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1.  Triclosan Exposure and Allergic Sensitization in Norwegian Children 
Allergy  2012;68(1):84-91.
Background
Exposure to the synthetic antimicrobial chemical, triclosan, used in personal care products, has been hypothesized to lead to allergic disease. We investigated whether triclosan exposure was associated with allergic sensitization and symptoms in 10-year old Norwegian children.
Methods
Urinary concentrations of triclosan were measured in one first morning void from 623 children, collected 2001– 2004. Logistic regression models, controlling for urine specific gravity, parental allergic disease, maternal education, and household income, were fitted for allergic sensitization (either skin prick test positivity or serum specific IgE ≥0.35 kU/L to at least one of 15 evaluated inhalant and food allergens), current rhinitis, and current asthma (questionnaire and exercise challenge test).
Results
The adjusted odds ratio (aOR) for allergic sensitization among those in the fourth quartile of triclosan concentration was 2.0 (95% confidence interval (CI): 1.1, 3.4) compared with the reference group (< the limit of detection) and the aOR per log10 unit increase in triclosan was 1.2 (95% CI: 1.0, 1.4). The aOR for current rhinitis was 1.9 (95% CI: 1.1, 3.4) for the fourth quartile and 1.2 (95% CI:0.97, 1.4) per log10 unit increase in triclosan.
Conclusion
Triclosan concentrations were associated with allergic sensitization, especially inhalant and seasonal allergens rather thanfood allergens. Current rhinitis was associated with the highest levels of triclosan, whereas no association was seen for current asthma. These results are consistent with recent findings in other studies and provide additional evidence for an association between triclosan and allergy.
doi:10.1111/all.12058
PMCID: PMC3515701  PMID: 23146048
allergy; antibacterial; asthma; rhinitis; triclosan
2.  GSTM1 and GSTP1 gene variants and the effect of air pollutants on lung function measures in South African children 
Background
Several genes are associated with an increased susceptibility to asthma, which may be exacerbated by ambient air pollution. These genes include GSTM1 (Glutathione-S-transferase M1 gene) and GSTP1 (Glutathione-S-transferase P1 gene), which may modulate the response to epithelial oxidative changes caused by air pollutant exposure. This study evaluated fluctuations in the forced expiratory volume in one second (FEV1) in relation to lagged daily averages of ambient air pollutants (SO2, NO2, NO, and PM10) while considering genotype as an effect modifier.
Methods
A longitudinal cohort of 129 schoolchildren of African descent from Durban, South Africa was assessed. GSTM1 (null vs. present genotype) and GSTP1 (Ile105Val; AA→AG/GG) genotypes were determined using standard techniques. SO2, NO2, NO and PM10 were measured continuously over a year using validated methods. The outcome was intraday variability in FEV1. Data were collected daily over a three week period in each of four seasons (2004–2005).
Results
Among the children tested, 27% had the GSTM1 null genotype and 81% carried the GSTP1 G allele. Approximately 26 out 104 children (25%) showed evidence of bronchial hyperreactivity, 13% reported having symptoms in keeping with persistent asthma, and a further 25% reported symptoms of mild intermittent asthma. PM10 and SO2 levels were moderately high relative to international guidelines. Neither GSTM1 nor GSTP1 genotypes alone were significantly associated with FEV1 intraday variability. In models not including genotype, FEV1 variability was statistically significantly associated only with NO2 for 5 day lags (% change in intraday variability in FEV1 per interquartile range =1.59, CI 0.58, 2.61). The GSTP1 genotype modified the effect of 3 days prior 24-hr average PM10 and increased FEV1 variability. A similar pattern was observed for lagged 3 day SO2 exposure (P interaction < 0.05). Adverse effects of these pollutants were limited to individuals carrying the G allele for this polymorphism.
Conclusion
Among this indigenous South African children cohort, the GSTP1 genotype modified the effects of ambient exposures to PM10 and SO2 and lung function. A plausible mechanism for these observed effects is decreased capacity to mount an effective response to oxidative stress associated with the GSTP1 AG+GG genotype.
doi:10.1002/ajim.22012
PMCID: PMC3414676  PMID: 22228263
air pollutants; asthma; child respiratory health; gene-environment interaction
3.  A systematic assessment of normalization approaches for the Infinium 450K methylation platform 
Epigenetics  2013;9(2):318-329.
The Illumina Infinium HumanMethylation450 BeadChip has emerged as one of the most popular platforms for genome wide profiling of DNA methylation. While the technology is wide-spread, systematic technical biases are believed to be present in the data. For example, this array incorporates two different chemical assays, i.e., Type I and Type II probes, which exhibit different technical characteristics and potentially complicate the computational and statistical analysis. Several normalization methods have been introduced recently to adjust for possible biases. However, there is considerable debate within the field on which normalization procedure should be used and indeed whether normalization is even necessary. Yet despite the importance of the question, there has been little comprehensive comparison of normalization methods. We sought to systematically compare several popular normalization approaches using the Norwegian Mother and Child Cohort Study (MoBa) methylation data set and the technical replicates analyzed with it as a case study. We assessed both the reproducibility between technical replicates following normalization and the effect of normalization on association analysis. Results indicate that the raw data are already highly reproducible, some normalization approaches can slightly improve reproducibility, but other normalization approaches may introduce more variability into the data. Results also suggest that differences in association analysis after applying different normalizations are not large when the signal is strong, but when the signal is more modest, different normalizations can yield very different numbers of findings that meet a weaker statistical significance threshold. Overall, our work provides useful, objective assessment of the effectiveness of key normalization methods.
doi:10.4161/epi.27119
PMCID: PMC3962542  PMID: 24241353
association testing; cotinine exposure; genome wide methylation profiling; normalization; reproducibility
4.  Phthalate Exposure and Allergy in the U.S. Population: Results from NHANES 2005–2006 
Environmental Health Perspectives  2013;121(10):1129-1134.
