Gastro-esophageal reflux disease (GERD) affects roughly 20% of United States adults. Its danger is not the symptom but the progression esophagitis → Barrett’s esophagus → esophageal adenocarcinoma (a cancer with ~20% five-year survival), plus aspiration pneumonia. This oracle estimates the causal reduction in esophagitis / reflux — the proximal mediator of those hard endpoints — achievable by combining therapies, using effect sizes from named trials. Cancer/mortality endpoints are largely inferred and flagged.
Tick the interventions to combine. Each shows its trial hazard ratio, 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 acid-exposure-mediator 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 distinct node; nearly all effects flow through the shared mediator esophageal acid exposure (acid-suppressants directly; fundoplication / weight loss / alginate via the reflux barrier). Acid exposure drives the esophagitis → Barrett’s → adenocarcinoma progression and the aspiration → pneumonia branch, both reaching mortality. Radiofrequency ablation is acid-independent — it ablates dysplastic tissue directly. Named confounders open back-door paths (adjusted). Illustrative of structure, not yet the identification engine.
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 for this domain: incretin drugs, surgery, diet, and activity overwhelmingly share the weight-loss / insulin-sensitivity pathway, so ~30% of their nominal effects overlap. A mediation analysis of semaglutide found ~80% of its MACE benefit is not mediated by weight loss, which is why ρ̄ is user-adjustable rather than fixed.
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-hazard-ratio 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 hazard ratio would be…". Isolates each intervention's marginal causal contribution after mediator-overlap removal, so shared-pathway agents are not double-credited.
| If not for… | HR without it | HR with full set | marginal RRR lost |
|---|
One-at-a-time sensitivity. Each intervention's hazard ratio is swung across its 95% confidence interval (others held at point estimate); the bar is the resulting swing in the combined front-door HR. A long bar means the combined estimate leans heavily on that single trial's precision.
Front-door (mediation) decomposition. Most GERD therapies act through one shared mediator — reduction of esophageal acid exposure. Each log-effect is split into an acid-mediated (indirect) and an acid-independent (direct) part. Indirect parts are pooled through the mediator with dose-response saturation (acid exposure cannot fall below zero — two acid-suppressants cannot each abolish the same acid), removing the mediator cross-correlation; direct parts keep the residual eigenvalue correlation at ρ̄. Radiofrequency ablation, which removes dysplastic tissue rather than acid, is therefore NOT discounted for overlap with the acid-suppressants.
| Intervention | HR | %acid↓ | acid-med | indirect logHR | direct logHR |
|---|
Which % of cross-correlation is appropriate? Not one number. The mediator overlap is fixed empirically by the acid-exposure saturation (currently removing — of the summed acid-mediated effect when acid-suppressants are stacked — adding an H2-antagonist to a proton-pump inhibitor barely lowers already-suppressed acid). The direct overlap is the residual ρ̄. Acid-mediated fractions are transparent, adjustable priors.
Front-door caveat (antithesis): the cited endpoints are mostly esophagitis healing / reflux control — a surrogate. Whether acid suppression prevents esophageal adenocarcinoma is largely unproven: AspECT showed only a modest composite benefit (time ratio 1.27), and Barrett’s progresses to cancer at just ~0.3–0.5%/year. The acid→cancer path is confounded (obesity, smoking). Indirect mortality estimates are upper bounds.
Select interventions to generate a plain-language summary.