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Find video protocols related to scientific articles indexed in Pubmed.
Testing departure from additivity in Tukey's model using shrinkage: application to a longitudinal setting.
Stat Med
PUBLISHED: 08-11-2014
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While there has been extensive research developing gene-environment interaction (GEI) methods in case-control studies, little attention has been given to sparse and efficient modeling of GEI in longitudinal studies. In a two-way table for GEI with rows and columns as categorical variables, a conventional saturated interaction model involves estimation of a specific parameter for each cell, with constraints ensuring identifiability. The estimates are unbiased but are potentially inefficient because the number of parameters to be estimated can grow quickly with increasing categories of row/column factors. On the other hand, Tukey's one-degree-of-freedom model for non-additivity treats the interaction term as a scaled product of row and column main effects. Because of the parsimonious form of interaction, the interaction estimate leads to enhanced efficiency, and the corresponding test could lead to increased power. Unfortunately, Tukey's model gives biased estimates and low power if the model is misspecified. When screening multiple GEIs where each genetic and environmental marker may exhibit a distinct interaction pattern, a robust estimator for interaction is important for GEI detection. We propose a shrinkage estimator for interaction effects that combines estimates from both Tukey's and saturated interaction models and use the corresponding Wald test for testing interaction in a longitudinal setting. The proposed estimator is robust to misspecification of interaction structure. We illustrate the proposed methods using two longitudinal studies-the Normative Aging Study and the Multi-ethnic Study of Atherosclerosis. Copyright © 2014 John Wiley & Sons, Ltd.
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Ambient particulate air pollution and microRNAs in elderly men.
Epidemiology
PUBLISHED: 07-31-2014
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Ambient particulate matter (PM) has been associated with mortality and morbidity for cardiovascular disease. MicroRNAs control gene expression at a posttranscriptional level. Altered microRNA expression has been reported in processes related to cardiovascular disease and PM exposure, such as systemic inflammation, endothelial dysfunction, and atherosclerosis. Polymorphisms in microRNA-related genes could influence response to PM.
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Long-term effects of traffic particles on lung function decline in the elderly.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 07-17-2014
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Few studies have been performed on air pollution effects on lung function in the elderly, a vulnerable population with low reserve capacity, and even fewer have looked at changes in the rate of lung function decline.
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Lead exposure, B vitamins, and plasma homocysteine in men 55 years of age and older: the VA normative aging study.
Environ. Health Perspect.
PUBLISHED: 06-04-2014
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Lead (Pb) exposure may influence the plasma concentration of homocysteine, a one-carbon metabolite associated with cardiovascular and neurodegenerative diseases. Little is known about the associations between Pb and homocysteine over time, or the potential influence of dietary factors.
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Effects of temperature and relative humidity on DNA methylation.
Epidemiology
PUBLISHED: 05-10-2014
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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.
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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.
Environ Health
PUBLISHED: 05-02-2014
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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.
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Influence of multiple APOE genetic variants on cognitive function in a cohort of older men - results from the Normative Aging Study.
BMC Psychiatry
PUBLISHED: 04-20-2014
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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.
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Epigenetic influences on associations between air pollutants and lung function in elderly men: the normative aging study.
Environ. Health Perspect.
PUBLISHED: 03-04-2014
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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.
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Chemerin levels as predictor of acute coronary events: a case-control study nested within the veterans affairs normative aging study.
Metab. Clin. Exp.
PUBLISHED: 02-18-2014
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Chemerin is a recently identified adipocytokine that has been positively correlated with the presence and severity of coronary artery disease (CAD). However, no studies have examined circulating chemerin levels as a predictor of acute coronary syndrome (ACS). The purpose of this study is to evaluate whether chemerin levels predict the onset of ACS.
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Mitochondrial haplogroups modify the effect of black carbon on age-related cognitive impairment.
Environ Health
PUBLISHED: 02-12-2014
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Traffic-related air pollution has been linked with impaired cognition in older adults, possibly due to effects of oxidative stress on the brain. Mitochondria are the main source of cellular oxidation. Haplogroups in mitochondrial DNA (mtDNA) mark individual differences in oxidative potential and are possible determinants of neurodegeneration. The aim of this study was to investigate whether mtDNA haplogroups determined differential susceptibility to cognitive effects of long-term exposure to black carbon (BC), a marker of traffic-related air pollution.
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Pessimistic orientation in relation to telomere length in older men: the VA normative aging study.
Psychoneuroendocrinology
PUBLISHED: 01-02-2014
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Recent research suggests pessimistic orientation is associated with shorter leukocyte telomere length (LTL). However, this is the first study to look not only at effects of pessimistic orientation on average LTL at multiple time points, but also at effects on the rate of change in LTL over time.
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Air pollution and gene-specific methylation in the Normative Aging Study: association, effect modification, and mediation analysis.
