Drug repositioning offers promising prospects for accelerating drug discovery by identifying potential drug–disease associations (DDAs) for existing drugs and diseases. Previous methods have generated meta-path-augmented node or graph embeddings for DDA prediction in drug–disease heterogeneous networks. However, these approaches rarely develop end-to-end frameworks for path instance-level representation learning as well as the further feature selection and aggregation. By leveraging the abundant topological information in path instances, more fine-grained and interpretable predictions can be achieved. To this end, we introduce deep multiple instance learning into drug repositioning by proposing a novel method called MilGNet. MilGNet employs a heterogeneous graph neural network (HGNN)-based encoder to learn drug and disease node embeddings. Treating each drug–disease pair as a bag, we designed a special quadruplet meta-path form and implemented a pseudo meta-path generator in MilGNet to obtain multiple meta-path instances based on network topology. Additionally, a bidirectional instance encoder enhances the representation of meta-path instances. Finally, MilGNet utilizes a multi-scale interpretable predictor to aggregate bag embeddings with an attention mechanism, providing predictions at both the bag and instance levels for accurate and explainable predictions. Comprehensive experiments on five benchmarks demonstrate that MilGNet significantly outperforms ten advanced methods. Notably, three case studies on one drug (Methotrexate) and two diseases (Renal Failure and Mismatch Repair Cancer Syndrome) highlight MilGNet’s potential for discovering new indications, therapies, and generating rational meta-path instances to investigate possible treatment mechanisms. The source code is available at https://github.com/gu-yaowen/MilGNet.
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