Chen Xuexin, Cai Ruichu, Huang Zhengting, Li Zijian, Zheng Jie, Wu Min
School of Computer Science, Guangdong University of Technology, No. 100 Waihuan Xi Road, Panyu, Guangdong, Guangzhou, 510006, China.
Pazhou Laboratory (Huangpu), No. 248 Pazhou Qiaotou Street, Haizhu, Guangdong Province, Guangzhou, 510335, China.
Brief Bioinform. 2025 Mar 4;26(2). doi: 10.1093/bib/bbaf142.
Synthetic lethality (SL) is a promising gene interaction for cancer therapy. Recent SL prediction methods integrate knowledge graphs (KGs) into graph neural networks (GNNs) and employ attention mechanisms to extract local subgraphs as explanations for target gene pairs. However, attention mechanisms often lack fidelity, typically generate a single explanation per gene pair, and fail to ensure trustworthy high-order structures in their explanations. To overcome these limitations, we propose Diverse Graph Information Bottleneck for Synthetic Lethality (DGIB4SL), a KG-based GNN that generates multiple faithful explanations for the same gene pair and effectively encodes high-order structures. Specifically, we introduce a novel DGIB objective, integrating a determinant point process constraint into the standard information bottleneck objective, and employ 13 motif-based adjacency matrices to capture high-order structures in gene representations. Experimental results show that DGIB4SL outperforms state-of-the-art baselines and provides multiple explanations for SL prediction, revealing diverse biological mechanisms underlying SL inference.
合成致死(SL)是一种很有前景的癌症治疗基因相互作用。最近的SL预测方法将知识图谱(KG)集成到图神经网络(GNN)中,并采用注意力机制提取局部子图作为目标基因对的解释。然而,注意力机制往往缺乏保真度,通常每个基因对只生成一个解释,并且无法确保其解释中高阶结构的可信度。为了克服这些限制,我们提出了用于合成致死的多样图信息瓶颈(DGIB4SL),这是一种基于KG的GNN,它可以为同一基因对生成多个可靠的解释,并有效地编码高阶结构。具体来说,我们引入了一个新颖的DGIB目标,将行列式点过程约束集成到标准信息瓶颈目标中,并使用13个基于基序的邻接矩阵来捕获基因表示中的高阶结构。实验结果表明,DGIB4SL优于当前最先进的基线方法,并为SL预测提供了多种解释,揭示了SL推理背后的多种生物学机制。