ORBIT: Annotation-Aware Empirical Enrichment and Semantic Reranking for Interpretable Functional-Class Recovery

Gene-set interpretation workflows are widely used to summarize transcriptomic and proteomic experiments, yet standard enrichment tools often return long, redundant result tables that require substantial manual consolidation. We developed ORBIT (Ontology-Ranked Biological Interpretation Tool), an annotation-aware interpretation workflow that combines empirical enrichment, semantic reranking, and redundancy-aware representative-term selection to prioritize interpretable functional summaries from gene sets. We evaluated ORBIT on a curated tiered benchmark of human functional-class gene sets spanning clean reference sets, size-ladder variants, and mixed-difficulty cases. On the 45-set core benchmark, ORBIT semantic achieved higher expected-class recovery than Enrichr and PANTHER Gene Ontology molecular-function baselines, with a mean reciprocal rank of 0.916 and top-1 recovery of 0.889. Bootstrap confidence intervals and paired permutation testing supported the robustness of this advantage, and supplemental analyses extended the comparison to g:Profiler. In a GPCR mixed-function case study, ORBIT compressed redundant enriched terms into semantic representative neighborhoods, illustrating how long enrichment outputs can be converted into reviewable biological summaries. We applied ORBIT across complementary transcriptomic analyses spanning single-cell immune-cell markers, interferon-beta stimulation, and breast-cancer subtype biology. In these settings, ORBIT condensed marker and differential-expression signatures into prioritized functional summaries with explicit links to the genes, cell types, and annotation classes supporting each result. Together, these applications show how ORBIT can move from ranked enrichment terms to structured biological interpretation, preserving the evidence trail from input genes to functional summaries.