Background: Environmental exposures to phthalates, particularly high-molecular-weight (HMW) phthalates, are suspected to contribute to allergy.
Objective: We assessed whether phthalate metabolites are associated with allergic symptoms and sensitization in a large nationally representative sample.
Methods: We used data on urinary phthalate metabolites and allergic symptoms (hay fever, rhinitis, allergy, wheeze, asthma) and sensitization from participants ≥ 6 years of age in the National Health and Nutrition Examination Survey (NHANES) 2005–2006. Allergen sensitization was defined as a positive response to at least one of 19 specific IgE antigens (≥ 0.35 kU/L). Odds ratios (ORs) per one log10 unit change in phthalate concentration were estimated using logistic regression adjusting for age, race, body mass index, gender, creatinine, and cotinine. Separate analyses were conducted for children (6–17 years of age) and adults.
Results: The HMW phthalate metabolite monobenzyl phthalate (MBzP) was the only metabolite positively associated with current allergic symptoms in adults (wheeze, asthma, hay fever, and rhinitis). Mono-(3-carboxypropyl) phthalate and the sum of diethylhexyl phthalate metabolites (both representing HMW phthalate exposures) were positively associated with allergic sensitization in adults. Conversely, in children, HMW phthalate metabolites were inversely associated with asthma and hay fever. Of the low-molecular-weight phthalate metabolites, monoethyl phthalate was inversely associated with allergic sensitization in adults (OR = 0.79; 95% CI: 0.70, 0.90).
Conclusion: In this cross-sectional analysis of a nationally representative sample, HMW phthalate metabolites, particularly MBzP, were positively associated with allergic symptoms and sensitization in adults, but there was no strong evidence for associations between phthalates and allergy in children 6–17 years of age.
Citation: Hoppin JA, Jaramillo R, London SJ, Bertelsen RJ, Salo PM, Sandler DP, Zeldin DC. 2013. Phthalate exposure and allergy in the U.S. population: results from NHANES 2005–2006. Environ Health Perspect 121:1129–1134; http://dx.doi.org/10.1289/ehp.1206211 [Online 25 June 2013].
doi:10.1289/ehp.1206211
PMCID: PMC3801456  PMID: 23799650
5.  Decline in Early Childhood Respiratory Tract Infections in the Norwegian Mother and Child Cohort Study after Introduction of Pneumococcal Conjugate Vaccination 
BACKGROUND
The seven-valent pneumococcal conjugate vaccine (PCV7) was introduced into the Norwegian Childhood Immunization Program in 2006. A substantial effectiveness of PCV7 immunization against invasive pneumococcal disease has been demonstrated, while evidence of the impact on respiratory tract infections are less consistent.
METHODS
This study included children participating in the Norwegian Mother and Child Cohort Study, which recruited pregnant women between 1999 and 2008. Maternal report of acute otitis media (AOM), lower respiratory tract infections (LRTIs) and asthma in the child was compared with PCV7 immunization status, as obtained from the Norwegian Immunization Registry. Generalized linear models with the log link function were used to report adjusted relative risks (RR) and 95% confidence intervals (CI).
RESULTS
For children who had received three or more PCV7 immunizations by 12 months of age, the adjusted relative risks of AOM and LRTIs between 12 and 18 months were 0.86 [95% CI: 0.81, 0.91] and 0.78 [95% CI: 0.70, 0.87] respectively, when compared with non-immunized children. A reduced risk of AOM, RR 0.92 [95% CI: 0.90, 0.94], and LRTIs, RR 0.75 [95%CI: 0.71, 0.80], between 18 and 36 months of age was also identified among children who had received 3 or more immunizations by 18 months. No association was seen between PCV7 immunization and asthma at 36 months of age.
CONCLUSION
Reduced incidence proportions of AOM and LRTIs before 36 months of age were observed among children immunized with PCV7 through the childhood immunization program.
doi:10.1097/INF.0b013e31825d2f76
PMCID: PMC3421039  PMID: 22627867
Pneumococcal conjugate vaccination; lower respiratory tract infections; acute otitis media; asthma
6.  Fungal and Atopic Sensitization are Low among Farmers in the Agricultural Health Study 
Clinical Summary
Prevalence of fungal sensitization and atopy was lower among farmers than the US population. Fungal sensitization was related to growing specific agricultural commodities.
doi:10.1016/j.jaci.2012.04.018
PMCID: PMC3387290  PMID: 22633325
fungal sensitization; atopy; agriculture; farmers; specific and total IgE
7.  STAT6 and LRP1 polymorphisms are associated with food allergen sensitization in Mexican children 
doi:10.1016/j.jaci.2012.03.012
PMCID: PMC3367076  PMID: 22534531
food allergy; food allergen sensitization; skin prick test; genetic association; candidate gene; single nucleotide polymorphism; Hispanic
8.  Traffic exposure and lung function in adults: the Atherosclerosis Risk in Communities study 
Thorax  2007;62(10):873-879.
