Replicated blood-based biomarkers for Myalgic Encephalomyelitis not explicable by inactivity, 2024, Beentjes, Ponting et al

[Simon M]

Did it say that there is no role for the mind? I thought it said that there is no evidence that it’s about thoughts. I’d say that’s true.

? I'm not sure what you said, I was responding to Robert.. But is surely depends on the results. If anxiety-related genes show up in DecodeME, or at least are prominent if not significant at the threshold, wouldn't that make it hard to rule out a role for them?

(I don't know what the results say about anxiety-related genes; I'm trying to figure out what evidence we would need to rule something out. But I doubt any single study, without replication, can rule anything out—and that's surely true for any finding of a modestly powered GWAS.)

 

[Utsikt]

? I'm not sure what you said, I was responding to Robert.. But is surely depends on the results. If anxiety-related genes show up in DecodeME, or at least are prominent if not significant at the threshold, wouldn't that make it hard to rule out a role for them?

(I don't know what the results say about anxiety-related genes; I'm trying to figure out what evidence we would need to rule something out. But I doubt any single study, without replication, can rule anything out—and that's surely true for any finding of a modestly powered GWAS.)

I was talking about the start of his reply:

We now have enough data to say with confidence that ME/CFS is a biological disease (or perhaps more than one disease)*. There is no doubt that ME/CFS affects the brain but there has never been any evidence that thoughts play any role in causing the disease.

He does not say that we know for sure that thoughts doesn’t play a role in causing the disease. He says that there has never been any evidence that it does.

Genes linked to anxiety is not evidence that thoughts are causing the disease. Nor are the speculations of BPS proponents. Or their questionnaires.

Robert’s statement shifts the burden of proof back to the people that made the claims - where it should be.

 

[Kitty]

I think it might be quite difficult, because proving that there isn't a substantial role for the mind might not be easy to do.

Exactly so.

Anyway, the question "Is it all in the mind?" shouldn't arise in the context of DecodeME. If it does, we can explain what a GWAS is and why it couldn't answer a question like that—even if we'd asked it, which we haven't. Obviously.

Being offered the opportunity to prove a negative is a bear trap, and we can't afford to fall into it. We have to refuse to take the bait.

 

[Simon M]

Robert’s statement shifts the burden of proof back to the people that made the claims - where it should be.

Sorry, I see what you mean. I'm not sure what case BPS proponents would make, so this feels like shadow boxing. And I don't think we can award the non-BPS view a knockout win without knowing BPS arguments. I expect that, at least, they would argue for the 'success' of CBT (which takes us back to the arguments about inappropriate controls, objective outcomes, etc, which hasn't ended the argument conclusively).

But imagine there are sub-threshold associations for anxiety-related genes or other potentially relevant ones, which would make the case arguable, especially as heritability is low, about 12% IIRC. That would counter the view that there is no evidence for thoughts playing ANY role in the illness, which is a strong claim. This is all speculative, without seeing the results, but it is hard to make strong claims without decisive evidence.

Of course, if there is no sign of anxiety-related genes (or any other genes that might be credibly argued to support a BPS role), then such a strong claim is highly plausible, though it would still await replication.

 

[Robert 1973]

That would counter the view that there is no evidence for thoughts playing ANY role in the illness, which is a strong claim.

I didn’t say that they don’t play any role on the illness. I said “there has never been any evidence that thoughts play any role in causing the disease”.

This is all speculative, without seeing the results, but it is hard to make strong claims without decisive evidence.

Absolutely, which is why I said “Depending on the the results of DecodeME”.

The DecodeME team will know the results long before they are published, which gives them an advantage over BPS critics. I also think this discussion demonstrates why it is sensible for the DecodeME spokespeople to rehearse how to respond to the type of questions they are likely to face from journalists under the influence of SMC.

Jonathan has said that he thinks we already have enough evidence to say that ME/CFS is one or maybe two diseases. I would be surprised if DecideME did not increase the confidence with which we can make that claim.

If BPS proponents want to claim that thoughts or beliefs play a causal role in perpetuating the disease(s) then the burden of proof must be placed on them to provide evidence in support of that view. I can’t see how a GWAS could provide such evidence, even if it found genes that are associated with anxiety or other psychiatric conditions, but they will probably try.

