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Bronchodilator responsiveness (BDR) in obstructive lung disease varies over time and may be associated with distinct clinical features.Is consistent BDR over time (always present) differentially associated with obstructive lung disease features relative to inconsistent (sometimes present) or never (never present) BDR in tobacco-exposed people with or without COPD?We retrospectively analyzed data from 2,269 tobacco-exposed participants in the Subpopulations and Intermediate Outcome Measures in COPD Study with or without COPD. We used various BDR definitions: change of ≥ 200 mL and ≥ 12% in FEVBoth consistent and inconsistent ATS-BDR were associated with asthma history and greater small airways disease (%parametric response mapping functional small airways disease) relative to never ATS-BDR in participants with GOLD stage 0 disease and the entire cohort. We observed similar findings using FEVDemonstration of BDR, even once, describes an obstructive lung disease phenotype with a history of asthma and greater small airways disease. Consistent demonstration of BDR indicated a high risk of lung function decline over time in the entire cohort and was associated with higher risk of progression to COPD in patients with GOLD stage 0 disease.

Background Small airways are known to be affected early in the course of chronic obstructive pulmonary disease (COPD); however, traditional spirometric indices may not accurately identify small airways disease. Research Question Can FEV3/FEV6 identify early airflow abnormalities and predict future clinically important respiratory-related outcomes, including development of COPD? Study Design and Methods We included eight hundred thirty-two current and former smokers with post-bronchodilator FEV1/FVC ≥0.7 from the SPIROMICS cohort. Participants were classified as having a reduced pre-bronchodilator FEV3/FEV6 based on lower limit of normal (LLN) values. Repeatability analysis was performed for FEV3 and FEV6. Regression modeling was used to evaluate the relationship between baseline FEV3/FEV6 and outcome measures including functional small airways disease on thoracic imaging and respiratory exacerbations. Interval censored analysis was used to assess progression to COPD. Results FEV3/FEV6 Interpretation FEV3/FEV6 is a routinely available and repeatable spirometric index which can be useful in the evaluation of early airflow obstruction in current and former smokers without COPD. A reduced FEV3/FEV6 can identify those at risk for future development of COPD and respiratory exacerbations.

ARIC (Atherosclerosis Risk In Communities) initiated community-based surveillance in 1987 for myocardial infarction and coronary heart disease (CHD) incidence and mortality and created a prospective cohort of 15,792 Black and White adults ages 45 to 64 years. The primary aims were to improve understanding of the decline in CHD mortality and identify determinants of subclinical atherosclerosis and CHD in Black and White middle-age adults. ARIC has examined areas including health disparities, genomics, heart failure, and prevention, producing more than 2,300 publications. Results have had strong clinical impact and demonstrate the importance of population-based research in the spectrum of biomedical research to improve health.

Background The relationship between 25-hydroxyvitamin D (25-OH-vitamin D) and COPD outcomes remains unclear. Using the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), we determined associations among baseline 25-OH-vitamin D and cross-sectional and longitudinal lung function and COPD exacerbations. Methods Serum 25-OH-vitamin D level was measured in stored samples from 1,609 SPIROMICS participants with COPD. 25-OH-vitamin D levels were modeled continuously and dichotomized as deficient ( Results Vitamin D deficiency was present in 21% of the cohort and was more prevalent in the younger, active smokers, and blacks. Vitamin D deficiency was independently associated with lower % predicted FEV1 (by 4.11%) at enrollment (95% CI, –6.90% to –1.34% predicted FEV1; P = .004), 1.27% predicted greater rate of FEV1 decline after 1 year (95% CI, –2.32% to –0.22% predicted/y; P = .02), and higher odds of any COPD exacerbation in the prior year (OR, 1.32; 95% CI, 1.00-1.74; P = .049). Each 10-ng/mL decrease in 25-OH-vitamin D was associated with lower baseline lung function (–1.04% predicted; 95% CI, –1.96% to –0.12% predicted; P = .03) and increased odds of any exacerbation in the year before enrollment (OR, 1.11; 95% CI, 1.01-1.22; P = .04). Conclusions Vitamin D deficiency is associated with worse cross-sectional and longitudinal lung function and increased odds of prior COPD exacerbations. These findings identify 25-OH-vitamin D levels as a potentially useful marker of adverse COPD-related outcomes.

