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1.  Factors influencing time-location patterns and their impact on estimates of exposure: The Multi-Ethnic Study of Atherosclerosis and Air Pollution 
We assessed time-location patterns and the role of individual- and residential-level characteristics on these patterns within the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) cohort and also investigated the impact of individual-level time-location patterns on individual-level estimates of exposure to outdoor air pollution. Reported time-location patterns varied significantly by demographic factors such as age, gender, race/ethnicity, income, education, and employment status. On average Chinese participants reported spending significantly more time indoors and less time outdoors and in transit than white, black, or Hispanic participants. Using a tiered linear regression approach, we predicted time indoors at home and total time indoors. Our model, developed using forward selection procedures, explained 43 percent of the variability in time spent indoors at home, and incorporated demographic, health, lifestyle, and built environment factors. Time-weighted air pollution predictions calculated using recommended time indoors from USEPA(1) overestimated exposures as compared to predictions made with MESA Air participant-specific information. These data fill an important gap in the literature by describing the impact of individual and residential characteristics on time-location patterns and by demonstrating the impact of population-specific data on exposure estimates.
PMCID: PMC4641036  PMID: 25921081
epidemiology; exposure modeling; personal exposure; population based studies
2.  Time-Location Patterns of a Diverse Population of Older Adults: The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) 
The primary aim of this analysis was to present and describe questionnaire data characterizing time-location patterns of an older, multi-ethnic population from six American cities. We evaluated consistency of results from repeated administration of this questionnaire and between this questionnaire and other questionnaires collected from participants of the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air). Participants reported spending most of their time inside their homes (average: 121 hours/week or 72%). More than 50% of participants reported spending no time in several of the location options, including at home outdoors, at work/volunteer/school locations indoors or outdoors, or in “other” locations outdoors. We observed consistency between self-reported time-location patterns from repeated administration of the time-location questionnaire and compared with other survey instruments. Comparisons to national cohorts demonstrated differences in time-location patterns in the MESA Air cohort due to differences in demographics, but the data showed similar trends in patterns by age, gender, season, and employment status. This study was the first to explicitly examine time-location patterns in an older, multi-ethnic population and the first to add data on Chinese participants. These data can be used to inform future epidemiological research of MESA Air and other studies that include diverse populations.
PMCID: PMC4641054  PMID: 25921083
epidemiology; personal exposure; population based studies
3.  Development of Long-term Spatiotemporal Models for Ambient Ozone in Six Metropolitan regions of the United States: The MESA Air Study 
Current epidemiologic studies rely on simple ozone metrics which may not appropriately capture population ozone exposure. For understanding health effects of long-term ozone exposure in population studies, it is advantageous for exposure estimation to incorporate the complex spatiotemporal pattern of ozone concentrations at fine scales.
To develop a geo-statistical exposure prediction model that predicts fine scale spatiotemporal variations of ambient ozone in six United States metropolitan regions.
We developed a modeling framework that estimates temporal trends from regulatory agency and cohort-specific monitoring data from MESA Air measurement campaigns and incorporates land use regression with universal kriging using predictor variables from a large geographic database. The cohort-specific data were measured at home and community locations. The framework was applied in estimating two-week average ozone concentrations from 1999 to 2013 in models of each of the six MESA Air metropolitan regions.
Ozone models perform well in both spatial and temporal dimensions at the agency monitoring sites in terms of prediction accuracy. City-specific leave-one (site)-out cross-validation R2 accounting for temporal and spatial variability ranged from 0.65 to 0.88 in the six regions. For predictions at the home sites, the R2 is between 0.60 and 0.91 for cross-validation that left out 10% of home sites in turn. The predicted ozone concentrations vary substantially over space and time in all the metropolitan regions.
Using the available data, our spatiotemporal models are able to accurately predict long-term ozone concentrations at fine spatial scales in multiple regions. The model predictions will allow for investigation of the long-term health effects of ambient ozone concentrations in future epidemiological studies.
PMCID: PMC5021184  PMID: 27642250
Ozone; spatio-temporal; geo-statistical model; multi-city; MESA Air
4.  Long-term outdoor air pollution and DNA methylation in circulating monocytes: results from the Multi-Ethnic Study of Atherosclerosis (MESA) 
Environmental Health  2016;15:119.
DNA methylation may mediate effects of air pollution on cardiovascular disease. The association between long-term air pollution exposure and DNA methylation in monocytes, which are central to atherosclerosis, has not been studied. We investigated the association between long-term ambient air pollution exposure and DNA methylation (candidate sites and global) in monocytes of adults (aged ≥55).
One-year average ambient fine particulate matter (PM2.5) and oxides of nitrogen (NOX) concentrations were predicted at participants’ (n = 1,207) addresses using spatiotemporal models. We assessed DNA methylation in circulating monocytes at 1) 2,713 CpG sites associated with mRNA expression of nearby genes and 2) probes mapping to Alu and LINE-1 repetitive elements (surrogates for global DNA methylation) using Illumina’s Infinium HumanMethylation450 BeadChip. We used linear regression models adjusted for demographics, smoking, physical activity, socioeconomic status, methyl-nutrients, and technical variables. For significant air pollution-associated methylation sites, we also assessed the association between expression of gene transcripts previously associated with these CpG sites and air pollution.
