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1.  Determinants of Children's Exhaled Nitric Oxide: New Insights from Quantile Regression 
PLoS ONE  2015;10(7):e0130505.
While the fractional concentration of exhaled nitric oxide (FeNO) has proven useful in asthma research, its exact role in clinical care remains unclear, in part due to unexplained inter-subject heterogeneity. In this study, we assessed the hypothesis that the effects of determinants of the fractional concentration of exhaled nitric oxide (FeNO) vary with differing levels of FeNO. In a population-based cohort of 1542 school children aged 12–15 from the Southern California Children's Health Study, we used quantile regression to investigate if the relationships of asthma, socio-demographic and clinical covariates with FeNO vary across its distribution. Differences in FeNO between children with and without asthma increased steeply as FeNO increased (Estimated asthma effects (in ppb) at selected 20th, 50th and 80th percentiles of FeNO are 2.4, 6.3 and 22.2, respectively) but the difference was steeper with increasing FeNO in boys and in children with active rhinitis (p-values<0.01). Active rhinitis also showed significantly larger effects on FeNO at higher concentrations of FeNO (Estimated active rhinitis effects (in ppb) at selected 20th, 50th and 80th percentiles of FeNO are 2.1, 5.7 and 14.3, respectively). Boys and children of Asian descent had higher FeNO than girls and non-Hispanic whites; these differences were significantly larger in those with higher FeNO (p-values<0.01). In summary, application of quantile regression techniques provides new insights into the determinants of FeNO showing substantially varying effects in those with high versus low concentrations.
PMCID: PMC4516246  PMID: 26214692
2.  Fractional exhaled nitric oxide in childhood is associated with 17q11.2-q12 and 17q12-q21 variants 
The fractional concentration of nitric oxide in exhaled air (FeNO) is a biomarker of eosinophilic airway inflammation and associated with childhood asthma. Identification of common genetic variants associated with childhood FeNO may help to define biological mechanisms related to specific asthma phenotypes.
To identify genetic variants associated with childhood FeNO, and their relation with asthma.
FeNO was measured in children aged 5 to 15 years. In 14 genome-wide association (GWA) studies (N = 8,858), we examined the associations of ~2.5 million single nucleotide polymorphisms (SNPs) with FeNO. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci (eQTLs) in genome-wide expression datasets of lymphoblastoid cell lines (N = 1,830), and were related with asthma in a previously published GWA dataset (cases: n=10,365; controls: n=16,110).
We identified 3 SNPs associated with FeNO: rs3751972 in LYR motif containing 9 (LYRM9) (P = 1.97×10−10) and rs944722 in inducible nitric oxide synthase 2 (NOS2) (P = 1.28×10−9) both located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB) (P = 1.88×10−8) at 17q12-q21. We found a cis eQTL for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. Rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. Rs8069176 at 17q12-q21, and not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma.
This study identified 3 variants associated with FeNO, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight in the regulation of FeNO. This study highlights that both shared and distinct genetic factors affect FeNO and childhood asthma.
PMCID: PMC4334587  PMID: 24315451
airway inflammation; asthma phenotypes; biomarker; genetics; genome-wide association study
3.  Bayesian Mixed Hidden Markov Models: A Multi-Level Approach to Modeling Categorical Outcomes with Differential Misclassification 
Statistics in medicine  2013;33(8):1395-1408.
Questionnaire-based health status outcomes are often prone to misclassification. When studying the effect of risk factors on such outcomes, ignoring any potential misclassification may lead to biased effect estimates. Analytical challenges posed by these misclassified outcomes are further complicated when simultaneously exploring factors for both the misclassification and health processes in a multi-level setting. To address these challenges, we propose a fully Bayesian Mixed Hidden Markov Model (BMHMM) for handling differential misclassification in categorical outcomes in a multi-level setting. The BMHMM generalizes the traditional Hidden Markov Model (HMM) by introducing random effects into three sets of HMM parameters for joint estimation of the prevalence, transition and misclassification probabilities. This formulation not only allows joint estimation of all three sets of parameters, but also accounts for cluster level heterogeneity based on a multi-level model structure. Using this novel approach, both the true health status prevalence and the transition probabilities between the health states during follow-up are modeled as functions of covariates. The observed, possibly misclassified, health states are related to the true, but unobserved, health states and covariates. Results from simulation studies are presented to validate the estimation procedure, to show the computational efficiency due to the Bayesian approach and also to illustrate the gains from the proposed method compared to existing methods that ignore outcome misclassification and cluster level heterogeneity. We apply the proposed method to examine the risk factors for both asthma transition and misclassification in the Southern California Children's Health Study (CHS).