Background
Traffic exposure is a major contributor to ambient air pollution for people living close to busy roads. The relationship between traffic exposure and lung function remains inconclusive in adults.
Methods
A cross‐sectional study was conducted to investigate the association between traffic exposure and lung function in the Atherosclerosis Risk in Communities (ARIC) study, a community based cohort of 15 792 middle aged men and women. Traffic density and distance to major roads were used as measures of traffic exposure.
Results
After controlling for potential confounders including demographic factors, personal and neighbourhood level socioeconomic characteristics, cigarette smoking and background air pollution, higher traffic density was significantly associated with lower forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) in women. Relative to the lowest quartile of traffic density, the adjusted differences across increasing quartiles were 5.1, −15.4 and −21.5 ml for FEV1 (p value of linear trend across the quartiles = 0.041) and 1.2, −23.4 and −34.8 ml for FVC (p trend = 0.010). Using distance from major roads as a simpler index of traffic related air pollution exposure, the FEV1 was −15.7 ml (95% CI −34.4 to 2.9) lower and the FVC was −24.2 ml (95% CI −46.2 to −2.3) lower for women living within 150 m compared with subjects living further away. There was no significant effect of traffic density or distance to major roads on lung function in men. The FEV1/FVC ratio was not significantly associated with traffic exposure in either men or women.
Conclusions
This is the largest published study of traffic exposure and pulmonary function in adults to date. These results add to growing evidence that chronic exposure to traffic related air pollution may adversely affect respiratory health.
doi:10.1136/thx.2006.073015
PMCID: PMC2094260  PMID: 17442705
9.  Pesticides and other agricultural factors associated with self‐reported farmer's lung among farm residents in the Agricultural Health Study 
Background
Farmer's lung, or hypersensitivity pneumonitis, is an important contributor to respiratory morbidity among farmers.
Methods
Using the 1993–7 enrolment data from the Agricultural Health Study, we conducted a cross‐sectional study of occupational risk factors for farmer's lung among ∼50 000 farmers and farm spouses in Iowa and North Carolina using hierarchical logistic regression controlling for age, state, and smoking status. Participants provided information on agricultural exposures, demographic characteristics, and medical history via self‐administered questionnaires. Approximately 2% of farmers (n = 481) and 0.2% of spouses (n = 51) reported doctor‐diagnosed farmer's lung during their lifetime. We assessed farmers and spouses separately due to different information on occupational exposure history. Only pesticide exposures represented lifetime exposure history, all other farm exposures represented current activities at enrolment.
Results
Among farmers, handling silage (OR = 1.41, 95% CI 1.10 to 1.82), high pesticide exposure events (OR = 1.75, 95% CI 1.39 to 2.21), and ever use of organochlorine (OR = 1.34, 95% CI 1.04 to 1.74) and carbamate pesticides (OR = 1.32, 95% CI 1.03 to 1.68) were associated with farmer's lung in mutually‐adjusted models. The insecticides DDT, lindane, and aldicarb were positively associated with farmer's lung among farmers. Current animal exposures, while not statistically significant, were positively associated with farmer's lung, particularly for poultry houses (OR = 1.55, 95% CI 0.93 to 2.58) and dairy cattle (OR = 1.28, 95% CI 0.86 to 1.89). The occupational data were more limited for spouses; however, we saw similar associations for dairy cattle (OR = 1.50, 95% CI 0.72 to 3.14) and organochlorine pesticides (OR = 1.29, 95% CI 0.64 to 2.59).
Conclusion
While historic farm exposures may contribute to the observed associations with pesticides, these results suggest that organochlorine and carbamate pesticides should be further evaluated as potential risk factors for farmer's lung.
doi:10.1136/oem.2006.028480
PMCID: PMC1945110  PMID: 17182642
10.  Dietary Isothiocyanates, Glutathione S-Transferase M1 (GSTM1), and Lung Cancer Risk in African Americans and Caucasians from Los Angeles County, California 
Nutrition and cancer  2009;61(4):492-499.
Isothiocyanates, found in cruciferous vegetables, are anti-carcinogenic. Racial differences in smoking do not fully account for the African American excess lung cancer incidence. African Americans consume more cruciferous vegetables than US Whites. Impact on lung cancer risk is unknown. Glutathione S transferase M1 (GSTM1) gene promotes urinary isothiocyanate excretion. We evaluated dietary isothiocyanates and lung cancer using a population-based case-control study of 933 African Americans and Caucasians (non-Hispanic US White) from Los Angeles County, California (311 cases; 622 controls). Broccoli, cauliflower, greens and cabbage food-frequency variables represented isothiocyanates. Isothiocyanates were protective for lung cancer risk. Adjusted odds ratio (OR) for the uppermost quartile, > 80 μMol isothiocyanates/week, compared to lowest, was 0.65 (95% confidence interval (CL) = 0.41 – 1.00, trend p = 0.02). Association was stronger among subjects with homozygous deletion of GSTM1 (OR=0.52; 95% CL = 0.31 – 0.86), than subjects with at least one GSTM1 copy (OR = 0.77; 95% CL = 0.49 – 1.21). Difference was not statistically significant (p = 0.16). Despite African Americans consuming more cruciferous vegetables, the isothiocyanate association did not vary by race (p=0.52). Reduced lung cancer risk with higher isothiocyanate intake may be slightly stronger among subjects with deletion of GSTM1.
