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1.  Association of maternal AGTR1 polymorphisms and preeclampsia: a systematic review and meta-analysis 
Systematic review and meta-analysis to investigate the association between maternal AGTR1 gene single nucleotide polymorphisms (SNPs) and preeclampsia (PE).
A systematic literature search was performed using PubMed, EMBASE, Scopus, and HuGE Literature Finder databases. The review was conducted according to PRISMA guidelines. Summary odds ratios (ORs) for the allelic and genotypic contrasts were calculated and compared to indicate the most appropriate genetic model for the polymorphism of interest. Among-study heterogeneity was assessed using the I2 statistic and publication bias was evaluated visually using funnel plots.
Seven maternal SNPs investigated with PE were found, but only AGTR1 +1166A>C accumulated sufficient evidence for meta-analysis. Summary ORs calculated from eight studies (10 populations involving 845 PE cases and 1150 controls) did not reveal an association between the +1166A>C polymorphism and PE (allelic OR = 1.19, 95% CI: 0.96–1.47). No evidence of publication bias and among-study heterogeneity was detected.
Meta-analysis findings did not support AGTR1 +1166A>C as a susceptibility locus for PE. Other AGTR1 SNPs require more study.
PMCID: PMC3635471  PMID: 22758920
angiotensin II receptor type 1; genetic association study; pregnancy; single nucleotide polymorphism
2.  Childhood body mass index and subsequent physician-diagnosed asthma: a systematic review and meta-analysis of prospective cohort studies 
BMC Pediatrics  2013;13:121.
Childhood asthma and obesity prevalence have increased in recent years suggesting a potential association. However, the direction of any association is poorly understood and the potential causal-relationship is unknown.
We examined the association between overweight/obesity, defined by body mass index (BMI) <18 years of age, and subsequent physician-diagnosed incident asthma at least one year after BMI assessment. We sought to explore potential effect modification by sex. PubMed and Embase were searched using keywords and restricted to subjects aged 0–18 years. There were no date or language restrictions. From each study we extracted: authors, publication date, location, overweight/obesity definitions, asthma definitions, number of participants, recruitment duration, description of cohort, follow-up time, adjusted effect estimates (with 95% CI) and estimates of subgroup analysis.
Six prospective cohort studies which focused on children <18 years of age met criteria for inclusion. The combined risk ratio (RR) of overweight was associated with asthma (RR = 1.35; 95% CI = 1.15, 1.58). In boys, the combined RR of overweight on asthma was significant (RR = 1.41; 95% CI = 1.05, 1.88). For girls, when BMI was defined by Z-score, the combined RR of overweight on asthma was also significant (RR = 1.19; 95% CI = 1.06, 1.34). The combined risk ratio (RR) of obesity was associated with asthma in both boys and girls (RR = 1.50; 95% CI = 1.22, 1.83), in boys only (RR = 1.40; 95% CI = 1.01, 1.93) and in girls only (RR = 1.53; 95% CI = 1.09, 2.14).
Overweight and, especially, obese children are at increased risk of subsequent physician diagnosed asthma in comparison to normal weight children. Except for sex, no studies reported any other potential effect modifiers. The observed sex effects were inconsistent.
PMCID: PMC3751452  PMID: 23941287
Asthma; Overweight; Obesity; Body mass index; Body weight; Pediatric
3.  Antibiotic Exposure by 6 Months and Asthma and Allergy at 6 Years: Findings in a Cohort of 1,401 US Children 
American Journal of Epidemiology  2010;173(3):310-318.
Many studies have reported that antibiotic use may be associated with increased risk of childhood asthma. Respiratory tract infections in small children may be difficult to distinguish from early symptoms of asthma, and studies may have been confounded by “protopathic” bias, where antibiotics are used to treat early symptoms of asthma. These analyses of a cohort including 1,401 US children assess the association between antibiotic use within the first 6 months of life and asthma and allergy at 6 years of age between 2003 and 2007. Antibiotic exposure was associated with increased risk of asthma (adjusted odds ratio = 1.52, 95% confidence interval (CI): 1.07, 2.16). The odds ratio if asthma was first diagnosed after 3 years of age was 1.66 (95% CI: 0.99, 2.79) and, in children with no history of lower respiratory infection in the first year of life, the odds ratio was 1.66 (95% CI: 1.12, 3.46). The adverse effect of antibiotics was particularly strong in children with no family history of asthma (odds ratio = 1.89, 95% CI: 1.00, 3.58) (Pinteraction = 0.03). The odds ratio for a positive allergy blood or skin test was 1.59 (95% CI: 1.10, 2.28). The results show that early antibiotic use was associated with asthma and allergy at 6 years of age, and that protopathic bias was unlikely to account for the main findings.
