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2.  Decreased response to inhaled steroids in overweight and obese asthmatic children 
Background
The mechanisms and consequences of the observed association between obesity and childhood asthma are unclear.
Objectives
To determine the effect of obesity on treatment responses to inhaled corticosteroids in asthmatic children.
Methods
We performed a post hoc analysis to evaluate the interaction between body mass index (BMI) and treatment with inhaled budesonide on lung function in the Childhood Asthma Management Program (CAMP) trial. Participants were then stratified into overweight/obese and non-overweight, and their response to inhaled budesonide was analyzed longitudinally over the 4 years of the trial.
Results
There was a significant interaction between BMI and budesonide for pre-BD FEV1/FVC (P=0.0007) and bronchodilator response (BDR) (P=0.049), and a non-significant trend for an interaction between BMI and budesonide on pre-BD FEV1 (P=0.15). Non-overweight children showed significant improvement with inhaled budesonide in lung function (FEV1, FEV1/FVC, and BDR) during the early (years 1–2) and late stages (years 3–4) of the trial. Overweight/obese children had improved FEV1 and BDR during the early but not the late stage of the trial, and showed no improvement in FEV1/FVC. When comparing time points where both groups showed significant response, the degree of improvement among non-overweight children was significantly greater than in overweight/obese children at most visits. Non-overweight children had a 44% reduction in the risk of ER visits or hospitalizations throughout the trial (P=0.001); there was no reduction in risk among overweight/obese (P=0.97).
Conclusions
Compared to children of normal weight, overweight/obese children in CAMP showed a decreased response to inhaled budesonide on measures of lung function and ER visits/hospitalizations for asthma.
doi:10.1016/j.jaci.2010.12.010
PMCID: PMC3056233  PMID: 21377042
Asthma; obesity; pediatric asthma; childhood obesity; budesonide
3.  An omnibus test for family-based association studies with multiple SNPs and multiple phenotypes 
We propose an omnibus family-based association test (MFBAT) that can be applied to multiple markers and multiple phenotypes and that has only one degree of freedom. The proposed test statistic extends current FBAT methodology to incorporate multiple markers as well as multiple phenotypes. Using simulation studies, power estimates for the proposed methodology are compared with the standard methodologies. On the basis of these simulations, we find that MFBAT substantially outperforms other methods, including haplotypic approaches and doing multiple tests with single single-nucleotide polymorphisms (SNPs) and single phenotypes. The practical relevance of the approach is illustrated by an application to asthma in which SNP/phenotype combinations are identified and reach overall significance that would not have been identified using other approaches. This methodology is directly applicable to cases in which there are multiple SNPs, such as candidate gene studies, cases in which there are multiple phenotypes, such as expression data, and cases in which there are multiple phenotypes and genotypes, such as genome-wide association studies that incorporate expression profiles as phenotypes. This program is available in the PBAT analysis package.
doi:10.1038/ejhg.2009.221
PMCID: PMC2874662  PMID: 20087406
family-based association testing (FBAT); genome-wide association studies; FBAT-PC; multiple marker; multiple phenotypes; multiple testing
4.  Patterns of inhaled corticosteroid use and asthma control in the Childhood Asthma Management Program Continuation Study 
Background
Daily controller medication use is recommended for children with persistent asthma to achieve asthma control.
Objective
To examine patterns of inhaled corticosteroid (ICS) use and asthma control in an observational study of children and adolescents with mild-to-moderate asthma (the Childhood Asthma Management Program Continuation Study).
Methods
We assessed patterns of ICS use during a 12-month period (consistent, intermittent, and none) and asthma control (well controlled vs poorly controlled). Multivariate logistic regression examined the association between pattern of ICS use and asthma control.
Results
Of 914 patients enrolled, 425 were recommended to continue receiving ICS therapy in the Childhood Asthma Management Program Continuation Study. Of these patients, 46% reported consistent ICS use and 20% reported no ICS use during year 1. By year 4, consistent ICS use decreased to 20%, whereas no ICS use increased to 57%; poorly controlled asthma was reported in 18% of encounters. In multivariate models controlling for age, sex, forced expiratory volume in 1 second, and asthma severity assessment, patients reporting consistent ICS use during a 12-month period were more likely to report poor asthma control (odds ratio, 1.6; 95% confidence interval, 1.2–2.1) compared with those reporting no ICS use.
