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1.  Traffic-Related Air Pollution and Selected Birth Defects in the San Joaquin Valley of California 
BACKGROUND
Birth defects are a leading cause of infant morbidity and mortality. Studies suggest associations between environmental contaminants and some structural anomalies, although evidence is limited and several anomalies have not been investigated previously.
METHODS
We used data from the California Center of the National Birth Defects Prevention Study and the Children's Health and Air Pollution Study to estimate the odds of 26 congenital birth defect phenotypes with respect to quartiles of seven ambient air pollutant and traffic exposures in California during the first 2 months of pregnancy, 1997 to 2006 (874 cases and 849 controls). We calculated odds ratios (adjusted for maternal race/ethnicity, education, and vitamin use; aOR) for 11 phenotypes that had at least 40 cases.
RESULTS
Few odds ratios had confidence intervals that did not include 1.0. Odds of esophageal atresia were increased for the highest versus lowest of traffic density (aOR = 2.8, 95% confidence interval [CI], 1.1–7.4) and PM10 exposure (aOR 4.9; 95% CI, 1.4–17.2). PM10 was associated with a decreased risk of hydrocephaly (aOR= 0.3; 95% CI, 0.1–0.9) and CO with decreased risk of anotia/microtia (aOR = 0.4; 95% CI, 0.2–0.8) and transverse limb deficiency (aOR = 0.4; 95% CI, 0.2–0.9), again reflecting highest versus lowest quartile comparisons.
CONCLUSION
Most analyses showed no substantive association between air pollution and the selected birth defects with few exceptions of mixed results.
doi:10.1002/bdra.23175
PMCID: PMC4264633  PMID: 24108522
congenital anomalies; air pollution; traffic; birth outcomes
2.  A cross-validation deletion–substitution–addition model selection algorithm: Application to marginal structural models 
The cross-validation deletion–substitution–addition (cvDSA) algorithm is based on data-adaptive estimation methodology to select and estimate marginal structural models (MSMs) for point treatment studies as well as models for conditional means where the outcome is continuous or binary. The algorithm builds and selects models based on user-defined criteria for model selection, and utilizes a loss function-based estimation procedure to distinguish between different model fits. In addition, the algorithm selects models based on cross-validation methodology to avoid “over-fitting” data. The cvDSA routine is an R software package available for download. An alternative R-package (DSA) based on the same principles as the cvDSA routine (i.e., cross-validation, loss function), but one that is faster and with additional refinements for selection and estimation of conditional means, is also available for download. Analyses of real and simulated data were conducted to demonstrate the use of these algorithms, and to compare MSMs where the causal effects were assumed (i.e., investigator-defined), with MSMs selected by the cvDSA. The package was used also to select models for the nuisance parameter (treatment) model to estimate the MSM parameters with inverse-probability of treatment weight (IPTW) estimation. Other estimation procedures (i.e., G-computation and double robust IPTW) are available also with the package.
doi:10.1016/j.csda.2010.02.002
PMCID: PMC4259156  PMID: 25505354
Cross-validation; Machine learning; Marginal structural models; Lung function; Cardiovascular mortality
3.  Polycyclic Aromatic Hydrocarbon Exposure and Wheeze in a Cohort of Children with Asthma in Fresno, CA 
Polycyclic aromatic hydrocarbons (PAHs) are found widely in the ambient air and result from combustion of various fuels and industrial processes. PAHs have been associated with adverse human health effects such as cognitive development, childhood IQ, and respiratory health. The Fresno Asthmatic Children’s Environment Study (FACES) enrolled 315 children ages 6-11 years with asthma in Fresno, CA and followed the cohort from 2000 to 2008. Subjects were evaluated for asthma symptoms in up to three 14-day panels per year. Detailed ambient pollutant concentrations were collected from a central site and outdoor pollutants were measured at 83 homes for at least one 5-day period. Measurements of particle-bound PAHs were used with land use regression models to estimate individual exposures to PAHs with 4-, 5- or 6-member rings (PAH456) and phenanthrene for the cohort (approximately 22 000 individual daily estimates). We used a cross-validation based algorithm for model fitting and a generalized estimated equation approach to account for repeated measures. Multiple lags and moving averages of PAH exposure were associated with increased wheeze for each of the three types of PAH exposure estimates. The odds ratios for asthmatics exposed to PAHs (ng/m3) ranged from 1.01 (95% CI, 1.00-1.02) to 1.10 (95% CI, 1.04-1.17)]. This trend for increased wheeze persisted among all PAHs measured. Phenanthrene was found to have a higher relative impact on wheeze. These data provide further evidence that PAHs contribute to asthma morbidity.
doi:10.1038/jes.2012.29
PMCID: PMC4219412  PMID: 22549720
Asthma; polycyclic aromatic hydrocarbons; PAH; air pollution
4.  Causal inference in epidemiological studies with strong confounding 
Statistics in medicine  2012;31(13):1380-1404.
