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1.  Diagnostic accuracy of the bronchodilator response in children 
The bronchodilator response (BDR) reflects the reversibility of airflow obstruction and is recommended as an adjunctive test to diagnose asthma. The validity of the commonly used definition of BDR, a 12% or greater change in FEV1 from baseline, has been questioned in childhood.
We sought to examine the diagnostic accuracy of the BDR test by using 3 large pediatric cohorts.
Cases include 1041 children with mild-to-moderate asthma from the Childhood Asthma Management Program.
Control subjects (nonasthmatic and nonwheezing) were chosen from Project Viva and Home Allergens, 2 population-based pediatric cohorts. Receiver operating characteristic curves were constructed, and areas under the curve were calculated for different BDR cutoffs.
A total of 1041 cases (59.7% male; mean age, 8.9 ± 2.1 years) and 250 control subjects (46.8% male; mean age, 8.7 ± 1.7 years) were analyzed, with mean BDRs of 10.7% ± 10.2% and 2.7% ± 8.4%, respectively. The BDR test differentiated asthmatic patients from nonasthmatic patients with a moderate accuracy (area under the curve, 73.3%).
Despite good specificity, a cutoff of 12% was associated with poor sensitivity (35.6%). A cutoff of less than 8% performed significantly better than a cutoff of 12% (P = .03, 8% vs 12%).
Our findings highlight the poor sensitivity associated with the commonly used 12% cutoff for BDR. Although our data show that a threshold of less than 8% performs better than 12%, given the variability of this test in children, we conclude that it might be not be appropriate to choose a specific BDR cutoff as a criterion for the diagnosis of asthma.
PMCID: PMC3759549  PMID: 23683464
Asthma; bronchodilator response; diagnosis
2.  A Multi-Center Ring Trial of Allergen Analysis using Fluorescent Multiplex Array Technology 
Journal of immunological methods  2012;387(0):89-95.
Consistent performance of allergen assays is essential to ensure reproducibility of exposure assessments for investigations of asthma and occupational allergic disease. This study evaluated intra- and inter-laboratory reproducibility of a fluorescent multiplex array, which simultaneously measures eight indoor allergens in a single reaction well.
A multi-center study was performed in nine laboratories in the US and Europe to determine the inter-laboratory variability of an 8-plex array for dust mite, cat, dog, rat, mouse and cockroach allergens. Aliquots of 151 dust extract samples were sent to participating centers and analyzed by each laboratory on three separate occasions. Agreement within and between laboratories was calculated by the concordance correlation coefficient (CCC).
Results were obtained for over 32,000 individual allergen measurements. Levels covered a wide range for all allergens from below the lower limit of detection (LLOD=0.1 - 9.8ng/ml) to higher than 6800ng/ml for all allergens except Mus m 1, which was up to 1700ng/ml. Results were reproducible within as well as between laboratories. Within laboratories, 94% of CCC were ≥0.90, and 80% of intra-laboratory results fell within a 10% coefficient of variance (CV%). Results between laboratories also showed highly significant positive correlations for all allergens (∼0.95, p<0.001). Overall means of results were comparable, and inter-laboratory CV% for all allergens except Rat n 1 ranged between 17.6% and 26.6%.
The data indicate that performance criteria for fluorescent multiplex array technology are reproducible within and between laboratories. Multiplex technology provides standardized and consistent allergen measurements that will streamline environmental exposure assessments in allergic disease.
PMCID: PMC3955085  PMID: 23085532
Allergen measurement; asthma; indoor air quality; immunoassay; multiplex array; occupational health
3.  Allergen sensitization is associated with increased DNA methylation in older men 
Variation in epigenetic modifications, arising from either environmental exposures or internal physiological changes, can influence gene expression, and may ultimately contribute to complex diseases such as asthma and allergies. We examined the association of asthma and allergic phenotypes with DNA methylation levels of retrotransposon-derived elements.