Conclusions
In this observational study of children and adolescents with mild-to-moderate asthma, most did not report continued use of ICS. Patients recommended to continue receiving ICS therapy and reporting consistent ICS use were less likely to report well-controlled asthma even after controlling for markers of asthma severity. Although residual confounding by severity cannot be ruled out, many children and adolescents may not achieve well-controlled asthma despite consistent use of ICS.
doi:10.1016/j.anai.2009.11.004
PMCID: PMC3040975  PMID: 20143642
5.  Predictors of Remitting, Periodic, and Persistent Childhood Asthma 
Background
The course of mild to moderate persistent asthma in children is not clearly established.
Objective
To determine the rate and predictors for remitting, periodic, and persistent asthma in adolescence.
Methods
The Childhood Asthma Management Program (CAMP) was a 4.3-year randomized, double-masked, multicenter trial in children with mild to moderate persistent asthma that compared continuous therapy with either budesonide or nedocromil, each to placebo, followed by 4 years observational follow-up period. Asthma activity during the observation period included remitting (no asthma activity in the last year), persistent (asthma activity in every quarter), and periodic asthma (neither remitting nor persistent).
Results
Asthma was identified as remitting in 6%, periodic in 39%, and persistent in 55% of the 909 participants, with no effect noted from earlier anti-inflammatory treatment during the CAMP trial. Within all three asthma activity categories, improvements in airway hyperresponsiveness, eosinophilia, and asthma morbidity were observed over time. Features at entry into CAMP associated with remitting vs. persistent asthma were lack of allergen sensitization and exposure to indoor allergens [OR=3.23, p<0.001], milder asthma [OR=2.01, p=0.03], older age [OR=1.23, p=0.01], less airway hyperresponsiveness (higher log methacholine FEV1 PC20 [OR=1.39, p=0.03]), higher pre-bronchodilator FEV1 % predicted [OR=1.05, p=0.02], and lower FVC % predicted [OR=0.96, p=0.04].
Conclusion
Remission of asthma in adolescence is infrequent and not impacted by 4 years of anti-inflammatory controller therapy. Factors such as sensitization and exposure, low lung function, and airway greater hyperresponsiveness decrease the likelihood of remitting asthma.
doi:10.1016/j.jaci.2009.10.037
PMCID: PMC2844768  PMID: 20159245
Remission; Natural history; Persistent asthma
6.  A novel custom resequencing array for dilated cardiomyopathy 
Purpose
Genetic tests for the most commonly mutated genes in dilated cardiomyopathy (DCM) can confirm a clinical diagnosis in the proband and inform family management. Presymptomatic family members can be identified, allowing for targeted clinical monitoring to minimize adverse outcomes. However, the marked locus and allelic heterogeneity associated with DCM have made clinical genetic testing challenging. Novel sequencing platforms have now opened up avenues for more comprehensive diagnostic testing while simultaneously decreasing test cost and turn around time.
Methods
By using a custom design based on triplicate resequencing and separate genotyping of known disease-causing variants, we developed the DCM CardioChip for efficient analysis of 19 genes previously implicated in causing DCM.
Results
The chip’s analytical sensitivity for known and novel substitution variants is 100% and 98%, respectively. In screening 73 previously tested DCM patients who did not carry clinically significant variants in 10 genes, 7 variants of likely clinical significance were identified in the remaining 9 genes included on the chip. Compared with traditional Sanger-based sequencing, test cost and turn around time were reduced by ~50%.
Conclusions
The DCM CardioChip is a highly efficient screening test with a projected clinical sensitivity of 26–29%.
PMCID: PMC3018746  PMID: 20474083
dilated cardiomyopathy; resequencing array; genetic test; locus heterogeneity
7.  An omnibus test for family-based association studies with multiple SNPs and multiple phenotypes 
We propose an omnibus family-based association test (MFBAT), that can be applied to multiple markers and multiple phenotypes and that has only 1 degree of freedom. The proposed test statistic extends current FBAT methodology to incorporate multiple markers as well as multiple phenotypes. Using simulation studies, power estimates for the proposed methodology are compared with the standard methodologies. Based on these simulations, we find that MFBAT substantially outperforms other methods including some haplotypic approaches and doing multiple tests with single SNPs and single phenotypes. The practical relevance of the approach is illustrated by an application to asthma where SNPs/phenotype combinations are identified and reach overall significance that would not have been identified using other approaches. This methodology is directly applicable to cases where there are multiple SNPs, such as candidate gene studies, cases where there are multiple phenotypes, such as expression data, and cases where there are multiple phenotypes and genotypes, such as genome-wide association studies that incorporate expression profiles as phenotypes. This program is available in the PBAT analysis package1.
