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1.  Susceptibility to Mortality in Weather Extremes: Effect Modification by Personal and Small Area Characteristics In a Multi-City Case-Only Analysis 
Epidemiology (Cambridge, Mass.)  2013;24(6):809-819.
Extremes of temperature have been associated with short-term increases in daily mortality. We identified subpopulations with increased susceptibility to dying during temperature extremes, based on personal demographics, small-area characteristics and preexisting medical conditions.
We examined Medicare participants in 135 U.S. cities and identified preexisting conditions based on hospitalization records prior to their deaths, from 1985–2006. Personal characteristics were obtained from the Medicare records, and area characteristics were assigned based on zip-code of residence. We conducted a case-only analysis of over 11 million deaths, and evaluated modification of the risk of dying associated with extremely hot days and extremely cold days, continuous temperatures, and water-vapor pressure. Modifiers included preexisting conditions, personal characteristics, zip-code-level population characteristics, and land-cover characteristics. For each effect modifier, a city-specific logistic regression model was fitted and then an overall national estimate was calculated using meta-analysis.
People with certain preexisting conditions were more susceptible to extreme heat, with an additional 6% (95% confidence interval= 4% – 8%) increase in the risk of dying on an extremely hot day in subjects with previous admission for atrial fibrillation, an additional 8% (4%–12%) in subjects with Alzheimer disease, and an additional 6% (3%–9%) in subjects with dementia. Zip-code level and personal characteristics were also associated with increased susceptibility to temperature.
We identified several subgroups of the population who are particularly susceptible to temperature extremes, including persons with atrial fibrillation.
PMCID: PMC4304207  PMID: 24045717
2.  Associations Between Short-term Changes in Air Pollution and Correlates of Arterial Stiffness: The Veterans Affairs Normative Aging Study, 2007–2011 
American Journal of Epidemiology  2013;179(2):192-199.
We investigated associations between short-term exposure to air pollution and central augmentation index and augmentation pressure, correlates of arterial stiffness, in a cohort of elderly men in the Boston, Massachusetts, metropolitan area. This longitudinal analysis included 370 participants from the Veterans Affairs Normative Aging Study with up to 2 visits between 2007 and 2011 (n = 445). Augmentation index (as %) and augmentation pressure (in mmHg) were measured at each visit by using radial artery applanation tonometry for pulse wave analysis and modeled in a mixed effects regression model as continuous functions of moving averages of air pollution exposures (over 4 hours and 1, 3, 7, and 14 days). The results suggest that short-term changes in air pollution were associated with augmentation index and augmentation pressure at several moving averages. Interquartile range (IQR) increases in 3-day average exposure to particles with aerodynamic diameter less than 2.5 μm (3.6-μg/m3 IQR increase) and sulfate (1.4-μg/m3 IQR increase) and 1-day average exposure to particle number counts (8,741-counts/cm3 IQR increase) were associated with augmentation index values that were 0.8% (95% confidence interval (CI): 0.2, 1.4), 0.6% (95% CI: 0.1, 1.2), and 1.7% (95% CI: 0.4, 2.9) higher, respectively. Overall, the findings were similar for augmentation pressure. The findings support the hypothesis that exposure to air pollution may affect vascular function.
PMCID: PMC3873113  PMID: 24227017
air pollution; particulate matter; pulse wave analysis
3.  Effects of Temperature and Relative Humidity on DNA Methylation 
Epidemiology (Cambridge, Mass.)  2014;25(4):561-569.
Previous studies have found relationships between DNA methylation and various environmental contaminant exposures. Associations with weather have not been examined. Because temperature and humidity are related to mortality even on non-extreme days, we hypothesized that temperature and relative humidity may affect methylation.
We repeatedly measured methylation on long interspersed nuclear elements (LINE-1), Alu, and 9 candidate genes in blood samples from 777 elderly men participating in the normative aging Study (1999–2009). We assessed whether ambient temperature and relative humidity are related to methylation on LINE-1 and Alu, as well as on genes controlling coagulation, inflammation, cortisol, DNA repair, and metabolic pathway. We examined intermediate-term associations of temperature, relative humidity, and their interaction with methylation, using distributed lag models.
Temperature or relative humidity levels were associated with methylation on tissue factor (F3), intercellular adhesion molecule 1 (ICAM-1), toll-like receptor 2 (TRL-2), carnitine O-acetyltransferase (CRAT), interferon gamma (IFN-γ), inducible nitric oxide synthase (iNOS), and glucocorticoid receptor, LINE-1, and Alu. For instance, a 5°c increase in 3-week average temperature in ICAM-1 methylation was associated with a 9% increase (95% confidence interval: 3% to 15%), whereas a 10% increase in 3-week average relative humidity was associated with a 5% decrease (−8% to −1%). The relative humidity association with ICAM-1 methylation was stronger on hot days than mild days.
DNA methylation in blood cells may reflect biological effects of temperature and relative humidity. Temperature and relative humidity may also interact to produce stronger effects.
PMCID: PMC4224120  PMID: 24809956
4.  Heat, Heat Waves, and Hospital Admissions among the Elderly in the United States, 1992–2006 
Environmental Health Perspectives  2014;122(11):1187-1192.
Background: Heat-wave frequency, intensity, and duration are increasing with global climate change. The association between heat and mortality in the elderly is well documented, but less is known regarding associations with hospital admissions.
Objectives: Our goal was to determine associations between moderate and extreme heat, heat waves, and hospital admissions for nonaccidental causes among Medicare beneficiaries ≥ 65 years of age in 114 cities across five U.S. climate zones.