We used data from 704 men (mean age 73) in the longitudinal Normative Aging Study to assess the relationship between asthma, allergic phenotypes and DNA methylation levels of the retrotransposon derived elements Alu and LINE-1. Retrotransposons represent a large fraction of the genome (> 30%), and are heavily methylated to prevent expression. Percent methylation of Alu and LINE-1 elements in peripheral white blood cells was quantified using PCR pyrosequencing. Data on sensitization to common allergens by skin prick testing, asthma, and methacholine responsiveness was gathered approximately 8 years prior to DNA methylation analysis.
Prior allergen sensitization was associated with increased methylation of Alu (β=0.32 [sensitized vs. non-sensitized], p value 0.003), in models adjusted for pack-years, BMI, smoking, air pollutants, percent eosinophils, white blood cell count and age. Of the men interviewed, 5 % of subjects reported diagnosis of asthma. Neither Alu, nor LINE-1 methylation was associated with asthma.
These data suggest that increased DNA methylation of repetitive elements may be associated with allergen sensitization, but does not appear to be associated with asthma. Future work is needed to identify potential underlying mechanisms for these relationships.
PMCID: PMC3730837  PMID: 23257623
allergen sensitization; DNA methylation; Alu; and LINE-1
4.  Multiple Microbial Exposures in the Home May Protect Against Asthma or Allergy in Childhood 
Experimental animal data on the gram-negative bacterial biomarker endotoxin suggest that persistence, dose and timing of exposure are likely to influence its effects on allergy and wheeze. In epidemiologic studies, endotoxin may be a sentinel marker for a microbial milieu, including gram-positive as well as gram-negative bacteria, that may influence allergy and asthma through components (pathogen-associated molecular patterns) that signal through innate Toll-like receptor pathways.
To determine the influence of current gram-negative and gram-positive bacterial exposures on asthma and allergic sensitization in school-aged children.
We examined the relationship between bacterial biomarkers and current asthma and allergic sensitization in 377 school-aged children in a birth-cohort study. We then evaluated the effects of school-age endotoxin, after controlling for exposure in early life.
Exposure to gram-negative bacteria was inversely associated with asthma and allergic sensitization at school-age (for > median endotoxin: prevalence odds ratio [POR] =0.34 [95% CI=0.2 to 0.7] for current asthma and prevalence ratio [PR]=0.77 [95% CI=0.6 to 0.97] for allergic sensitization). In contrast, elevated gram-positive bacteria in the bed was inversely associated with current asthma (POR= 0.41, 95% CI=0.2 to 0.9) but not with allergic sensitization (POR=1.07, 95% CI=0.8 to 1.4). School-age endotoxin exposure remained protective in models for allergic disease adjusted for early-life endotoxin.
Both gram-negative and gram-positive bacterial exposures are associated with decreased asthma symptoms, but may act through different mechanisms to confer protection. Endotoxin exposure in later childhood is not simply a surrogate of early life exposure; it has independent protective effects on allergic disease.
PMCID: PMC3730840  PMID: 20412140
childhood asthma; allergic sensitization; endotoxin; peptidoglycan
5.  Association of variants in innate immune genes with asthma and eczema 
The innate immune pathway is important in the pathogenesis of asthma and eczema. However, only a few variants in these genes have been associated with either disease. We investigate the association between polymorphisms of genes in the innate immune pathway with childhood asthma and eczema. In addition, we compare individual associations with those discovered using a multivariate approach.
Using a novel method, case control based association testing (C2BAT), 569 single nucleotide polymorphisms (SNPs) in 44 innate immune genes were tested for association with asthma and eczema in children from the Boston Home Allergens and Asthma Study and the Connecticut Childhood Asthma Study. The screening algorithm was used to identify the top SNPs associated with asthma and eczema. We next investigated the interaction of innate immune variants with asthma and eczema risk using Bayesian networks.
