Should ME/CFS genetic research focus on using post-COVID ME/CFS and recovered COVID controls?

Very good points. It might be more trouble than it's worth if it only controls for a tiny portion of the phenomenon.
Still a useful exercise to think about, though! I think it just speaks to the limitations of GWAS (or any big data screening approach, really) and the danger of making runaway conclusions about mechanism solely on the basis of those results.
 
I think it just speaks to the limitations of GWAS (or any big data screening approach, really) and the danger of making runaway conclusions about mechanism solely on the basis of those results.
Yes, my main fear that prompted the post was the ambiguity of, for example, an HLA allele finding. It might just cause people to get sick more severely and more often, which doesn't really seem that interesting in terms of how to treat ME/CFS if the subsequent disease process has nothing to do with HLA. There are ways that HLA could be central to the disease process, as Jonathan pointed out, but I'm just thinking about how to unravel if that is the case or not.
 
One point that may be relevant is that HLA pobably has relatively little to do with severity of acute infection. It takes many days for the HLA-mediated adaptive response to evolve. Nasty infections probably kill you before that. There are reasons to think that the adaptive immune response is more about not getting an illness twice than surviving one (and about providing a priming system for newborn adaptive immune systems).

There may be exceptions to this though. EBV would be a good candidate because a severe acute case is often one that progressively worsens over three weeks or so.
 
Yes, my main fear that prompted the post was the ambiguity of, for example, an HLA allele finding. It might just cause people to get sick more severely and more often, which doesn't really seem that interesting in terms of how to treat ME/CFS if the subsequent disease process has nothing to do with HLA. There are ways that HLA could be central to the disease process, as Jonathan pointed out, but I'm just thinking about how to unravel if that is the case or not.
It’s a good concern to have, and I think ultimately it’ll come down to mechanistic studies to confirm or deny. The aftermath of DecodeME will probably be a series of studies hypothesizing “well these genes suggest XYZ process might be involved, do we see additional evidence of that pathway being relevant? And if so, does targeting that process lead to any symptom improvement?”

And that will probably lead to a frustrating series of “nope, that’s not it” findings over a period of time. But I’m hopeful it’ll converge to an answer soon enough. It’ll just be prudent to keep that ambiguity in mind when we get the DecodeME results, and keep up the same level of scrutiny for any studies that follow up on it.
 
This discussion and talk of variety and severity of infection at onset brings me back to thinking about variety and severity of ME/CFS, how much noise there would be in milder cases vs more severe and if we have enough severe cases (a few thousand in DecodeME) to usefully get information in that group alone.
 
Still a useful exercise to think about, though! I think it just speaks to the limitations of GWAS (or any big data screening approach, really) and the danger of making runaway conclusions about mechanism solely on the basis of those results.
I always thought of a GWAS study as being hypothesis generating rather than giving the answer. I think that is how they are more generally seen. So in ME/CFS research this means that if say DECODE comes up with come genes of interest then this could translate to research projects that explore those potential mechanisms. Rather than a conclusion that it is those mechanisms.
 
I suppose the broader question on how useful studying LC is for advancing MECFS knowledge depends on whether we think it's the same phenomenon or whether we think MECFS & LCMECFS is a heterogeneous family of diseases?

If the latter then studying just one variant will only really advance knowledge of that one and if studying multitrigger MECFS, then you would think ideally clustering and networking type analytics techniques akin to those precision life have been using would ideally need to be involved, along with more sizeable cohorts to define subtypes?
 
Does getting ME relate to infection severity? I had the impression that it didn't
I'm not sure that it's been studied much. I was mostly just extrapolating based the potential link in long COVID. Though even if severity isn't associated with ME/CFS, it seems likely that frequency of getting infections would be associated. If someone never gets infections, they can't get a post-infectious illness. (Though maybe in these people the same illness eventually starts without the infectious trigger anyway.)

I found this about severity and post-infection fatigue (PIF):

The international collaborative on fatigue following infection (COFFI), 2018, Katz et al [Article] [S4ME]
Results: Preliminary analyses indicated that risk factors for non-recovery from PIF included lower physical fitness, female gender, severity of the acute sickness response, and autonomic dysfunction.

Also note @jnmaciuch says the severity question isn't even settled in long COVID:
It's very much up for debate--I did a deep dive on it about a month ago when I was searching for citations on that claim for a LC publication. There's evidence on both sides to some extent, the main issue is extreme inconsistency in how it's assessed.

