Lack of Evidence for Well-Separated Clinical Phenotypes in Surgically Treated Infective Endocarditis Using Routine Clinical Variables: A Machine Learning Approach

Background: Infective endocarditis (IE) is characterized by marked heterogeneity in microbiological etiology, clinical presentation, valvular involvement, and patient complexity, which complicates risk stratification. Unsupervised machine learning has been proposed to identify latent clinical phenotypes in complex diseases; however, whether IE exhibits a natural cluster structure remains unclear. Methods: In a cohort of 739 patients undergoing surgery for IE, unsupervised clustering was performed using K-medoids based on Gower distance to account for mixed-type variables, which is a common scenario in clinical settings. The optimal number of clusters was selected by maximizing the average silhouette width and the gap statistic. Density and semi-parametric algorithms (K-prototypes, KAMILA, hierarchical clustering, and HDBSCAN) were applied as a sensitivity analysis. Differences in postoperative outcomes across clusters were explored using logistic regression. Results: K-medoids clustering identified three patient groups; however, the average silhouette width was low (0.129), indicating very weak separation between clusters. Sensitivity analysis confirmed the absence of a natural cluster structure. Despite this, a descriptive comparison of forced clusters revealed a gradient of clinical severity, with one group characterized by older age, higher comorbidity burden, complex infection features, and worse postoperative outcomes. Conclusions: Unsupervised clustering did not identify natural clinical phenotypes in surgically treated IE, likely reflecting the extreme intrinsic heterogeneity of the disease. Although forced clustering highlighted clinically interpretable gradients of risk, these groups should not be considered true latent phenotypes. Alternative approaches, such as continuous risk modeling, may be more appropriate for patient stratification in IE.