Gestational Weight Gain and Birth Outcome: A Comparison of Methods of Accounting for Gestational Age.

Cross-sectional studies of total gestational weight gain (GWG) and perinatal outcomes have used different approaches to operationalize GWG and adjust for duration of gestation. Using birth records from California (2007-2017), Nevada (2010-2017), and Oregon (2008-2017), we compared 3 commonly used approaches to estimate associations between GWG and cesarean delivery, small-for-gestational-age birth, and low birth weight (LBW): 1) the Institute of Medicine-recommended GWG ranges at a given gestational week, 2) total weight gain categories directly adjusting for gestational age as a covariate, and 3) weight-gain-for-gestational-age z scores derived from an external longitudinal reference population. Among 5,461,130 births, the 3 methods yielded similar conclusions for cesarean delivery and small-for-gestational-age birth. However, for LBW, some associations based on z scores were in the opposite direction of methods 1 and 2, paradoxically suggesting that higher GWG increases risk of LBW. This was due to a greater proportion of preterm births among those with high z scores, and controlling for gestational age in the z score model brought the results in line with the other methods. We conclude that the use of externally derived GWG z scores based on ongoing pregnancies can yield associations confounded by duration of pregnancy when the outcome is strongly associated with gestational age at delivery.

Source-Apportioned PM2.5 and Cardiorespiratory Emergency Department Visits: Accounting for Source Contribution Uncertainty.

BACKGROUND: Despite evidence suggesting that air pollution-related health effects differ by emissions source, epidemiologic studies on fine particulate matter (PM2.5) infrequently differentiate between particles from different sources. Those that do rarely account for the uncertainty of source apportionment methods. METHODS: For each day in a 12-year period (1998-2010) in Atlanta, GA, we estimated daily PM2.5 source contributions from a Bayesian ensemble model that combined four source apportionment methods including chemical transport and receptor-based models. We fit Poisson generalized linear models to estimate associations between source-specific PM2.5 concentrations and cardiorespiratory emergency department visits (n = 1,598,117). We propagated uncertainty in the source contribution estimates through analyses using multiple imputation. RESULTS: Respiratory emergency department visits were positively associated with biomass burning and secondary organic carbon. For a 1 µg/m increase in PM2.5 from biomass burning during the past 3 days, the rate of visits for all respiratory outcomes increased by 0.4% (95% CI 0.0%, 0.7%). There was less evidence for associations between PM2.5 sources and cardiovascular outcomes, with the exception of ischemic stroke, which was positively associated with most PM2.5 sources. Accounting for the uncertainty of source apportionment estimates resulted, on average, in an 18% increase in the standard error for rate ratio estimates for all respiratory and cardiovascular emergency department visits, but inflation varied across specific sources and outcomes, ranging from 2% to 39%. CONCLUSIONS: This study provides evidence of associations between PM2.5 sources and some cardiorespiratory outcomes and quantifies the impact of accounting for variability in source apportionment approaches.

Impact of fluid overload and infection on respiratory adverse event development during induction therapy for childhood acute myeloid leukemia.

BACKGROUND: Treatment-related morbidity and mortality occur frequently in childhood acute myeloid leukemia (AML) induction. Yet the contributions of respiratory adverse events (AEs) within this population are poorly understood. Furthermore, the roles of fluid overload (FO) and infection in AML pulmonary complications have been inadequately examined. OBJECTIVES: To describe the incidence, categories, and grades of respiratory AEs and to assess the associations of FO and infection on respiratory AE development in childhood AML induction. METHODS: We retrospectively examined the induction courses of a cohort of de novo pediatric AML patients for any NCI CTCAE grade 2 to 5 respiratory AE, FO, and systemic/pulmonary infection occurrence. Demographic, disease, and treatment-related data were abstracted. Descriptive, univariate, survival, and multivariable analyses were conducted. RESULTS: Among 105 eligible subjects from 2009 to 2016, 49.5% (n = 52) experienced 63 discrete respiratory AEs. FO occurred in 28.6% of subjects (n = 30), with half occurring within 24 hours of hospitalization. Positive FO status < 10 days (aHR 5.5, 95% CI 2.3-12.8), ≥ 10 days (aHR 13, 95% CI 4.1-41.8), and positive infection status ≥ 10 days into treatment (aHR 14.9, 5.4-41.6) were each independently associated with AE development. CONCLUSIONS: We describe a higher incidence of respiratory AEs during childhood AML induction than previously illustrated. FO occurs frequently and early in this course. Late infections and FO at any time frame were strongly associated with AE development. Interventions focused on the prevention and management of FO and infectious respiratory complications could be instrumental in reducing preventable treatment-related morbidity and mortality.

