The Subtype-Free Average Causal Effect for Heterogeneous Disease Etiology

TL;DR

This paper introduces the Subtype-Free Average Causal Effect (SF-ACE), a new causal estimand for understanding how exposures like smoking affect specific disease subtypes, accounting for heterogeneity and untestable assumptions.

Contribution

It proposes the SF-ACE using principal stratification, explores its identification under various assumptions, and develops sensitivity analysis and estimators, including a doubly-robust method.

Findings

Applied to cohort data, revealing heterogeneity in smoking's effect on colorectal cancer subtypes.

Developed multiple estimators, including a doubly-robust one, for the SF-ACE.

Provided sensitivity analysis techniques to assess assumptions' impact.

Abstract

Studies have shown that the effect an exposure may have on a disease can vary for different subtypes of the same disease. However, existing approaches to estimate and compare these effects largely overlook causality. In this paper, we study the effect smoking may have on having colorectal cancer subtypes defined by a trait known as microsatellite instability (MSI). We use principal stratification to propose an alternative causal estimand, the Subtype-Free Average Causal Effect (SF-ACE). The SF-ACE is the causal effect of the exposure among those who would be free from other disease subtypes under any exposure level. We study non-parametric identification of the SF-ACE, and discuss different monotonicity assumptions, which are more nuanced than in the standard setting. As is often the case with principal stratum effects, the assumptions underlying the identification of the SF-ACE from the data are untestable and can be too strong. Therefore, we also develop sensitivity analysis methods that relax these assumptions. We present three different estimators, including a doubly-robust estimator, for the SF-ACE. We implement our methodology for data from two large cohorts to study the heterogeneity in the causal effect of smoking on colorectal cancer with respect to MSI subtypes.