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Mediation analysis is a valuable approach to examine pathways in epidemiological research. Prospective cohort studies are often conducted to study biological mechanisms and often collect longitudinal measurements on each participant. Mediation formulae for longitudinal data have been developed. Here, we formalize the natural direct and indirect effects using a causal framework with potential outcomes that allows for an interaction between the exposure and the mediator. To allow different types of longitudinal measures of the mediator and outcome, we assume two generalized mixed-effects models for both the mediator and the outcome. The model for the mediator has subject-specific random intercepts and random exposure slopes for each cluster, and the outcome model has random intercepts and random slopes for the exposure, the mediator, and their interaction. We also expand our approach to settings with multiple mediators and derive the mediated effects, jointly through all mediators. Our method requires the absence of time-varying confounding with respect to the exposure and the mediator. This assumption is achieved in settings with exogenous exposure and mediator, especially when exposure and mediator are not affected by variables measured at earlier time points. We apply the methodology to data from the Normative Aging Study and estimate the direct and indirect effects, via DNA methylation, of air pollution, and temperature on intercellular adhesion molecule 1 (ICAM-1) protein levels. Our results suggest that air pollution and temperature have a direct effect on ICAM-1 protein levels (i.e. not through a change in ICAM-1 DNA methylation) and that temperature has an indirect effect via a change in ICAM-1 DNA methylation. [ABSTRACT FROM AUTHOR]

Epidemiological studies investigating the human health effects of PM2.5 are susceptible to exposure measurement errors, a form of bias in exposure estimates, since they rely on data from a limited number of PM2.5 monitors within their study area. Satellite data can be used to expand spatial coverage, potentially enhancing our ability to estimate location- or subject-specific exposures to PM2.5, but some have reported poor predictive power. A new methodology was developed to calibrate aerosol optical depth (AOD) data obtained from the Moderate Resolution Imaging Spectroradiometer (MODIS). Subsequently, this method was used to predict ground daily PM 2.5 concentrations in the New England region. 2003 MODIS AOD data corresponding to the New England region were retrieved, and PM 2.5 concentrations measured at 26 US Environmental Protection Agency (EPA) PM2.5 monitoring sites were used to calibrate the AOD data. A mixed effects model which allows day-today variability in daily PM2.5-AOD relationships was used to predict location-specific PM 2.5 levels. PM2.5 concentrations measured at the monitoring sites were compared to those predicted for the corresponding grid cells. Both cross-sectional and longitudinal comparisons between the observed and predicted concentrations suggested that the proposed new calibration approach renders MODIS AOD data a potentially useful predictor of PM2.5 concentrations. Furthermore, the estimated PM2.5 levels within the study domain were examined in relation to air pollution sources. Our approach made it possible to investigate the spatial patterns of PM2.5 concentrations within the study domain. [ABSTRACT FROM AUTHOR]

Background: Long-term exposure to particulate air pollution has been associated with an increased risk of dying from cardiopulmonary and ischemic heart disease, yet few studies have evaluated cardiovascular end points other than mortality. We investigated the relationship between long-term exposure to traffic and occurrence of acute myocardial infarction (AMI) in a case-control study.Methods: A total of 5,049 confirmed cases of AMI were identified between 1995 and 2003 as part of the Worcester Heart Attack Study, a community-wide study examining changes over time in the incidence of AMI among greater Worcester, Massachusetts, residents. Population controls were selected from Massachusetts resident lists. We used cumulative traffic within 100 m of subjects' residence and distance from major roadway as proxies for exposure to traffic-related air pollution. We estimated the relationship between exposure to traffic and occurrence of AMI using logistic regression, and we adjusted for the following potential confounders: age, sex, section of the study area, point sources emissions of particulate matter with aerodynamic diameter < 2.5 microm, area socioeconomic characteristics, and percentage of open space.Results: An increase in cumulative traffic near the home was associated with a 4% increase in the odds of AMI per interquartile range [95% confidence interval (CI), 2-7%], whereas living near a major roadway was associated with a 5% increase in the odds of AMI per kilometer (95% CI, 3-6%).Conclusions: These results provide support for an association between long-term exposure to traffic and the risk of AMI. [ABSTRACT FROM AUTHOR]

Epidemiological studies have reported increased morbidity in human populations following inhalation of elevated levels of urban particulate matter. These responses are especially prevalent in populations with chronic obstructive pulmonary diseases, including chronic bronchitis. Toxicological studies have reported altered pulmonary function and increased pulmonary inflammation following particulate inhalation in the laboratory setting. However, most of these studies have utilized artificial particles that may not accurately mimic outdoor air pollutant conditions. Few studies have utilized actual urban air particle samples in inhalation studies. In the present study, the effects of inhaled concentrated urban air particulates on pulmonary function and pulmonary inflammation are addressed. Normal rats and rats with chronic bronchitis induced by ~200 ppm SO2 for 6 wk were subsequently subjected to filtered air or concentrated air particles (CAPs). Twelve rats per group in 4 groups (48 rats total) were exposed for 5h/day for 3 consecutive days. The CAPs aerosol levels were 206, 733, and 607 mug/m3 (MMAD=0.18 mum, sigmag=2.9) on days 1, 2, and 3, respectively. Following the final day of exposure, pulmonary function parameters, including peak expiratory flow (PEF), tidal volume (TV), respiratory frequency (RF), and minute volume (MV), were measured and compared to preexposure baseline levels. Twenty-four hours following the final day of exposure, bronchoalveolar lavage was performed for total cell counts, differential cell counts, and total lavage protein levels. Pulmonary responses to CAPs in chronic bronchitic animals indicated a significant increase in tidal volume as well as peak expiratory flow. In CAPs-exposed animals without underlying bronchitis, significantly increased tidal volume was observed. Significant pulmonary inflammation was observed in the CAPs-exposed animals, particularly those with chronic bronchitis. Significant increases in neutrophils, lymphocytes, and total lavage protein were observed. These results suggest two distinct mechanistic responses to inhaled particles: a stress-type pulmonary function response marked by increases in flow and volume, that is, deeper breathing; and acute pulmonary inflammation marked by cellular influx, particularly neutrophils. From these data it is concluded that inhaled urban air particles alter pulmonary breathing parameters and increase pulmonary inflammation. [ABSTRACT FROM AUTHOR]