Biomarkers for ME/CFS - discussion thread on the next steps for testing biomarkers, and why we need them

[EndME]

Jarod Younger was saying on youtube recently (2024 Stanford ME/CFS meeting) that different working groups are seeing subgroups with tests showing different pathologies.

If one does identify pathologies that seems to be the more likely scenario to me.

However, for the previously mentioned studies it would appear that this scenario is unlikely to be the case as we have seen over and over again, as it is far more likely that those studies have neither identified different subgroups nor different pathologies and are far more likely to have accidentally identified different sources of noise and then grouped those noises into arbitrary subgroups without actually having ever found a signal in the first place.

 

[Kitty]

Jarred Younger's talk made me wonder about subgroups, which are presumably common in all kinds of disease.

But in chronic conditions, can subgroups usually be identified reasonably reliably before a genetic susceptibility, a pathological mechanism, or a drug treatment is found?

Or is identifying them more a consequence of one or other of those?

 

[Eleanor]

like Type 1 and Type 2 diabetes maybe?

 

[Mij]

They've done studies using the term "type 3 diabetes" to describe Alzheimer's that involves the brain and has molecular and biochemical features that overlap with both types of diabetes.

 

[tuppence]

This is a pervasive myth. I worked on rheumatoid arthritis for 35 years and we made huge progress - enough to keep almost all patients well all the time. But there is no diagnostic test for rheumatoid. GPs think there is and that is a huge problem because people with rheumatoid with negative tests (a significant proportion early on) can get sent away without a diagnosis.

If patients are not being diagnosed in good time it is because doctors are not trained properly to listen to the symptoms. A test doesn't help make them better doctors.[

But being sent away from the GP’s and clinics with an unsubstantiated and unexplained diagnosis of Psychological ME/CFS because as they have repeatedly held over us for the last several decades there is no biomarker diagnostic test for the illness, is the reality of the patients and their carers experience of the common HCP’s reaction to their symptom presentation.

Your’s and your colleagues huge success in treating rheumatoid in those same decades is to be congratulated and is undoubtedly an example of medicine at its very best.

It highlights however Medicines complete failure over those same decades not just to fail to find any effective treatments for ME/CFS, but also that they are putting forward a false narrative of lack of biological markers to support a psychological misdiagnosis and mistreatment of an illness ME/CFS, which is considered by many HCP’s to be as disabling as the severest of other illnesses.

The medical profession can’t have it both ways. You highlight this disparity of treatment outcome across illness as being because Doctors are not being trained properly. This begs the question of what is the actual training deficit for Doctors and why is it not being addressed by those responsible for setting medical standards of clinical practice and ensuring that training of Doctors allows/requires them to meet those standards.

 

[Trish]

I get the argument that really well trained doctors don't rely on biomarkers for diagnoses.

But most of us in the UK with ME/CFS only have access to GP's who are clueless about diagnosing and managing ME/CFS, and persist in seeing us as having psychosomatic tiredness, and telling us to try to get more exercise, and referring us to therapist run clinics spouting misinformation and advising pacing up.

In that context surely it is understandable that we long for a biomarker that makes it clear our disease has a biological basis. I long for the day when a GP looks at my blood test results, and says, your test shows you have ME/CFS, hands me a sensible guide to pacing, and offers to support my application for benefits, and the benefits agency lists the positive test result as grounds for awarding benefits.

Of course, even more importantly, I long for the day when whatever biomarkers are found indicate a route to effective treatment.

If it turns out treatment comes before biomarker, even better, as effectiveness of a biomedical treatment is in itself a sort of biomarker.

 

[hotblack]

It feels like we’re trying to solve two different problems with two different tests. One is to help with what has gone wrong within our bodies. The other is to help with what has gone wrong within the healthcare system.

In an ideal world the latter could and should be fixed in more appropriate ways, but we are where we are I guess. I see some irony in wanting to fix a psychological and social problem within the medical establishment with a biological test. You’ve got to see the funny side sometimes…

 

[Jonathan Edwards]

But being sent away from the GP’s and clinics with an unsubstantiated and unexplained diagnosis of Psychological ME/CFS because as they have repeatedly held over us for the last several decades there is no biomarker diagnostic test for the illness, is the reality of the patients and their carers experience of the common HCP’s reaction to their symptom presentation.