After correction for multiple comparisons, 7 SNPs in 6 genes (CARD25, TGFB1, LY96, ACAA1, DEFB1, and IFNG) were associated with asthma (adjusted p-value<0.02), while 5 SNPs in 3 different genes (CD80, STAT4, and IRAKI) were significantly associated with eczema (adjusted p-value < 0.02). None of these SNPs were associated with both asthma and eczema. Bayesian network analysis identified 4 SNPs that were predictive of asthma and 10 SNPs that predicted eczema. Of the genes identified using Bayesian networks, only CD80 was associated with eczema in the single-SNP study. Using novel methodology that allows for screening and replication in the same population, we have identified associations of innate immune genes with asthma and eczema. Bayesian network analysis suggests that additional SNPs influence disease susceptibility via SNP interactions.
Our findings suggest that innate immune genes contribute to the pathogenesis of asthma and eczema, and that these diseases likely have different genetic determinants.
PMCID: PMC3412627  PMID: 22192168
asthma; Bayesian network; genetic association; eczema; innate immunity
6.  Alu and LINE-1 methylation and lung function in the normative ageing study 
BMJ Open  2012;2(5):e001231.
To investigate the association between methylation of transposable elements Alu and long-interspersed nuclear elements (LINE-1) and lung function.
Cohort study.
Outpatient Veterans Administration facilities in greater Boston, Massachusetts, USA.
Individuals from the Veterans Administration Normative Aging Study, a longitudinal study of aging in men, evaluated between 1999 and 2007. The majority (97%) were white.
Primary and secondary outcome measures
Primary predictor was methylation, assessed using PCR-pyrosequencing after bisulphite treatment. Primary outcome was lung function as assessed by spirometry, performed according to American Thoracic Society/European Respiratory Society guidelines at the same visit as the blood draws.
In multivariable models adjusted for age, height, body mass index (BMI), pack-years of smoking, current smoking and race, Alu hypomethylation was associated with lower forced expiratory volume in 1 s (FEV1) (β=28 ml per 1% change in Alu methylation, p=0.017) and showed a trend towards association with a lower forced vital capacity (FVC) (β=27 ml, p=0.06) and lower FEV1/FVC (β=0.3%, p=0.058). In multivariable models adjusted for age, height, BMI, pack-years of smoking, current smoking, per cent lymphocytes, race and baseline lung function, LINE-1 hypomethylation was associated with more rapid decline of FEV1 (β=6.9 ml/year per 1% change in LINE-1 methylation, p=0.005) and of FVC (β=9.6 ml/year, p=0.002).
In multiple regression analysis, Alu hypomethylation was associated with lower lung function, and LINE-1 hypomethylation was associated with more rapid lung function decline in a cohort of older and primarily white men from North America. Future studies should aim to replicate these findings and determine if Alu or LINE-1 hypomethylation may be due to specific and modifiable environmental exposures.
PMCID: PMC3488751  PMID: 23075571
Epidemiology; Genetics
7.  Allergen exposure modifies the relation of sensitization to FENO levels in children at risk for allergy and asthma 
Studies on airway inflammation, measured as fraction exhaled nitric oxide (FENO), have focused on its relation to control of asthma, but the contribution of allergen exposure to elevation of FENO is unknown.
We evaluated (1) whether FENO was elevated in children with allergic sensitization or asthma; (2) whether specific allergen exposure increased FENO levels in sensitized, but not in unsensitized children; and (3) whether sedentary behavior increased FENO, independent of allergen exposures.
At age 12, in a birth cohort of children with parental history of allergy or asthma, we measured bed dust allergen (dust mite, cat, cockroach) by ELISA; specific allergic sensitization primarily by specific IgE ; and respiratory disease (current asthma, rhinitis, and wheeze) and hours of TV viewing/video game playing by questionnaire. Children performed spirometry maneuvers before and after bronchodilator responses, and had FENO measured using electrochemical detection methods (NIOX MINO).
