Adam A. Szpiro

Association between air pollution and coronary artery calcification within six metropolitan areas in the USA (the Multi-Ethnic Study of Atherosclerosis and Air Pollution): a longitudinal cohort study

BACKGROUND Long-term exposure to fine particulate matter less than 2.5 μm in diameter (PM2.5) and traffic-related air pollutant concentrations are associated with cardiovascular risk. The disease process underlying these associations remains uncertain. We aim to assess association between long-term exposure to ambient air pollution and progression of coronary artery calcium and common carotid artery intima-media thickness. METHODS In this prospective 10-year cohort study, we repeatedly measured coronary artery calcium by CT in 6795 participants aged 45-84 years enrolled in the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) in six metropolitan areas in the USA. Repeated scans were done for nearly all participants between 2002 and 2005, for a subset of participants between 2005 and 2007, and for half of all participants between 2010 and 2012. Common carotid artery intima-media thickness was measured by ultrasound in all participants at baseline and in 2010-12 for 3459 participants. Residence-specific spatio-temporal pollution concentration models, incorporating community-specific measurements, agency monitoring data, and geographical predictors, estimated concentrations of PM2.5 and nitrogen oxides (NOX) between 1999 and 2012. The primary aim was to examine the association between both progression of coronary artery calcium and mean carotid artery intima-media thickness and long-term exposure to ambient air pollutant concentrations (PM2.5, NOX, and black carbon) between examinations and within the six metropolitan areas, adjusting for baseline age, sex, ethnicity, socioeconomic characteristics, cardiovascular risk factors, site, and CT scanner technology. FINDINGS In this population, coronary calcium increased on average by 24 Agatston units per year (SD 58), and intima-media thickness by 12 μm per year (10), before adjusting for risk factors or air pollutant exposures. Participant-specific pollutant concentrations averaged over the years 2000-10 ranged from 9.2-22.6 μg PM2.5/m(3) and 7.2-139.2 parts per billion (ppb) NOX. For each 5 μg PM2.5/m(3) increase, coronary calcium progressed by 4.1 Agatston units per year (95% CI 1.4-6.8) and for each 40 ppb NOX coronary calcium progressed by 4.8 Agatston units per year (0.9-8.7). Pollutant exposures were not associated with intima-media thickness change. The estimate for the effect of a 5 μg/m(3) higher long-term exposure to PM2.5 in intima-media thickness was -0.9 μm per year (95% CI -3.0 to 1.3). For 40 ppb higher NOX, the estimate was 0.2 μm per year (-1.9 to 2.4). INTERPRETATION Increased concentrations of PM2.5 and traffic-related air pollution within metropolitan areas, in ranges commonly encountered worldwide, are associated with progression in coronary calcification, consistent with acceleration of atherosclerosis. This study supports the case for global efforts of pollution reduction in prevention of cardiovascular diseases. FUNDING US Environmental Protection Agency and US National Institutes of Health.

Confounding and exposure measurement error in air pollution epidemiology

Studies in air pollution epidemiology may suffer from some specific forms of confounding and exposure measurement error. This contribution discusses these, mostly in the framework of cohort studies. Evaluation of potential confounding is critical in studies of the health effects of air pollution. The association between long-term exposure to ambient air pollution and mortality has been investigated using cohort studies in which subjects are followed over time with respect to their vital status. In such studies, control for individual-level confounders such as smoking is important, as is control for area-level confounders such as neighborhood socio-economic status. In addition, there may be spatial dependencies in the survival data that need to be addressed. These issues are illustrated using the American Cancer Society Cancer Prevention II cohort. Exposure measurement error is a challenge in epidemiology because inference about health effects can be incorrect when the measured or predicted exposure used in the analysis is different from the underlying true exposure. Air pollution epidemiology rarely if ever uses personal measurements of exposure for reasons of cost and feasibility. Exposure measurement error in air pollution epidemiology comes in various dominant forms, which are different for time-series and cohort studies. The challenges are reviewed and a number of suggested solutions are discussed for both study domains.

Prospective study of particulate air pollution exposures, subclinical atherosclerosis, and clinical cardiovascular disease: The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air).