Review of Acellular Assays of Ambient Particulate Matter Oxidative Potential: Methods and Relationships with Composition, Sources, and Health Effects.

Oxidative stress is a potential mechanism of action for particulate matter (PM) toxicity and can occur when the body's antioxidant capacity cannot counteract or detoxify harmful effects of reactive oxygen species (ROS) due to an excess presence of ROS. ROS are introduced to the body via inhalation of PM with these species present on and/or within the particles (particle-bound ROS) and/or through catalytic generation of ROS in vivo after inhaling redox-active PM species (oxidative potential, OP). The recent development of acellular OP measurement techniques has led to a surge in research across the globe. In this review, particle-bound ROS techniques are discussed briefly while OP measurements are the focus due to an increasing number of epidemiologic studies using OP measurements showing associations with adverse health effects in some studies. The most common OP measurement techniques, including the dithiothreitol assay, glutathione assay, and ascorbic acid assay, are discussed along with evidence for utility of OP measurements in epidemiologic studies and PM characteristics that drive different responses between assay types (such as species composition, emission source, and photochemistry). Overall, most OP assays respond to metals like copper than can be found in emission sources like vehicles. Some OP assays respond to organics, especially photochemically aged organics, from sources like biomass burning. Select OP measurements have significant associations with certain cardiorespiratory end points, such as asthma, congestive heart disease, and lung cancer. In fact, multiple studies have found that exposure to OP measured using the dithiothreitol and glutathione assays drives higher risk ratios for certain cardiorespiratory outcomes than PM mass, suggesting OP measurements may be integrating the health-relevant fraction of PM and will be useful tools for future health analyses. The compositional impacts, including species and emission sources, on OP could have serious implications for health-relevant PM exposure. Though more work is needed, OP assays show promise for health studies as they integrate the impacts of PM species and properties on catalytic redox reactions into one measurement, and current work highlights the importance of metals, organic carbon, vehicles, and biomass burning emissions to PM exposures that could impact health.

Short-term association between ambient temperature and homicide in South Africa: a case-crossover study.

BACKGROUND: Criminology research has traditionally investigated sociodemographic predictors of crime, such as sex, race, age, and socioeconomic status. However, evidence suggests that short-term fluctuations in crime often vary more than long-term trends, which sociodemographic factors cannot explain. This has redirected researchers to explore how environmental factors, such as meteorological variables, influence criminal behavior. In this study we investigate the association between daily ambient temperature and homicide incidence in South Africa, a country with one of the highest homicide rates in the world. METHODS: Mortality data was from South Africa's civil registration system and includes all recorded deaths in the country from 1997 to 2013 (17 years). Daily temperature was from the National Oceanographic and Atmospheric Association of the United States and South Africa's Agricultural Research Council. Data were analyzed using a time-stratified case-crossover design with conditional logistic regression. We delineated cases as either "definite" (ICD-10 codes X85-Y09, n = 68,356) or "probable" homicides (ICD-10 codes W25-W26, W32-W34, W50, Y22-Y24, Y28-Y29, n = 177,873). Case periods were defined as the day on which a death occurred. Control periods were selected using a day-of-week match within the same month and district. Analyses investigated same-day and lagged effects of maximum, mean and minimum temperature. RESULTS: A one-degree Celsius increase in same-day maximum temperature - our a priori metric of choice - was associated with a 1.5% (1.3-1.8%) increase in definite homicides and a 1.2% (1.1-1.3%) increase in total (definite + probable) homicides. Significant (p < 0.05) positive associations were also observed when applying other temperature metrics (mean, minimum) and lags (1, 0-1). The shape of the association did not display any clear non-linearities. There was no evidence of confounding by public holidays or air pollution. CONCLUSIONS: This study suggests a positive association between daily ambient temperature and homicide in South Africa. This temperature-health relationship may be of particular concern in the context of climate change. The ability to include meteorological variables as a predictor of criminal activity and violent behavior could prove valuable in resource allocation for crime prevention efforts.