PMCID: PMC4221103  PMID: 24254432
Asthma; Bayesian Mixed Hidden Markov Model (BMHMM); Differential Misclassification; MCMC; Multi-Level Model
4.  Predictors of intra-community variation in air quality 
Air quality has emerged as a key determinant of important health outcomes in children and adults. This study aims to identify factors that influence local, within-community air quality, and to build a model for traffic-related air pollution (TRP).We utilized concentrations of NO2, NO, and total oxides of nitrogen (NOx), which were measured at 942 locations in 12 southern California communities. For each location, population density, elevation, land-use, and several indicators of traffic were calculated. A spatial random effects model was used to study the relationship of these predictors to each TRP.Variation in TRP was strongly correlated with traffic on nearby freeways and other major roads, and also with population density and elevation. After accounting for traffic, categories of land-use were not associated with the pollutants. Traffic had a larger relative impact in small urban (low regional pollution) communities than in large urban (high regional pollution) communities. For example, our best fitting model explained 70% of the variation in NOx in large urban areas and 76% in small urban areas. Compared with living at least 1,500m from a freeway, living within 250m of a freeway was associated with up to a 41% increase in TRP in a large urban area, and up to a 75% increase in small urban areas.Thus, traffic strongly affects local air quality in large and small urban areas, which has implications for exposure assessment and estimation of health risks.
PMCID: PMC4391642  PMID: 22252279
traffic-related air pollution; nitrogen oxides; exposure assessment; traffic; land-use; spatial random effects
5.  Social environment and asthma: Associations with crime and No Child Left Behind programs 
The relationship between asthma and socioeconomic status remains unclear. We investigated how neighborhood, school and community social environments were associated with incident asthma in Southern California school children.
New onset asthma was measured over three years of follow-up in the Children’s Health Study cohort. Multilevel random effects models assessed associations between social environments and asthma, adjusted for individual risk factors. Subjects resided in 274 neighborhoods and attended one of 45 schools in 13 communities. Neighborhoods and communities were characterized by measures of deprivation, income inequality and racial segregation. Communities were further described by crime rates. Information on schools included whether a school received funding related to the Title 1 No Child Left Behind program, which aims to reduce academic underachievement in disadvantaged populations.
Increased risk for asthma was observed in subjects attending schools receiving Title I funds compared to those from schools without funding (adjusted hazard ratio 1.71, 95% CI 1.14–2.58), and residing in communities with higher rates of larceny crime (adjusted hazard ratio 2.02, 95% CI 1.08–3.02 across the range of 1827 incidents per 100,000 population).
Risk for asthma was higher in areas of low socioeconomic status, possibly due to unmeasured risk factors or chronic stress.
PMCID: PMC4384703  PMID: 21071562
asthma; multilevel models; socio-economic; air pollution
6.  A Longitudinal Cohort Study of Body Mass Index and Childhood Exposure to Secondhand Tobacco Smoke and Air Pollution: The Southern California Children’s Health Study 
Environmental Health Perspectives  2014;123(4):360-366.
Childhood body mass index (BMI) and obesity prevalence have been associated with exposure to secondhand smoke (SHS), maternal smoking during pregnancy, and vehicular air pollution. There has been little previous study of joint BMI effects of air pollution and tobacco smoke exposure.
Information on exposure to SHS and maternal smoking during pregnancy was collected on 3,318 participants at enrollment into the Southern California Children’s Health Study. At study entry at average age of 10 years, residential near-roadway pollution exposure (NRP) was estimated based on a line source dispersion model accounting for traffic volume, proximity, and meteorology. Lifetime exposure to tobacco smoke was assessed by parent questionnaire. Associations with subsequent BMI growth trajectory based on annual measurements and attained BMI at 18 years of age were assessed using a multilevel modeling strategy.
Maternal smoking during pregnancy was associated with estimated BMI growth over 8-year follow-up (0.72 kg/m2 higher; 95% CI: 0.14, 1.31) and attained BMI (1.14 kg/m2 higher; 95% CI: 0.66, 1.62). SHS exposure before enrollment was positively associated with BMI growth (0.81 kg/m2 higher; 95% CI: 0.36, 1.27) and attained BMI (1.23 kg/m2 higher; 95% CI: 0.86, 1.61). Growth and attained BMI increased with more smokers in the home. Compared with children without a history of SHS and NRP below the median, attained BMI was 0.80 kg/m2 higher (95% CI: 0.27, 1.32) with exposure to high NRP without SHS; 0.85 kg/m2 higher (95% CI: 0.43, 1.28) with low NRP and a history of SHS; and 2.15 kg/m2 higher (95% CI: 1.52, 2.77) with high NRP and a history of SHS (interaction p-value 0.007). These results suggest a synergistic effect.
