Biomedical subjects

W James Gauderman

Publications and source records attributed to W James Gauderman.

At least 37 records · Page 2Linked to original sources

PubMed2004

Th1 and Th2 cytokines and IgE levels in identical twins with varying levels of cigarette consumption.

Some have suggested that tobacco smoke may skew the immune system toward a Th2 pattern, however the effects of genetics or childhood exposures could explain these results. We compared PMBC supernatant or serum Th1 (INF-gamma) and Th2 (IL-4, IL-5, and IL-13) cytokine and IgE levels in members of 45 pairs of nonasthmatic monozygotic twins with varying levels of current cigarette consumption to determine if smoking was associated with Th1/Th2 function after accounting for genetic factors. A statistically significant dose-response was observed between levels of smoking and IL-13 (p=0.05). Mean IL-13 level among heavy smokers (20+ cigarettes/day) was 146% higher than that among nonsmokers (+26.2 pg/mL; p=0.04). The mean IL-5 level among heavy smokers was 166% higher than that among light (<20 cigarettes/day) smokers (+3.4 pg/mL; p=0.03). No statistically significant differences in INF-gamma, IL-4, or IgE levels were observed. Smoking appears to be associated with increased levels of IL-13.

Cytokines↗

PubMed2004

Effects of ambient air pollutants on asthma medication use and wheezing among fourth-grade school children from 12 Southern California communities enrolled in The Children's Health Study.

To investigate the effects of 12 monthly average air pollution levels on monthly prevalence of respiratory morbidity, the authors examined retrospective questionnaire data on 2034 4th-grade children from 12 Southern California communities that were enrolled in The Children's Health Study. Wheezing during the spring and summer months was associated with community levels of airborne particulate matter with a diameter < or = 10 microm (PM10) (odds ratio (OR) = 2.91; 95% confidence interval (CI) = 1.46-5.80), but was not associated with community levels of ozone, nitrogen dioxide, PM2.5 (diameter < or = 2.5), nitric acid, or formic acid. Logistic regression was performed on data stratified into two seasonal groups, spring/summer and fall/winter. Among asthmatics, the monthly prevalence of asthma medication use was associated with monthly levels of ozone, nitric acid, and acetic acid (OR = 1.80 [95%CI = 1.19-2.70]; OR = 1.80 [95%CI = 1.23-2.65]; OR = 1.57 [95% CI = 1.11-2.21]; respectively). Asthma medication use was more prevalent among children who spent more time outdoors--with consequential exposure to ozone--than among children who spent more time indoors (OR = 3.07 [95%CI = 1.61-5.86]; OR = 1.31 [95%CI = 0.47-2.71]; respectively). The authors concluded that monthly variations in some ambient air pollutants were associated with monthly respiratory morbidity among school children.

Air Pollutants↗

PubMed2003

Segregation and linkage analysis for longitudinal measurements of a quantitative trait.

We present a method for using slopes and intercepts from a linear regression of a quantitative trait as outcomes in segregation and linkage analyses. We apply the method to the analysis of longitudinal systolic blood pressure (SBP) data from the Framingham Heart Study. A first-stage linear model was fit to each subject's SBP measurements to estimate both their slope over time and an intercept, the latter scaled to represent the mean SBP at the average observed age (53.7 years). The subject-specific intercepts and slopes were then analyzed using segregation and linkage analysis. We describe a method for using the standard errors of the first-stage intercepts and slopes as weights in the genetic analyses. For the intercepts, we found significant evidence of a Mendelian gene in segregation analysis and suggestive linkage results (with LOD scores >or= 1.5) for specific markers on chromosomes 1, 3, 5, 9, 10, and 17. For the slopes, however, the data did not support a Mendelian model, and thus no formal linkage analyses were conducted.

Adult Children↗

PubMed2003

Multiple imputation methods for longitudinal blood pressure measurements from the Framingham Heart Study.