Exposure to Mobile Source Air Pollution in Early-life and Childhood Asthma Incidence: The Kaiser Air Pollution and Pediatric Asthma Study.

BACKGROUND: Early-life exposure to traffic-related air pollution exacerbates childhood asthma, but it is unclear what role it plays in asthma development. METHODS: The association between exposure to primary mobile source pollutants during pregnancy and during infancy and asthma incidence by ages 2 through 6 was examined in the Kaiser Air Pollution and Pediatric Asthma Study, a racially diverse birth cohort of 24,608 children born between 2000 and 2010 and insured by Kaiser Permanente Georgia. We estimated concentrations of mobile source fine particulate matter (PM2.5, µg/m), nitrogen oxides (NOX, ppb), and carbon monoxide (CO, ppm) at the maternal and child residence using a Research LINE source dispersion model for near-surface releases. Asthma was defined using diagnoses and medication dispensings from medical records. We used binomial generalized linear regression to model the impact of exposure continuously and by quintiles on asthma risk. RESULTS: Controlling for covariates and modeling log-transformed exposure, a 2.7-fold increase in first year of life PM2.5 was associated with an absolute 4.1% (95% confidence interval, 1.6%, 6.6%) increase in risk of asthma by age 5. Quintile analysis showed an increase in risk from the first to second quintile, but similar risk across quintiles 2-5. Risk differences increased with follow-up age. Results were similar for NOX and CO and for exposure during pregnancy and the first year of life owing to high correlation. CONCLUSIONS: Results provide limited evidence for an association of early-life mobile source air pollution with childhood asthma incidence with a steeper concentration-response relationship observed at lower levels of exposure.

Caesarean delivery, childhood asthma, and effect modification by sex: An observational study and meta-analysis.

BACKGROUND: Numerous studies indicate caesarean delivery is associated with childhood asthma. Sex-specific associations were reported in four of these studies, and in all four studies, the estimated association between caesarean delivery and asthma was of greater magnitude among girls, although most report a lack of evidence of multiplicative interaction. METHODS: We assessed potential effect modification by sex, on the additive and multiplicative scales, of the association between caesarean delivery and asthma by ages 2 through 6 in up to 17 075 racially diverse children from a retrospective birth cohort, the Kaiser Air Pollution and Pediatric Asthma (KAPPA) Study. We also conducted a random-effects meta-analysis, combining our sex-stratified results (using the odds ratio for compatibility with previous studies) with previously published results. RESULTS: Adjusted risk differences for caesarean delivery and asthma in the KAPPA cohort were higher among girls than boys at every follow-up age. By age 5, caesarean delivery was associated with an absolute 3.8% (95% confidence interval [CI] 0.4%, 7.3%) higher asthma risk among girls and a 1.9% (95% CI -1.7, 5.4) higher risk among boys. The summary odds ratio from the meta-analysis for caesarean delivery and asthma among girls was 1.26 (95% CI 1.14, 1.39) and 1.08 (95% CI 0.98, 1.20) among boys (P = 0.036). CONCLUSIONS: Higher, but imprecise, estimates for females across five studies should motivate investigators to estimate sex-specific associations for caesarean delivery and asthma and to explore biological mechanisms or sex-dependent biases that could explain this possible heterogeneity.

Effect of infant feeding practices on iron status in a cohort study of Bolivian infants.

