Miscellaneous Research Thread

It is popular in some communities to attribute ME/CFS to "deconditioning", "unhelpful illness beliefs", and various kinds of "stress".

In this piece in Slate Barry Marshall, the researcher who discovered the cause of ulcers, says the following:

A lot of these things that are supposedly caused by stress, you try to track down the reason for that link, and there isn’t one, except the fact that we don’t have any better cause. Everything that’s supposedly caused by stress, I tell people there’s a Nobel Prize there if you find out the real cause.
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That seems likely in our case.

Also a reminder to read about ulcers in @ME/CFS Science Blog's excellent blog series about psychosomatic medicine, who apparently already have discovered this quote.

Edit: This quote also seems relevant to us:

Are you saying that there was no basically no empirical evidence to support the stress-and-acid hypothesis?
You can always find stress in someone’s life if you want to. You ask a few questions and eventually it’s, “Yes, I admit, I was worried about something recently.” So they tried to find evidence for stress causing ulcers, and whenever they had an experiment which worked, it would just be blown out of all proportion, and everyone would get so much publicity out of it that you would think, “Ah, at last, it’s proven.” But the data was very bad. And in fact there was plenty of evidence showing that stress didn’t make much difference.
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Liie said:
It is popular in some communities to attribute ME/CFS to "deconditioning", "unhelpful illness beliefs", and various kinds of "stress".

In this piece in Slate Barry Marshall, the researcher who discovered the cause of ulcers, says the following:



That seems likely in our case.

Also a reminder to read about ulcers in @ME/CFS Science Blog's excellent blog series about psychosomatic medicine, who apparently already have discovered this quote.

Edit: This quote also seems relevant to us:
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What's ironic is that one of the most important features of intelligence is the ability to generalize knowledge. This is something LLMs struggle with, and why they had to look at millions of pictures of dogs of all sorts of races from all sorts of angles and different lighting and do the same with any other type of dog-looking animal, while a child can see a handful of dogs and nail it right away.

And on this medicine is showing a total inability work it out. The profession is showing less ability to generalize knowledge than the current state of LLMs.

Because this is a generalizable problem. What happened to ulcers is what happened to a lot of other conditions and the features and context are exactly the same. But this one has a crooked ear, and so isn't identified as a dog. This other one had a ball in its mouth, and it hadn't seen that before.

The social intelligence aspect seems broken here. Instead of being more than the sum of its parts, it's significantly worse. Ironically, there is a problem of alignment here, one of the most significant topics in AI. "What if the AI has a different agenda than those who use it?" Well, we know how it fails miserably when humans are out of alignment.

As if we can master AI alignment while human alignment is mostly out of whack.
 
Perhaps doesn't require its own thread but there's a recent publication analysing smartwatch derived vs. self-reported recovery outcomes in COVID-19, influenza and group A strep in a 2-year prospective cohort study:

https://www.sciencedirect.com/science/article/pii/S2589750025001384

Haven't been able to read through but given recent interest in wearables for assessing outcomes in ME/CFS trials etc there may be something of relevance in this.
 

This image gallery shows what the various clinical presentations associated with the COVID-19 (SARS-CoV-2) virus that have been documented during the coronavirus pandemic and in the years since with long COVID patients

Originally thought to be a disease limited to the respiratory system, COVID was quickly found to impact many areas of the body.
The virus caused responses in many people that resulted in increased clotting of the blood, which can lead to pulmonary embolism, strokes, heart attacks and thrombosis in other organs leading to infarcts.
Severe inflammatory responses from COVID also cause rashes, nerve damage, myocarditis, pericarditis and brain hemorrhages.
The virus usually causes mild or asymptomatic illness in kids, but a couple of weeks after infection can result in the rare presentation of multi-system inflammatory syndrome in children (MIS-C).
Ongoing research is also shedding light on long-term damage caused to the body by COVID, including issues in the lungs, brain and heart. Long-COVID symptoms have become a major area of research since 2021 This gallery offers medical imaging examples in all of these areas and newer findings from 2025.

