Clustering of disease trajectories with explainable machine learning: A case study on postoperative delirium phenotypes

The identification of phenotypes within complex diseases is a fundamental component of personalized medicine, which aims to adapt healthcare to individual patient characteristics. Postoperative delirium (POD) is a complex neuropsychiatric condition with significant heterogeneity in its clinical manifestations and underlying pathophysiology. We hypothesize that POD comprises several distinct phenotypes, which cannot be directly observed in clinical practice. Identifying these phenotypes could enhance our understanding of POD pathogenesis and facilitate the development of targeted prevention and treatment strategies. In this paper, we propose an approach that combines supervised machine learning for personalized POD risk prediction with unsupervised clustering technique to uncover potential POD phenotypes. We first demonstrate our approach using synthetic data, where we simulate patient cohorts with predefined phenotypes based on distinct sets of informative features. We aim to mimic any clinical disease with our synthetic data generation method. By training a predictive model and computing SHapley Additive exPlanations (SHAP), we show that clustering patients in the SHAP feature scoring space successfully recovers the true underlying phenotypes, outperforming clustering in the raw feature space. We then present a case study using real-world data from a cohort of elderly POD patients. We train machine learning models on heterogeneous electronic health record data covering the preoperative, intraoperative and postoperative stages to predict personalized POD risk. Subsequent clustering of patients based on their SHAP feature scores reveals distinct subgroups with differing clinical characteristics and risk profiles, potentially representing POD phenotypes. These results showcase the utility of our approach in uncovering clinically relevant subtypes of complex disorders like POD, paving the way for more precise and personalized treatment strategies.