doi:10.1038/ejhg.2009.221
PMCID: PMC2874662  PMID: 20087406
Family-based association testing (FBAT); genome-wide association studies; FBAT-PC; multiple marker; multiple phenotypes; multiple testing
8.  Repeatability of Response to Asthma Medications 
Background
Pharmacogenetic studies of drug response in asthma assume that patients respond consistently to a treatment but that treatment response varies across patients, however, no formal studies have demonstrated this.
Objective
To determine the repeatability of commonly used outcomes for treatment response to asthma medications: bronchodilator response, forced expiratory volume in 1 second (FEV1), and provocative concentration of methacholine producing a 20% decline in FEV1 (PC20).
Methods
The Childhood Asthma Management Program (CAMP) was a multi-center clinical trial of children randomized to receiving budesonide, nedocromil, or placebo. We determined the intraclass correlation coefficient (ICC) for each outcome over repeated visits over four years in CAMP using mixed effects regression models. We adjusted for the covariates: age, race/ethnicity, height, family income, parental education, and symptom score. We incorporated each outcome for each child as repeated outcome measurements and stratified by treatment group.
Results
The ICC for bronchodilator response was 0.31 in the budesonide group, 0.35 in the nedocromil group, and 0.40 in the placebo group, after adjusting for covariates. The ICC for FEV1 was 0.71 in the budesonide group, 0.60 in the nedocromil group, and 0.69 in the placebo group, after adjusting for covariates. The ICC for PC20 was 0.67 in the budesonide and placebo groups and 0.73 in the nedocromil group, after adjusting for covariates.
Conclusion
The within treatment group repeatability of FEV1 and PC20 are high; thus these phenotypes are heritable. FEV1 and PC20 may be better phenotypes than bronchodilator response for studies of treatment response in asthma.
doi:10.1016/j.jaci.2008.10.015
PMCID: PMC2980870  PMID: 19064281
asthma; drug response; heritability; bronchodilator; pharmacogenetics
9.  Vitamin D, the immune system and asthma 
The effects of vitamin D on bone metabolism and calcium homeostasis have long been recognized. Emerging evidence has implicated vitamin D as a critical regulator of immunity, playing a role in both the innate and cell-mediated immune systems. Vitamin D deficiency has been found to be associated with several immune-mediated diseases, susceptibility to infection and cancer. Recently, there has been increasing interest in the possible link between vitamin D and asthma. Further elucidation of the role of vitamin D in lung development and immune system function may hold profound implications for the prevention and treatment of asthma.
doi:10.1586/eci.09.53
PMCID: PMC2812815  PMID: 20161622
asthma; autoimmune disease; immune system regulation; T-regulatory cell; vitamin D; vitamin D deficiency
10.  Impact of Population Stratification on Family-Based Association Tests with Longitudinal Measurements 
Several family-based approaches for testing genetic association with traits obtained from longitudinal or repeated measurement studies have been previously proposed. These approaches utilize the multivariate data more efficiently by using estimated optimal weights to combine univariate tests. We show that these FBAT approaches are still robust against hidden population stratification, but their power can be heavily affected since the estimated weights might provide poor approximation of the true theoretical optimal weights with the presence of population stratification. We introduce a permutation-based approach FBAT-MinP and an equal combination approach FBAT-EW, both of which do not involve the use of estimated weights. Through simulation studies, FBAT-MinP and FBAT-EW are shown to be powerful even in the presence of population stratification, when other approaches may substantially lose their power. An application of these approaches to the Childhood Asthma Management Program (CAMP) study data for testing an association between body mass index and a previously reported candidate SNP is given as an example.
doi:10.2202/1544-6115.1398
PMCID: PMC2861319  PMID: 19222384
11.  Glutathione-S-Transferase M1, Obesity, Statins, and Autonomic Effects of Particles 
Rationale: Air pollution by particulate matter (PM) has been associated with cardiovascular deaths, although the mechanism of action is unclear. One proposed pathway is through disturbances of the autonomic control of the heart.