This gallery is periodically updated with the newest images at the bottom.
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@SNT Gatchaman maybe of interest to you?
 
Some recommendations from a genetics researcher I was talking to about DecodeME results:

Systematic differences in discovery of genetic effects on gene expression and complex traits - PMC

Most signals in genome-wide association studies (GWAS) of complex traits implicate noncoding genetic variants with putative gene regulatory effects. However, currently identified regulatory variants, notably expression quantitative trait loci ...
pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
From Jonathan Pritchard's lab, an explanation for why eQTL data may provide limited usefulness re: GWAS results

Extreme Polygenicity of Complex Traits Is Explained by Negative Selection - PMC

Complex traits and common diseases are extremely polygenic, their heritability spread across thousands of loci. One possible explanation is that thousands of genes and loci have similarly important biological effects when mutated. However, we ...
pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
A tangential argument to above, giving an evolutionary argument for why genetic associations of complex traits tend to display an "upper bound" on heritability

[edit: basically answering the question “if pathway X is so important to disease Y, why don’t people with Y all have mutations in the most important genes in pathway X?”]
 
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jnmaciuch said:

Systematic differences in discovery of genetic effects on gene expression and complex traits - PMC

Most signals in genome-wide association studies (GWAS) of complex traits implicate noncoding genetic variants with putative gene regulatory effects. However, currently identified regulatory variants, notably expression quantitative trait loci ...
pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
From Jonathan Pritchard's lab, an explanation for why eQTL data may provide limited usefulness re: GWAS results
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Interesting! I've only read the the first paper so far, but it looks like what they have shown is basically that variants associated with complex traits (GWAS hits) and variants associated with changes in gene expression (eQTL hits) tend to be fundamentally different in several ways.
Using carefully matched analyses, we have shown that GWAS hits are biased toward more constrained genes, toward genes with functions in many GO categories, toward transcription factors and toward genes with complex regulatory landscapes; eQTLs are biased away from all these categories. Meanwhile, eQTLs show a strong promoter bias that is largely absent from GWAS hits. These systematic differences cannot easily be explained by the fact that we have not yet studied all cell types.
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They suggest that a substantial proportion of GWAS findings likely won't be explained by finding matching eQTLs, even if we continue to study larger and larger samples and look for eQTLs in more cell types.

While they say worthwhile findings might be continue to be found with eQTL studies, these are their suggestions for closing the gap where eQTLs won't apply:
Alternatively, various orthogonal methods, including models that predict the regulatory activity of variants from the DNA sequence62,63, and emerging functional assays including massively parallel reporter assays, or CRISPR-based variant-editing or enhancer-silencing should not be biased by selection in the same way, although every method has its own limitations64–66. We anticipate that combinations of genome-scale techniques will ultimately help close the colocalization gap.
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They also make a good point in the introduction of that first paper that will probably be relevant for DecodeME: that eQTL data really only looks at how a SNP influences gene expression during “steady state”. If the gene is relevant during something transient, like an immune response or something that gets stimulated by particular neural input, it might be a completely different story than what eQTL data shows at “baseline” conditions
 
I skimmed the second paper while very foggy. They developed a mathematical model to support this claim made in their abstract:
Complex traits and common diseases are extremely polygenic, their heritability spread across thousands of loci. One possible explanation is that thousands of genes and loci have similarly important biological effects when mutated. However, we hypothesize that for most complex traits, relatively few genes and loci are critical, and negative selection—purging large-effect mutations in these regions—leaves behind common-variant associations in thousands of less critical regions instead.
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It's kind of fascinating to me that the process of selecting against the obvious/straightforward causes of a disease inadvertently also kind of hides those causes information-theoretically.

The comment at the end of the discussion might be relevant to DecodeME:
Polygenicity has not precluded GWASs from producing biological insights,10 and our results suggest guidelines to accelerate their progress. First, GWAS follow-up studies should prioritize genes with evidence of constraint, as most critical disease genes are constrained. Loss-of-function variants provide a useful metric of constraint;45 for GWASs, a maximally informative constraint metric might incorporate noncoding variation,58 gene expression data,59 and functional predictions.60
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So, of the genes under consideration for ME/CFS, we might be most interested in the ones without loss-of-function variants?

