Why are patient pleas about subtyping and stratifying in studies seemingly falling on deaf ears?

[BrightCandle]

New crux: trials should collect all possible data, within the limits of their funding, be it patient surveys, past drug responses, biomarkers, on-site testing, etc. and stratify results based on that data.

You can't do that because then you can select all the responders, effectively ignoring the control and introduce your own bias into the results. This is the thing to understand, we have a noisy signal you can't just select the responders to find some random post hoc grouping.

ME/CFS has a high placebo bias in it, you have to choose who you are testing and what counts as a significant result from the outset or you introduce bias. If you get a signal but its only some people then what you hope is you captured why, if you didn't then you have to guess and do another trial. But if you get no signal then there isn't a response group to go hunting for, its just the random nature of the disease as shown by the control also doing the same.

 

[EndME]

I think ya'll are getting hung up on subtypes. Let's forget about subtypes, or we will go back and forth about semantic category error debates all day.

New crux: trials should collect all possible data, within the limits of their funding, be it patient surveys, past drug responses, biomarkers, on-site testing, etc. and stratify results based on that data.

Sure, but people have to understand the issues surrounding such post-hoc analysis and that in general this gets you nowhere. The more analysis you conduct the more problems you get. That's the whole point of primary and secondary outcome measures.

The type of thing people are often advocating for, as seen in the Rapamycin study, are prime example of how to not run studies!

I can run a million different analysis of people "responding" in trials suggesting that they are responding due to x,y,z, and I'm talking about the placebo-group!

Fluge and Mella are a good example. They gather as much data as possible, but tend to not be led astray by post-hoc analysis (even if the NK-cell count might be a red-herring).

 

[EndME]

Generally speaking a clinical trial is supposed to test a specific hypothesis so that a question can be answered, not examine the possibility of all hypotheses so that all questions remain open.

 

[Liface]

The post hoc analysis introducing bias is totally noted, but there should be no issue with pre-specified subgroup reporting based on a bunch of different markers. If they enroll patients and pre-register that they'll report outcomes stratified by PEM severity, MCAS symptoms, and illness severity, that's all most patients are asking for - that baseline phenotyping appears in the results section, even as exploratory/hypothesis-generating.

Hell, they can even report a null result for the group, but give us something!

 

[EndME]

The post hoc analysis introducing bias is totally noted, but there should be no issue with pre-specified subgroup reporting based on a bunch of different markers. If they enroll patients and pre-register that they'll report outcomes stratified by PEM severity, MCAS symptoms, and illness severity, that's all most patients are asking for - that baseline phenotyping appears in the results section, even as exploratory/hypothesis-generating.

The problem is that there are generally a priori no useful markers. Some patients may think differently but that is the reality. Maybe one should argue that for ME/CFS illness severity should be a variable that should always be looked into as exploratory outcome measure (and some studies also do that, certainly Fluge and Mella have analysed this) but the general problem is probably power here as only mild/moderate people tend to participate in trials and that cut-offs for severity levels can be quite arbitrary itself. But one would stratify according to illness severity for very different reasons then for the things you mention above and I think some of what you suggest is nonsense. I'm not sure what you even mean by PEM severity, many trials look at changes in DSQ scores, but I'm not quite sure what that captures and the DSQ is widely criticised and F&M now also use FUNCAP as exploratory outcome, I'm not sure what else would be wanted on that end.

It is not hard to generate hypothesis that carry no value. The opposite is the tricky part.

Fluge and Mella have shown how to run trials for ME/CFS. Others have shown how not to do it. People should simply follow in the footsteps of F&M or make specific suggestions for improvement. It's not that hard.

If anything researchers should just make all data available for analysis, that should be a standard. But more often then not a null result is a null result is a null result.

 

[Kitty]

I think ya'll are getting hung up on subtypes.

That'll happen if you start a discussion with:

It was heartening on Twitter today to to see so many patients as outraged as I am at the continued lack of subtyping and stratification in Long COVID and ME trials

 

[Verity]

If this opinion holds, you would agree that an Ivrabradine trial would read out exactly the same in someone with ME-POTS as someone without?

A few thoughts come to mind on this.

I think what @EndME said about an Ivabradine trial is quite reasonable.

