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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.  Modifying roles of glutathione S-transferase polymorphisms on the association between cumulative lead exposure and cognitive function 
Neurotoxicology  2013;0:10.1016/j.neuro.2013.08.002.
Glutathione-S-transferase gene (GST) polymorphisms can result in variable ability of these enzymes to remove electrophilic substrates. We investigated whether the GSTP1 Val105 and GSTM1 deletion polymorphisms modify the lead-cognitive function association.
We used repeated measures analysis to compare the association between cumulative lead biomarkers—bone lead measured using K-shell X-Ray Fluorescence—and Mini-Mental State Exam (MMSE) score by GST variants, adjusted for covariates, among Normative Aging Study participants, a Boston-based prospective cohort of men. We had complete data for 698 men (providing 1292 observations) for GSTM1 analyses and 595 men (providing 1142 observations) for GSTP1 analyses.
A 15 μg/g higher tibia lead concentration (interquartile range of tibia lead) was associated with a 0.24 point decrement in MMSE score among GSTP1 Val105 variant carriers, which was significantly stronger than the association among men with only wild-type alleles (p=0.01). The association among GSTP1 Val105 carriers was comparable to that of 3 years of age in baseline MMSE scores. The association between tibia lead and MMSE score appeared progressively steeper in participants with increasingly more GSTP1 Val105 alleles. A modest association between tibia lead and lower MMSE score was seen among participants with the GSTM1 deletion polymorphism. Neither of the glutathione S-transferase variants was independently associated with cognitive function, nor with lead biomarker measures. The results pertaining to patella lead were similar to those observed for tibia lead.
Our results suggest that the GSTP1 Val105 polymorphism confers excess susceptibility to the cognitive effects of cumulative lead exposure.
PMCID: PMC3844089  PMID: 23958642
Lead; Glutathione S-transferase; Cognitive function; Environmental exposure; Gene-environment interaction
5.  Short-Term Exposure to Air Pollution and Lung Function in the Framingham Heart Study 
Rationale: Short-term exposure to ambient air pollution has been associated with lower lung function. Few studies have examined whether these associations are detectable at relatively low levels of pollution within current U.S. Environmental Protection Agency (EPA) standards.
Objectives: To examine exposure to ambient air pollutants within EPA standards and lung function in a large cohort study.
Methods: We included 3,262 participants of the Framingham Offspring and Third Generation cohorts living within 40 km of the Harvard Supersite monitor in Boston, Massachusetts (5,358 examinations, 1995–2011) who were not current smokers, with previous-day pollutant levels in compliance with EPA standards. We compared lung function (FEV1 and FVC) after previous-day exposure to particulate matter less than 2.5 μm in diameter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) in the “moderate” range of the EPA Air Quality Index to exposure in the “good” range. We also examined linear relationships between moving averages of pollutant concentrations 1, 2, 3, 5, and 7 days before spirometry and lung function.
Measurements and Main Results: Exposure to pollutant concentrations in the “moderate” range of the EPA Air Quality Index was associated with a 20.1-ml lower FEV1 for PM2.5 (95% confidence interval [CI], −33.4, −6.9), a 30.6-ml lower FEV1 for NO2 (95% CI, −60.9, −0.2), and a 55.7-ml lower FEV1 for O3 (95% CI, −100.7, −10.8) compared with the “good” range. The 1- and 2-day moving averages of PM2.5, NO2, and O3 before testing were negatively associated with FEV1 and FVC.
Conclusions: Short-term exposure to PM2.5, NO2, and O3 within current EPA standards was associated with lower lung function in this cohort of adults.
PMCID: PMC3919078  PMID: 24200465
chronic obstructive pulmonary disease; asthma; air pollutants; U.S. Environmental Protection Agency
6.  Short-term airborne particulate matter exposure alters the epigenetic landscape of human genes associated with the mitogen-activated protein kinase network: a cross-sectional study 
Environmental Health  2014;13(1):94.
