BVSIMC: Bayesian Variable Selection-Guided Inductive Matrix Completion for Improved and Interpretable Drug Discovery

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 27.4%, with gains across all eight datasets and improvements in overall response prediction. These results demonstrate how matched drug contrasts turn complementary screens into shared molecular supervision for unseen-drug response prediction while preserving native gene measurements.

Many biomedical challenges can be posed as tensor completion problems where the observed entries of a multidimensional array (a tensor) are used to impute the missing values. In such settings, incorporating side information about the modes of the tensor, such as gene-gene similarity, can significantly enhance the solutions of the completion problem. Most existing tensor completion methods can only incorporate side information in the form of matrices. In this study, we introduce a novel framework to incorporate side information in the form of tensors. Our new approach, called Coupled Tensor-Tensor Completion (CTTC), leverages the hidden connections among multimodal tensors to improve tensor completion performance. In addition to practical utility, CTTC has theoretical foundations in distance metric learning and group theory. We derive an alternating algorithm to solve the CTTC optimization problem and establish its convergence to a stationary point. Finally, we show that CTTC outperforms state-of-the-art tensor completion methods at predicting drug effects. Results: Compared with other tensor completion methods, including HaLRTC, CTRC, Cell, and NTDDR, CTTC demonstrates superior run-time and RSE tensor completion accuracy on two benchmark datasets, DTD and LINCS.

Predicting how a cell's transcriptome responds to a drug it has never seen is a core, hard problem in computational cell biology: recent benchmarks show complex models often fail to beat trivial baselines once test compounds are held out by chemistry. We study one cell line and assay, THP-1 cells profiled by DRUG-seq, scored by the active-compound weighted MSE(wMSE) of the VCPI prediction contest. We propose a staged approach: dumb baselines (untreated control and mean training-compound response) that the field keeps failing to beat; non-parametric retrieval (a Tanimoto-weighted average of a held-out compound's nearest training compounds); and a fusion stage combining a frozen chemistry embedding with retrieval-support features to predict the residual over the mean, with an uncertainty head and gene programs. On the released VCPI THP-1 drug-seq data (14,026 training compounds), under a Bemis-Murcko scaffold split, the model ranking inverts depending on the metric. Under an inverse-variance per-gene proxy, a regularized linear regression on Morgan fingerprints appears to win over the deep models, retrieval, and ChemBERTa -- the textbook "simple baselines win" result. But under the contest's true active-set metric (per-(gene, compound) Mejia weights, validated against the official scorer; mean baseline 0.535 vs the organizers' 0.507 reference), that reverses: the deep models win, our fusion decoder significantly beats the linear fingerprint baseline (-0.012 wMSE, paired bootstrap p < 10^-4), and the proxy's winner becomes the worst chemistry-aware predictor. Picking the metric picks the winner -- to our knowledge the first demonstration on real held-out drug chemistry of the metric-calibration effect established largely on genetic perturbation. We release a reproducible pipeline wired to the official scorer that emits a valid submission over the real 1064 x 12,995 grid.