Lloyd E Chambless’s research while affiliated with University of North Carolina at Chapel Hill and other places

BACKGROUND: Investigation of alterations to retinal microvasculature may contribute towards understanding the role of such changes in the pathophysiology of several chronic non-communicable diseases. The objective here was to evaluate the validity and reproducibility of retinal arteriole and venule diameter measurements made by Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) graders. DESIGN AND SETTING: Cross-sectional study at six teaching and research institutions. METHODS: To evaluate validity, each of 25 retinal images from the University of Wisconsin (gold standard) was measured by five ELSA-Brasil graders. To evaluate reproducibility, 105 images across the spectrum of vessel diameters were selected from 12,257 retinal images that had been obtained between 2010 and 2012, and each image was reexamined by the same grader and by an independent grader. All measurements were made using the Interactive Vessel Analysis (IVAN) software. Bland-Altman plots, paired t tests and intraclass correlation coefficients (ICCs) were analyzed. RESULTS: Mean differences between ELSA-Brasil and gold-standard readings were 0.16 µm (95% CI -0.17-0.50; P = 0.31) for central retinal artery equivalent (CRAE), -0.21 µm (95% CI -0.56-0.14; P = 0.22) for central retinal vein equivalent (CRVE) and 0.0005 (95% CI -0.008-0.009; P = 0.55) for arteriole/venule ratio (AVR). Intragrader ICCs were 0.77 (95% CI 0.67-0.86) for CRAE, 0.90 (95% CI 0.780.96) for CRVE and 0.70 (0.55-0.83) for AVR. Intergrader ICCs were 0.75 (95% CI 0.64-0.85) for CRAE, 0.90 (95% CI 0.79-0.96) for CRVE and 0.68 (95% CI 0.55-0.82) for AVR. CONCLUSIONS: Retinal microvascular diameter measurements are valid and present moderate to high intra and intergrader reproducibility in ELSA-Brasil.

2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Several studies have shown that diabetes confers a higher relative risk of vascular mortality among women than among men, but whether this increased relative risk in women exists across age groups and within defined levels of other risk factors is uncertain. We aimed to determine whether differences in established risk factors, such as blood pressure, BMI, smoking, and cholesterol, explain the higher relative risks of vascular mortality among women than among men. Methods: In our meta-analysis, we obtained individual participant-level data from studies included in the Prospective Studies Collaboration and the Asia Pacific Cohort Studies Collaboration that had obtained baseline information on age, sex, diabetes, total cholesterol, blood pressure, tobacco use, height, and weight. Data on causes of death were obtained from medical death certificates. We used Cox regression models to assess the relevance of diabetes (any type) to occlusive vascular mortality (ischaemic heart disease, ischaemic stroke, or other atherosclerotic deaths) by age, sex, and other major vascular risk factors, and to assess whether the associations of blood pressure, total cholesterol, and body-mass index (BMI) to occlusive vascular mortality are modified by diabetes. Results: Individual participant-level data were analysed from 980 793 adults. During 9·8 million person-years of follow-up, among participants aged between 35 and 89 years, 19 686 (25·6%) of 76 965 deaths were attributed to occlusive vascular disease. After controlling for major vascular risk factors, diabetes roughly doubled occlusive vascular mortality risk among men (death rate ratio [RR] 2·10, 95% CI 1·97–2·24) and tripled risk among women (3·00, 2·71–3·33; χ2 test for heterogeneity p<0·0001). For both sexes combined, the occlusive vascular death RRs were higher in younger individuals (aged 35–59 years: 2·60, 2·30–2·94) than in older individuals (aged 70–89 years: 2·01, 1·85–2·19; p=0·0001 for trend across age groups), and, across age groups, the death RRs were higher among women than among men. Therefore, women aged 35–59 years had the highest death RR across all age and sex groups (5·55, 4·15–7·44). However, since underlying confounder-adjusted occlusive vascular mortality rates at any age were higher in men than in women, the adjusted absolute excess occlusive vascular mortality associated with diabetes was similar for men and women. At ages 35–59 years, the excess absolute risk was 0·05% (95% CI 0·03–0·07) per year in women compared with 0·08% (0·05–0·10) per year in men; the corresponding excess at ages 70–89 years was 1·08% (0·84–1·32) per year in women and 0·91% (0·77–1·05) per year in men. Total cholesterol, blood pressure, and BMI each showed continuous log-linear associations with occlusive vascular mortality that were similar among individuals with and without diabetes across both sexes. Interpretation: Independent of other major vascular risk factors, diabetes substantially increased vascular risk in both men and women. Lifestyle changes to reduce smoking and obesity and use of cost-effective drugs that target major vascular risks (eg, statins and antihypertensive drugs) are important in both men and women with diabetes, but might not reduce the relative excess risk of occlusive vascular disease in women with diabetes, which remains unexplained. Funding: UK Medical Research Council, British Heart Foundation, Cancer Research UK, European Union BIOMED programme, and National Institute on Aging (US National Institutes of Health).