Exposure to air particulate matter is known to elevate blood biomarkers of inflammation and to increase cardiopulmonary morbidity and mortality. Major components of airborne particulate matter typically include black carbon from traffic and sulfates from coal-burning power plants. DNA methylation is thought to be sensitive to these environmental toxins and possibly mediate environmental effects on clinical outcomes via regulation of gene networks. The underlying mechanisms may include epigenetic modulation of major inflammatory pathways, yet the details remain unclear.
We sought to elucidate how short-term exposure to air pollution components, singly and/or in combination, alter blood DNA methylation in certain inflammation-associated gene networks, MAPK and NF-κB, which may transmit the environmental signal(s) and influence the inflammatory pathway in vivo. To this end, we utilized a custom-integrated workflow—molecular processing, pollution surveillance, biostatical analysis, and bioinformatic visualization—to map novel human (epi)gene pathway-environment interactions.
Specifically, out of 84 MAPK pathway genes considered, we identified 11 whose DNA methylation status was highly associated with black carbon exposure, after adjusting for potential confounders—age, sulfate exposure, smoking, blood cell composition, and blood pressure. Moreover, after adjusting for these confounders, multi-pollutant analysis of synergistic DNA methylations significantly associated with sulfate and BC exposures yielded 14 MAPK genes. No associations were found with the NF-κB pathway.
Exposure to short-term air pollution components thus resulted in quantifiable epigenetic changes in the promoter areas of MAPK pathway genes. Bioinformatic mapping of single- vs. multi-exposure-associated epigenetic changes suggests that these alterations might affect biological pathways in nuanced ways that are not simply additive or fully predictable via individual-level exposure assessments.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-069X-13-94) contains supplementary material, which is available to authorized users.
PMCID: PMC4273424  PMID: 25395096
7.  Residential Proximity to High Traffic Roadways and Post-Stroke Mortality 
Living in areas with higher levels of ambient air pollution has been associated with a higher incidence of ischemic stroke and all-cause mortality, but less is known about the relationship between traffic related pollution and long term survival following stroke.
We identified consecutive patients admitted to Beth Israel Deaconess Medical Center with ischemic stroke between 1999 and 2008 and determined distance to the nearest roadway with an average daily traffic count >10,000 vehicles/day. Categories of residential proximity were defined as ≤100 meters (m), 100 to 200, 200 to ≤400 or > 400m from a busy roadway. We identified deaths through June 2012 using the Social Security Death Index and used Cox proportional hazards models adjusted for medical history, and socioeconomic factors to calculate hazard ratios for the association between residential proximity to a high traffic roadway and all-cause mortality.
Among 1683 stroke patients with complete data, there were 950 deaths [median follow-up = 4.6 years]. We observed higher post-stroke mortality among people living closer to high traffic roadways. Patients living ≤100m from high traffic roadways had a 20% (95% CI: 1%, 43%) higher rate of post-stroke mortality than patients living >400m away (p-trend=0.02).
In this study, living close to a high traffic roadway was associated with an elevated mortality rate. This relationship remained statistically significant after adjustment for individual and neighborhood- level factors, providing evidence that traffic-related pollution is associated with a higher mortality rate among stroke survivors.
PMCID: PMC4066388  PMID: 23721619
8.  Blood pressure and cognition:Factors that may account for their inconsistent association 
Epidemiology (Cambridge, Mass.)  2013;24(6):10.1097/EDE.0b013e3182a7121c.
Studies of hypertension and cognition variously report adverse, null and protective associations. We evaluated evidence supporting three potential explanations for this variation: an effect of hypertension duration, an effect of age at hypertension initiation, and selection bias due to dependent censoring.
The Normative Aging Study is a prospective cohort study of men in the greater Boston area. Participants completed study visits, including hypertension assessment, every 3-5 years starting in 1961. 758 of 1284 men eligible at baseline completed cognitive assessment between 1992 and 2005; we used the mean age-adjusted cognitive test z-score from their first assessment to quantify cognition. We estimated how becoming hypertensive and increasing age at onset and duration since hypertension initiation affect cognition. We used inverse probability of censoring weights to reduce and quantify selection bias.
