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

Thank you @Chris Ponting, @Simon M, Sjoerd, Ava, Julia, Amanda, Nima and Gemma

Some suggestions:

For the purpose of this particular paper I would suggest simply stating that more females than males have an ME/CFS diagnosis. It's not relevant here whether it's 3:1 or 5:1 or whatever

Ref #51 only describes post-exertional fatigue, also states this gets better with exercise. Can't categorically discount PEM happening here - could be the authors gave a poor description of PEM due to their focus on fatigue, and that the study cited for the improvement with exercise is just as poor as the ME GET studies - but if there is PEM in primary biliary cholangitis this paper doesn't show it.

For anaemia only intensive exercise is contraindicated, other exercise is still recommended. It's probably the same for the other conditions. I wonder if this section is necessary to have at all? Or if it can be made less specific? Really all that can be claimed is that some types of exercise are contraindicated in some health conditions, typically (always?) that's intensive exercise which is cautioned against, and nobody is recommending intensive exercise for ME

In fact, on reflection, much of the introduction section could be shortened significantly as it has little relevance to the study itself. IMO there's really no need for every ME study to repeat all the general background and stats (which are often poorly evidenced), instead just link to a review on all that (sorry, can't think of a good one on top of my head). All that's needed for this particular study are the bits in bold

 

I tend to agree with @Ravn about not needing a lot of background on ME/CFS, and also with @Hutan 's post (on the epidemiology thread) on sex ratio.

Just as a technical point. My main concern about internet recruitment originally was that the GWAS might pick up an allele linked to behaviour that included answering internet calls. The defence would be that we do not know of any such alleles and if they had a major influence they might have been picked up in other studies.

But we do have one genetic difference that is well known to be associated with behaviours relating to health care and that is the XX, XY difference. Rates of attending GPs and outpatients are confounded by female-related health issues in long adults, which is where differences are regularly reported. But we know that women are more likely to deliberately take up healthy diets (regardless of whether they stick to them!). My guess is that a call for volunteers for an ME/CFS study is likely, for a complicated combination of reasons, to be overweighted towards women responders by a factor of 1.5-1.7. I have no data but that means that for me the most likely interpretation of a 5:1 response is that it reflects a 3:1 prevalence.

Maybe, as Rain says, the safest thing, not to raise hares about methodology, is just not to quote a figure. It isn't relevant beyond there being a female predominance.

 

Can we set up a new thread on this topic? It throws up some interesting questions in the context of 'maybe things moving forward' for the future and with implementation of guideline etc, but I think I got the impression point 1. was a key issue when I last read about it.

Then I realise if it is being commonly used in some big countries then there might by now be more info on that? it would also just be interesting to get an idea how many have been/are being run these days etc. ..

 

I suspect that, because Workwell carries them out privately for individuals needing evidence for insurance or pension claims, many of the results aren't published. We would probably only hear about those run as part of trials.

 

Although they might let us know what the demand is for these days?

 

Maybe, but it's possible the answer would be "That's commercially sensitive information"!

 

But, if it is/was commercially sensitive then that very information would itself be commercially sensitive.

Down the rabbit hole we go, again.

 

Yes. Statements about ME being a mainly female illness are very worrying, as this risks ME being seen as a 'women's problem' and therefore not to be taken seriously. The immediate thing that struck me, as mentioned by a few other posters, is that it may simply be that women may more actively seek help and to take part in trials, whereas it may be more of a 'guy thing' to not talk about it and not join trials. This may skew people's perceptions.

There's an account on Twitter some folks here may know of, called Royal Free 1955, that posts old news articles about ME. What strikes me in the 1980s-early 1990s articles, is how many feature male sufferers. When I got ME in 1983 I only met 3 people with ME and all were men. Now with social networking I know many men with it. Yet nowadays, news media portray it as more a women's issue. It's a disturbing shift.

 

I’ve processed the text of the paper to remove figures, references, URLs and formatting to make it better for text to speech engines and attached it to his post. I’ve also uploaded the audio to soundcloud. It’s not great quality but is hopefully easier than reading for some.