At a false discovery rate of 0.05, five candidate CpGs (cg20455854, cg07855639, cg07598385, cg17360854, and cg23599683) had methylation significantly associated with PM2.5 and none were associated with NOX. Cg20455854 had the smallest p-value for the association with PM2.5 (p = 2.77 × 10−5). mRNA expression profiles of genes near three of the PM2.5-associated CpGs (ANKHD1, LGALS2, and ANKRD11) were also significantly associated with PM2.5 exposure. Alu and LINE-1 methylation were not associated with long-term air pollution exposure.
We observed novel associations between long-term ambient air pollution exposure and site-specific DNA methylation, but not global DNA methylation, in purified monocytes of a multi-ethnic adult population. Epigenetic markers may provide insights into mechanisms underlying environmental factors in complex diseases like atherosclerosis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12940-016-0202-4) contains supplementary material, which is available to authorized users.
PMCID: PMC5131503  PMID: 27903268
Air pollution; PM2.5; NOX; ANKHD1; LGALS2; ANKRD11; BAZ2B; PPIE; DNA methylation
5.  Individual and Neighborhood Socioeconomic Status and the Association between Air Pollution and Cardiovascular Disease 
Environmental Health Perspectives  2016;124(12):1840-1847.
Long-term fine particulate matter (PM2.5) exposure is linked with cardiovascular disease, and disadvantaged status may increase susceptibility to air pollution-related health effects. In addition, there are concerns that this association may be partially explained by confounding by socioeconomic status (SES).
We examined the roles that individual- and neighborhood-level SES (NSES) play in the association between PM2.5 exposure and cardiovascular disease.
The study population comprised 51,754 postmenopausal women from the Women’s Health Initiative Observational Study. PM2.5 concentrations were predicted at participant residences using fine-scale regionalized universal kriging models. We assessed individual-level SES and NSES (Census-tract level) across several SES domains including education, occupation, and income/wealth, as well as through an NSES score, which captures several important dimensions of SES. Cox proportional-hazards regression adjusted for SES factors and other covariates to determine the risk of a first cardiovascular event.
A 5 μg/m3 higher exposure to PM2.5 was associated with a 13% increased risk of cardiovascular event [hazard ratio (HR) 1.13; 95% confidence interval (CI): 1.02, 1.26]. Adjustment for SES factors did not meaningfully affect the risk estimate. Higher risk estimates were observed among participants living in low-SES neighborhoods. The most and least disadvantaged quartiles of the NSES score had HRs of 1.39 (95% CI: 1.21, 1.61) and 0.90 (95% CI: 0.72, 1.07), respectively.
Women with lower NSES may be more susceptible to air pollution-related health effects. The association between air pollution and cardiovascular disease was not explained by confounding from individual-level SES or NSES.
Chi GC, Hajat A, Bird CE, Cullen MR, Griffin BA, Miller KA, Shih RA, Stefanick ML, Vedal S, Whitsel EA, Kaufman JD. 2016. Individual and neighborhood socioeconomic status and the association between air pollution and cardiovascular disease. Environ Health Perspect 124:1840–1847;
PMCID: PMC5132637  PMID: 27138533
6.  Neighborhood-Scale Spatial Models of Diesel Exhaust Concentration Profile Using 1-Nitropyrene and Other Nitroarenes 
Environmental science & technology  2015;49(22):13422-13430.
With emerging evidence that diesel exhaust exposure poses distinct risks to human health, the need for fine-scale models of diesel exhaust pollutants is growing. We modeled the spatial distribution of several nitrated polycyclic aromatic hydrocarbons (NPAHs) to identify fine-scale gradients in diesel exhaust pollution in two Seattle, WA neighborhoods. Our modeling approach fused land-use regression, meteorological dispersion modeling, and pollutant monitoring from both fixed and mobile platforms. We applied these modeling techniques to concentrations of 1-nitropyrene (1-NP), a highly specific diesel exhaust marker, at the neighborhood scale. We developed models of two additional nitroarenes present in secondary organic aerosol: 2-nitro-pyrene and 2-nitrofluoranthene. Summer predictors of 1-NP, including distance to railroad, truck emissions, and mobile black carbon measurements, showed a greater specificity to diesel sources than predictors of other NPAHs. Winter sampling results did not yield stable models, likely due to regional mixing of pollutants in turbulent weather conditions. The model of summer 1-NP had an R2 of 0.87 and cross-validated R2 of 0.73. The synthesis of high-density sampling and hybrid modeling was successful in predicting diesel exhaust pollution at a very fine scale and identifying clear gradients in NPAH concentrations within urban neighborhoods.