BACKGROUND: Iron deficiency (ID) is the most common micronutrient deficiency worldwide, with potentially severe consequences on child neurodevelopment. Though exclusive breastfeeding (EBF) is recommended for 6 months, breast milk has low iron content. This study aimed to estimate the effect of the length of EBF on iron status at 6 - 8 months of age among a cohort of Bolivian infants. METHODS: Mother-infant pairs were recruited from 2 hospitals in El Alto, Bolivia, and followed from one through 6 - 8 months of age. Singleton infants > 34 weeks gestational age, iron-sufficient at baseline, and completing blood draws at 2 and 6 - 8 months of age were eligible for inclusion (N = 270). Ferritin was corrected for the effect of inflammation. ID was defined as inflammation-corrected ferritin < 12 µg/L, and anemia was defined as altitude-corrected hemoglobin < 11 g/dL; IDA was defined as ID plus anemia. The effect of length of EBF (infant received only breast milk with no other liquids or solids, categorized as < 4, 4 - 6, and > 6 months) was assessed for ID, IDA, and anemia (logistic regression) and ferritin (Fer) and hemoglobin (Hb, linear regression). RESULTS: Low iron status was common among infants at 6 - 8 months: 56% of infants were ID, 76% were anemic, and 46% had IDA. EBF of 4 months and above was significantly associated with ID as compared with EBF <  4 months (4 - 6 months: OR 2.0 [1.1 - 3.4]; > 6 months: 3.3 [1.0 - 12.3]), but not with IDA (4 - 6 months: OR 1.4 [0.8 - 2.4]; > 6 months: 2.2 [0.7 - 7.4]), or anemia (4 - 6 months: OR 1.4 [0.7 - 2.5]; > 6 months: 1.5 [0.7 - 7.2]). Fer and Hb concentrations were significantly lower with increasing months of EBF. CONCLUSIONS: Results suggest a relationship between prolonged EBF and ID, but are not sufficient to support changes to current breastfeeding recommendations. More research is needed in diverse populations, including exploration of early interventions to address infant IDA.

Effects of anthropogenic emissions on aerosol formation from isoprene and monoterpenes in the southeastern United States.

Secondary organic aerosol (SOA) constitutes a substantial fraction of fine particulate matter and has important impacts on climate and human health. The extent to which human activities alter SOA formation from biogenic emissions in the atmosphere is largely undetermined. Here, we present direct observational evidence on the magnitude of anthropogenic influence on biogenic SOA formation based on comprehensive ambient measurements in the southeastern United States (US). Multiple high-time-resolution mass spectrometry organic aerosol measurements were made during different seasons at various locations, including urban and rural sites in the greater Atlanta area and Centreville in rural Alabama. Our results provide a quantitative understanding of the roles of anthropogenic SO2 and NOx in ambient SOA formation. We show that isoprene-derived SOA is directly mediated by the abundance of sulfate, instead of the particle water content and/or particle acidity as suggested by prior laboratory studies. Anthropogenic NOx is shown to enhance nighttime SOA formation via nitrate radical oxidation of monoterpenes, resulting in the formation of condensable organic nitrates. Together, anthropogenic sulfate and NOx can mediate 43-70% of total measured organic aerosol (29-49% of submicron particulate matter, PM1) in the southeastern US during summer. These measurements imply that future reduction in SO2 and NOx emissions can considerably reduce the SOA burden in the southeastern US. Updating current modeling frameworks with these observational constraints will also lead to more accurate treatment of aerosol formation for regions with substantial anthropogenic-biogenic interactions and consequently improve air quality and climate simulations.

A New Method for Partial Correction of Residual Confounding in Time-Series and Other Observational Studies.

