ObjectiveTo evaluate the effectiveness of Monocyte Distribution Width (MDW) in predicting sepsis outcomes in emergency department (ED) patients compared to other hematologic parameters and vital signs, and to determine whether routine parameters could substitute MDW in machine learning models. MethodsWe conducted a retrospective analysis of data from 10,229 ED patients admitted to a large regional safety-net hospital in Cleveland, Ohio who had suspected infections and developed sepsis-associated poor outcomes. We developed a new analytical framework consisting of seven data models and an ensemble of high accuracy machine learning (ML) algorithms (accuracy values ranging from 0.83 to 0.90) to predict sepsis-associated poor outcomes (3-day intensive care unit stay or death). Local Interpretable Model-Agnostic Explanation (LIME) and Shapley Additive Value (SHAP) interpretability methods were utilized to assess the contributions of individual hematologic parameters. ResultsThe ML interpretability analysis indicated that the predictive value of MDW is significantly reduced when other hematological parameters and vital signs are considered. The results suggest that complete blood count with differential (CBD-DIFF) alongside vital signs can effectively replace MDW in high accuracy machine learning algorithms for screening poor outcome associated with sepsis. ConclusionMDW, although a newly approved biomarker for sepsis, does not significantly enhance prediction models when combined with routinely available parameters and vital signs. Hospitals, especially those with resource constraints, can rely on existing parameters with high accuracy machine learning models to predict sepsis outcomes effectively, thereby reducing the need for specialized tests like MDW.