PMCID: PMC5026850  PMID: 26501773
7.  Prediction of fine particulate matter chemical components with a spatio-temporal model for the Multi-Ethnic Study of Atherosclerosis cohort 
Although cohort studies of the health effects of PM2.5 have developed exposure prediction models to represent spatial variability across participant residences, few models exist for PM2.5 components. We aimed to develop a city-specific spatio-temporal prediction approach to estimate long-term average concentrations of four PM2.5 components including sulfur, silicon, and elemental and organic carbon for the Multi-Ethnic Study of Atherosclerosis cohort, and to compare predictions to those from a national spatial model. Using 2-week average measurements from a cohort-focused monitoring campaign, the spatio-temporal model employed selected geographic covariates in a universal kriging framework with the data-driven temporal trend. Relying on long-term means of daily measurements from regulatory monitoring networks, the national spatial model employed dimension-reduced predictors using universal kriging. For the spatio-temporal model, the cross-validated and temporally-adjusted R2 was relatively higher for EC and OC, and in the Los Angeles and Baltimore areas. The cross-validated R2s for both models across the six areas were reasonably high for all components except silicon. Predicted long-term concentrations at participant homes from the two models were generally highly correlated across cities but poorly correlated within cities. The spatio-temporal model may be preferred for city-specific health analyses, whereas both models could be used for multi-city studies.
PMCID: PMC5104659  PMID: 27189258
empirical/statistical models; epidemiology; exposure modeling; particulate matter
8.  Job strain, occupational category, and hypertension prevalence: The Multi-Ethnic Study of Atherosclerosis 
To assess associations of occupational categories and job characteristics with prevalent hypertension.
We analyzed 2,517 Multi-Ethnic Study of Atherosclerosis (MESA) participants, working 20+ hours per week, in 2002–4.
Higher job decision latitude was associated with a lower prevalence of hypertension, prevalence ratio (PR)=0.78 (95% CI 0.66–0.91) for the top vs. bottom quartile of job decision latitude. However, associations differed by occupation: decision latitude was associated with a higher prevalence of hypertension in healthcare support occupations (interaction p=.02). Occupation modified associations of gender with hypertension: a higher prevalence of hypertension in women (vs men) was observed in healthcare support and in blue-collar occupations (interaction p=.03).
Lower job decision latitude is associated with hypertension prevalence in many occupations. Further research is needed to determine reasons for differential impact of decision latitude and gender on hypertension across occupations.
PMCID: PMC4636023  PMID: 26539765
job strain; occupation; blood pressure; hypertension
9.  Ambient Air Pollution Exposures and Risk of Parkinson Disease 
Environmental Health Perspectives  2016;124(11):1759-1765.
Few epidemiologic studies have evaluated the effects of air pollution on the risk of Parkinson disease (PD).
We investigated the associations of long-term residential concentrations of ambient particulate matter (PM) < 10 μm in diameter (PM10) and < 2.5 μm in diameter (PM2.5) and nitrogen dioxide (NO2) in relation to PD risk.
Our nested case–control analysis included 1,556 self-reported physician-diagnosed PD cases identified between 1995 and 2006 and 3,313 controls frequency-matched on age, sex, and race. We geocoded home addresses reported in 1995–1996 and estimated the average ambient concentrations of PM10, PM2.5, and NO2 using a national fine-scale geostatistical model incorporating roadway information and other geographic covariates. Air pollutant exposures were analyzed as both quintiles and continuous variables, adjusting for matching variables and potential confounders.
We observed no statistically significant overall association between PM or NO2 exposures and PD risk. However, in preplanned subgroup analyses, a higher risk of PD was associated with higher exposure to PM10 (ORQ5 vs. Q1 = 1.65; 95% CI: 1.11, 2.45; p-trend = 0.02) among women, and with higher exposure to PM2.5 (ORQ5 vs. Q1 = 1.29; 95% CI: 0.94, 1.76; p-trend = 0.04) among never smokers. In post hoc analyses among female never smokers, both PM2.5 (ORQ5 vs. Q1 = 1.79; 95% CI: 1.01, 3.17; p-trend = 0.05) and PM10 (ORQ5 vs. Q1 = 2.34; 95% CI: 1.29, 4.26; p-trend = 0.01) showed positive associations with PD risk. Analyses based on continuous exposure variables generally showed similar but nonsignificant associations.
Overall, we found limited evidence for an association between exposures to ambient PM10, PM2.5, or NO2 and PD risk. The suggestive evidence that exposures to PM2.5 and PM10 may increase PD risk among female never smokers warrants further investigation.
Liu R, Young MT, Chen JC, Kaufman JD, Chen H. 2016. Ambient air pollution exposures and risk of Parkinson disease. Environ Health Perspect 124:1759–1765;
PMCID: PMC5089873  PMID: 27285422
10.  Variant Discovery and Fine Mapping of Genetic Loci Associated with Blood Pressure Traits in Hispanics and African Americans 
PLoS ONE  2016;11(10):e0164132.