Methods: We used Medicare inpatient billing records and city-specific data on temperature, humidity, and ozone from 1992 through 2006 in a time-stratified case-crossover design to estimate the association between hospitalization and moderate [90th percentile of apparent temperature (AT)] and extreme (99th percentile of AT) heat and heat waves (AT above the 95th percentile over 2–8 days). In sensitivity analyses, we additionally considered confounding by ozone and holidays, different temperature metrics, and alternate models of the exposure–response relationship.
Results: Associations between moderate heat and hospital admissions were minimal, but extreme heat was associated with a 3% (95% CI: 2%, 4%) increase in all-cause hospital admissions over the subsequent 8 days. In cause-specific analyses, extreme heat was associated with increased hospitalizations for renal (15%; 95% CI: 9%, 21%) and respiratory (4%; 95% CI: 2%, 7%) diseases, but not for cardiovascular diseases. An added heat-wave effect was observed for renal and respiratory admissions.
Conclusion: Extreme heat is associated with increased hospital admissions, particularly for renal causes, among the elderly in the United States.
Citation: Gronlund CJ, Zanobetti A, Schwartz JD, Wellenius GA, O’Neill MS. 2014. Heat, heat waves, and hospital admissions among the elderly in the United States, 1992–2006. Environ Health Perspect 122:1187–1192;
PMCID: PMC4216145  PMID: 24905551
5.  Acclimatization across space and time in the effects of temperature on mortality: a time-series analysis 
Environmental Health  2014;13(1):89.
Climate change has increased the days of unseasonal temperature. Although many studies have examined the association between temperature and mortality, few have examined the timing of exposure where whether this association varies depending on the exposure month even at the same temperature. Therefore, we investigated monthly differences in the effects of temperature on mortality in a study comprising a wide range of weather and years, and we also investigated heterogeneity among regions.
We analyzed 38,005,616 deaths from 148 cities in the U.S. from 1973 through 2006. We fit city specific Poisson regressions to examine the effect of temperature on mortality separately for each month of the year, using penalized splines. We used cluster analysis to group cities with similar weather patterns, and combined results across cities within clusters using meta-smoothing.
There was substantial variation in the effects of the same temperature by month. Heat effects were larger in the spring and early summer and cold effects were larger in late fall. In addition, heat effects were larger in clusters where high temperatures were less common, and vice versa for cold effects.
The effects of a given temperature on mortality vary spatially and temporally based on how unusual it is for that time and location. This suggests changes in variability of temperature may be more important for health as climate changes than changes of mean temperature. More emphasis should be placed on warnings targeted to early heat/cold temperature for the season or month rather than focusing only on the extremes.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-069X-13-89) contains supplementary material, which is available to authorized users.
PMCID: PMC4271464  PMID: 25352015
Temperature and mortality; Acclimation; Acclimatization; Climate change; Global warming
6.  Isolated and synergistic effects of PM10 and average temperature on cardiovascular and respiratory mortality 
Revista de Saúde Pública  2014;48(6):881-888.
To analyze the effect of air pollution and temperature on mortality due to cardiovascular and respiratory diseases.
We evaluated the isolated and synergistic effects of temperature and particulate matter with aerodynamic diameter < 10 µm (PM10) on the mortality of individuals > 40 years old due to cardiovascular disease and that of individuals > 60 years old due to respiratory diseases in Sao Paulo, SP, Southeastern Brazil, between 1998 and 2008. Three methodologies were used to evaluate the isolated association: time-series analysis using Poisson regression model, bidirectional case-crossover analysis matched by period, and case-crossover analysis matched by the confounding factor, i.e., average temperature or pollutant concentration. The graphical representation of the response surface, generated by the interaction term between these factors added to the Poisson regression model, was interpreted to evaluate the synergistic effect of the risk factors.
No differences were observed between the results of the case-crossover and time-series analyses. The percentage change in the relative risk of cardiovascular and respiratory mortality was 0.85% (0.45;1.25) and 1.60% (0.74;2.46), respectively, due to an increase of 10 μg/m3 in the PM10 concentration. The pattern of correlation of the temperature with cardiovascular mortality was U-shaped and that with respiratory mortality was J-shaped, indicating an increased relative risk at high temperatures. The values for the interaction term indicated a higher relative risk for cardiovascular and respiratory mortalities at low temperatures and high temperatures, respectively, when the pollution levels reached approximately 60 μg/m3.
The positive association standardized in the Poisson regression model for pollutant concentration is not confounded by temperature, and the effect of temperature is not confounded by the pollutant levels in the time-series analysis. The simultaneous exposure to different levels of environmental factors can create synergistic effects that are as disturbing as those caused by extreme concentrations.
PMCID: PMC4285836
Particulate Matter, adverse effects; Temperature; Cardiovascular Diseases, mortality; Respiratory Tract Diseases, mortality; Air Pollution; Time Series Studies
7.  Associations between Changes in City and Address Specific Temperature and QT Interval - The VA Normative Aging Study 
PLoS ONE  2014;9(9):e106258.
The underlying mechanisms of the association between ambient temperature and cardiovascular morbidity and mortality are not well understood, particularly for daily temperature variability. We evaluated if daily mean temperature and standard deviation of temperature was associated with heart rate-corrected QT interval (QTc) duration, a marker of ventricular repolarization in a prospective cohort of older men.
This longitudinal analysis included 487 older men participating in the VA Normative Aging Study with up to three visits between 2000–2008 (n = 743). We analyzed associations between QTc and moving averages (1–7, 14, 21, and 28 days) of the 24-hour mean and standard deviation of temperature as measured from a local weather monitor, and the 24-hour mean temperature estimated from a spatiotemporal prediction model, in time-varying linear mixed-effect regression. Effect modification by season, diabetes, coronary heart disease, obesity, and age was also evaluated.