Our findings strengthen emerging evidence that exposure to tobacco smoke and NRP contribute to development of childhood obesity and suggest that combined exposures may have synergistic effects.
McConnell R, Shen E, Gilliland FD, Jerrett M, Wolch J, Chang CC, Lurmann F, Berhane K. 2015. A longitudinal cohort study of body mass index and childhood exposure to secondhand tobacco smoke and air pollution: the Southern California Children’s Health Study. Environ Health Perspect 123:360–366;
PMCID: PMC4384197  PMID: 25389275
7.  Childhood obesity and proximity to urban parks and recreational resources: A longitudinal cohort study 
Health & place  2010;17(1):207-214.
The objective of the research was to assess how proximity to parks and recreational resources affects the development of childhood obesity through a longitudinal study. Data were collected on 3173 children aged 9–10 from 12 communities in Southern California in 1993 and 1996. Children were followed for eight years to collect longitudinal information, including objectively measured body mass index (BMI). Multilevel growth curve models were used to assess associations between attained BMI growth at age 18 and numerous environmental variables, including park space and recreational program access. For park acres within a 500 meter distance of children’s homes, there were significant inverse associations with attained BMI at age 18. Effect sizes were larger for boys than for girls. Recreation programs within a 10 km buffer of children’s homes were significantly and inversely associated with achieved levels in BMI at age 18, with effect sizes for boys also larger than those for girls. We conclude that children with better access to park and recreational resources are less likely to experience significant increases in attained BMI.
PMCID: PMC4380517  PMID: 21075670
obesity; built environment; parks and recreation; GIS; multilevel growth curve models
8.  Factors Influencing Whether Children Walk to School 
Health & place  2013;22:153-161.
Few studies have evaluated multiple levels of influence simultaneously on whether children walk to school. A large cohort of 4,338 subjects from ten communities was used to identify the determinants of walking through (1) a one-level logistic regression model for individual-level variables and (2) a two-level mixed regression model for individual and school-level variables. Walking rates were positively associated with home-to-school proximity, greater age, and living in neighborhoods characterized by lower traffic density. Greater land use mix around the home was, however, associated with lower rates of walking. Rates of walking to school were also higher amongst recipients of the Free and Reduced Price Meals Program and attendees of schools with higher percentage of English language learners. Designing schools in the same neighborhood as residential districts should be an essential urban planning strategy to reduce walking distance to school. Policy interventions are needed to encourage children from higher socioeconomic status families to participate in active travel to school and to develop walking infrastructures and other measures that protect disadvantaged children.
PMCID: PMC4363112  PMID: 23707968
walking to school; Children's Health Study; multilevel analysis; landscape metrics; Los Angeles
9.  The Effect of Ambient Air Pollution on Exhaled Nitric Oxide in the Children’s Health Study 
The European respiratory journal  2010;37(5):1029-1036.
We assessed the effect of daily variations in ambient air pollutants on exhaled nitric oxide (FeNO) using data from a cohort of schoolchildren with large differences in air pollutant exposures from the Children’s Health Study.
Based on a cohort of 2240 schoolchildren from 13 Southern California communities, cumulative lagged average regression models were fitted to determine the association between FeNO and ambient air pollution levels from central site monitors with lags of up to 30 days prior to FeNO testing.
Daily 24-hr cumulative lagged averages of PM2.5 (over 1–8 days) and PM10 (over 1–7 days), as well as 10AM–6PM cumulative lagged average of O3 (over 1–23 days) were significantly associated with 17.42% (p<0.01), 9.25% (P<0.05) and 14.25% (p<0.01) higher FeNO levels over the inter-quartile range of 7.5 μg/m3, 12.97 μg/m3, and 15.42 ppb, respectively. The effects of PM2.5, PM10 and O3 were higher in the warm season. The PM effects were robust to adjustments for effects of O3 and temperature and did not vary by asthma or allergy status.
In Summary, short-term increases in PM2.5, PM10, and O3 were associated with airway inflammation independent of asthma and allergy status, with PM10 effects significantly higher in the warm season.
PMCID: PMC4340653  PMID: 20947676
Air pollution; Airway inflammation; Children’s respiratory health; Environmental epidemiology; Exhaled nitric oxide
10.  Automobile Traffic around the Home and Attained Body Mass Index: A Longitudinal Cohort Study of Children aged 10–18 Years 
Preventive medicine  2009;50(0 1):S50-S58.
The objective of this study is to examine the relationship between measured traffic density near the homes of children and attained body mass index (BMI) over an eight-year follow up.
Children aged 9–10 years were enrolled across multiple communities in Southern California in 1993 and 1996 (n = 3318). Children were followed until age 18 or high school graduation to collect longitudinal information, including annual height and weight measurements. Multilevel growth curve models were used to assess the association between BMI levels at age 18 and traffic around the home.