Epigenetics
PUBLISHED: 01-02-2014
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The mechanisms by which air pollution has multiple systemic effects in humans are not fully elucidated, but appear to include inflammation and thrombosis. This study examines whether concentrations of ozone and components of fine particle mass are associated with changes in methylation on tissue factor (F3), interferon gamma (IFN-?), interleukin 6 (IL-6), toll-like receptor 2 (TLR-2), and intercellular adhesion molecule 1 (ICAM-1). We investigated associations between air pollution exposure and gene-specific methylation in 777 elderly men participating in the Normative Aging Study (1999-2009). We repeatedly measured methylation at multiple CpG sites within each gene's promoter region and calculated the mean of the position-specific measurements. We examined intermediate-term associations between primary and secondary air pollutants and mean methylation and methylation at each position with distributed-lag models. Increase in air pollutants concentrations was significantly associated with F3, ICAM-1, and TLR-2 hypomethylation, and IFN-? and IL-6 hypermethylation. An interquartile range increase in black carbon concentration averaged over the four weeks prior to assessment was associated with a 12% reduction in F3 methylation (95% CI: -17% to -6%). For some genes, the change in methylation was observed only at specific locations within the promoter region. DNA methylation may reflect biological impact of air pollution. We found some significant mediated effects of black carbon on fibrinogen through a decrease in F3 methylation, and of sulfate and ozone on ICAM-1 protein through a decrease in ICAM-1 methylation.
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Associations between changes in city and address specific temperature and QT interval--the VA Normative Aging Study.
PLoS ONE
PUBLISHED: 01-01-2014
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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.
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A novel genetic score approach using instruments to investigate interactions between pathways and environment: application to air pollution.
PLoS ONE
PUBLISHED: 01-01-2014
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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 (p(interaction)?=?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 (p(interaction)?=?0.12), CRP (p(interaction)?=?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.
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Variants of Asthma and Chronic Obstructive Pulmonary Disease Genes and Lung Function Decline in Aging.
J. Gerontol. A Biol. Sci. Med. Sci.
PUBLISHED: 11-19-2013
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A substantial proportion of the general population has low lung function, and lung function is known to decrease as we age. Low lung function is a feature of several pulmonary disorders, such as uncontrolled asthma and chronic obstructive pulmonary disease. The objective of this study is to investigate the association of polymorphisms in asthma and chronic obstructive pulmonary disease candidate genes with rates of lung function decline in a general population sample of aging men.
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Associations Between Short-term Changes in Air Pollution and Correlates of Arterial Stiffness: The Veterans Affairs Normative Aging Study, 2007-2011.
Am. J. Epidemiol.
PUBLISHED: 11-13-2013
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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 ?m (3.6-?g/m(3) IQR increase) and sulfate (1.4-?g/m(3) IQR increase) and 1-day average exposure to particle number counts (8,741-counts/cm(3) 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.
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Associations between arrhythmia episodes and temporally and spatially resolved black carbon and particulate matter in elderly patients.
Occup Environ Med
PUBLISHED: 10-18-2013
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Ambient air pollution has been associated with sudden deaths, some of which are likely due to ventricular arrhythmias. Defibrillator discharge studies have examined the association of air pollution with arrhythmias in sensitive populations. No studies have assessed this association using residence-specific estimates of air pollution exposure.
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Propensity score-based diagnostics for categorical response regression models.
Stat Med
PUBLISHED: 07-15-2013
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For binary or categorical response models, most goodness-of-fit statistics are based on the notion of partitioning the subjects into groups or regions and comparing the observed and predicted responses in these regions by a suitable chi-squared distribution. Existing strategies create this partition based on the predicted response probabilities, or propensity scores, from the fitted model. In this paper, we follow a retrospective approach, borrowing the notion of balancing scores used in causal inference to inspect the conditional distribution of the predictors, given the propensity scores, in each category of the response to assess model adequacy. We can use this diagnostic under both prospective and retrospective sampling designs, and it may ascertain general forms of misspecification. We first present simple graphical and numerical summaries that can be used in a binary logistic model. We then generalize the tools to propose model diagnostics for the proportional odds model. We illustrate the methods with simulation studies and two data examples: (i) a case-control study of the association between cumulative lead exposure and Parkinsons disease in the Boston, Massachusetts, area and (ii) and a cohort study of biomarkers possibly associated with diabetes, from the VA Normative Aging Study. Copyright © 2013 John Wiley & Sons, Ltd.
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Novel likelihood ratio tests for screening gene-gene and gene-environment interactions with unbalanced repeated-measures data.
Genet. Epidemiol.
PUBLISHED: 03-29-2013
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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.
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Association between blood pressure and DNA methylation of retrotransposons and pro-inflammatory genes.