One of the identifiability assumptions of causal effects defined by marginal structural model (MSM) parameters is the experimental treatment assignment (ETA) assumption. Practical violations of this assumption frequently occur in data analysis when certain exposures are rarely observed within some strata of the population. The inverse probability of treatment weighted (IPTW) estimator is particularly sensitive to violations of this assumption; however, we demonstrate that this is a problem for all estimators of causal effects. This is due to the fact that the ETA assumption is about information (or lack thereof) in the data. A new class of causal models, causal models for realistic individualized exposure rules (CMRIER), is based on dynamic interventions. CMRIER generalize MSM, and their parameters remain fully identifiable from the observed data, even when the ETA assumption is violated, if the dynamic interventions are set to be realistic. Examples of such realistic interventions are provided. We argue that causal effects defined by CMRIER may be more appropriate in many situations, particularly those with policy considerations. Through simulation studies, we examine the performance of the IPTW estimator of the CMRIER parameters in contrast to that of the MSM parameters. We also apply the methodology to a real data analysis in air pollution epidemiology to illustrate the interpretation of the causal effects defined by CMRIER.
doi:10.1002/sim.4469
PMCID: PMC4113478  PMID: 22362629
causal inference; dynamic treatment regimes; IPTW estimator
5.  Ambient Air Pollution and Traffic Exposures and Congenital Heart Defects in the San Joaquin Valley of California 
Background
Congenital anomalies are a leading cause of infant morbidity and mortality. Studies suggest associations between environmental contaminants and some anomalies, although evidence is limited.
Methods
We used data from the California Center of the National Birth Defects Prevention Study and the Children's Health and Air Pollution Study to estimate the odds of 27 congenital heart defects with respect to quartiles of 7 ambient air pollutant and traffic exposures in California during the first two months of pregnancy, 1997–2006 (N=813 cases and N=828 controls).
Results
Particulate matter <10 microns (PM10) was associated with pulmonary valve stenosis (aOR4th Quartile=2.6; 95% CI: 1.2, 5.7) and perimembranous ventricular septal defects (aOR3rd Quartile=2.1; 95% CI: 1.1, 3.9) after adjusting for maternal race-ethnicity, education and multivitamin use. PM2.5 was associated with transposition of the great arteries (aOR3rd Quartile=2.6; 95% CI: 1.1, 6.5) and inversely associated with perimembranous ventricular septal defects (aOR4th Quartile=0.5; 95% CI: 0.2, 0.9). Secundum atrial septal defects were inversely associated with carbon monoxide (aOR4th Quartile=0.4; 95% CI: 0.2, 0.8) and PM2.5 (aOR4th Quartile=0.5; 95% CI: 0.3, 0.8). Traffic density was associated with muscular ventricular septal defects (aOR4th Quartile=3.0, 95% CI: 1.2, 7.8) and perimembranous ventricular septal defects (aOR3rd Quartile =2.4; 95% CI: 1.3, 4.6), and inversely associated with transposition of the great arteries (aOR4th Quartile=0.3; 95% CI: 0.1, 0.8).
Conclusions
PM10 and traffic density may contribute to the occurrence of pulmonary valve stenosis and ventricular septal defects, respectively. The results were mixed for other pollutants and had little consistency with previous studies.
doi:10.1111/ppe.12055
PMCID: PMC3694598  PMID: 23772934
6.  The Association of Ambient Air Pollution and Traffic Exposures With Selected Congenital Anomalies in the San Joaquin Valley of California 
American Journal of Epidemiology  2013;177(10):1074-1085.
Congenital anomalies are a leading cause of infant mortality and are important contributors to subsequent morbidity. Studies suggest associations between environmental contaminants and some anomalies, although evidence is limited. We aimed to investigate whether ambient air pollutant and traffic exposures in early gestation contribute to the risk of selected congenital anomalies in the San Joaquin Valley of California, 1997–2006. Seven exposures and 5 outcomes were included for a total of 35 investigated associations. We observed increased odds of neural tube defects when comparing the highest with the lowest quartile of exposure for several pollutants after adjusting for maternal race/ethnicity, education, and multivitamin use. The adjusted odds ratio for neural tube defects among those with the highest carbon monoxide exposure was 1.9 (95% confidence interval: 1.1, 3.2) compared with those with the lowest exposure, and there was a monotonic exposure-response across quartiles. The highest quartile of nitrogen oxide exposure was associated with neural tube defects (adjusted odds ratio = 1.8, 95% confidence interval: 1.1, 2.8). The adjusted odds ratio for the highest quartile of nitrogen dioxide exposure was 1.7 (95% confidence interval: 1.1, 2.7). Ozone was associated with decreased odds of neural tube defects. Our results extend the limited body of evidence regarding air pollution exposure and adverse birth outcomes.
doi:10.1093/aje/kws367
PMCID: PMC3697063  PMID: 23538941
air pollution; birth outcomes; congenital anomalies; traffic
7.  Hypertension and Low HDL-Cholesterol were Associated with Reduced Kidney Function Across the Age Spectrum: A Collaborative Study 
Annals of epidemiology  2013;23(3):106-111.
Purpose
To determine if the associations among established risk factors and reduced kidney function vary by age.
Methods
We pooled cross-sectional data from 14,788 non-diabetics aged 40–100 years in 4 studies: Cardiovascular Health Study, Health, Aging, and Body Composition Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-Stage Disease cohort.