A history of hypertension diagnosis predicted lower cognition. Increasing duration since hypertension initiation predicted lower mean cognitive z-score (-0.02 standard units per year increase [95% confidence interval= -0.04 to -0.001]), independent of age at onset. Comparing participants with and without hypertension, we observed noteworthy differences in mean cognitive score only for those with a long duration since hypertension initiation, regardless of age at onset. Age at onset was not associated with cognition independent of duration. Analyses designed to quantify selection bias suggested upward bias.
Previous findings of null or protective associations between hypertension and cognition likely reflect the study of persons with short duration since hypertension initiation. Selection bias may also contribute to cross-study heterogeneity.
PMCID: PMC3818218  PMID: 24030502
9.  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
10.  Prenatal Organochlorine and Methylmercury Exposure and Memory and Learning in School-Age Children in Communities Near the New Bedford Harbor Superfund Site, Massachusetts 
Environmental Health Perspectives  2014;122(11):1253-1259.
Background: Polychlorinated biphenyls (PCBs), organochlorine pesticides, and methylmercury (MeHg) are environmentally persistent with adverse effects on neurodevelopment. However, especially among populations with commonly experienced low levels of exposure, research on neurodevelopmental effects of these toxicants has produced conflicting results.
Objectives: We assessed the association of low-level prenatal exposure to these contaminants with memory and learning.
Methods: We studied 393 children, born between 1993 and 1998 to mothers residing near a PCB-contaminated harbor in New Bedford, Massachusetts. Cord serum PCB, DDE (dichlorodiphenyldichloroethylene), and maternal peripartum hair mercury (Hg) levels were measured to estimate prenatal exposure. Memory and learning were assessed at 8 years of age (range, 7–11 years) using the Wide Range Assessment of Memory and Learning (WRAML), age-standardized to a mean ± SD of 100 ± 15. Associations with each WRAML index—Visual Memory, Verbal Memory, and Learning—were examined with multivariable linear regression, controlling for potential confounders.
Results: Although cord serum PCB levels were low (sum of four PCBs: mean, 0.3 ng/g serum; range, 0.01–4.4), hair Hg levels were typical of the U.S. fish-eating population (mean, 0.6 μg/g; range, 0.3–5.1). In multivariable models, each microgram per gram increase in hair Hg was associated with, on average, decrements of –2.8 on Visual Memory (95% CI: –5.0, –0.6, p = 0.01), –2.2 on Learning (95% CI: –4.6, 0.2, p = 0.08), and –1.7 on Verbal Memory (95% CI: –3.9, 0.6, p = 0.14). There were no significant adverse associations of PCBs or DDE with WRAML indices.
Conclusions: These results support an adverse relationship between low-level prenatal MeHg exposure and childhood memory and learning, particularly visual memory.
Citation: Orenstein ST, Thurston SW, Bellinger DC, Schwartz JD, Amarasiriwardena CJ, Altshul LM, Korrick SA. 2014. Prenatal organochlorine and methylmercury exposure and memory and learning in school-age children in communities near the New Bedford Harbor Superfund Site, Massachusetts. Environ Health Perspect 122:1253–1259;
PMCID: PMC4216164  PMID: 25062363
11.  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
12.  Air pollution exposure and lung function in highly exposed subjects in Beijing, China: a repeated-measure study 
Exposure to ambient particulate matter (PM) has been associated with reduced lung function. Elemental components of PM have been suggested to have critical roles in PM toxicity, but their contribution to respiratory effects remains under-investigated. We evaluated the effects of traffic-related PM2.5 and its elemental components on lung function in two highly exposed groups of healthy adults in Beijing, China.