Higher mean temperature as measured from the local monitor, and estimated from the prediction model, was associated with longer QTc at moving averages of 21 and 28 days. Increased 24-hr standard deviation of temperature was associated with longer QTc at moving averages from 4 and up to 28 days; a 1.9°C interquartile range increase in 4-day moving average standard deviation of temperature was associated with a 2.8 msec (95%CI: 0.4, 5.2) longer QTc. Associations between 24-hr standard deviation of temperature and QTc were stronger in colder months, and in participants with diabetes and coronary heart disease.
In this sample of older men, elevated mean temperature was associated with longer QTc, and increased variability of temperature was associated with longer QTc, particularly during colder months and among individuals with diabetes and coronary heart disease. These findings may offer insight of an important underlying mechanism of temperature-related cardiovascular morbidity and mortality in an older population.
PMCID: PMC4169528  PMID: 25238150
8.  Evidence on Vulnerability and Susceptibility to Health Risks Associated With Short-Term Exposure to Particulate Matter: A Systematic Review and Meta-Analysis 
American Journal of Epidemiology  2013;178(6):865-876.
Although there is strong evidence that short-term exposure to particulate matter is associated with health risks, less is known about whether some subpopulations face higher risks. We identified 108 papers published after 1995 and summarized the scientific evidence regarding effect modification of associations between short-term exposure to particulate matter and the risk of death or hospitalization. We performed a meta-analysis of estimated mortality associations by age and sex. We found strong, consistent evidence that the elderly experience higher risk of particular matter­–associated hospitalization and death, weak evidence that women have higher risks of hospitalization and death, and suggestive evidence that those with lower education, income, or employment status have higher risk of death. Meta-analysis showed a statistically higher risk of death of 0.64% (95% confidence interval (CI): 0.50, 0.78) for older populations compared with 0.34% (95% CI: 0.25, 0.42) for younger populations per 10 μg/m3 increase of particulate matter with aerodynamic diameter ≤10 μm. Women had a slightly higher risk of death of 0.55% (95% CI: 0.41, 0.70) compared with 0.50% (95% CI: 0.34, 0.54) for men, but these 2 risks were not statistically different. Our synthesis on modifiers for risks associated with particulate matter can aid the design of air quality policies and suggest directions for future research. Studies of biological mechanisms could be informed by evidence of differential risks by population, such as by sex and preexisting conditions.
PMCID: PMC3775545  PMID: 23887042
age; effect modifiers; hospital admissions; mortality; particulate matter; PM10; PM2.5; socioeconomic status
9.  A framework to spatially cluster air pollution monitoring sites in US based on the PM2.5 composition 
Environment international  2013;59:10.1016/j.envint.2013.06.003.
Heterogeneity in the response to PM2.5 is hypothesized to be related to differences in particle composition across monitoring sites which reflect differences in source types as well as climatic and topographic conditions impacting different geographic locations. Identifying spatial patterns in particle composition is a multivariate problem that requires novel methodologies.
Use cluster analysis methods to identify spatial patterns in PM2.5 composition. Verify that the resulting clusters are distinct and informative.
109 monitoring sites with 75% reported speciation data during the period 2003–2008 were selected. These sites were categorized based on their average PM2.5 composition over the study period using k-means cluster analysis. The obtained clusters were validated and characterized based on their physico-chemical characteristics, geographic locations, emissions profiles, population density and proximity to major emission sources.
Overall 31 clusters were identified. These include 21 clusters with 2 or more sites which were further grouped into 4 main types using hierarchical clustering. The resulting groupings are chemically meaningful and represent broad differences in emissions. The remaining clusters, encompassing single sites, were characterized based on their particle composition and geographic location.
The framework presented here provides a novel tool which can be used to identify and further classify sites based on their PM2.5 composition. The solution presented is fairly robust and yielded groupings that were meaningful in the context of air-pollution research.
PMCID: PMC3878877  PMID: 23850585
Multi-pollutant mixtures; Cluster analysis; Effect modification; Air pollution profiles; k-Means
10.  Associations of Fine Particulate Matter Species with Mortality in the United States: A Multicity Time-Series Analysis 
Environmental Health Perspectives  2014;122(8):837-842.
Background: Epidemiological studies have examined the association between PM2.5 and mortality, but uncertainty remains about the seasonal variations in PM2.5-related effects and the relative importance of species.
Objectives: We estimated the effects of PM2.5 species on mortality and how infiltration rates may modify the association.
Methods: Using city–season specific Poisson regression, we estimated PM2.5 effects on approximately 4.5 million deaths for all causes, cardiovascular disease (CVD), myocardial infarction (MI), stroke, and respiratory diseases in 75 U.S. cities for 2000–2006. We added interaction terms between PM2.5 and monthly average species-to-PM2.5 proportions of individual species to determine the relative toxicity of each species. We combined results across cities using multivariate meta-regression, and controlled for infiltration.
Results: We estimated a 1.18% (95% CI: 0.93, 1.44%) increase in all-cause mortality, a 1.03% (95% CI: 0.65, 1.41%) increase in CVD, a 1.22% (95% CI: 0.62, 1.82%) increase in MI, a 1.76% (95% CI: 1.01, 2.52%) increase in stroke, and a 1.71% (95% CI: 1.06, 2.35%) increase in respiratory deaths in association with a 10-μg/m3 increase in 2-day averaged PM2.5 concentration. The associations were largest in the spring. Silicon, calcium, and sulfur were associated with more all-cause mortality, whereas sulfur was related to more respiratory deaths. County-level smoking and alcohol were associated with larger estimated PM2.5 effects.
