Overcoming Heterogeneity in Pediatric Asthma: Tobacco Smoke and Asthma Characteristics Within Phenotypic Clusters in an African American Cohort

Abstract

Objective. Asthma in children and adolescents is a heterogeneous syndrome comprised of multiple subgroups with variable disease expression and response to environmental exposures. The goal of this study was to define homogeneous phenotypic clusters within a cohort of children and adolescents with asthma and to determine overall and within-cluster associations between environmental tobacco smoke (ETS) exposure and asthma characteristics. Methods. A combined hierarchical/k-means cluster analysis of principal component variables was used to define phenotypic clusters within a cohort of 6- to 20-year-old urban and largely minority subjects. Results. Among the 154 subjects, phenotypic cluster analysis defined three independent clusters (Cluster 1 [n = 57]; Cluster 2 [n = 33]; Cluster 3 [n = 58]). A small fourth cluster (n = 6) was excluded. Patients in Cluster 1 were predominantly males, with a relative abundance of neutrophils in their nasal washes. Patients in Cluster 2 were predominantly females with high body mass index percentiles and later-onset asthma. Patients in Cluster 3 had higher eosinophil counts in their nasal washes and lower Asthma Control Test™ (ACT) scores. Within-cluster regression analysis revealed several significant associations between ETS exposure and phenotypic characteristics that were not present in the overall cohort. ETS exposure was associated with a significant increase in nasal wash neutrophils (beta coefficient = 0.73 [95% confidence interval, CI: 0.11 to 1.35]; p = .023) and a significant decrease in ACT score (−5.17 [−8.42 to −1.93]; p = .003) within Cluster 1 and a significant reduction in the bronchodilator-induced % change in forced expiratory volume in one second (FEV₁) (−36.32 [−62.18 to −10.46]; p = .009) within Cluster 3. Conclusions. Clustering techniques defined more homogeneous subgroups, allowing for the detection of otherwise undetectable associations between environmental tobacco smoke exposure and asthma characteristics.

Keywords :

• asthma
• cluster analysis
• eosinophils
• neutrophils
• phenotype
• tobacco smoke pollution

Acknowledgments

Angela Benton carried out these studies while a Master's student in the Genomics and Bioinformatics Program of the Columbian College of Arts and Sciences at the George Washington University. Funding support was provided to R.J.F. by grants K23RR020069, P20MD000198, and M01RR020359 from the National Institutes of Health, Bethesda, Maryland, a Sheldon C. Siegel Investigator Award Grant from the Asthma and Allergy Foundation of America, and by institutional grants from Children's National Medical Center, Washington, DC.