Enhanced osteoporotic fracture prediction in postmenopausal women using Bayesian optimization of machine learning models with genetic risk score

Abstract

Abstract This study aimed to enhance the fracture risk prediction accuracy in major osteoporotic fractures (MOFs) and hip fractures (HFs) by integrating genetic profiles, machine learning (ML) techniques, and Bayesian optimization. The genetic risk score (GRS), derived from 1,103 risk single nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS), was formulated for 25,772 postmenopausal women from the Women's Health Initiative dataset. We developed four ML models: Support Vector Machine (SVM), Random Forest, XGBoost, and Artificial Neural Network (ANN) for binary fracture outcome and 10-year fracture risk prediction. GRS and FRAX clinical risk factors (CRFs) were used as predictors. Death as a competing risk was accounted for in ML models for time-to-fracture data. ML models were subsequently fine-tuned through Bayesian optimization, which displayed marked superiority over traditional grid search. Evaluation of the models' performance considered an array of metrics such as accuracy, weighted F1 Score, the area under the precision-recall curve (PRAUC), and the area under the receiver operating characteristic curve (AUC) for binary fracture predictions, and the C-index, Brier score, and dynamic mean AUC over a 10-year follow-up period for fracture risk predictions. We found that GRS-integrated XGBoost with Bayesian optimization is the most effective model, with an accuracy of 91.2% (95% CI: 90.4–92.0%) and an AUC of 0.739 (95% CI: 0.731–0.746) in MOF binary predictions. For 10-year fracture risk modeling, the XGBoost model attained a C-index of 0.795 (95% CI: 0.783–0.806) and a mean dynamic AUC of 0.799 (95% CI: 0.788–0.809). Compared to FRAX, the XGBoost model exhibited a categorical net reclassification improvement (NRI) of 22.6% (P = .004). A sensitivity analysis, which included BMD but lacked GRS, reaffirmed these findings. Furthermore, portability tests in diverse non-European groups, including Asians and African Americans, underscored the model's robustness and adaptability. This study accentuates the potential of combining genetic insights and optimized ML in strengthening fracture predictions, heralding new preventive strategies for postmenopausal women.