Conclusions: Our study showed an increased risk of mortality associated with PM2.5, which varied with seasons and species. The results suggest that mass alone might not be sufficient to evaluate the health effects of particles.
Citation: Dai L, Zanobetti A, Koutrakis P, Schwartz JD. 2014. Associations of fine particulate matter species with mortality in the United States: a multicity time-series analysis. Environ Health Perspect 122:837–842;
PMCID: PMC4123030  PMID: 24800826
11.  A national case-crossover analysis of the short-term effect of PM2.5 on hospitalizations and mortality in subjects with diabetes and neurological disorders 
Environmental Health  2014;13:38.
Diabetes and neurological disorders are a growing burden among the elderly, and may also make them more susceptible to particulate air matter with aerodynamic diameter less than 2.5 μg (PM2.5). The same biological responses thought to effect cardiovascular disease through air pollution-mediated systemic oxidative stress, inflammation and cerebrovascular dysfunction could also be relevant for diabetes and neurodegenerative diseases.
We conducted multi-site case-crossover analyses of all-cause deaths and of hospitalizations for diabetes or neurological disorders among Medicare enrollees (>65 years) during the period 1999 to 2010 in 121 US communities. We examined whether 1) short-term exposure to PM2.5 increases the risk of hospitalization for diabetes or neurological disorders, and 2) the association between short-term exposure to PM2.5 and all-cause mortality is modified by having a previous hospitalization of diabetes or neurological disorders.
We found that short term exposure to PM2.5 is significantly associated with an increase in hospitalization risks for diabetes (1.14% increase, 95% CI: 0.56, 1.73 for a 10 μg/m3 increase in the 2 days average), and for Parkinson’s disease (3.23%, 1.08, 5.43); we also found an increase in all-cause mortality risks (0.64%, 95% CI: 0.42, 0.85), but we didn’t find that hospitalization for diabetes and neurodegenerative diseases modifies the association between short term exposure to PM2.5 and all-cause mortality.
We found that short-term exposure to fine particles increased the risk of hospitalizations for Parkinson’s disease and diabetes, and of all-cause mortality. While the association between short term exposure to PM2.5 and mortality was higher among Medicare enrollees that had a previous admission for diabetes and neurological disorders than among Medicare enrollees that did not had a prior admission for these diseases, the effect modification was not statistically significant. We believe that these results provide useful insights regarding the mechanisms by which particles may affect the brain. A better understanding of the mechanisms will enable the development of new strategies to protect individuals at risk and to reduce detrimental effects of air pollution on the nervous system.
PMCID: PMC4064518  PMID: 24886318
PM2.5; Diabetes; Neurological disorders; Mortality risk; Hospitalizations
12.  Ambient particulate air pollution and microRNAs in elderly men 
Ambient particulate matter (PM) has been associated with mortality and morbidity for cardiovascular disease (CVD). MicroRNAs control gene expression at a post-transcriptional level. Altered microRNA expression has been reported in processes related to CVD and PM exposure, e.g. systemic inflammation, endothelial dysfunction and atherosclerosis. Polymorphisms in microRNA-related genes could influence response to PM.
We investigated the association of exposure to ambient particles in several time windows (4-hours to 28-days moving averages) and blood-leukocyte expression changes in fourteen candidate microRNAs, in 153 elderly males from the Normative Aging Study (examined 2005–2009). Potential effect modification by six single nucleotide polymorphisms (SNPs) in three microRNA-related genes was investigated. Fine PM (PM2.5), black carbon, organic carbon and sulfates were measured at a stationary ambient monitoring site. Linear regression models, adjusted for potential confounders, were used to assess effects of particles and SNP-by-pollutant interaction. An in silico pathways analysis was performed on target genes of miRNAs associated with the pollutants.
We found a negative association for pollutants in all moving averages and miR-1, -126, -135a, -146a, -155, -21, -222 and -9. The strongest associations were observed with the 7-day moving averages for PM2.5 and black carbon and with the 48-hour moving averages for organic carbon. The association with sulfates was stable across the moving averages. The in silico pathway analysis identified 18 pathways related to immune response shared by at least two miRNAs; in particular, the “HMGB1/RAGE signaling pathway” was shared by miR-126, -146a, -155, -21 and -222.
No important associations were observed for miR-125a-5p, -125b, -128, -147, -218 and -96. We found significant SNP-by-pollutant interactions for rs7813, rs910925 and rs1062923 in GEMIN4 and black carbon and PM2.5 for miR-1, -126, -146a, -222 and -9, and for rs1640299 in DGCR8 and SO42− for miR-1 and -135a.
Exposure to ambient particles could cause a downregulation of microRNAs involved in processes related to PM exposure. Polymorphisms in GEMIN4 and DGCR8 could modify these associations.
PMCID: PMC3977338  PMID: 24257509
13.  Air Pollution Exposure and Abnormal Glucose Tolerance during Pregnancy: The Project Viva Cohort 
Environmental Health Perspectives  2014;122(4):378-383.
Background: Exposure to fine particulate matter (PM with diameter ≤ 2.5 μm; PM2.5) has been linked to type 2 diabetes mellitus, but associations with hyperglycemia in pregnancy have not been well studied.
Methods: We studied Boston, Massachusetts–area pregnant women without known diabetes. We identified impaired glucose tolerance (IGT) and gestational diabetes mellitus (GDM) during pregnancy from clinical glucose tolerance tests at median 28.1 weeks gestation. We used residential addresses to estimate second-trimester PM2.5 and black carbon exposure via a central monitoring site and spatiotemporal models. We estimated residential traffic density and roadway proximity as surrogates for exposure to traffic-related air pollution. We performed multinomial logistic regression analyses adjusted for sociodemographic covariates, and used multiple imputation to account for missing data.