The Beijing Truck Driver Air Pollution Study (BTDAS) included 60 truck drivers and 60 office workers evaluated in 2008. On two days separated by 1-2 weeks, we measured lung function at the end of the work day, personal PM2.5, and nine elemental components of PM2.5 during eight hours of work, i.e., elemental carbon (EC), potassium (K), sulfur (S), iron (Fe), silicon (Si), aluminum (Al), zinc (Zn), calcium (Ca), and titanium (Ti). We used covariate-adjusted mixed-effects models including PM2.5 as a covariate to estimate the percentage change in lung function associated with an inter-quartile range (IQR) exposure increase.
The two groups had high and overlapping exposure distributions with mean personal PM2.5 of 94.6 μg/m3 (IQR: 48.5-126.6) in office workers and 126.8 μg/m3 (IQR: 73.9-160.5) in truck drivers. The distributions of the nine elements showed group-specific profiles and generally higher levels in truck drivers. In all subjects combined, forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) did not significantly correlate with PM2.5. However, FEV1 showed negative associations with concentrations of four elements: Si (-3.07%, 95% CI: -5.00; -1.11, IQR: 1.54), Al (-2.88%, 95% CI: -4.91; -0.81, IQR: 0.86), Ca (-1.86%, 95% CI: -2.95; -0.76, IQR: 1.33), and Ti (-2.58%, 95% CI: -4.44; -0.68, IQR: 0.03), and FVC showed negative associations with concentrations of three elements: Si (-3.23%, 95% CI: -5.61; -0.79), Al (-3.26%, 95% CI: -5.73; -0.72), and Ca (-1.86%, 95% CI: -3.23; -0.47). In stratified analysis, Si, Al, Ca, and Ti showed associations with lung function only among truck drivers, and no significant association among office workers.
Selected elemental components of PM2.5 showed effects on lung function that were not found in analyses of particle levels alone.
Electronic supplementary material
The online version of this article (doi:10.1186/s12989-014-0051-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4192276  PMID: 25272992
Lung function; Metals; Particulate matter; Traffic exposure; FEV1; FVC
13.  A prototype tobacco-associated oral squamous cell carcinoma classifier using RNA from brush cytology 
Oral cancer in the form of squamous cell carcinoma (OSCC) is typically detected in advanced stages when treatment is complex and may not be curative. The need for surgical biopsy may contribute to delays in diagnosis and impede early detection. Multiple studies of RNA from surgically obtained tumor samples have revealed many genes differentially expressed with this disease. We sought to determine if the identified mRNAs could be used as markers by a noninvasive detection system for OSCC using RNA from brush cytology.
Levels of mRNAs from 21 genes known to be differentially expressed in head and neck squamous cell carcinoma surgical samples, compared to controls, were shown to be quantifiable in oral brush cytology samples. These mRNAs were quantified in a training set of 14 tumor and 20 nonmalignant brush cytology samples from tobacco/betel nut users. The measurement of two additional mRNAs and analysis using support vector machines produced an algorithm for class prediction of these cancers.
This OSCC classifier based on the levels of 5 mRNAs in RNA from brush cytology initially showed 0.93 sensitivity and 0.91 specificity in differentiating OSCC from benign oral mucosal lesions based on leave-one-out cross-validation. When used on a test set of 19 samples from 6 OSCCs and 13 nonmalignant oral lesions we found misclassification of only one OSCC and one benign lesion.
This shows the promise of using RNA from brush cytology for early OSCC detection and the potential for clinical usage of this noninvasive classifier.
PMCID: PMC3740027  PMID: 23590359
oral squamous cell carcinoma; brush cytology; RNA; gene expression; tobacco
14.  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
15.  The Association of Meningococcal Disease with Influenza in the United States, 1989–2009 
PLoS ONE  2014;9(9):e107486.
Importance and Objective
Prior influenza infection is a risk factor for invasive meningococcal disease. Quantifying the fraction of meningococcal disease attributable to influenza could improve understanding of viral-bacterial interaction and indicate additional health benefits to influenza immunization.