Despite the substantial burden of hypertension in US minority populations, few genetic studies of blood pressure have been conducted in Hispanics and African Americans, and it is unclear whether many of the established loci identified in European-descent populations contribute to blood pressure variation in non-European descent populations. Using the Metabochip array, we sought to characterize the genetic architecture of previously identified blood pressure loci, and identify novel cardiometabolic variants related to systolic and diastolic blood pressure in a multi-ethnic US population including Hispanics (n = 19,706) and African Americans (n = 18,744). Several known blood pressure loci replicated in African Americans and Hispanics. Fourteen variants in three loci (KCNK3, FGF5, ATXN2-SH2B3) were significantly associated with blood pressure in Hispanics. The most significant diastolic blood pressure variant identified in our analysis, rs2586886/KCNK3 (P = 5.2 x 10−9), also replicated in independent Hispanic and European-descent samples. African American and trans-ethnic meta-analysis data identified novel variants in the FGF5, ULK4 and HOXA-EVX1 loci, which have not been previously associated with blood pressure traits. Our identification and independent replication of variants in KCNK3, a gene implicated in primary hyperaldosteronism, as well as a variant in HOTTIP (HOXA-EVX1) suggest that further work to clarify the roles of these genes may be warranted. Overall, our findings suggest that loci identified in European descent populations also contribute to blood pressure variation in diverse populations including Hispanics and African Americans—populations that are understudied for hypertension genetic risk factors.
PMCID: PMC5063457  PMID: 27736895
11.  DNA Methylation of the Aryl Hydrocarbon Receptor Repressor Associations with Cigarette Smoking and Subclinical Atherosclerosis 
Tobacco smoke contains numerous agonists of the aryl-hydrocarbon receptor (AhR) pathway, and activation of the AhR pathway was shown to promote atherosclerosis in mice. Intriguingly, cigarette smoking is most strongly and robustly associated with DNA modifications to an AhR pathway gene, the aryl-hydrocarbon receptor repressor (AHRR). We hypothesized that altered AHRR methylation in monocytes, a cell type sensitive to cigarette smoking and involved in atherogenesis, may be a part of the biological link between cigarette smoking and atherosclerosis.
Methods and Results
DNA methylation profiles of AHRR in monocytes (542 CpG sites ± 150kb of AHRR, using Illumina 450K array) were integrated with smoking habits and ultrasound-measured carotid plaque scores from 1,256 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Methylation of cg05575921 significantly associated (p = 6.1×10−134) with smoking status (current vs. never). Novel associations between cg05575921 methylation and carotid plaque scores (p = 3.1×10−10) were identified, which remained significant in current and former smokers even after adjusting for self-reported smoking habits, urinary cotinine, and well-known CVD risk factors. This association replicated in an independent cohort using hepatic DNA (n = 141). Functionally, cg05575921 was located in a predicted gene expression regulatory element (enhancer), and had methylation correlated with AHRR mRNA profiles (p = 1.4×10−17) obtained from RNA sequencing conducted on a subset (n = 373) of the samples.
These findings suggest AHRR methylation may be functionally related to AHRR expression in monocytes, and represents a potential biomarker of subclinical atherosclerosis in smokers.
PMCID: PMC4618776  PMID: 26307030
smoking; atherosclerosis; gene expression/regulation; epidemiology; epigenetics; DNA methylation
12.  Chemical characterization and in vitro toxicity of diesel exhaust particulate matter generated under varying conditions 
Epidemiologic studies have linked diesel exhaust (DE) to cardiovascular and respiratory morbidity and mortality, as well as lung cancer. DE composition is known to vary with many factors, although it is unclear how this influences toxicity. We generated eight DE atmospheres by applying a 2×2×2 factorial design and altering three parameters in a controlled exposure facility: (1) engine load (27 vs 82 %), (2) particle aging (residence time ~5 s vs ~5 min prior to particle collection), and (3) oxidation (with or without ozonation during dilution). Selected exposure concentrations of both diesel exhaust particles (DEPs) and DE gases, DEP oxidative reactivity via DTT activity, and in vitro DEP toxicity in murine endothelial cells were measured for each DE atmosphere. Cell toxicity was assessed via measurement of cell proliferation (colony formation assay), cell viability (MTT assay), and wound healing (scratch assay). Differences in DE composition were observed as a function of engine load. The mean 1-nitropyrene concentration was 15 times higher and oxidative reactivity was two times higher for low engine load versus high load. There were no substantial differences in measured toxicity among the three DE exposure parameters. These results indicate that alteration of applied engine load shifts the composition and can modify the biological reactivity of DE. While engine conditions did not affect the selected in vitro toxicity measures, the change in oxidative reactivity suggests that toxicological studies with DE need to take into account engine conditions in characterizing biological effects.
PMCID: PMC4628827  PMID: 26539254
Air pollution; Diesel exhaust; Varying exposure conditions; Physicochemical properties; In vitro toxicity
13.  Objectively measured sleep characteristics and prevalence of coronary artery calcification: The Multi-Ethnic Study of Atherosclerosis Sleep Study 
Thorax  2015;70(9):880-887.