Summary Background Former smokers now outnumber current smokers in many developed countries, and current smokers are smoking fewer cigarettes per day. Some data suggest that lung function decline normalises with smoking cessation; however, mechanistic studies suggest that lung function decline could continue. We hypothesised that former smokers and low-intensity current smokers have accelerated lung function decline compared with never-smokers, including among those without prevalent lung disease. Methods We used data on six US population-based cohorts included in the NHLBI Pooled Cohort Study. We restricted the sample to participants with valid spirometry at two or more exams. Two cohorts recruited younger adults (≥17 years), two recruited middle-aged and older adults (≥45 years), and two recruited only elderly adults (≥65 years) with examinations done between 1983 and 2014. FEV1 decline in sustained former smokers and current smokers was compared to that of never-smokers by use of mixed models adjusted for sociodemographic and anthropometric factors. Differential FEV1 decline was also evaluated according to duration of smoking cessation and cumulative (number of pack-years) and current (number of cigarettes per day) cigarette consumption. Findings 25 352 participants (ages 17–93 years) completed 70 228 valid spirometry exams. Over a median follow-up of 7 years (IQR 3–20), FEV1 decline at the median age (57 years) was 31·01 mL per year (95% CI 30·66–31·37) in sustained never-smokers, 34·97 mL per year (34·36–35·57) in former smokers, and 39·92 mL per year (38·92–40·92) in current smokers. With adjustment, former smokers showed an accelerated FEV1 decline of 1·82 mL per year (95% CI 1·24–2·40) compared to never-smokers, which was approximately 20% of the effect estimate for current smokers (9·21 mL per year; 95% CI 8·35–10·08). Compared to never-smokers, accelerated FEV1 decline was observed in former smokers for decades after smoking cessation and in current smokers with low cumulative cigarette consumption ( Interpretation Former smokers and low-intensity current smokers have accelerated lung function decline compared with never-smokers. These results suggest that all levels of smoking exposure are likely to be associated with lasting and progressive lung damage. Funding National Institutes of Health, National Heart Lung and Blood Institute, and US Environmental Protection Agency.

Background A lower prevalence of atrial fibrillation (AF), but paradoxically higher burden of cardiovascular disease risk factors, has been observed among African Americans compared to Whites in studies of AF identified by mostly 12-lead electrocardiograms (ECGs) and clinically. Methods We performed 48-hour ambulatory electrocardiography (aECG) in a biracial sample of 1,193 participants in the Atherosclerosis Risk in Communities (ARIC) (mean age = 78 years, 62% African Americans, 64% female). Atrial fibrillation was identified from aECG, study visit ECGs, and discharge codes from cohort hospitalizations. We used covariate-adjusted logistic regression to estimate prevalence odds ratios (ORs) for AF in African Americans versus Whites, with adjustment for sampling and nonresponse. Results African Americans were more likely than Whites to have hypertension and diabetes but less likely to have coronary heart disease. The prevalence of AF detected by aECG or ARIC study ECG (adjusted for age and coronary heart disease) was lower in African Americans than Whites (2.7% vs 5.0%). White men had a higher (although not significant) AF prevalence of 7.8% compared to the other race and gender groups at 2.3%-2.8%. The adjusted OR for AF was 0.49 (0.24-0.99) comparing African Americans to Whites. Findings were similar when AF was defined to include prior AF hospitalizations (OR = 0.42, 0.25-0.72). There were no significant differences by race for asymptomatic or paroxysmal AF. Conclusions Atrial fibrillation was less prevalent in African American than white older adults, regardless of detection method. Although overall detection of new AF cases with aECG was low, future studies should consider longer-term monitoring to characterize AF by race.