Methods exist to detect residual confounding in epidemiologic studies. One requires a negative control exposure with 2 key properties: 1) conditional independence of the negative control and the outcome (given modeled variables) absent confounding and other model misspecification, and 2) associations of the negative control with uncontrolled confounders and the outcome. We present a new method to partially correct for residual confounding: When confounding is present and our assumptions hold, we argue that estimators from models that include a negative control exposure with these 2 properties tend to be less biased than those from models without it. Using regression theory, we provide theoretical arguments that support our claims. In simulations, we empirically evaluated the approach using a time-series study of ozone effects on asthma emergency department visits. In simulations, effect estimators from models that included the negative control exposure (ozone concentrations 1 day after the emergency department visit) had slightly or modestly less residual confounding than those from models without it. Theory and simulations show that including the negative control can reduce residual confounding, if our assumptions hold. Our method differs from available methods because it uses a regression approach involving an exposure-based indicator rather than a negative control outcome to partially correct for confounding.

Estimating Acute Cardiorespiratory Effects of Ambient Volatile Organic Compounds.

BACKGROUND: The health effects of ambient volatile organic compounds (VOCs) have received less attention in epidemiologic studies than other commonly measured ambient pollutants. In this study, we estimated acute cardiorespiratory effects of ambient VOCs in an urban population. METHODS: Daily concentrations of 89 VOCs were measured at a centrally-located ambient monitoring site in Atlanta and daily counts of emergency department visits for cardiovascular diseases and asthma in the five-county Atlanta area were obtained for the 1998-2008 period. To understand the health effects of the large number of species, we grouped these VOCs a priori by chemical structure and estimated the associations between VOC groups and daily counts of emergency department visits in a time-series framework using Poisson regression. We applied three analytic approaches to estimate the VOC group effects: an indicator pollutant approach, a joint effect analysis, and a random effect meta-analysis, each with different assumptions. We performed sensitivity analyses to evaluate copollutant confounding. RESULTS: Hydrocarbon groups, particularly alkenes and alkynes, were associated with emergency department visits for cardiovascular diseases, while the ketone group was associated with emergency department visits for asthma. CONCLUSIONS: The associations observed between emergency department visits for cardiovascular diseases and alkenes and alkynes may reflect the role of traffic exhaust, while the association between asthma visits and ketones may reflect the role of secondary organic compounds. The different patterns of associations we observed for cardiovascular diseases and asthma suggest different modes of action of these pollutants or the mixtures they represent.

Early deterioration of iron status among a cohort of Bolivian infants.

Iron deficiency (ID) and iron deficiency anemia (IDA) are major contributors to infant and maternal morbidity worldwide. There is limited longitudinal data on iron status in young infants and on methods to adjust iron biomarkers for inflammation. We aimed to quantify the prevalence of inflammation-adjusted ID, anemia, and IDA over the first year in a cohort of Bolivian infants and their mothers. Healthy mother-infant dyads were recruited from two peri-urban hospitals. Infants provided three blood draws (2, 6-8, and 12-18 months; N = 160); mothers provided two blood draws (1 and 6-8 months postpartum [plus third anemia measurement at 12-18 months]; N = 250). Blood was analyzed for hemoglobin, ferritin, soluble transferrin receptor, C-reactive protein (CRP), and alpha(1)-acid glycoprotein (AGP). Iron biomarkers were adjusted for inflammation using CRP and AGP; hemoglobin cutoffs were adjusted for altitude. Inflammation (elevated CRP or AGP) was 17% among toddlers 12-18 months of age. ID (inflammation-adjusted ferritin) increased with age (<1%, 56%, and 79% at each blood draw), as did anemia and IDA (anemia: 70%, 76%, and 81%; IDA: <1%, 46%, and 68%). Maternal ID declined from the first to second assessment (39% vs. 27%). Inflammation-adjusted ID prevalence was up to 15 percentage points higher than unadjusted estimates. The high prevalence of ID, anemia, and IDA in this cohort of Bolivian infants beginning at 6-8 months of age suggests that early interventions may be necessary in vulnerable populations.

Analysis of RPE morphometry in human eyes.