Results
Hypertension and low HDL-cholesterol were associated with reduced cystatin C-based estimated glomerular filtration rate (eGFR) across the age spectrum. In adjusted analyses, hypertension was associated with a 2.3 (95% CI 0.1, 4.4), 5.1 (4.1, 6.1), and 6.9 (3.0, 10.4) mL/min/1.73 m2 lower eGFR in participants 40–59, 60–79, and 80+ years, respectively (p-value for interaction <0.001). The association of low HDL-cholesterol with reduced kidney function was also greater in the older age groups: 4.9 (3.5, 6.3), 7.1 (CI 6.0, 8.3), 8.9 (CI 5.4, 11.9) mL/min/1.73 m2 (p-value for interaction <0.001). Smoking and obesity were associated with reduced kidney function in participants under 80 years. All estimates of the potential population impact of the risk factors were modest.
Conclusions
Hypertension, obesity, smoking, and low HDL-cholesterol are modestly associated with reduced kidney function in non-diabetics. The associations of hypertension and HDL-cholesterol with reduced kidney function appear stronger in older adults.
doi:10.1016/j.annepidem.2012.12.004
PMCID: PMC3570601  PMID: 23313266
Chronic kidney insufficiency; aged; hypertension; cholesterol; obesity; smoking
8.  Fungi and pollen exposure in the first months of life and risk of early childhood wheezing 
Thorax  2009;64(4):10.1136/thx.2007.090241.
BACKGROUND
Many studies have found that risk of childhood asthma varies by month of birth, but few have examined ambient aeroallergens as an explanatory factor.
OBJECTIVE
To examine whether birth during seasons of elevated ambient fungal spore or pollen concentrations is associated with risk of early wheezing or blood levels of Th1- and Th2-type cells at 24 months of age.
METHODS
514 children were enrolled before birth and followed to 24 months of age. Early wheezing was determined from medical records and Th1 and Th2-type cells were measured in peripheral blood using flow cytometry. Ambient aeroallergen concentrations were measured throughout the study period and discrete seasons of high spore and pollen concentrations were defined.
RESULTS
A seasonal pattern was observed, with birth in the fall-winter (the fungal spore season) associated with increased odds of early wheezing (adjusted odds ratio = 3.1; 95% confidence interval: 1.3, 7.4). Increasing mean daily concentrations of basidiospores and ascospores in the first three months of life were associated with increased odds of wheeze, as were increasing mean daily concentrations of total and specific pollen types. Levels of Th1 cells at age 24 months were positively associated with mean fungal spore concentrations and negatively associated with mean pollen concentrations in the first three months of life.
CONCLUSIONS
Children with higher exposure to fungal spores and pollen in the first three months of life were at increased risk of early wheezing. This association was independent of other seasonal factors, including ambient PM2.5 levels and lower respiratory infections.
doi:10.1136/thx.2007.090241
PMCID: PMC3882001  PMID: 19240083
asthma; wheeze; birth season; mold; pollen; epidemiology
9.  Exposure to Traffic-related Air Pollution During Pregnancy and Term Low Birth Weight: Estimation of Causal Associations in a Semiparametric Model 
American Journal of Epidemiology  2012;176(9):815-824.
Traffic-related air pollution is recognized as an important contributor to health problems. Epidemiologic analyses suggest that prenatal exposure to traffic-related air pollutants may be associated with adverse birth outcomes; however, there is insufficient evidence to conclude that the relation is causal. The Study of Air Pollution, Genetics and Early Life Events comprises all births to women living in 4 counties in California's San Joaquin Valley during the years 2000–2006. The probability of low birth weight among full-term infants in the population was estimated using machine learning and targeted maximum likelihood estimation for each quartile of traffic exposure during pregnancy. If everyone lived near high-volume freeways (approximated as the fourth quartile of traffic density), the estimated probability of term low birth weight would be 2.27% (95% confidence interval: 2.16, 2.38) as compared with 2.02% (95% confidence interval: 1.90, 2.12) if everyone lived near smaller local roads (first quartile of traffic density). Assessment of potentially causal associations, in the absence of arbitrary model assumptions applied to the data, should result in relatively unbiased estimates. The current results support findings from previous studies that prenatal exposure to traffic-related air pollution may adversely affect birth weight among full-term infants.
doi:10.1093/aje/kws148
PMCID: PMC3571254  PMID: 23045474
air pollution; confounding factors (epidemiology); infant, low birth weight; pregnancy
10.  Daytime Secretion of Salivary Cortisol and Alpha-Amylase in Preschool-Aged Children with Autism and Typically Developing Children 
We examined daytime salivary cortisol and salivary alpha-amylase (sAA) secretion levels and variability in preschool-aged children with autism (AUT) and typically developing children (TYP). Fifty-two subjects (26 AUT and 26 TYP) were enrolled. Salivary samples were obtained at waking, midday, and bedtime on two consecutive days at three phases (baseline, 3 months later, 6 months later). There were modest increases in waking cortisol and sAA levels in AUT relative to TYP, but the increases were not statistically significant. Important differences were observed in cortisol and sAA variability between AUT and TYP. There was also a graded response among AUT by functional status—cortisol and sAA secretion levels were higher when IQ was lower.
doi:10.1007/s10803-012-1522-z
PMCID: PMC3602445  PMID: 22477468
Autism; Children; Salivary cortisol; Salivary alpha-amylase; Diurnal; Variability
11.  The Role of Ambient Ozone in Epidemiologic Studies of Heat-Related Mortality 
Environmental Health Perspectives  2012;120(12):1627-1630.
