Latent Variation in Pathogen Strain-specific Effects Under Multiple-Versions-of-Treatment Theory

Evidence-informed infectious disease policy requires estimates of the health effects of infections. However, pathogenic variation, whereby the risk of adverse outcomes depends on the strain-specific characteristics of the pathogen, might complicate the study of many infectious agents. Here, we consider the interpretation of epidemiologic studies of infectious diseases when there is such heterogeneity in strain-specific effects and when information on strain composition is unavailable. We use potential outcomes and causal inference theory for analyses in the presence of multiple versions of treatment to argue that oft-reported quantities in these studies have a causal interpretation that depends on population frequencies of infecting strains. Moreover, as in other contexts where the treatment-variation-irrelevance assumption might be violated, transportability requires additional considerations, beyond those needed for noncompound exposures. This discussion, considering potential heterogeneity in strain-specific effects, will facilitate the interpretation of epidemiologic studies and also highlight the value of pathogen subtype data.