Second, counter-intuitively, follow-up studies should prioritize associations that do not map to coding regions or large-effect regulatory elements—instead having weak or context-dependent regulatory effects—since SNPs with strongly deleterious effects on their target gene are less likely to implicate strongly pathogenic genes. As our ability to interrogate the gene-regulatory effects of GWAS SNPs improves,60, 61, 62 a potential pitfall would be to prioritize GWAS SNPs with the largest regulatory effects.
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This seems more forward-looking since my sense is, at the moment, we can barely tell which SNPs are regulating which genes, much less how strongly?
 
A perceived injustice? Querying the ‘social’ in the biopsychosocial approach to vulvodynia

Includes a description of the author's experience with a "biopsychosocial" pain-management programme in New Zealand. Very familiar; many of the same issues that we face...

A critical factor in this confusion is that researchers and clinicians differ as to whether they perceive tissue irregularities or maladaptive neuroplasticity as the key driver of symptoms and target for intervention, even when clinical presentation is similar. Recently, there has been a push from the pain sciences to conceptualise vulvodynia as a central sensitisation disorder or form of ‘complex pain without relevant nociception’,
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As someone who lives with vulvodynia, I have had my own encounter with the biopsychosocial approach through a pain management programme, which began with a 2-hour meeting with a doctor, a physiotherapist and a clinical psychologist. Prior to this meeting, I was invited to complete a series of quantitative questionnaires on my pain and its impacts on my life, aimed at determining whether I ‘catastrophise’ about my pain or exhibit ‘maladaptive’ coping behaviours.
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Furthermore, my PMP endorsed corporate-style metaphors that championed individual choice and transcendence over chronic pain, such as ‘be the boss of your pain, don’t let your pain be the boss of you!’ despite some group members experiencing significant and long-standing impairment. Feeling frustrated, I began to query this individualistic focus and what I felt was a corresponding erasure of contextual influences on pain experience.
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For example, my physiotherapist, who believed vulvodynia to have a psychogenic cause, would often downplay the need for pain medication, chirping that ‘the brain decides how much pain there’s going to be!’ The inference was that merely stating this would have significant pain-relieving effects. This is despite the pain at the time being severe and difficult to manage, to the extent that I feel I would have been unable to progress to physiotherapy without medication.
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In conclusion, I contend that there is a line of thinking within scholarly research, health intervention practice and commodity marketing that not only oversimplifies and minimises the role of structural factors in the experience of vulvodynia (and other chronic pain conditions) but can also operate to police and pathologise ‘perceptions’ of injustice as well as the adoption of a disability identity.
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Earlier in the treatment journey, I encountered a physiotherapist who believed that vestibulodynia was specifically caused by being raised with strict religious values that contribute to guilt around sex. As such, I found myself working to convince this physiotherapist that I do not come from a particularly religious family and did not hold strongly fearful views about sex prior to the pain (although certainly having pain has produced fear around it). The physiotherapist then began to wonder if my postgraduate education could be the problem, suggesting that I might be watching too many films involving ‘abused women’, generating a somatic response.
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Earlier in the treatment journey, I encountered a physiotherapist who believed that vestibulodynia was specifically caused by being raised with strict religious values that contribute to guilt around sex. As such, I found myself working to convince this physiotherapist that I do not come from a particularly religious family and did not hold strongly fearful views about sex prior to the pain (although certainly having pain has produced fear around it). The physiotherapist then began to wonder if my postgraduate education could be the problem, suggesting that I might be watching too many films involving ‘abused women’, generating a somatic response.
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What century is this even? It's so weird how belief systems have mostly shifted from believing in one thing to believing in nothing and anything at the same time. This is exactly what is going on in the deep sewers of conspiracy fantasy communities, but so much worse because it's professionally encouraged.
 
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