Replicated blood-based biomarkers for ME/CFS not explained by inactivity [preprint], 2024, Beentjes et al

[kushami]

https://meassociation.org.uk/2024/0...rkers-for-me-cfs-not-explained-by-inactivity/

Myalgic Encephalomyelitis (ME; sometimes referred to as chronic fatigue syndrome) is a relatively common and female-biased disease of unknown pathogenesis that profoundly decreases patients’ health-related quality-of-life.

ME diagnosis is hindered by the absence of robustly defined and specific biomarkers that are easily measured from available sources such as blood, and unaffected by ME patients’ low level of physical activity.

Previous studies of blood biomarkers have not yielded replicated results, perhaps due to low study sample sizes (n < 100). Here, we use UK Biobank (UKB) data for up to 1,455 ME cases and 131,303 population controls to discover hundreds of molecular and cellular blood traits that differ significantly between cases and controls.

Importantly, 116 of these traits are replicated, as they are significant for both female and male cohorts. Our analysis used semi-parametric efficient estimators, an initial Super Learner fit followed by a one-step correction, three types of mediators, and natural direct and indirect estimands, to decompose the average effect of ME status on molecular and cellular traits.

Strikingly, these trait differences cannot be explained by ME cases’ restricted activity. Of 3,237 traits considered, ME status had a significant effect on only one, via the “Duration of walk” (UKB field 874) mediator. By contrast, ME status had a significant direct effect on 290 traits (9%). As expected, these effects became more significant with increased stringency of case and control definition.

Significant female and male traits were indicative of chronic inflammation, insulin resistance and liver disease. Individually, significant effects on blood traits, however, were not sufficient to cleanly distinguish cases from controls. Nevertheless, their large number, lack of sex-bias, and strong significance, despite the ‘healthy volunteer’ selection bias of UKB participants, keep alive the future ambition of a blood-based biomarker panel for accurate ME diagnosis.

 

[kushami]

My summary:

Researchers found 116 differences in molecular and cellular blood traits between ME/CFS blood samples and healthy control blood samples taken from the UK Biobank.

These differences could not be used to say whether one person did or did not have ME/CFS, but were significant enough to clearly distinguish the two populations.

The 116 differences point to chronic inflammation, insulin resistance and liver disease, among other things. None are connected to inactivity.

 

[Blazer95]

thanks for sharing but i cant believe we still talk about me/cfs about being a psych problem.

the evidence is 120% clear.

 

[linusbert]

thanks for sharing but i cant believe we still talk about me/cfs about being a psych problem.

the evidence is 120% clear.

the evidence is, that its 100% a psych problem , but not on the patient side

 

[Oliver3]

Isn't this describing metabolic syndrome?

 

[southwestforests]

the evidence is, that its 100% a psych problem , but not on the patient side

 

[southwestforests]

thanks for sharing but i cant believe we still talk about me/cfs about being a psych problem.

Indeed.

Dad and I were several days ago reviewing his experience of being diagnosed with ME/CFS in the mid 1980s by US Military doctors and psychiatrists in Virginia.

WAY BACK THEN the psychiatric doctors and medical doctors both said, declared, asserted,
SHOWED,
that ME/CFS WAS NOT psychiatric/psychological in its origin.

DO YOU UNDERSTAND THAT - IN THE 1980s !!!

And here 40 years later, FORTY YEARS LATER!!!, the civilian medical industrial establishment is STILL populated by a bunch of natural born arrogant idiots.

And I encounter them.

And it causes health care problems.

There is a lot said both positive and negative about military and specifically Veterans Administration, VA, health care.
And it is true that WW2 veteran Grandfather W had some bad experiences.
But, damn, sam, my Dad gets magnitudes, MAGNITUDES, better ME/CFS health care from the VA than I have EVER gotten from civilian doctors and paid for by Mediwedontcare and Medicaintnoaid.

Then again, he WAS their first medical retirement with that and fibromyalgia, so I suspect he is to this day something of a guinea pig and research subject.

Last I saw his medical records at a disability review hearing something like a decade back they were 3 feet thick from all the documentation of all the tests and investigations and treatments.

Last I saw my medical records before they went all electronic they were something like 3/8 an inch thick.

AND ...

Those military doctors have known, KNOWN, something was wrong with his blood all this time.
Last I heard a few months ago, they still do not know what exactly it is, or why it is, but they KNOW something in his blood is dysfunctional because there are tests which show it.

Well, this has gone down an unplanned path and turned in to something of a resentment laden rant.
Oh well, it is what it is.
And I am an unhappy camper who has been documentably harmed by supposed "health care".
And I resent that.
Really, really, really, resent that.

 

[bad1080]

None are connected to inactivity.

of the patient, a gene or something else?

 

[kushami]

of the patient, a gene or something else?

Of the patient. Their point being that you can’t explain away the differences between the healthy controls and the ME/CFS samples by saying the differences are caused by inactivity.

I don’t know the details of how biomarkers could be affected by inactivity, but I’m sure there’s been plenty of research on it.

The point is that the 116 differences they found were due to the illness itself, not to patients being inactive.

I imagine the reason they stressed this was to strogly refute the wrong idea of saying that people caused the illness themselves by staying in bed.

