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Identification of Clinical Sub-Phenotypes of Sickle Cell Disease Using Latent Class Analysis
Shaina M Willen1,2, Ann M Brunson2, Oyebimpe O Adesina2
1Divisions of Pulmonary Medicine and Hematology/Oncology, Department of Pediatrics, University of California Davis, Sacramento, California, USA.
Insights
Sickle cell disease sub-phenotypes were identified using latent class analysis. Vaso-occlusive and hemolytic patterns emerged, impacting mortality risk and informing targeted therapies.
Area of Science:
- Hematology
- Genetics
- Epidemiology
Background:
- Sickle cell disease (SCD) presents with variable severity, influenced by genetic and environmental factors.
- Previous research suggested distinct hemolytic and vaso-occlusive sub-phenotypes, but data were limited.
- Identifying precise SCD sub-phenotypes is crucial for understanding disease progression and tailoring treatments.
Purpose of the Study:
- To utilize latent class analysis (LCA) to identify distinct complication-based sub-phenotypes in a large, longitudinal cohort of SCD patients.
- To stratify these sub-phenotypes by sex and age group to uncover sex-specific and age-dependent patterns.
- To evaluate the association between identified sub-phenotypes and mortality risk.
Main Methods:
- A cohort of 7636 SCD patients was assembled from California administrative databases (1991-2019).
- Disease complications were extracted using ICD-9/10 codes, including vaso-occlusive episodes (VOE), acute chest syndrome (ACS), and chronic kidney disease (CKD).
- Latent class analysis (LCA) was performed, stratified by sex, and repeated in a younger sub-cohort (≤25 years).
Main Results:
- LCA identified four classes in the overall cohort: Vaso-Occlusive, Hemolytic, Overlap, and Low Complications.
- Males exhibited higher incidences of ACS, avascular necrosis (AVN), and leg ulcers/CKD at different ages.
- The Vaso-Occlusive, Hemolytic, and Overlap classes were associated with significantly elevated mortality risk (HR 1.3-2.4).
- In the younger cohort, a Hemolytic sub-phenotype showed the worst survival outcomes (HR 7.8).
Conclusions:
- Latent class analysis confirms the existence of distinct vaso-occlusive and hemolytic sub-phenotypes in sickle cell disease.
- The predominance of low-complication groups suggests a significant portion of patients experience milder disease trajectories.
- Age-specific differences in sub-phenotype prevalence and outcomes highlight the evolving nature of SCD phenotypes, informing targeted therapeutic strategies and clinical trial designs.
Abstract:
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.
