Bison: Cross-Dataset Learning for Unseen-Compound Perturbation Prediction

Yunfan Liu, Kasra Ghorbani, Yufei Huang, Zicheng Liu, Jiangbin Zheng +4

Predicting transcriptional responses to unseen compounds is limited by fragmented chemical coverage and heterogeneous experimental platforms and gene panels. To assess molecular generalization across these settings, we build on Chem-PerturBridge to benchmark eight datasets with 16,771 compounds, withholding test compounds from every training dataset. This comparison reveals that high overall response agreement can coexist with weak prediction of drug-specific differences, despite reproducible signals across repeated measurements. To exploit complementary chemical supervision while targeting these differences, we introduce Bison: a shared gene representation connects native panels, while two discrete diffusion models compose context-dependent responses with molecular deviations learned through matched drug-contrast supervision. A single Bison model jointly trained across all eight datasets achieves the highest mean overall-response and drug-contrast Pearson correlations on the full benchmark in comparison with 11 methods trained independently per dataset. Compared with dataset-specific training of the same architecture, joint training increases mean drug-contrast correlation by…