Missing data are a great concern in longitudinal studies, because few subjects will have complete data and missingness could be an indicator of an adverse outcome. Analyses that exclude potentially informative observations due to missing data can be inefficient or biased. To assess the extent of these problems in the context of genetic analyses, we compared case-wise deletion to two multiple imputation methods available in the popular SAS package, the propensity score and regression methods. For both the real and simulated data sets, the propensity score and regression methods produced results similar to case-wise deletion. However, for the simulated data, the estimates of heritability for case-wise deletion and the two multiple imputation methods were much lower than for the complete data. This suggests that if missingness patterns are correlated within families, then imputation methods that do not allow this correlation can yield biased results.

Adult↗

PubMed2003

IL-6 levels and genotype are associated with risk of young adult Hodgkin lymphoma.

Identical twins of young adult Hodgkin lymphoma case subjects are much more likely to develop the disease compared with fraternal twins of case subjects, suggesting a genetic determinant. Interleukin 6 (IL-6) levels are increased in patients with Hodgkin lymphoma and are correlated with a poor prognosis. We hypothesized that a heritable abnormality in IL-6 regulation may predispose to young adult Hodgkin lymphoma. We obtained blood specimens from 88 young adult Hodgkin lymphoma case subjects and their twins as well as from 87 matched control subjects. IL-6 was measured from unstimulated peripheral blood mononuclear cell (PBMC) supernatant with enzyme-linked immunosorbent assays (ELISAs) and compared by using analysis of covariance. Unaffected identical twins of case subjects (surrogate case subjects) had a 87.8% higher IL-6 level compared with matched control subjects (mean difference, +483.7 pg/mL, P =.04). Analysis of the IL-6 174G>C promoter polymorphism genotypes showed that risk decreased with an increasing number of C alleles (P =.01). The CC (low secreting) genotype was associated with a decreased risk of young adult Hodgkin lymphoma relative to the GG (high secreting) genotype (odds ratio [OR] =.29; P =.03). Risk was decreased for both nodular sclerosis and other subtypes. Persons with genetically determined lower IL-6 levels may be less susceptible to young adult Hodgkin lymphoma.

Adolescent↗

PubMed2003

Children's lung function and antioxidant vitamin, fruit, juice, and vegetable intake.

The authors investigated the relation between children's pulmonary function and intake of fruits, vegetables, juices, and vitamins A, C, and E by examining cross-sectional data from 2,566 children in the Children's Health Study collected during 1997-1998. Low total vitamin C intake (< or =10th percentile) was associated with deficits in forced vital capacity for both boys and girls and with deficits in flows that were larger in girls (forced expiratory volume in 1 second (FEV1), -3.3%, 95% confidence interval (CI): -6.0, -0.5; forced expiratory flow between 25% and 75% of forced vital capacity (FEF(25-75)), -5.5%, 95% CI: -10.5, -0.3) compared with boys (FEV1, -2.3%, 95% CI: -4.8, 0.3; FEF(25-75), -2.4%, 95% CI: -7.4, 2.8). Low dietary vitamin E intake was associated with lower FEF(25-75) (boys: FEF(25-75), -8.9%, 95% CI: -14.2, -3.3; girls: FEF(25-75), -2.5%, 95% CI: -8.3, 3.7). Deficits in FEF(25-75) were associated with low dietary vitamin A intake in girls (FEF(25-75), -7.9%, 95% CI: -12.7, -2.8) and with low total vitamin A intake in boys with asthma (FEF(25-75), -15.6%, 95% CI: -27.6, -1.6). Low intakes of orange and other fruit juices, which were the largest source of vitamin C, were associated with deficits in forced vital capacity and FEV1 in boys. In summary, lung function levels were lower in children with inadequate dietary antioxidant vitamin intake.

Adolescent↗

PubMed2003

Obesity and the risk of newly diagnosed asthma in school-age children.

