Unpaired Data Empowers Association Tests

To achieve a holistic view of the underlying mechanisms of human diseases, the biomedical research community is moving toward harvesting retrospective data available in Electronic Healthcare Records (EHRs). The first step for causal understanding is to perform association tests between types of potentially high-dimensional biomedical data, such as genetic, blood biomarkers, and imaging data. To obtain a reasonable power, current methods require a substantial sample size of individuals with both data modalities. This prevents researchers from using much larger EHR samples that include individuals with at least one data type, limits the power of the association test, and may result in higher false discovery rate. We present a new method called the Semi-paired Association Test (SAT) that makes use of both paired and unpaired data. In contrast to classical approaches, incorporating unpaired data allows SAT to produce better control of false discovery and, under some conditions, improve the association test power. We study the properties of SAT theoretically and empirically, through simulations and application to real studies in the context of Chronic Obstructive Pulmonary Disease. Our method identifies an association between the high-dimensional characterization of Computed Tomography (CT) chest images and blood biomarkers as well as the expression of dozens of genes involved in the immune system.