PMCID: PMC3105273  PMID: 21190986
anti-bacterial agents; asthma; child; cohort studies; hypersensitivity
4.  Prenatal Exposure to Acetaminophen and Asthma in Children 
Obstetrics and gynecology  2009;114(6):1295-1306.
To estimate whether prenatal exposure to acetaminophen is associated with risk of diagnosed asthma and asthma symptoms in children.
The authors prospectively followed 1,505 pregnant women and their children until 6 years (±3 months) of life. Acetaminophen use in the first and third trimesters of pregnancy was assessed before 24 weeks of gestation and within 1 month of delivery, and asthma in children was assessed when the child was 6 years old. Adjusted odds ratios (aORs) were derived from logistic regression models controlling for potential confounders.
Acetaminophen was used by 69% of women during pregnancy. Use of acetaminophen did not significantly increase the risk of asthma (aOR 0.76, 95% confidence interval [CI] 0.53–1). Acetaminophen use during both the first and the third trimester was associated with a significantly reduced risk of asthma (aOR 0.59, 95% CI 0.36–0.98). There was no evidence of a dose response, and consumption greater than 10,400 mg (32 tablets) a month did not increase risk (aOR 0.99, 95% CI 0.19–5.30).
Our results suggest that acetaminophen use during pregnancy does not increase risk of asthma in children.
PMCID: PMC3237391  PMID: 19935033
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.  Does Chocolate Intake During Pregnancy Reduce the Risks of Preeclampsia and Gestational Hypertension? 
Annals of epidemiology  2010;20(8):584-591.
Chocolate consumption is associated with favorable levels of blood pressure and other cardiovascular disease risk markers. We analyzed a prospective cohort study to determine if regular chocolate intake during pregnancy is associated with reduced risks of preeclampsia and gestational hypertension (GH).
Subjects were recruited from 13 prenatal care practices in Connecticut (1988-1991). In-person interviews were administered at <16 weeks gestation to ascertain risk factors for adverse pregnancy outcomes. Hospital delivery and prenatal records were abstracted to classify preeclampsia (n=58), GH (n=158), and normotensive pregnancies (n=2351). Chocolate consumption (servings/week) during the 1st and 3rd trimesters was ascertained at initial interview and immediately postpartum, respectively. Consumers of <1 serving/week comprised the referent group. Adjusted odds ratios (aOR) were estimated using logistic regression.
Chocolate intake was more frequent among normotensives (80.7%) than preeclamptics (62.5%) or GH women (75.8%), and associated with reduced odds of preeclampsia (1st trimester: aOR=0.55, 95% CI: 0.32-0.95; 3rd trimester: aOR=0.56, 95% CI: 0.32-0.97). Only 1st trimester intake was associated with reduced odds of GH (aOR=0.65, 95% CI: 0.45-0.87).
These findings provide additional evidence of the benefits of chocolate. Prospective studies are needed to confirm and delineate protective effects of chocolate intake on risk of preeclampsia.
PMCID: PMC2901253  PMID: 20609337
Chocolate; Gestational Hypertension; Preeclampsia; Pregnancy
7.  Folic acid supplementation in early pregnancy and asthma in children aged six 
To assess whether folic acid intake during the first trimester of pregnancy is related to asthma in the offspring by the age of 6 years.
Study design
Prospective cohort study of 1,499 women who were followed from first trimester of pregnancy. Their children were followed until they were 6 years old.
51% of the women used folic acid in the month before conception and 88% in the third month of pregnancy. The adjusted OR per 100 microgram increase in average daily intake of folic acid was 0.98 (95% CI:0.93-1.04). For categories of daily folate intake, there was no evidence of associations with childhood asthma nor evidence of any dose response relation for any time period (all ptrend>0.05)
Our results do not support any association of folic acid supplementation in pregnancy and asthma risk in offspring by age 6 years.
