Exposure to sub-chronic and long-term particulate air pollution and heart rate variability in an elderly cohort: the Normative Aging Study

Background: Short-term particulate air pollution exposure is associated with reduced heart rate variability (HRV), a risk factor for cardiovascular morbidity and mortality, in many studies. Associations with sub-chronic or long-term exposures, however, have been sparsely investigated. We evaluated the effect of fine particulate matter (PM2.5) and black carbon (BC) exposures on HRV in an elderly cohort: the Normative Aging Study. Methods: We measured power in high frequency (HF) and low frequency (LF), standard deviation of normal-to-normal intervals (SDNN), and the LF:HF ratio among participants from the Greater Boston area. Residential BC exposures for 540 men (1161 study visits, 2000–2011) were estimated using a spatio-temporal land use regression model, and residential PM2.5 exposures for 475 men (992 visits, 2003–2011) were modeled using a hybrid satellite based and land-use model. We evaluated associations between moving averages of sub-chronic (3–84 day) and long-term (1 year) pollutant exposure estimates and HRV parameters using linear mixed models. Results: One-standard deviation increases in sub-chronic, but not long-term, BC were associated with reduced HF, LF, and SDNN and an increased LF:HF ratio (e.g., 28 day BC: −2.3 % HF [95 % CI:−4.6, −0.02]). Sub-chronic and long-term PM2.5 showed evidence of relations to an increased LF and LF:HF ratio (e.g., 1 year PM: 21.0 % LF:HF [8.6, 34.8]), but not to HF or SDNN, though the effect estimates were very imprecise and mostly spanned the null. Conclusions: We observed some evidence of a relation between longer-term BC and PM2.5 exposures and changes in HRV in an elderly cohort. While previous studies focused on short-term air pollution exposures, our results suggest that longer-term exposures may influence cardiac autonomic function. Electronic supplementary material The online version of this article (doi:10.1186/s12940-015-0074-z) contains supplementary material, which is available to authorized users

Changing body habitus among healthy older men: The NAS Boston VA study of weight stability in healthy male volunteers aged 40-80 years

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28972/1/0000809.pd

Improving estimation and prediction in linear regression incorporating external information from an established reduced model

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143779/1/sim7600_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143779/2/sim7600.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143779/3/sim7600-sup-0001-Supplementary.pd

Novel Likelihood Ratio Tests for Screening Gene‐Gene and Gene‐Environment Interactions With Unbalanced Repeated‐Measures Data

There has been extensive literature on modeling gene‐gene interaction (GGI) and gene‐environment interaction (GEI) in case‐control studies with limited literature on statistical methods for GGI and GEI in longitudinal cohort studies. We borrow ideas from the classical two‐way analysis of variance literature to address the issue of robust modeling of interactions in repeated‐measures studies. While classical interaction models proposed by Tukey and Mandel have interaction structures as a function of main effects, a newer class of models, additive main effects and multiplicative interaction (AMMI) models, do not have similar restrictive assumptions on the interaction structure. AMMI entails a singular value decomposition of the cell residual matrix after fitting the additive main effects and has been shown to perform well across various interaction structures. We consider these models for testing GGI and GEI from two perspectives: likelihood ratio test based on cell means and a regression‐based approach using individual observations. Simulation results indicate that both approaches for AMMI models lead to valid tests in terms of maintaining the type I error rate, with the regression approach having better power properties. The performance of these models was evaluated across different interaction structures and 12 common epistasis patterns. In summary, AMMI model is robust with respect to misspecified interaction structure and is a useful screening tool for interaction even in the absence of main effects. We use the proposed methods to examine the interplay between the hemochromatosis gene and cumulative lead exposure on pulse pressure in the Normative Aging Study.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99643/1/gepi21744-sup-0001-si.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/99643/2/gepi21744.pd

A Novel Genetic Score Approach Using Instruments to Investigate Interactions between Pathways and Environment: Application to Air Pollution

Air pollution has been associated with increased systemic inflammation markers. We developed a new pathway analysis approach to investigate whether gene variants within relevant pathways (oxidative stress, endothelial function, and metal processing) modified the association between particulate air pollution and fibrinogen, C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). Our study population consisted of 822 elderly participants of the Normative Aging Study (1999–2011). To investigate the role of biological mechanisms and to reduce the number of comparisons in the analysis, we created pathway-specific scores using gene variants related to each pathway. To select the most appropriate gene variants, we used the least absolute shrinkage and selection operator (Lasso) to relate independent outcomes representative of each pathway (8-hydroxydeoxyguanosine for oxidative stress, augmentation index for endothelial function, and patella lead for metal processing) to gene variants. A high genetic score corresponds to a higher allelic risk profile. We fit mixed-effects models to examine modification by the genetic score of the weekly air pollution association with the outcome. Among participants with higher genetic scores within the oxidative stress pathway, we observed significant associations between particle number and fibrinogen, while we did not find any association among participants with lower scores (pinteraction = 0.04). Compared to individuals with low genetic scores of metal processing gene variants, participants with higher scores had greater effects of particle number on fibrinogen (pinteraction = 0.12), CRP (pinteraction = 0.02), and ICAM-1 (pinteraction = 0.08). This two-stage penalization method is easy to implement and can be used for large-scale genetic applications