Background: Several studies have shown that diabetes confers a higher relative risk of vascular mortality among women than among men, but whether this increased relative risk in women exists across age groups and within defined levels of other risk factors is uncertain. We aimed to determine whether differences in established risk factors, such as blood pressure, BMI, smoking, and cholesterol, explain the higher relative risks of vascular mortality among women than among men. Methods: In our meta-analysis, we obtained individual participant-level data from studies included in the Prospective Studies Collaboration and the Asia Pacific Cohort Studies Collaboration that had obtained baseline information on age, sex, diabetes, total cholesterol, blood pressure, tobacco use, height, and weight. Data on causes of death were obtained from medical death certificates. We used Cox regression models to assess the relevance of diabetes (any type) to occlusive vascular mortality (ischaemic heart disease, ischaemic stroke, or other atherosclerotic deaths) by age, sex, and other major vascular risk factors, and to assess whether the associations of blood pressure, total cholesterol, and body-mass index (BMI) to occlusive vascular mortality are modified by diabetes. Results: Individual participant-level data were analysed from 980 793 adults. During 9·8 million person-years of follow-up, among participants aged between 35 and 89 years, 19 686 (25·6%) of 76 965 deaths were attributed to occlusive vascular disease. After controlling for major vascular risk factors, diabetes roughly doubled occlusive vascular mortality risk among men (death rate ratio [RR] 2·10, 95% CI 1·97-2·24) and tripled risk among women (3·00, 2·71-3·33; χ2 test for heterogeneity p<0·0001). For both sexes combined, the occlusive vascular death RRs were higher in younger individuals (aged 35-59 years: 2·60, 2·30-2·94) than in older individuals (aged 70-89 years: 2·01, 1·85-2·19; p=0·0001 for trend across age groups), and, across age groups, the death RRs were higher among women than among men. Therefore, women aged 35-59 years had the highest death RR across all age and sex groups (5·55, 4·15-7·44). However, since underlying confounder-adjusted occlusive vascular mortality rates at any age were higher in men than in women, the adjusted absolute excess occlusive vascular mortality associated with diabetes was similar for men and women. At ages 35-59 years, the excess absolute risk was 0·05% (95% CI 0·03-0·07) per year in women compared with 0·08% (0·05-0·10) per year in men; the corresponding excess at ages 70-89 years was 1·08% (0·84-1·32) per year in women and 0·91% (0·77-1·05) per year in men. Total cholesterol, blood pressure, and BMI each showed continuous log-linear associations with occlusive vascular mortality that were similar among individuals with and without diabetes across both sexes. Interpretation: Independent of other major vascular risk factors, diabetes substantially increased vascular risk in both men and women. Lifestyle changes to reduce smoking and obesity and use of cost-effective drugs that target major vascular risks (eg, statins and antihypertensive drugs) are important in both men and women with diabetes, but might not reduce the relative excess risk of occlusive vascular disease in women with diabetes, which remains unexplained. Funding: UK Medical Research Council, British Heart Foundation, Cancer Research UK, European Union BIOMED programme, and National Institute on Aging (US National Institutes of Health).

