Asthma in children and adolescents is a heterogeneous syndrome comprised of multiple poorly-defined subgroups with variable disease expression and response to environmental exposures (e.g. environmental tobacco smoke [ETS], vitamin D, allergens). ETS exposure induces a respiratory epithelial response that is mediated in part by oxidative stress. Although the mechanism behind this epithelial response is not completely understood, asthmatic respiratory epithelium appears to be more susceptible. Vitamin D has been shown to be positively associated with pulmonary function. Additionally, there is an emerging consensus that vitamin D deficiency increases risk of acute respiratory tract infections and might also increase the severity of chronic asthma. Environmental allergens lead to airway inflammation associated with recruitment and activation of eosinophils. In mice, allergen exposure induces platelet migration to the airways that is necessary for eosinophil recruitment and activation. These findings were extended into human asthma to provide initial evidence for a positive association between platelet activation and eosinophil activation in human airways.
In this thesis, the goal was to define homogeneous phenotypic clusters within a cohort of children and adolescents with asthma in order to reduce heterogeneity and thereby identify otherwise undetectable associations. 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. 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.
Regression analysis was used to explore associations in the overall asthmatic cohort and within each cluster between asthma characteristics and either ETS exposure (i.e. quantitative urine cotinine), plasma 25-hydroxyvitamin D, or markers of eosinophil and platelet activation (i.e. [eosinophil cationic protein] ECP and p-selectin levels, respectively, in nasal washes). While no significant associations were found in the overall cohort between quantitative urine cotinine and asthma characteristics, several significant associations were revealed within the more homogeneous clusters. Plasma 25-hydroxyvitamin D was significantly associated with one allergic marker in the overall cohort, and that association was found to be stronger within Cluster 3. ECP, in the overall cohort, was significantly and negatively associated with two asthma characteristics and p-selectin was associated with one of these. When looking within Cluster 3, these associations were stronger than what was found in the overall cohort and one additional association that was not present in the overall cohort was found to be significant within the cluster. Furthermore, significant associations were identified between p-selectin and three asthma characteristics within Clusters 1 and 2.
This thesis extends the usefulness of cluster analysis to define more homogeneous subgroups by allowing for the detection of otherwise undetectable associations among ETS exposure, vitamin D, allergic inflammation, and asthma characteristics. Together, these techniques provide a framework in which to better understand complex disease expression patterns.
|Advisor:||Freishtat, Robert J.|
|School:||The George Washington University|
|Department:||Genomics and Bioinformatics|
|School Location:||United States -- District of Columbia|
|Source:||MAI 49/06M, Masters Abstracts International|
|Subjects:||Health sciences, Bioinformatics|
|Keywords:||Allergic inflammation, Asthma, Cluster analysis, Phenotype, Tobacco smoke exposure, Vitamin D|
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