Int J Epidemiol
PUBLISHED: 03-20-2013
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Methylation of deoxyribonucleic acid (DNA) is an epigenetic regulator of gene expression that changes with age, but its contribution to aging-related disorders, including high blood pressure (BP), is still largely unknown. We examined the relation of BP to the methylation of retrotransposon sequences of DNA and of selected candidate genes.
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Structural equation modeling of parasympathetic and sympathetic response to traffic air pollution in a repeated measures study.
Environ Health
PUBLISHED: 01-29-2013
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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.
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Optimism in relation to inflammation and endothelial dysfunction in older men: the VA Normative Aging Study.
Psychosom Med
PUBLISHED: 09-23-2011
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Recent research suggests that optimism may reduce the risk of incident cardiovascular disease, but the mechanisms have not been determined. This study examines the association of optimism with change in inflammation and endothelial function over time in men.
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Associations of toenail arsenic, cadmium, mercury, manganese, and lead with blood pressure in the normative aging study.
Environ. Health Perspect.
PUBLISHED: 08-30-2011
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Arsenic, cadmium, mercury, and lead are associated with cardiovascular disease in epidemiologic research. These associations may be mediated by direct effects of the metals on blood pressure (BP) elevation. Manganese is associated with cardiovascular dysfunction and hypotension in occupational cohorts.
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Longitudinal changes in bone lead levels: the VA Normative Aging Study.
J. Occup. Environ. Med.
PUBLISHED: 07-27-2011
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Bone lead is a cumulative measure of lead exposure that can also be remobilized. We examined repeated measures of bone lead over 11 years to characterize long-term changes and identify predictors of tibia and patella lead stores in an elderly male population.
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Forced expiratory volume in 1 second and cognitive aging in men.
J Am Geriatr Soc
PUBLISHED: 06-30-2011
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To evaluate forced expiratory volume in 1 second (FEV(1) , a measure of overall lung function), long-term average FEV(1) , and rate of decline in FEV(1) in relation to cognition and cognitive decline in older men.
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Ambient pollutants, polymorphisms associated with microRNA processing and adhesion molecules: the Normative Aging Study.
Environ Health
PUBLISHED: 05-21-2011
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Particulate air pollution has been associated with cardiovascular morbidity and mortality, but it remains unclear which time windows and pollutant sources are most critical. MicroRNA (miRNA) is thought to be involved in cardiovascular regulation. However, little is known about whether polymorphisms in genes that process microRNAs influence response to pollutant exposure. We hypothesized that averaging times longer than routinely measured one or two day moving averages are associated with higher soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) levels, and that stationary and mobile sources contribute differently to these effects. We also investigated whether single nucleotide polymorphisms (SNPs) in miRNA-processing genes modify these associations.
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Healthy psychological functioning and incident coronary heart disease: the importance of self-regulation.
Arch. Gen. Psychiatry
PUBLISHED: 04-06-2011
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Studies have documented effects of positive and negative emotion on the risk of developing coronary heart disease (CHD), leading investigators to speculate about the importance of effective self-regulation for good health. Little work has directly assessed the role of self-regulation in risk of incident CHD.
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Prospective cohort study of lead exposure and electrocardiographic conduction disturbances in the Department of Veterans Affairs Normative Aging Study.
Environ. Health Perspect.
PUBLISHED: 03-16-2011
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No studies have examined the association between cumulative low-level lead exposure and the prospective development of electrocardiographic conduction abnormalities, which may mediate the association between lead and several cardiovascular end points.
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Ambient temperature, air pollution, and heart rate variability in an aging population.
Am. J. Epidemiol.
PUBLISHED: 03-08-2011
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Studies show that ambient temperature and air pollution are associated with cardiovascular disease and that they may interact to affect cardiovascular events. However, few epidemiologic studies have examined mechanisms through which ambient temperature may influence cardiovascular function. The authors examined whether temperature was associated with heart rate variability (HRV) in a Boston, Massachusetts, study population and whether such associations were modified by ambient air pollution concentrations. The population was a cohort of 694 older men examined between 2000 and 2008. The authors fitted a mixed model to examine associations between temperature and air pollution and their interactions with repeated HRV measurements, adjusting for covariates selected a priori on the basis of their previous studies. Results showed that higher ambient temperature was associated with decreases in HRV measures (standard deviation of normal-to-normal intervals, low-frequency power, and high-frequency power) during the warm season but not during the cold season. These warm-season associations were significantly greater when ambient ozone levels were higher (>22.3 ppb) but did not differ according to levels of ambient fine (?2.5 ?m) particulate matter. The authors conclude that temperature and ozone, exposures to both of which are expected to increase with climate change, might act together to worsen cardiovascular health and/or precipitate cardiovascular events via autonomic nervous system dysfunction.
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Prolonged exposure to particulate pollution, genes associated with glutathione pathways, and DNA methylation in a cohort of older men.
Environ. Health Perspect.
