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Learning Multi-Types of Neighbor Node Attributes and Semantics by Heterogeneous Graph Transformer and Multi-View Attention for Drug-Related Side-Effect Prediction

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journal contribution
posted on 2023-10-18, 02:57 authored by Ping Xuan, Peiru Li, Hui CuiHui Cui, Meng Wang, Toshiya Nakaguchi, Tiangang Zhang
Since side-effects of drugs are one of the primary reasons for their failure in clinical trials, predicting their side-effects can help reduce drug development costs. We proposed a method based on heterogeneous graph transformer and capsule networks for side-effect-drug-association prediction (TCSD). The method encodes and integrates attributes from multiple types of neighbor nodes, connection semantics, and multi-view pairwise information. In each drug-side-effect heterogeneous graph, a target node has two types of neighbor nodes, the drug nodes and the side-effect ones. We proposed a new heterogeneous graph transformer-based context representation learning module. The module is able to encode specific topology and the contextual relations among multiple kinds of nodes. There are similarity and association connections between the target node and its various types of neighbor nodes, and these connections imply semantic diversity. Therefore, we designed a new strategy to measure the importance of a neighboring node to the target node and incorporate different semantics of the connections between the target node and its multi-type neighbors. Furthermore, we designed attentions at the neighbor node type level and at the graph level, respectively, to obtain enhanced informative neighbor node features and multi-graph features. Finally, a pairwise multi-view feature learning module based on capsule networks was built to learn the pairwise attributes from the heterogeneous graphs. Our prediction model was evaluated using a public dataset, and the cross-validation results showed it achieved superior performance to several state-of-the-art methods. Ablation experiments undertaken demonstrated the effectiveness of heterogeneous graph transformer-based context encoding, the position enhanced pairwise attribute learning, and the neighborhood node category-level attention. Case studies on five drugs further showed TCSD’s ability in retrieving potential drug-related side-effect candidates, and TCSD inferred the candidate side-effects for 708 drugs.

Funding

The work was supported by the Natural Science Foundation of China (61972135, 62172143, 62372282); STU Scientific Research Initiation Grant (NTF22032); and the Natural Science Foundation of Heilongjiang Province (LH2023F044).

History

Publication Date

2023-09-09

Journal

Molecules

Volume

28

Issue

18

Article Number

6544

Pagination

18p.

Publisher

Multidisciplinary Digital Publishing Institute

ISSN

1420-3049

Rights Statement

© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).