doi:10.1080/01635580902752270
PMCID: PMC3617906  PMID: 19838921
lung neoplasms; isothiocyanates; Brassica; GSTM1; African Americans
11.  Folic acid supplements in pregnancy and early childhood respiratory health 
Archives of disease in childhood  2008;94(3):180-184.
Background
Folate supplementation is recommended for pregnant women to reduce the risk of congenital malformations. Maternal intake of folate supplements during pregnancy might also influence childhood immune phenotypes via epigenetic mechanisms.
Objective
To investigate the relationship between folate supplements in pregnancy and risk of lower respiratory tract infections and wheeze in children through 18 months of age.
Methods
In the Norwegian Mother and Child Cohort Study, questionnaire data collected at several time points in pregnancy and after birth, from 32,077 children born between 2000 and 2005, were used to assess effects of folate supplements during pregnancy on respiratory outcomes up to 18 months of age, accounting for other supplements in pregnancy and supplementation in infancy.
Results
Folate supplements in the first trimester were associated with increased risk of wheeze and respiratory tract infections up to 18 months of age. Adjusting for exposure later in pregnancy and in infancy, the relative risk of wheeze for children exposed to folic acid supplements in the first trimester was 1.06 (95% confidence interval: 1.03, 1.10), for lower respiratory tract infections the relative risk was 1.09 (95% confidence interval: 1.02, 1.15), and for hospitalizations for lower respiratory tract infections the relative risk was 1.24 (95% confidence interval: 1.09, 1.41).
Conclusions
Folic acid supplements in pregnancy were associated with a slightly increased risk of wheeze and lower respiratory tract infections up to 18 months of age. Results support possible epigenetic influences of methyl donors in maternal diet during pregnancy on respiratory health in children.
doi:10.1136/adc.2008.142448
PMCID: PMC3612898  PMID: 19052032
Dietary Supplements; Folic acid; Pregnancy; Respiratory Tract Infections; Wheezing
12.  GSTM1, GSTP1 and NQO1 polymorphisms and susceptibility to atopy and airway hyperresponsiveness among South African schoolchildren 
Lung  2010;188(5):409-414.
Gluthathione-S-Transferases (GSTM1 and GSTP1) and Nicotinamide Quinone Oxidoreductase (NQO1) genes play an important role in cellular protection against oxidative stress which has been linked to asthma pathogenesis. We investigated whether common, functional polymorphisms in GSTM1, GSTP1 and NQO1 influences airway hyperreactivity (AHR) and atopy among schoolchildren in South Africa.
Genomic DNA was extracted from 317 primary schoolchildren, aged 9–11 years, from urban, low socioeconomic communities of Durban, South Africa. GSTM1 (null vs present genotype), GSTP1 (Ile105Val; AA→AG+GG) and NQO1 (Pro/187Ser; CC→CT/TT) genotypes were determined using polymerase chain reaction (PCR) methods. Atopy was defined as positive skin prick tests to any of several common allergens. Airway hyperreactivity (AHR) was evaluated by pulmonary function testing before and after methacholine challenge.
Among the children, 30% were GSTM1 null, 65% carried the G allele for GSTP1 and 36% carried the C allele for NQO1. The frequency of GSTM1, GSTP1 and NQO1 variants among our South African sample was similar to frequencies found in similar ethnic groups worldwide. Marked airway reactivity (PC20 ≤ 2 mg/ml) was found in 10.3% of children and approximately 40% of them were atopic. No significant associations were identified for GSTM1 and NQO1 with either AHR or atopy. A significant protective effect against atopy was found among children with one or two copies of the GSTP1 G allele.
doi:10.1007/s00408-010-9246-3
PMCID: PMC3611889  PMID: 20526719
genetic polymorphism; gluthathione-S-transferases; nicotinamide quinone oxidoreductase; oxidative stress; atopy; AHR
13.  Occupation and the Prevalence of Respiratory Health Symptoms and Conditions: The Atherosclerosis Risk in Communities Study 
Objectives
To examine associations between occupation and respiratory health in a large, population-based cohort of adults in the United States.
Methods
Data from 15,273 participants, aged 45-64 years, in the Atherosclerosis Risk in Communities (ARIC) study were used to examine associations of current or most recent job held with the prevalence of self-reported chronic cough, chronic bronchitis, wheeze, asthma, and measures of lung function collected by spirometry.
Results
Eleven percent of participants reported wheeze and 9% were classified as having airway obstruction. Compared to individuals in managerial and administrative jobs, increased prevalences of respiratory outcomes were observed among participants in selected occupations, including construction and extractive trades (wheeze: prevalence ratio [PR]: 1.92, 95% confidence interval [CI]: 1.35, 2.73; airway obstruction: PR: 1.31, 95% CI: 1.05, 1.65).
