FastMI-HGNet: A Two-Stream Heterogeneous Graph Neural Network for Multi-Omics Disease Classification.

Background/Objectives: Multi-omics datasets are increasingly used for disease classification, but differences in scale, distribution, and resolution across omics layers complicate their integration. Conventional fusion approaches may overlook nonlinear cross-omics dependencies and structured sample-feature relationships. Here, we propose FastMI-HGNet, a two-stream heterogeneous graph neural network for multi-omics disease classification. Methods: The framework uses fast mutual information (FastMI) to construct dependency edge priors for a heterogeneous graph that connects sample and feature nodes. A Transformer-based data stream captures vector-level feature interactions, while a graph attention stream models structural dependencies among samples and molecular features. An uncertainty-aware ensemble further improves stability under small-sample and noisy multi-omics settings. Results: Evaluated on five public multi-omics benchmarks-ROSMAP, LGG, BRCA, and the more challenging COAD tumor-stage classification task, together with KIPAN as a ceiling-level proof-of-concept benchmark-FastMI-HGNet achieved competitive classification performance while supporting interpretable biomarker prioritization. In BRCA, SHAP-based analysis highlighted model-prioritized genes such as FOXC1 and SOX10. Conclusions: FastMI-HGNet supports interpretable multi-omics disease classification and biomarker prioritization.