BACKGROUND: Chronic respiratory symptoms and exacerbation-like events are common among ever-smokers without airflow limitation on spirometry. The pathobiology of respiratory disease in this subgroup remains poorly defined, but may be due to underlying inflammation that overlaps with COPD or asthma. We hypothesized that symptoms, exacerbations, and functional measures of disease severity among smokers with preserved spirometry would be associated with markers of systemic inflammation, similar to what is reported in bone fide COPD, rather than elevated type 2 inflammation, which is often present in asthma. METHODS: We measured inflammatory markers associated with COPD (C-reactive protein [CRP], fibrinogen, soluble tumor necrosis factor receptors [sTNFRSF1A and sTNFRSF1B], and blood/sputum neutrophils) and type 2 inflammation (IgE and blood/sputum eosinophils) in smokers with preserved spirometry (postbronchodilator FEV(1)/FVC ≥ 0.70) from the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS). We evaluated the relationship of these markers with respiratory symptom burden (dichotomized by a COPD assessment test score cutoff of 10, diagnosis of chronic bronchitis), exacerbations, 6-minute walk distance, and lung function on the basis of FEV(1). RESULTS: CRP was associated with increased symptom burden (on the basis of COPD assessment test score and diagnosis of chronic bronchitis) and a greater number of exacerbations in the year before study enrollment. sTNFRSF1A was associated with symptom burden on the basis of COPD assessment test score. CRP and sTNFRSF1A levels negatively correlated with 6-minute walk distance. IgE and eosinophils were not associated with these outcomes. CONCLUSIONS: Markers of inflammation including CRP and sTNFRSF1A are enriched among symptomatic smokers with preserved spirometry, suggesting an overlap with the underlying pathophysiology of COPD.

Neighborhood poverty has been associated with poor health outcomes. Previous studies have also identified adverse respiratory effects of long-term ambient ozone. Factors associated with neighborhood poverty may accentuate the adverse impact of ozone on respiratory health.To evaluate whether neighborhood poverty modifies the association between ambient ozone exposure and respiratory morbidity including symptoms, exacerbation risk, and radiologic parameters, among participants of the SPIROMICS AIR cohort study.Spatiotemporal models incorporating cohort-specific monitoring estimated 10-year average outdoor ozone concentrations at participants' homes. Adjusted regression models were used to determine the association of ozone exposure with respiratory outcomes, accounting for demographic factors, education, individual income, body mass index (BMI), and study site. Neighborhood poverty rate was defined by percentage of families living below federal poverty level per census tract. Interaction terms for neighborhood poverty rate with ozone were included in covariate-adjusted models to evaluate for effect modification.1874 participants were included in the analysis, with mean (± SD) age 64 (± 8.8) years and FEVIndividuals with COPD in high poverty neighborhoods have higher susceptibility to adverse respiratory effects of ambient ozone exposure, after adjusting for individual factors. These findings highlight the interaction between exposures associated with poverty and their effect on respiratory health.

BACKGROUND: High N-terminal pro-brain natriuretic peptide (NT-proBNP) during COPD exacerbations is associated with worse clinical outcomes. The prognostic value of NT-proBNP measured during clinical stability has not been well characterized. METHODS: We studied SPIROMICS participants 40–80 years of age with COPD GOLD spirometric stages 1–4. The association between baseline NT-proBNP and incident COPD exacerbations within one year of follow-up was tested using zero-inflated Poisson regression models adjusted for age, gender, race, body mass index, current smoking status, smoking history, FEV(1) percent predicted, COPD Assessment Test score, exacerbation history, total lung capacity on chest CT and cardiovascular disease (any of coronary artery disease, myocardial infarction or congestive heart failure). RESULTS: Among 1,051 participants (mean age 66.1 years, 41.4% women), mean NT-proBNP was 608.9 pg/ml. Subjects in GOLD stage D had the highest mean NT-proBNP. After one year of follow-up, 268 participants experienced one or more COPD exacerbations. One standard deviation increase in baseline NT-proBNP was associated with a 13% increase in the risk of incident exacerbations (incident risk ratio 1.13; 95% CI 1.06–1.19; p

Background and aims No prospective study has investigated whether individuals with respiratory impairments, including chronic obstructive pulmonary disease (COPD) and restrictive lung disease (RLD), are at increased risk of abdominal aortic aneurysm (AAA). We aimed to prospectively investigate whether those respiratory impairments are associated with increased AAA risk. Methods In 1987–1989, the Atherosclerosis Risk in Communities (ARIC) study followed 14,269 participants aged 45–64 years, without a history of AAA surgery, through 2011. Participants were classified into four groups, “COPD” [forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC)

Active smoking in stable COPD subjects significantly increased eosinophil accumulation in the distal airspaces, but not in sputum or peripheral blood. Our findings support the need to investigate this cell-type as a potential driver of COPD symptomatology and progression.