Design, Setting and Participants
A time series analysis of the association of influenza and meningococcal disease using hospitalizations in 9 states from 1989–2009 included in the State Inpatient Databases from the Agency for Healthcare Research and Quality and the proportion of positive influenza tests by subtype reported to the Centers for Disease Control. The model accounts for the autocorrelation of meningococcal disease and influenza between weeks, temporal trends, co-circulating respiratory syncytial virus, and seasonality. The influenza-subtype-attributable fraction was estimated using the model coefficients. We analyzed the synchrony of seasonal peaks in hospitalizations for influenza, respiratory syncytial virus, and meningococcal disease.
Results and Conclusions
In 19 of 20 seasons, influenza peaked≤2 weeks before meningococcal disease, and peaks were highly correlated in time (ρ = 0.95; P <.001). H3N2 and H1N1 peaks were highly synchronized with meningococcal disease while pandemic H1N1, B, and respiratory syncytial virus were not. Over 20 years, 12.8% (95% CI, 9.1–15.0) of meningococcal disease can be attributable to influenza in the preceding weeks with H3N2 accounting for 5.2% (95% CI, 3.0–6.5), H1N1 4.3% (95% CI, 2.6–5.6), B 3.0% (95% CI, 0.8–4.9) and pH1N1 0.2% (95% CI, 0–0.4). During the height of influenza season, weekly attributable fractions reach 59%. While vaccination against meningococcal disease is the most important prevention strategy, influenza vaccination could provide further protection, particularly in young children where the meningococcal disease vaccine is not recommended or protective against the most common serogroup.
PMCID: PMC4180274  PMID: 25265409
16.  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
17.  Effect modification by Transferrin C2 polymorphism on lead exposure, hemoglobin levels, and IQ 
Neurotoxicology  2013;38:17-22.
Iron deficiency and lead exposure remain significant public health issues in many parts of the world and are both independently associated with neurocognitive deficits. Polymorphisms in iron transport pathways have been shown to modify the absorption and toxicity of lead.
We hypothesized that the transferrin (TF) C2 polymorphism modifies the effects of lead and hemoglobin on intelligence.
Children aged 3–7 years (N=708) were enrolled from 12 primary schools in Chennai, India. The Binet-Kamat Scale of Intelligence were administered to ascertain intelligence quotient (IQ). Venous blood was analyzed for lead and hemoglobin levels. Genotyping for the TF C2 polymorphism (rs1049296) was carried out using a MassARRAY iPLEXTM platform. Stratified analyses and interaction models, using generalized estimating equations, were examined to explore interactions between lead, hemoglobin, and TF C2 categories.
A one-unit increase in log blood lead and 1 g/dl higher hemoglobin was associated with −7.7 (95% CI: −13.6, −1.8) and 1.7 (95% CI 1.4, 2.1) IQ points, respectively, among children carrying the C2 variant. In comparison, among children who had the homozygous wildtype allele, the same increment of lead and hemoglobin were associated with -−2.1(95% CI: −6.5, 2.4) and 2.8(95% CI:1.5, 4.0) IQ points, respectively. There was a significant interaction between lead (p=0.04) and hemoglobin (p=0.07) with the C2 variant.
Children who carry the TF C2 variant may be more susceptible to the neurotoxic effects of lead exposure and less protected by higher levels of hemoglobin.
PMCID: PMC3770761  PMID: 23732512
lead; hemoglobin; iron; transferrin; intelligence quotient (IQ); genotype
18.  Using Forecast and Observed Weather Data to Assess Performance of Forecast Products in Identifying Heat Waves and Estimating Heat Wave Effects on Mortality 
Environmental Health Perspectives  2014;122(9):912-918.
Background: Heat wave and health warning systems are activated based on forecasts of health-threatening hot weather.
Objective: We estimated heat–mortality associations based on forecast and observed weather data in Detroit, Michigan, and compared the accuracy of forecast products for predicting heat waves.
