Symptom-conditioned prediction of comorbidity in the hEDS–POTS–MCAS triad
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Background
Hypermobile Ehlers–Danlos syndrome (hEDS), postural orthostatic tachycardia syndrome (POTS) and mast cell activation syndrome (MCAS) are reported to co-occur frequently. It is unclear how strongly, whether symptom profiles sharpen prediction of a second diagnosis given a first, and whether the published literature can support such inference at all.
Methods
We pooled 22 published cohorts—aggregate prevalence data, no primary human-subjects data—using Bayesian hierarchical random-effects models on the logit scale, and propagated the resulting posteriors through naive and tempered symptom updating. We introduce a feasibility screen derived from the Fréchet–Hoeffding bounds that tests whether separately pooled marginals can describe a single population, and we characterise the identifiability of latent class structure under disease-selected sampling.
Results
Directed comorbidity is strongly asymmetric: π POTS|hEDS = 46.6% (95% CrI [32.5, 61.5]) against π hEDS|POTS = 12.1% ([3.5, 38.5]), a near-fourfold gap, with π MCAS|POTS lowest at 3.9% ([0.7, 21.6]). Prediction intervals exceed credible intervals throughout, indicating substantial between-cohort heterogeneity. The feasibility screen finds 26 of 102 testable cells (25.5%) incompatible with any joint distribution; critically, 21 of these fail the upper Fréchet bound and are invisible to the one-sided screen that is the natural first implementation. Among cells surviving the screen, symptom evidence is informative in four of six directions—ℙ(hEDS|POTS, S ) rises from 12.1% to 49.7% on a four-symptom panel under tempered updating, and ℙ(POTS|MCAS, S ) from 49.5% to 82.1%—but inert in both hEDS-cohort directions. A pathway-dispersion contrast excludes zero in two of six directions, in opposite signs and by margins of 0.1–0.2 percentage points, consistent with chance at this number of comparisons. We show latent class structure is not identified from disease-selected aggregate data, and that the single cohort reporting trivariate structure ( N = 8) yields an exactly balanced table (OR = 1.00, 95% CI [0.063, 15.99]).
Conclusions
The pooled directional probabilities are usable as clinical priors, with intervals wide enough to preclude precision. Symptom-conditioned prediction is supported in some directions but not those most often invoked clinically, and every estimate rests on cohorts dominated by self-reported ascertainment. The principal methodological contribution is the two-sided feasibility screen: applied here it shows that a quarter of the testable literature cannot describe one coherent population, and that a one-sided implementation understates this sixfold.