Background & Aims Studies assessing alcohol as a population level risk factor for cirrhosis typically focus on per capita consumption. However, clinical studies indicate that daily intake is a strong predictor of alcoholic cirrhosis. We aimed to identify the determinants of alcohol's contribution to the global cirrhosis burden and to evaluate the influence of daily drinking on a population level. Methods We performed a comprehensive analysis of the WHO 2014 Global Status Report on Alcohol and Health. We categorized countries by heavy or moderate drinking based on daily consumption, using U.S. Department of Agriculture definitions of heavy drinking. Additional data on cirrhosis cofactors were also obtained. Uni- and multivariate models were fitted to identify independent predictors of the alcohol-attributable fraction of cirrhosis. Results The WHO 2014 Report found that half of cirrhosis mortality worldwide is attributable to alcohol, approximating 60% in North America and Europe. In an integrative multivariate model, the designation of countries by moderate or heavy daily drinking had the strongest influence on the weight of alcohol in the cirrhosis burden. The relative contribution from alcohol increased by 11% with a transition from the moderate to heavy classification ( p Conclusions Heavy daily drinking on a population level significantly influences the weight of alcohol in the cirrhosis burden. Reducing heavy drinking should be considered as an important target for public health monitoring and policies. Lay summary We carried out an analysis of the WHO 2014 Global Status Report on Alcohol and Health, and categorized countries by their level of drinking (heavy or moderate). We found that half of the global cirrhosis cases, and 60% in both North America and Europe are associated with alcohol intake. We concluded that on a population level heavy daily drinking significantly influences the impact of alcohol on the cirrhosis burden.

OBJECTIVE: Younger persons with COPD report worse health-related quality of life (HRQL) than do older individuals. The factors explaining these differences remain unclear. The objective of this article was to explore factors associated with age-related differences in HRQL in COPD. METHODS: Cross-sectional analysis of participants with COPD, any Global Initiative for Chronic Obstructive Lung Disease grade of airflow limitation, and ≥ 50 years old in two cohorts: the Genetic Epidemiology of COPD (COPDGene) study and the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS). We compared St. George's Respiratory Questionnaire (SGRQ) scores by age group: middle-aged (age, 50-64) vs older (age, 65-80) adults. We used multivariate linear modeling to test associations of age with HRQL, adjusting for demographic and clinical characteristics and comorbidities. RESULTS: Among 4,097 participants in the COPDGene study (2,170 middle-aged and 1,927 older adults) SGRQ total scores were higher (worse) among middle-aged (mean difference, -4.2 points; 95% CI, -5.7 to -2.6; P < .001) than older adults. Age had a statistically significant interaction with dyspnea (P < .001). Greater dyspnea severity (modified Medical Research Council ≥ 2, compared with 0-1) had a stronger association with SGRQ score among middle-aged (β, 24.6; 95% CI, 23.2-25.9) than older-adult (β, 21.0; 95% CI, 19.6-22.3) participants. In analyses using SGRQ as outcome in 1,522 participants in SPIROMICS (598 middle-aged and 924 older adults), we found similar associations, confirming that for the same severity of dyspnea there is a stronger association with HRQL among younger individuals. CONCLUSIONS: Age-related differences in HRQL may be explained by a higher impact of dyspnea among younger subjects with COPD. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00608764 and No.: NCT01969344; URL: www.clinicaltrials.gov.

