Abstract
BackgroundAsthma is one of the leading chronic illnesses among children in the United States. Asthma prevalence is higher among African Americans (11.2%) compared to European Americans (7.7%). Bronchodilator medications are part of the first-line therapy, and the rescue medication, for acute asthma symptoms. Bronchodilator drug response (BDR) varies substantially among different racial/ethnic groups. Asthma prevalence in African Americans is only 3.5% higher than that of European Americans, however, asthma mortality among African Americans is four times that of European Americans; variation in BDR may play an important role in explaining this health disparity. To improve our understanding of disparate health outcomes in complex phenotypes such as BDR, it is important to consider interactions between environmental and biological variables.ResultsWe evaluated the impact of pairwise and three-variable interactions between environmental, social, and biological variables on BDR in 233 African American youth with asthma using Visualization of Statistical Epistasis Networks (ViSEN). ViSEN is a non-parametric entropy-based approach able to quantify interaction effects using an information-theory metric known as Information Gain (IG). We performed analyses in the full dataset and in sex-stratified subsets. Our analyses identified several interaction models significantly, and suggestively, associated with BDR. The strongest interaction significantly associated with BDR was a pairwise interaction between pre-natal smoke exposure and socioeconomic status (full dataset IG: 2.78%, p = 0.001; female IG: 7.27%, p = 0.004)). Sex-stratified analyses yielded divergent results for females and males, indicating the presence of sex-specific effects.ConclusionsOur study identified novel interaction effects significantly, and suggestively, associated with BDR in African American children with asthma. Notably, we found that all of the interactions identified by ViSEN were “pure” interaction effects, in that they were not the result of strong main effects on BDR, highlighting the complexity of the network of biological and environmental factors impacting this phenotype. Several associations uncovered by ViSEN would not have been detected using regression-based methods, thus emphasizing the importance of employing statistical methods optimized to detect both additive and non-additive interaction effects when studying complex phenotypes such as BDR. The information gained in this study increases our understanding and appreciation of the complex nature of the interactions between environmental and health-related factors that influence BDR and will be invaluable to biomedical researchers designing future studies.
Highlights
Asthma is one of the leading chronic illnesses among children in the United States
We found that all of the interactions identified by Visualization of Statistical Epistasis Networks (ViSEN) were “pure” interaction effects, in that they were not the result of strong main effects on Bronchodilator drug response (BDR), highlighting the complexity of the network of biological and environmental factors impacting this phenotype
Several associations uncovered by ViSEN would not have been detected using regression-based methods, emphasizing the importance of employing statistical methods optimized to detect both additive and non-additive interaction effects when studying complex phenotypes such as BDR
Summary
Asthma prevalence is higher among African Americans (11.2%) compared to European Americans (7.7%). Asthma prevalence in African Americans is only 3.5% higher than that of European Americans, asthma mortality among African Americans is four times that of European Americans; variation in BDR may play an important role in explaining this health disparity. Asthma is the most disparate common disease in pediatric populations, with asthma prevalence, morbidity, and mortality rates varying widely by racial/ethnic group [3]. Rates of asthma prevalence and mortality are two and four times higher, respectively, in African American children compared to European American children [3]. Measures of asthma morbidity, including emergency department visits and missed school days, are higher in African American children compared to their European American counterparts [4]. Recent years have shown an increase in the inclusion of African Americans in large scale biomedical studies; this population is still comparatively understudied when contrasted with efforts aimed at European American populations [5, 6]
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