PUBLISHED: 03-08-2011
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DNA methylation is a potential pathway linking environmental exposures to disease. Exposure to particulate air pollution has been associated with increased cardiovascular morbidity and mortality, and lower blood DNA methylation has been found in processes related to cardiovascular morbidity.
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Medium-term exposure to traffic-related air pollution and markers of inflammation and endothelial function.
Environ. Health Perspect.
PUBLISHED: 02-24-2011
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Exposure to traffic-related air pollution (TRAP) contributes to increased cardiovascular risk. Land-use regression models can improve exposure assessment for TRAP.
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Relation between high-density lipoprotein cholesterol and survival to age 85 years in men (from the VA normative aging study).
Am. J. Cardiol.
PUBLISHED: 02-04-2011
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No previous researchers have sought to determine whether high-density lipoprotein (HDL) cholesterol levels are associated with survival to 85 years of age in a prospective cohort of aging men. We selected 652 men (mean age 65 years) enrolled in the VA Normative Aging Study who had ? 1 HDL cholesterol level documented during the study and who were old enough on the date of HDL cholesterol measurement to reach 85 years of age by the end of follow-up (July 1, 2008). We categorized initial HDL cholesterol into < 40 mg/dl (reference group), 40 to 49 mg/dl, or ? 50 mg/dl. Information on co-morbidities, lifestyle factors, measured lipid parameters, and medications were collected during triennial visits. We used proportional hazards to determine hazard ratios (HRs) for mortality before age 85 years for each category of initial HDL cholesterol compared to the reference adjusting for co-morbidities, calculated low-density lipoprotein cholesterol, medications, smoking, body mass index, and alcohol consumption. Treating HDL cholesterol as a continuous predictor, we also determined the HR for each 10-mg/dl increment in HDL cholesterol. Fully adjusted HR (95% confidence interval) for survival to 85 years of age for participants with an initial HDL cholesterol level ? 50 mg/dl compared to the reference was 0.72 (0.53 to 0.98). Each 10-mg/dl increment in HDL cholesterol was associated with a 14% (HR 0.86, 0.78 to 0.96) decrease in risk of mortality before 85 years of age. In conclusion, after adjusting for other factors associated with longevity, higher HDL cholesterol levels were significantly associated with survival to 85 years of age.
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Lead concentrations in relation to multiple biomarkers of cardiovascular disease: the Normative Aging Study.
Environ. Health Perspect.
PUBLISHED: 01-19-2011
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Lead exposure has been associated with cardiovascular disease (CVD) in animal and human studies. However, the mechanisms of action have not been fully elucidated. We therefore examined the relationship between lead and multiple biomarkers of CVD.
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Annual ambient black carbon associated with shorter telomeres in elderly men: Veterans Affairs Normative Aging Study.
Environ. Health Perspect.
PUBLISHED: 12-06-2010
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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.
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Relationship between outdoor temperature and blood pressure.
Occup Environ Med
PUBLISHED: 09-23-2010
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Cardiovascular mortality has been linked to changes in outdoor temperature. However, the mechanisms behind these effects are not well established. We aimed to study the effect of outdoor temperature on blood pressure, as increased blood pressure is a risk factor for cardiovascular death.
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Predictors of global methylation levels in blood DNA of healthy subjects: a combined analysis.
Int J Epidemiol
PUBLISHED: 09-15-2010
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Estimates of global DNA methylation from repetitive DNA elements, such as Alu and LINE-1, have been increasingly used in epidemiological investigations because of their relative low-cost, high-throughput and quantitative results. Nevertheless, determinants of these methylation measures in healthy individuals are still largely unknown. The aim of this study was to examine whether age, gender, smoking habits, alcohol drinking and body mass index (BMI) are associated with Alu or LINE-1 methylation levels in blood leucocyte DNA of healthy individuals.
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Ischemic heart disease and stroke in relation to blood DNA methylation.
Epidemiology
PUBLISHED: 09-01-2010
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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.
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Repetitive element hypomethylation in blood leukocyte DNA and cancer incidence, prevalence, and mortality in elderly individuals: the Normative Aging Study.
Cancer Causes Control
PUBLISHED: 06-13-2010
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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.
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Effect modification of air pollution on Urinary 8-Hydroxy-2-Deoxyguanosine by genotypes: an application of the multiple testing procedure to identify significant SNP interactions.
Environ Health
PUBLISHED: 05-13-2010
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Air pollution is associated with adverse human health, but mechanisms through which pollution exerts effects remain to be clarified. One suggested pathway is that pollution causes oxidative stress. If so, oxidative stress-related genotypes may modify the oxidative response defenses to pollution exposure.
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Associations between outdoor temperature and markers of inflammation: a cohort study.
Environ Health
PUBLISHED: 04-08-2010
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Associations between ambient temperature and cardiovascular mortality are well established. This study investigated whether inflammation could be part of the mechanism leading to temperature-related cardiovascular deaths.
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Outdoor temperature is associated with serum HDL and LDL.