We tested whether objectively measured indices of obstructive sleep apnea (OSA) and sleep quality are associated with coronary artery calcification (CAC) prevalence independent of obesity, a classic confounder.
A total of 1,465 Multi-Ethnic Study of Atherosclerosis participants [mean age 68 years], who were free of clinical cardiovascular disease, had both coronary CT and in-home polysomnography and actigraphy. OSA categories were defined by apnea-hypopnea index (AHI). Prevalence ratios for CAC >0 and >400 (high burden) were calculated.
Participants with severe OSA (AHI ≥ 30; 14.6%) were more likely to have prevalent CAC, relative to those with no evidence of OSA, after adjustment for demographics and smoking status [1.16 (95% CI: 1.06–1.26)], body mass index [1.11 (1.02–1.21)], and traditional cardiovascular risk factors [1.10 (1.01–1.19)]. Other markers of hypoxemia tended to be associated with higher prevalence of CAC >0. For CAC >400 a higher prevalence was observed with both a higher arousal index and less slow-wave sleep. Overall, associations were somewhat stronger among younger participants, but did not vary by sex or race/ethnicity.
In this population-based multiethnic sample severe OSA was associated with subclinical coronary artery disease (CAC >0), independent of obesity and traditional cardiovascular risk factors. Furthermore, the associations of the arousal index and slow wave sleep with high CAC burden suggest that higher nightly sympathetic nervous system activation is also a risk factor. These findings highlight the potential importance in measuring disturbances in OSA as well as in sleep fragmentation as possible risk factors for coronary artery disease.
PMCID: PMC4858321  PMID: 26156526
sleep apnea; coronary artery calcification; Multi-Ethnic Study of Atherosclerosis (MESA)
14.  Breast Cancer Risk in Relation to Ambient Air Pollution Exposure at Residences in the Sister Study Cohort 
Some but not all past studies reported associations between components of air pollution and breast cancer, namely fine particulate matter ≤ 2.5 μm (PM2.5) and nitrogen dioxide (NO2). It is yet unclear whether risks differ according to estrogen receptor (ER) and progesterone receptor (PR) status.
This analysis includes 47,591 women from the Sister Study cohort enrolled from August 2003-July 2009, in whom 1,749 invasive breast cancer cases arose from enrollment to January 2013. Using Cox proportional hazards and polytomous logistic regression, we estimated breast cancer risk associated with residential exposure to NO2, PM2.5, and PM10.
While breast cancer risk overall was not associated with PM2.5 (Hazards ratio [HR] = 1.03; 95% CI: 0.96–1.11), PM10 (HR = 0.99; 95% CI: 0.98–1.00), or NO2 (HR = 1.02; 95% CI: 0.97–1.07), the association with NO2 differed according to ER/PR subtype (p = 0.04). For an interquartile range (IQR) difference of 5.8 parts per billion (ppb) in NO2, the relative risk (RR) of ER+/PR+ breast cancer was 1.10 (95% CI: 1.02–1.19), while there was no evidence of association with ER−/PR− (RR=0.92; 95% CI: 0.77–1.09; pinteraction=0.04).
Within the Sister Study cohort, we found no significant associations between air pollution and breast cancer risk overall. But we observed an increased risk of ER+/PR+ breast cancer associated with NO2.
Though these results suggest there is no substantial increased risk for breast cancer overall in relation to air pollution, NO2, a marker of traffic related air pollution, may differentially affect ER+/PR+ breast cancer.
PMCID: PMC4686338  PMID: 26464427
Air pollution; Breast cancer risk; Particulate matter; Nitrogen dioxide; Cancer survival
15.  Does air pollution accelerate progression of atherosclerosis? 
PMCID: PMC4683016  PMID: 21087708
subclinical atherosclerosis; carotid intima-media thickness; air pollution; particulate matter; traffic
16.  Particulate Matter Exposure and Cardiopulmonary Differences in the Multi-Ethnic Study of Atherosclerosis 
Environmental Health Perspectives  2016;124(8):1166-1173.
Particulate matter (PM) exposure may directly affect the pulmonary vasculature. Although the pulmonary vasculature is not easily measurable, differential associations for right ventricular (RV) and left ventricular (LV) mass may provide an indirect assessment of pulmonary vascular damage.
We tested whether long-term exposure to PM < 2.5 μm (PM2.5) is associated with greater RV mass and RV mass/end-diastolic volume ratio relative to the LV.
The Multi-Ethnic Study of Atherosclerosis performed cardiac magnetic resonance (CMR) imaging among participants 45–84 years old without clinical cardiovascular disease in 2000–2002 in six U.S. cities. A fine-scale spatiotemporal model estimated ambient PM2.5 exposure in the year before CMR; individually weighted estimates accounted for indoor exposure to ambient PM2.5. Linear regression models were adjusted for demographics, anthropometrics, smoking status, cardiac risk factors, and LV parameters, with additional adjustment for city.