Thinking subgrouping is unnecessary and thinking two trials would look exactly the same are not the same things. If POTS is genuinely common in ME/CFS and the drug works well, you shouldn’t need to separate out the POTS patients to get a signal. If POTS has nothing to do with ME, or if the drug is ineffective or barely effective, you won’t get a clear signal but might be able to monkey with the data via “subgrouping” until you do.

An Ivabradine trial would either be for POTS, not for ME/CFS, or it would be for OI, not specifically POTS, in ME/CFS patients. The trial should be designed according to whatever the researchers are actually trying to target. Separating out POTS patients when you mean to treat ME patients with OI doesn’t make sense to me. Calling it an ME trial if you mean to run a POTS trial also doesn’t make sense to me.

 

[Peter T]

I feel it is at present unfair to criticise researchers for not taking into account subtypes of ME/CFS when what they might be is purely speculative. However I would agree we still desperately need good observational/descriptive studies of both ME/CFS and Long Covid so that we have a better idea of the variation both within over time and between individuals.

Then this might give us a clearer idea of what symptom patterns exist, and potentially give clues as to what factors might distinguish any subgroups if they exist.

 

[Verity]

Generally speaking, I don’t think testing drugs like Ivabradine that are meant to treat specific symptoms or comorbidities on people with those symptoms or comorbidities is “subtyping,” so maybe there is a terminology issue in this thread. The presence of a symptom or a comorbidity alone does not necessarily imply a subtype. Most diseases have more possible symptoms and comorbidities than most individual patients have, but that doesn’t mean these diseases have tons of subtypes.

I have hair loss probably from cutaneous lupus and need additional treatment for that on top of plaquenil, but people with CLE and consequent hair loss don’t constitute a “subtype” of CLE. I don’t have some different thing from all the other CLE patients without hair loss that causes me to have a totally different overall drug response or that implies a fundamentally different core problem, which is usually the scenario I hear ME patients talking about when they talk about subtyping.

 

[Trish]

If this opinion holds, you would agree that an Ivrabradine trial would read out exactly the same in someone with ME-POTS as someone without?

Given that ivabradine is used for reducing heart rate, the trial would presumably be a POTs trial, not an ME/CFS trial. Why would you test Ivabradine for people who don't have POTS?

 

[ME/CFS Science Blog]

I think there's a few subtleties here and much of the outrage on Twitter I've seen in the past often came from basic misunderstandings of trial methodology.

Agree, thanks for writing this out EndME.

 

[Liface]

Given that ivabradine is used for reducing heart rate, the trial would presumably be a POTs trial, not an ME/CFS trial. Why would you test Ivabradine for people who don't have POTS?

This question would be better posed to our researchers, who are busy enrolling all types of patients in every treatment trial they do without filtering for the appropriate "subtype"! (feel free to insert another word there if that's triggering for you)

Generally speaking, I don’t think testing drugs like Ivabradine that are meant to treat specific symptoms or comorbidities on people with those symptoms or comorbidities is “subtyping,” so maybe there is a terminology issue in this thread. The presence of a symptom or a comorbidity alone does not necessarily imply a subtype. Most diseases have more possible symptoms and comorbidities than most individual patients have, but that doesn’t mean these diseases have tons of subtypes.

There are clearly groupings of symptoms that are correlated with each other.

Does everyone fit into one neat category? No. But there are correlations, and there is more signal than noise.

Examples:

Mast cell

flushing, hives, GI cramping, food/chemical sensitivities, anaphylactoid reactions, itching

Autonomic / POTS

orthostatic tachycardia, presyncope, palpitations, temperature dysregulation, coat-hanger pain

Neurological

brain fog, sensory hypersensitivity, headache, word-finding failure, sleep dysfunction

 

[Trish]

This question would be better posed to our researchers, who are busy enrolling all types of patients in every treatment trial they do without filtering for the appropriate "subtype"! (feel free to insert another word there if that's triggering for you)

The point I was trying to make was that if someone is testing a treatment intended to address particular symptoms or comorbidities that some people with ME/CFS have, whether hives or migraines or POTS, or irritable bowel symptoms, then they need to test the treatment with samples of people who have that symptom.

If the treatment is intended to treat ME/CFS itself, for example to try to reduce or eliminate PEM episodes that everyone with ME/CFS has, then it matters less which other comorbidities the person has. There woud be less need for 'subtyping' according to which comorbidities the people have so long as they fit the criteria for ME/CFS incuding PEM.

