Graph generative and adversarial strategy-enhanced node feature learning and self-calibrated pairwise attribute encoding for prediction of drug-related side effects.

Abstract

Background: Inferring drug-related side effects is beneficial for reducing drug development cost and time. Current computational prediction methods have concentrated on graph reasoning over heterogeneous graphs comprising the drug and side effect nodes. However, the various topologies and node attributes within multiple drug-side effect heterogeneous graphs have not been completely exploited. Methods: We proposed a new drug-side effect association prediction method, GGSC, to deeply integrate the diverse topologies and attributes from multiple heterogeneous graphs and the self-calibration attributes of each drug-side effect node pair. First, we created two heterogeneous graphs comprising the drug and side effect nodes and their related similarity and association connections. Since each heterogeneous graph has its specific topology and node attributes, a node feature learning strategy was designed and the learning for each graph was enhanced from a graph generative and adversarial perspective. We constructed a generator based on a graph convolutional autoencoder to encode the topological structure and node attributes from the whole heterogeneous graph and then generate the node features embedding the graph topology. A discriminator based on multilayer perceptron was designed to distinguish the generated topological features from the original ones. We also designed representation-level attention to discriminate the contributions of topological representations from multiple heterogeneous graphs and adaptively fused them. Finally, we constructed a self-calibration module based on convolutional neural networks to guide pairwise attribute learning through the features of the small latent space. Results: The comparison experiment results showed that GGSC had higher prediction performance than several state-of-the-art prediction methods. The ablation experiments demonstrated the effectiveness of topological enhancement learning, representation-level attention, and self-calibrated pairwise attribute learning. In addition, case studies over five drugs demonstrated GGSC's ability in discovering the potential drug-related side effect candidates. Conclusion: We proposed a drug-side effect association prediction method, and the method is beneficial for screening the reliable association candidates for the biologists to discover the actual associations.