Background: A large and growing literature investigating the role of extreme heat on mortality has conceptualized the role of ambient ozone in various ways, sometimes treating it as a confounder, sometimes as an effect modifier, and sometimes as a co-exposure. Thus, there is a lack of consensus about the roles that temperature and ozone together play in causing mortality.
Objectives: We applied directed acyclic graphs (DAGs) to the topic of heat-related mortality to graphically represent the subject matter behind the research questions and to provide insight on the analytical options available.
Discussion: On the basis of the subject matter encoded in the graphs, we assert that the role of ozone in studies of temperature and mortality is a causal intermediate that is affected by temperature and that can also affect mortality, rather than a confounder.
Conclusions: We discuss possible questions of interest implied by this causal structure and propose areas of future work to further clarify the role of air pollutants in epidemiologic studies of extreme temperature.
doi:10.1289/ehp.1205251
PMCID: PMC3548272  PMID: 22899622
causality; confounding variables; epidemiology; extreme heat; mortality; ozone
12.  Causal inference in longitudinal studies with history-restricted marginal structural models 
A new class of Marginal Structural Models (MSMs), History-Restricted MSMs (HRMSMs), was recently introduced for longitudinal data for the purpose of defining causal parameters which may often be better suited for public health research or at least more practicable than MSMs (6, 2). HRMSMs allow investigators to analyze the causal effect of a treatment on an outcome based on a fixed, shorter and user-specified history of exposure compared to MSMs. By default, the latter represent the treatment causal effect of interest based on a treatment history defined by the treatments assigned between the study’s start and outcome collection. We lay out in this article the formal statistical framework behind HRMSMs. Beyond allowing a more flexible causal analysis, HRMSMs improve computational tractability and mitigate statistical power concerns when designing longitudinal studies. We also develop three consistent estimators of HRMSM parameters under sufficient model assumptions: the Inverse Probability of Treatment Weighted (IPTW), G-computation and Double Robust (DR) estimators. In addition, we show that the assumptions commonly adopted for identification and consistent estimation of MSM parameters (existence of counterfactuals, consistency, time-ordering and sequential randomization assumptions) also lead to identification and consistent estimation of HRMSM parameters.
doi:10.1214/07-EJS050
PMCID: PMC3475192  PMID: 23087778
causal inference; counterfactual; marginal structural model; longitudinal study; IPTW; G-computation; Double Robust
13.  Antihypertensive Medication Use and Change in Kidney Function in Elderly Adults: A Marginal Structural Model Analysis 
Background:
The evidence for the effectiveness of antihypertensive medication use for slowing decline in kidney function in older persons is sparse. We addressed this research question by the application of novel methods in a marginal structural model.
Methods:
Change in kidney function was measured by two or more measures of cystatin C in 1,576 hypertensive participants in the Cardiovascular Health Study over 7 years of follow-up (1989–1997 in four U.S. communities). The exposure of interest was antihypertensive medication use. We used a novel estimator in a marginal structural model to account for bias due to confounding and informative censoring.
Results:
The mean annual decline in eGFR was 2.41 ± 4.91 mL/min/1.73 m2. In unadjusted analysis, antihypertensive medication use was not associated with annual change in kidney function. Traditional multivariable regression did not substantially change these estimates. Based on a marginal structural analysis, persons on antihypertensives had slower declines in kidney function; participants had an estimated 0.88 (0.13, 1.63) ml/min/1.73 m2 per year slower decline in eGFR compared with persons on no treatment. In a model that also accounted for bias due to informative censoring, the estimate for the treatment effect was 2.23 (−0.13, 4.59) ml/min/1.73 m2 per year slower decline in eGFR.
Conclusion:
In summary, estimates from a marginal structural model suggested that antihypertensive therapy was associated with preserved kidney function in hypertensive elderly adults. Confirmatory studies may provide power to determine the strength and validity of the findings.
doi:10.2202/1557-4679.1320
PMCID: PMC3204667  PMID: 22049266
aged; kidney function; hypertension; marginal structural model
14.  Is There an Association Between Lifetime Cumulative Exposure and Acute Pulmonary Responses to Ozone? 
Objective
To investigate the potential effects of lifetime cumulative ozone (O3) exposure on acute pulmonary responses to O3.
Methods
Fifteen healthy subjects from a larger cohort of young adults were exposed to 200 ppb O3 for 4 hours followed by bronchoscopy and bronchoalveolar lavage 18 hours later. Lung function, symptom questionnaires, and blood samples were obtained before and after each exposure. Subjects’ lifetime cumulative O3 exposures were estimated from residential histories and air-quality monitoring data.