 

[Simon M]

I also think this discussion demonstrates why it is sensible for the DecodeME spokespeople to rehearse how to respond to the type of questions they are likely to face from journalists under the influence of SMC.

I agree, and that's why I was joining the discussion

If BPS proponents want to claim that thoughts or beliefs play a causal role in perpetuating the disease(s) then the burden of proof must be placed on them to provide evidence in support of that view. I can’t see how a GWAS could provide such evidence, even if it found genes that are associated with anxiety or other psychiatric conditions, but they will probably try.

GWAS are good at providing causal evidence. If there is a link to anxiety-related genes, or other relevant jeans – even if subthreshold in. DecodeME – that coup support the BPS claim to a degree. They've always accepted that they are biological triggers, so finding evidence for that in a GWAS won't cause them to change their mind. It depends what the evidence is.


Seems to me there are lots of possibilities, and it would be helpful to consider all the lines of arguments at this point. We don't know what the results are, and it's not clear what arguments psychosocial proponents will put forward.

 

[Utsikt]

Sorry, I see what you mean. I'm not sure what case BPS proponents would make, so this feels like shadow boxing. And I don't think we can award the non-BPS view a knockout win without knowing BPS arguments. I expect that, at least, they would argue for the 'success' of CBT (which takes us back to the arguments about inappropriate controls, objective outcomes, etc, which hasn't ended the argument conclusively).

No worries! I feel like Robert’s statement actually avoids their arguments and just encourages us to move one from the old ways. It’s how a politician would answer by focusing on their point.

But imagine there are sub-threshold associations for anxiety-related genes or other potentially relevant ones, which would make the case arguable, especially as heritability is low, about 12% IIRC. That would counter the view that there is no evidence for thoughts playing ANY role in the illness, which is a strong claim. This is all speculative, without seeing the results, but it is hard to make strong claims without decisive evidence.

How would the presence of anxiety-related genes be evidence that thoughts are be involved in causing or maintaining the disease?

Of course, if there is no sign of anxiety-related genes (or any other genes that might be credibly argued to support a BPS role), then such a strong claim is highly plausible, though it would still await replication.

You only need replication for definitive proof of absence. The suggested argument is that there is no evidence for presence. If there are no BPS-related genes (whatever that may be) in DecodeME, there would not be any evidence for the BPS view.

 

[Utsikt]

For future reference, here is a recent study on genes and anxiety:

https://www.s4me.info/threads/gene-discovery-and-biological-insights-into-anxiety-disorders-from-a-large-scale-multi-ancestry-genome-wide-association-study-2025-friligkou-et-al.44724/

 

[Trish]

GWAS are good at providing causal evidence. If there is a link to anxiety-related genes, or other relevant jeans – even if subthreshold in. DecodeME – that would support the BPS claim.

I'm not sure I follow the logic of this. I would not expect there to be a single gene found that on its own causes ME/CFS. I thought the point was to look for multiple genes that indicate particular pathways are affected. So if genes A to H are implicated in ME/CFS, and genes D and K to S are implicated in anxiety, the fact that gene D is implicated in both doesn't mean ME/CFS is caused by or related to anxiety directly. Or have I oversimplified that to absurdity?

Also I don't think there's any reliable direct evidence that having an anxiety disorder predisposes to getting ME/CFS. I think Leonard Jason's study that tested students before they got EBV induced ME/CFS found no predisposing increase in psychiatric symptoms. And studies of pwME using the whole SF-36 set of questions only found the physical function related parts were higher in pwME than controls, not the psychosocial ones.

 

[Jonathan Edwards]

'DecideME', exactly.

 

[Jonathan Edwards]

And I don't think anybody is going to find anxiety genes. Most of the brain genes that have been linked to disease are linked to all sorts of things and mostly not anxiety.

Edit: at least until September last!

 

[dave30th]

However, I think it would be worth spending some time working out how best to respond to that type of questioning (eg Are you claiming this proves it’s not all in the head? … It’s a combination of physical and mental, isn’t it?)