PMCID: PMC3246127  PMID: 21982024
childhood asthma; folic acid; pregnancy
8.  Association between XRCC1 polymorphism 399 G->A and glioma among Caucasians: a systematic review and meta-analysis 
BMC Medical Genetics  2012;13:97.
The x-ray cross complementing group 1 gene (XRCC1) is crucial to proper repair of DNA damage such as single-strand DNA breaks. A non-synonymous polymorphism in XRCC1, 399 G → A, has been shown to reduce effectiveness of such DNA repair and has been associated with the risk of certain cancers. The known risk for glioma from high dose ionizing radiation makes associations between this polymorphism and glioma of particular interest.
A systematic literature review and meta-analysis was conducted to explore the association between XRCC1 399 G → A and glioma. Subgroup analyses by grade, gender, genotyping method, country in which study was conducted, and study size were conducted when data were available and validity of the results were assessed by influence analyses and exploration of potential publication bias.
Six studies were eligible for meta-analysis including data on 2,362 Caucasian glioma cases and 3,085 Caucasian controls. Pooled analysis yielded a significant association between the variant of interest and risk of glioma (OR = 1.17, 95% CI: 1.05-1.30) which was found to be disproportionately driven by a single study. Exclusion of this study, in an influence analysis, produced no statistically significant evidence of association with glioma (OR = 1.10, 95% CI: 0.98-1.23), and no evidence of publication bias.
This meta-analysis does not suggest a major role of the XRCC1 399 G → A polymorphism in influencing risk of glioma among Caucasians. Future studies should report data separately for glioma subtypes to permit stratified analyses for Grade III and Grade IV glioma and examine other polymorphisms in this gene.
PMCID: PMC3560258  PMID: 23101479
Glioma; XRCC1; Polymorphisms; Meta-analysis
9.  A systematic review and meta-analysis of prospective studies on the association between maternal cigarette smoking and preterm delivery 
We have attempted to quantify the most up-to-date estimate of the association between cigarette smoking by the mother and preterm delivery. Studies were selected for inclusion in this review if they were prospective, reported data stratified across at least two levels of maternal smoking, and defined preterm delivery on the basis of gestational age. In a meta-analysis we combined results from multiple studies that reported on preterm delivery and maternal smoking during pregnancy. Pooled odds ratios were computed for various strata of smoking intensity with the Mantel-Haenszel fixed-effects model. Twenty studies met all inclusion criteria and were included in meta-analysis. The pooled point estimate from 20 prospective studies on any maternal smoking versus no maternal smoking was 1.27 (95% confidence interval, 1.21-1.33). Subgroup analyses stratifying maternal smoking on number of cigarettes per day suggest a dose-response relationship at low to moderate levels of smoking, which was not further increased at high levels of smoking. A nonsignificant level of publication bias appears to exist in the smoking-preterm delivery literature. Cigarette smoking is a preventable risk factor that is associated with preterm delivery. Consistent results across many study populations and research designs and evidence of a dose-response relationship support its causal role in preterm delivery.
PMCID: PMC2706697  PMID: 10694353
Preterm delivery; cigarette smoking; meta-analysis
10.  Whole-exome sequencing of a pedigree segregating asthma 
BMC Medical Genetics  2012;13:95.
Despite the success of genome-wide association studies for asthma, few, if any, definitively causal variants have been identified and there is still a substantial portion of the heritability of the disease yet to be discovered. Some of this “missing heritability” may be accounted for by family-specific coding variants found to be segregating with asthma.
To identify family-specific variants segregating with asthma, we recruited one family from a previous study of asthma as reporting multiple asthmatic and non-asthmatic children. We performed whole-exome sequencing on all four children and both parents and identified coding variants segregating with asthma that were not found in other variant databases.
Ten novel variants were identified that were found in the two affected offspring and affected mother, but absent in the unaffected father and two unaffected offspring. Of these ten, variants in three genes (PDE4DIP, CBLB, and KALRN) were deemed of particular interest based on their functional prediction scores and previously reported function or asthma association. We did not identify any common risk variants segregating with asthma, however, we did observe an increase in the number of novel, nonsynonymous variants in asthma candidate genes in the asthmatic children compared to the non-asthmatic children.