Results
Acute exposure to O3 caused decrements in forced expiratory volume in 1 second (FEV1), maximal mid-expiratory flow rate (FEF25–75), and forced expiratory flow rate at 75% of forced vital capacity (FEF75), and an increase in plasma clara cell protein (CC16) level. Changes in CC16 and lower respiratory symptoms, but not in lung function, were positively correlated with lifetime cumulative O3 exposure.
Conclusion
Higher lifetime cumulative O3 exposure was associated with airway injury and respiratory symptom responses, but not with airway inflammatory or lung function responses, to acute O3 exposure.
doi:10.1097/JOM.0b013e318162f5eb
PMCID: PMC3321313  PMID: 18332784
15.  Usual Physical Activity and Hip Fracture in Older Men: An Application of Semiparametric Methods to Observational Data 
American Journal of Epidemiology  2011;173(5):578-586.
Few studies have examined the relation between usual physical activity level and rate of hip fracture in older men or applied semiparametric methods from the causal inference literature that estimate associations without assuming a particular parametric model. Using the Physical Activity Scale for the Elderly, the authors measured usual physical activity level at baseline (2000–2002) in 5,682 US men ≥65 years of age who were enrolled in the Osteoporotic Fractures in Men Study. Physical activity levels were classified as low (bottom quartile of Physical Activity Scale for the Elderly score), moderate (middle quartiles), or high (top quartile). Hip fractures were confirmed by central review. Marginal associations between physical activity and hip fracture were estimated with 3 estimation methods: inverse probability-of-treatment weighting, G-computation, and doubly robust targeted maximum likelihood estimation. During 6.5 years of follow-up, 95 men (1.7%) experienced a hip fracture. The unadjusted risk of hip fracture was lower in men with a high physical activity level versus those with a low physical activity level (relative risk = 0.51, 95% confidence interval: 0.28, 0.92). In semiparametric analyses that controlled confounding, hip fracture risk was not lower with moderate (e.g., targeted maximum likelihood estimation relative risk = 0.92, 95% confidence interval: 0.62, 1.44) or high (e.g., targeted maximum likelihood estimation relative risk = 0.88, 95% confidence interval: 0.53, 2.03) physical activity relative to low. This study does not support a protective effect of usual physical activity on hip fracture in older men.
doi:10.1093/aje/kwq405
PMCID: PMC3105440  PMID: 21303805
aged; confounding factors (epidemiology); exercise; hip fractures; men; motor activity; prospective studies
16.  Secondhand Smoke, Vascular Disease, and Dementia Incidence: Findings From the Cardiovascular Health Cognition Study 
American Journal of Epidemiology  2010;171(3):292-302.
Recent studies have found that smoking is associated with an increased risk of dementia, but the effects of secondhand smoke (SHS) on dementia risk are not known to have previously been studied. The authors used Cox proportional hazards marginal structural models to examine the association between self-reported lifetime household SHS exposure and risk of incident dementia over 6 years among 970 US participants in the Cardiovascular Health Cognition Study (performed from 1991 to 1999) who were never smokers and were free of clinical cardiovascular disease (CVD), dementia, and mild cognitive impairment at baseline. In addition, because prior studies have found that SHS is associated with increased risk of CVD and that CVD is associated with increased risk of dementia, the authors tested for interactions between SHS and measures of clinical and subclinical CVD on dementia risk. Moderate (16–25 years) and high (>25 years) SHS exposure levels were not independently associated with dementia risk; however, subjects with >25 years of SHS exposure and >25% carotid artery stenosis had a 3-fold increase (hazard ratio = 3.00, 95% confidence interval: 1.03, 9.72) in dementia risk compared with subjects with no/low (0–15 years) SHS exposure and ≤25% carotid artery stenosis. High lifetime SHS exposure may increase the risk of dementia in elderly with undiagnosed CVD.
doi:10.1093/aje/kwp376
PMCID: PMC2878108  PMID: 20051462
aged; dementia; longitudinal studies; models, statistical; tobacco smoke pollution
17.  Age and cystatin C in healthy adults: a collaborative study 
Background. Kidney function declines with age, but a substantial portion of this decline has been attributed to the higher prevalence of risk factors for kidney disease at older ages. The effect of age on kidney function has not been well described in a healthy population across a wide age spectrum.
Methods. The authors pooled individual-level cross-sectional data from 18 253 persons aged 28–100 years in four studies: the Cardiovascular Health Study; the Health, Aging and Body Composition Study; the Multi-Ethnic Study of Atherosclerosis and the Prevention of Renal and Vascular End-Stage Disease cohort. Kidney function was measured by cystatin C. Clinical risk factors for kidney disease included diabetes, hypertension, obesity, smoking, coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure.
Results. Across the age range, there was a strong, non-linear association of age with cystatin C concentration. This association was substantial, even among participants free of clinical risk factors for kidney disease; mean cystatin C levels were 46% higher in participants 80 and older compared with those <40 years (1.06 versus 0.72 mg/L, P < 0.001). Participants with one or more risk factors had higher cystatin C concentrations for a given age, and the age association was slightly stronger (P < 0.001 for age and risk factor interaction).