Objective A large body of epidemiologic data strongly suggests an association between excess adiposity and coronary artery disease (CAD). Low adiponectin levels, a hormone secreted only from adipocytes, have been associated with an increased risk of CAD in observational studies. However, these associations cannot clarify whether this relationship is causal or due to a shared set of causal factors or even confounding. Genome-wide association studies have identified common variants that influence adiponectin levels, providing valuable tools to examine the genetic relationship between adiponectin and CAD. Methods Using 145 genome wide significant SNPs for adiponectin from the ADIPOGen consortium ( n = 49,891), we tested whether adiponectin-decreasing alleles influenced risk of CAD in the CARDIoGRAM consortium ( n = 85,274). Results In single-SNP analysis, 5 variants among 145 SNPs were associated with increased risk of CAD after correcting for multiple testing ( P −4 ). Using a multi-SNP genotypic risk score to test whether adiponectin levels and CAD have a shared genetic etiology, we found that adiponectin-decreasing alleles increased risk of CAD ( P = 5.4 × 10 −7 ). Conclusion These findings demonstrate that adiponectin levels and CAD have a shared allelic architecture and provide rationale to undertake a Mendelian randomization studies to understand if this relationship is causal.

The Combined Pharmacotherapies and Behavioral Interventions (COMBINE) Study sought to answer questions about the benefits of combining behavioral and pharmacological interventions (naltrexone and acamprosate) in alcohol-dependent patients. Our goals were to identify trajectories of heavy drinking before randomization in COMBINE, to characterize patients in these trajectories, and to assess whether prerandomization trajectories predict drinking outcomes. We analyzed daily indicators of heavy drinking 90 days before randomization using a trajectory-based approach. Each patient was assigned to the most likely prerandomization heavy-drinking trajectory, and the baseline characteristics of participants in the baseline trajectories were compared. The main and interactive effects of these trajectories and treatment factors (acamprosate, naltrexone, or combined behavioral intervention) on summary drinking measures during active treatment (16 weeks) were assessed. We identified five trajectories of heavy drinking prerandomization: “T1: frequent heavy drinkers”; “T2: very frequent heavy drinkers”; “T3: nearly daily heavy drinkers”; “T4: daily heavy drinkers”; and “T5: daily heavy drinkers stopping early” before randomization. Trajectory membership was significantly associated with all drinking outcomes. Patients in “T5: daily heavy drinkers stopping early” had comparable drinking outcomes to those in “T1: frequent heavy drinkers,” whereas the remaining trajectories were associated with significantly worse outcomes. The baseline trajectory did not interact significantly with the treatment condition. These exploratory analyses confirmed the hypothesis that baseline trajectories predict postrandomization drinking outcomes. Interestingly, “T5: daily heavy drinkers stopping early” had outcomes that were comparable to the least severe baseline trajectory “T1: frequent heavy drinkers,” and baseline trajectories of heavy drinking did not moderate the treatment effects.

COMBINE is the largest study of pharmacotherapy for alcoholism in the United States to date, designed to answer questions about the benefits of combining behavioral and pharmacological interventions. Trajectory-based analyses of daily drinking data allowed identification of distinct drinking trajectories in smaller studies and demonstrated significant naltrexone effects even when primary analyses on summary drinking measures were unsuccessful. The objective of this study was to replicate and refine trajectory estimation and to assess effects of naltrexone, acamprosate and therapy on the probabilities of following particular trajectories in COMBINE. It was hypothesized that different treatments may affect different trajectories of drinking.We conducted exploratory analyses of daily indicators of any drinking and heavy drinking using a trajectory-based approach and assessed trajectory membership probabilities and odds ratios for treatment effects.We replicated the trajectories ("abstainer", "sporadic drinker", "consistent drinker") established previously in smaller studies. However, greater numbers of trajectories better described the heterogeneity of drinking over time. Naltrexone reduced the chance to follow a "nearly daily" trajectory and Combined Behavioral Intervention (CBI) reduced the chance to be in an "increasing to nearly daily" trajectory of any drinking. The combination of naltrexone and CBI increased the probability of membership in a trajectory in which the frequency of any drinking declined over time. Trajectory membership was associated with different patterns of treatment compliance.The trajectory-analyses identified specific patterns of drinking that were differentially influenced by each treatment and provided support for hypotheses about the mechanisms by which these treatments work.