The 4,041 included participants had a mean age of 61.5 years, and 47% were never smokers. The mean ambient PM2.5 was 16.4 μg/m3 and individually weighted PM2.5 was 11.0 μg/m3. PM2.5 exposure was associated with greater RV mass [ambient: 0.11 g per 5 μg/m3 (95% CI: –0.05, 0.27); individually weighted: 0.20 g per 5 μg/m3 (95% CI: 0.04, 0.36)] and a greater RV mass/end-diastolic volume ratio conditional on LV parameters. City-adjusted results for RV mass were of greater magnitude and were statistically significant for both measures of PM2.5, whereas those for RV mass/end-diastolic volume ratio were attenuated.
Long-term PM2.5 exposures were associated with greater RV mass and RV mass/end-diastolic volume ratio conditional on the LV; however, additional adjustment for city attenuated the RV mass/end-diastolic volume findings. These findings suggest that PM2.5 exposure may be associated with subclinical cardiopulmonary differences in this general population sample.
Aaron CP, Chervona Y, Kawut SM, Diez Roux AV, Shen M, Bluemke DA, Van Hee VC, Kaufman JD, Barr RG. 2016. Particulate matter exposure and cardiopulmonary differences in the Multi-Ethnic Study of Atherosclerosis. Environ Health Perspect 124:1166–1173;
PMCID: PMC4977039  PMID: 26859533
17.  Distribution and Burden of Newly Detected Coronary Artery Calcium (CAC): Results from the Multi-Ethnic Study of Atherosclerosis (MESA) 
The transition from no coronary artery calcium (CAC) to detectable CAC is important, as even mild CAC is associated with increased cardiovascular events. We sought to characterize the anatomical distribution and burden of newly detectable CAC over 10-years follow-up.
We evaluated 3112 participants (mean age 58, 64% female) with baseline CAC=0 from the Multi-Ethnic Study of Atherosclerosis (MESA). Participants underwent repeat CAC testing at different time intervals (between 2–10 years after baseline) per MESA protocol. Among participants who developed CAC on a follow-up scan, we used logistic regression and marginal probability modeling to describe the coronary distribution and burden of new CAC by age, gender, and race/ethnicity after adjustment for cardiovascular risk factors and time-to-detection.
A total of 1125 participants developed detectable CAC during follow-up with mean time-to-detection of 6.1 ± 3 years. New CAC was most commonly isolated to one vessel (72% of participants), with the left anterior descending (44% of total) most commonly affected followed by the right coronary (12%), left circumflex (10%) and left main (6%). These patterns were similar across age, gender, and race/ethnicity. In multivariable models, residual predictors of multi-vessel CAC (28% of total) included male gender, African-American or Hispanic race/ethnicity, hypertension, obesity, and diabetes. At the first detection of CAC>0, burden was usually low with median Agatston CAC score of 7.1, and <5% with CAC scores >100.
New onset CAC most commonly involves just one vessel, occurs in the left anterior descending artery, has low CAC burden. New CAC can be detected at an early stage when aggressive preventive strategies may provide benefit.
PMCID: PMC4476056  PMID: 26088381
Coronary artery calcium; Left anterior descending artery; Right coronary artery; Left main artery; Left circumflex artery
18.  Exposure to Traffic-Related Air Pollution in Relation to Progression in Physical Disability among Older Adults 
Environmental Health Perspectives  2016;124(7):1000-1008.
Physical disability is common though not inevitable in older age and has direct bearing on a person’s ability to perform activities essential for self-care and independent living. Air pollution appears to increase the risk of several chronic diseases that contribute to the progression of disability.
We evaluated long-term exposure to traffic-related air pollution (TRAP) in relation to progression in physical disability.
We conducted our investigation within the Chicago Health and Aging Project. We measured participants’ exposures to TRAP using two surrogates: residential proximity to major roads (1993 onwards) and ambient concentrations of oxides of nitrogen (NOX; 1999 onwards), predicted via a geographic information systems-based spatiotemporal smoothing model (cross-validation R2 = 0.87) that incorporated community-based monitoring and resolved intraurban exposure gradients at a spatial scale of tens of meters. Participants’ lower-extremity physical ability was assessed every 3 years (1993–2012) via tandem stand, chair stand, and timed walking speed.
In multivariable-adjusted analyses (n = 5,708), higher long-term NOX exposure was associated with significantly faster progression in disability. Compared with the 5-year decline in physical ability score among participants in the lowest quartile of NOX exposure, decline among those in the highest exposure quartile was 1.14 units greater (95% confidence interval [CI]: –1.86, –0.42), equivalent to 3 additional years of decline among those in the lowest exposure quartile. The association was linear across the continuum of NOX exposure: per 10-ppb increment in exposure, the 5-year decline in physical ability score was 0.87 unit greater (95% CI: –1.35, –0.39). Proximity to a major road was not associated with disability progression (n = 9,994).
These data join a growing body of evidence suggesting that TRAP exposures may accelerate aging-related declines in health.
