GOLDEN fusion: a graph-oriented learning with domain-embedding network fusion for generating super gene sets in functional genomics

The integrative analysis of gene sets, networks, and pathways is pivotal for deciphering omics data in translational biomedical research. To significantly increase gene coverage and enhance the utility of gene sets from diverse sources, we introduced pathways, annotated gene lists, and gene signatures (PAGs) enriched with metadata to represent biological functions. Furthermore, we established PAG-PAG networks by leveraging gene member similarity and gene regulations. However, in practice, high similarity in descriptions and gene membership often produces redundant, lengthy PAG lists, leading to gene set enrichment results that are difficult to interpret. We present Graph-Oriented Learning with Domain-Embedding Network (GOLDEN) fusion, an integrative framework that jointly leverages (i) connection-based embeddings derived from PAG-PAG relationships and (ii) semantic-based embeddings learned from PAG descriptions with a large language model (LLM). The two representations are combined via early fusion with a tunable weighting to produce a unified embedding on which clustering identifies concise, higher-level super-PAG. To assess when clustering is appropriate, we introduce a Connection Disparity Index, trained on synthetic stochastic block models, as a proxy for network "clusterability." We further optimize the number of clusters with consensus clustering. On Gene Ontology Annotation biological process benchmarks, GOLDEN fusion recovers is-a structure more accurately than either connection-only or semantic-only baselines, demonstrating consistent gains in Adjusted Rand Index and Normalized Mutual Information. Finally, we generate summaries for each super-PAG by synthesizing its member PAG descriptions using a comparative analysis of LLMs. GOLDEN fusion provides an integrated framework for interpreting omics results.