To determine the relation between obesity and new-onset asthma among school-age children, the authors examined longitudinal data from 3,792 participants in the Children's Health Study (Southern California) who were asthma-free at enrollment. New cases of physician-diagnosed asthma, height, weight, lung function, and risk factors for asthma were assessed annually at five school visits between 1993 and 1998. Incidence rates were calculated, and proportional hazards regression models were fitted to estimate the adjusted relative risks of new-onset asthma associated with percentile of body mass index (weight (kg)/height (m)(2)) and indicators of overweight (>85th body mass index percentile) and obesity (>95th body mass index percentile). The risk of new-onset asthma was higher among children who were overweight (relative risk (RR) = 1.52, 95% confidence interval (CI): 1.14, 2.03) or obese (RR = 1.60, 95% CI: 1.08, 2.36). Boys had an increased risk associated with being overweight (RR = 2.06, 95% 1.33, 3.18) in comparison with girls (RR = 1.25, 95% CI: 0.83, 1.88). The effect of being overweight was greater in nonallergic children (RR = 1.77, 95% CI: 1.26, 2.49) than in allergic children (RR = 1.16, 95% CI: 0.63, 2.15). The authors conclude that being overweight is associated with an increased risk of new-onset asthma in boys and in nonallergic children.

Adolescent↗

PubMed2003

Prospective study of air pollution and bronchitic symptoms in children with asthma.

The relationship of bronchitic symptoms to ambient particulate matter and to particulate elemental and organic carbon (OC), nitrogen dioxide (NO2), and other gaseous pollutants was examined in a cohort of children with asthma in 12 Southern California communities. Symptoms, assessed yearly by questionnaire from 1996 to 1999, were associated with the yearly variability of particulate matter with aerodynamic diameter less than 2.5 microg (odds ratio [OR] 1.09/microg/m3; 95% confidence interval [CI] 1.01-1.17), OC (OR 1.41/microg/m3; 95% CI 1.12-1.78), NO2 (OR 1.07/ppb; 95% CI 1.02-1.13), and ozone (OR 1.06/ppb; 95% CI 1.00-1.12). The ORs associated with yearly within-community variability in air pollution were larger than the effect of the between-community 4-year average concentrations. In two pollutant models, the effects of yearly variation in OC and NO2 were only modestly reduced by adjusting for other pollutants, except in a model containing both OC and NO2; the effects of all other pollutants were reduced after adjusting for OC or NO2. We conclude that OC and NO2 deserve greater attention as potential causes of the chronic symptoms of bronchitis in children with asthma and that previous cross-sectional studies may have underestimated the risks associated with air pollution.

Adolescent↗

PubMed2003

Candidate gene association analysis for a quantitative trait, using parent-offspring trios.

With the increasing availability of genetic data, many studies of quantitative traits focus on hypotheses related to candidate genes, and also gene-environment (G x E) and gene-gene (G x G) interactions. In a population-based sample, estimates and tests of candidate gene effects can be biased by ethnic confounding, also known as population stratification bias. This paper demonstrates that even a modest degree of ethnic confounding can lead to unacceptably high type I error rates for tests of genetic effects. The parent-offspring trio design is reviewed, and several forms of the quantitative transmission disequilibrium test (QTDT) are summarized. A variation of the QTDT (QTDTM) is described that is based on a linear regression model with multiple intercepts, one per parental mating type. This and other models are expanded to allow testing of G x E and G x G interactions. A method for computing required sample sizes using direct computations is described. Sample size requirements for tests of genetic main effects and G x E and G x G interactions are compared across various QTDT approaches to infer their efficiencies relative to one another. The QTDTM is found to meet or exceed the efficiency of other QTDT approaches. For example, the QTDTM is approximately 3% more efficient than the QTDT of Rabinowitz ([1997] Hum. Hered. 47:342-350) for testing a genetic main effect, but can be as much as twice as efficient for testing G x E interaction, and three times more efficient for testing G x G interaction.

