Machine learning based prioritisation of genes associated with osteoarthritis joint damage in animals.

To systematically prioritise unstudied genes for their potential to modulate joint damage phenotypes in animal models of osteoarthritis (OA). We curated 567 known protein-coding OA-associated genes from the literature and integrated them with 1139 uniformly processed skeletal transcriptomic response datasets and a human protein-protein interaction network to prioritise unstudied candidate OA genes. Three machine learning models, XGBoost, SVM, and Random Forest, were trained using repeated 5-fold cross-validation and evaluated on an independent test set of the latest literature-reported associations. Model interpretability was assessed using SHAP values analysis. The XGBoost model achieved the highest performance on the held-out test dataset, with an AUROC of 0.84 (95% CI: 0.81-0.87). As expected, key predictive features included transcriptomic responses from both animal models and human OA tissues, as well as protein-protein interaction network features. Notably, SHAP value analysis highlighted specific biological pathways including oxidative phosphorylation and complement factor pathways as influential in the model. The top-prioritised genes included regulators of the NF-κB pathway, such as IER3, SOCS3, and NFKBIA. Incorporation of OpenTargets druggability data highlighted putative clinically tractable genes for further investigation, including MMP2 and MAP3K8. Our trained machine learning model effectively prioritised newly reported OA-associated genes, demonstrating its potential as a systematic gene prioritisation tool. An accompanying SkeletalVis R package enables researchers to explore over 1000 transcriptomic responses and the trained model predictions for their own studies.