This is the first report applying exome sequencing to identify asthma susceptibility variants. Despite having sequenced only one family segregating asthma, we have identified several potentially functional variants in interesting asthma candidate genes. This will provide the basis for future work in which more families will be sequenced to identify variants across families that cluster within genes.
PMCID: PMC3563469  PMID: 23046476
Asthma; Whole-exome sequencing; PDE4DIP; CBLB; KALRN
11.  Genome-wide association study identifies a maternal copy-number deletion in PSG11 enriched among preeclampsia patients 
Specific genetic contributions for preeclampsia (PE) are currently unknown. This genome-wide association study (GWAS) aims to identify maternal single nucleotide polymorphisms (SNPs) and copy-number variants (CNVs) involved in the etiology of PE.
A genome-wide scan was performed on 177 PE cases (diagnosed according to National Heart, Lung and Blood Institute guidelines) and 116 normotensive controls. White female study subjects from Iowa were genotyped on Affymetrix SNP 6.0 microarrays. CNV calls made using a combination of four detection algorithms (Birdseye, Canary, PennCNV, and QuantiSNP) were merged using CNVision and screened with stringent prioritization criteria. Due to limited DNA quantities and the deleterious nature of copy-number deletions, it was decided a priori that only deletions would be selected for assay on the entire case-control dataset using quantitative real-time PCR.
The top four SNP candidates had an allelic or genotypic p-value between 10-5 and 10-6, however, none surpassed the Bonferroni-corrected significance threshold. Three recurrent rare deletions meeting prioritization criteria detected in multiple cases were selected for targeted genotyping. A locus of particular interest was found showing an enrichment of case deletions in 19q13.31 (5/169 cases and 1/114 controls), which encompasses the PSG11 gene contiguous to a highly plastic genomic region. All algorithm calls for these regions were assay confirmed.
CNVs may confer risk for PE and represent interesting regions that warrant further investigation. Top SNP candidates identified from the GWAS, although not genome-wide significant, may be useful to inform future studies in PE genetics.
PMCID: PMC3476390  PMID: 22748001
Copy-number variant; Genome-wide association study; Microarray analysis; Preeclampsia; Single nucleotide polymorphism
12.  Why animal studies are often poor predictors of human reactions to exposure 
PMCID: PMC2746847  PMID: 19297654
13.  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
14.  Interpretation of 2002 Centers for Disease Control Guidelines for Group B Streptococcus and Evolving Provider Practice Patterns 
American journal of perinatology  2010;28(2):97-102.
We investigated if clinicians were altering their care of group B streptococcus (GBS)-positive women in labor to achieve 4 hours of intrapartum antibiotic prophylaxis based on their interpretation of the 2002 Centers for Disease Control (CDC) guidelines on prevention of perinatal GBS disease. We surveyed all clinicians with privileges on the labor floor at our institution about their interpretation and clinical application of the 2002 CDC guidelines. Seventy of 96 eligible clinicians (72.9%) completed our survey. In our survey, only 22.9% of clinicians reported not altering their management of labor in GBS-positive pregnancies that achieved less than 4 hours of prophylaxis. These alterations included “laboring down” or delaying pushing; turning off or decreasing an oxytocin infusion; or delaying or avoiding artificial rupture of membranes. Clinicians are altering their management of labor to attempt to achieve 4 hours of intrapartum prophylaxis. The 2002 CDC guidelines do not specifically recommend prolonging labor and are being interpreted differently in the clinical setting than the authors may have intended. The effects and consequences of this interpretation are unknown.
PMCID: PMC3224803  PMID: 20640975
Group B streptococcus; intrapartum prophylaxis; CDC guidelines; early onset neonatal sepsis
15.  Trends in One-Year Recurrent Ischemic Stroke among the Elderly in the USA: 1994–2002 
Background and Purpose
Of the 795,000 strokes occurring in the USA each year, over 20% are recurrent events. Little is known about how the rates of recurrent stroke in the country have changed over time. Our objective was to determine national trends in 1-year recurrent ischemic stroke rates by US county among the elderly from 1994 to 2002.