PURPOSE: To describe the RPE morphometry of healthy human eyes regarding age and topographic location using modern computational methods with high accuracy and objectivity. We tested whether there were regional and age-related differences in RPE cell area and shape. METHODS: Human cadaver donor eyes of varying ages were dissected, and the RPE flatmounts were immunostained for F-actin with AF635-phalloidin, nuclei stained with propidium iodide, and imaged with confocal microscopy. Image analysis was performed using ImageJ (NIH) and CellProfiler software. Quantitative parameters, including cell density, cell area, polygonality of cells, number of neighboring cells, and measures of cell shape, were obtained from these analyses to characterize individual and groups of RPE cells. Measurements were taken from selected areas spanning the length of the temporal retina through the macula and the mid-periphery to the far periphery. RESULTS: Nineteen eyes from 14 Caucasian donors of varying ages ranging from 29 to 80 years were used. Along a horizontal nasal to temporal meridian, there were differences in several cell shape and size characteristics. Generally, the cell area and shape was relatively constant and regular except in the far periphery. In the outer third of the retina, the cell area and shape differed from the inner two-thirds statistically significantly. In the macula and the far periphery, an overall decreasing trend in RPE cell density, percent hexagonal cells, and form factor was observed with increasing age. We also found a trend toward increasing cell area and eccentricity with age in the macula and the far periphery. When individuals were divided into two age groups, <60 years and ≥60 years, there was a higher cell density, lower cell area, lower eccentricity, and higher form factor in the younger group in the macula and the far periphery (p<0.05 for all measurements). No statistically significant differences in RPE morphometry between age groups were found in the mid-periphery. CONCLUSIONS: Human cadaver RPE cells differ mainly in area and shape in the outer one third compared to the inner two-thirds of the temporal retina. RPE cells become less dense and larger, lose their typical hexagonal shape, and become more oval with increasing age.

Evaluating early-life asthma definitions as a marker for subsequent asthma in an electronic medical record setting.

BACKGROUND: Case definitions for asthma incidence in early life vary between studies using medical records to define disease. This study assessed the impact of different approaches to using medical records on estimates of asthma incidence by age 3 and determined the validity of early-life asthma case definitions in predicting school-age asthma. METHODS: Asthma diagnoses and medications by age 3 were used to classify 7103 children enrolled in Kaiser Permanente Georgia according to 14 definitions of asthma. School-age asthma was defined as an asthma diagnosis between ages 5 and 8. Sensitivity (probability of asthma by age 3 given school-age asthma), specificity (probability of no asthma by age 3 given no school-age asthma), positive and negative predictive values (probability of (no) school-age asthma given (no) asthma by age 3), and likelihood ratios (combining sensitivity and specificity) were used to determine predictive ability. RESULTS: 9.0-35.2% of children were classified as asthmatic by age 3 depending on asthma case definition. Early-life asthma classifications were more specific than sensitive and were better at identifying children who would not have school-age asthma (negative predictive values: 80.7-86.6%) than at predicting children who would have school-age asthma (positive predictive values: 43.5-71.5%). CONCLUSIONS: Choice of case definition had a large impact on the estimate of asthma incidence. While ability to predict school-age asthma was limited, several case definitions performed similarly to clinical asthma prediction tools used in previous asthma research (e.g., the Asthma Predictive Index).

Refined assessment of associations between drinking water residence time and emergency department visits for gastrointestinal illness in Metro Atlanta, Georgia.

Recent outbreak investigations suggest that a substantial proportion of waterborne disease outbreaks are attributable to water distribution system issues. In this analysis, we examine the relationship between modeled water residence time (WRT), a proxy for probability of microorganism intrusion into the distribution system, and emergency department visits for gastrointestinal (GI) illness for two water utilities in Metro Atlanta, USA during 1993-2004. We also examine the association between proximity to the nearest distribution system node, based on patients' residential address, and GI illness using logistic regression models. Comparing long (≥90th percentile) with intermediate WRTs (11th to 89th percentile), we observed a modestly increased risk for GI illness for Utility 1 (OR = 1.07, 95% CI: 1.02-1.13), which had substantially higher average WRT than Utility 2, for which we found no increased risk (OR = 0.98, 95% CI: 0.94-1.02). Examining finer, 12-hour increments of WRT, we found that exposures >48 h were associated with increased risk of GI illness, and exposures of >96 h had the strongest associations, although none of these associations was statistically significant. Our results suggest that utilities might consider reducing WRTs to <2-3 days or adding booster disinfection in areas with longer WRT, to minimize risk of GI illness from water consumption.