Yes, but you have to factor into this the fact that human beings think they know how they are making decisions but very often get that wrong. Doctors are a prime example. There was a very nice paper in the 1980s by John Kirwan that showed that rheumatologists do not actually make decisions the way they think they do. Their explanations to patients do not actually reflect the way they have come to a decision.

So when GPs say there is no diagnostic test for ME/CFS (if in fact they do) what they are really saying is that there are no tests that show that something is wrong with your physiology. In rheumatoid if the CRP level is 55 then the GP will say to themselves "there's something pretty bad going on here, better ask a rheumatologist". But CRP is not a diagnostic test for RA.

GPs do think that they are doing 'diagnostic tests' much of the time. But the supposed diagnostic test for RA, the rheumatoid factor, is in fact so unreliable that more people without RA have a positive test than people with RA. GPs shouldn't even use it because it is only of value when interpreted in the context of specialist knowledge.

So we have a combination of doctors not using tests very expertly and also misunderstanding the way they use tests ,even when it is sensible.

People raise the question as to why doctors are not trained to think more clearly. Sadly, I think the reality is that most human beings don't think very clearly and that however much you teach them how to, a large proportion never change much. And of course you need the trainers to think clearly, and the trainers are mostly the second rate academics who got dumped with the training schedule because they don't have much research.

It is all very complicated, but the point remains that when scientists start looking for test results that might move us forward both with understanding ME/CFS and making it credible (because it is partly understood) they need to be aware that looking for 'diagnostic tests' is a red herring. Biomarker is a less loaded term but I never use it because it is almost as bad - a buzz word from the 1980s that just means an abnormal test result.

So I think it is worth pointing out to scientists that we are not looking for a diagnostic test. Trying to persuade GPs that what they think they use as a diagnostic often isn't in fact a diagnostic test is probably hitting one's head against the wall.

The real problem as I see it is that any young person with intelligence these days goes into making money rather than science. The razor sharp intellects of clinical science of the 1970s no longer exist as far as I can see. They are all working for Goldman Sachs. Which is why almost no progress has been made in many fields of medicine in the lat 20 years - with the main exception of cancer with the benefit of DNA work.

 

[Jonathan Edwards]

Maybe one simple way to put the point is that if a test T is found reliably to show up in a reasonable proportion of people with ME/CFS it will be a sort of 'diagnostic test' but a diagnostic test for type T ME/CFS and whether or not 95% of people with ME/CFS have it doesn't matter. Further research will be on type T ME/CFS and non-T ME/CFS separately.

 

[rvallee]

If it turns out treatment comes before biomarker, even better, as effectiveness of a biomedical treatment is in itself a sort of biomarker.

Probably even more important. If Marshall's team had been able to show that ulcers are likely caused by bacteria but didn't go through the extreme step of curing it on himself, providing an effective treatment, it likely would have been dismissed for years until a series of trials would have provided the evidence, which likely would have been delayed by institutional paralysis trying to avoid embarrassing the profession.

It's not enough to convince MDs. Here they have to face the fact that they have been catastrophically wrong and caused immense harm for decades, the bar is raised impossibly high for us for that reason. Which was also the case with ulcers, and it took effective treatments to get over the last hurdle.

For that reason I doubt that even with a clear biomarker anything changes for patients. Research can finally get going, if it gets funded, but until there's effective treatment, I strongly doubt it. We have to clear the ego hurdle and it's the tallest one of all.

 

[Hoopoe]

If we only need some way to show that physiology in ME is abnormal, then the 2-day CPET, invasive CPET, and hypoperfusion findings should offer something good enough? Or is it not good enough yet?

 

[Jonathan Edwards]

If we only need some way to show that physiology in ME is abnormal, then the 2-day CPET, invasive CPET, and hypoperfusion findings should offer something good enough? Or is it not good enough yet?

I think the two problems with the CPET findings is that 1) they are not consistent across the patients - different patients show different patterns, even if mean values for the group are different. 2) Although findings do not seem to be attributable simply to inactivity they may nevertheless indicate some downstream change due to shifts in muscle usage patterns or some other knock-on effect from whatever is causing symptoms. A test that helps us understand has to fit into some reasonably obvious causal story.

I don't think evidence of hypo perfusion has been replicated sufficiently for us to have confidence in its reality. And again, posture and activity changes might have a knock-on effect on circulation.