One-year recurrent stroke rates following incident ischemic stroke (ICD-9 433, 434, 436) among all fee-for-service Medicare beneficiaries were determined by US county for 1994–1996, 1997–1999, and 2000–2002. Bayesian spatiotemporal Poisson modeling was used to determine county-specific trends in recurrent stroke rates over time with risk adjustment for demographics, medical history and comorbid conditions.
The analysis included more than 2.5 million beneficiaries (56% women; mean age: 78 years; 87% white; n = 957,933 for 1994–1996; n = 838,330 for 1996–1999; n = 895,916 for 2000–2002) aggregated to all 3,118 US counties. After adjustment for changing patient demographics and comorbidities, there was a 4.5% decrease in recurrent stroke rates from 1994–1996 (13.2%) to 2000–2002 (12.6%; p for trend <0.0001). The geographic and temporal patterns were not uniform; the recurrent stroke rates decreased within sections of the Southeast (the ‘stroke belt’), but increased in counties in the middle and western sections of the USA.
The overall recurrent ischemic stroke rates declined by almost 5% from 1994 to 2002, but temporal patterns varied markedly by region. Additional research is needed to identify the reasons for this geographic disparity.
PMCID: PMC2978738  PMID: 20881382
Acute ischemic stroke; Geographic pattern; Time trends; Recurrent stroke
16.  Integrated Exposure Modeling: A Model Using GIS and GLM 
Statistics in medicine  2010;29(1):116-129.
Traffic exhaust is a source of air contaminants that have adverse health effects. Quantification of traffic as an exposure variable is complicated by aerosol dispersion related to variation in layout of roads, traffic density, meteorology, and topography. A statistical model is presented which uses Geographic Information Systems (GIS) technology to incorporate variables into a generalized linear model that estimates distribution of traffic-related pollution. Exposure from a source is expressed as an integral of a function proportional to average daily traffic and a nonparametric dispersion function which takes the form of a step, polynomial or spline model. The method may be applied using standard regression techniques for fitting generalized linear models. Modifiers of pollutant dispersion such as wind direction, meteorology, and landscape features can also be included. Two examples are given to illustrate the method. The first employs data from a study in which NO2 (a known pollutant from automobile exhaust) was monitored outside of 138 Connecticut homes, providing a model for estimating NO2 exposure. In a second example, estimated levels of nitrogen dioxide (NO2) from the model, as well as a separate spatial model, were used to analyze traffic-related health effects in a study of 761 infants.
PMCID: PMC3182125  PMID: 19823976
Traffic; Dispersion models; Geographic Information Systems; Generalized Linear Models; Splines
17.  Association between reduced copy-number at T-cell receptor gamma (TCRγ) and childhood allergic asthma: a possible role for somatic mosaicism 
Mutation research  2010;690(1-2):89-94.
Asthma is a chronic inflammatory disease of the lungs which affects more than 6.5 million American children. A family-based genome-wide association study of copy-number variation identified an association between decreased copy-number at TCRγ and childhood allergic asthma. TCRγ encodes the T-cell receptor gamma glycoprotein, a cell-surface protein found on T-cells and involved in cell-mediated immunity. Using quantitative real-time PCR, we sought to determine if copy-number variation at TCRα, TCRβ or TCRγ was associated with childhood allergic asthma in an independent cohort of 94 cases and 455 controls using DNA from buccal swabs. Copy-number variation at these loci is well-known, but appears to be dominated by somatic mutations. Genotyping results indicated that copy-number variants at these genes are largely somatic mutations, as inheritance did not show Mendelian consistency. In these mosaic cell populations, copy-number was significantly reduced among asthmatic children at TCRγ (p = 0.0199), but was not associated at TCRα or TCRβ (p = 0.7972 and 0.8585, respectively). These findings support the association between reduced copy-number at TCRγ and childhood allergic asthma. Further work is needed to resolve whether reduced copy-number at TCRγ predisposes individuals to asthma, or whether deletion of this gene is a somatic response to the disease.
PMCID: PMC2914201  PMID: 20553737
T-cell receptor gamma; Copy Number Variant; allergic asthma; mosaicism
18.  Association of CD14 -260 (-159) C>T and asthma: a systematic review and meta-analysis 
BMC Medical Genetics  2011;12:93.
