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 (DPP) constraint into the standard IB 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.

Synthetic lethality (SL) prediction is used to identify if the co-mutation of two genes results in cell death. The prevalent strategy is to abstract SL prediction as an edge classification task on gene nodes within SL data and achieve it through graph neural networks (GNNs). However, GNNs suffer from limitations in their message passing mechanisms, including over-smoothing and over-squashing issues. Moreover, harnessing the information of non-SL gene relationships within large-scale multi-omics data to facilitate SL prediction poses a non-trivial challenge. To tackle these issues, we propose a new multi-omics sampling-based graph transformer for SL prediction (MSGT-SL). Concretely, we introduce a shallow multi-view GNN to acquire local structural patterns from both SL and multi-omics data. Further, we input gene features that encode multi-view information into the standard self-attention to capture long-range dependencies. Notably, starting with batch genes from SL data, we adopt parallel random walk sampling across multiple omics gene graphs encompassing them. Such sampling effectively and modestly incorporates genes from omics in a structure-aware manner before using self-attention. We showcase the effectiveness of MSGT-SL on real-world SL tasks, demonstrating the empirical benefits gained from the graph transformer and multi-omics data.

Synthetic lethality (SL) is a promising concept for novel discovery of anti-cancer drug targets. However, wet-lab experiments for detecting SLs are faced with various challenges, such as high cost, low consistency across platforms or cell lines. Therefore, computational prediction methods are needed to address these issues. This paper proposes a novel SL prediction method, named SL2MF, which employs logistic matrix factorization to learn latent representations of genes from the observed SL data. The probability that two genes are likely to form SL is modeled by the linear combination of gene latent vectors. As known SL pairs are more trustworthy than unknown pairs, we design importance weighting schemes to assign higher importance weights for known SL pairs and lower importance weights for unknown pairs in SL2MF. Moreover, we also incorporate biological knowledge about genes from protein-protein interaction (PPI) data and Gene Ontology (GO). In particular, we calculate the similarity between genes based on their GO annotations and topological properties in the PPI network. Extensive experiments on the SL interaction data from SynLethDB database have been conducted to demonstrate the effectiveness of SL2MF.