Methods: We derived and compared apparent temperature (AT) and heat wave days (with heat waves defined as ≥ 2 days of daily mean AT ≥ 95th percentile of warm-season average) from weather observations and six different forecast products. We used Poisson regression with and without adjustment for ozone and/or PM10 (particulate matter with aerodynamic diameter ≤ 10 μm) to estimate and compare associations of daily all-cause mortality with observed and predicted AT and heat wave days.
Results: The 1-day-ahead forecast of a local operational product, Revised Digital Forecast, had about half the number of false positives compared with all other forecasts. On average, controlling for heat waves, days with observed AT = 25.3°C were associated with 3.5% higher mortality (95% CI: –1.6, 8.8%) than days with AT = 8.5°C. Observed heat wave days were associated with 6.2% higher mortality (95% CI: –0.4, 13.2%) than non–heat wave days. The accuracy of predictions varied, but associations between mortality and forecast heat generally tended to overestimate heat effects, whereas associations with forecast heat waves tended to underestimate heat wave effects, relative to associations based on observed weather metrics.
Conclusions: Our findings suggest that incorporating knowledge of local conditions may improve the accuracy of predictions used to activate heat wave and health warning systems.
Citation: Zhang K, Chen YH, Schwartz JD, Rood RB, O’Neill MS. 2014. Using forecast and observed weather data to assess performance of forecast products in identifying heat waves and estimating heat wave effects on mortality. Environ Health Perspect 122:912–918;
PMCID: PMC4154209  PMID: 24833618
19.  Acute Exposure to Air Pollution Triggers Atrial Fibrillation 
The aim of the present study is to evaluate the association of air pollution with the onset of atrial fibrillation (AF).
Air pollution in general and more specifically particulate matter has been associated with cardiovascular events. Although ventricular arrhythmias are traditionally thought to convey the increased cardiovascular risk, AF may also contribute.
Patients with dual chamber implantable cardioverter defibrillators (ICDs) were enrolled and followed prospectively. The association of AF onset with air quality including ambient PM2.5, black carbon, sulfate, particle number, NO2, SO2, and O3 in the 24 hours prior to the arrhythmia was examined utilizing a case-crossover analysis. In sensitivity analyses, associations with air pollution between 2 and 48 hours prior to the AF were examined.
Of 176 patients followed for an average of 1.9 years, 49 patients had 328 episodes of AF lasting ≥ 30 seconds. Positive but nonsignificant associations were found for PM2.5 in the prior 24 hours, but stronger associations were found with shorter exposure windows. The odds of AF increased by 26% (95% CI 8% to 47%) for each 6.0 µg/m3 increase in PM2.5 in the 2 hours prior to the event (p=0.004). The odds of AF was highest at the upper quartile of mean PM2.5.
Particulate matter was associated with increased odds of AF onset within hours following exposure in patients with known cardiac disease. Air pollution is an acute trigger of AF, likely contributing to the pollution-associated adverse cardiac outcomes observed in epidemiological studies.
PMCID: PMC3752319  PMID: 23770178
Air pollution; Atrial fibrillation; Particulate matter; Traffic
20.  Automatic Determination of an Anatomical Coordinate System for a Three-Dimensional Model of the Human Patella 
Journal of biomechanics  2013;46(12):2093-2096.
Measuring the in vivo 3-D kinematics of the patella requires a repeatable anatomical coordinate system (ACS). The purpose of this study was to develop an algorithm to determine an ACS using the patella’s unique morphology.
An ACS was automatically constructed that aligned the proximal/distal (PD) axis with the posterior vertical ridge. Inter-subject ACS repeatability was determined by registering all patellae and their associated ACSs to a reference patella.
The mean angle between the reference patella ACS and each subject's axes was less than 2.5° and the 95%CI was1.0°−4.0.
Here, we presented an anatomical coordinate system that is independent of the observer’s subjective judgement or orientation of the knee within the scanner.
PMCID: PMC3729621  PMID: 23791087
Patella; Kinematics; Biplanar Videoradiography; Computed Tomography; Anatomical Coordinate System; In Vivo; Patellofemoral
21.  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
22.  Influence of multiple APOE genetic variants on cognitive function in a cohort of older men – results from the Normative Aging Study 
BMC Psychiatry  2014;14(1):223.
