A Responsible Framework for Assessing, Selecting, and Explaining Machine Learning Models in Cardiovascular Disease Outcomes Among People With Type 2 Diabetes: Methodology and Validation Study.

Background: Building machine learning models that are interpretable, explainable, and fair is critical for their trustworthiness in clinical practice. Interpretability, which refers to how easily a human can comprehend the mechanism by which a model makes predictions, is often seen as a primary consideration when adopting a machine learning model in health care. However, interpretability alone does not necessarily guarantee explainability, which offers stakeholders insights into a model's predicted outputs. Moreover, many existing frameworks for model evaluation focus primarily on maximizing predictive accuracy, overlooking the broader need for interpretability, fairness, and explainability. Objective: This study proposes a 3-stage machine learning framework for responsible model development through model assessment, selection, and explanation. We demonstrate the application of this framework for predicting cardiovascular disease (CVD) outcomes, specifically myocardial infarction (MI) and stroke, among people with type 2 diabetes (T2D). Methods: We extracted participant data comprised of people with T2D from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) dataset (N=9635), including demographic, clinical, and biomarker records. Then, we applied hold-out cross-validation to develop several interpretable machine learning models (linear, tree-based, and ensemble) to predict the risks of MI and stroke among patients with diabetes. Our 3-stage framework first assesses these models via predictive accuracy and fairness metrics. Then, in the model selection stage, we quantify the trade-off between accuracy and fairness using area under the curve (AUC) and Relative Parity of Performance Scores (RPPS), wherein RPPS measures the greatest deviation of all subpopulations compared with the population-wide AUC. Finally, we quantify the explainability of the chosen models using methods such as SHAP (Shapley Additive Explanations) and partial dependence plots to investigate the relationship between features and model outputs. Results: Our proposed framework demonstrates that the GLMnet model offers the best balance between predictive performance and fairness for both MI and stroke. For MI, GLMnet achieves the highest RPPS (0.979 for gender and 0.967 for race), indicating minimal performance disparities, while maintaining a high AUC of 0.705. For stroke, GLMnet has a relatively high AUC of 0.705 and the second-highest RPPS (0.961 for gender and 0.979 for race), suggesting it is effective across both subgroups. Our model explanation method further highlights that the history of CVD and age are the key predictors of MI, while HbA1c and systolic blood pressure significantly influence stroke classification. Conclusions: This study establishes a responsible framework for assessing, selecting, and explaining machine learning models, emphasizing accuracy-fairness trade-offs in predictive modeling. Key insights include: (1) simple models perform comparably to complex ensembles; (2) models with strong accuracy may harbor substantial differences in accuracy across demographic groups; and (3) explanation methods reveal the relationships between features and risk for MI and stroke. Our results underscore the need for holistic approaches that consider accuracy, fairness, and explainability in interpretable model design and selection, potentially enhancing health care technology adoption.