For traffic within 150 m around the child’s home, there were significant positive associations with attained BMI for both sexes at age 18. With the 300 m traffic buffer, associations for both male and female growth in BMI were positive, but significantly elevated only in females. These associations persisted even after controlling for numerous potential confounding variables.
This analysis yields the first evidence of significant effects from traffic density on BMI levels at age 18 in a large cohort of children. Traffic is a pervasive exposure in most cities, and our results identify traffic as a major risk factor for the development of obesity in children.
PMCID: PMC4334364  PMID: 19850068
Traffic; built environment; children; overweight and obesity; geographic information systems; multilevel models; cohort study
11.  Longitudinal Effects of Air Pollution on Exhaled Nitric Oxide: The Children’s Health Study 
To assess the effects of long-term variations in ambient air pollutants on longitudinal changes in exhaled nitric oxide (FeNO), a potentially useful biomarker of eosinophilic airway inflammation, based on data from the southern California Children’s Health Study.
Based on a cohort of 1,211 schoolchildren from 8 Southern California communities with FeNO measurements in 2006/07 and 2007/08, regression models adjusted for short-term effects of air pollution were fitted to assess the association between changes in annual long-term exposures and changes in FeNO.
Increases in annual average concentrations of 24-hr average NO2 and PM2.5 (scaled to the interquartile range (IQR) of 1.8 ppb and 2.4 μg/m3, respectively) were associated with a 2.29 ppb (CI=[0.36,4.21]; p =0.02) and a 4.94 ppb (CI=[1.44,8.47]; p = 0.005) increase in FeNO, respectively, after adjustments for short term effects of the respective pollutants. In contrast, changes in annual averages of PM10 and O3 were not significantly associated with changes in FeNO. These findings did not differ significantly by asthma status.
Changes in annual average exposure to current levels of ambient air pollutants are significantly associated with changes in FeNO levels in children, independent of short-term exposures and asthma status. Use of this biomarker in population-based epidemiologic research has great potential for assessing the impact of changing real world mixtures of ambient air pollutants on children’s respiratory health.
PMCID: PMC4310696  PMID: 24696513
Air pollution; chronic exposures; Children’s respiratory health; Environmental epidemiology; Exhaled nitric oxide; Airway inflammation
Pediatric pulmonology  2013;48(9):885-896.
"Extended" (multiple-flow) measurements of exhaled nitric oxide (FeNO) potentially can distinguish proximal and distal airway inflammation, but have not been evaluated previously in large populations. We performed extended NO testing within a longitudinal study of a school-based population, to relate bronchial flux (J'awNO) and peripheral NO concentration (CalvNO) estimates with respiratory health status determined from questionnaires. We measured FeNO at 30, 50, 100, and 300 ml/sec in 1640 subjects aged 12–15 from 8 communities, then estimated J'awNO and CalvNO from linear and nonlinear regressions of NO output vs. flow. J'awNO, as well as FeNO at all flows, showed influences of asthma, allergy, Asian or African ancestry, age, and height (positive), and of weight (negative), generally corroborating past findings. By contrast, CalvNO results were inconsistent across different extended NO regression models, and appeared more sensitive to small measurement artifacts. Conclusions: Extended NO testing is feasible in field surveys of young populations. In interpreting results, size, age, and ethnicity require attention, as well as instrumental and environmental artifacts. J'awNO and conventional FeNO provide similar information, probably reflecting proximal-airway inflammation. CalvNO may give additional information relevant to peripheral-airway, alveolar, or systemic pathology. However, it needs additional research, including testing of populations with independently verifiable peripheral or systemic pathology, to optimize measurement technique and interpretation.
PMCID: PMC3748140  PMID: 23687084
exhaled nitric oxide; airway inflammation; airways; asthma; allergy; epidemiology; public health; population survey
13.  The association between contextual socioeconomic factors and prevalent asthma in a cohort of southern California school children 
Social science & medicine (1982)  2007;65(8):1792-1806.
