A Network-Structured Bayesian Hierarchical Model for Sparse Mutation-Drug Response Associations: Application to Cancer Pharmacogenomics

Abstract

We develop a network-structured Bayesian hierarchical model for sparse association mapping between genomic alterations and quantitative treatment-response phenotypes. The framework combines a Gaussian Markov random field prior that borrows strength across pathway-connected genes, a global-local horseshoe prior inducing sparsity, and a conjugate Gibbs sampler requiring no Metropolis-Hastings steps. Though broadly applicable to high-dimensional settings with known predictor networks, we validate it using cancer cell-line drug-sensitivity data. Applied to GDSC2 ($N=951$ cell lines, $G=219$ driver genes, $D=295$ drugs), the model identifies 126 gene-drug associations (0.195\% of 64{,}605 pairs), concentrated in EZH2 (45 drugs, all sensitivity-direction, mean effect $-0.911$ $\ln$IC50) and KMT2D (36 drugs, all sensitivity-direction, mean effect $-0.496$ $\ln$IC50). These markers show external support in an independent PRISM screen (1{,}518 compounds), with KMT2D achieving complete directional replication (36/36) and EZH2 partial replication (8/12). Five-fold cross-validated predictive log-likelihood confirms each prior layer's value: the full model outperforms the no-network ablation by $+3{,}109$ log-units per fold and the no-horseshoe ablation by $+14{,}039$ log-units, consistently across folds. Simulations under three scenarios show the full model achieves the highest precision and lowest false-discovery rate throughout, while the network prior improves sensitivity recovery under network-structured signal. A tissue-stratified extension identifies coherent subgroup refinements, including lung-specific EGFR-inhibitor sensitivity and skin-specific BRAF-Dabrafenib sensitivity. These results show the framework identifies sparse, interpretable, externally supported drug-sensitivity markers while enabling principled investigation of tissue-specific departures from shared effects.