Subtyping by age of onset as objective method for reducing heterogeneity in studies

[Hoopoe]

Identifying subtypes of ME/CFS has the potential to greatly accelerate research, however definitions of subtypes of ME/CFs only make sense if they reflect a true underlying biological difference.

It occurred to me that subtyping by age of onset could be reliable method for selecting a more homogeneous group of patients. In ME/CFS we seem to have two distinct peaks in the age of onset: one around 15, another around 35-40 (in women). These two peaks must reflect, at least in part, two different biological vulnerabilities that emerge during development and aging, two different paths that led to a ME/CFS-like illness.

Selecting patients with similar age of onset is presumably a way of selecting patients with similar age-related biological vulnerabilities. It doesn't depend on knowing what these factors are.

 

[Jonathan Edwards]

That makes sense.

 

[Felis Catus]

How about grouping by different illness trajectories? E.g. progressive, relapsing-remmiting (with and without remissions),... Or just progressive vs others.

Admittedly, it would require a certain illness duration to get an idea about someone's trajectory.

 

[V.R.T.]

How about grouping by different illness trajectories? E.g. progressive, relapsing-remmiting (with and without remissions),... Or just progressive vs others.

Admittedly, it would require a certain illness duration to get an idea about someone's trajectory.

I think subtyping by trajectories is seriously complicated by the fact deterioration often occurs following sustined overexertion and changes the nature of the illness. For the first three and a half years after my definite onset I was mild and my illness was very 'durable' - I always came back to baseline capacity after overdoing it and crashing hard (I was undiagnosed and didn't understand PEM or what was happening to me so I messed myself up regularly!).

Then after GETing myself to moderate I started to deteriorate through crashes more. Since becoming severe four or five months later, I've been up and down but never back up to moderate.

How would we subtype for that? Someone who always used to bounce back but then doesn't anymore?

 

[neophyte32]

Exactly the same as @V.R.T.

And then there are those who developed it after COVID, after mononucleosis, after a toxic reaction to a medication, a concussion, emotional trauma… Is it really the same “disease”, or at least the same subgroup ?

And then it gets even more complicated. One of my friends developed almost exactly the same symptoms as I did, although he has been ill for less time — since 2024 according to him, whereas mine started in 2022. Yet we both became bedbound at roughly the same time, in March 2025.

LDA improved me dramatically and pulled me out of the very severe state within just a few days, whereas a single drop completely devastated him.

He can now barely eat, weighs only 50 kg, and needs to go to hospital. His condition is critical.

It is incredibly difficult to make sense of.

 

[V.R.T.]

And then there are those who developed it after COVID, after mononucleosis, after a toxic reaction to a medication, a concussion, emotional trauma… Is it really the same “disease”, or at least the same subgroup ?

I think subtyping by trigger is something people are proposing - although I'm really not sure we can credit accounts of emotional trauma causing MECFS. Especially when we know asymptomatic or very mild covid can trigger long covid so presumably the same is true for other viruses.

 

[Felis Catus]

It is incredibly difficult to make sense of.

It is. Your friend's story is very sad. It's cases like that or similar, where people end up severe or very severe within the first few years that makes me particularly interested in whether there's something different to those cases where people keep relapsing-remmiting or stable for decades.

I'm sure many who deteriorated can point out to GET, infections, treatments and/or other triggering events. Yet there are patients who didn't permanently deteriorate with any of that. There is no shortage of people who keep going out every 5-7-10 days and crashing after each outing only to bounce back and do it again, for years or decades. As one of those who deteriorated rather quickly in comparison, I can't help but wonder about underlying biological differences.

 

[V.R.T.]

It is. Your friend's story is very sad. It's cases like that or similar, where people end up severe or very severe within the first few years that makes me particularly interested in whether there's something different to those cases where people keep relapsing-remmiting or stable for decades.

I'm sure many who deteriorated can point out to GET, infections, treatments and/or other triggering events. Yet there are patients who didn't permanently deteriorate with any of that. There is no shortage of people who keep going out every 5-7-10 days and crashing after each outing only to bounce back and do it again, for years or decades. As one of those who deteriorated rather quickly in comparison, I can't help but wonder about underlying biological differences.

Maybe there should be three catagories - people who have remained stable, people who deterioated quickly and people who have had one or more large deteriorations after e.g. GET but had several years of stability at the start of their illness.

 

[Felis Catus]

Maybe there should be three catagories - people who have remained stable, people who deterioated quickly and people who have had one or more large deteriorations after e.g. GET but had several years of stability at the start of their illness.

To be honest, I haven't thought this through and how groups in a study investigating it should be defined. I could and still can see the messy business of attempting to do it. Nevertheless, I thought it might be worth putting it out there for discussion as I find this question (why some people deteriorate while others keep bouncing back) one of the most intriguing ones. And before the discussion goes in the direction of "some people don't have the support needed to rest", I had it and deteriorated regardless.

 

[Utsikt]

That sounds like a reasonable thing to check for. Maybe you’d need to exclude the people in the middle. Looking at the graphs, early onset could be up until 18, and later onset could be after 28. I’m sure there are some calculations that could tell us the optimal cutoffs.

 

[justlxsa]

And before the discussion goes in the direction of "some people don't have the support needed to rest", I had it and deteriorated regardless.

same here.

and I got my first symptoms when I was 18 so I‘d personally find both approaches very interesting.

Actually all 3 because the trigger question seems to be worth researching too and Charité for example already does this with postinfectious/ non postinfectious and comparisons between different postinfectious triggers.
For me it’s a tougher question because I don’t know exactly what my initial trigger was. Sure I was sick often in these months before- but I can’t pinpoint one event to it. The symptoms were very mild at first and as I was never as fit immunesystem- wise as my friends or classmates, I didn’t realise that I was getting sick sick. But I already had PEM.

Then I got the Covid vaccine 3 months later and I instantly was moderate- severe.

So If there was a research project and I would be participating I wouldn’t know what to tell them about the onset- trigger.
unknown?
postinfectious?
the vaccine?