Background Knowledge on the origins of the social gradient in stroke incidence in different populations is limited. This study aims to estimate the burden of educational class inequalities in stroke incidence and to assess the contribution of risk factors in determining these inequalities across Europe. Materials and methods The MORGAM (MOnica Risk, Genetics, Archiving and Monograph) Study comprises 48 cohorts recruited mostly in the 1980s and 1990s in four European regions using standardised procedures for baseline risk factor assessment and fatal and non-fatal stroke ascertainment and adjudication during follow-up. Among the 126 635 middle-aged participants, initially free of cardiovascular diseases, generating 3788 first stroke events during a median follow-up of 10 years, we estimated differences in stroke rates and HRs for the least versus the most educated individuals. Results Compared with their most educated counterparts, the overall age-adjusted excess hazard for stroke was 1.54 (95% CI 1.25 to 1.91) and 1.41 (95% CI 1.16 to 1.71) in least educated men and women, respectively, with little heterogeneity across populations. Educational class inequalities accounted for 86–413 and 78–156 additional stroke events per 100 000 person-years in the least compared with most educated men and women, respectively. The additional events were equivalent to 47%–130% and 40%–89% of the average incidence rates. Inequalities in risk factors accounted for 45%–70% of the social gap in incidence in the Nordic countries, the UK and Lithuania-Kaunas (men), but for no more than 17% in Central and South Europe. The major contributors were cigarette smoking, alcohol intake and body mass index. Conclusions Social inequalities in stroke incidence contribute substantially to the disease rates in Europe. Healthier lifestyles in the most disadvantaged individuals should have a prominent impact in reducing both inequalities and the stroke burden.

Background: The combined effect of social status and risk factors on the absolute risk of cardiovascular disease has been insufficiently investigated, but results provide guidance on who could benefit most through prevention. Methods: We followed 77,918 cardiovascular disease-free individuals aged 35-74 years at baseline, from 38 cohorts covering Nordic and Baltic countries, the UK and Central Europe, for a median of 12 years. Using Fine-Gray models in a competing-risks framework we estimated the effect of the interaction of education with smoking, blood pressure and body weight on the cumulative risk of incident acute coronary heart disease and stroke. Results: Compared with more educated smokers, the less educated had an added increase in absolute risk of cardiovascular disease of 3.1% (95% confidence interval + 0.1%, +6.2%) in men and of 1.5% (-1.9%, +5.0%) in women, consistent across smoking categories. Conversely, the interaction was negative for overweight: -2.6% (95% CI: -5.6%, +0.3%) and obese: -3.6% (-7.6%, +0.4%) men, suggesting that the more educated would benefit more from the same reduction in body weight. A weaker interaction was observed for body weight in women, and for blood pressure in both genders. Less educated men and women with a cluster of two or more risk factors had an added cardiovascular disease risk of 3.6% (+0.1%, +7.0%) and of 2.6% (-0.5%, +5.6%), respectively, compared with their more educated counterparts. Conclusions: Socially disadvantaged subjects have more to gain from lifestyle and blood pressure modification, hopefully reducing both their risk and also social inequality in disease.