Conclusions
Specific occupations are associated with adverse respiratory health.
doi:10.1097/JOM.0b013e31823e3a52
PMCID: PMC3275692  PMID: 22157701
ARIC study; epidemiology; occupation; respiratory tract disease
14.  Delivery by Cesarean Section and Early Childhood Respiratory Symptoms and Disorders 
American Journal of Epidemiology  2011;174(11):1275-1285.
Studies have indicated that children delivered by cesarean section are at an increased risk of developing wheezing and asthma. This could be the result of an altered immune system development due to delayed gut colonization or of increased neonatal respiratory morbidity. The authors examined the associations between delivery by cesarean section and the development of wheezing, asthma, and recurrent lower respiratory tract infections in children up to 36 months of age among 37,171 children in the Norwegian Mother and Child Cohort Study. Generalized linear models were used in the multivariable analysis. Children delivered by cesarean section had an increased likelihood of current asthma at 36 months of age (relative risk = 1.17, 95% confidence interval: 1.03, 1.32), and the association was stronger among children of nonatopic mothers (relative risk = 1.33, 95% confidence interval: 1.12, 1.58). No increased risk of wheezing or recurrent lower respiratory tract infections was seen among children delivered by cesarean section. Findings were similar among children delivered by acute and elective cesarean section. In conclusion, children delivered by cesarean section may have an increased risk of current asthma at 36 months, but residual confounding cannot be excluded. In future prospective studies, investigators should reexamine this association in different age groups.
doi:10.1093/aje/kwr242
PMCID: PMC3254156  PMID: 22038100
asthma; cesarean section; respiratory sounds; respiratory tract infections
15.  High validity of mother-reported use of anti-asthmatics among children: a comparison with a population-based prescription database 
Journal of clinical epidemiology  2011;64(8):878-884.
Objectives
To examine the validity of: 1) maternal questionnaire report of children's use of anti-asthmatics using a prescription database as the reference standard, 2) dispensed anti-asthmatics as a measure of asthma using maternal report of children's asthma as the reference standard.
Study Design and Setting
3394 children in the Norwegian Mother and Child Cohort Study (MoBa) aged seven were linked to the Norwegian Prescription Database (NorPD). Maternal report of both children's use of anti-asthmatics during the preceding year and of the presence of asthma was compared with data on dispensed anti-asthmatics.
Results
2056 mothers responded and reported use of anti-asthmatics the previous year in 125 of 147 children who had been dispensed anti-asthmatics (sensitivity 85.0%). Of 1909 children with no dispensed anti-asthmatics, 1848 had no maternal report of anti-asthmatic use (specificity 96.8%). Mothers reported current asthma in 133 (6.5% of 2056) children, including 122 (5.9%) reported as verified by a doctor. Of these 122, 98 had been dispensed anti-asthmatics during the preceding year (sensitivity 80.3%). Only 1.2% of the children without reported asthma were dispensed anti-asthmatics.
Conclusion
Mother-reported use of anti-asthmatics during the previous year among 7 year old children is highly valid. Dispensed anti-asthmatics would be a useful proxy for the presence of current asthma when disease data are not available.
doi:10.1016/j.jclinepi.2010.10.014
PMCID: PMC3124572  PMID: 21232920
asthma; children; mother-reported; pharmacoepidemiology; prescription database; validity
16.  Oral contraceptive pill use before pregnancy and respiratory outcomes in early childhood 
Oral contraceptive pills (OCPs) are often used soon before, and sometimes during, pregnancy. A few studies have suggested that OCP use before pregnancy may increase risks for childhood respiratory outcomes, but data are inconclusive. No studies have analyzed the two types of OCPs, estrogen-progestin combined pills and progestin-only pills, separately. In the Norwegian Mother and Child Cohort Study (MoBa), we prospectively examined associations of OCP use before pregnancy, by type, with lower respiratory tract infections in 60,225 children followed to 6 months old, lower respiratory tract infections and wheezing in 42,520 children followed to 18 months old, and asthma in 24,472 children followed to 36 months old. We used logistic regression to estimate odds ratios and their 95% confidence intervals crudely and with adjustment for a wide range of potential confounders. Combined pills were used much more commonly than progestin-only pills. Taking combined pills before pregnancy was not associated with lower respiratory tract infections, wheezing, or asthma. Progestin-only pill use in the year before pregnancy had a slight positive association with wheezing at 6–8 months old [adjusted odds ratio (95% confidence interval)=1.19 (1.05–1.34)]. Our finding that combined pill use before pregnancy was not related to respiratory outcomes should provide reassurance to the vast majority of mothers using OCPs before becoming pregnant. The small association with progestin-only pill use and early respiratory outcomes may reflect uncontrolled confounding or other bias but does suggest that these two types of pills should be examined separately in future analyses of respiratory and other childhood outcomes.
doi:10.1111/j.1399-3038.2010.01135.x
PMCID: PMC3140614  PMID: 21294776
17.  Association of the Calcyon Neuron-Specific Vesicular Protein Gene (CALY) With Adolescent Smoking Initiation in China and California 
American Journal of Epidemiology  2011;173(9):1039-1048.