APOE is the biomarker with the greatest known influence on cognitive function; however, the effect of complex haplotypes involving polymorphisms rs449647, rs405509, rs440446, rs429358 and rs7412 has never been studied in older populations.
We evaluated APOE polymorphisms using multiplex PCR for genotyping and Mini-Mental State Examination (MMSE) to evaluate cognitive function in 819 individuals from VA Normative Aging Study.
Combinatorial analysis of all polymorphisms and individual analysis of polymorphisms rs449647, rs405509, rs440446 and rs7412 did not show any association with cognitive performance. Polymorphism rs429358 was associated with better cognitive performance (odds of MMSE ≤ 25 = 0.63, 95% CI 0.42-0.95; p = 0.03) in the oldest subsample (5th quintile of age) (odds of MMSE ≤ 25 = 0.34; 95% CI 0.13-0.86; p = 0.02). APOE allele ε4 was also associated with better cognitive performance (odds of MMSE ≤ 25 = 0.61, 95% CI 0.40-0.94; p = 0.02), also in the oldest subsample (odds of MMSE ≤ 25 = 0.35, 95% CI 0.14-0.90; p = 0.03).
These results suggest a beneficial effect of polymorphism rs429358 in the oldest men.
Electronic supplementary material
The online version of this article (doi:10.1186/s12888-014-0223-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4149270  PMID: 25085564
APOE; Epsilon; Alleles; Haplotypes; Cognitive decline; Aging; Genetic variants
23.  Reduced lung cancer mortality and exposure to synthetic fluids and biocide in the auto manufacturing industry 
Water-based soluble and synthetic metalworking fluids (MWF) used in auto manufacturing may be contaminated by endotoxin from Gram-negative bacteria, a possible anticarcinogen via increased immuno-surveillance. The effectiveness of biocide, generally added to limit bacterial growth is unknown. We investigated whether an inverse relationship between lung cancer and synthetic MWF and biocide – as surrogates of endotoxin exposure – persisted in an extended follow-up of autoworkers.
A nested case–control analysis was performed within a retrospective cohort study of 46 399 auto manufacturing workers. Follow-up began in 1941 and was extended from 1985–1995. Mortality rate ratios (MRR) were estimated in Cox regression models for lung cancer as discrete and smoothed functions of cumulative exposure to synthetic MWF (mg/m3 per year) and years exposed to biocide with both synthetic and soluble MWF. The analysis was also restricted to the subcohort hired on or after 1941 and stratified by follow-up period.
The splines suggested a non-linear inverse exposure–response for lung cancer mortality with increasing endotoxin exposure. Overall, the greatest reduction in mortality was observed among those with the highest exposure [MRR 0.63, 95% confidence interval (95% CI) 0.39–0.98] at the 99th percentile of exposure (15.8 mg/m3 per year). Evidence for an inverse effect was limited to the earlier follow-up period. Effect modification by biocide was marginally significant (P=0.07); the protective effect of synthetic MWF was observed only for those who were co-exposed.
The protective effect of synthetic MWF against lung cancer mortality persisted through the extended period of follow-up, although attenuated, and was observed only among workers with co-exposure to biocide and synthetic MWF.
PMCID: PMC4108426  PMID: 20835688
auto manufacturing industry; biocide; cohort study; endotoxin; exposure; lung cancer; lung cancer mortality; metalworking fluid; mortality; occupational epidemiology; retrospective cohort study; synthetic biocide; synthetic fluid
24.  Ambient Air Pollution and Depressive Symptoms in Older Adults: Results from the MOBILIZE Boston Study 
Environmental Health Perspectives  2014;122(6):553-558.
Background: Exposure to ambient air pollution, particularly from traffic, has been associated with adverse cognitive outcomes, but the association with depressive symptoms remains unclear.
