High-Dimensional Sensitivity Analysis for Genomic Studies: An Adversarial Framework for Learning Worst-Case Latent Confounders

Abstract

High-dimensional genomics studies are frequently confounded by unmeasured biological processes that obscure disease-specific signals. While existing workflows can estimate these latent confounders, they fail to quantify how robust a discovery is to varying levels of hypothetical confounding. We introduce sensGAN, a deep-learning adversarial framework that systematically explores the confounding spectrum by learning “worst-case” latent variables that nullify the most gene associations under novel predictive-gain constraints. By identifying the minimum confounding strength required to explain away an observed effect, our method shifts the paradigm toward a formal, quantitative sensitivity analysis. In diverse simulations, sensGAN accurately recovers latent structures and outperforms existing methods in identifying confoundersensitive genes. Applied to human Alzheimer’s disease microglia, our framework prioritizes robust disease pathways while successfully isolating signals driven by unmeasured co-occurring neurodegenerative pathologies. Our method is publicly available, deposited at the GitHub repository yifanlinz/AD-sensitivity-ICML.