Acid Suppression and Esophageal Adenocarcinoma: A Critique of Causal Inference

This paper examines the inferential framework used to attribute the positive association between acid-suppressive therapy (AS) and esophageal adenocarcinoma (EAC) to confounding by gastroesophageal reflux disease (GERD), a common indication for AS. The experimental literature has proposed several hypotheses by which AS may increase EAC risk, and reviews of the in vivo literature have suggested that the AS--EAC association may be causal. At the same time, clinical guidelines maintain that the AS--EAC association likely reflects confounding by GERD and cite the findings of decades-old observational studies that either estimate the AS--EAC association among those without reflux-related indications or estimate a common treatment OR after adjusting for the presence of GERD as a main-effect covariate. This paper first examines the causal hypotheses described in the in vivo literature and establishes that the patient's underlying reflux burden is a presupposed effect modifier under each of these hypotheses. It then argues that the epidemiologic findings presented to clinicians as reassuring evidence against causality do not distinguish confounding by GERD from any of these hypotheses.