Multi-center epidemiological studies must ascertain that their measurements are accurate and reliable. For laboratory measurements, reliability can be assessed through investigation of reproducibility of measurements in the same individual. In this paper, we present results from the quality control analysis of the baseline laboratory measurements from the ELSA-Brasil study. The study enrolled 15,105 civil servants at 6 research centers in 3 regions of Brazil between 2008-2010, with multiple biochemical analytes being measured at a central laboratory. Quality control was ascertained through standard laboratory evaluation of intra- and inter-assay variability and test-retest analysis in a subset of randomly chosen participants. An additional sample of urine or blood was collected from these participants, and these samples were handled in the same manner as the original ones, locally and at the central laboratory. Reliability was assessed with the intraclass correlation coefficient (ICC), estimated through a random effects model. Coefficients of variation (CV) and Bland-Altman plots were additionally used to assess measurement variability. Laboratory intra and inter-assay CVs varied from 0.86% to 7.77%. From test-retest analyses, the ICCs were high for the majority of the analytes. Notably lower ICCs were observed for serum sodium (ICC=0.50; 95%CI=0.31-0.65) and serum potassium (ICC=0.73; 95%CI=0.60-0.83), due to the small biological range of these analytes. The CVs ranged from 1 to 14%. The Bland-Altman plots confirmed these results. The quality control analyses showed that the collection, processing and measurement protocols utilized in the ELSA-Brasil produced reliable biochemical measurements. © 2016, Associacao Brasileira de Divulgacao Cientifica. All rights reserved.

Background and aims: Biomarkers and atherosclerosis imaging have been studied individually for association with incident cardiovascular disease (CVD); however, limited data exist on whether the biomarkers are associated with events with a similar magnitude in the presence of atherosclerosis. In this study, we assessed whether the presence of atherosclerosis as measured by carotid intima media thickness (cIMT) affects the association between biomarkers known to be associated with coronary heart disease (CHD) and incident cardiovascular disease (CVD) in a primary prevention cohort. Methods: 8127 participants from the ARIC study (4th visit, 1996-1998) were stratified as having minimal, mild, or substantial atherosclerosis by cIMT. Levels of C-reactive protein, lipoprotein-associated phospholipase A2, cardiac troponin T, N-terminal pro-brain natriuretic peptide, lipoprotein(a), cystatin C, and urine albumin to creatinine ratio were measured in each participant. Hazard ratios were used to determine the relationship between the biomarkers and incident CHD, stroke, and CVD in each category of atherosclerosis. Results: While each of the biomarkers was significantly associated with risk of events overall, we found no significant differences noted in the strength of association of biomarkers with CHD, stroke, and CVD when analyzed by degree of atherosclerosis. Conclusions: These findings suggest that the level of atherosclerosis does not significantly influence the association between biomarkers and CVD.

Objective: To estimate the burden of social inequalities in coronary heart disease (CHD) and to identify their major determinants in 15 European populations. Methods: The MORGAM (MOnica Risk, Genetics, Archiving and Monograph) study comprised 49 cohorts of middle-aged European adults free of CHD (110 928 individuals) recruited mostly in the mid-1980s and 1990s, with comparable assessment of baseline risk and follow-up procedures. We derived three educational classes accounting for birth cohorts and used regression-based inequality measures of absolute differences in CHD rates and HRs (ie, Relative Index of Inequality, RII) for the least versus the most educated individuals. Results: N=6522 first CHD events occurred during a median follow-up of 12 years. Educational class inequalities accounted for 343 and 170 additional CHD events per 100 000 person-years in the least educated men and women compared with the most educated, respectively. These figures corresponded to 48% and 71% of the average event rates in each gender group. Inequalities in CHD mortality were mainly driven by incidence in the Nordic countries, Scotland and Lithuania, and by 28-day case-fatality in the remaining central/South European populations. The pooled RIIs were 1.6 (95% CI 1.4 to 1.8) in men and 2.0 (1.7 to 2.4) in women, consistently across population. Risk factors accounted for a third of inequalities in CHD incidence; smoking was the major mediator in men, and High-Density-Lipoprotein (HDL) cholesterol in women. Conclusions: Social inequalities in CHD are still widespread in Europe. Since the major determinants of inequalities followed geographical and gender-specific patterns, European-level interventions should be tailored across different European regions.