Asthma is a phenotypically diverse disease with genetic susceptibility. A single nucleotide polymorphism (SNP) in the CD14 gene at position -260 (also known as -159) C>T has been inconsistently associated with asthma. The aim of this study was to estimate the combined likelihood of developing asthma given the CD14 -260C>T genotype.
Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic search and meta-analysis of the literature was conducted to estimate the association between this SNP and asthma. Planned subgroup analyses were performed to detect potential sources of heterogeneity from selected study characteristics. Post-hoc sensitivity analysis was performed to identify studies exerting excessive influence on among-study heterogeneity and combined effects.
Meta-analysis of 23 studies yielded a non-significant overall association with high heterogeneity across studies. After restricting analysis to studies using atopic asthma and non-atopic non-asthma case-control phenotypes and excluding studies influencing heterogeneity, the genotype-specific odds ratios (ORs) suggested a codominant model. Carriers of the TT and CT genotypes were about 33% less likely (OR = 0.67, 95% CI: 0.54-0.84) and about 20% less likely (OR = 0.80, 95% CI: 0.66-0.95), respectively, to have atopic asthma compared to carriers of the CC genotype. Among-study heterogeneity may be explained by overly broad asthma phenotype definitions, gene-environment interactions, and gene-gene interactions.
A protective dose-response relationship between the CD14 -260T allele and atopic asthma susceptibility was observed. These results demonstrate the importance of precisely specified case-control groups as well as the need to assess interactions in the investigation of complex diseases such as asthma.
PMCID: PMC3148550  PMID: 21745379
19.  Geographic Variation in One-Year Recurrent Ischemic Stroke Rates for Elderly Medicare Beneficiaries in the USA 
Neuroepidemiology  2010;34(2):123-129.
While geographic disparities in stroke mortality are well documented, there are no data describing geographic variation in recurrent stroke. Accordingly, we evaluated geographic variations in 1-year recurrent ischemic stroke rates in the USA with adjustment for patient characteristics.
One-year recurrent stroke rates for ischemic stroke (International Classification of Diseases, 9th Revision codes 433, 434 and 436) following hospital discharge were calculated by county for all fee-for-service Medicare beneficiaries from 2000 to 2002. The rates were standardized and smoothed using a bayesian conditional autoregressive model that was risk-standardized for patients’ age, gender, race/ethnicity, prior hospitalizations, Deyo comorbidity score, acute myocardial infarction, congestive heart failure, diabetes, hypertension, dementia, cancer, chronic obstructive pulmonary disease and obesity.
The overall 1-year recurrent stroke rate was 9.4% among 895,916 ischemic stroke patients (mean age: 78 years; 56.6% women; 86.6% White, 9.7% Black and 1.2% Latino/Hispanic). The rates varied by geographic region and were highest in the South and in parts of the West and Midwest. Regional variation was present for all racial/ethnic subgroups and persisted after adjustment for individual patient characteristics.
Almost 1 in 10 hospitalized ischemic stroke patients was readmitted for an ischemic stroke within 1 year. There was heterogeneity in recurrence patterns by geographic region. Further work is needed to understand the reasons for this regional variability.
PMCID: PMC2837886  PMID: 20068358
Stroke, recurrent; Small-area analysis; Variation, geographic; Recurrence
20.  Association of pediatric asthma severity with exposure to common household dust allergens 
Environmental research  2009;109(6):768-774.
Reducingexposure to household dust inhalant allergens has been proposed as one strategy to reduce asthma.
To examine the dose response relationships and health impact of five common household dust allergens on disease severity, quantified using both symptom frequency and medication use, in atopic and non-atopic asthmatic children.
Asthmatic children (N=300) aged 4–12 years were followed for one year. Household dust samples from two indoor locations were analyzed for allergens including dust mite (Der p 1, Der f 1), cat (Fel d 1), dog (Can f 1), cockroach (Bla g 1). Daily symptoms and medication use were collected in monthly telephone interviews. Annual disease severity was examined in models including allergens, specific IgE sensitivity and adjusted for age, gender, atopy, ethnicity, and mother’s education.
Der p 1 house dust mite allergen concentration of 2.0 + μg/g from the main room and the child’s bed was related to increased asthma severity independent of allergic status (respectively, OR 2.93, 95% CI 1.37, 6.30 for 2.0 –10.0 μg/g and OR 2.55 95% CI 1.13, 5.73 for ≥ 10.0 μg/g). Higher pet allergen levels were associated with greater asthma severity, but only for those sensitized (cat OR 2.41 95% CI 1.19, 4.89; dog OR 2.06 95% CI 1.01, 4.22).
