Improving Generalizability of Hip Fracture Risk Prediction via Domain Adaptation Across Multiple Cohorts

Accurate fracture risk prediction is important for osteoporosis management, but commonly used clinical tools may not fully use information available in electronic health records (EHRs) and dual-energy X-ray absorptiometry (DXA) reports. We developed and externally validated time-to-event fracture prediction models among adults aged 50 years or older with clinically obtained DXA reports in 2 US health care systems. The development cohort was derived from NewYork-Presbyterian/Weill Cornell Medical Center and the external validation cohort from the Indiana Network for Patient Care. Predictors included demographics, lifestyle factors, prior fracture, comorbidities, medication exposures, osteoporosis treatment history, and DXA-derived T-scores extracted from radiology reports. The outcome was time from index DXA to first incident fragility fracture identified from structured diagnosis codes. We evaluated penalized Cox regression, random survival forest, gradient-boosting survival, and XGBoost survival models using 2 prespecified predictor settings and compared discrimination with clinically reported FRAX major osteoporotic fracture probabilities. The development cohort included 11,510 adults, of whom 858 sustained incident fragility fractures; the external validation cohort included 1,932 adults, of whom 180 sustained fractures. In internal validation, the expanded Cox model achieved a mean Harrell C-index of 0.779, compared with 0.653 for FRAX. In external validation, the corresponding Cox model achieved a Harrell C-index of 0.714, compared with 0.590 for FRAX; gradient-boosting survival had the highest external discrimination (0.725). EHR- and DXA-enhanced models showed better discrimination than clinically reported FRAX scores in this DXA-tested population, but calibration assessment, prospective evaluation, and implementation workflow assessment are needed before clinical use.

Purpose: To compare dual-energy X-ray absorptiometry (DXA)-derived hip skeletal phenotypes in relation to hip fracture risk using prespecified confounder adjustment and to assess whether phenotypes ranked by their backdoor-adjusted average treatment effects (ATEs) improve risk stratification. Methods: We analyzed 21,098 UK Biobank participants with linked health records, hip DXA-derived skeletal measures, and prespecified covariates. Sixteen phenotypes spanning bone mineral content (BMC), bone mineral density (BMD), and T-score across hip-related regions were evaluated. Confounder selection was guided by a prespecified directed acyclic graph (DAG). Backdoor-adjusted ATEs were estimated on the absolute risk-difference scale per standard deviation (SD) increase. Effect heterogeneity was evaluated for total femur BMD, and downstream prediction was assessed using clinical variables combined with phenotypes ranked by ATE magnitude. Results: Among 21,098 participants, 115 had hip fractures. All 16 phenotypes showed negative backdoor-adjusted ATEs per SD increase. The largest ATEs were observed for total femur BMC and total femur BMD, each with a risk difference of -0.0047, corresponding to approximately 4.7 fewer hip fractures per 1,000 participants per SD higher phenotype value. Conditional effects of total femur BMD were stronger among older participants and those with lower BMI. In prediction, clinical variables plus the top 11 ATE-ranked phenotypes achieved higher AUC than FRAX with femoral neck BMD (0.842 vs. 0.709), with higher sensitivity (0.748 vs. 0.443) and similar specificity (0.793 vs. 0.777). Conclusion: DXA-derived hip skeletal phenotypes differed in their backdoor-adjusted ATEs. Phenotype-level causal evaluation may help identify informative DXA measures for risk stratification.

Domain adaptation aims to mitigate performance degradation caused by distribution shifts between a labeled source domain and an unlabeled or sparsely labeled target domain. Most existing approaches estimate domain discrepancy either in feature space or in prediction space. However, these single-perspective strategies overlook a critical problem under domain shift: the reliability of the signals used for alignment. In practice, both learned representations and semantic predictions may become unreliable, and treating all target samples equally can lead to misleading alignment and suboptimal transfer. We introduce trust-aware domain adaptation, a principled framework that models domain discrepancy through the reliability of feature and prediction signals. Central to our approach is the Joint Feature-Prediction Discrepancy (JFPD), a unified formulation that jointly captures representation divergence and prediction divergence while weighting their contributions by sample-specific trust. Trust is quantified via two complementary mechanisms: uncertainty-aware trust, derived from prediction entropy to suppress unreliable predictions, and semantic-alignment trust, computed from prototype similarity in feature space to emphasize well-aligned representations. By prioritizing confident and semantically consistent samples while down-weighting noisy or ambiguous ones, JFPD provides a reliability-aware estimate of domain discrepancy. We further integrate JFPD into a training objective that guides adaptation toward trustworthy regions of the target domain. Experiments on standard benchmarks demonstrate that the proposed framework consistently achieves superior adaptation performance and yields discrepancy estimates that correlate with target-domain error. This work addresses, for the first time, the importance of modeling trust in the interaction between features and predictions for domain adaptation.