CrossADR: enhancing adverse drug reactions prediction for combination pharmacotherapy with cross-layer feature integration and cross-level associative learning

TL;DR

CrossADR is a hierarchical graph neural network framework that improves prediction of adverse drug reactions in combination therapies by integrating multi-scale biological data and capturing dynamic organ-level dependencies.

Contribution

It introduces a novel cross-layer feature integration and cross-level associative learning approach with a gated-residual-flow graph neural network for enhanced ADR prediction.

Findings

Achieves state-of-the-art performance on a large drug combination dataset.

Provides high-resolution insights into drug-protein interactions and pathways.

Demonstrates robustness across diverse experimental scenarios.

Abstract

Combination pharmacotherapy offers substantial therapeutic advantages but also poses substantial risks of adverse drug reactions (ADRs). The accurate prediction of ADRs with interpretable computational methods is crucial for clinical safety management, drug development, and precision medicine. However, managing ADRs remains a challenge due to the vast search space of drug combinations and the complexity of physiological responses. Current graph-based architectures often struggle to effectively integrate multi-scale biological information and frequently rely on fixed association matrices, which limits their ability to capture dynamic organ-level dependencies and generalize across diverse datasets. Here we propose CrossADR, a hierarchical framework for organ-level ADR prediction through cross-layer feature integration and cross-level associative learning. It incorporates a gated-residual-flow graph neural network to fuse multi-scale molecular features and utilizes a learnable ADR embedding space to dynamically capture latent biological correlations across 15 organ systems. Systematic evaluation on the newly constructed CrossADR-Dataset-covering 1,376 drugs and 946,000 unique combinations-demonstrates that CrossADR consistently achieves state-of-the-art performance across 80 distinct experimental scenarios and provides high-resolution insights into drug-related protein protein interactions and pathways. Overall, CrossADR represents a robust tool for cross-scale biomedical information integration, cross-layer feature integration as well as cross-level associative learning, and can be effectively utilized to prevent ADRs in clinical decision-making.