FENO was elevated in children with current asthma (32.2 ppb), wheeze (27.0 ppb), or rhinitis (23.2ppb) as compared to individuals without these respective symptoms/diagnoses (16.4 ppb to 16.6 ppb, p< 0.005 for all comparisons). Allergic sensitization to indoor allergens (cat, dog, dust mite) predicted higher levels of FENO, and explained one third of the variability of FENO. FENO levels were highest in children both sensitized and exposed to dust mite. Greater than 10 hours of weekday TV viewing was associated with a 0.64 log increase in FENO, after controlling indoor allergen exposure, BMI and allergic sensitization.
Allergen exposures and sedentary behavior (TV viewing/ video game playing), may increase airway inflammation, measured as FENO.
PMCID: PMC3137133  PMID: 21463890
Asthma; dust mite; cat; allergens; exhaled NO; allergic sensitization; home environment
8.  Effects of endotoxin exposure on childhood asthma risk are modified by a genetic polymorphism in ACAA1 
BMC Medical Genetics  2011;12:158.
Polymorphisms in the endotoxin-mediated TLR4 pathway genes have been associated with asthma and atopy. We aimed to examine how genetic polymorphisms in innate immunity pathways interact with endotoxin to influence asthma risk in children.
In a previous analysis of 372 children from the Boston Home Allergens and the Connecticut Childhood Asthma studies, 7 SNPs in 6 genes (CARD15, TGFB1, LY96, ACAA1, DEFB1 and IFNG) involved in innate immune pathways were associated with asthma, and 5 SNPs in 3 genes (CD80, STAT4, IRAK2) were associated with eczema. We tested these SNPs for interaction with early life endotoxin exposure (n = 291), in models for asthma and eczema by age 6.
We found a significant interaction between endotoxin and a SNP (rs156265) in ACAA1 (p = 0.0013 for interaction). Increased endotoxin exposure (by quartile) showed protective effects for asthma in individuals with at least one copy of the minor allele (OR = 0.39 per quartile increase in endotoxin, 95% CI 0.15 to 1.01). Endotoxin exposure did not reduce the risk of asthma in children homozygous for the major allele.
Our findings suggest that protective effects of endotoxin exposure on asthma may vary depending upon the presence or absence of a polymorphism in ACAA1.
PMCID: PMC3252252  PMID: 22151743
9.  Home Characteristics as Predictors of Bacterial and Fungal Microbial Biomarkers in House Dust 
Environmental Health Perspectives  2010;119(2):189-195.
Measurement of fungal and bacterial biomarkers can be costly, but it is not clear whether home characteristics can be used as a proxy of these markers, particularly if the purpose is to differentiate specific classes of biologic exposures that have similar sources but may have different effects on allergic disease risk.
We evaluated home characteristics as predictors of multiple microbial biomarkers, with a focus on common and unique determinants and with attention to the extent of their explanatory ability.
In 376 Boston-area homes enrolled in a cohort study of home exposures and childhood asthma, we assessed the relationship between home characteristics gathered by questionnaire and measured gram-negative bacteria (GNB) (endotoxin and C10:0, C12:0, and C14:0 3-hydroxy fatty acids), gram-positive bacteria (GPB) (N-acetyl muramic acid), and fungal biomarkers [ergosterol and (1→6) branched, (1→3) β-d glucans] in bed and family room dust.
Home characteristics related to dampness were significant predictors of all microbial exposures; water damage or visible mold/mildew in the home was associated with a 20–66% increase in GNB levels. Report of cleaning the bedroom at least once a week was associated with reduced GNB, GPB, and fungi. Presence of dogs or cats predicted increases in home bacteria or fungi. The proportion of variance in microbial biomarkers explained by home characteristics ranged from 4.2% to 19.0%.
Despite their associations with multiple microbial flora, home characteristics only partially explain the variability in microbial biomarker levels and cannot substitute for specific microbial measurements in studies concerned with distinguishing effects of specific classes of microbes.
PMCID: PMC3040605  PMID: 20965804
bacteria; dampness; fungi; home characteristics; indoor exposure; respiratory health

Results 1-9 (9)