Purpose To describe the three-year incidence and cumulative prevalence of retinopathy and its risk factors. Design Population-based, prospective cohort study in four US communities. Methods In the Atherosclerosis Risk in Communities (ARIC) Study, 981 participants had retinal photography of one randomly selected eye at the third examination (1993 to 1995) and three years later at the fourth examination (1996). Photographs were graded on both occasions for retinopathy signs (for example, microaneurysm, retinal hemorrhage, and/or cotton-wool spots). Incidence was defined as participants without retinopathy at the third examination who developed retinopathy at the fourth examination, and cumulative prevalence was defined to include incident retinopathy as well as participants who had retinopathy at both the third and fourth examinations. Results The three-year incidence and cumulative prevalence of any retinopathy in the whole cohort was 3.8% and 7.7%, respectively. In multivariable analysis, incident retinopathy was related to higher mean arterial blood pressure (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.0 to 2.3, per standard deviation increase in risk factor levels), fasting serum glucose (OR 1.6, 95% CI 1.3 to 2.1), serum total cholesterol (OR 1.4, 95% CI 1.0, 2.0), and plasma fibrinogen (OR 1.4, 95% CI 1.1 to 1.9). Among persons without diabetes, the three-year incidence and cumulative prevalence of nondiabetic retinopathy was 2.9% and 4.3%, respectively. Incident nondiabetic retinopathy was related to higher mean arterial blood pressure (OR 1.4, 95% CI 0.9 to 2.3) and fasting serum glucose (OR 1.5, 95% CI 1.0 to 2.3). Among persons with diabetes, the three-year incidence and cumulative prevalence of diabetic retinopathy was 10.1% and 27.2%, respectively. Conclusions Retinopathy signs occur frequently in middle-aged people, even in those without diabetes. Hypertension and hyperglycemia are risk factors for incident retinopathy.

Objective To examine the association of age-related macular degeneration (AMD) with incident coronary heart disease (CHD) and all-cause mortality. Design Population-based prospective cohort study. Participants From the Atherosclerosis Risk in Communities Study (n = 12 536; age range, 49–73 years). Methods Participants had retinal photographs of one eye taken between 1993 and 1995. Photographs were evaluated for the presence of early and late AMD signs according to the Wisconsin grading system. Incident CHD events (acute myocardial infarction, silent myocardial infarction, fatal CHD, and cardiac revascularization procedures) and all-cause mortality were identified prospectively using standardized methods. Main Outcome Measures Incident CHD events and all-cause mortality. Results Of 11 414 persons at risk of CHD, there were 555 (4.9%) with AMD at baseline, of whom 540 were early AMD and 15 were late AMD cases. Over a 10-year follow-up, 922 persons developed an incident CHD event. After controlling for age, gender, race, systolic and diastolic blood pressure, pack-years of cigarette smoking, and other variables, early AMD was not associated with incident CHD (relative risk, 1.08; 95% confidence interval, 0.82–1.42). However, individuals with late AMD were significantly more likely to have an incident CHD event, with 4 CHD events among the 15 participants with late AMD at baseline (10-year cumulative incidence, 30.9%) as compared with 918 CHD events among the 11 399 participants without late AMD (incidence of 10.0%; P = 0.049, Fisher exact test). In the full cohort (n = 12 536), early AMD was not significantly associated with all-cause mortality. However, individuals with late AMD were more likely to die (10-year cumulative mortality rate, 23.5%) than those without late AMD (mortality rate, 8.9%; P = 0.088, Fisher exact test). Conclusions These data provide no evidence of an association between early AMD signs with incident CHD and all-cause mortality in middle-aged persons. Individuals with late AMD appear to have a higher rate of CHD events than those without late AMD, but due to a small number of late AMD cases, this finding should be interpreted cautiously.

