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

Abstract

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.

Version 1: https://www.medrxiv.org/content/10.1101/2024.08.26.24312606v1

Version 2: https://www.medrxiv.org/content/10.1101/2024.08.26.24312606v2

 

Twitter thread from Chris Ponting

"#ME is clear to see in the blood of 1,455 #pwME <New Preprint, not peer reviewed> 116 blood molecules or cells are significantly different between #pwME and population controls & in both females & males & these differences are NOT due to inactivity 1/4

Only for a handful of 3,237 blood traits was ME’s effect explained partially by inactivity. By contrast, ME had a significant direct effect - not due to inactivity - on 290 traits. Note: no single trait/molecule can cleanly distinguish #pwME from controls 2/4

For this we used up to 1,455 #pwME in UK Biobank and 131,303 controls – the largest ME blood ‘omics study to date. Results were highly reproducible between females and males indicating that female and male ME are similar 3/4

Such a large number of replicated and diverse blood biomarkers that differentiate ME cases from controls should now dispel any lingering perception that ME is psychosomatic This was a fab collaboration including @AvaKhamseh, @nshejazi and Sjoerd Beentjes. 4/4"

 

"Cases self-reported a diagnosis of ‘Chronic Fatigue Syndrome’ (CFS) in verbal interview at their first visit to a UKB Assessment Centre (UKB field 20002); also, either they answered “Yes” to the question “Have you ever been told by a doctor that you have Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?” in the ‘Experience of Pain Questionnaire’ (PQ) (2019-2020) (UKB field 120010), or they did not complete the PQ. They further reported an overall health rating (UKB field 2178) of ‘Poor’ or ‘Fair’ at baseline, and were of known genetic sex"

 

It would be interesting to know what some of these molecular are.

 

Is this as groundbreaking as I'm hoping? How impactful do we expect this to be? I don't know how to put this research into context.

 

Another question I have…How feasible or indeed useful would it be to reproduce this with UK ME CFS Biobank samples? Or other international biobanks?

 

I think this data is from the UK biobank.

 

I may be wrong and the naming gets confusing but this looks like the larger UK Biobank rather than the smaller ME focussed UK ME CFS Biobank.

 

Ah ok, I didn't know those were separate things.

 

There looks to be more detailed info in the paper although I’ve only had a quick look.

 

I think it’s very important as perhaps the final nail in the coffin of the deconditioning hypothesis. Inactivity accounted for very little of the differences between people with CFS/ ME and healthy controls.

Without having comparable data for psychological illnesses such as depression, it’s stretching a point to say that it shows ME is not psychosomatic.

this is a big data study, with over 1300 patients. I’m not up with the latest size of the UK ME/CFS biobank, but I think it’s around a few hundred? That’s probably not enough to detect most of these differences. But because their patients will be more severe and much better diagnosed, it might give a stronger signal.

There is data in the paper, starting with figure 2 a. I believe there are also supplementary tables, possibly in the PDF.

https://www.medrxiv.org/content/10.1101/2024.08.26.24312606v1.full.pdf

 

This link has the same Twitter thread but also contains the figures
https://threadreaderapp.com/thread/1828809116745351582.html

 

One more study suggesting impaired liver function. Perhaps the time has come to perform Fibroscan tests in ME patients.

 

It's great to see mathematicians getting involved, but it seems the first author, a post-doc, might only be tangentially involved with ME work at Edinburgh. On first look this seems like high-quality work. Also it's weird seeing a paper on ME typeset in LaTeX.

 

from the paper

Another thought/question I have is how much these fundings correlate with results from the Raman spectroscopy study from a while back (https://onlinelibrary.wiley.com/doi/10.1002/advs.202302146) which I seem to remember showed changes around lipid metabolism as well as other changes.

 

It's great to see new people getting involved in ME - this is exactly what the field needs, and hopefully there will be more new faces - and more from those just starting to publish in ME. Chris Ponting has got new people intersted.

 

As an author, I'd really welcome any suggestions that might improve how this paper describes the science - including, for example, citations in the Introduction. We'd like to improve it before it is submitted to a journal for peer review. Please do email me, but my apologies in advance if I don't get back to you quickly. Thanks.

If I may I'd like to say how this project came about. First came Simon McGrath's clear view of the non-biomedical hypotheses of ME, including the proposed influence of deconditioning on ME symptoms. I next introduced this to Sjoerd and Ava (who are both exceptionally talented early career group leaders at the University of Edinburgh). They drew the diagram in Figure 1 which showed how the analysis should be done. Julia and Amanda worked over a summer to implement models, and Nima worked with Sjoerd & Ava on these too. Gemma provided important insight into how ME case (and control) definitions could be improved. This is an excellent example of interdisciplinary research. Except for Gemma's PhD stipend, this project was not funded, instead relying on much working-outside-of-hours with long discussions. I am proud that - with Ava and Sjoerd (and Gemma) - we continue to work on other ME studies as swiftly as we can.

 

At first glance this looks like a very useful piece of work, & excellent that others are becoming involved in ME research at Edinburgh. I was also struck by an ME paper being produced in LaTeX!

I haven't been able to read through it thoroughly yet but skimming through I was very curious about the statement that "primary biliary cholangitis is accompanied by. . . post-exertional malaise [51]". Ref 51 is to Jopson et al. "Understanding and Treating Fatigue in Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis" (Clin Liver Dis 20 (2016) 131-142). It is not open-access so here are a few snippets:

I'd note three significant differences between what is described here and the PEM of ME: firstly, that there is clearly increased fatigue & subjective weakness but little evidence of all the other symptoms we get with PEM - there's certainly no flu-like malaise being described; secondly, that these patients "pay the price" the following day but not for a markedly prolonged period, and thirdly that they feel less fatigued in the morning and become worse throughout the day (I don't know if we have any hard data on this but I'm the opposite: I feel at my worst in the mornings; afternoons are always a little easier). Although the potential mechanisms of fatigue in PSC & PBC are interesting I think it doubtful that these patients have PEM as we understand it.