Trial By Error: Professor Chris Ponting on the NIH’s Findings and the Latest on the Genome-Wide Association Study Update

By David Tuller, DrPH

When the US National Institutes of Health released its lengthy ME/CFS study last month with much fanfare and publicity, the London-based Science Media Centre asked Professor Chris Ponting, among other experts, to provide comment. The study–“Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome”–was published by Nature Communications. It included in-depth findings from 17 ME/CFS patients and 21 healthy controls and caused much anger and distress among members of the patient community, particular over its focus on a bizarre construct called “effort preference” as a core factor.

Professor Ponting, a geneticist at the University of Edinburgh, is leading a genome-wide association study (GWAS), DecodeME, that has gathered thousands of DNA samples from ME/CFS patients in the UK. His comments about the study indicated he wasn’t especially impressed. I spoke with him the other day to see if he had further impressions. Because of Zoom glitches, I’m posting an edited transcript of our conversation.


Tuller: Chris, you were asked by the Science Media Centre to comment on it, and you gave what I’d call a muted, tempered response. You described what they did but didn’t have much else to say. I wonder you’ve had some more time to reflect on it.

Ponting: I think I was given 45 minutes to read the paper before commenting. Having read it now, I probably would have tempered my response even further than it was. I will not be saying anything different about the study from what others have said, and I’m sure you’re not surprised to hear that. It’s essentially a small cohort study. And the cohort has been investigated in a variety of different ways.

I must admit that about halfway through reading it, I kind of lost focus. Mainly I realized that the cohort size was so small I wasn’t going to take anything away from it or learn anything from it. It wasn’t going to tell me definitively what I should be interested in, or what I should not be interested in. And that for me was a disappointment, a major disappointment in terms of figuring out possible avenues of exploration.

Tuller: You mean where to go in terms of research?

Ponting: Yes. I want to know where to go next. What should be done next? Where should the field be going? So that was the first disappointment. And then I also came to the view that these are a series of observations without any major overarching mechanistic question that has been asked or answered. Some of these observations I can understand well, because they’re molecular and cellular, and others I know almost nothing about.

What the study basically found is that these 17 people are unwell and are different from the healthy volunteers in a variety of ways. But we already know they’re unwell. That’s not telling me anything new. What I would like to know is, mechanistically, what’s going wrong with the 17 individuals? That question was not addressed.

Tuller: They seem to focus on this effort preference construct as a mechanism for something or other.

Ponting: Well, what they have is a series of observations whose interpretation is this effort preference idea. But that’s still an interpretation that can’t be falsified. And it’s the interpretation of these observations that’s engendered a lot of the controversy. I would want any interpretation to be tested further as to its validity. I don’t think that interpretation will be.

What I really wanted by the end was that they would have said, ‘We think we know what causes ME, and if we’re right, then we do this other experiment that would then say whether we’re right or wrong.’ Whereas what happened was they just offered their interpretation of the data rather than a mechanistic understanding that would lead immediately to an experiment that would decide whether it was true or false.

I like experiments that intervene, in which you can see the reactions. For example, they didn’t do a 2-day C-PET. That way you could have seen the differences within the same individuals. Experiments like that can be used to infer mechanisms, whereas direct observations can’t separate causes and consequences. The NIH effort was basically a cross-sectional study that found associations. And it’s hard to tell what they mean. So I don’t see the study as a step forward.

Tuller: So do you think it was a waste of 8 million dollars, if that’s what the cost actually was?

Ponting: That’s the number that’s being spread around. I’m an optimist. I’m not going to say it was entirely wasted. But I was very disappointed with the results. It might have unintended consequences. It may be that the response to this intramural study will trigger something which is hopefully better and more sustained and with more breadth, and focused on mechanisms

Tuller: Now that we’ve covered that, why don’t you take a moment for an update on the GWAS study and what people can expect in terms of timing?

Ponting: We recently announced that there’s been a delay in the study. It’s disappointing, because I wanted and I still want to do this project as rapidly as we can to get to the answers, whatever they are, as soon as we can. But we’ve been held back by the DNA extraction process not being as rapid as we expected. On the positive side, the funders have been great. They recognized that this wasn’t our fault and so they’ve given us enough funds for another year. The funding now finishes not this August, but August of 2025.

Otherwise, it’s coming along. All the DNA extractions will be done soon. We’ll get about 18,000 overall which is slightly smaller number than we wanted at the beginning, which was 20,000. But that’s still a huge number and represents a massive amount of energy expended by the community in the UK. And I’ll always be grateful for that.

3 thoughts on “Trial By Error: Professor Chris Ponting on the NIH’s Findings and the Latest on the Genome-Wide Association Study Update”

  1. Was the NIH study a complete waste of money? To me, no, it wasn’t, because it taught me one important thing – use broader criteria and patients without ME/CFS will slip through the net. With the criteria used, it seems that 4 patients were still mislabelled with ME/CFS even though they went through the expert panel stage too, leaving 17 remaining with supposed ME/CFS. That’s really not a good rate and I think shows that both clinical and research criteria need to be narrower. Please correct me if I’m mistaken but I understand that the DecodeME study is no better in that regard? It has a bigger cohort, yes, but what will it tell us? (Don’t get me wrong, I really hope the DecodeME study turns up something meaningful, but I’m not putting any money on it.) It’s fine for patient groups to be inclusive – patients with unresolving fatigue all suffer from the same history of woeful research in this area and many can’t know beyond doubt what caused their illness – but it surely does nobody any good to have flabby criteria that allow this level of misdiagnosis? That was my takeaway and I didn’t need to read it in depth for that to jump out at me.

  2. What I mean is, even $8 million, if that was the cost of the NIH study, would be a small price to pay if it corrects decades of misdirected international research and squandered opportunity.

  3. Lady Shambles

    I muse Colleen has really distilled what many (most?) patients, those who are mindful of the long history, politics and science of this disease, actually think about this study.

    I hope this link works, I know this site finds links problematical so I’ll hyphenate each end of the link (copy and pasting without those hyphens will be necessary): -

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