 

[Nightsong]

Although that golden age of medicine is over I think progress may well still come about not merely from genetic studies but also from combining various large data sources with advanced analytic techniques; the recent schizophrenia paper is a reasonable example of that, coupling large-scale genetic & transcriptomic datasets so as to identify relevant molecular pathways in the context of an illness where large numbers of genetic variants have been previously identified but understanding their functional impact has been difficult.

As for the CPET results there may be between-group differences but they're not particularly striking and don't seem to correlate well with illness severity. And the hypoperfusion studies: in addition to being less than robust if cerebral hypoperfusion was the result of some unknown pathomechanism underpinning ME/CFS, wouldn't we also expect some cases to spin sufficiently out of control to result in ischaemic injury?

 

[bobbler]

As long as a disease like ME/CFS remains contested, a diagnostic test can benefit patients. With disability and health insurance claims challenged far too frequently, and a skeptical public that can include family and friends, a diagnostic that can rise above those challenges would be welcome. It has been MIA for too long.

I’m not 100% sure. I think those who do that to us just reach gif that one as stage one in sophism it doesn’t mean if you fix it they will shut up.

it won’t make them think the illness is as devastating as it is, or stop them choosing to be persuaded that whatever caused the symptoms it’s thinking that can fix it or be the difference between being the ‘lying bed’ type and the ‘goes to work and looks normal’ type (even though that type has a screaming body they know is being made worse and are being coerced by nudges based on the ‘not that bad/psychosomatic’ bs.

peoples attitude might change when we find things that seem treatable one day and outs under under a specialty that then is actually genuinely interested in how we do outcome wise rather than rehab using us as puppets knowing full well being made to do more and say we feel more hopeful after three months with huge dollops of coercion and social pressure isn’t that , but it makes for a nicer careeer maker to make claim of ‘dealing with’ these people for society

with the required pretence we are consenting and happy even though it’s just surrounding us with people conning us to do the wrong thing gif our bodies so they tint have to care then forcing us to ‘smile’ because we are scared of the threats so everyfeels better and that pretence they are ‘doing good’ because some are happy snd it’s not just traumatising people means they can keep their conscience clean and claim it’s ‘help’.

when there is an actual scientific tests that can show the illness getting WORSE however that might help , because it then helps at least debunk the naff Kidd yourself treatments and all their claims and gives clues that back up what we might say about smaller things that might help some of us. We’d actually be able to measure the underlying ‘thing’

so there’s a fine line. But looking fir a positive/negative isn’t as much of a game changer as other things could be

anything finer might be helpful for research however? Anything with real clues to help understanding probably better. I don’t know whether you get to choose any of this or these things pop out as they do when you are looking for all three in a general ‘what is this thing’ anyway?

 

[bobbler]

The pathophysiology of delayed PEM biomarker would be very useful. Early signs of molecular changes that occur that could possibly prevent harm and worsening before they occur would be very helpful.

Agree on this. I think demonstrating the full cycle of PEM and nailing if possible the link to deterioration is important

 

[bobbler]

It feels like we’re trying to solve two different problems with two different tests. One is to help with what has gone wrong within our bodies. The other is to help with what has gone wrong within the healthcare system.

In an ideal world the latter could and should be fixed in more appropriate ways, but we are where we are I guess. I see some irony in wanting to fix a psychological and social problem within the medical establishment with a biological test. You’ve got to see the funny side sometimes…

Spot on

 

[bobbler]

Probably even more important. If Marshall's team had been able to show that ulcers are likely caused by bacteria but didn't go through the extreme step of curing it on himself, providing an effective treatment, it likely would have been dismissed for years until a series of trials would have provided the evidence, which likely would have been delayed by institutional paralysis trying to avoid embarrassing the profession.

It's not enough to convince MDs. Here they have to face the fact that they have been catastrophically wrong and caused immense harm for decades, the bar is raised impossibly high for us for that reason. Which was also the case with ulcers, and it took effective treatments to get over the last hurdle.

For that reason I doubt that even with a clear biomarker anything changes for patients. Research can finally get going, if it gets funded, but until there's effective treatment, I strongly doubt it. We have to clear the ego hurdle and it's the tallest one of all.

I agree. But do make the point that in Uk ulcer treatment or people who are young and get barn door ulcer symptoms are seemingly pushed down a pathway assuming ‘it’s stress’ first - I say first because quite quickly they end up in hospital visiting blood and it seems investigation there goes from the other end looking at worst possibilities first.