Spatial variation in childhood asthma and a recent increase in prevalence indicate that environmental factors play a significant role in the etiology of this important disease. Socioeconomic position (SEP) has been associated inversely and positively with childhood asthma. These contradictory results indicate a need for systematic research about SEP and asthma. Pathways have been suggested for effects of SEP on asthma at both the individual and community level. We examined the relationship of prevalent asthma to community-level indicators of SEP among 5762 children in 12 Southern California, using a multilevel random effects model. Estimates of community-level SEP were derived by summarizing census block group-level data using a novel method of weighting by the proportion of the block groups included in a community-specific bounding rectangle that contained 95% of local study subjects. Community characteristics included measures of male unemployment, household income, low education (i.e. no high school diploma), and poverty. There was a consistent inverse association between male unemployment and asthma across the inter-quartile range of community unemployment rates, indicating that asthma rates increase as community SEP increases. The results were robust to individual-level confounding, methods for summarizing census block group data to the community level, scale of analysis (i.e. community-level vs. neighborhood-level) and the modeling algorithm. The positive association between SEP and prevalent childhood asthma might be explained by differential access to medical care that remains unmeasured, by the hygiene hypothesis (e.g. lower SES may associate with higher protective exposures to endotoxin in early life), or by SEP acting as a proxy for unmeasured neighborhood characteristics.
PMCID: PMC4098912  PMID: 17658674
USA; neighborhood; childhood asthma; multi-level modeling; socioeconomic position; contextual factors
This study examined associations of asthma with school commuting time.
Time on likely school commute route was used as a proxy for on-road air pollution exposure among 4741 elementary school children at enrollment into the Children's Health Study. Lifetime asthma and severe wheeze (including multiple attacks, nocturnal or with shortness of breath) were reported by parents.
In asthmatic children, severe wheeze was associated with commuting time (odds ratio (OR) 1.54 across the 9-minute 5%-95% exposure distribution; 95% confidence interval (CI) 1.01,2.36). The association was stronger in analysis restricted to asthmatic children with commuting times five minutes or longer (OR 1.97; 95% CI 1.02,3.77). No significant associations were observed with asthma prevalence.
Among asthmatics, severe wheeze was associated with relatively short school commuting times. Further investigation of effects of on-road pollutant exposure is warranted.
PMCID: PMC4083079  PMID: 20657304
air pollution; asthma; child; epidemiology; traffic; commuting
15.  Traffic-related air pollution and obesity formation in children: a longitudinal, multilevel analysis 
Environmental Health  2014;13:49.
Biologically plausible mechanisms link traffic-related air pollution to metabolic disorders and potentially to obesity. Here we sought to determine whether traffic density and traffic-related air pollution were positively associated with growth in body mass index (BMI = kg/m2) in children aged 5–11 years.
Participants were drawn from a prospective cohort of children who lived in 13 communities across Southern California (N = 4550). Children were enrolled while attending kindergarten and first grade and followed for 4 years, with height and weight measured annually. Dispersion models were used to estimate exposure to traffic-related air pollution. Multilevel models were used to estimate and test traffic density and traffic pollution related to BMI growth. Data were collected between 2002–2010 and analyzed in 2011–12.
Traffic pollution was positively associated with growth in BMI and was robust to adjustment for many confounders. The effect size in the adjusted model indicated about a 13.6% increase in annual BMI growth when comparing the lowest to the highest tenth percentile of air pollution exposure, which resulted in an increase of nearly 0.4 BMI units on attained BMI at age 10. Traffic density also had a positive association with BMI growth, but this effect was less robust in multivariate models.
Traffic pollution was positively associated with growth in BMI in children aged 5–11 years. Traffic pollution may be controlled via emission restrictions; changes in land use that promote jobs-housing balance and use of public transit and hence reduce vehicle miles traveled; promotion of zero emissions vehicles; transit and car-sharing programs; or by limiting high pollution traffic, such as diesel trucks, from residential areas or places where children play outdoors, such as schools and parks. These measures may have beneficial effects in terms of reduced obesity formation in children.
PMCID: PMC4106205  PMID: 24913018
Childhood obesity; Air pollution; Traffic; California
17.  Exhaled Nitric Oxide, Susceptibility and New-Onset Asthma in the Children’s Health Study 
The European respiratory journal  2010;37(3):523-531.
A substantial body of evidence suggests an etiologic role of inflammation and oxidative/nitrosative stress in asthma pathogenesis. Fractional concentration of nitric oxide in exhaled air (FeNO) may provide a non-invasive marker of oxidative/nitrosative stress and aspects of airway inflammation. We examined whether children with elevated FeNO are at increased risk for new-onset asthma.
We prospectively followed 2206 asthma-free children (age 7–10 years) who participated in the Children’s Health Study. We measured FeNO and followed these children for three years to ascertain incident asthma cases. Cox proportional hazard models were fitted to examine the association between FeNO and new-onset asthma.
We found that FeNO was associated with increased risk of new-onset asthma. Children with the highest quartile of FeNO had more than a two-fold increased risk of new-onset asthma compared to those with the lowest quartile (hazard ratio: 2.1; 95% confidence interval: 1.3–3.5). This effect did not vary by child’s history of respiratory allergic symptoms. However, the effect of elevated FeNO on new-onset asthma was most apparent among those without a parental history of asthma.