Environ. Res.
PUBLISHED: 04-06-2010
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While exposures to high and low air temperatures are associated with cardiovascular mortality, the underlying mechanisms are poorly understood. The risk factors for cardiovascular disease include high levels of total cholesterol and low-density lipoprotein (LDL), and low levels of high-density lipoprotein (HDL). We investigated whether temperature was associated with changes in circulating lipid levels, and whether this might explain part of the association with increased cardiovascular events.
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Repetitive element DNA methylation and circulating endothelial and inflammation markers in the VA normative aging study.
Epigenetics
PUBLISHED: 03-23-2010
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Lower blood DNA methylation has been associated with atherosclerosis and high cardiovascular risk. Mechanisms linking DNA hypomethylation to increased cardiovascular risk are still largely unknown. In a population of community-dwelling elderly individuals, we evaluated whether DNA methylation in LINE-1 repetitive element, heavily methylated sequences dispersed throughout the human genome, was associated with circulating Vascular Cell Adhesion Molecule-1 (VCAM-1), Inter- Cellular Adhesion Molecule-1 (ICAM-1), and C-reactive protein (CRP).
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Cumulative lead exposure and age-related hearing loss: the VA Normative Aging Study.
Hear. Res.
PUBLISHED: 03-22-2010
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Although lead has been associated with hearing loss in occupational settings and in children, little epidemiologic research has been conducted on the impact of cumulative lead exposure on age-related hearing loss in the general population. We determined whether bone lead levels, a marker of cumulative lead exposure, are associated with decreased hearing ability in 448 men from the Normative Aging Study, seen between 1962 and 1996 (2264 total observations). Air conduction hearing thresholds were measured at 0.25-8 kHz and pure-tone averages (PTA) (mean of 0.5, 1, 2 and 4 kHz) were computed. Tibia and patella lead levels were measured using K X-ray fluorescence between 1991 and 1996. In cross-sectional analyses, after adjusting for potential confounders including occupational noise, patella lead levels were significantly associated with poorer hearing thresholds at 2, 3, 4, 6 and 8 kHz and PTA. The odds of hearing loss significantly increased with patella lead levels. We also found significant positive associations between tibia lead and the rate change in hearing thresholds at 1, 2, and 8 kHz and PTA in longitudinal analyses. Our results suggest that chronic low-level lead exposure may be an important risk factor for age-related hearing loss and reduction of lead exposure could help prevent or delay development of age-related hearing loss.
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Black carbon exposures, blood pressure, and interactions with single nucleotide polymorphisms in MicroRNA processing genes.
Environ. Health Perspect.
PUBLISHED: 03-05-2010
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Black carbon (BC) is a marker of traffic pollution that has been associated with blood pressure (BP), but findings have been inconsistent. MicroRNAs (miRNAs) are emerging as key regulators of gene expression, but whether polymorphisms in genes involved in processing of miRNAs to maturity influence susceptibility to BC has not been elucidated.
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Traffic-related air pollution and QT interval: modification by diabetes, obesity, and oxidative stress gene polymorphisms in the normative aging study.
Environ. Health Perspect.
PUBLISHED: 03-01-2010
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Acute exposure to ambient air pollution has been associated with acute changes in cardiac outcomes, often within hours of exposure.
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Air pollution and homocysteine: more evidence that oxidative stress-related genes modify effects of particulate air pollution.
Epidemiology
PUBLISHED: 01-30-2010
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Ambient particles are associated with cardiovascular events and recently with total plasma homocysteine. High total plasma homocysteine is a risk for human health. However, the biologic mechanisms are not fully understood. One of the putative pathways is through oxidative stress. We aimed to examine whether associations of PM2.5 and black carbon with homocysteine were modified by genotypes including HFE H63D, C282Y, CAT (rs480575, rs1001179, rs2284367, and rs2300181), NQO1 (rs1800566), GSTP1 I105V, GSTM1, GSTT1 (deletion vs. nondeletion), and HMOX-1 (any short vs. both long). We attempted to replicate identified genes in an analysis of heart rate variability and in other outcomes reported in the literature.
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Biomarkers of lead exposure and DNA methylation within retrotransposons.
Environ. Health Perspect.
PUBLISHED: 01-11-2010
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DNA methylation is an epigenetic mark that regulates gene expression. Changes in DNA methylation within white blood cells may result from cumulative exposure to environmental metals such as lead. Bone lead, a marker of cumulative exposure, may therefore better predict DNA methylation than does blood lead.
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Air pollution, obesity, genes and cellular adhesion molecules.
Occup Environ Med
PUBLISHED: 11-02-2009
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Particulate matter has been associated with acute cardiovascular outcomes, but our understanding of the mechanism is incomplete. We examined the association between particulate matter and cell adhesion molecules. We also investigated the modifying effect of genotype and phenotype variation to gain insight into the relevant biological pathways for this association.