Conclusions. There is a strong, non-linear association of age with kidney function, even in healthy individuals. An important area for research will be to investigate the mechanisms that lead to deterioration of kidney function in apparently healthy persons.
doi:10.1093/ndt/gfp474
PMCID: PMC2904248  PMID: 19749145
ageing; chronic kidney disease; cystatin C; epidemiology
18.  Temporal and Spatial Patterns of Ambient Endotoxin Concentrations in Fresno, California 
Environmental Health Perspectives  2010;118(10):1490-1496.
Background
Endotoxins are found in indoor dust generated by human activity and pets, in soil, and adsorbed onto the surfaces of ambient combustion particles. Endotoxin concentrations have been associated with respiratory symptoms and the risk of atopy and asthma in children.
Objective
We characterized the temporal and spatial variability of ambient endotoxin in Fresno/Clovis, California, located in California’s Central Valley, to identify correlates and potential predictors of ambient endotoxin concentrations in a cohort of children with asthma [Fresno Asthmatic Children’s Environment Study (FACES)].
Methods
Between May 2001 and October 2004, daily ambient endotoxin and air pollutants were collected at the central ambient monitoring site of the California Air Resources Board in Fresno and, for shorter time periods, at 10 schools and indoors and outdoors at 84 residences in the community. Analyses were restricted to May–October, the dry months during which endotoxin concentrations are highest.
Results
Daily endotoxin concentration patterns were determined mainly by meteorologic factors, particularly the degree of air stagnation. Overall concentrations were lowest in areas distant from agricultural activities. Highest concentrations were found in areas immediately downwind from agricultural/pasture land. Among three other measured air pollutants [fine particulate matter, elemental carbon (a marker of traffic in Fresno), and coarse particulate matter (PMc)], PMc was the only pollutant correlated with endotoxin. Endotoxin, however, was the most spatially variable.
Conclusions
Our data support the need to evaluate the spatial/temporal variability of endotoxin concentrations, rather than relying on a few measurements made at one location, in studies of exposure and and respiratory health effects, particularly in children with asthma and other chronic respiratory diseases.
doi:10.1289/ehp.0901602
PMCID: PMC2957934  PMID: 20494854
bioaerosols; endotoxin
19.  Short-Term Effects of Air Pollution on Wheeze in Asthmatic Children in Fresno, California 
Environmental Health Perspectives  2010;118(10):1497-1502.
Background
Although studies have demonstrated that air pollution is associated with exacerbation of asthma symptoms in children with asthma, little is known about the susceptibility of subgroups, particularly those with atopy.
Objective
This study was designed to evaluate our a priori hypothesis that identifiable subgroups of asthmatic children are more likely to wheeze with exposure to ambient air pollution.
Methods
A cohort of 315 children with asthma, 6–11 years of age, was recruited for longitudinal follow-up in Fresno, California (USA). During the baseline visit, children were administered a respiratory symptom questionnaire and allergen skin-prick test. Three times a year, participants completed 14-day panels during which they answered symptom questions twice daily. Ambient air quality data from a central monitoring station were used to assign exposures to the following pollutants: particulate matter ≤ 2.5 μm in aerodynamic diameter, particulate matter between 2.5 and 10 μm in aerodynamic diameter (PM10–2.5), elemental carbon, nitrogen dioxide (NO2), nitrate, and O3.
Results
For the group as a whole, wheeze was significantly associated with short-term exposures to NO2 [odds ratio (OR) = 1.10 for 8.7-ppb increase; 95% confidence interval (CI), 1.02–1.20] and PM10–2.5 (OR = 1.11 for 14.7-μg/m3 increase; 95% CI, 1.01–1.22). The association with wheeze was stronger for these two pollutants in children who were skin-test positive to cat or common fungi and in boys with mild intermittent asthma.
Conclusion
A pollutant associated with traffic emissions, NO2, and a pollutant with bioactive constituents, PM10–2.5, were associated with increased risk of wheeze in asthmatic children living in Fresno, California. Children with atopy to cat or common fungi and boys with mild intermittent asthma were the subgroups for which we observed the largest associations.
doi:10.1289/ehp.0901292
PMCID: PMC2957935  PMID: 20570778
air pollution; asthma; atopy; coarse particulate matter; nitrogen dioxide; wheeze
20.  Serum Creatinine and Functional Limitation in Elderly Persons 
Background
Creatinine is a commonly used measure of kidney function, but serum levels are also influenced by muscle mass. We hypothesized that higher serum creatinine would be associated with self-reported functional limitation in community-dwelling elderly.
Methods
Subjects (n = 1,553) were participants in the Study of Physical Performance and Age-Related Changes in Sonomans, a cohort to study aging and physical function. We explored three strategies to account for the effects of muscle mass on serum creatinine.