For example, the studies I looked at varied on whether or not age was accounted for as a covariate (since age was strongly associated with severe disease to begin with), whether LC was defined by long-term physical and cognitive deficit or simply the persistence of one or more symptoms after infection, and whether there was enough data from non-hospitalized LC cases to accurately judge prevalence from mild infection.

As one example, the research team I was part of put out this study showing no correlation with severity amongst hospitalized patients. Granted, all were hospitalized, so it is skewed in that way. Though we did have a good number of mild cases that didn't exhibit high respiratory distress and were discharged after just a few days with no or minimal treatments.
 
I'm not sure that it's been studied much.

Maybe because it hasn't really emerged as a factor in people's descriptions of onset? If you developed ME/CFS after needing hospital treatment for an infection, you'd usually say so—unplanned hospitalisation is a significant event.

It doesn't seem to come up much, though, not even in informal chitchat.

Though even if severity isn't associated with ME/CFS, it seems likely that frequency of getting infections would be associated.

Maybe? But the proportion of cases associated with EBV might give the lie to it.

It's even possible EBV could trigger ME/CFS years after a childhood infection. Or in people who're infected as adults but get no glandular fever symptoms; their ME/CFS appears to develop out of the blue.

I'm not convinced severity of infection is really necessary as a factor, and it would be impractical to measure frequency. We probably aren't aware of some of the infections we've had because our immune systems dealt with them silently.
 
I'm not convinced severity of infection is really necessary as a factor, and it would be impractical to measure frequency. We probably aren't aware of some of the infections we've had because our immune systems dealt with them silently.
Also people report getting ME after being vaccinated which is a weak infection (i.e. in causes the immune system to work). I had assumed that there maybe a state where if in that state when the immune system in activated more than normal it could cause ME.
 
Does getting ME relate to infection severity? I had the impression that it didn't
Evidence so far suggests it does not at all. The lie is simply kept alive because it has been asserted for so long, medicine lacks the tools to assess it reliably, and it's too convenient in order to suppress the whole issue. In the early days of the ideology, it was simply asserted, as it provided a convenient excuse for deconditioning.

In fact, without it, deconditioning literally makes no sense. So much that we have recently seen studies that absurdly include a reduction in activity levels, where the conditioning that results form it is its own cause. Even though that's been fully debunked, but beliefs matter more and so here we still are. Hell, it was just a few years ago that we had a study, I think by Wyller or Knoop, where they noted that the pwME they included had reasonably good activity levels, and therefore fatigue must be independent of activity levels. Even as they keep measuring activity levels. Pure insanity.

There is a slight uptick in LC rates when the threshold of severity is defined by hospitalization, but it seems to be more about the kind of tissue and organ damage, such as from pneumonia, that isn't found in the chronic illness category, and evidence so far mostly shows that those commonly recover. I don't remember any good studies that compared PEM prevalence, but it's not as if good studies are in abundance here.
 
There is a slight uptick in LC rates when the threshold of severity is defined by hospitalization, but it seems to be more about the kind of tissue and organ damage, such as from pneumonia, that isn't found in the chronic illness category, and evidence so far mostly shows that those commonly recover. I don't remember any good studies that compared PEM prevalence, but it's not as if good studies are in abundance here.
As you say we need to be careful with long covid as some have ME like disease but it seems to cover a whole range of other long term issues.
 
If someone never gets infections, they can't get a post-infectious illness. (Though maybe in these people the same illness eventually starts without the infectious trigger anyway.)
Or non-symptomatic? Or would that be on a spectrum of severity?
Maybe because it hasn't really emerged as a factor in people's descriptions of onset? If you developed ME/CFS after needing hospital treatment for an infection, you'd usually say so—unplanned hospitalisation is a significant event.
I think I’ve mentioned mine was possibly triggered after ending up in hospital after a kidney infection wasn’t treated properly and went bad. I do seem to be a rarity but the descriptions of post-sepsis syndrome and ME/CFS do seem similar so I’ve often wondered if there’s something to learn there.

But tbh have never been entirely sure if I had a mild ME/CFS beforehand which was just made worse by all this. There are many different explanations which could fit.

Either way severity of infection doesn’t seem to be required for ME/CFS but it may contribute to chances, just as different infections may do so. Is it because COVID was new and so widespread it seems to have caused so many people to have long lasting symptoms or is there something about the virus or how many people got badly hit by it? We don’t seem to know. That there are still so many questions seems to show a lack of intellectual curiosity by some and how much people have been happy to just move on.
 
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