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Periodontitis and incidence of cerebrovascular disease in men.
Ann. Neurol.
PUBLISHED: 10-23-2009
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To identify associations between periodontitis and incidence of cerebrovascular disease.
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A prospective study of bone lead concentration and death from all causes, cardiovascular diseases, and cancer in the Department of Veterans Affairs Normative Aging Study.
Circulation
PUBLISHED: 09-08-2009
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Blood lead concentration has been associated with mortality from different causes in several studies. Many effects of lead exposure that might increase risk of death are likely to result from cumulative exposure, for which bone lead is a better biomarker than blood lead. The association between bone lead levels and mortality has not been explored.
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Association between low-level environmental arsenic exposure and QT interval duration in a general population study.
Am. J. Epidemiol.
PUBLISHED: 08-21-2009
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High-level arsenic exposure is consistently associated with QT prolongation, a risk factor for arrhythmia and sudden cardiac death. Arsenic may act on QT by increasing cardiac calcium currents. The authors hypothesized that low-level arsenic exposure would be associated with QT duration and that this effect would be stronger among persons not using calcium channel blockers. They performed a cross-sectional analysis in elderly men from the Normative Aging Study to analyze associations between toenail arsenic and QT and heart rate-corrected QT (QTc) durations and to examine effect modification by calcium channel blocker use, using linear regression and adjusting for potential confounders. Participants were examined in Boston, Massachusetts, between 2000 and 2002 or in 2006. An interquartile range increase in arsenic concentration was associated with a 3.8-millisecond increase in QT (95% confidence interval: 0.82, 6.8) and a 2.5-millisecond increase in QTc (95% confidence interval: 0.11, 4.9). There was no evidence of effect modification by medication use for either QT (P = 0.93) or QTc (P = 0.58). The authors observed positive associations between a biomarker of arsenic exposure and QT duration but found no evidence of effect modification by calcium channel blocker use, possibly because of modest power.
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Candidate genes for respiratory disease associated with markers of inflammation and endothelial dysfunction in elderly men.
Atherosclerosis
PUBLISHED: 02-19-2009
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Inflammation and endothelial dysfunction are important risk factors for cardiovascular disease (CVD). We hypothesized that candidate genes selected for a study of asthma and chronic obstructive pulmonary disorder (COPD) are associated with markers of systemic inflammation and endothelial dysfunction in an aging population.
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Iron metabolism genes, low-level lead exposure, and QT interval.
Environ. Health Perspect.
PUBLISHED: 01-24-2009
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Cumulative exposure to lead has been shown to be associated with depression of electrocardiographic conduction, such as QT interval (time from start of the Q wave to end of the T wave). Because iron can enhance the oxidative effects of lead, we examined whether polymorphisms in iron metabolism genes [hemochromatosis (HFE), transferrin (TF) C2, and heme oxygenase-1 (HMOX-1)] increase susceptibility to the effects of lead on QT interval in 613 community-dwelling older men.
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Fruit, vegetable, and fish consumption and heart rate variability: the Veterans Administration Normative Aging Study.
Am. J. Clin. Nutr.
PUBLISHED: 01-21-2009
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Higher intakes of fruit, vegetables, and dark fish may prevent sudden cardiac death and arrhythmias, but the exact mechanisms are not fully understood.
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Decline in genomic DNA methylation through aging in a cohort of elderly subjects.
Mech. Ageing Dev.
PUBLISHED: 01-20-2009
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Loss of genomic DNA methylation has been found in a variety of common human age-related diseases. Whether DNA methylation decreases over time as individuals age is unresolved. We measured DNA methylation in 1097 blood DNA samples from 718 elderly subjects between 55 and 92 years of age (1-3 samples/subjects), who have been repeatedly evaluated over an 8-year time span in the Boston area Normative Aging Study. DNA methylation was measured using quantitative PCR-Pyrosequencing analysis in Alu and LINE-1 repetitive elements, heavily methylated sequences with high representation throughout the human genome. Age at the visit was negatively associated with Alu element methylation (beta=-0.12 %5mC/year, p=0.0005). A weaker association was observed with LINE-1 elements (beta=-0.06 %5mC/year, p=0.049). We observed a significant decrease in average Alu methylation over time, with a -0.2 %5mC change (p=0.012) compared to blood samples collected up to 8 years earlier. The longitudinal decline in Alu methylation was linear and highly correlated with time since the first measurement (beta=-0.089 %5mC/year, p<0.0001). In contrast, average LINE-1 methylation did not vary over time [p=0.51]. Our results demonstrate a progressive loss of DNA methylation in repetitive elements dispersed throughout the genome.
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Black carbon exposure, oxidative stress genes, and blood pressure in a repeated-measures study.
Environ. Health Perspect.
