Immune-mediated skin disease is common: atopic dermatitis affects ~16.5 million United States adults and psoriasis ~7–9 million (~24 million combined). Rarely fatal, but a major driver of itch, sleep loss, disability, depression and — in severe psoriasis — a debated cardiovascular signal. This oracle estimates the causal reduction in skin inflammation — the shared mediator — from topical, biologic, oral and phototherapy options, using effect sizes from named trials. For education, not individual medical advice.
Tick the interventions to combine. Each shows its trial effect estimate, 95% confidence interval (CI), E-value, mechanism, and citation. ★ = in the current Pareto effective set but not yet ticked.
Headline is the front-door estimate: shared inflammation overlap removed via dose-response saturation; residual direct-effect overlap removed via the eigenvalue model at ρ̄.
Under monotonicity + exogeneity (E-value bounds the exogeneity assumption).
Faithful causal directed acyclic graph (DAG). Each therapy is a node; most act through the shared mediator skin inflammation, which drives skin severity, itch/quality-of-life and (in severe psoriasis) systemic inflammation / cardiovascular risk. IL-23/IL-17 biologics may act partly independently on systemic inflammation. Named confounders open back-door paths (adjusted). Illustrative of structure. Mediator cascade: interventions attach to the node they act on (local / topical → systemic immune), which converge on the disease state and thence the endpoint — drawing the intermediate mediators explicitly is what exposes d-separation and per-channel saturation.
Eigenvalue diagnostics for the selected interventions under an equicorrelation matrix (off-diagonal ρ̄). A large λmax relative to k signals redundancy; n_eff is the effective number of independent interventions actually contributing.
On mechanistic grounds ρ̄ ≈ 0.30 is defensible: agents overwhelmingly converge on the same cutaneous inflammatory cascade (type-2 in atopic dermatitis, IL-23/IL-17 in psoriasis), so a substantial fraction of their effects overlap and combining a topical with a systemic agent yields diminishing incremental clearance. ρ̄ is user-adjustable because class-switching (e.g. topical + biologic) captures partly non-overlapping mechanisms. Most of the overlap is now handled structurally by the mediator nodes (same-node substitutes saturate); ρ̄ governs only the residual correlation among direct effects.
Minimum-effective-set analysis. Set a target combined risk reduction; the model finds the smallest set of interventions — accounting for front-door mediator overlap — that reaches it, and highlights them. If the target exceeds what all interventions together can achieve, the full set is shown (never an empty one). "Apply" ticks exactly that set.
Monte Carlo propagation. Each selected intervention's log-effect is sampled from a normal distribution implied by its 95% CI; samples are combined with the same eigenvalue overlap discount. 5,000 draws.
Intervening on the selected set S with Pearl's do-operator (setting the interventions, not merely observing them). Contrast against do(∅) = no intervention.
For each intervention: "if not for this one, the combined front-door effect would be…". Isolates each intervention's marginal causal contribution after mediator-overlap removal, so shared-pathway agents are not double-credited.
| If not for… | RR without it | RR with full set | marginal RRR lost |
|---|
One-at-a-time sensitivity. Each intervention's effect is swung across its 95% confidence interval (others held at point estimate); the bar is the resulting swing in the combined front-door effect. A long bar means the combined estimate leans heavily on that single trial's precision.
Front-door (mediation) decomposition. Most therapies act through one shared mediator — reduction of skin inflammation. Each log-effect is split into an inflammation-mediated (indirect) and an inflammation-independent (direct) part. Indirect parts are pooled through the mediator with dose-response saturation (skin clearance saturates — you cannot clear below zero), removing the mediator cross-correlation; direct parts keep the residual eigenvalue correlation at ρ̄. IL-23/IL-17 biologics, with a partly systemic (CVD) effect, are not fully discounted against topicals. Here mediated effects are pooled WITHIN each cascade node (dose-response saturation of substitutes) and composed in SERIES across nodes (d-separated channels), with the per-node reductions reported so the channel structure is visible.
| Intervention | RR | %inflam | med-frac | indirect log | direct log |
|---|
Which % of cross-correlation is appropriate? Not one number. The mediator overlap is fixed empirically by the inflammation saturation (currently removing — of the summed mediated effect when interventions are stacked). Note a domain caveat: atopic-dermatitis agents (dupilumab, JAK) and psoriasis biologics (IL-23/IL-17, TNF) treat different diseases and are essentially never co-prescribed — a pooled estimate only applies within a disease. Inflammation-mediated fractions are transparent, adjustable priors.
Front-door caveat (antithesis): the endpoint is skin clearance (EASI/PASI response) — a surrogate. The morbidity and (contested) cardiovascular translations are partly observational, and stringent responder thresholds versus placebo overstate real-world open-label effectiveness.
Select interventions to generate a plain-language summary.