Our results indicate that children with elevated FeNO are at increased risk for new-onset asthma, especially if they have no parental history of asthma.
PMCID: PMC4020940  PMID: 20634264
Incident Asthma; Exhaled Nitric Oxide; Airway Inflammation
18.  Inflammatory Cytokine Response to Ambient Particles Varies due to Field Collection Procedures 
In vitro assays of biological activity induced by particulate matter (PM) are a tool for investigating mechanisms of PM health effects. They have potential application to exposure assessment in chronic disease epidemiology. However, there has been little reporting of the impact of real-world PM collection techniques on assay results. Therefore, we examined the effect of sampling duration and postsampling delays in freezing on PM-induced biological activity. Duplicate samples of respirable ambient Los Angeles PM were collected on polyurethane foam filters during 17 days and during three contemporaneous consecutive shorter periods. After collection, one duplicate was stored at ambient temperature for 24 hours before freezing; the other was frozen immediately. Cytokine response (IL-1β, IL-6, IL-8, and TNF-α) to PM aqueous extract was assessed in THP-1 cells, a model for evaluating monocyte/macrophage lineage cell responses. There was consistent 3- to 4-fold variation in PM-induced cytokine levels across the three collection intervals. Compared with levels induced by PM pooled across the three periods, continuously collected PM-induced levels were reduced by 25% (IL-6) to 39% (IL-8). The pattern of cytokine gene expression response was similar. Cytokine level variation by time to freezing was not statistically significant. PM-induced inflammatory response varied substantially over a weekly time scale. We conclude that long PM sampling interval induced less activity than the average of equivalent shorter consecutive sampling intervals. Time to freezing was less important. Implications for development of metrics of long-term spatial variation in biological exposure metrics for study of chronic disease merit further investigation.
PMCID: PMC3653609  PMID: 23306836
air pollution; toxicology; exposure assessment; epidemiology
19.  Household endotoxin levels and the risk of non-Hodgkin lymphoma 
Cancer causes & control : CCC  2013;24(2):357-364.
Endotoxin, a component of the outer membrane of gram-negative bacteria, elicits a strong innate and inflammatory immune response associated with secretion of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α). Because TNF-α polymorphisms that increase TNF-α production are associated with an increased risk of non-Hodgkin lymphoma (NHL), we hypothesized that increased levels of household endotoxin would be associated with an increased NHL risk.
We evaluated this association in the National Cancer Institute/Surveillance, Epidemiology and End Result (NCI/SEER) NHL multi-center population-based case-control study. Used vacuum cleaner bags were collected from participants during a home interview. Dust samples from the bags of 594 cases and 442 controls were analyzed for endotoxin (Endotoxin Unit [EU]/mg of dust) using the kinetic chromogenic Limulus amebocyte lysate assay. Multivariable logistic regression was used to estimate the effect of endotoxin on NHL risk adjusted for age, sex, race, education, study center, and farm exposure.
Endotoxin was not associated with NHL overall (odds ratio [OR] for highest quartile of endotoxin levels = 0.81, 95% confidence interval [CI]= 0.55,1.20; P for trend=0.35), or with diffuse large B-cell lymphoma (OR= 0.63, 95% CI= 0.34, 1.16; P= 0.31) or follicular lymphoma (OR= 0.1.07, 95% CI=0.61, 1.89; P=0.73) subtypes. Both working and living on a farm were associated with higher household endotoxin levels compared to never working (P=0.009) or living (P=0.01) on a farm. Excluding farmers from the analysis did not change the results.
We found no evidence of a role for household endotoxin in NHL etiology.
PMCID: PMC3800025  PMID: 23277417
Endotoxin; Non-Hodgkin lymphoma; Epidemiology; Farming; Risk; Case-control
20.  Estimation of Parameters in the Two-Compartment Model for Exhaled Nitric Oxide 
PLoS ONE  2014;9(1):e85471.
The fractional concentration of exhaled nitric oxide (FeNO) is a biomarker of airway inflammation that is being increasingly considered in clinical, occupational, and epidemiological applications ranging from asthma management to the detection of air pollution health effects. FeNO depends strongly on exhalation flow rate. This dependency has allowed for the development of mathematical models whose parameters quantify airway and alveolar compartment contributions to FeNO. Numerous methods have been proposed to estimate these parameters using FeNO measured at multiple flow rates. These methods—which allow for non-invasive assessment of localized airway inflammation—have the potential to provide important insights on inflammatory mechanisms. However, different estimation methods produce different results and a serious barrier to progress in this field is the lack of a single recommended method. With the goal of resolving this methodological problem, we have developed a unifying framework in which to present a comprehensive set of existing and novel statistical methods for estimating parameters in the simple two-compartment model. We compared statistical properties of the estimators in simulation studies and investigated model fit and parameter estimate sensitivity across methods using data from 1507 schoolchildren from the Southern California Children's Health Study, one of the largest multiple flow FeNO studies to date. We recommend a novel nonlinear least squares model with natural log transformation on both sides that produced estimators with good properties, satisfied model assumptions, and fit the Children's Health Study data well.