Objectives: We tested the hypothesis that such disturbances are mediated by PM increasing oxidative stress by examining the association between PM and the high-frequency (HF) component of heart rate variability as modified by the presence or absence of the allele for glutathione-S-transferase M1 (GSTM1) and the use of statins, obesity, high neutrophil counts, higher blood pressure, and older age.
Methods: We examined the association between particles less than 2.5 μM in aerodiameter (PM2.5) and HF in 497 participants in the Normative Aging Study, using linear regression controlling for covariates.
Main Results: A 10-μg/m3 increase in PM2.5 during the 48 h before HF measurement was associated with a 34% decrease in HF, 95% confidence interval (−9%, −52%), in subjects without the allele, but had no effect in subjects with GSTM1 present. Among GSTM1-null subjects, the use of statins eliminated the effect of PM2.5. Obesity and high neutrophil counts also worsened the PM effects with or without GSTM1.
Conclusion: The effects of PM2.5 on HF appear to be mediated by reactive oxygen species. This may be a key pathway for the adverse effects of combustion particles.
doi:10.1164/rccm.200412-1698OC
PMCID: PMC2718454  PMID: 16020798
genetic polymorphisms; heart rate variability; oxidative stress; particles
12.  Extracting principal diagnosis, co-morbidity and smoking status for asthma research: evaluation of a natural language processing system 
Background
The text descriptions in electronic medical records are a rich source of information. We have developed a Health Information Text Extraction (HITEx) tool and used it to extract key findings for a research study on airways disease.
Methods
The principal diagnosis, co-morbidity and smoking status extracted by HITEx from a set of 150 discharge summaries were compared to an expert-generated gold standard.
Results
The accuracy of HITEx was 82% for principal diagnosis, 87% for co-morbidity, and 90% for smoking status extraction, when cases labeled "Insufficient Data" by the gold standard were excluded.
Conclusion
We consider the results promising, given the complexity of the discharge summaries and the extraction tasks.
doi:10.1186/1472-6947-6-30
PMCID: PMC1553439  PMID: 16872495
13.  A Brief Targeted Review of Susceptibility Factors, Environmental Exposures, Asthma Incidence, and Recommendations for Future Asthma Incidence Research 
Environmental Health Perspectives  2006;114(4):634-640.
Relative to research on effects of environmental exposures on exacerbation of existing asthma, little research on incident asthma and environmental exposures has been conducted. However, this research is needed to better devise strategies for the prevention of asthma. The U.S. Environmental Protection Agency (EPA) and National Institute of Environmental Health Sciences held a conference in October 2004 to collaboratively discuss a future research agenda in this area. The first three articles in this mini-monograph summarize the discussion on potential putative environmental exposure; they include an overview of asthma and conclusions of the workshop participants with respect to public health actions that could currently be applied to the problem and research needs to better understand and control the induction and incidence of asthma, the potential role of indoor/outdoor air pollutants in the induction of asthma), and biologics in the induction of asthma. Susceptibility is a key concept in the U.S. EPA “Asthma Research Strategy” document and is associated with the U.S. EPA framework of protecting vulnerable populations from potentially harmful environmental exposures. Genetics, age, and lifestyle (obesity, diet) are major susceptibility factors in the induction of asthma and can interact with environmental exposures either synergistically or antagonistically. Therefore, in this fourth and last article we consider a number of “susceptibility factors” that potentially influence the asthmatic response to environmental exposures and propose a framework for developing research hypotheses regarding the effects of environmental exposures on asthma incidence and induction.
doi:10.1289/ehp.8381
PMCID: PMC1440793  PMID: 16581558
asthma; epidemiology; genetics; hygiene hypothesis; incidence; obesity; occupational asthma; smoking; susceptibility; windows of exposure and age (in utero, childhood, adult, elderly)
14.  Neonatal immune responses to TLR2 stimulation: Influence of maternal atopy on Foxp3 and IL-10 expression 
Respiratory Research  2006;7(1):40.
Background
Maternal atopic background and stimulation of the adaptive immune system with allergen interact in the development of allergic disease. Stimulation of the innate immune system through microbial exposure, such as activation of the innate Toll-like-receptor 2 (TLR2), may reduce the development of allergy in childhood. However, little is known about the immunological effects of microbial stimulation on early immune responses and in association with maternal atopy.