Although previous investigations have indicated a role for genetic factors in smoking initiation, the underlying genetic mechanisms are still unknown. In 2,339 adolescents from a Chinese Han population in the Wuhan Smoking Prevention Trial (Wuhan, China, 1998–1999), the authors explored the association of 57 genes in the dopamine pathway with smoking initiation. Using a conservative approach for declaring significance, positive findings were further examined in an independent sample of 603 Caucasian adolescents followed for up to 10 years as part of the Children's Health Study (Southern California, 1993–2009). The authors identified 1 single nucleotide polymorphism (rs2298122) in the calcyon neuron-specific vesicular protein gene (CALY) that was positively associated with smoking initiation in females (odds ratio = 2.21, 95% confidence interval: 1.49, 3.27; P = 8.4 × 10−5) in the Wuhan Smoking Prevention Trial cohort, and they replicated the association in females from the Children's Health Study cohort (hazard rate ratio = 2.05, 95% confidence interval: 1.27, 3.31; P = 0.003). These results suggest that the CALY gene may influence smoking initiation in adolescents, although the potential roles of underlying psychological characteristics that may be components of the smoking-initiation phenotype, such as impulsivity or novelty-seeking, remain to be explored.
doi:10.1093/aje/kwq471
PMCID: PMC3121219  PMID: 21415033
adolescent; dopamine; genetic association studies; smoking
18.  Traffic exposure and incident venous thromboembolism in the Atherosclerosis Risk in Communities (ARIC) Study 
Summary
Background
Two recent case-control studies in Italy reported that long-term exposure to particulate air pollution or living near major traffic roads was associated with an increased risk of deep vein thrombosis (DVT). No prospective evidence exists about long-term traffic-related air pollution and incident venous thromboembolism (VTE).
Objectives
To examine the association between long-term traffic exposure and incident VTE in a population-based prospective cohort study.
Methods
We studied 13,143 middle-aged men and women in the Atherosclerosis Risk in Communities Study without history of DVT or pulmonary embolus (PE) at baseline examination (1987-1989). Geographical Information System (GIS)-mapped traffic density and distance to major roads in the four study communities served as measures of traffic exposure. We examined the association between traffic exposure and incident VTE using proportional hazards regression models.
Results
405 subjects developed VTE through 2005. Traffic density was not significantly associated with VTE. Relative to those in the lowest quartile of traffic density, the adjusted hazard ratios across increasing quartiles were 1.18 (95%CI 0.88-1.57), 0.99 (95%CI 0.74-1.34) and 1.14 (95%CI 0.86-1.51) (p for trend across quartiles = 0.64). For residents living within 150 meters of major roads compared to subjects living further away, the adjusted hazard ratio was 1.16 (95%CI 0.95-1.42, p=0.14).
Conclusions
This first prospective study in the general population does not support an association between air pollution exposure or traffic proximity and risk of DVT. More data may be needed to clarify whether traffic or air pollution influences the risk of VTE.
doi:10.1111/j.1538-7836.2011.04210.x
PMCID: PMC3071427  PMID: 21255249
traffic exposure; VTE; air pollution; cohort
19.  Occupation and three-year incidence of respiratory symptoms and lung function decline: the ARIC Study 
Respiratory Research  2012;13(1):24.
Background
Specific occupations are associated with adverse respiratory health. Inhalation exposures encountered in these jobs may place workers at risk of new-onset respiratory disease.
Methods
We analyzed data from 8,967 participants from the Atherosclerosis Risk in Communities (ARIC) study, a longitudinal cohort study. Participants included in this analysis were free of chronic cough and phlegm, wheezing, asthma, chronic bronchitis, emphysema, and other chronic lung conditions at the baseline examination, when they were aged 45-64 years. Using data collected in the baseline and first follow-up examination, we evaluated associations between occupation and the three-year incidence of cough, phlegm, wheezing, and airway obstruction and changes in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) measured by spirometry. All associations were adjusted for age, cigarettes per day, race, smoking status, and study center.
Results
During the approximately three-year follow-up, the percentage of participants developing chronic cough was 3%; chronic phlegm, 3%; wheezing, 3%; and airway obstruction, defined as FEV1 < lower limit of normal (LLN) and FEV1/FVC < LLN, 2%. The average annual declines in FEV1 and FVC were 56 mL and 66 mL, respectively, among men and 40 mL and 52 mL, respectively, among women. Relative to a referent category of managerial and administrative support occupations, elevated risks of new-onset chronic cough and chronic phlegm were observed for mechanics and repairers (chronic cough: RR: 1.81, 95% CI: 1.02, 3.21; chronic phlegm: RR: 2.10, 95% CI: 1.23, 3.57) and cleaning and building service workers (chronic cough: RR: 1.85, 95% CI: 1.01, 3.37; chronic phlegm: RR: 2.28, 95% CI: 1.27, 4.08). Despite the elevated risk of new-onset symptoms, employment in cleaning and building services was associated with attenuated lung function decline, particularly among men, who averaged annual declines in FEV1 and FVC of 14 mL and 23 mL, respectively, less than the declines observed in the referent population.
