Preprint Distinct Symptom Clusters Reflect Pathophysiological Mechanisms in ME/CFS, 2025, Habermann-Horstmeier et al

[forestglip]

Distinct Symptom Clusters Reflect Pathophysiological Mechanisms in ME/CFS

Habermann-Horstmeier, Lotte; Horstmeier, Lukas M.

[Line breaks added]

Introduction
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe multisystemic disease with a broad spectrum of symptoms. A previous study showed evidence that certain symptoms often occur together in ME/CFS patients. Therefore, literature-based, hypothesis-driven ME/CFS symptom groups have now been formed. This study aimed to empirically test and validate these ME/CFS symptom clusters using statistical methods.

Methods
Symptom responses from 748 adult ME/CFS patients (≥ 20 years; 608 female, 137 male, 3 non-binary) in the APAV-ME/CFS study were analyzed. Participants were recruited by self-activation and snowball sampling. Reported symptoms were assigned to predefined groups aligned with known pathophysiological hypotheses. Exploratory and Confirmatory Factor Analyses, followed by Structural Equation Modeling (SEM), assessed the coherence and distinctiveness of each cluster. To assess the robustness of the findings, the same analyses were repeated on a stratified, randomized training dataset.

Results
Brain subgroup symptoms (brain fog, sensory hypersensitivity, visual disturbances, sleep disturbances, headaches) formed a single coherent factor with high loadings and excellent fit (RMSEA = 0.021; CFI = 0.996). Gastrointestinal ( Gut ) symptoms demonstrated stronger internal consistency than immunological ( Immune ) symptoms.

Model comparisons favored a two-factor Gut versus Immune structure over a unidimensional model. All analyses consistently identified internally coherent, distinct symptom groups with robust fit indices. SEM incorporating a common latent factor also yielded excellent fit for the vegetative symptom complex ( Vegetative ).

Conclusions
Findings reinforce ME/CFS as a complex neuro-immunological multisystem disease and show that symptoms can be attributed to functional body systems. Symptom-based subgrouping may support pathophysiology-guided diagnosis and inform the development of individualized therapeutic approaches.

Web | DOI | Research Square | Preprint

 

[Creekside]

Does anyone else think this analysis seems a lot like seeing pattern in the stars and attributing meaning to human personality?

 

[ScoutB]

Yea I’m too foggy to understand their process, so maybe this is unfair, but I'm kind of skeptical when one of the symptom clusters they’ve come up with is basically head-based symptoms.

 

[Jonathan Edwards]

Seems more like looking at meat and two veg on a plate and saying 'Gee, the veg is green and has leaves and the spuds are sort of round and buttery and the meat is reddish and juicy. Three things!!'

 

[obeat]

The gut has plenty of immune cells and is highly innervated so is it a neuro immune organ rather than just a digestion tube?

 

[DHagen]

Coming at this from a position of extreme ignorance and likely simply repeating what is obvious from the start to all here: I spent longer trying to follow this than was good for me, but my understanding is that essentially they sought to identify/create "clusters" of symptoms, that is, groups of symptoms that have been demonstrated in other circumstances to stem from a known, common cause. Having created these categories, they then looked to see whether pwME who had one symptom were more likely to also have some of the other symptoms within the same cluster. Believing themselves to have found that this is the case, they hypothesize that ME/CFS is either producing the same physiological problem responsible elsewhere for each "cluster" of symptoms, or something very similar, and that future research should consequently focus on treating these particular problems and exploring what can cause these particular problems.
Setting aside the validity of their methodology, which I am not equipped to deal with, does this seem essentially correct?

 

[Utsikt]

they sought to identify/create "clusters" of symptoms, that is, groups of symptoms that have been demonstrated in other circumstances to stem from a known, common cause.

I thought they chose the clusters based on hypothesised mechanisms?

The Exploratory (EFA) and Confirmatory Factor Analysis (CFA) then showed whether the previously defined, hypothesis-driven and pathophysiologically based subgroups were actually statistically detectable clusters.

Intro to results:

In the following, hypothesis-led subgroups will be compared with the empirical-statistical symptom groups.

 

[DHagen]

I thought they chose the clusters based on hypothesised mechanisms?

From the introduction:

It is expected that symptom groups can be identified that can be related to known pathophysiological processes, especially in the central and autonomic nervous systems.

Taken together with the passage you quoted, I understood this to mean that the "hypothesis" was that these mechanisms were also active in ME/CFS, not that they could cause these symptoms at all (which they hold to be established), but I could well be mistaken!

 

[poetinsf]

We already know that symptoms tend to cluster, so I don't know what new things the paper brings. They essentially took what is known, put them in some arbitrary buckets of "functional body systems" and then concluded that these functional body systems can be the causes of those symptoms.

I wish they would stop pursuing the notion that ME/CFS is some exotic, complicated multi-systemic disease. The symptoms are complicated, but the cause may not. It could be, and more likely than not if you ask me, a simple hypersensitivity to some immune signal unleashing a constellation of symptoms.

 

[poetinsf]

It's rather funny that they ignored the universal symptoms that define ME/CFS and then surmised from the clustering of non-core symptoms that ME/CFS is multisystemic. You'd think it would be more productive to focus on and pursue the cause of the universal ones.

 

[DHagen]

Possibly worth noting, for those skimming, that this is apparently Part 2 of a 5-part series.

The present analysis is the second part of a five-stage series of studies on the symptoms of ME/CFS. In the first, exploratory part of the study series, there was no correlation between the duration of the disease and the frequency of the individual symptoms for most symptoms. However, there were indications of differences between the sexes and a parallel occurrence of individual symptoms [8]. We therefore wondered whether it would be possible to identify such symptom groups and then relate them to known pathophysiological correlations in order to develop gender-appropriate preventive or therapeutic approaches at a later stage.

 

[Utsikt]

Sounds like a way to end up with individualised treatment recommendations based on whatever hypotheses that are currently being hyped..

 

[rvallee]

We already know that symptoms tend to cluster, so I don't know what new things the paper brings. They essentially took what is known, put them in some arbitrary buckets of "functional body systems" and then concluded that these functional body systems can be the causes of those symptoms.

I wish they would stop pursuing the notion that ME/CFS is some exotic, complicated multi-systemic disease. The symptoms are complicated, but the cause may not. It could be, and more likely than not if you ask me, a simple hypersensitivity to some immune signal unleashing a constellation of symptoms.

They also vary too much over time. I can't even remember another study that bothered to track this, it's always single points in time. The only study that did this was the second Body Politic one, and it showed how those symptom profiles shift and wane massively over the course of the illness. Symptoms at 3 months, 6, 12, and so on varied by huge amounts.

This essentially nullifies those attempts, but it's been essentially ignored because there have been at least a dozen, maybe even several dozens, studies trying to come up with those clusters, and most likely if they kept tracking symptoms in their cohort, they would find that their clusters move around far too much to be of value, and that's before we get to the fact that even in single points in time assessments there is a huge overlap.

All of which is frustrating because to me it seems like the most important thing to study here is that whatever the cause is, it has to account for those wild fluctuations, which significantly restricts the set of plausible hypotheses. But instead we only ever see studies that are performed naively, never trying to account for facts that are known.

 

[Sean]

And this, ladies and gentlemen, is why relying on superficial correlations is so dangerous.