Systematic detection of predictive gene sets by semantics-based selection

Abstract

The Gene Ontology (GO) is a public resource that describes gene functions and characteristics through a structured vocabulary of standardised terms. It currently contains annotations for over 1.5 million gene products, each linked to one or more GO terms. In this study, we propose integrating this GO-based semantic structure into machine learning systems for medical diagnostics. This approach serves a dual purpose: first, to prioritise genes that are semantically relevant to a given clinical task, thereby refining model input; and second, to enable the analysis of biologically predefined gene sets, which may reveal novel mechanisms underlying disease. Evaluated across 16 benchmark data sets spanning diverse medical domains, our GO term-informed gene selection method generally outperformed models trained on full gene sets. Further analysis of individual GO terms not only enhanced classification performance but also identified high-performing, task-specific gene subsets that were overlooked during initial gene selection. Our findings demonstrate that Gene Ontology can be effectively leveraged for semantics-aware gene selection in clinical machine learning. Moreover, systematically evaluating individual GO terms offers a scalable strategy to uncover new, testable biological hypotheses–revealing gene functions that might otherwise remain hidden when examining only broadly selected gene combinations.