Conclusions
Employment in mechanic and repair jobs and cleaning and building service occupations are associated with increased incidence of respiratory symptoms. Specific occupations affect the respiratory health of adults without pre-existing respiratory health symptoms and conditions, though long-term health consequences of inhalation exposures in these jobs remain largely unexplored.
doi:10.1186/1465-9921-13-24
PMCID: PMC3352304  PMID: 22433119
ARIC study; epidemiology; occupation; respiratory tract disease
20.  Questionnaire Predictors of Atopy in a US Population Sample: Findings From the National Health and Nutrition Examination Survey, 2005–2006 
American Journal of Epidemiology  2011;173(5):544-552.
Allergic conditions and biochemical measures are both used to characterize atopy. To assess questionnaires’ ability to predict biochemical measures of atopy, the authors used data on 5 allergic conditions (allergy, hay fever, eczema, rhinitis, and itchy rash) and serum-specific immunoglobulin E (IgE) levels from the 2005–2006 National Health and Nutrition Examination Survey. Atopy was defined as 1 or more positive specific IgEs (≥0.35 kU/L). Questionnaire responses were assessed for sensitivity, specificity, and positive and negative predictive values for atopy. In this population-based US sample, 44% of participants were specific IgE-positive and 53% reported at least 1 allergic condition. Discordance between atopy and allergic conditions was considerable; 37% of persons with atopy reported no allergic condition, and 48% of persons who reported an allergic condition were not atopic. Thus, no combination of self-reported allergic conditions achieved both high sensitivity and high specificity for IgE. The positive predictive value of reported allergic conditions for atopy ranged from 50% for eczema to 72% for hay fever, while the negative predictive value ranged from 57% for eczema to 65% for any condition. Given the high proportion of asymptomatic participants who were specific IgE-positive and persons who reported allergic conditions but were specific IgE-negative, it is unlikely that questionnaires will ever capture the same participants as those found to be atopic by biochemical measures.
doi:10.1093/aje/kwq392
PMCID: PMC3105435  PMID: 21273397
hypersensitivity; immunoglobulin E; questionnaires; sensitivity and specificity
21.  Using Imputed Genotypes for Relative Risk Estimation in Case-Parent Studies 
American Journal of Epidemiology  2011;173(5):553-559.
Meta-analyses of genome-wide association studies are often based on imputed single nucleotide polymorphism (SNP) data, because component studies were genotyped using different platforms. One would like to include case-parent triad studies along with case-control studies in such meta-analyses. However, there are no published methods for estimating relative risks from imputed data for case-parent triad studies. The authors propose a method for estimating the relative risk for a variant SNP allele based on a log-additive model. Their simulations first confirm that the proposed method performs well with genotyped SNP data. As an empirical test of the method's behavior with imputed SNPs, the authors then apply it to chromosome 22 data from the Mexico City Childhood Asthma Study (1998–2003). For chromosome 22, the authors had data on 7,293 SNPs that were both genotyped and imputed using the software MACH, which relies on linkage disequilibrium with nearby SNPs. Correlation between estimated relative risks based on the actual genotypes and those based on the imputed genotypes was remarkably high (r2 = 0.95), validating this method of relative risk estimation for the case-parent study design. This method should be useful to investigators who wish to conduct meta-analyses using imputed SNP data from both case-parent triad and case-control studies.
doi:10.1093/aje/kwq363
PMCID: PMC3291117  PMID: 21296892
epidemiologic methods; genome-wide association study; genotype; imputation; meta-analysis; risk
22.  Genome-Wide Meta-Analysis of Joint Tests for Genetic and Gene-Environment Interaction Effects 
Human Heredity  2011;70(4):292-300.
Background
There is growing interest in the study of gene-environment interactions in the context of genome-wide association studies (GWASs). These studies will likely require meta-analytic approaches to have sufficient power.
Methods
We describe an approach for meta-analysis of a joint test for genetic main effects and gene-environment interaction effects. Using simulation studies based on a meta-analysis of five studies (total n = 10,161), we compare the power of this test to the meta-analysis of marginal test of genetic association and the meta-analysis of standard 1 d.f. interaction tests across a broad range of genetic main effects and gene-environment interaction effects.
Results
We show that the joint meta-analysis is valid and can be more powerful than classical meta-analytic approaches, with a potential gain of power over 50% compared to the marginal test. The standard interaction test had less than 1% power in almost all the situations we considered. We also show that regardless of the test used, sample sizes far exceeding those of a typical individual GWAS will be needed to reliably detect genes with subtle gene-environment interaction patterns.
Conclusion
The joint meta-analysis is an attractive approach to discover markers which may have been missed by initial GWASs focusing on marginal marker-trait associations.
doi:10.1159/000323318
PMCID: PMC3085519  PMID: 21293137
Gene-environment interaction; Genome-wide scan; Meta-analysis; Case-control association analysis; Complex disease
23.  Mortality in the Agricultural Health Study, 1993–2007 
American Journal of Epidemiology  2010;173(1):71-83.