PMCID: PMC3894971  PMID: 24465571
21.  Childhood Air Pollutant Exposure and Carotid Artery Intima-Media Thickness in Young Adults 
Circulation  2012;126(13):1614-1620.
Exposure to ambient air pollutants increases risk for cardiovascular health outcomes in adults. The contribution of childhood air pollutant exposure to cardiovascular health has not been thoroughly evaluated.
Methods and results
The Testing Responses on Youth study consists of 861 college students recruited from the University of Southern California in 2007–2009. Participants attended one study visit during which blood pressure, heart rate and carotid artery intima-media thickness (CIMT) were assessed. Self-administered questionnaires collected information about health and socio-demographic characteristics and a 12-hr fasting blood sample was drawn for lipid and biomarker analyses. Residential addresses were geocoded and used to assign cumulative air pollutant exposure estimates based on data derived from the U.S. Environmental Protection Agency’s Air Quality System (AQS) database. The associations between CIMT and air pollutants were assessed using linear regression analysis. Mean CIMT was 603 μm (± 54 SD). A 2 standard deviation (SD) increase in childhood (aged 0–5 years) or elementary school (aged 6–12) O3 exposure was associated with a 7.8 μm (95% CI −0.3, 15.9) or 10.1 μm (95% CI 1.8, 18.5) higher CIMT, respectively. Lifetime exposure to O3 showed similar but non-significant associations. No associations were observed for PM2.5, PM10 or NO2 although adjustment for these pollutants strengthened the childhood O3 associations.
Childhood exposure to O3 may be a novel risk factor for CIMT in a healthy population of college students. Regulation of air pollutants and efforts that focus on limiting childhood exposures continue to be important public health goals.
PMCID: PMC3474843  PMID: 22896588
atherosclerosis; cardiovascular diseases; carotid arteries; epidemiology; pediatrics
22.  Organized Physical Activity in Young School Children Predicts Subsequent 4-Year Change in Body Mass Index 
To determine whether participation in organized outdoor team sports and structured indoor non-school activity programs in kindergarten and first grade predicted subsequent 4-year change in Body Mass Index (BMI) across the adiposity rebound period of childhood.
Longitudinal cohort study.
Forty-five schools in 13 communities across Southern California.
Largely Hispanic and non-Hispanic white children (N = 4,550; average age at study entry 6.60 years, standard deviation 0.65).
Main Exposures
Parents completed questionnaires assessing physical activity, demographic characteristics and other relevant covariates at baseline. Data on built and social environmental variables were linked to the neighborhood around children’s homes using geographical information systems (GIS).
Main Outcome Measures
Each child’s height and weight were measured annually during 4-years of follow-up.
After adjusting for several confounders, BMI increased at a 0.05 unit per year slower rate for children who participated in outdoor organized team sports at least twice per week as compared to children who did not. For participation in each additional indoor non-school structured activity classes, lessons, and program, BMI increased at a 0.05 unit per year slower rate, and the attained BMI level at age 10 was 0.48 units lower.
Engagement in organized sports and activity programs as early as kindergarten and the first grade may result in smaller increases in BMI during the adiposity rebound period of childhood.
PMCID: PMC3415326  PMID: 22869403
23.  Prenatal Exposure to Urban Air Nanoparticles in Mice Causes Altered Neuronal Differentiation and Depression-Like Responses 
PLoS ONE  2013;8(5):e64128.
Emerging evidence suggests that excessive exposure to traffic-derived air pollution during pregnancy may increase the vulnerability to neurodevelopmental alterations that underlie a broad array of neuropsychiatric disorders. We present a mouse model for prenatal exposure to urban freeway nanoparticulate matter (nPM). In prior studies, we developed a model for adult rodent exposure to re-aerosolized urban nPM which caused inflammatory brain responses with altered neuronal glutamatergic functions. nPMs are collected continuously for one month from a local freeway and stored as an aqueous suspension, prior to re-aerosolization for exposure of mice under controlled dose and duration. This paradigm was used for a pilot study of prenatal nPM impact on neonatal neurons and adult behaviors. Adult C57BL/6J female mice were exposed to re-aerosolized nPM (350 µg/m3) or control filtered ambient air for 10 weeks (3×5 hour exposures per week), encompassing gestation and oocyte maturation prior to mating. Prenatal nPM did not alter litter size, pup weight, or postnatal growth. Neonatal cerebral cortex neurons at 24 hours in vitro showed impaired differentiation, with 50% reduction of stage 3 neurons with long neurites and correspondingly more undifferentiated neurons at Stages 0 and 1. Neuron number after 24 hours of culture was not altered by prenatal nPM exposure. Addition of exogenous nPM (2 µg/ml) to the cultures impaired pyramidal neuron Stage 3 differentiation by 60%. Adult males showed increased depression-like responses in the tail-suspension test, but not anxiety-related behaviors. These pilot data suggest that prenatal exposure to nPM can alter neuronal differentiation with gender-specific behavioral sequelae that may be relevant to human prenatal exposure to urban vehicular aerosols.