Results
We observed a J-shaped association of creatinine with functional limitation. Above the study-specific mean creatinine (0.97 mg/dL in women and 1.15 mg/dL in men), the unadjusted odds ratio of functional limitation per standard deviation (0.20 mg/dL in women and 0.23 mg/dL in men) higher creatinine was 2.27 (95% confidence interval [CI] 1.75–2.94, p < .001) in women and 1.42 (95% CI 1.12–1.80, p = .003) in men. This association was inverted in persons with creatinine levels below the mean. Adjustment for muscle mass did not have an important effect on the association between creatinine and functional limitation. These associations remained after multivariable adjustment for demographics and health conditions but were statistically significant only in women.
Conclusions
In elderly adults, higher creatinine levels are associated with functional limitation, consistent with prior literature that has demonstrated reduced physical performance in persons with kidney disease. However, the association of low creatinine levels with functional limitation suggests that creatinine levels are influenced by factors other than kidney function and muscle mass in the elderly.
doi:10.1093/gerona/gln037
PMCID: PMC2655007  PMID: 19181716
Aging; Creatinine; Kidney disease; Mobility limiation
21.  Identification and Education of Adolescents with Asthma in an Urban School District: Results from a Large-scale Asthma Intervention 
Journal of Urban Health   2008;85(3):361-374.
Asthma is a leading cause of hospitalizations, acute care utilization, health care costs, and school absences in children. Asthma morbidity is disproportionately high in inner city populations. In general, community-based public health interventions to reduce asthma morbidity have had modest success due in part to their limited reach and low participation by the targeted population. Adolescents have been especially difficult to reach. A coalition of community organizations developed a school-based, population-level system to identify, prioritize, and provide interventions for middle school children with asthma in a large urban school district in Oakland, CA. Nearly 92% (n = 8,326) of students in the targeted schools took an asthma case identification survey. Of those students who took the survey, 17.5% (n = 1,458) had active asthma and were eligible for services. Among those identified with active asthma, 83% (n = 1,217) voluntarily attended asthma self-management classes at school. The 4-week curriculum previously has been shown to significantly improve several indicators of asthma control in this population. Retention was high—72% of students who enrolled attended at least three of the four curriculum sessions. Many higher-risk students were subsequently referred to and enrolled in off-site asthma services. Large school districts with incomplete or inadequate health records, high asthma prevalence, and internal or external services available for students with asthma may benefit from a similar model. A system such as the one described may be an effective public health strategy for school districts, health departments, and community coalitions addressing asthma or other conditions with high childhood prevalence.
Electronic supplementary material
The online version of this article (doi:10.1007/s11524-008-9266-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s11524-008-9266-y
PMCID: PMC2329749  PMID: 18330708
Case identification; Coalition; Inner city; School-based; Middle school
22.  Cytokines and other immunological biomarkers in children's environmental health studies 
Toxicology letters  2007;172(1-2):48-59.
Environmental exposures (e.g. pesticides, air pollution, and environmental tobacco smoke) during prenatal and early postnatal development have been linked to a growing number of childhood diseases including allergic disorders and leukemia. Because the immune response plays a critical role in each of these diseases, it is important to study the effects of toxicants on the developing immune system. Children's unique susceptibility to environmental toxicants has become an important focus of the field of immunotoxicology and the use of immune biomarkers in molecular epidemiology of children's environmental health is a rapidly expanding field of research. In this review, we discuss how markers of immune status and immunotoxicity are being applied to pediatric studies, with a specific focus on the various methods used to analyze T-helper-1/2 (Th1/Th2) cytokine profiles. Furthermore, we review recent data on the effects of children's environmental exposures to volatile organic compounds, metals, and pesticides on Th1/Th2 cytokine profiles and the associations of Th1/Th2 profiles with adverse health outcomes such as pediatric respiratory diseases, allergies, cancer and diabetes. Although cytokine profiles are increasingly used in children's studies, there is still a need to acquire distribution data for different ages and ethnic groups of healthy children. These data will contribute to the validation and standardization of cytokine biomarkers for future studies. Application of immunological markers in epidemiological studies will improve the understanding of mechanisms that underlie associations between environmental exposures and immune-mediated disorders.
doi:10.1016/j.toxlet.2007.05.017
PMCID: PMC2047341  PMID: 17624696
biomarkers; immune system; environmental exposures; pesticides; asthma; health outcomes
23.  The impact of generic-only drug benefits on patients' use of inhaled corticosteroids in a Medicare population with asthma 
Background
Patients face increasing insurance restrictions on prescription drugs, including generic-only coverage. There are no generic inhaled corticosteroids (ICS), which are a mainstay of asthma therapy, and patients pay the full price for these drugs under generic-only policies. We examined changes in ICS use following the introduction of generic-only coverage in a Medicare Advantage population from 2003–2004.
Methods
Subjects were age 65+, with asthma, prior ICS use, and no chronic obstructive pulmonary disorder (n = 1,802). In 2004, 74.0% switched from having a $30 brand-copayment plan to a generic-only coverage plan (restricted coverage); 26% had $15–25 brand copayments in 2003–2004 (unrestricted coverage). Using linear difference-in-difference models, we examined annual changes in ICS use (measured by days-of-supply dispensed). There was a lower-cost ICS available within the study setting and we also examined changes in drug choice (higher- vs. lower-cost ICS). In multivariable models we adjusted for socio-demographic, clinical, and asthma characteristics.