Objectives: We investigated the association between exposure to ambient air and traffic pollution and the presence of depressive symptoms among 732 Boston-area adults ≥ 65 years of age (78.1 ± 5.5 years, mean ± SD).
Methods: We assessed depressive symptoms during home interviews using the Revised Center for Epidemiological Studies Depression Scale (CESD-R). We estimated residential distance to the nearest major roadway as a marker of long-term exposure to traffic pollution and assessed short-term exposure to ambient fine particulate matter (PM2.5), sulfates, black carbon (BC), ultrafine particles, and gaseous pollutants, averaged over the 2 weeks preceding each assessment. We used generalized estimating equations to estimate the odds ratio (OR) of a CESD-R score ≥ 16 associated with exposure, adjusting for potential confounders. In sensitivity analyses, we considered CESD-R score as a continuous outcome and mean annual residential BC as an alternate marker of long-term exposure to traffic pollution.
Results: We found no evidence of a positive association between depressive symptoms and long-term exposure to traffic pollution or short-term changes in pollutant levels. For example, we found an OR of CESD-R score ≥ 16 of 0.67 (95% CI: 0.46, 0.98) per interquartile range (3.4 μg/m3) increase in PM2.5 over the 2 weeks preceding assessment.
Conclusions: We found no evidence suggesting that ambient air pollution is associated with depressive symptoms among older adults living in a metropolitan area in attainment of current U.S. regulatory standards.
Citation: Wang Y, Eliot MN, Koutrakis P, Gryparis A, Schwartz JD, Coull BA, Mittleman MA, Milberg WP, Lipsitz LA, Wellenius GA. 2014. Ambient air pollution and depressive symptoms in older adults: results from the MOBILIZE Boston Study. Environ Health Perspect 122:553–558;
PMCID: PMC4050499  PMID: 24610154
25.  Epigenetic Influences on Associations between Air Pollutants and Lung Function in Elderly Men: The Normative Aging Study 
Environmental Health Perspectives  2014;122(6):566-572.
Background: Few studies have been performed on pulmonary effects of air pollution in the elderly—a vulnerable population with low reserve capacity—and mechanisms and susceptibility factors for potential effects are unclear.
Objectives: We evaluated the lag structure of air pollutant associations with lung function and potential effect modification by DNA methylation (< or ≥ median) at 26 individual CpG sites in nine candidate genes in a well-characterized cohort of elderly men.
Methods: We measured forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1), and blood DNA methylation one to four times between 1999 and 2009 in 776 men from the Normative Aging Study. Air pollution was measured at fixed monitors 4 hr to 28 days before lung function tests. We used linear mixed-effects models to estimate the main effects of air pollutants and effect modification by DNA methylation.
Results: An interquartile range (IQR) increase in subchronic exposure (3 to 28 days cumulated), but not in acute exposure (during the previous 4 hr, or the current or previous day), to black carbon, total and nontraffic particles with aerodynamic diameter ≤ 2.5 μm (PM2.5), carbon monoxide, and nitrogen dioxide was associated with a 1–5% decrease in FVC and FEV1 (p < 0.05). Slope estimates were greater for FVC than FEV1, and increased with cumulative exposure. The estimates slopes for air pollutants (28 days cumulated) were higher in participants with low (< median) methylation in TLR2 at position 2 and position 5 and high (≥ median) methylation in GCR.
Conclusions: Subchronic exposure to traffic-related pollutants was associated with significantly reduced lung function in the elderly; nontraffic pollutants (particles, ozone) had weaker associations. Epigenetic mechanisms related to inflammation and immunity may influence these associations.
Citation: Lepeule J, Bind MAC, Baccarelli AA, Koutrakis P, Tarantini L, Litonjua A, Sparrow D, Vokonas P, Schwartz JD. 2014. Epigenetic influences on associations between air pollutants and lung function in elderly men: the Normative Aging Study. Environ Health Perspect 122:566–572;
PMCID: PMC4050500  PMID: 24602767

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