The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) was initiated in 2004 to investigate the relation between individual-level estimates of long-term air pollution exposure and the progression of subclinical atherosclerosis and the incidence of cardiovascular disease (CVD). MESA Air builds on a multicenter, community-based US study of CVD, supplementing that study with additional participants, outcome measurements, and state-of-the-art air pollution exposure assessments of fine particulate matter, oxides of nitrogen, and black carbon. More than 7,000 participants aged 45-84 years are being followed for over 10 years for the identification and characterization of CVD events, including acute myocardial infarction and other coronary artery disease, stroke, peripheral artery disease, and congestive heart failure; cardiac procedures; and mortality. Subcohorts undergo baseline and follow-up measurements of coronary artery calcium using computed tomography and carotid artery intima-medial wall thickness using ultrasonography. This cohort provides vast exposure heterogeneity in ranges currently experienced and permitted in most developed nations, and the air monitoring and modeling methods employed will provide individual estimates of exposure that incorporate residence-specific infiltration characteristics and participant-specific time-activity patterns. The overarching study aim is to understand and reduce uncertainty in health effect estimation regarding long-term exposure to air pollution and CVD.

Exposure to traffic and left ventricular mass and function: the Multi-Ethnic Study of Atherosclerosis.

RATIONALE Ambient air pollution has been associated with heart failure morbidity and mortality. The mechanisms responsible for these associations are unknown but may include the effects of traffic-related pollutants on vascular or autonomic function. OBJECTIVES We assessed the cross-sectional relation between long-term air pollution, traffic exposures, and important end-organ measures of alterations in cardiac function-left ventricular mass index (LVMI) and ejection fraction-in the Multi-Ethnic Study of Atherosclerosis, a multicenter study of adults without previous clinical cardiovascular disease. METHODS A total of 3,827 eligible participants (aged 45-84 yr) underwent cardiac magnetic resonance imaging between 2000 and 2002. We estimated air pollution exposures using residential proximity to major roadways and interpolated concentrations of fine particulate matter (less than 2.5 microns in diameter). We examined adjusted associations between these exposures and left ventricular mass and function. MEASUREMENTS AND MAIN RESULTS Relative to participants living more than 150 m from a major roadway, participants living within 50 m of a major roadway showed an adjusted 1.4 g/m(2) (95% CI, 0.3-2.5) higher LVMI, a difference in mass corresponding to a 5.6 mm Hg greater systolic blood pressure. Ejection fraction was not associated with proximity to major roadways. Limited variability in estimates of fine particulate matter was observed within cities, and no associations with particulate matter were found for either outcome after adjustment for center. CONCLUSIONS Living in close proximity to major roadways is associated with higher LVMI, suggesting chronic vascular end-organ damage from a traffic-related environmental exposure. Air pollutants or another component of roadway proximity, such as noise, could be responsible.

Pragmatic Estimation of a Spatio-Temporal Air Quality Model With Irregular Monitoring Data

Statistical analyses of the health effects of air pollution have increasingly used GIS-based covariates for prediction of ambient air quality in “land-use” regression models. More recently these regression models have accounted for spatial correlation structure in combining monitoring data with land-use covariates. The current paper builds on these concepts to address spatio-temporal prediction of ambient concentrations of particulate matter with aerodynamic diameter less than 2.5 μm (PM2.5) on the basis of a model representing spatially varying seasonal trends and spatial correlation structures. Our hierarchical methodology provides a pragmatic approach that fully exploits regulatory and other supplemental monitoring data which jointly define a complex spatio-temporal monitoring design. We explain the elements of the computational approach, including estimation of smoothed empirical orthogonal functions (SEOFs) as basis functions for temporal trend, spatial (“land use”) regression by Partial Least Squares (PLS), modeling of spatio-temporal correlation structure, and generalized universal kriging prediction of ambient exposure for subjects in the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) project. Analyses are demonstrated in detail for the South California study area of the MESA Air project using AQS monitoring data from 2000 to 2006 and supplemental MESA Air monitoring data beginning in 2005. Results of application of the modeling and estimation methodology are presented also for five other MESA Air metropolitan study areas across the country with comments on current and future research developments.

Vascular Responses to Long- and Short-Term Exposure to Fine Particulate Matter : MESA Air (Multi-Ethnic Study of Atherosclerosis and Air Pollution)