PMCID: PMC3667185  PMID: 23734187
24.  Carotid artery intima-media thickness in college students: race/ethnicity matters 
Atherosclerosis  2011;217(2):441-446.
Racial/ethnic differences in common carotid artery intima-media thickness (CIMT) and in risk factors associated with CIMT have been predominantly observed in middle-aged and older individuals. We aimed to characterize racial/ethnic differences CIMT and other cardiovascular risk factors in a healthy, young-adult population.
College students were recruited as part of a study to characterize determinants of atherogenesis. Students were eligible if they were lifetime non-smokers, lived in the United States since six months of age, and attended high school in the United States. Blood pressure, heart rate, height, and weight were measured, B-mode carotid ultrasound was performed, questionnaires were administered and a 12-hr fasting blood sample was collected. Associations between CIMT and other variables were assessed in 768 students aged 18 to 25 years using linear regression analysis.
In models adjusted for common cardiovascular risk factors, sex exhibited the strongest influence on CIMT, with men having 15.4 µm larger CIMT compared to women (95%CI 6.6, 24.2). Race/ethnicity was also strongly associated with CIMT. African Americans had 17.3 µm greater CIMT (95% CI −0.3, 34.8) compared to non Hispanic Whites, whereas Asians and Hispanic Whites had 14.3 (95%CI −24.3, −4.4) and 15.4 (95%CI −26.2, −4.7) µm smaller CIMT, respectively. BMI and systolic blood pressure were positively associated with CIMT.
The risk factors associated with atherogenesis later in life are already present and observable in college-aged young adults, so targeted campaigns to reduce life-long cardiovascular disease burden should be initiated earlier in life to improve public health.
PMCID: PMC3146627  PMID: 21679950
CIMT; SBP; race; ethnicity; young adults
25.  Randomized Controlled Trial to Improve Adiposity, Inflammation, and Insulin Resistance in Obese African-American and Latino Youth 
Obesity (Silver Spring, Md.)  2011;20(4):811-818.
The purpose of this study was to examine ethnic differences in the metabolic responses to a 16-week intervention designed to improve insulin sensitivity (SI), adiposity, and inflammation in obese African-American and Latino adolescents. A total of 100 participants (African Americans: n = 48, Latino: n = 52; age: 15.4 ± 1.1 years, BMI percentile: 97.3 ± 3.3) were randomly assigned to interventions: control (C; n = 30), nutrition (N; n = 39, 1×/week focused on decreasing sugar and increasing fiber intake), or nutrition + strength training (N+ST; n = 31, 2×/week). The following were measured at pre- and postintervention: strength, dietary intake, body composition (dual-energy X-ray absorptiometry/magnetic resonance imaging) and glucose/insulin indexes (oral glucose tolerance test (OGTT)/intravenous glucose tolerance test (IVGTT)) and inflammatory markers. Overall, N compared to C and N+ST reported significant improvements in SI (+16.5% vs. −32.3% vs. −6.9% respectively, P < 0.01) and disposition index (DI: +15.5% vs. −14.2% vs. −13.7% respectively, P < 0.01). N+ST compared to C and N reported significant reductions in hepatic fat fraction (HFF: −27.3% vs. −4.3% vs. 0% respectively, P < 0.01). Compared to N, N+ST reported reductions in plasminogen activator inhibitor-1 (PAI-1) (−38.3% vs. +1.0%, P < 0.01) and resistin (−18.7% vs. +11.3%, P = 0.02). There were no intervention effects for all other measures of adiposity or inflammation. Significant intervention by ethnicity interactions were found for African Americans in the N group who reported increases in total fat mass, 2-h glucose and glucose incremental areas under the curve (IAUC) compared to Latinos (P’s < 0.05). These interventions yielded differential effects with N reporting favorable improvements in SI and DI and N+ST reporting marked reductions in HFF and inflammation. Both ethnic groups had significant improvements in metabolic health; however some improvements were not seen in African Americans.
PMCID: PMC3106142  PMID: 21293446

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