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

Andy

Andy

Retired committee member
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

Myalgic Encephalomyelitis (ME; sometimes referred to as chronic fatigue syndrome [CFS]) is a relatively common and female-biased disease of unknown pathogenesis that pro- foundly decreases patients’ health-related quality-of-life. ME/CFS 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/CFS patients’ low level of physical activity. Pre- vious 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/CFS 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/CFS status on molecular and cellular traits. Strikingly, these trait differences cannot be explained by ME/CFS cases’ restricted activity. Of 3,237 traits considered, ME/CFS status had a significant effect on only one, via the “Duration of walk” (UKB field 874) mediator. By contrast, ME/CFS 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. Signifi- cant 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/CFS diagnosis.
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Version 2: https://www.medrxiv.org/content/10.1101/2024.08.26.24312606v2
 
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Twitter thread from Chris Ponting

https://twitter.com/user/status/1828809116745351582
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"#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"
 
Sasha said:
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.
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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.

Trish said:
I hope the samples from the UK ME/CFS biobank will be tested to see if the finding it replicated, as that's a much more carefully diagnosed cohort.
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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.

Jonathan Edwards said:
It would be interesting to know what some of these molecular are.
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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
 
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Andy said:
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"
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This link has the same Twitter thread but also contains the figures
https://threadreaderapp.com/thread/1828809116745351582.html
 
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.
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One more study suggesting impaired liver function. Perhaps the time has come to perform Fibroscan tests in ME patients.
 
from the paper
Our findings provide strong and replicated evidence for chronic low-level inflammation (elevated CRP and cystatin-C levels, and platelet, leukocyte and neutrophil counts), insulin resistance (elevated triglycerides-to-HDL-C ratio, ALT, ALP, GGT and HbA1c) and/or liver disease (elevated ALT, ALP, and GGT, and low urea levels) in ME (Fig. 2A). ME is thus portrayed by insulin resistance and systemic inflammation, with liver inflammation and dysfunction likely affecting lipid metabo- lism and the balance between HDL and LDL cholesterol. To our knowledge, the overall combination of blood marker changes we observed does not present in any other disease.
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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.
 
InitialConditions said:
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.
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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.
 
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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:
The classic clinical scenario is of a young patient with PBC who has mild disease that has responded well to ursodeoxycholic acid (UDCA) therapy in terms of liver biochemistry, but who is still experiencing profound fatigue. This classic fatigue has two elements. The first is a sense of “brain fog,” clouded thinking and poor concentration that may have been bad enough to cause problems at work. Patients may feel the need to sleep during the day but fight against it.
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The second is a sense of profound peripheral weakness, like the “batteries have run down” in their muscles. Patients have good days and bad days but sense that they “pay the price” the following day if they exert themselves. Typically, patients feel less fatigued in the morning and get progressively worse during the day. This makes evenings difficult and shift work challenging. Fatigued patients often decrease their activity, particularly nonessential activ- ities, such as paid employment or caring for children, with a knock-on effect on social life and relationships that can lead to increasing social isolation.
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In patients with PBC the evidence to support a central component to fatigue includes the clinical associations seen in the disease, imaging findings, and neurophysiologic abnormalities. In terms of clinical associations, fatigue in PBC is associated with sleep abnormality (in the absence of any association with obstructive sleep apnea) and depression (although the potential for this to be a secondary phenomenon is important to remember). Fatigue also has a circadian rhythm in PBC, which is redolent of other centrally mediated phenomena, with fatigue typically being worse later in the day. The sleep abnormality association is with sleep initiation, with increased sleep latency typically being accompanied by significant daytime somnolence. Stimulant agents, such as modafinil, are effective for reducing daytime somnolence and where this benefit is seen fatigue severity is also typically reduced.
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Autonomic dysfunction is also seen in PBC and can be a significant clinical problem through increasing susceptibility to falls (increased risk of vasomotor-mediated falls is as important a contributor to risk of fractures in PBC as osteoporosis) and through a strong association with fatigue and cognitive impairment. Indeed, the presence of autonomic dysfunction at baseline is associated with increased risk of progressive deterioration in cognitive function over follow-up. Autonomic dysfunction is associated with impaired cerebral autoregulation, and the areas of the brain demonstrated to show significant change are those where the autonomic centers are located, suggesting that the clinical phenomenon of autonomic dysfunction is also centrally mediated.
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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.
 
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