Algorithms↗

PubMed2003

Longitudinal data analysis in pedigree studies.

Longitudinal family studies provide a valuable resource for investigating genetic and environmental factors that influence long-term averages and changes over time in a complex trait. This paper summarizes 13 contributions to Genetic Analysis Workshop 13, which include a wide range of methods for genetic analysis of longitudinal data in families. The methods can be grouped into two basic approaches: 1) two-step modeling, in which repeated observations are first reduced to one summary statistic per subject (e.g., a mean or slope), after which this statistic is used in a standard genetic analysis, or 2) joint modeling, in which genetic and longitudinal model parameters are estimated simultaneously in a single analysis. In applications to Framingham Heart Study data, contributors collectively reported evidence for genes that affected trait mean on chromosomes 1, 2, 3, 5, 8, 9, 10, 13, and 17, but most did not find genes affecting slope. Applications to simulated data suggested that even for a gene that only affected slope, use of a mean-type statistic could provide greater power than a slope-type statistic for detecting that gene. We report on the results of a small experiment that sheds some light on this apparently paradoxical finding, and indicate how one might form a more powerful test for finding a slope-affecting gene. Several areas for future research are discussed.

Cardiovascular Diseases↗

PubMed2003

Regression models for linkage: issues of traits, covariates, heterogeneity, and interaction.

Regression methods offer a common framework to analyze linkage for quantitative trait loci as well as linkage for affection status using affected sib-pairs. Although numerous papers on regression methods for linkage have been published, some common themes and important caveats tend to be scattered across the literature. For example, the typical approach is to regress a function of traits on identical-by-descent (IBD) information, but the reversal (regression of IBD on a function of traits) offers important insights. A second example is the use of regression equations to assess linkage heterogeneity or gene-environment interaction, and why these two different etiologies are difficult to distinguish with affected sib-pair data. A third example has to do with the differences, and similarities, between linear regression and non-linear regression methods for affected sib-pair data. The purposes of this paper are to review some recent developments in the linkage regression framework, to emphasize strengths and weaknesses of various proposed methods, and to highlight some important assumptions and caveats.

Data Interpretation, Statistical↗

PubMed2002

Effects of glutathione-S-transferase M1, T1, and P1 on childhood lung function growth.

The effects of glutathione-S-transferase (GST) M1, GSTT1, and GSTP1 genotypes on lung function growth were investigated in 1,940 children enrolled in the Children's Health Study as fourth graders (aged 8-11 years) in two cohorts during 1993 and 1996 and were followed annually over a 4-year period. Genotypes for GSTM1 and GSTT1 and GSTP1 codon 105 variants (ile105 and val105) were determined using DNA from buccal cell specimens. We used two-level regression models to estimate the effects of GSTM1, GSTT1, and GSTP1 genotypes on the adjusted annual average lung function growth. GSTM1 null was associated with deficits in annual growth rates for FVC (-0.21%; 95% confidence interval [CI], -0.40, -0.03) and FEV(1) (-0.27%; 95% CI, -0.50, -0.04). Children who were homozygous for the GSTP1 val105 allele had slower lung function growth (FVC -0.35%; 95% CI, -0.62, -0.07; and FEV(1) -0.34%; 95% CI, -0.68, 0.00) than children with one or more ile105 alleles. Children with asthma who were homozygous for the GSTP1 val105 allele had substantially larger deficits in FVC, FEV(1), and maximal mid-expiratory flow than children without asthma. The deficits in FVC and FEV(1) growth associated with both GSTM1 null and the GSTP1 val105 allele were largest and were statistically significant in non-Hispanic white children. We conclude that GSTM1 and GSTP1 genotypes are associated with lung function growth in school children.

Case-Control Studies↗

PubMed2002

Effects of glutathione S-transferase M1, maternal smoking during pregnancy, and environmental tobacco smoke on asthma and wheezing in children.

