Large-Scale Labeling and Assessment of Sex Bias in Publicly Available Expression Data

ABSTRACT Women are at more than 1.5-fold higher risk for clinically relevant adverse drug events. While this higher prevalence is partially due to gender-related effects, biological sex differences likely also impact drug response. Publicly available gene expression databases provide a unique opportunity for examining drug response at a cellular level. However, missingness and heterogeneity of metadata prevent large-scale identification of drug exposure studies and limit assessments of sex bias. To address this, we trained organism-specific models to infer sample sex from gene expression data, and used entity normalization to map metadata cell line and drug mentions to existing ontologies. Using this method, we infer sex labels for 450,371 human and 245,107 mouse microarray and RNA-seq samples from refine.bio. Overall, we find slight female bias (52.1%) in human samples and (62.5%) male bias in mouse samples; this corresponds to a majority of single sex studies, split between female-only and male-only (33.3% vs 18.4% in human and 31.0% vs 30.4% in mouse respectively). In drug studies, we find limited evidence for sex-sampling bias overall; however, specific categories of drugs, including human cancer and mouse nervous system drugs, are enriched in female-only and male-only studies respectively. Our expression-based sex labels allow us to further examine the complexity of cell line sex and assess the frequency of metadata sex label misannotations (2-5%). We make our inferred and normalized labels, along with flags for misannotated samples, publicly available to catalyze the routine use of sex as a study variable in future analyses.