Machine learning-based prediction of major amputation risk after initial limb-preserving surgery in diabetic foot.

Background: Accurate preoperative prediction of whether an initially limb-preserving strategy in diabetic foot management will culminate in minor or major amputation remains a clinical challenge. This study aimed to develop and evaluate using two temporally separated cohorts a machine-learning framework using routinely available baseline clinical, laboratory, and selected imaging and vascular variables. Methods: Two temporally separated cohorts were used, with Dataset 1 for model development and Dataset 2 for temporally separated evaluation. A 20-repetition stratified outer-split workflow was implemented, incorporating two-step feature selection, Optuna-based hyperparameter optimization, training-only SMOTE, and threshold tuning to maximize the F2-score under a recall constraint of ≥0.70. Six classifiers were evaluated using average precision (AP), ROC-AUC, recall, precision, specificity, accuracy, and Brier score. Results: The major-amputation group exhibited a more severe baseline phenotype, including higher inflammatory burden, worse neuropathy and wound severity, and a higher prevalence of necrotizing fasciitis. Internally, multilayer perceptron achieved the highest AP (55.9% ± 13.6%). In external evaluation, k-nearest neighbors achieved the highest AP (65.1% ± 10.2%) and recall (72.8% ± 19.6%), whereas multilayer perceptron showed higher precision and specificity. Key contributors included necrotizing fasciitis, neuropathy severity, hemoglobin, PEDIS classification, and inflammatory indices. Conclusion: These findings suggest that prediction of amputation level is feasible, validated in a temporally separated cohort, and clinically interpretable, and may support future decision-support applications, although further validation is required before clinical implementation.