Maybe them taking the antibiotics are bad too literally too has been part of this.

here a test would help and it may exist but isn’t being done. And yes you add it up and is gp appt are expensive and short in supply the ‘go away for two weeks’ approach is more expensive than the treatment fir pylori on its own. I t do not know whether this attitude to this finding continues in hospitals here.

there is something afoot here with gp control having pushed ‘stress first’ onto all gps through them being controlled by decision trees they must follow.

 

[rvallee]

Although that golden age of medicine is over

I'd say the easy age of medicine is over. The golden age is yet to happen. It's missing a key piece of technology: AI. Medicine won't really be viable until AI in a similar way as engineering couldn't take off before computers. Not just research but especially clinical medicine. Everything is in chronic shortage.

There was a time around the early 20th century and up to a bit past the middle when making major discoveries was like shooting fish in a barrel. But most of it was pure chance. It was the easy stuff. Easy-ish, anyway. There was a similar time in physics, when 1-2 people could work and discover a few elements or other discoveries that changed everything. Now physics projects can involve thousands of people and take many decades. Medicine hasn't gone through that transition yet, hasn't developed the tools and methods for it.

The rest is hard. It needs better tools, and they're not ready yet. Bit funny that medicine is one of oldest disciplines. It shows. Damn does it show.

 

[dratalanta]

It feels like we’re trying to solve two different problems with two different tests. One is to help with what has gone wrong within our bodies. The other is to help with what has gone wrong within the healthcare system.

That’s how I see it too.

The difference between a blood test and a patient history is that patients do not have conscious control over their physiology.

A test that differentiates ME/CFS patients from sedentary controls but does not identify the cause will not prove that ME/CFS is not psychological. But it would suggest that individuals with a positive result are not lying about their experience.

There is a grey area in many doctors’ minds between somatisation and deceit. While doctors may refer to the ostensible BPS model of ME/CFS as illness without disease, many clinicians treat individual patients as if they are exaggerating ordinary sensations or indeed actively fabricating and misrepresenting symptoms.

We know a test will be considered useful for patients’ experience of interacting with the world because people are already arranging private 2-day CPETs. Not only does that test provide no information about the illness that was not available from asking the patient; it also induces PEM and so has medium-term harmful effects on all but the most mildly affected patients. Nonetheless patients are asking for that test (and in some cases are asked to provide ot by insurers) because it shows they are telling the truth when they describe the sensation of physical exhaustion as part of PEM.

It is regrettable that this is the starting point for many patients’ interactions with doctors. In an ideal world, patients would be asking researchers to focus on identifying the causes of the illness, not on helping individuals to convince their family doctors they are not making it up. But here we are - and so long as there is societal support for the sick and disabled for which medical gatekeeping is required, here we will remain.

 

[Robert 1973]

I have often written that we need investment in research to develop diagnostic tests and treatments.

What I mean by that is that we need tests which show physiological abnormalities which will 1) enable doctors to make more specific and accurate diagnoses, and 2) help scientists to develop effective treatments.

Any diagnostic test which enabled doctors to differentiate a subgroup of patients with ME/CFS (however large or small) who have a different pathology to other patients with ME/CFS would be extremely useful. Even if it didn’t point to any particular abnormal pathology or physiology, and even if there were no treatments, a diagnostic test or tests that enabled doctors to make more accurate prognoses would make a huge difference.

We know that many people recover from post-viral syndromes within 2 years but that recovery is rare thereafter. If a hypothetical diagnostic test of any sort could differentiate between post-viral illness that resolved within 2 years and that which doesn’t – that would be huge. (I’m not convinced it that his could not already be done by observation if there were more physician-led clinics, with specialist research nurses, studying these illnesses properly.)


Some people seem to mistakenly use the terms “diagnostic test” and “biomarker” synonymously. To me, we need to identify both. Identifying biomarkers will improve understanding of what is going wrong in people with ME/CFS. If those biomarkers could be used as diagnostic tests (ie to make more accurate or specific diagnoses and/or more accurate prognoses) that would be even better.

NB When I refer to making more accurate diagnoses, I don’t mean identifying “real ME”. Anyone who meets any of the useful diagnostic criteria for ME/CFS has ME/CFS by definition. But diagnostic tests might enabled us to give different subgroups of people with ME/CFS different, more specific diagnoses. We also know that many people are misdiagnosed with ME/CFS and later found to have a different condition which is causing their symptoms. Diagnostic tests should help to reduced misdiagnosis.