Results: Of 2,093 women, 65 (3%) had IGT and 118 (6%) had GDM. Second-trimester spatiotemporal exposures ranged from 8.5 to 15.9 μg/m3 for PM2.5 and from 0.1 to 1.7 μg/m3 for black carbon. Traffic density was 0–30,860 vehicles/day × length of road (kilometers) within 100 m; 281 (13%) women lived ≤ 200 m from a major road. The prevalence of IGT was elevated in the highest (vs. lowest) quartile of exposure to spatiotemporal PM2.5 [odds ratio (OR) = 2.63; 95% CI: 1.15, 6.01] and traffic density (OR = 2.66; 95% CI: 1.24, 5.71). IGT also was positively associated with other exposure measures, although associations were not statistically significant. No pollutant exposures were positively associated with GDM.
Conclusions: Greater exposure to PM2.5 and other traffic-related pollutants during pregnancy was associated with IGT but not GDM. Air pollution may contribute to abnormal glycemia in pregnancy.
Citation: Fleisch AF, Gold DR, Rifas-Shiman SL, Koutrakis P, Schwartz JD, Kloog I, Melly S, Coull BA, Zanobetti A, Gillman MW, Oken E. 2014. Air pollution exposure and abnormal glucose tolerance during pregnancy: the Project Viva Cohort. Environ Health Perspect 122:378–383;
PMCID: PMC3984217  PMID: 24508979
14.  Brachial Artery Responses to Ambient Pollution, Temperature, and Humidity in People with Type 2 Diabetes: A Repeated-Measures Study 
Environmental Health Perspectives  2014;122(3):242-248.
Background: Extreme weather and air pollution are associated with increased cardiovascular risk in people with diabetes.
Objectives: In a population with diabetes, we conducted a novel assessment of vascular brachial artery responses both to ambient pollution and to weather (temperature and water vapor pressure, a measure of humidity).
Methods: Sixty-four 49- to 85-year-old Boston residents with type 2 diabetes completed up to five study visits (279 repeated measures). Brachial artery diameter (BAD) was measured by ultrasound before and after brachial artery occlusion [i.e., flow-mediated dilation (FMD)] and before and after nitroglycerin-mediated dilation (NMD). Ambient concentrations of fine particulate mass (PM2.5), black carbon (BC), organic carbon (OC), elemental carbon, particle number, and sulfate were measured at our monitoring site; ambient concentrations of carbon monoxide, nitrogen dioxide, and ozone were obtained from state monitors. Particle exposure in the home and during each trip to the clinic (home/trip exposure) was measured continuously and as a 5-day integrated sample. We used linear models with fixed effects for participants, adjusting for date, season, temperature, and water vapor pressure on the day of each visit, to estimate associations between our outcomes and interquartile range increases in exposure.
Results: Baseline BAD was negatively associated with particle pollution, including home/trip–integrated BC (–0.02 mm; 95% CI: –0.04, –0.003, for a 0.28 μg/m3 increase in BC), OC (–0.08 mm; 95% CI: –0.14, –0.03, for a 1.61 μg/m3 increase) as well as PM2.5, 5-day average ambient PM2.5, and BC. BAD was positively associated with ambient temperature and water vapor pressure. However, exposures were not consistently associated with FMD or NMD.
Conclusion: Brachial artery diameter, a predictor of cardiovascular risk, decreased in association with particle pollution and increased in association with ambient temperature in our study population of adults with type 2 diabetes.
Citation: Zanobetti A, Luttmann-Gibson H, Horton ES, Cohen A, Coull BA, Hoffmann B, Schwartz JD, Mittleman MA, Li Y, Stone PH, de Souza C, Lamparello B, Koutrakis P, Gold DR. 2014. Brachial artery responses to ambient pollution, temperature, and humidity in people with type 2 diabetes: a repeated-measures study. Environ Health Perspect 122:242–248;
PMCID: PMC3948021  PMID: 24398072
15.  Short Term Effects of Particle Exposure on Hospital Admissions in the Mid-Atlantic States: A Population Estimate 
PLoS ONE  2014;9(2):e88578.
Many studies report significant associations between PM2.5 (particulate matter <2.5 micrometers) and hospital admissions. These studies mostly rely on a limited number of monitors which introduces exposure error, and excludes rural and suburban populations from locations where monitors are not available, reducing generalizability and potentially creating selection bias.
Using prediction models developed by our group, daily PM2.5 exposure was estimated across the Mid-Atlantic (Washington D.C., and the states of Delaware, Maryland, New Jersey, Pennsylvania, Virginia, New York and West Virginia). We then investigated the short-term effects of PM2.5 exposures on emergency hospital admissions of the elderly in the Mid-Atlantic region.We performed case-crossover analysis for each admission type, matching on day of the week, month and year and defined the hazard period as lag01 (a moving average of day of admission exposure and previous day exposure).
We observed associations between short-term exposure to PM2.5 and hospitalization for all outcomes examined. For example, for every 10-µg/m3 increase in short-term PM 2.5 there was a 2.2% increase in respiratory diseases admissions (95% CI = 1.9 to 2.6), and a 0.78% increase in cardiovascular disease (CVD) admission rate (95% CI = 0.5 to 1.0). We found differences in risk for CVD admissions between people living in rural and urban areas. For every10-µg/m3 increase in PM 2.5 exposure in the ‘rural’ group there was a 1.0% increase (95% CI = 0.6 to 1.5), while for the ‘urban’ group the increase was 0.7% (95% CI = 0.4 to 1.0).