A general, multivariate definition of causal effects in epidemiology.

Population causal effects are often defined as contrasts of average individual-level counterfactual outcomes, comparing different exposure levels. Common examples include causal risk difference and risk ratios. These and most other examples emphasize effects on disease onset, a reflection of the usual epidemiological interest in disease occurrence. Exposure effects on other health characteristics, such as prevalence or conditional risk of a particular disability, can be important as well, but contrasts involving these other measures may often be dismissed as non-causal. For example, an observed prevalence ratio might often viewed as an estimator of a causal incidence ratio and hence subject to bias. In this manuscript, we provide and evaluate a definition of causal effects that generalizes those previously available. A key part of the generalization is that contrasts used in the definition can involve multivariate, counterfactual outcomes, rather than only univariate outcomes. An important consequence of our generalization is that, using it, one can properly define causal effects based on a wide variety of additional measures. Examples include causal prevalence ratios and differences and causal conditional risk ratios and differences. We illustrate how these additional measures can be useful, natural, easily estimated, and of public health importance. Furthermore, we discuss conditions for valid estimation of each type of causal effect, and how improper interpretation or inferences for the wrong target population can be sources of bias.

Reactive Oxygen Species Generation Linked to Sources of Atmospheric Particulate Matter and Cardiorespiratory Effects.

Exposure to atmospheric fine particulate matter (PM2.5) is associated with cardiorespiratory morbidity and mortality, but the mechanisms are not well understood. We assess the hypothesis that PM2.5 induces oxidative stress in the body via catalytic generation of reactive oxygen species (ROS). A dithiothreitol (DTT) assay was used to measure the ROS-generation potential of water-soluble PM2.5. Source apportionment on ambient (Atlanta, GA) PM2.5 was performed using the chemical mass balance method with ensemble-averaged source impact profiles. Linear regression analysis was used to relate PM2.5 emission sources to ROS-generation potential and to estimate historical levels of DTT activity for use in an epidemiologic analysis for the period of 1998-2009. Light-duty gasoline vehicles (LDGV) exhibited the highest intrinsic DTT activity, followed by biomass burning (BURN) and heavy-duty diesel vehicles (HDDV) (0.11 ± 0.02, 0.069 ± 0.02, and 0.052 ± 0.01 nmol min(-1) µg(-1)source, respectively). BURN contributed the largest fraction to total DTT activity over the study period, followed by LDGV and HDDV (45, 20, and 14%, respectively). DTT activity was more strongly associated with emergency department visits for asthma/wheezing and congestive heart failure than PM2.5. This work provides further epidemiologic evidence of a biologically plausible mechanism, that of oxidative stress, for associations of adverse health outcomes with PM2.5 mass and supports continued assessment of the utility of the DTT activity assay as a measure of ROS-generating potential of particles.

Disease fatality and bias in survival cohorts.

OBJECTIVES: Simulate how the effect of exposure on disease occurrence and fatality influences the presence and magnitude of bias in survivor cohorts, motivated by an actual survivor cohort under study. METHODS: We simulated a cohort of 50,000 subjects exposed to a disease-causing exposure over time and followed forty years, where disease incidence was the outcome of interest. We simulated this 'inception' cohort under different assumptions about the effect of exposure on disease occurrence and fatality after disease occurrence. We then created a corresponding 'survivor' (or 'cross-sectional') cohort, where cohort enrollment took place at a specific date after exposure began in the inception cohort; subjects dying prior to that enrollment date were excluded. The disease of interest caused all deaths in our simulations, but was not always fatal. In the survivor cohort, person-time at risk began before enrollment for all subjects who did not die prior to enrollment. We compared exposure-disease associations in each inception cohort to those in corresponding survivor cohorts to determine how different assumptions impacted bias in the survivor cohorts. All subjects in both inception and survivor cohorts were considered equally susceptible to the effect of exposure in causing disease. We used Cox proportional hazards regression to calculate effect measures. RESULTS: There was no bias in survivor cohort estimates when case fatality among diseased subjects was independent of exposure. This was true even when the disease was highly fatal and more highly exposed subjects were more likely to develop disease and die. Assuming a positive exposure-response in the inception cohort, survivor cohort rate ratios were biased downwards when case fatality was greater with higher exposure. CONCLUSIONS: Survivor cohort effect estimates for fatal outcomes are not always biased, although precision can decrease.

