ExPath: Towards Explaining Targeted Pathways for Biological Knowledge Bases (2502.18026v1)

Abstract: Biological knowledge bases provide systemically functional pathways of cells or organisms in terms of molecular interaction. However, recognizing more targeted pathways, particularly when incorporating wet-lab experimental data, remains challenging and typically requires downstream biological analyses and expertise. In this paper, we frame this challenge as a solvable graph learning and explaining task and propose a novel pathway inference framework, ExPath, that explicitly integrates experimental data, specifically amino acid sequences (AA-seqs), to classify various graphs (bio-networks) in biological databases. The links (representing pathways) that contribute more to classification can be considered as targeted pathways. Technically, ExPath comprises three components: (1) a large protein LLM (pLM) that encodes and embeds AA-seqs into graph, overcoming traditional obstacles in processing AA-seq data, such as BLAST; (2) PathMamba, a hybrid architecture combining graph neural networks (GNNs) with state-space sequence modeling (Mamba) to capture both local interactions and global pathway-level dependencies; and (3) PathExplainer, a subgraph learning module that identifies functionally critical nodes and edges through trainable pathway masks. We also propose ML-oriented biological evaluations and a new metric. The experiments involving 301 bio-networks evaluations demonstrate that pathways inferred by ExPath maintain biological meaningfulness. We will publicly release curated 301 bio-network data soon.