The rise in childhood asthma prevalence suggests a role for environmental factors in the etiology of this evolving epidemic; however, genetics also influence the occurrence of asthma. Glutathione S-transferase (GST) M1 may play a role in asthma and wheezing occurrence among those exposed to tobacco smoke, as it functions in pathways involved in asthma pathogenesis such as xenobiotic metabolism and antioxidant defenses. Effects of GSTM1 genotype, maternal smoking during pregnancy, and childhood environmental tobacco smoke (ETS) exposure on asthma and wheezing were investigated in 2,950 children enrolled in 4th, 7th, and 10th grade classrooms in 12 Southern California communities. The effects of in utero exposure to maternal smoking on asthma and wheezing occurrence were largely restricted to children with GSTM1 null genotype. Among GSTM1 null children, in utero exposure was associated with increased prevalence of early onset asthma (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.0-2.5), asthma with current symptoms (OR 1.7, 95% CI 1.1-2.8), persistent asthma (OR 1.6, 95% CI 1.1-2.4), lifetime history of wheezing (OR 1.8, 95% CI 1.3-2.5), wheezing with exercise (OR 2.1, 95% CI 1.3-3.3), wheezing requiring medication (OR 2.2, 95% CI 1.4-3.4), and emergency room visits in the past year (OR 3.7, 95% CI 1.9-7.3). Among children with GSTM1 (+) genotype, in utero exposure was not associated with asthma or wheezing. Our findings indicate that there are important long-term effects of in utero exposure in a genetically susceptible group of children.

Adolescent↗

PubMed2002

Association between air pollution and lung function growth in southern California children: results from a second cohort.

A cohort of 1,678 Southern California children, enrolled as fourth graders in 1996, was followed for 4 years to determine whether the growth in lung function of the children was associated with their exposure to ambient air pollutants. These subjects comprised the second cohort of fourth grade children participating in the Children's Health Study. Significant deficits in lung function growth rate were associated with exposure to acid vapor, NO(2), particles with aerodynamic diameter less than 2.5 microm (PM(2.5)), and elemental carbon. For example, the average annual growth rates of maximal midexpiratory flow and forced expiratory volume in 1 second were reduced by approximately 11% (p = 0.005) and 5% (p = 0.03), respectively, across the observed range of acid exposure. Exposure to acid vapor was also associated with reductions in the ratio of maximal midexpiratory flow to forced vital capacity (p = 0.02), whereas exposure to ozone was correlated with reduced growth in peak flow rate (p = 0.006). Larger deficits in lung function growth rate were observed in children who reported spending more time outdoors. These findings provide important replication of our previous findings of an effect of air pollution on lung function growth that were based on the first fourth-grade cohort from the Children's Health Study (Am J Respir Crit Care Med 2000;162:1383-1390).

Air Pollutants↗

PubMed2002

Sample size requirements for association studies of gene-gene interaction.

In the study of complex diseases, it may be important to test hypotheses related to gene-gene (G x G) interaction. The success of such studies depends critically on obtaining adequate sample sizes. In this paper, the author investigates sample size requirements for studies of G x G interaction, focusing on four study designs: the matched-case-control design, the case-sibling design, the case-parent design, and the case-only design. All four designs provide an estimate of interaction on a multiplicative scale, which is used as a unifying theme in the comparison of sample size requirements. Across a variety of genetic models, the case-only and case-parent designs require fewer sampling units (cases and case-parent trios, respectively) than the case-control (pairs) or case-sibling (pairs) design. For example, the author describes an asthma study of two common recessive genes for which 270 matched case-control pairs would be required to detect a G x G interaction of moderate magnitude with 80% power. By comparison, the same study would require 319 case-sibling pairs but only 146 trios in the case-parent design or 116 cases in the case-only design. A software program that computes sample size for studies of G x G interaction and for studies of gene-environment (G x E) interaction is freely available (http://hydra.usc.edu/gxe).