I think you say something like, Of course emotional/mental states can impact ongoing disease processes, but that's very different from claiming that they cause the disease in the first place. With ME, the goal is to find the pathophysiological mechanisms behind the symptoms while also paying attention to emotional/mental fall-out that also needs to be addressed.

 

[Hutan]

If anxiety-related genes show up in DecodeME, or at least are prominent if not significant at the threshold, wouldn't that make it hard to rule out a role for them?

I think we'd have to think about how a particular gene might have been linked to anxiety in other genetic studies.

Turning up to the doctor with vague symptoms, fatigue, generalised pain, is going to have many doctors assuming they have a case of MUPS on their hands, and they have been educated that anxiety and depression are part and parcel of MUPS. If the person says they are worried and feeling sad, they may well accumulate diagnoses of depression and anxiety disorder in their diagnostic odyssey.

Someone might have a chronic illness and be worried - we've seen the anxiety surveys that ask questions like 'do you keep worrying about the future?' 'are you worried about your health?'. There are many situations where being worried is the normal and healthy response; it is wrong to see that as a diagnosable disorder, but unfortunately that happens.

Someone might have cardiovascular problems that create feelings of anxiety, for example, low blood supply to the brain, and so be diagnosed with anxiety, even though the symptoms are not caused by faulty thinking.

It is possible that some people with other health conditions including anxiety and depression are misdiagnosed as having ME/CFS.

(Probably even just being a woman is correlated with being given an anxiety diagnosis, and probably being a woman is correlated with being given an ME/CFS diagnosis. Therefore, being given an anxiety diagnosis is correlated with being given an ME/CFS diagnosis.)

For those reasons, I would not be at all surprised to find that some of the genes associated with diagnoses of anxiety and depression are also associated with diagnoses of ME/CFS. I expect the DecodeME people are aware of these biases and can highlight them, should that be necessary.

 

[Utsikt]

Good point, @Hutan

The ways we measure anxiety for research purposes has a lot of false positives for ill health, poor socioeconomic circumstances, etc. due to the way the questionnaires are worded. The same goes for diagnoses by practitioners that are used inappropriately.

 

[rvallee]

Sorry, I see what you mean. I'm not sure what case BPS proponents would make, so this feels like shadow boxing. And I don't think we can award the non-BPS view a knockout win without knowing BPS arguments.

Having read BPS arguments for the last 8 years, across hundreds of papers, presentations, educational material and so on...

I have no idea what those views are, and I don't think they do either. I have never seen a coherent argument for them, and don't think there is such a thing. As you said, it's more like boxing shadows, they simply take the form of whatever reality isn't, forever out of reach.

 

[Robert 1973]

Of course emotional/mental states can impact ongoing disease processes,

I don’t think I would say that – a bit too close to saying that unhelpful thoughts can perpetuate the illness for my liking!

 

[Utsikt]

I think you say something like, Of course emotional/mental states can impact ongoing disease processes, but that's very different from claiming that they cause the disease in the first place.

That’s what Wyller is saying, that ME/CFS is a stress response that’s being perpetuated by thoughts and behaviours. Any trigger/cause will do in his model.

 

[Turtle]

I don't understand the anxiety gene being such a big thing. So what!!
Let all the other genes do the talking. BPS is worried, why should we. I stopped taking that crowd serious anyway.

The only thing they've ever done is claiming ME/CFS is psychological because the doctor's tests didn't show anything.
Maybe( most probably) the doctor did not order the right tests.

I had CPET just 40% VO2max, exercise intolerance, check, AT at 1 1/2 minute, metabolic problems, check.
Tilt table test, -25% CBF, OI, check. No NK-cell reactivity, CD4-CD8 numbers upside down, immuun problems, check.
High lipids, no high cholesterol, check.

And above all a proper assessment by a proper psychologist. No questionares, but DSM 3 and 4.
"No disorder was found that could cause or continue the complaints".

Nothing has been proven, many members say, o yah, I did as n=1

 

[Trish]

Perhaps one way to argue is to see if the anxiety related genes also turn up in the genetic predisposition for other physical diseases.

 

[Robert 1973]

'DecideME', exactly.

Sometimes autocorrect is genius. My favourite was when it changed Wessely to Weaselly

I’m also liking the new emoji range. I see @Trish has one for herself