OBJECTIVES This study evaluated the association of long- and short-term air pollutant exposures with flow-mediated dilation (FMD) and baseline arterial diameter (BAD) of the brachial artery using ultrasound in a large multicity cohort. BACKGROUND Exposures to ambient air pollution, especially long-term exposure to particulate matter <2.5 μm in aerodynamic diameter (PM(2.5)), are linked with cardiovascular mortality. Short-term exposure to PM(2.5) has been associated with decreased FMD and vasoconstriction, suggesting that adverse effects of PM(2.5) may involve endothelial dysfunction. However, long-term effects of PM(2.5) on endothelial dysfunction have not been investigated. METHODS FMD and BAD were measured by brachial artery ultrasound at the initial examination of the Multi-Ethnic Study of Atherosclerosis. Long-term PM(2.5) concentrations were estimated for the year 2000 at each participants residence (n = 3,040) using a spatio-temporal model informed by cohort-specific monitoring. Short-term PM(2.5) concentrations were based on daily central-site monitoring in each of the 6 cities. RESULTS An interquartile increase in long-term PM(2.5) concentration (3 μg/m(3)) was associated with a 0.3% decrease in FMD (95% confidence interval [CI] of difference: -0.6 to -0.03; p = 0.03), adjusting for demographic characteristics, traditional risk factors, sonographers, and 1/BAD. Women, nonsmokers, younger participants, and those with hypertension seemed to show a greater association of PM(2.5) with FMD. FMD was not significantly associated with short-term variation in PM(2.5) (-0.1% per 12 μg/m(3) daily increase [95% CI: -0.2 to 0.04] on the day before examination). CONCLUSIONS Long-term PM(2.5) exposure was significantly associated with decreased endothelial function according to brachial ultrasound results. These findings may elucidate an important pathway linking air pollution and cardiovascular mortality.

Long-term exposure to air pollution and markers of inflammation, coagulation, and endothelial activation a repeat-measures analysis in the multi-ethnic study of atherosclerosis (MESA)

Background: 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. Methods: 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. Results: 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. Conclusions: These data are consistent with the hypothesis that long-term exposure to air pollution is related to some markers of inflammation and fibrinolysis.

Air pollution and the microvasculature: a cross-sectional assessment of in vivo retinal images in the population-based Multi-Ethnic Study of Atherosclerosis (MESA).

Sara Adar and colleagues show that residing in locations with higher air pollution concentrations and experiencing daily increases in air pollution are associated with narrower retinal arteriolar diameters in older individuals, thus providing a link between air pollution and cardiovascular disease.

Control for Population Structure and Relatedness for Binary Traits in Genetic Association Studies via Logistic Mixed Models

Linear mixed models (LMMs) are widely used in genome-wide association studies (GWASs) to account for population structure and relatedness, for both continuous and binary traits. Motivated by the failure of LMMs to control type I errors in a GWAS of asthma, a binary trait, we show that LMMs are generally inappropriate for analyzing binary traits when population stratification leads to violation of the LMMs constant-residual variance assumption. To overcome this problem, we develop a computationally efficient logistic mixed model approach for genome-wide analysis of binary traits, the generalized linear mixed model association test (GMMAT). This approach fits a logistic mixed model once per GWAS and performs score tests under the null hypothesis of no association between a binary trait and individual genetic variants. We show in simulation studies and real data analysis that GMMAT effectively controls for population structure and relatedness when analyzing binary traits in a wide variety of study designs.

Exposure measurement error in PM2.5 health effects studies: a pooled analysis of eight personal exposure validation studies.

BackgroundExposure measurement error is a concern in long-term PM2.5 health studies using ambient concentrations as exposures. We assessed error magnitude by estimating calibration coefficients as the association between personal PM2.5 exposures from validation studies and typically available surrogate exposures.MethodsDaily personal and ambient PM2.5, and when available sulfate, measurements were compiled from nine cities, over 2 to 12 days. True exposure was defined as personal exposure to PM2.5 of ambient origin. Since PM2.5 of ambient origin could only be determined for five cities, personal exposure to total PM2.5 was also considered. Surrogate exposures were estimated as ambient PM2.5 at the nearest monitor or predicted outside subjects’ homes. We estimated calibration coefficients by regressing true on surrogate exposures in random effects models.ResultsWhen monthly-averaged personal PM2.5 of ambient origin was used as the true exposure, calibration coefficients equaled 0.31 (95% CI:0.14, 0.47) for nearest monitor and 0.54 (95% CI:0.42, 0.65) for outdoor home predictions. Between-city heterogeneity was not found for outdoor home PM2.5 for either true exposure. Heterogeneity was significant for nearest monitor PM2.5, for both true exposures, but not after adjusting for city-average motor vehicle number for total personal PM2.5.ConclusionsCalibration coefficients were <1, consistent with previously reported chronic health risks using nearest monitor exposures being under-estimated when ambient concentrations are the exposure of interest. Calibration coefficients were closer to 1 for outdoor home predictions, likely reflecting less spatial error. Further research is needed to determine how our findings can be incorporated in future health studies.