Identification of Clinical Sub-Phenotypes of Sickle Cell Disease Using Latent Class Analysis

Sickle cell disease (SCD), a monogenic disorder, exhibits variable severity due to genetic and environmental modifiers. Prior studies have proposed hemolytic and vaso-occlusive sub-phenotypes based on limited data. We used latent class analysis (LCA) to identify complication-based sub-phenotypes in a large longitudinal cohort. From California administrative databases (1991-2019), we assembled a cohort of 7636 SCD patients (53% female). Disease-related complications (e.g., vaso-occlusive episodes [VOE], acute chest syndrome [ACS], avascular necrosis [AVN], chronic kidney disease [CKD], pulmonary hypertension, stroke, gallbladder disease, sepsis, obstructive lung disease, venous-thromboembolism [VTE], and leg ulcers) were extracted via ICD-9/10 codes. LCA models, stratified by sex, identified classes; we repeated the analysis in a younger sub-cohort (≤ 25 years; n = 2210). Males had higher cumulative incidences for recurrent ACS, AVN, gallbladder disease, obstructive lung disease (age 20), and leg ulcers/CKD (age 40). LCA revealed four classes in both sexes: Vaso-Occlusive (high VOE/ACS/AVN; 23% males, 15% females), Hemolytic (high CKD/pulmonary hypertension/stroke; 8% males, 13% females), Overlap (both patterns; 8% each), and Low Complications (62%-63%). In the younger cohort, classes were Vaso-Occlusive (8%), Hemolytic (3%), ACS-dominant (12%), and Low Complications (78%). Vaso-Occlusive, Hemolytic, and Overlap classes had elevated mortality (HR 1.3-2.4, p < 0.05) versus Low Complications; in youth, Hemolytic had the worst survival (HR 7.8, p < 0.001). LCA confirms the presence of vaso-occlusive and hemolytic sub-phenotypes, with low-complication groups predominant. Age-specific differences suggest evolving phenotypes, which can inform future targeted therapies and trials.