Predicting Rejection Risk in Heart Transplantation: An Integrated Clinical-Histopathologic Framework for Personalized...

Cardiac allograft rejection (CAR) remains the leading cause of early graft failure after heart transplantation (HT). Current diagnostics, including histologic grading of endomyocardial biopsy (EMB) and blood-based assays, lack accurate predictive power for future CAR risk. We developed a predictive model integrating routine clinical data with quantitative morphologic features extracted from routine EMBs to demonstrate the precision-medicine potential of mining existing data sources in post-HT care.

In a retrospective cohort of 484 HT recipients with 1,188 EMB encounters within 6 months post-transplant, we extracted 370 quantitative pathology features describing lymphocyte infiltration and stromal architecture from digitized H&E-stained slides. Longitudinal clinical data comprising 268 variables-including lab values, immunosuppression records, and prior rejection history-were aggregated per patient. Using the XGBoost algorithm with rigorous cross-validation, we compared models based on four different data sources: clinical-only, morphology-only, cross-sectional-only, and fully integrated longitudinal data. The top predictors informed the derivation of a simplified Integrated Rejection Risk Index (IRRI), which relies on just 4 clinical and 4 morphology risk facts. Model performance was evaluated by AUROC, AUPRC, and time-to-event hazard ratios.

The fully integrated longitudinal model achieved superior predictive accuracy (AUROC 0.86, AUPRC 0.74). IRRI stratified patients into risk categories with distinct future CAR hazards: high-risk patients showed a markedly increased CAR risk (HR=6.15, 95% CI: 4.17-9.09), while low-risk patients had significantly reduced risk (HR=0.52, 95% CI: 0.33-0.84). This performance exceeded models based on just cross-sectional or single-domain data, demonstrating the value of multi-modal, temporal data integration.

By integrating longitudinal clinical and biopsy morphologic features, IRRI provides a scalable, interpretable tool for proactive CAR risk assessment. This precision-based approach could support risk-adaptive surveillance and immunosuppression management strategies, offering a promising pathway toward safer, more personalized post-HT care with the potential to reduce unnecessary procedures and improve outcomes.

What is new? Current tools for cardiac allograft monitoring detect rejection only after it occurs and are not designed to forecast future risk. This leads to missed opportunities for early intervention, avoidable patient injury, unnecessary testing, and inefficiencies in care.We developed a machine learning-based risk index that integrates clinical features, quantitative biopsy morphology, and longitudinal temporal trends to create a robust predictive framework.The Integrated Rejection Risk Index (IRRI) provides highly accurate prediction of future allograft rejection, identifying both high- and low-risk patients up to 90 days in advance - a capability entirely absent from current transplant management. What are the clinical implications? Integrating quantitative histopathology with clinical data provides a more precise, individualized estimate of rejection risk in heart transplant recipients.This framework has the potential to guide post-transplant surveillance intensity, immunosuppressive management, and patient counseling.Automated biopsy analysis could be incorporated into digital pathology workflows, enabling scalable, multicenter application in real-world transplant care.