 

It looks like the protein with the greatest significance for men only is BCHE (adjusted p=0.0003) which is a cholinesterase - Butyrylcholinesterase.



Its function appears to be as a non specific cholinesterase that is structurally similar to acetylcholinesterase, but that in addition to just acetylcholine it also breaks other chain lengths acylcholines as well as certain drugs. It's produced in the liver and it's blood levels can be indicative of liver function supposedly.

Its cohen's d effect size from the raw data is 0.8, and its Total Effect is also significant in the paper. I'd be curious to see what the raw data looks like as a strip scatter plot. With cohen's d=0.8, normal distributions, and the sample sizes used here I guess it might look something like this simulation I made:



@Jonathan Edwards I know you had some interesting theories around acetylcholinergic neurons - do you have any thoughts on this? Given the possible link of gulf war illness to nerve agents that affect cholinesterase, and to the slight possibility that Wuest's study has picked up something with ACh nerve endings in their muscle biopsy staining, could this be interesting?

 

To compare some of the lipid findings to previous studies that have done lipidomics:

This thread's paper describes low levels of phosphatidylcholine, sphingolipids (types of membrane lipid) and high levels of triglycerides.

Low levels of phospholipids and sphingolipids are also seen in Che & Lipkin et al 2022, but triglyceride levels are more conflicting as there are high unsaturated but low saturated levels - this is also a female only effect:


Naviaux et al 2016 replicate low phospholipids and sphingolipids - but do not report on triglycerides so it's unclear if it's not significant or not measured.


Hoel et al 2021 replicate low phospholipids (PC,PE,LPC) and high triglycerides (TAG). However it reports no difference in sphingolipids (SM, CER)/ if anything slightly increased sphingolipids.



Most other metabolomics studies do not measure lipid levels, though there are difference in free fatty acids in the 2 day CPET paper by Hanson's group. I'm sure there are other lipidomics papers I have missed.

EDIT: Also one of the significant proteins in the combined analysis in this thread's paper is the maybe relevant seeming 'Phosphatidylcholine-sterol acyltransferase' (adjusted p = 0.023).

 

High leptin levels seen in this thread's paper in men, was also seen in Hoel et al 2021

 

I think this is a key point. I don't think it is addressed in the paper and maybe some analysis should be made.

I am travelling but hope to get some detailed comments down for Chris and co within a week or so. I think there are some major issues to sort out in relation to confounding co-morbidities and the uncertainties around ascertainment of an ME/CFS diagnosis.

I think the identification of superoxide dismutase 3 and complement proteins may be an important finding but I suspect that many of the other findings reflect confounding factors that increase the chance of a CFS diagnosis through all sorts of routes. (They are probably the expected markers of other predisposers to persistent fatigue in this age group.) The study may turn out to be a useful dry run for DecodeME in terms of assessing the risks of selection biases. Fortunately, I think these are going to be greater in this cohort than the Decode cohort. Comparing the two may give some very useful information about essentials for recruitment methodology.

 

Fascinating.
What more can I say!

The lipid shifts may be more than just confounding co-morbidities too, but I think these oddball findings like SOD3 and BCHE are easier places to start.

 

Germain et al 2020 reported higher sphingolipids than controls. It seems phosphatidylcholine wasn't significant.

 

So as not to take this thread too far off topic I've made a separate thread for it. Hopefully somebody there will be able to suggest some good general reviews suitable for linking to.
https://www.s4me.info/threads/how-to-write-a-good-introduction-for-an-me-cfs-paper.40017/

 

I know very little about this sort of biochemistry but choline seems to crop up everywhere.

 

At least in my case it doesnt fit together.
The first 8 years I had a mild case of ME/CFS. I couldnt do sport anymore but I tried to walk a lot to keep my condition even if I was often very exhausted.
My cholesterol level was always perfect but I had high level of triglycerides. Also my BMI was good. My metabolic doctor was always surprised. She proposed to me to eat more vegetarian food. The more my food was vegetarian the worse my triglycerids were. Later I had stomach problems and I tried low carb diet and I was very surprised, my triglycerides vere perfect.