I am wondering if someone here would be kind enough to explain what ”subgroups” means in the context of ME/CFS. I hear the word mentioned very often, but I don’t get it. I understand that patients fall into categories depending on what triggered the disease, but what I don’t understand is why people say that we might need different treatments for different subgroups. If scientists discover what causes PEM, or fatigue, wouldn’t take apply to everyone with ME/CFS? Wouldn’t finding a treatment for PEM work for all people who have ME/CFS? Thank you!
Someone probably has a better explanation than me, but the way I understand it ME is defined quite losely, fatigue and symptoms that get worse with exercise, and we don’t have strong data of biological issues. On top of that it has so many different symptoms that can present in some people but not others. It’s a very heterogeneous clinical entity. Therefore, the assumption is that there isn’t “one thing” that’s causing this clinical presentation, but likely different biological mechanisms, not necessarily impacting all patients, so there would be “subgroups” of ME just as there are different types of arthritis or diabetes.
Those categories might be less enlightening than we think anyway, though of course they're worth capturing in study data in case they're important. For instance people like me, who can't tick the 'infectious onset' box, are unlikely to be certain their illness wasn't triggered that way because infections don't always cause obvious or memorable symptoms. Nobody really knows anyway, to be honest. It's possible they will turn out to be right, but they could just as well be wrong.
"Sub-groups" have sometimes been used as a convenient "get out of jail free" card by researchers who couldn't find clear signals in their data taken as a whole, but who could find signals (often still in the realms of wishful thinking) if they sliced their (often already small) samples into (even) smaller groups. They have also been used by researchers of interventions, again to post hoc select out "responders", so that they could claim a positive result. So, 'sub-grouping' is a very popular concept among researchers. And, with some good reason. I mean, I groan every time I see a study of Long Covid that combines elderly people who have suffered overt lung damage as a result of a very severe Covid-19 infection with 25 year olds who probably meet ME/CFS criteria, and aims to find some proteomic or something-omic commonality that is the answer to Long Covid. Even in ME/CFS, there may be sub-groups and certainly there are some mis-diagnoses. I do think that some skepticism is warranted whenever researchers start talking about sub-groups though, even just male/female subgroups - it's a sign to look hard at their data analysis approach. We have seen some ridiculous "sub-grouping" of ME/CFS done, which is of course announced as some terrific breakthrough. Kitty's answer is appropriate for a very big range of questions to do with ME/CFS.
Some of the issue is about inferences made and I can see this concept being particularly relevant for eg the Lind research priorities looking at whether any existing things help and when we think about the likelihood of at least different downstream effects of the same thing in bodies with different susceptibilities to different things and indeed some people with different severities that don’t overlap exactly as we even think with overall severity eg someone mild could have quite severe POTS or cognitive symptoms vs other aspects I guess or vice versa I know B12 injections haven’t cured my ME/CFS overall but if I didn’t have them I would be significantly struggling with screens and migraines for example compared to if I do . But not all people have that symptom or my background body wise or what I went through in lead up (having already had me/cfs but then got worse) the conclusion if day 20% of people did significantly benefit in a really important function like me shouldn’t of course be that it cures all me/cfs and should be enforced as treatment. But lowest common denominator ing those who have an important difference with those it doesn’t help to say ‘noone benefits who has me/cfs’ also isn’t correct as you say it depends on the robustness and sample size anyway before hand and on the scientific ability /ness of those writing it to be able to be accurate in what such things can infer and can’t re: population (and external validity) it might represent and what it actually helped with - it could be another common downstream or susceptibility ‘on top of’ me/cfs just like I’m sure other diseases have some people getting either an added something else whether it’s ’an arm of’ or due to a susceptibility combining with other things being present in body or what not The other interesting thing on the sun type theme is if there are common comorbidities some have when they get me/cfs and/or develop later into having it. Yes you’d ideally like to know (eg fir genes) what is ‘explained by’ that other illness but it would also help in those who aren’t yet diagnosed or don’t even develop that ‘other comorbidity) but might have similar typing vs other people with me/cfs. As it could point to upstream or downstream vulnerabilities that perhaps give clues as to the ‘overall’ me/cfs for all that is washing through