To examine the association between the apolipoprotein E (APOE) gene and early age-related maculopathy (ARM) in middle-aged persons.Population-based cross-sectional study.Participants from the Atherosclerosis Risk in Communities Study (n = 10139; age range, 49-73 years).Retinal photography was performed on 1 randomly selected eye, and grading for presence of ARM was carried out using a modification of the Wisconsin ARM Grading System. Early ARM was defined as the presence of either soft drusen alone, retinal pigment epithelial depigmentation alone, or a combination of soft drusen with increased retinal pigment and/or depigmentation. DNA extracted from blood samples of participants were analyzed for common allelic variants of the APOE gene (epsilon2, epsilon3, and epsilon4).Presence of early ARM on retinal photographs.The prevalence of early ARM was similar in participants with different APOE genotypes: epsilon2/epsilon2 (5.9%), epsilon2/epsilon3 (5.2%), epsilon2/epsilon4 (3.2%), epsilon3/epsilon3 (5.2%), epsilon3/epsilon4 (4.9%), and epsilon4/epsilon4 (4.1%). After controlling for age, gender, race, cigarette smoking, and other factors, early ARM was not associated with APOE genotypes, with an odds ratio (OR) of 1.35 (95% confidence interval [CI], 0.54-3.38) for epsilon2/epsilon2 genotype, an OR of 1.06 (95% CI, 0.80-1.40) for epsilon2/epsilon3 genotype, an OR of 0.63 (95% CI, 0.32-1.24) for epsilon2/epsilon4 genotype, an OR of 0.99 (95% CI, 0.80-1.24) for epsilon3/epsilon4 genotype, and an OR of 0.88 (95% CI, 0.47-1.63) for epsilon4/epsilon4 genotype, as compared with epsilon3/epsilon3 genotype (reference). No associations were found for specific early ARM signs or in analyses stratified by age, gender, race, or cigarette smoking status.These data provide no evidence of a strong association between the APOE gene and early ARM in middle-aged persons. This suggests that APOE is not likely a major determinant of the early stages of ARM in younger people. However, our study does not exclude the possibility of a weaker association or that APOE may influence only the development of late ARM in older populations, as reported in other studies.

Risk prediction functions for incident coronary heart disease (CHD) were estimated using data from the Atherosclerosis Risk in Communities (ARIC) Study, a prospective study of CHD in 15,792 persons recruited in 1987-1989 from four U.S. communities, with follow-up through 1998. Predictivity of which individuals had incident CHD was assessed by increase in area under ROC curves resulting from adding nontraditional risk factors and markers of subclinical disease to a basic model containing only traditional risk factors. We also assessed the increase in population attributable risk. The additional factors were body mass index; waist-hip ratio; sport activity index; forced expiratory volume; plasma fibrinogen, factor VIII, von Willebrand factor, and Lp(a); heart rate; Keys score; pack-years smoking; and subclinical disease marker carotid intima-media thickness. These factors substantially improved prediction of future CHD for men, less for women, and also increased attributable risks.

Purpose The aim of this report is to describe the prevalence of retinopathy and its associations with atherosclerosis and vascular risk factors in people with diabetes. Design Cross-sectional study. Participants Persons with diabetes, having gradable fundus photographs, from a biracial population-based cohort of adults (ages 51–72 years), and living in four United States communities (Forsyth County, North Carolina; the city of Jackson, Mississippi; suburbs of Minneapolis, Minnesota; and Washington County, Maryland) were studied from 1993 to 1995. Methods Lesions typical of diabetic retinopathy were detected by grading a 45° color fundus photograph of one eye of each participant, using a modification of the Airlie House classification system. Main outcome measure Severity of diabetic retinopathy (none, minimal nonproliferative, moderate nonproliferative, severe nonproliferative, and proliferative) and macular edema. Results Retinopathy was detected in 328/1600 (20.5%) of those with diabetes; 114/1724 (6.6%) had hard exudate, 28/1600 (1.8%) had proliferative diabetic retinopathy, and 27/1662 (1.6%) had macular edema. The prevalence of diabetic retinopathy was higher in blacks (27.7%) compared with whites (16.7%). Controlling for duration of diabetes, serum glucose, systolic blood pressure, and type of diabetes medications taken, severity of retinopathy was associated with carotid artery intima-media wall thickness (odds ratio [OR]/0.1-mm thickness 1.09; 95% confidence interval [CI], 1.01, 1.17; P = 0.01), serum albumin (OR/0.1 g/dl 0.94; 95% CI, 0.88, 0.99; P = 0.02), but not race (OR blacks versus whites,1.24; 95% CI, 0.88, 1.75; P = 0.21). Severity of diabetic retinopathy was not associated with coronary artery disease or stroke history or any of the plasma lipids studied. Controlling for age, gender, duration of diabetes, serum glucose, and type of diabetes medications taken, the presence of retinal hard exudates was associated with plasma low-density lipoprotein cholesterol (OR/10 mg/dl 1.18; 95% CI, 1.09, 1.29; P P = 0.04) but not race or blood pressure. Conclusions These data suggest that plasma lipids are associated with the presence of hard exudate and that carotid artery intima-media wall thickness is associated with retinopathy, but other manifestations of atherosclerosis and most of its risk factors are not associated with severity of diabetic retinopathy.