Case-Control Studies↗

PubMed2002

Asthma in exercising children exposed to ozone: a cohort study.

BACKGROUND: Little is known about the effect of exposure to air pollution during exercise or time spent outdoors on the development of asthma. We investigated the relation between newly-diagnosed asthma and team sports in a cohort of children exposed to different concentrations and mixtures of air pollutants. METHODS: 3535 children with no history of asthma were recruited from schools in 12 communities in southern California and were followed up for up to 5 years. 265 children reported a new diagnosis of asthma during follow-up. We assessed risk of asthma in children playing team sports at study entry in six communities with high daytime ozone concentrations, six with lower concentrations, and in communities with high or low concentrations of nitrogen dioxide, particulate matter, and inorganic-acid vapour. FINDINGS: In communities with high ozone concentrations, the relative risk of developing asthma in children playing three or more sports was 3.3 (95% CI 1.9-5.8), compared with children playing no sports. Sports had no effect in areas of low ozone concentration (0.8, 0.4-1.6). Time spent outside was associated with a higher incidence of asthma in areas of high ozone (1.4, 1.0-2.1), but not in areas of low ozone. Exposure to pollutants other than ozone did not alter the effect of team sports. INTERPRETATION: Incidence of new diagnoses of asthma is associated with heavy exercise in communities with high concentrations of ozone, thus, air pollution and outdoor exercise could contribute to the development of asthma in children.

Adolescent↗

PubMed2002

Sample size requirements for matched case-control studies of gene-environment interaction.

Consideration of gene-environment (GxE) interaction is becoming increasingly important in the design of new epidemiologic studies. We present a method for computing required sample size or power to detect GxE interaction in the context of three specific designs: the standard matched case-control; the case-sibling, and the case-parent designs. The method is based on computation of the expected value of the likelihood ratio test statistic, assuming that the data will be analysed using conditional logistic regression. Comparisons of required sample sizes indicate that the family-based designs (case-sibling and case-parent) generally require fewer matched sets than the case-control design to achieve the same power for detecting a GxE interaction. The case-sibling design is most efficient when studying a dominant gene, while the case-parent design is preferred for a recessive gene. Methods are also presented for computing sample size when matched sets are obtained from a stratified population, for example, when the population consists of multiple ethnic groups. A software program that implements the method is freely available, and may be downloaded from the website http://hydra.usc.edu/gxe.

Black or African American↗

PubMed2002

Impact of respiratory illness on expiratory flow rates in normal, asthmatic, and allergic children.

We examined the effects of current respiratory illness (RI) on pulmonary function (PF) in 1,103 subjects who underwent spirometry at schools twice within a 4-month period. Before spirometry, subjects were asked if they had a "cold or other chest illness" during the previous month, and if so, whether they had fully recovered. Those who had not recovered were considered to have an RI. We found that children without RI at their first PF test who reported RI on retest had significantly lower forced expiratory volume in 1 sec (FEV(1)) (-0.8%), peak expiratory flow rate (PEFR) (-2.2%), forced expiratory flow between 25-75% of vital capacity (FEF(25-75)) (-3.5%), and forced expiratory flow at 75% of vital capacity (FEF(75)) (-5.1%) than those without RI on both test and retest. Restriction of subjects to those without a history of doctor-diagnosed asthma did not appreciably change these findings. Children with hay fever had significantly larger RI-associated decreases for FEV(1), FEF(25-75), and FEF(75), but not PEFR, than those without hay fever. Among asthmatic subjects, those with active asthma had larger RI-associated decreases in FEF(25-75) and FEF(75), but not PEFR, than those without asthma. There was limited evidence that small airway losses were greater in children less than 12.5 years old. We conclude that RI in children who are well enough to attend school may reduce expiratory flow rates. These effects are greater for children with active asthma or hay fever than in those without, and may be inversely related to age.

Adolescent↗