Methods
We analyzed immune responses of cord blood mononuclear cells (CBMC) from 50 healthy neonates (31 non-atopic and 19 atopic mothers). Cells were stimulated with the TLR2 agonist peptidoglycan (Ppg) or the allergen house dust mite Dermatophagoides farinae (Derf1), and results compared to unstimulated cells. We analyzed lymphocyte proliferation and cytokine secretion of CBMC. In addition, we assessed gene expression associated with T regulatory cells including the transcription factor Foxp3, the glucocorticoid-induced TNF receptor (GITR), and the cytotoxic lymphocyte antigen 4 (CTLA4). Lymphocyte proliferation was measured by 3H-Thymidine uptake, cytokine concentrations determined by ELISA, mRNA expression of T cell markers by real-time RT-PCR.
Results
Ppg stimulation induced primarily IL-10 cytokine production, in addition to IFN-γ, IL-13 and TNF-α secretion. GITR was increased following Ppg stimulation (p = 0.07). Ppg-induced IL-10 production and induction of Foxp3 were higher in CBMC without, than with maternal atopy (p = 0.04, p = 0.049). IL-10 production was highly correlated with increased expression of Foxp3 (r = 0.53, p = 0.001), GITR (r = 0.47, p = 0.004) and CTLA4 (r = 0.49, p = 0.003), independent of maternal atopy.
Conclusion
TLR2 stimulation with Ppg induces IL-10 and genes associated with T regulatory cells, influenced by maternal atopy. Increased IL-10 and Foxp3 induction in CBMC of non-atopic compared to atopic mothers, may indicate an increased capacity to respond to microbial stimuli.
doi:10.1186/1465-9921-7-40
PMCID: PMC1435749  PMID: 16551363
15.  A delta-aminolevulinic acid dehydratase (ALAD) polymorphism may modify the relationship of low-level lead exposure to uricemia and renal function: the normative aging study. 
Environmental Health Perspectives  2003;111(3):335-341.
In this study we investigated whether a known delta-aminolevulinic acid dehydratase (ALAD) exon 4 polymorphism has a modifying effect on the association of blood or bone lead level with uricemia and indices of renal function among middle-aged and elderly men. We performed a cross-sectional study of subjects who participated between 1991 and 1995 in the Department of Veterans Affairs Normative Aging Study. Information on blood lead levels, bone lead levels (measured by K-shell X-ray fluorescence), serum uric acid, serum creatinine, estimated creatinine clearance, and ALAD polymorphism status was available in 709 subjects. Regression models were constructed to examine the relationships of serum uric acid, serum creatinine, and estimated creatinine clearance to blood or bone lead level, stratified by genotype. We also adjusted for age, body mass index, blood pressure, smoking, alcohol consumption, and ingestion of analgesic medications (n = 638). Of the 709 subjects, 7 (1%) and 107 (15%) were homozygous and heterozygous for the variant (ALAD-2) allele, respectively. The mean (range) serum uric acid and creatinine levels were 6.5 (2.9-10.6) and 1.2 (0.6-2.5) mg/dL. No significant differences were found in serum uric acid, serum creatinine, or estimated creatinine clearance by ALAD genotype. However, after adjusting for other potential confounders, we found a significant linear relationship between serum uric acid and patella bone lead (p = 0.040) among the ALAD 1-2/2-2 genotype individuals above a threshold patellar lead level of 15 micro g/g. In contrast, among the wild-type (ALAD 1-1) individuals, there was a suggestion of a significant linear relationship of serum uric acid with patella bone lead (p = 0.141), but only after a threshold of 101 micro g/g. There was evidence of a significant (p = 0.025) interaction of tibia lead with genotype (ALAD 1-1 vs. ALAD 1-2/2-2) regarding serum creatinine as an outcome, but in the same linear regression model tibia lead alone was not a significant predictor of serum creatinine. Conversely, for estimated creatinine clearance, patella lead, but not the interaction of patella lead with genotype, was a significantly independent predictor (p = 0.026). Our findings suggest that ALAD genotype may modify the effect of lead on the renal excretion of uric acid as well as overall renal function among middle-aged and elderly men who had community (nonoccupational) exposures to lead. Additional research is needed to ascertain whether this constitutes a true gene-environment interaction and, if so, its clinical impact.
PMCID: PMC1241391  PMID: 12611663

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