So are you really talking about subtyping, or are you talking about co-morbidities?

 

[PageofME]

But it seems that that patients have been shouting into the void for years, and how trials are run hasn't changed.

An influential part of the LC community is advocating to treat it all (different LC types that are subtyped in research and ME/CFS) as one illness on a spectrum. I am not sure whether we can therefore say that patients demand differently but are not heard.

 

[PageofME]

I think that the diagnostic criteria should be enhanced by distinguishing patients with flu-like remitting-relapsing episodes (with all the other symptoms following) and patients who don't have flu-like episodes. I am convinced that those who don't feel flu-like don't have the same illness as I have.

Today I read somewhere here that a member thinks they have a rheumatoid, autoimmune illness and are misdiagnosed with ME. I find this very interesting because I have a friend with a CFS diagnosis who is housebound for many years because of energy limits but whose illness looks very different from mine.

Also, she's now with a rheumatologist and feels a lot better on some drug from that area.

 

[PageofME]

Iwasaki concluded in her ME/CFS liquor study that two similar and distinct pathological patterns showed up.

Cerebrospinal fluid immune phenotyping reveals distinct immunotypes of myalgic encephalomyelitis/chronic fatigue syndrome - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex heterogeneous multiorgan disease that can have severe impact on individuals' quality of life. Diagnosis of ME/CFS is based on symptom presentation, and a significant goal for the field is to establish meaningful subtypes...

pubmed.ncbi.nlm.nih.gov

 

[Felis Catus]

An influential part of the LC community is advocating to treat it all (different LC types that are subtyped in research and ME/CFS) as one illness on a spectrum. I am not sure whether we can therefore say that patients demand differently but are not heard.

I think a part of the LC community is certainly advocating for subtyping but I'm not sure people really understand what and how. Initially I thought it was about separating ME/CFS, various organ demage, etc. but even when a study is done on ME/CFS triggered by COVID, people are calling for subtyping (how?), especially if they wanted a trial to work and it didn't.

I think some private doctors are fueling subtype narrative, so they can keep prescribing inefficient drugs.

 

[Kitty]

This question would be better posed to our researchers, who are busy enrolling all types of patients in every treatment trial they do without filtering for the appropriate "subtype"! (feel free to insert another word there if that's triggering for you)

It's not triggering and I didn't author what you quoted anyway. It was Trish who asked, quite reasonably, why anyone would prescribe a drug to treat tachycardia to people without tachycardia.

I'm only arguing against crap research, and that includes trialling drugs we have no reason to think work, and setting up trials with arbitrary categories we have no reason to think differentiate meaningful subsets.

If it continues, and if patients keep putting up with it, we'll still be here in another 20 years. I've already done 50 years with ME/CFS, so you'll forgive my world-weariness. Like a lot of people here I've seen cycles of poor work being repeated over and over, and believe me it gets very boring.

 

[PageofME]

I think some private doctors are fueling subtype narrative, so they can keep prescribing inefficient drugs.

Smart. Sometimes I'm glad I'm not rich.

 

[Utsikt]

@Liface

I don’t understand what you’re suggesting.

Gathering data on what kinds of symptoms the participants have is a good idea. The same goes for blood samples and other data like steps, time spent lying down, etc. But we have no clue about how to use that data to meaningfully divide the participants into groups beforehand. And it’s not from a lack of trying - there have been quite a lot of papers published on various analyses of supposed subgroups.

Fluge and Mella analysed the data from the pilot of Dara and found that those classified as responders had more NK cells at baseline compared to those classified as non-responders. Based on this, they set a requirement of a least 125 (can’t remember the unit) for NK cells to be included in the next trial.

We have no idea if NK cells are relevant, or how they are relevant, but they chose to do it in an attempt to maximise the chance that if Dara works for some, it will show up in ResetME.

When we have a trial with a positive result, it might be easier to figure out if a measurement is relevant. But each analysis would still only generate a hypothesis, which would have to be tested in subsequent trials.

To give an example of how difficult it is to subgroup patients: they still have not been able to figure it out for MS. Some argue for differentiating between those with attacks and remissions, and those with progressive decline, but newer studies suggest that everyone progress and that each attack takes you closer to being in the progressive decline category. Maybe it’s something else.

Until we get an understanding of actual pathology, there’s no reason to hope for any subgrouping.