Predicting respiratory infection and symptoms development using gene set enrichment scores and machine learning

Recent advancements in precision medicine enable personalized predictions grounded in individual-level genetic data. However, relying solely on a single type of data can decrease prediction accuracy and limit the biological interpretability of the resulting models. Incorporating predefined genetic knowledge, such as derived gene sets, can improve performance and provide deeper biological insights for complex diseases, including respiratory infections. This study aimed to evaluate the usability of enrichment scores (ES), calculated using gene sets from the Molecular Signatures Database (MSigDB), as a feature representation for machine learning models to predict respiratory viral infections and symptom development. In addition, the proposed feature representation approach was extensively compared with the de facto gene-level expression representation. A total of 36,834 predefined gene sets were compiled from the MSigDB, and their ES values were calculated. Experiments used the GSE73072 dataset from Gene Expression Omnibus, containing gene expression profiles before and after virus exposure. Various machine learning and feature selection algorithms were applied to ES-based and probe-level feature sets. The results showed that both feature representation approaches achieved an area under the precision-recall curve (AUPRC) value greater than 0.90 for all tasks. Compared with the Respiratory Viral DREAM Challenge leaderboard phase, our models showed a 14.8% improvement in pre-exposure predictions (T0) and a 17.4% improvement in symptom classification. Using enrichment scores as a feature representation generally resulted in better performance than probe-level representation when predicting respiratory infections and symptom development. Identifying key gene sets through feature selection and comparing them with essential genes for respiratory viruses enabled a more comprehensive analysis, providing deeper insights into the pathways that contribute to these predictions.