that system. I guess that’s why the PEM but and other symptoms moving towards being better specified instead of the bps type push to a more and more generic fatigue and persistent any old symptoms (and trying to even disappear those) is so important so we know when one ends and the other thing is present or a misdiagnosis etc I agree that missed diagnosis is likely a common group in me/cfs given how cynically cfs was used - I just don’t know how many don’t actually have PEM and also have me/cfs as well as something else vs maybe some having ‘something else’ I think there is definitely a big difference which could be a sub type in that some people don’t get sleep reversal, even due to PEM . And some say they can’t sleep in or feel worse if they do etc whereas if you are in the different group then that’s the one that feels incredibly alien - and scary alien given how terrifyingly damaging someone enforcing sleep hygiene (as if trying to live in the world with appointments and work times etc isn’t enough) is if you have it , I’d say worse than GETvor basically sane as because it leads to over exertion and body being stuck in not being able to rest and exerting mode due to it. now here it depends on your sample (what is externally valid and representative of this split?) , your measures used but also all sorts in the treatment methodology because you can imagine how just things like taking a tablet 3 times a day at a precise time mightnt be too arduous fir those who don’t get those issues but , particularly if combined with being just after having had to have a hectic first day (travel or even just a zoom or long call and instructions) putting someone in PEM or over-exertion suddenly having to take a tablet at 8am, 2pm, 7pm could be a real issue if someone needs to sleep then and cycle it back round. so I guess it depends as a term on context as to what we might mean.
I think one of the reasons people raise the possibility of subgroups, as others have said, is the enormous variability we see within and between people with ME. It is possible that there are different clinically meaningful subgroups within ME, or it could be that once we understand the significant etiological factors this variability will just fade into irrelevance. On a personal level for much of the thirty years of my ME its variation seemed unpredictable, until I had the concepts of PEM, OI, food intolerances, sensory hypersensitivities and their interaction. Obviously this doesn’t explain the underlying condition but it does make my personal experience seem less random, more manageable. Other biomedical pathologies also display significant variation in symptom patterns, for example CVAs or MS, but the underlying aetiology means that they are meaningful groupings for the purpose of understanding/research/treatment/management. Currently we see PEM as an indicator that ME/CFS is a meaningful clinical grouping in a way that characterising the condition as primarily fatigue never was. As we understand PEM more I hope the concept of ME/CFS becomes clearer, though there is always the risk it just fragments.
I think we should remain open minded about sub-groups. But I also expect that any apparent sub-groups are most likely to be artefacts of poor methodology, mainly imprecise diagnostic criteria.
I think subgroups refers to presentations (OI vs no OI) or responses to factors (what effect supplemental B3 has, for example) rather than the core dysfunction. Not everyone "shot with a 9 mm bullet" responds the same (headshot vs skimming the butt), so there are subgroups. Nope, due to subgroups or individual factors. I found a treatment for me that blocked PEM 100%, and eventually cured it, but it hasn't had the same effect for anyone else so far. Why it doesn't work the same for everyone is because our bodies are incredibly complex. We're not rolled off the same assembly line built with standard parts, at least not above the molecular level.
That’s the part I struggle with. How can different biological mechanisms create the same unique characteristic, namely PEM? To me it makes more sense that we all have the same underlying problem, but added to that, we also have more ”personalized” symptoms. But yeah… we can only assume things, until science gives us an answer.
Maybe DecodeME will shed some light on the matter. But so far, from what I’m reading, it is clear nobody really knows.
At the ME-clinic where I received my diagnosis before it was closed down, they gave patients B12 shots on prescription. I know several people who say the shots help them tremendously. I could not take B12 shots as they caused me severe palpitations. But the first time I took a shot, I had an amazing experience: in the evening all my brain fog cleared suddenly. It was like I was seeing the world in Technicolor again.
I think the same will probably turn out to be the case for people with bona fide ME/CFS. They will have a common underlying mechanism, but with some variations.
I was misdiagnosed for a decade, until I finally got a referral to an ME-specialist, who immediatedly recognized what I had. Until we have some sort of objective test for the disease, there will always be people like me who have ME/CFS but get bounced around with incorrect diagnoses, and people who are told they have the disease, when in fact, they don’t.
