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 mechanisms by which AS may increase the risk of EAC—either by altering the properties of refluxate or enhancing proliferation in reflux-injured tissue—and reviews of the in vivo literature have suggested that the AS–EAC association may be causal. At the same time, clinical guidelines have long maintained that the AS–EAC association reflects confounding by GERD, and cite observational studies that estimate either the AS–EAC association among those without GERD or the treatment odds ratio upon adjusting for GERD as a main-effect covariate. This paper first outlines the causal hypotheses articulated in the in vivo literature and establishes that the patient's underlying reflux burden is an effect modifier under each of these hypotheses. It then argues that the epidemiologic findings presented in clinical guidelines as reassuring evidence against causality have been widely misread, as they do not inherently distinguish confounding by GERD from the causal structures implied by any of these hypotheses.