Results
In 2003 subjects had an average of 188 days of ICS supply. Restricted compared with unrestricted coverage was associated with reductions in ICS use from 2003–2004 (-15.5 days-of-supply, 95% confidence interval (CI): -25.0 to -6.0). Among patients using higher-cost ICS drugs in 2003 (n = 662), more restricted versus unrestricted coverage subjects switched to the lower-cost ICS in 2004 (39.8% vs. 10.3%). Restricted coverage was not associated with decreased ICS use (2003–2004) among patients who switched to the lower-cost ICS (18.7 days-of-supply, CI: -27.5 to 65.0), but was among patients who did not switch (-38.6 days-of-supply, CI: -57.0 to -20.3). In addition, restricted coverage was associated with decreases in ICS use among patients with both higher- and lower-risk asthma (-15.0 days-of-supply, CI: -41.4 to 11.44; and -15.6 days-of-supply, CI: -25.8 to -5.3, respectively).
Conclusion
In this elderly population, patients reduced their already low ICS use in response to losing drug coverage. Switching to the lower-cost ICS mitigated reductions in use among patients who previously used higher-cost drugs. Additional work is needed to assess barriers to switching ICS drugs and the clinical effects of these drug use changes.
doi:10.1186/1472-6963-8-151
PMCID: PMC2488344  PMID: 18638405
24.  Early Environmental Exposures and Intracellular Th1/Th2 Cytokine Profiles in 24-Month-Old Children Living in an Agricultural Area 
Environmental Health Perspectives  2006;114(12):1916-1922.
Background
Children who reside in agricultural settings are potentially exposed to higher levels of organophosphate (OP) pesticides, endotoxin, and allergens than their urban counterparts. Endotoxin and allergens stimulate maturation of the immune response in early childhood, but little is known about the effect of exposures to OPs or to the three combined.
Objectives
In this study, we investigated the relationships between these exposures and T-helper 1 (Th1) and T-helper 2 (Th2) cytokines, biomarkers of allergic asthma, in the subjects of CHAMA-COS (Center for the Health Assessment of Mothers and Children of Salinas), a longitudinal birth cohort in Salinas Valley, California. Exposures were ascertained by interviewer-administered questionnaires and by home visits, and clinical diagnoses were abstracted from medical records. Blood samples were collected at 12 and 24 months of age and analyzed for Th1/Th2 status by flow cytometric detection of intracellular interferon-γ/interleukin-4 cytokine expression.
Findings
Mean Th2 levels were significantly higher in children with doctor-diagnosed asthma and children with wheezing at 2 years of age. In a multiple linear regression model, exclusive breast-feeding at 1 month and pet ownership were associated with 35.3% (p < 0.01) and 34.5% (p = 0.01) increases in Th1, respectively. Maternal agricultural work and presence of gas stove in the home were associated with a 25.9% increase (p = 0.04) and 46.5% increase (p < 0.01) in Th2, respectively.
Conclusions
Asthma and wheeze outcomes in children at 24 months of age are associated with elevated Th2 status in children at an early age. Our data further suggest that early exposures to an agricultural environment, breast-feeding, pets, and gas stoves affect the development of children’s Th1/Th2 immune response.
doi:10.1289/ehp.9306
PMCID: PMC1764130  PMID: 17185285
allergen; breast-feeding; children; endotoxin; flow cytometry; interferon-γ; interleukin-4; organophosphate; pesticide; T-helper cytokines
25.  Air pollution and hospital admissions for ischemic heart disease in persons with congestive heart failure or arrhythmia. 
Environmental Health Perspectives  2002;110(12):1247-1252.
We examined whether ischemic heart disease (IHD) hospital admissions were associated with air pollutants in those with and without secondary diagnoses of arrhythmia (ARR) or congestive heart failure (CHF). We assessed the occurrence of increased vulnerability among persons with these conditions to daily variations in ozone, carbon monoxide, nitrogen dioxide, or particulate matter less than or equal to 10 micro m in aerodynamic diameter (PM10). The study population consisted of members of a large health maintenance organization residing in the South Coast Air Basin of California from 1988 to 1995. After adjustment for day of week, study year, and smoothing splines for day of study, temperature, and relative humidity, CO and NO2 were both associated with admissions with the greatest effects for CO. A 1-ppm increase in 8-hr average CO was associated with a 3.60% [95% confidence interval (CI), 1.62-5.63%] increase in same-day IHD admissions in persons with a secondary diagnosis of CHF, a 2.99% (95% CI, 1.80-4.19%) increase in persons with a secondary diagnosis of ARR, and a 1.62% (95% CI, 0.65-2.59%) increase in IHD admissions in persons without either secondary diagnosis. Air pollution was most strongly associated with myocardial infarction hospital admissions. The vulnerability of the secondary CHF subgroup may be due to a greater prevalence of myocardial infarction primary diagnoses and not the modifying effect of CHF. This study suggests that people with IHD and accompanying CHF and/or ARR constitute a sensitive subgroup in relation to the effects of criteria ambient air pollutants associated with motor vehicle combustion.
PMCID: PMC1241113  PMID: 12460805

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