Air pollution and acute respiratory infections among children 0-4 years of age: an 18-year time-series study.

Upper and lower respiratory infections are common in early childhood and may be exacerbated by air pollution. We investigated short-term changes in ambient air pollutant concentrations, including speciated particulate matter less than 2.5 µm in diameter (PM2.5), in relation to emergency department (ED) visits for respiratory infections in young children. Daily counts of ED visits for bronchitis and bronchiolitis (n = 80,399), pneumonia (n = 63,359), and upper respiratory infection (URI) (n = 359,246) among children 0-4 years of age were collected from hospitals in the Atlanta, Georgia, area for the period 1993-2010. Daily pollutant measurements were combined across monitoring stations using population weighting. In Poisson generalized linear models, 3-day moving average concentrations of ozone, nitrogen dioxide, and the organic carbon fraction of particulate matter less than 2.5 µm in diameter (PM2.5) were associated with ED visits for pneumonia and URI. Ozone associations were strongest and were observed at low (cold-season) concentrations; a 1-interquartile range increase predicted a 4% increase (95% confidence interval: 2%, 6%) in visits for URI and an 8% increase (95% confidence interval: 4%, 13%) in visits for pneumonia. Rate ratios tended to be higher in the 1- to 4-year age group compared with infants. Results suggest that primary traffic pollutants, ozone, and the organic carbon fraction of PM2.5 exacerbate upper and lower respiratory infections in early life, and that the carbon fraction of PM2.5 is a particularly harmful component of the ambient particulate matter mixture.

Modification of the effect of ambient air pollution on pediatric asthma emergency visits: susceptible subpopulations.

BACKGROUND: Children may have differing susceptibility to ambient air pollution concentrations depending on various background characteristics of the children. METHODS: Using emergency department (ED) data linked with birth records from Atlanta, Georgia, we identified ED visits for asthma or wheeze among children 2 to 16 years of age from 1 January 2002 through 30 June 2010 (n = 109,758). We stratified by preterm delivery, term low birth weight, maternal race, Medicaid status, maternal education, maternal smoking, delivery method, and history of a bronchiolitis ED visit. Population-weighted daily average concentrations were calculated for 1-hour maximum carbon monoxide and nitrogen dioxide; 8-hour maximum ozone; and 24-hour average particulate matter less than 10 microns in diameter, particulate matter less than 2.5 microns in diameter (PM2.5), and the PM2.5 components sulfate, nitrate, ammonium, elemental carbon, and organic carbon, using measurements from stationary monitors. Poisson time-series models were used to estimate rate ratios for associations between 3-day moving average pollutant concentrations and daily ED visit counts and to investigate effect-measure modification by the stratification factors. RESULTS: Associations between pollutant concentrations and asthma exacerbations were larger among children born preterm and among children born to African American mothers. Stratification by race and preterm status together suggested that both factors affected susceptibility. The largest estimated effect size (for an interquartile range increase in pollution) was observed for ozone among preterm births to African American mothers: rate ratio = 1.138 (95% confidence interval = 1.077-1.203). In contrast, the rate ratio for the ozone association among full-term births to mothers of other races was 1.025 (0.970-1.083). CONCLUSIONS: Results support the hypothesis that children vary in their susceptibility to ambient air pollutants.