PUBLISHED: 01-19-2009
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Particulate matter (PM) air pollution has been associated with cardiovascular morbidity and mortality, and elevated blood pressure (BP) is a known risk factor for cardiovascular disease. A small number of studies have investigated the relationship between PM and BP and found mixed results. Evidence suggests that traffic-related air pollution contributes significantly to PM-related cardiovascular effects.
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Rapid DNA methylation changes after exposure to traffic particles.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 01-08-2009
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Exposure to particulate air pollution has been related to increased hospitalization and death, particularly from cardiovascular disease. Lower blood DNA methylation content is found in processes related to cardiovascular outcomes, such as oxidative stress, aging, and atherosclerosis.
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Allergen sensitization is associated with increased DNA methylation in older men.
Int. Arch. Allergy Immunol.
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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.
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Structural equation modeling of the inflammatory response to traffic air pollution.
J Expo Sci Environ Epidemiol
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Several epidemiological studies have reported conflicting results on the effect of traffic-related pollutants on markers of inflammation. In a Bayesian framework, we examined the effect of traffic pollution on inflammation using structural equation models (SEMs). We studied measurements of C-reactive protein (CRP), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble intracellular adhesion molecule-1 (sICAM-1) for 749 elderly men from the Normative Aging Study. Using repeated measures SEMs, we fit a latent variable for traffic pollution that is reflected by levels of black carbon, carbon monoxide, nitrogen monoxide and nitrogen dioxide to estimate its effect on a latent variable for inflammation that included sICAM-1, sVCAM-1 and CRP. Exposure periods were assessed using 1-, 2-, 3-, 7-, 14- and 30-day moving averages previsit. We compared our findings using SEMs with those obtained using linear mixed models. Traffic pollution was related to increased inflammation for 3-, 7-, 14- and 30-day exposure periods. An inter-quartile range increase in traffic pollution was associated with a 2.3% (95% posterior interval (PI): 0.0-4.7%) increase in inflammation for the 3-day moving average, with the most significant association observed for the 30-day moving average (23.9%; 95% PI: 13.9-36.7%). Traffic pollution adversely impacts inflammation in the elderly. SEMs in a Bayesian framework can comprehensively incorporate multiple pollutants and health outcomes simultaneously in air pollution-cardiovascular epidemiological studies.
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Alu and LINE-1 methylation and lung function in the normative ageing study.
BMJ Open
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To investigate the association between methylation of transposable elements Alu and long-interspersed nuclear elements (LINE-1) and lung function.
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Arsenic exposure and DNA methylation among elderly men.
Epidemiology
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Arsenic exposure has been linked to epigenetic modifications such as DNA methylation in in-vitro and animal studies. This association has also been explored in highly exposed human populations, but studies among populations environmentally exposed to low arsenic levels are lacking.
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Vitamin D deficiency, smoking, and lung function in the Normative Aging Study.
Am. J. Respir. Crit. Care Med.
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Rationale: Vitamin D has immunomodulatory and antiinflammatory effects that may be modified by cigarette smoke and may affect lung function. Objectives: To examine the effect of vitamin D deficiency and smoking on lung function and lung function decline. Methods: A total of 626 men from the Normative Aging Study had 25-hydroxyvitamin D levels measured at three different times between 1984 and 2003 with concurrent spirometry. Vitamin D deficiency was defined as serum level ? 20 ng/ml. Statistical analysis was performed using multivariable linear regression and mixed effects models. Measurements and Main Results: In the overall cohort, there was no significant effect of vitamin D deficiency on lung function or on lung function decline. In both cross-sectional and longitudinal multivariable models, there was effect modification by vitamin D status on the association between smoking and lung function. Cross-sectional analysis revealed lower lung function in current smokers with vitamin D deficiency (FEV(1), FVC, and FEV(1)/FVC; P ? 0.0002), and longitudinal analysis showed more rapid rates of decline in FEV(1) (P = 0.023) per pack-year of smoking in subjects with vitamin D deficiency as compared with subjects who were vitamin D sufficient. Conclusions: Vitamin D deficiency was associated with lower lung function and more rapid lung function decline in smokers over 20 years in this longitudinal cohort of elderly men. This suggests that vitamin D sufficiency may have a protective effect against the damaging effects of smoking on lung function. Future studies should seek to confirm this finding in the context of smoking and other exposures that affect lung function.
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Air pollution and DNA methylation: interaction by psychological factors in the VA Normative Aging Study.
Am. J. Epidemiol.