Weuve J, Kaufman JD, Szpiro AA, Curl C, Puett RC, Beck T, Evans DA, Mendes de Leon CF. 2016. Exposure to traffic-related air pollution in relation to progression in physical disability among older adults. Environ Health Perspect 124:1000–1008;
PMCID: PMC4937863  PMID: 27022889
19.  Risk Factors for Long-Term Coronary Artery Calcium Progression in the Multi-Ethnic Study of Atherosclerosis 
Coronary artery calcium (CAC) detected by noncontrast cardiac computed tomography scanning is a measure of coronary atherosclerosis burden. Increasing CAC levels have been strongly associated with increased coronary events. Prior studies of cardiovascular disease risk factors and CAC progression have been limited by short follow-up or restricted to patients with advanced disease.
Methods and Results
We examined cardiovascular disease risk factors and CAC progression in a prospective multiethnic cohort study. CAC was measured 1 to 4 times (mean 2.5 scans) over 10 years in 6810 adults without preexisting cardiovascular disease. Mean CAC progression was 23.9 Agatston units/year. An innovative application of mixed-effects models investigated associations between cardiovascular disease risk factors and CAC progression. This approach adjusted for time-varying factors, was flexible with respect to follow-up time and number of observations per participant, and allowed simultaneous control of factors associated with both baseline CAC and CAC progression. Models included age, sex, study site, scanner type, and race/ethnicity. Associations were observed between CAC progression and age (14.2 Agatston units/year per 10 years [95% CI 13.0 to 15.5]), male sex (17.8 Agatston units/year [95% CI 15.3 to 20.3]), hypertension (13.8 Agatston units/year [95% CI 11.2 to 16.5]), diabetes (31.3 Agatston units/year [95% CI 27.4 to 35.3]), and other factors.
CAC progression analyzed over 10 years of follow-up, with a novel analytical approach, demonstrated strong relationships with risk factors for incident cardiovascular events. Longitudinal CAC progression analyzed in this framework can be used to evaluate novel cardiovascular risk factors.
PMCID: PMC4599452  PMID: 26251281
atherosclerosis; calcium; risk factors
22.  Adopting Clean Fuels and Technologies on School Buses. Pollution and Health Impacts in Children 
Rationale: More than 25 million American children breathe polluted air on diesel school buses. Emission reduction policies exist, but the health impacts to individual children have not been evaluated.
Methods: Using a natural experiment, we characterized the exposures and health of 275 school bus riders before, during, and after the adoption of clean technologies and fuels between 2005 and 2009. Air pollution was measured during 597 trips on 188 school buses. Repeated measures of exhaled nitric oxide (FeNO), lung function (FEV1, FVC), and absenteeism were also collected monthly (1,768 visits). Mixed-effects models longitudinally related the adoption of diesel oxidation catalysts (DOCs), closed crankcase ventilation systems (CCVs), ultralow-sulfur diesel (ULSD), or biodiesel with exposures and health.
Measurements and Main Results: Fine and ultrafine particle concentrations were 10–50% lower on buses using ULSD, DOCs, and/or CCVs. ULSD adoption was also associated with reduced FeNO (−16% [95% confidence interval (CI), −21 to −10%]), greater changes in FVC and FEV1 (0.02 [95% CI, 0.003 to 0.05] and 0.01 [95% CI, −0.006 to 0.03] L/yr, respectively), and lower absenteeism (−8% [95% CI, −16.0 to −0.7%]), with stronger associations among patients with asthma. DOCs, and to a lesser extent CCVs, also were associated with improved FeNO, FVC growth, and absenteeism, but these findings were primarily restricted to patients with persistent asthma and were often sensitive to control for ULSD. No health benefits were noted for biodiesel. Extrapolating to the U.S. population, changed fuel/technologies likely reduced absenteeism by more than 14 million/yr.
Conclusions: National and local diesel policies appear to have reduced children’s exposures and improved health.
PMCID: PMC4476560  PMID: 25867003
particulate matter; air pollution; asthma; absenteeism; lung function
23.  Asthma Predicts Cardiovascular Disease Events: The Multi-Ethnic Study of Atherosclerosis 
To identify and characterize an association between persistent asthma and cardiovascular disease (CVD) risk in the Multi-Ethnic Study of Atherosclerosis (MESA).
Approach and Results
MESA is a longitudinal prospective study of an ethnically diverse cohort of individuals free of known CVD at its inception. Presence and severity of asthma were assessed in the MESA at Exam 1. Persistent asthma was defined as asthmatics using controller medications (inhaled corticosteroids, leukotriene inhibitors, oral corticosteroids) and intermittent asthma as asthmatics not using controller medications. Participants were followed for a mean (standard deviation) 9.1 (2.8) years for development of incident CVD (coronary death, myocardial infarction, angina, stroke, and CVD death). Multivariable Cox regression models were used to assess associations of asthma and CVD.
