Prior-Informed Graph Skeleton Learning for ncRNA–Drug Resistance Association Prediction

Abstract

Identifying the associations between non-coding RNAs and drug resistance (RDRAs) is crucial for uncovering resistance mechanisms and screening effective biomarkers. However, existing graph-based methods typically rely on purely data-driven learning and commonly assume a simplified noise independence hypothesis, overlooking the complex dependencies among feature, structural, and label noise in biomedical networks. This leads to issues such as spurious associations, poor generalization, and lack of interpretability for noisy association prediction tasks. To address these challenges, we propose Prior-RDRGSE, a prior-knowledge-guided dependency-aware graph learning framework. This framework integrates both dependency-aware graph noise modeling and domain knowledge into graph representation learning. Specifically, we first construct a heterogeneous bipartite graph and employ a deep generative inference encoder to jointly infer the underlying clean graph structure and the association signals, thereby explicitly modeling and purifying the intertwined complex noise within the network. Next, we design a resistance-semantics-conditioned interaction module that injects disease-specific and mechanism-related semantic priors into attention queries, explicitly guiding subnetwork interactions in a biologically plausible manner. Furthermore, we introduce a resistance consistency constraint based on KL divergence, which regularizes model training by aligning the learned association distribution with prior distributions derived from clinical and literature data. Comprehensive experiments demonstrate that Prior-RDRGSE achieves state-of-the-art performance in RDRA prediction and significantly outperforms existing methods.