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DNA methylation is a potential pathway linking air pollution to disease. Studies indicate that psychological functioning modifies the association between pollution and morbidity. The authors estimated the association of DNA methylation with ambient particulate matter less than 2.5 µm in diameter (PM(2.5)) and black carbon, using mixed models. DNA methylation of the inducible nitric oxide synthase gene, iNOS, and the glucocorticoid receptor gene, GCR, was measured by quantitative polymerase chain reaction pyrosequencing of 1,377 blood samples from 699 elderly male participants in the VA Normative Aging Study (1999-2009). The authors also investigated whether this association was modified by psychological factors including optimism or pessimism, anxiety, and depression. iNOS methylation was decreased after acute exposure to both black carbon and PM(2.5). A 1-?g/m(3) increase in exposure to black carbon in the 4 hours preceding the clinical examination was associated with a 0.9% decrease in 5-methylcytosine (95% CI: 0.4, 1.4) in iNOS, and a 10-?g/m(3) increase in exposure to PM(2.5) was associated with a 0.6% decrease in 5-methylcytosine (95% CI: 0.03, 1.1) in iNOS. Participants with low optimism and high anxiety had associations that were 3-4 times larger than those with high optimism or low anxiety. GCR methylation was not associated with particulate air pollution exposure.
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Folate network genetic variation predicts cardiovascular disease risk in non-Hispanic white males.
J. Nutr.
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Genes functioning in folate-mediated 1-carbon metabolism are hypothesized to play a role in cardiovascular disease (CVD) risk beyond the current narrow focus on the MTHFR 677 C?T (rs1801133) polymorphism. Using a cohort study design, we investigated whether sequence variants in the network of folate-related genes, particularly in genes encoding proteins related to SHMT1, predict CVD risk in 1131 men from the Normative Aging Study. A total of 330 single nucleotide polymorphisms (SNPs) in 52 genes, selected for function and gene coverage, were assayed on the Illumina GoldenGate platform. Age- and smoking-adjusted genotype-phenotype associations were estimated in regression models. Using a nominal P ? 5.00 × 10(-3) significance threshold, 8 SNPs were associated with CVD risk in single locus analyses. Using a false discovery rate (FDR) threshold (P-adjusted ?1.00 × 10(-1)), a SNP in the GGH gene remained associated with reduced CVD risk, with a stronger association in early onset CVD cases (<55 y). A gene × folate interaction (MAT2B) and 2 gene × vitamin B-12 interactions (BHMT, SLC25A32) reached the FDR P-adjusted ?2.00 × 10(-1) threshold. Three biological hypotheses related to SHMT1 were explored and significant gene × gene interactions were identified for TYMS by UBE2N, FTH1 by CELF1, and TYMS by MTHFR. Variations in genes other than MTHFR and those directly involved in homocysteine metabolism are associated with CVD risk in non-Hispanic white males. This work supports a role for SHMT1-related genes and nuclear folate metabolism, including the thymidylate biosynthesis pathway, in mediating CVD risk.
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Gene promoter methylation is associated with lung function in the elderly: the Normative Aging Study.
Epigenetics
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Lung function is a strong predictor of mortality. While inflammatory markers have been associated with lung function decrease, pathways are still poorly understood and epigenetic changes may participate in lung function decline mechanisms. We studied the cross-sectional association between DNA methylation in nine inflammatory genes and lung function in a cohort of 756 elderly men living in the metropolitan area of Boston. Participants donated a blood sample for DNA methylation analysis and underwent spirometry at each visit every 3 to 5 y from 1999-2006. We used separate multivariate mixed effects regression models to study the association between each lung function measurement and DNA methylation within each gene. Decreased CRAT, F3 and TLR2 methylation was significantly associated with lower lung function. One interquartile range (IQR) decrease in DNA methylation was associated with lower forced vital capacity (FVC) and forced expiratory volume in one second (FEV 1), respectively by 2.94% (p < 10 (-4)) and 2.47% (p < 10 (-3)) for F3, and by 2.10% (p < 10 (-2)) and 2.42% (p < 10 (-3)) for TLR2. Decreased IFN? and IL6 methylation was significantly associated with better lung function. One IQR decrease in DNA methylation was associated with higher FEV 1 by 1.75% (p = 0.02) and 1.67% (p = 0.05) for IFN? and IL6, respectively. These data demonstrate that DNA methylation may be part of the biological processes underlying the lung function decline and that IFN? and IL6 may have ambivalent roles through activation of negative feedback.
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Lifestyle change and high-density lipoprotein change: the US Department of Veterans Affairs Normative Aging Study.
Clin Cardiol
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We sought to determine whether lifestyle modifications are associated with high-density lipoprotein cholesterol (HDL-C) change in a cohort with long-term follow-up.
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Association between long-term exposure to traffic particles and blood pressure in the Veterans Administration Normative Aging Study.
Occup Environ Med
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Particulate air pollution is associated with cardiovascular events, but the mechanisms are not fully understood. The main objective was to assess the relationship between long-term exposure to traffic-related air pollution and blood pressure (BP).
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Residential black carbon exposure and circulating markers of systemic inflammation in elderly males: the normative aging study.
Environ. Health Perspect.
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Traffic-related particles (TRPs) are associated with adverse cardiovascular events. The exact mechanisms are unclear, but systemic inflammatory responses likely play a role.
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