The 6,792 participants were 62.2 (standard deviation 10.2) years old: 47% male (28% African-American, 22% Hispanic, 12% Chinese). Persistent asthmatics (N=156), compared to intermittent (N=511) and non-asthmatics (N=6125), respectively had higher C-reactive protein (1.2 [1.2] vs 0.9 [1.2] vs 0.6 [1.2] mg/L) and fibrinogen (379 [88] vs 356 [80] vs 345 [73] mg/dL) levels. Persistent asthmatics had the lowest unadjusted CVD-free survival rate of 84.1%, 95% confidence interval (78.9–90.3%) compared with intermittent asthmatics 91.1% (88.5–93.8%) and non-asthmatics 90.2% (89.4–91%). Persistent asthmatics had greater risk of CVD events than non-asthmatics (HR 1.6 [95% 1.01–2.5, p=0.040]), even after adjustment for age, sex, race, CVD risk factors, and anti-hypertensive and lipid medication use.
In this large multi-ethnic cohort, persistent asthmatics had a higher CVD event rate than non-asthmatics.
PMCID: PMC4441553  PMID: 25908767
Atherosclerosis; Asthma; Epidemiology; Risk Factors
24.  Long-term Exposure to Air Pollution and Markers of Inflammation, Coagulation, and Endothelial Activation 
Epidemiology (Cambridge, Mass.)  2015;26(3):310-320.
Air pollution is associated with cardiovascular disease, and systemic inflammation may mediate this effect. We assessed associations between long- and short-term concentrations of air pollution and markers of inflammation, coagulation, and endothelial activation.
We studied participants from the Multi-Ethnic Study of Atherosclerosis from 2000 to 2012 with repeat measures of serum C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen, D-dimer, soluble E-selectin, and soluble Intercellular Adhesion Molecule-1. Annual average concentrations of ambient fine particulate matter (PM2.5), individual-level ambient PM2.5 (integrating indoor concentrations and time–location data), oxides of nitrogen (NOx), nitrogen dioxide (NO2), and black carbon were evaluated. Short-term concentrations of PM2.5 reflected the day of blood draw, day prior, and averages of prior 2-, 3-, 4-, and 5-day periods. Random-effects models were used for long-term exposures and fixed effects for short-term exposures. The sample size was between 9,000 and 10,000 observations for CRP, IL-6, fibrinogen, and D-dimer; approximately 2,100 for E-selectin; and 3,300 for soluble Intercellular Adhesion Molecule-1.
After controlling for confounders, 5 µg/m3 increase in long-term ambient PM2.5 was associated with 6% higher IL-6 (95% confidence interval = 2%, 9%), and 40 parts per billion increase in long-term NOx was associated with 7% (95% confidence interval = 2%, 13%) higher level of D-dimer. PM2.5 measured at day of blood draw was associated with CRP, fibrinogen, and E-selectin. There were no other positive associations between blood markers and short- or long-term air pollution.
These data are consistent with the hypothesis that long-term exposure to air pollution is related to some markers of inflammation and fibrinolysis.
PMCID: PMC4455899  PMID: 25710246
25.  Metal mixtures in urban and rural populations in the US: The Multi-Ethnic Study of Atherosclerosis and the Strong Heart Study☆ 
Environmental research  2016;147:356-364.
Natural and anthropogenic sources of metal exposure differ for urban and rural residents. We searched to identify patterns of metal mixtures which could suggest common environmental sources and/or metabolic pathways of different urinary metals, and compared metal-mixtures in two population-based studies from urban/sub-urban and rural/town areas in the US: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Strong Heart Study (SHS).
We studied a random sample of 308 White, Black, Chinese-American, and Hispanic participants in MESA (2000–2002) and 277 American Indian participants in SHS (1998–2003). We used principal component analysis (PCA), cluster analysis (CA), and linear discriminant analysis (LDA) to evaluate nine urinary metals (antimony [Sb], arsenic [As], cadmium [Cd], lead [Pb], molybdenum [Mo], selenium [Se], tungsten [W], uranium [U] and zinc [Zn]). For arsenic, we used the sum of inorganic and methylated species (∑As).
All nine urinary metals were higher in SHS compared to MESA participants. PCA and CA revealed the same patterns in SHS, suggesting 4 distinct principal components (PC) or clusters (∑As-U-W, Pb-Sb, Cd-Zn, Mo-Se). In MESA, CA showed 2 large clusters (∑As-Mo-Sb-U-W, Cd-Pb-Se-Zn), while PCA showed 4 PCs (Sb-U-W, Pb-Se-Zn, Cd-Mo, ∑As). LDA indicated that ∑As, U, W, and Zn were the most discriminant variables distinguishing MESA and SHS participants.
In SHS, the ∑As-U-W cluster and PC might reflect groundwater contamination in rural areas, and the Cd-Zn cluster and PC could reflect common sources from meat products or metabolic interactions. Among the metals assayed, ∑As, U, W and Zn differed the most between MESA and SHS, possibly reflecting disproportionate exposure from drinking water and perhaps food in rural Native communities compared to urban communities around the US.
PMCID: PMC4827253  PMID: 26945432
Metals; Urine; Biomarker; Statistical methods; Exposure sources

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