Causal Discovery of Radiation Response Mechanisms in Human Cells

Next-generation sequencing technologies, including RNA-sequencing, provide genome-wide measurements of gene expression and enable broad explorations of biomarkers and mechanisms underlying disease and treatment response. Bioinformatics tools for processing this data, such as differential expression analysis, are largely univariate, linear, and rely on predefined pathway knowledge annotations, which limits their ability to capture nonlinear and multivariate gene interactions. This paper explores the application of causal discovery to characterizing transcriptional responses to radiation as a function of dose rate in human cells. By jointly modeling radiation perturbations and gene expression, we learn directed gene networks that capture important regulatory relationships beyond correlation and exhibit significant enrichment of known radiation response pathways compared to baseline approaches. We find that inferred causal graphs reveal structured network features such as high in-degree housekeeping genes and high out-degree transcription factors. Further analysis suggests a hierarchical organization of stress response pathways and triggered cell death pathways. This work highlights the potential of causal discovery in healthcare settings with applications to understanding response mechanisms, identifying regulatory targets, and improving interpretation of complex genomic data.