Introduction and aim: There are limited comparative data on social inequalities in stroke morbidity across Europe. We aimed to assess the magnitude of educational class inequalities in stroke mortality, incidence and 1-year case-fatality in European populations. Methods: The MORGAM study comprised 45 cohorts from Finland, Denmark, Sweden, Northern Ireland, Scotland, France, Germany, Italy, Lithuania, Poland and Russia, mostly recruited in mid 1980s-early 90s. Baseline data collection and follow-up (median 12 years) for fatal and non-fatal strokes adhered to MONICA-like procedures. Stroke mortality was defined according to the underlying cause of death (ICD-IX codes 430-438 or ICD-X I60-I69). We derived 3 educational classes from population-, sex- and birth year-specific tertiles of years of schooling. We estimated the age-adjusted difference in event rates, and the age- and risk factor-adjusted hazard ratios (HRs), between the bottom and the top of the educational class distribution from sex- and population-specific Poisson and Cox regression models, respectively. The association between 1-year case-fatality and education was estimated through logistic models adjusted for risk factors. Results: Among the 91,563 CVD-free participants aged 35-74 at baseline, 1037 stroke deaths and 3902 incident strokes occurred during follow-up. Low education accounted for 26 additional stroke deaths per 100,000 person-years in men (95%CI: 9 to 42), and 19 (7 to 32) in women. In both genders, inequalities in fatal stroke rates were larger in the East EU and in the Nordic Countries populations. The age-adjusted pooled HRs of first stroke, fatal or non-fatal, for the least educated men and women were 1.52 (95%CI: 1.29-1.78) and 1.51 (1.25-1.81), respectively, consistently across populations. Adjustment for smoking, blood pressure, HDL-cholesterol and diabetes attenuated the pooled HRs to 1.34 (95%CI: 1.14-1.57) in men and 1.29 (1.07-1.55) in women. A significant association between low education and increased 1-year case-fatality was observed in Northern Sweden only. Conclusions: Social inequalities in stroke incidence are widespread in most European populations, and less than half of the gap is explained by major risk factors.

Background: Recent animal studies suggest that artificially sweetened beverage (ASB) consumption increases diabetes risk. Objective: We examined the relation of ASB intake with newly diagnosed diabetes and measures of glucose homeostasis in a large Brazilian cohort of adults. Methods: We used cross-sectional data from 12,884 participants from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). ASB use was assessed by questionnaire and newly diagnosed diabetes by a 2-h 75-g oral glucose tolerance test and/or glycated hemoglobin. Logistic and linear regression analyses were performed to examine the association of ASB consumption with diabetes and continuous measures of glucose homeostasis, respectively. Results: Although ASB consumption was not associated with diabetes in logistic regression analyses after adjustment for body mass index (BMI; in kg/m2 ) overall, the association varied across BMI categories (P-interaction = 0.04). Among those with a BMI <25, we found a 15% increase in the adjusted odds of diabetes for each increase in the frequency of ASB consumption per day (P = 0.001); compared with nonusers, ASB users presented monotonic increases in the adjusted ORs (95% CIs) of diabetes with increased frequency of consumption: 1.03 (0.60, 1.77), 1.43 (0.93, 2.20), 1.62 (1.08, 2.44), and 2.51 (1.40, 4.50) for infrequent, 1–2, 3–4, and >4 times/d, respectively. In linear regression analyses, among normal-weight individuals, greater ASB consumption was also associated with increased fasting glucose concentrations (P = 0.01) and poorer b-cell function (P = 0.009). No such associations were seen for those with BMI $25. In fact, in overweight or obese participants, greater ASB consumption was significantly associated with improved indexes of insulin resistance and 2-h postload glucose. Conclusions: Normal-weight, but not excess-weight, individuals with greater ASB consumption presented diabetes more frequently and had higher fasting glucose and poorer b-cell function