Comparing agricultural cohorts with the general population is challenging because the general healthiness of farmers may mask potential adverse health effects of farming. Using data from the Agricultural Health Study, a cohort of 89,656 pesticide applicators and their spouses (N = 89, 656) in North Carolina and Iowa, the authors computed standardized mortality ratios (SMRs) comparing deaths from time of the enrollment (1993–1997) through 2007 to state-specific rates. To compensate for the cohort's overall healthiness, relative SMRs were estimated by calculating the SMR for each cause relative to the SMR for all other causes. In 1,198,129 person-years of follow-up, 6,419 deaths were observed. The all-cause mortality rate was less than expected (SMRapplicators = 0.54, 95% confidence interval (CI): 0.52, 0.55; SMRspouses = 0.52, 95% CI: 0.50, 0.55). SMRs for all cancers, heart disease, and diabetes were significantly below 1.0. In contrast, applicators experienced elevated numbers of machine-related deaths (SMR = 4.15, 95% CI: 3.18, 5.31), motor vehicle nontraffic accidents (SMR = 2.80, 95% CI: 1.81, 4.14), and collisions with objects (SMR = 2.12, 95% CI: 1.25, 3.34). In the relative SMR analysis for applicators, the relative mortality ratio was elevated for lymphohematopoietic cancers, melanoma, and digestive system, prostate, kidney, and brain cancers. Among spouses, relative SMRs exceeded 1.0 for lymphohematopoietic cancers and malignancies of the digestive system, brain, breast, and ovary. Unintentional fatal injuries remain an important risk for farmers; mortality ratios from several cancers were elevated relative to other causes.
doi:10.1093/aje/kwq323
PMCID: PMC3025641  PMID: 21084556
agriculture; healthy worker effect; mortality; neoplasms; pesticides; wounds and injuries
24.  Ancestral Components of Admixed Genomes in a Mexican Cohort 
PLoS Genetics  2011;7(12):e1002410.
For most of the world, human genome structure at a population level is shaped by interplay between ancient geographic isolation and more recent demographic shifts, factors that are captured by the concepts of biogeographic ancestry and admixture, respectively. The ancestry of non-admixed individuals can often be traced to a specific population in a precise region, but current approaches for studying admixed individuals generally yield coarse information in which genome ancestry proportions are identified according to continent of origin. Here we introduce a new analytic strategy for this problem that allows fine-grained characterization of admixed individuals with respect to both geographic and genomic coordinates. Ancestry segments from different continents, identified with a probabilistic model, are used to construct and study “virtual genomes” of admixed individuals. We apply this approach to a cohort of 492 parent–offspring trios from Mexico City. The relative contributions from the three continental-level ancestral populations—Africa, Europe, and America—vary substantially between individuals, and the distribution of haplotype block length suggests an admixing time of 10–15 generations. The European and Indigenous American virtual genomes of each Mexican individual can be traced to precise regions within each continent, and they reveal a gradient of Amerindian ancestry between indigenous people of southwestern Mexico and Mayans of the Yucatan Peninsula. This contrasts sharply with the African roots of African Americans, which have been characterized by a uniform mixing of multiple West African populations. We also use the virtual European and Indigenous American genomes to search for the signatures of selection in the ancestral populations, and we identify previously known targets of selection in other populations, as well as new candidate loci. The ability to infer precise ancestral components of admixed genomes will facilitate studies of disease-related phenotypes and will allow new insight into the adaptive and demographic history of indigenous people.
Author Summary
Admixed individuals, such as African Americans and Latinos, arise from mating between individuals from different continents. Detailed knowledge about the ancestral origin of an admixed population not only provides insight regarding the history of the population itself, but also affords opportunities to study the evolutionary biology of the ancestral populations. Applying novel statistical methods, we analyzed the high-density genotype data of nearly 1,500 Mexican individuals from Mexico City, who are admixed among Indigenous Americans, Europeans, and Africans. The relative contributions from the three continental-level ancestral populations vary substantially between individuals. The European ancestors of these Mexican individuals genetically resemble Southern Europeans, such as the Spaniard and the Portuguese. The Indigenous American ancestry of the Mexicans in our study is largely attributed to the indigenous groups residing in the southwestern region of Mexico, although some individuals have inherited varying degrees of ancestry from the Mayans of the Yucatan Peninsula and other indigenous American populations. A search for signatures of selection, focusing on the parts of the genomes derived from an ancestral population (e.g. Indigenous American), identifies regions in which a genetic variant may have been favored by natural selection in that ancestral population.
doi:10.1371/journal.pgen.1002410
PMCID: PMC3240599  PMID: 22194699
25.  Joint testing of genotype and ancestry association in admixed families 
Genetic epidemiology  2010;34(8):783-791.
Current genome-wide association studies (GWAS) often involve populations that have experienced recent genetic admixture. Genotype data generated from these studies can be used to test for association directly, as in a non-admixed population. As an alternative, these data can be used to infer chromosomal ancestry, and thus allow for admixture mapping. We quantify the contribution of allele-based and ancestry-based association testing under a family-design, and demonstrate that the two tests can provide non-redundant information. We propose a joint testing procedure, which efficiently integrates the two sources information. The efficiencies of the allele, ancestry and combined tests are compared in the context of a GWAS. We discuss the impact of population history and provide guidelines for future design and analysis of GWAS in admixed populations.
doi:10.1002/gepi.20520
PMCID: PMC3103820  PMID: 21031451

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