Investigation of Growth Differentiation Factor 15 as a Prognostic Biomarker for Major Adverse Limb Events in Peripheral Artery Disease

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Background/Objectives: Peripheral artery disease (PAD) impacts more than 200 million individuals globally and leads to mortality and morbidity secondary to progressive limb dysfunction and amputation. However, clinical management of PAD remains suboptimal, in part because of the lack of standardized biomarkers to predict patient outcomes. Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine that has been studied extensively in cardiovascular disease, but its investigation in PAD remains limited. This study aimed to use explainable statistical and machine learning methods to assess the prognostic value of GDF15 for limb outcomes in patients with PAD. Methods: This prognostic investigation was carried out using a prospectively enrolled cohort comprising 454 patients diagnosed with PAD. At baseline, plasma GDF15 levels were measured using a validated multiplex immunoassay. Participants were monitored over a two-year period to assess the occurrence of major adverse limb events (MALE), a composite outcome encompassing major lower extremity amputation, need for open/endovascular revascularization, or acute limb ischemia. An Extreme Gradient Boosting (XGBoost) model was trained to predict 2-year MALE using 10-fold cross-validation, incorporating GDF15 levels along with baseline variables. Model performance was primarily evaluated using the area under the receiver operating characteristic curve (AUROC). Secondary model evaluation metrics were accuracy, sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV). Prediction histogram plots were generated to assess the ability of the model to discriminate between patients who develop vs. do not develop 2-year MALE. For model interpretability, SHapley Additive exPlanations (SHAP) analysis was performed to evaluate the relative contribution of each predictor to model outputs. Results: The mean age of the cohort was 71 (SD 10) years, with 31% (n = 139) being female. Over the two-year follow-up period, 157 patients (34.6%) experienced MALE. The XGBoost model incorporating plasma GDF15 levels and demographic/clinical features achieved excellent performance for predicting 2-year MALE in PAD patients: AUROC 0.84, accuracy 83.5%, sensitivity 83.6%, specificity 83.7%, PPV 87.3%, and NPV 86.2%. The prediction probability histogram for the XGBoost model demonstrated clear separation for patients who developed vs. did not develop 2-year MALE, indicating strong discrimination ability. SHAP analysis showed that GDF15 was the strongest predictive feature for 2-year MALE, followed by age, smoking status, and other cardiovascular comorbidities, highlighting its clinical relevance. Conclusions: Using explainable statistical and machine learning methods, we demonstrated that plasma GDF15 levels have important prognostic value for 2-year MALE in patients with PAD. By integrating clinical variables with GDF15 levels, our machine learning model can support early identification of PAD patients at elevated risk for adverse limb events, facilitating timely referral to vascular specialists and aiding in decisions regarding the aggressiveness of medical/surgical treatment. This precision medicine approach based on a biomarker-guided prognostication algorithm offers a promising strategy for improving limb outcomes in individuals with PAD.

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