用双分支Transformer融合多组学与药物结构,提升抗癌药效预测精度。
DeepDTF: Dual-Branch Transformer Fusion for Multi-Omics Anticancer Drug Response Prediction
- 双分支架构分别处理细胞系组学和药物分子图,融合跨模态特征
- 在冷启动评估下达到1.248的RMSE、0.987的AUC,分类错误降低9.5%
- 可解释性强,通过SHAP和通路富集揭示关键基因与生物学机制
癌症药物反应因多层面分子异质性而差异显著,亟需计算支持实现精准肿瘤学。尽管深度药物反应模型已有进展,但高维多组学与化学结构化药物之间的稳健对齐仍面临跨模态错位和归纳偏置不足的挑战。本文提出DeepDTF,一种端到端的双分支Transformer融合框架,用于联合对数IC50回归与药物敏感性分类。细胞系分支使用针对不同组学类型的编码器,结合Transformer模块捕捉长程依赖;药物分支将化合物表示为分子图,采用GNN-Transformer融合局部拓扑与全局上下文。组学与药物表征由基于Transformer的模块融合,建模跨模态交互并缓解特征错位。在公开药理基因组基准上,5折冷启动细胞系评估中,DeepDTF在所有组学设置下持续优于强基线,全组学输入时达RMSE=1.248、R²=0.875、AUC=0.987,分类误差(1-ACC)降低9.5%。此外,通过SHAP基因归因和预排序GSEA通路富集,提供生物可解释性分析。
原文摘要 · Abstract (English)
Cancer drug response varies widely across tumors due to multi-layer molecular heterogeneity, motivating computational decision support for precision oncology. Despite recent progress in deep CDR models, robust alignment between high-dimensional multi-omics and chemically structured drugs remains challenging due to cross-modal misalignment and limited inductive bias. We present DeepDTF, an end-to-end dual-branch Transformer fusion framework for joint log(IC50) regression and drug sensitivity classification. The cell-line branch uses modality-specific encoders for multi-omics profiles with Transformer blocks to capture long-range dependencies, while the drug branch represents compounds as molecular graphs and encodes them with a GNN-Transformer to integrate local topology with global context. Omics and drug representations are fused by a Transformer-based module that models cross-modal interactions and mitigates feature misalignment. On public pharmacogenomic benchmarks under 5-fold cold-start cell-line evaluation, DeepDTF consistently outperforms strong baselines across omics settings, achieving up to RMSE=1.248, R^2=0.875, and AUC=0.987 with full multi-omics inputs, while reducing classification error (1-ACC) by 9.5%. Beyond accuracy, DeepDTF provides biologically grounded explanations via SHAP-based gene attributions and pathway enrichment with pre-ranked GSEA.
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