Our findings showed that PM2.5 exposure was associated with hospital admissions for all respiratory, cardio vascular disease, stroke, ischemic heart disease and chronic obstructive pulmonary disease admissions. In addition, we demonstrate that our AOD (Aerosol Optical Depth) based exposure models can be successfully applied to epidemiological studies investigating the health effects of short-term exposures to PM2.5.
PMCID: PMC3917892  PMID: 24516670
16.  Short-Term Changes in Ambient Temperature and Risk of Ischemic Stroke 
Despite consistent evidence of a higher short-term risk of cardiovascular mortality associated with ambient temperature, there have been discrepant findings on the association between temperature and ischemic stroke. Moreover, few studies have considered potential confounding by ambient fine particulate matter air pollution <2.5 μm in diameter (PM2.5) and none have examined the impact of temperature changes on stroke in the subsequent hours rather than days. The aim of this study was to evaluate whether changes in temperature trigger an ischemic stroke in the following hours and days and whether humid days are particularly harmful.
We reviewed the medical records of 1,705 patients residing in the metropolitan region of Boston, Mass., USA, who were hospitalized with neurologist-confirmed ischemic stroke, and we abstracted data on the time of symptom onset and clinical characteristics. We obtained hourly meteorological data from the National Weather Service station and hourly PM2.5 data from the Harvard ambient monitoring station. We used the time-stratified case-crossover design to assess the association between ischemic stroke and apparent temperature averaged over 1-7 days prior to stroke onset adjusting for PM2.5. We assessed whether differences in apparent temperature trigger a stroke within shorter time periods by examining the association between stroke onset and apparent temperature levels averaged in 2-hour increments prior to stroke onset (0-2 h through 36-38 h). We tested whether the association varied by health characteristics or by PM2.5, ozone or relative humidity.
The incidence rate ratio of ischemic stroke was 1.09 (95% confidence interval 1.01-1.18) following a 5°C decrement in average apparent temperature over the 2 days preceding symptom onset. The higher risk associated with cooler temperatures peaked in the first 14-34 h. There was no statistically significant difference in the association between temperature and ischemic stroke across seasons. The risk of ischemic stroke was not meaningfully different across subgroups of patients defined by health characteristics. The association between ischemic stroke and ambient temperature was stronger on days with higher levels of relative humidity.
Lower temperatures are associated with a higher risk of ischemic stroke onset in both warm and cool seasons, and the risk is higher on days with higher levels of relative humidity. Based on this study and the body of literature on ambient temperature and cardiovascular events, identifying methods for mitigating cardiovascular risk may be warranted.
PMCID: PMC3934677  PMID: 24575110
Ischemic stroke; Environment; Particulate matter; Epidemiology

17.  Allergen sensitization is associated with increased DNA methylation in older men 
Variation in epigenetic modifications, arising from either environmental exposures or internal physiological changes, can influence gene expression, and may ultimately contribute to complex diseases such as asthma and allergies. We examined the association of asthma and allergic phenotypes with DNA methylation levels of retrotransposon-derived elements.
We used data from 704 men (mean age 73) in the longitudinal Normative Aging Study to assess the relationship between asthma, allergic phenotypes and DNA methylation levels of the retrotransposon derived elements Alu and LINE-1. Retrotransposons represent a large fraction of the genome (> 30%), and are heavily methylated to prevent expression. Percent methylation of Alu and LINE-1 elements in peripheral white blood cells was quantified using PCR pyrosequencing. Data on sensitization to common allergens by skin prick testing, asthma, and methacholine responsiveness was gathered approximately 8 years prior to DNA methylation analysis.
Prior allergen sensitization was associated with increased methylation of Alu (β=0.32 [sensitized vs. non-sensitized], p value 0.003), in models adjusted for pack-years, BMI, smoking, air pollutants, percent eosinophils, white blood cell count and age. Of the men interviewed, 5 % of subjects reported diagnosis of asthma. Neither Alu, nor LINE-1 methylation was associated with asthma.
These data suggest that increased DNA methylation of repetitive elements may be associated with allergen sensitization, but does not appear to be associated with asthma. Future work is needed to identify potential underlying mechanisms for these relationships.
PMCID: PMC3730837  PMID: 23257623
allergen sensitization; DNA methylation; Alu; and LINE-1
18.  Comparing exposure metrics for classifying ‘dangerous heat’ in heat wave and health warning systems 
Environment International  2012;46:23-29.
Heat waves have been linked to excess mortality and morbidity, and are projected to increase in frequency and intensity with a warming climate. This study compares exposure metrics to trigger heat wave and health warning systems (HHWS), and introduces a novel multi-level hybrid clustering method to identify potential dangerously hot days. Two-level and three-level hybrid clustering analysis as well as common indices used to trigger HHWS, including spatial synoptic classification (SSC); and 90th, 95th, and 99th percentiles of minimum and relative minimum temperature (using a 10 day reference period), were calculated using a summertime weather dataset in Detroit from 1976 to 2006. The days classified as ‘hot’ with hybrid clustering analysis, SSC, minimum and relative minimum temperature methods differed by method type. SSC tended to include the days with, on average, 2.6 °C lower daily minimum temperature and 5.3 °C lower dew point than days identified by other methods. These metrics were evaluated by comparing their performance in predicting excess daily mortality. The 99th percentile of minimum temperature was generally the most predictive, followed by the three-level hybrid clustering method, the 95th percentile of minimum temperature, SSC and others. Our proposed clustering framework has more flexibility and requires less substantial meteorological prior information than the synoptic classification methods. Comparison of these metrics in predicting excess daily mortality suggests that metrics thought to better characterize physiological heat stress by considering several weather conditions simultaneously may not be the same metrics that are better at predicting heat-related mortality, which has significant implications in HHWSs.
