered to Congress. Following the publication of SEID the CDC added Myalgic Encephalomyelitis to the the American ICD CM on Oct 2, 2015 as G93.3. This is the code for ME with brain/spine inflammation representative by the ICC, Ramsay and/or Hyde. Dr Klimas has publicly stated that the IOM/SEID was not intended to replace patients with ME. It was written as a clinical tool to treat patients with CFS because those are who they are seeing in their clinic. SEID is the name that was supposed to replace the anomaly of ME/CFS. The American ICD CM lists CFS as R53.82 which is the exact opposite of what this so called study proposes to do. If participants are chosen from the Fukuda, IOM, CCC hybrid criteria then the study is for those with CFS aka ME/CFS because the only criteria that is built for research is the Fukuda. Let’s also note that IOM/SEID also skyrocketed the prevalence of ME/CFS into a one size fits all.

    I’m not buying into the excuse that the ICC is too difficult to use by scientists. That’s either laziness or a political excuse. Patients don’t like being this sick either so have some compassion and remember who criteria is supposed to help. You can’t treat a patient with breast cancer the same way you would treat Luekemia. They are both cancer but have organic distinctions. I’m appalled at how criteria is being stretched & conflated to the point that only the scientist achieves gratification because this way they get paid. One size does not fit all so have a little courage to think about the patients who have the pleasure of dealing with Encephalomyelitis every second of the day. Perhaps it’s time to Seriously consider moving Myalgic Encephalomyelitis out of PVFS and into the classification of Encephalomyelitis as an Organic Brain Disease of the CNS because that’s what it is. Killing us by neglect isn’t the answer. Myalgic Encephalomyelitis as per the ICC can be diagnosed within 6 weeks using Neuroimaging and viral testing. I want to believe that scientists care about us enough to do their best but you are definitely making it difficult.

  • Benjamin Blumberg, PhD 27 June 2020, 12:30 am

    This sort of back-and-forth is unfortunately the staple diet of us present and former bug-hunters. Compare the present dispute concerning the presence of HHV-6 in Alzheimer’s Disease. The Duffy group (Readhead et al, 2018) say that HHV-6A and B, as well as HHV-7 may be causally linked with AD, while Jacobson’s group (Allnutt et al, 2020) say NO. So what’s up, docs? My own opinion is that the size of the haystack matters less than the power of the search tool (GWA). And a search for molecules is MUCH better and more scientific than a search for behaviours.

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