Higher levels of Der p 1 and pet allergens were associated with asthma severity, but Der p 1 remained an independent risk factor after accounting for pet allergens and regardless of Der p 1 specific IgE status.
PMCID: PMC2706291  PMID: 19473655
pediatric asthma; household dust allergens; Der p1; dust mite; pet allergens
21.  Tissue Biomarkers for Prognosis in Cutaneous Melanoma: A Systematic Review and Meta-analysis 
In the clinical management of early-stage cutaneous melanoma, it is critical to determine which patients are cured by surgery alone and which should be treated with adjuvant therapy. To assist in this decision, many groups have made an effort to use molecular information. However, although there are hundreds of studies that have sought to assess the potential prognostic value of molecular markers in predicting the course of cutaneous melanoma, at this time, no molecular method to improve risk stratification is part of recommended clinical practice. To help understand this disconnect, we conducted a systematic review and meta-analysis of the published literature that reported immunohistochemistry-based protein biomarkers of melanoma outcome. Three parallel search strategies were applied to the PubMed database through January 15, 2008, to identify cohort studies that reported associations between immunohistochemical expression and survival outcomes in melanoma that conformed to the REMARK criteria. Of the 102 cohort studies, we identified only 37 manuscripts, collectively describing 87 assays on 62 distinct proteins, which met all inclusion criteria. Promising markers that emerged included melanoma cell adhesion molecule (MCAM)/MUC18 (all-cause mortality [ACM] hazard ratio [HR] = 16.34; 95% confidence interval [CI] = 3.80 to 70.28), matrix metalloproteinase-2 (melanoma-specific mortality [MSM] HR = 2.6; 95% CI = 1.32 to 5.07), Ki-67 (combined ACM HR = 2.66; 95% CI = 1.41 to 5.01), proliferating cell nuclear antigen (ACM HR = 2.27; 95% CI = 1.56 to 3.31), and p16/INK4A (ACM HR = 0.29; 95% CI = 0.10 to 0.83, MSM HR = 0.4; 95% CI = 0.24 to 0.67). We further noted incomplete adherence to the REMARK guidelines: 14 of 27 cohort studies that failed to adequately report their methods and nine studies that failed to either perform multivariable analyses or report their risk estimates were published since 2005.
PMCID: PMC2720709  PMID: 19318635
22.  Chocolate Consumption in Pregnancy and Reduced Likelihood of Preeclampsia 
Epidemiology (Cambridge, Mass.)  2008;19(3):459-464.
Preeclampsia is a major pregnancy complication with cardiovascular manifestations. Recent studies suggest that chocolate consumption may benefit cardiovascular health.
We studied the association of chocolate consumption with risk of preeclampsia in a prospective cohort study of 2291 pregnant women who delivered a singleton livebirth between September 1996 and January 2000. Chocolate consumption was measured by self report in the first and third trimesters, and by umbilical cord serum concentrations of theobromine, the major methylxanthine component of chocolate. Preeclampsia was assessed by detailed medical record review for 1943 of the women. We derived adjusted odds ratios (aOR) and 95% confidence intervals (CIs) from logistic regression models controlling for potential confounders.
Preeclampsia developed in 3.7% (n = 63) of 1681 women. Cord serum theobromine concentrations were negatively associated with preeclampsia (aOR = 0.31; CI = 0.11–0.87 for highest compared with lowest quartile). Self-reported chocolate consumption estimates also were inversely associated with preeclampsia. Compared with women consuming under 1 serving of chocolate weekly, women consuming 5+ servings per week had decreased risk: aOR = 0.81 with consumption in the first 3 months of pregnancy (CI = 0.37–1.79) and 0.60 in the last 3 months (0.30–1.24).
Our results suggest that chocolate consumption during pregnancy may lower risk of preeclampsia. However, reverse causality may also contribute to these findings.
PMCID: PMC2782959  PMID: 18379424
23.  Household airborne Penicillium associated with peak expiratory flow variability in asthmatic children 
Exposure to airborne fungi has been associated with increased airway hyperreactivity and asthma prevalence.