 

[kushami]

Summary article that explains a bit more:
https://meassociation.org.uk/?p=140811

Can anyone find a simple list of the 116 traits? I want to read them out of curiosity but the paper is a bit too mathematical/statisticky for my brain to find this info. Presuming it might be in one of the appendices, which are spreadsheets.

 

[kushami]

I wish @Pyrrhus were here to provide some pithy comments.

 

[Mary]

Those military doctors have known, KNOWN, something was wrong with his blood all this time.
Last I heard a few months ago, they still do not know what exactly it is, or why it is, but they KNOW something in his blood is dysfunctional because there are tests which show it.

Would it be possible to find out exactly what those tests are? Because I think for most of us, our standard blood work always looks normal. So apparently your father's doctors have done testing that very few, if any of us, have had done.

 

[Mary]

Significant female and male traits were indicative of chronic inflammation, insulin resistance and liver disease.

This doesn't seem meaningful to me. Millions of people have insulin resistance from eating the wrong foods, millions are diabetic etc. But they don't have ME/CFS. And chronic inflammation can go hand in hand with insulin resistance. And my liver seems to be just fine - my numbers are always in the good range.

I wish something else had shown up!

 

[southwestforests]

Would it be possible to find out exactly what those tests are?

I've not had luck there so far. I do not have direct access to those doctors & Dad is dealing with effects of dementia and earlier this year a stroke.

 

[Mary]

I've not had luck there so far. I do not have direct access to those doctors & Dad is dealing with effects of dementia and earlier this year a stroke.

Sorry to hear about your dad. I'm sure you've probably already looked into this, but it seems it would be a good idea to get a medical power of attorney for him, if you're able to do so - just for his medical care, if not accessing his records, though it might give you access to his records.

 

[southwestforests]

it would be a good idea to get a medical power of attorney for him

Done several years ago, my brother in Tennessee has that, even being a disabled vet himself he is by far the healthiest and most able of the four of us.

 

[Eastman]

... Millions of people have insulin resistance from eating the wrong foods, millions are diabetic etc. But they don't have ME/CFS...

Liver disease could be a necessary but not sufficient condition for ME/CFS.

... And my liver seems to be just fine - my numbers are always in the good range.

Are your albumin numbers also just fine?

 

[Mary]

Are your albumin numbers also just fine?

I don't think I've ever had this test. I don't have any symptoms of liver disease. Appetite and digestion are fine, as is blood work.

 

[Mary]

@Eastman - you might find this interesting: https://forums.phoenixrising.me/thr...ers-for-me-in-big-data-pre-print-study.92816/

David Tuller, noted, very knowledgeable and long-time ME/CFS advocate, interviews one of the study authors, Chris Ponting about the study. Here's a little bit of what Ponting had to say in the interview:

I don’t think it would be all that surprising if people who had chronic inflammation in the body, with reduced liver function or whatever, felt chronically fatigued. I wonder then – could this study be picking up on a group of people who could possibly be a different group from those who have post-viral chronic fatigue? To my mind, the diagnosis of ME/CFS has been so lazily and liberally applied by doctors that just going by patients reporting that they have a CFS diagnosis probably doesn’t mean all that much. However, it sounds to me like a distinct group has been identified here and if that leads to some sort of biomarker panel that can pick out that group, then that has to be a good thing. The question then would be, what happens to all those patients with ME/CFS diagnoses whose results don’t come back positive with that panel of tests? I’m sure there will be a very large number of them. This marks a good start I think but, from my own experience, it’s extremely easy to get diagnosed with ME/CFS when your symptoms are completely different – and I mean miles apart – from others who have the diagnosis. It’s a massive mess that needs sorting but this does seem to me to be a good step in the right direction (and it’s nice to know that no link was found to inactivity/deconditioning).

So apparently the patient cohort used in the study were not rigorously screened to meet a strict ME/CFS criteria. As B. Rob noted in the interview:

I’m a tad disappointed the biobank didn’t screen for a strict ME/CFS criteria. Preferably the Canadian Consensus Criteria. As those that have self diagnosed or been incorrectly diagnosed do create unnecessary noise in studies.

It's very true if someone has liver disease they're going to be fatigued and probably have inflammation, etc. But that's not ME/CFS. And if liver disease were part of the criteria for ME/CFS I think we would have many many posts by people with symptoms of liver disease, which we don't.

 

[Eastman]

So apparently the patient cohort used in the study were not rigorously screened to meet a strict ME/CFS criteria...

This does create uncertainty in the finding, but apparently not enough for Chris Ponting to actually say that the identified markers are not applicable to ME/CFS, only that there may be a different subgroup.

And if liver disease were part of the criteria for ME/CFS I think we would have many many posts by people with symptoms of liver disease, which we don't.

Just because they don't say they have symptoms of liver disease does not mean they don't. In reality, many symptoms reported in this forum overlap with symptoms of liver disease. Most people simply aren't aware of the possible link because they think that the liver is simply for digestion and detoxification.

Note that this paper is in line with the model proposed by mariovitali that ME/CFS is the result of an infection in a patient with liver dysfunction, a model based on his AI-based research. The more I know about the liver, the more I see the plausibility of this model and I think researchers should explore this lead further. Remember that most people with the infections that are thought to lead to ME/CFS don't end up with the condition. Clearly, there is a differentiating factor in those who do and we need to find out what that factor is.