PMCID: PMC3401591  PMID: 22673187
Air mass; Heat wave; Heat health warning system; Model-based clustering; Temperature
19.  Repetitive element hypomethylation in blood leukocyte DNA and cancer incidence, prevalence and mortality in elderly individuals: the Normative Aging Study 
Cancer causes & control : CCC  2010;22(3):437-447.
Global genomic hypomethylation is a common epigenetic event in cancer that mostly results from hypomethylation of repetitive DNA elements. Case-control studies have associated blood leukocyte DNA hypomethylation with several cancers. Because samples in case-control studies are collected after disease development, whether DNA hypomethylation is causal or just associated with cancer development is still unclear.
In 722 elderly subjects from the Normative Aging Study cohort, we examined whether DNA methylation in repetitive elements (Alu, LINE-1) was associated with cancer incidence (30 new cases, median follow-up: 89 months), prevalence (205 baseline cases), and mortality (28 deaths, median follow-up: 85 months). DNA methylation was measured by bisulfite pyrosequencing.
Individuals with low LINE-1 methylation (
These findings suggest that individuals with lower repetitive element methylation are at high risk of developing and dying from cancer.
PMCID: PMC3752839  PMID: 21188491
Repetitive elements; DNA methylation; Epigenetics; Blood; Cancer risk
Environmental Health  2013;12:68.
Fine particle (PM2.5) pollution related to combustion sources has been linked to a variety of adverse health outcomes. Although poorly understood, it is possible that organic carbon (OC) species, particularly those from combustion-related sources, may be partially responsible for the observed toxicity of PM2.5. The toxicity of the OC species may be related to their chemical structures; however, few studies have examined the association of OC species with health impacts.
We categorized 58 primary organic compounds by their chemical properties into 5 groups: n-alkanes, hopanes, cyclohexanes, PAHs and isoalkanes. We examined their impacts on the rate of daily emergency hospital admissions among Medicare recipients in Atlanta, GA and Birmingham, AL (2006–2009), and Dallas, TX (2006–2007). We analyzed data in two stages; we applied a case-crossover analysis to simultaneously estimate effects of individual OC species on cause-specific hospital admissions. In the second stage we estimated the OC chemical group-specific effects, using a multivariate weighted regression.
Exposures to cyclohexanes of six days and longer were significantly and consistently associated with increased rate of hospital admissions for CVD (3.40%, 95%CI = (0.64, 6.24%) for 7-d exposure). Similar increases were found for hospitalizations for ischemic heart disease and myocardial infarction. For respiratory related hospital admissions, associations with OC groups were less consistent, although exposure to iso-/anteiso-alkanes was associated with increased respiratory-related hospitalizations.
Results suggest that week-long exposures to traffic-related, primary organic species are associated with increased rate of total and cause-specific CVD emergency hospital admissions. Associations were significant for cyclohexanes, but not hopanes, suggesting that chemical properties likely play an important role in primary OC toxicity.
PMCID: PMC3765898  PMID: 23981468
Emergency hospital admissions; Fine particles; Medicare; Primary organic particles
Epidemiology (Cambridge, Mass.)  2008;19(4):563-570.
Extreme temperatures have been associated with increased mortality worldwide. The extent to which air pollutants may confound or modify this association remains unclear.
We examined the association between mean apparent temperature and total mortality in 9 cities across the United States during the warm season (May to September) from 1999 to 2002. We applied case-crossover and time-series analyses, adjusting for day of the week and season in time-series analysis. City-specific estimates were then combined using a meta-analysis. A total of 213,438 deaths for all causes occurred in these cities during the study period.
We found that mortality increased with apparent temperature. A 5.5°C (10°F) increase in apparent temperature was associated with an increase in mortality of 1.8% (95% confidence interval = 1.09% to 2.5%) when using case-crossover analysis and with an increase of 2.7% (2.0% to 3.5%) using the time-series analysis.
This study provides evidence of increased mortality due to elevated apparent temperature exposure, with no confounding or effect modification due to air pollution.
PMCID: PMC3722554  PMID: 18467963
Epidemiology (Cambridge, Mass.)  2010;21(6):819-828.
Epigenetic features such as DNA hypomethylation have been associated with conditions related to cardiovascular risk. We evaluated whether lower blood DNA methylation in heavily methylated repetitive sequences predicts the risk of ischemic heart disease and stroke.
We quantified blood DNA methylation of LINE-1 repetitive elements through PCR-pyrosequencing in 712 elderly individuals from the Boston-area Normative Aging Study. We estimated risk-factor adjusted relative risks (RRs) for ischemic heart disease and stroke at baseline (242 prevalent cases); as well as in incidence (44 new cases; median follow-up, 63 months); and subsequent mortality from ischemic heart disease (86 deaths; median follow-up, 75 months).
Blood LINE-1 hypomethylation was associated with baseline ischemic heart disease (RR=2.1 [95% confidence interval = 1.2 to 4.0] for lowest vs. highest methylation quartile) and for stroke (2.5 [0.9 to 7.5]). Among participants free of baseline disease, individuals with methylation below the median also had higher risk of developing ischemic heart disease (4.0 [1.8 to 8.9]) or stroke (5.7 [0.8 to 39.5]). In the entire cohort, persons with methylation below the median had higher mortality from ischemic heart disease (3.3 [1.3 to 8.4]) and stroke (2.8 [0.6 to 14.3]). Total mortality was also increased (2.0 [1.2 to 3.3]). These results were confirmed in additional regression models using LINE-1 methylation as a continuous variable.