Effects of Air Pollution on Heart Rate Variability: The VA Normative Aging Study

Reduced heart rate variability (HRV), a marker of poor cardiac autonomic function, has been associated with air pollution, especially fine particulate matter [< 2.5 μm in aerodynamic diameter (PM(2.5))]. We examined the relationship between HRV [standard deviation of normal-to-normal intervals (SDNN), power in high frequency (HF) and low frequency (LF), and LF:HF ratio] and ambient air pollutants in 497 men from the Normative Aging Study in greater Boston, Massachusetts, seen between November 2000 and October 2003. We examined 4-hr, 24-hr, and 48-hr moving averages of air pollution (PM(2.5), particle number concentration, black carbon, ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide). Controlling for potential confounders, HF decreased 20.8% [95% confidence interval (CI), 4.6–34.2%] and LF:HF ratio increased 18.6% (95% CI, 4.1–35.2%) per SD (8 μg/m(3)) increase in 48-hr PM(2.5). LF was reduced by 11.5% (95% CI, 0.4–21.3%) per SD (13 ppb) increment in 4-hr O(3). The associations between HRV and PM(2.5) and O(3) were stronger in people with ischemic heart disease (IHD) and hypertension. The associations observed between SDNN and LF and PM(2.5) were stronger in people with diabetes. People using calcium-channel blockers and beta-blockers had lower associations between O(3) and PM(2.5) with LF. No effect modification by other cardiac medications was found. Exposures to PM(2.5) and O(3) are associated with decreased HRV, and history of IHD, hypertension, and diabetes may confer susceptibility to autonomic dysfunction by air pollution

Associations between Changes in City and Address Specific Temperature and QT Interval - The VA Normative Aging Study

Background: 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. Methods: 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. Results: 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. Conclusion/Significance 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

Forced Expiratory Volume in 1 Second and Cognitive Aging in Men

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87022/1/j.1532-5415.2011.03487.x.pd

Structural equation modeling of parasympathetic and sympathetic response to traffic air pollution in a repeated measures study

Background: Traffic-related air pollution has been associated to a range of adverse health impacts, including decreased heart rate variability (HRV). The association between traffic-related pollution and HRV, however, has varied by traffic-related or HRV marker as well as by study, suggesting the need for a more comprehensive and integrative approach to examining air pollution-mediated biological impacts on these outcomes. In a Bayesian framework, we examined the effect of traffic pollution on HRV using structural equation models (SEMs) and looked at effect modification by participant characteristics. Methods: We studied measurements of 5 HRV markers [high frequency (HF), low frequency (LF), 5-min standard deviation of normal-to-normal intervals (SDNN), square root of the mean squared differences of successive normal-to-normal intervals (rMSSD), and LF/HF ratio (LF/HF)] for 700 elderly men from the Normative Aging Study. Using SEMs, we fit a latent variable for traffic pollution that is reflected by levels of carbon monoxide, nitrogen monoxide, nitrogen dioxide, and black carbon (BC) to estimate its effect on latent variable for parasympathetic tone that included HF, SDNN and rMSSD, and the sympathetic tone marker, LF/HF. Exposure periods were assessed using 4-, 24-, 48-, 72-hour moving average pre-visit. We compared our main effect findings using SEMs with those obtained using linear mixed models. Results: Traffic pollution was not associated with mean parasympathetic tone and LF/HF for all examined moving averages. In Bayesian linear mixed models, however, BC was related to increased LF/HF, an inter quartile range (IQR) increase in BC was associated with a 6.5% (95% posterior interval (PI): -0.7%, 14.2%) increase in mean LF/HF 24-hours later. The strongest association observed was for the 4-hour moving average (10.1%; 95% PI: 3.0%, 17.6%). The effect of traffic on parasympathetic tone was stronger among diabetic as compared to non-diabetic participants. Specifically, an IQR increase in traffic pollution in the 48-hr prior to the clinic visit was associated with a 44.3% (95% PI: -67.7%, -4.2%) lower mean parasympathetic tone among diabetics, and a 7.7% (95% PI: -18.0%, 41.4%) higher mean parasympathetic tone among non-diabetics. Conclusions: BC was associated with adverse changes LF/HF in the elderly. Traffic pollution may decrease parasympathetic tone among diabetic elderly

Annual Ambient Black Carbon Associated with Shorter Telomeres in Elderly Men: Veterans Affairs Normative Aging Study

Background: Telomere length reflects biological age and is inversely associated with risk of cardiovascular disease (CVD). Ambient air pollution is associated with CVD, but its effect on telomere length is unknown. Objective: We investigated whether ambient black carbon (BC), a marker for traffic-related particles, is associated with telomere length in the Normative Aging Study (NAS). Methods: Among 165 never-smoking men from the NAS, leukocyte telomere length (LTL) was measured repeatedly approximately every 3 years from 1999 through 2006 using quantitative real-time polymerase chain reaction (qRT-PCR). BC concentration at their residences during the year before each LTL measurement was estimated based on a spatiotemporal model calibrated with BC measurements from 82 locations within the study area. Results: The median [interquartile range (IQR)] annual moving-average BC concentration was 0.32 (0.20–0.45) μg/m3. LTL, expressed as population-standardized ratio of telomere repeat to single-copy gene copy numbers, had a geometric mean (geometric SD) of 1.25 (1.42). We used linear mixed-effects models including random subject intercepts and adjusted for several potential confounders. We used inverse probability of response weighting to adjust for potential selection bias due to loss to follow-up. An IQR increase in annual BC (0.25 μg/m3) was associated with a 7.6% decrease (95% confidence interval, −12.8 to −2.1) in LTL. We found evidence of effect modification, with a stronger association among subjects ≥ 75 years of age compared with younger participants (p = 0.050) and statin medications appearing protective of the effects of BC on LTL (p = 0.050). Conclusions: Telomere attrition, linked to biological aging, may be associated with long-term exposures to airborne particles, particularly those rich in BC, which are primarily related to automobile traffic