X-LDA: An interpretable and knowledge-informed heterogeneous graph learning framework for LncRNA-disease association prediction

Abstract

The identification of disease-related long noncoding RNAs (lncRNAs) is beneficial to unravel the intricacies of gene expression regulation and epigenetic signatures. Computational methods provide a cost-effective means to explore lncRNA-disease associations (LDAs). However, these methods often lack interpretability, leaving their predictions less convincing to biological and medical researchers. We propose an interpretable and knowledge-informed heterogeneous graph learning framework based on graph patch convolution and integrated gradients to predict LDAs and provides intuitive explanations for its predictions, called X-LDA. The heterogeneous graph is the foundation of the predictions of LDAs, we construct the knowledge-informed heterogeneous graph including LDAs drawn from biological experiments, lncRNA similarities rooted in gene sequences, disease similarities constructed based on disease categorizations. To integrate diverse biological premises and facilitate interpretability, we define nine distinct graph patch types, which encapsulate essential topological relationships within lncRNA-disease node pairs. X-LDA is designed to employ parameter sharing and multi-convolution kernels to grasp common and multiple perspectives of the graph patches, respectively. This approach culminates in the fusion of various semantic information into context embeddings. These post-hoc explanations hinge on graph patch features and integrated gradients, shedding light on the underlying factors driving predictions. Cross validation experiment on the dataset curated from databases and literatures demonstrates that the superior performance of X-LDA in comparison to nine state-of-the-art methods of three categories. X-LDA achieves a larger average area under the receiver operating curve 0.9891 (by at least 6.68%), and a larger average area under the precision–recall curve 0.7907 (by at least 23.2%) than competitive methods. The results of our well-designed ablation and interpretability experiments and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis demonstrate X-LDA’s robustness, learnability, predictability, and interpretability. The applicability of X-LDA is also demonstrated through a case study involving the investigation of associated lncRNAs in prostate cancer, colorectal cancer, and breast cancer.