Subjects with prevalent IHD and stroke exhibited lower LINE-1 methylation. In longitudinal analyses, persons with lower LINE-1 methylation were at higher risk for incident ischemic heart disease and stroke, and for total mortality.
PMCID: PMC3690659  PMID: 20805753
Epidemiology (Cambridge, Mass.)  2012;23(2):332-340.
Previous studies suggest that air pollution is related to thrombosis, inflammation, and endothelial dysfunction. Mechanisms and sources of susceptibility are still unclear. One possibility is that these associations can be modified by DNA methylation states.
We conducted a cohort study with repeated measurements of fibrinogen, C-reactive protein, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in 704 elderly men participating in the Veterans Administration Normative Aging Study (2000-2009). We investigated short- and intermediate-term air pollution effects on these blood markers, and epigene-environment interactions by DNA methylation of Alu, LINE-1, tissue factor (F3), Toll-Like Receptor 2 (TLR-2), and ICAM-1.
We found effects of particle number, black carbon, nitrogen dioxide (NO2), and carbon monoxide (CO) on fibrinogen. Ozone was a significant predictor of C-reactive protein and ICAM-1. Particle number, black carbon, NO2, CO, PM2.5, and sulfates were associated with ICAM-1and VCAM-1. An interquartile range increase in 24-hour exposure for NO2; was associated with a 1.7% (95% confidence interval = 0.2% to 3.3%) increase in fibrinogen for ozone a 10.8% (2.2% to 20.0%) increase in C-reactive protein for particle number, a 5.9% (3.6% to 8.3%) increase in ICAM-1; and for PM2.5 a 3.7% (1.7% to 5.8%) increase in VCAM-1. The air pollution effect was stronger among subjects having higher Alu, lower LINE-1, tissue factor, or TLR-2 methylation status.
We observed associations of traffic-related pollutants on fibrinogen, and both traffic and secondary particles on C-reactive protein, ICAM-1, and VCAM-1. There was effect modification by DNA methylation status, indicating that epigenetic states can convey susceptibility to air pollution.
PMCID: PMC3285258  PMID: 22237295
Environmental Health  2012;11:82.
The health effects of particulate air pollution are widely recognized and there is some evidence that the magnitude of these effects vary by particle component. We studied the effects of ambient fine particles (aerodynamic diameter < 2.5μm, PM2.5) and their components on cause-specific mortality in Santiago, Chile, where particulate pollution is a major public health concern.
Air pollution was collected in a residential area in the center of Santiago. Daily mortality counts were obtained from the National Institute of Statistic. The associations between PM2.5 and cause-specific mortality were studied by time series analysis controlling for time trends, day of the week, temperature and relative humidity. We then included an interaction term between PM2.5 and the monthly averages of the mean ratios of individual elements to PM2.5 mass.
We found significant effects of PM2.5 on all the causes analyzed, with a 1.33% increase (95% CI: 0.87-1.78) in cardiovascular mortality per 10μg/m3 increase in the two days average of PM2.5. We found that zinc was associated with higher cardiovascular mortality. Particles with high content of chromium, copper and sulfur showed stronger associations with respiratory and COPD mortality, while high zinc and sodium content of PM2.5 amplified the association with cerebrovascular disease.
Our findings suggest that PM2.5 with high zinc, chromium, copper, sodium, and sulfur content have stronger associations with mortality than PM2.5 mass alone in Santiago, Chile. The sources of particles containing these elements need to be determined to better control their emissions.
PMCID: PMC3519772  PMID: 23116481
Air pollution; Mortality; PM2.5; Elements
BMJ Open  2012;2(5):e001231.
To investigate the association between methylation of transposable elements Alu and long-interspersed nuclear elements (LINE-1) and lung function.
Cohort study.
Outpatient Veterans Administration facilities in greater Boston, Massachusetts, USA.
Individuals from the Veterans Administration Normative Aging Study, a longitudinal study of aging in men, evaluated between 1999 and 2007. The majority (97%) were white.
Primary and secondary outcome measures
Primary predictor was methylation, assessed using PCR-pyrosequencing after bisulphite treatment. Primary outcome was lung function as assessed by spirometry, performed according to American Thoracic Society/European Respiratory Society guidelines at the same visit as the blood draws.
In multivariable models adjusted for age, height, body mass index (BMI), pack-years of smoking, current smoking and race, Alu hypomethylation was associated with lower forced expiratory volume in 1 s (FEV1) (β=28 ml per 1% change in Alu methylation, p=0.017) and showed a trend towards association with a lower forced vital capacity (FVC) (β=27 ml, p=0.06) and lower FEV1/FVC (β=0.3%, p=0.058). In multivariable models adjusted for age, height, BMI, pack-years of smoking, current smoking, per cent lymphocytes, race and baseline lung function, LINE-1 hypomethylation was associated with more rapid decline of FEV1 (β=6.9 ml/year per 1% change in LINE-1 methylation, p=0.005) and of FVC (β=9.6 ml/year, p=0.002).
In multiple regression analysis, Alu hypomethylation was associated with lower lung function, and LINE-1 hypomethylation was associated with more rapid lung function decline in a cohort of older and primarily white men from North America. Future studies should aim to replicate these findings and determine if Alu or LINE-1 hypomethylation may be due to specific and modifiable environmental exposures.
PMCID: PMC3488751  PMID: 23075571
Epidemiology; Genetics

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