To investigate the association between common indoor fungi and airway hyperreactivity measured by peak expiratory flow variability in asthmatic children.
Children 6 to 12 years of age (n = 225) with a physician diagnosis of asthma were enrolled in the study to have their peak expiratory flow recorded twice daily during a 2-week period. Genus-specific, quantitative, in-home airborne mold concentrations were measured. Logistic regression models were used to examine the relationship between a mean peak expiratory flow variability greater than 18.5% (75th percentile) and any mold in the home (total mold, Cladosporium, Penicillium, Aspergillus, and Alternaria).
Mold was detected in 93% of the homes. The most common molds were Cladosporium in 72% and Penicillium in 42% of the samples. Controlling for sex, ethnicity, age, and winter season of sampling, Penicillium measured in the home was associated with a mean peak expiratory flow variability greater than 18.5% (odds ratio, 2.4; 95% confidence interval, 1.2–4.8). Greater peak expiratory flow variability was not associated with total mold or other mold measured in the home.
Exposure to airborne Penicillium is associated with increased peak expiratory flow variability in asthmatic children.
PMCID: PMC2746059  PMID: 19663123
24.  Symptoms and Medication Use in Children with Asthma and Traffic-Related Sources of Fine Particle Pollution 
Environmental Health Perspectives  2009;117(7):1168-1174.
Exposure to ambient fine particles [particulate matter ≤ 2.5 μm diameter (PM2.5)] is a potential factor in the exacerbation of asthma. National air quality particle standards consider total mass, not composition or sources, and may not protect against health impacts related to specific components.
We examined associations between daily exposure to fine particle components and sources, and symptoms and medication use in children with asthma.
Children with asthma (n = 149) 4–12 years of age were enrolled in a year-long study. We analyzed particle samples for trace elements (X-ray fluorescence) and elemental carbon (light reflectance). Using factor analysis/source apportionment, we identified particle sources (e.g., motor vehicle emissions) and quantified daily contributions. Symptoms and medication use were recorded on study diaries. Repeated measures logistic regression models examined associations between health outcomes and particle exposures as elemental concentrations and source contributions.
More than half of mean PM2.5 was attributed to traffic-related sources motor vehicles (42%) and road dust (12%). Increased likelihood of symptoms and inhaler use was largest for 3-day averaged exposures to traffic-related sources or their elemental constituents and ranged from a 10% increased likelihood of wheeze for each 5-μg/m3 increase in particles from motor vehicles to a 28% increased likelihood of shortness of breath for increases in road dust. Neither the other sources identified nor PM2.5 alone was associated with increased health outcome risks.
Linking respiratory health effects to specific particle pollution composition or sources is critical to efforts to protect public health. We associated increased risk of symptoms and inhaler use in children with asthma with exposure to traffic-related fine particles.
PMCID: PMC2717146  PMID: 19654929
childhood asthma; fine particle pollution; PM2.5; respiratory morbidity; source apportionment; traffic pollution
25.  Prenatal Caffeine Assessment: Fetal and Maternal Biomarkers or Self Reported Intake? 
Annals of epidemiology  2008;18(3):172-178.
To examine associations among measures of caffeine exposure including maternal urine, umbilical cord blood, and maternal self report.
Pregnant women were recruited from 56 obstetric practices and 15 clinics associated with six hospitals in Connecticut and Massachusetts between September 1996 and January 2000; 3,633 women were enrolled. Maternal urine throughout pregnancy and umbilical cord blood samples were analyzed for caffeine, paraxanthine, theophylline, and theobromine. Maternal caffeine intake was assessed throughout pregnancy.
Urinary and cord blood biomarkers were correlated with reported intake throughout pregnancy (range r =0.35–0.66; p<0.0001). Infants of smokers had higher cord blood concentrations of paraxanthine, reflecting faster caffeine metabolism in smokers, and cord blood paraxanthine levels were more strongly correlated with intake in smokers.
Maternal self reported intake may still be the optimal and most valid measure of antenatal caffeine exposure, since biomarkers do not reflect exposure over pregnancy.
PMCID: PMC2275917  PMID: 18083538
biomarkers; caffeine; cord blood; pregnancy; self-report

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