Feather bedding has been inversely associated with child wheeze and also with house dust mite (HDM) allergen levels. We conducted a cross-sectional analysis of the childhood component of a birth cohort study. Our aim was to examine the relation between feather bedding and HDM sensitization and airway disease. A total of 498 children (84% of eligible) residing in Northern Tasmania in 1997 who were eligible for the Tasmanian Infant Health Survey at birth in 1988 or 1989 participated. Outcome measures included atopic sensitization to Dermatophagoides farinae or Dermatophagoides pteronyssinus allergens, spirometric lung function, and child respiratory symptoms using questions from the ISAAC study. HDM sensitization was strongly associated with frequent wheeze (more than 12 episodes of wheeze compared with no wheeze in the past year) (rate ratio [RR], 19.61; confidence interval [CI], 6.94-55.56) but only weakly associated with asthma ever (RR, 1.65; CI, 1.30-2.09). Feather quilt use was associated with reduced HDM sensitization (adjusted RR [ARR], 0.60; CI, 0.45-0.80) and also reduced frequent wheeze episodes over the past year (ARR, 0.24; CI, 0.07-0.86). The reduction in wheeze was more evident among HDM-sensitized children. These findings are consistent with the possible mechanisms for feather bedding of a reduction in initial HDM sensitization and an improvement in respiratory symptoms among HDM-sensitized children. However, prospective studies are required to fully exclude selection bias. © 2002 Elsevier Science Inc. All rights reserved.

Summary Background Retinal microvascular abnormalities reflect damage from hypertension and other vascular processes. We examined the relation of such abnormalities to incident stroke. Methods A cohort of 10 358 men and women (aged 51 to 72 years) living in four US communities underwent retinal photography and standard grading for retinal microvascular abnormalities. The calibres of all retinal arterioles and venules were measured after digital conversion of the photographs, and a summary arteriole-to-venule ratio (AVR) was calculated as an index of arteriolar narrowing (smaller AVR indicates greater narrowing). Cases of incident stroke admitted to hospital were identified and validated by case record reviews. Findings Over an average of 3.5 years, 110 participants had incident strokes. After adjustment for age, sex, race, 6-year mean arterial blood pressure, diabetes, and other stroke risk factors, most retinal microvascular characteristics were predictive of incident stroke, with adjusted relative risks of 2.58 (1.59-4.20) for any retinopathy, 3.11 (1.71-5.65) for microaneurysms, 3.08 (1.42-6.68) for soft exudates, 2.55 (1.27-5.14) for blot haemorrhages, 2.26 (1.00-5.12) for flame-shaped haemorrhages, and 1.60 (1.03-2.47) for arteriovenous nicking. The relative risk of stroke increased with decreasing AVR (p=0.03). The associations were similar for ischaemic strokes specifically, and for strokes in individuals with hypertension, either with or without diabetes. Interpretation Retinal microvascular abnormalities are related to incident stroke. The findings support microvascular role in the pathogenesis of stroke. They suggest that retinal photography may be useful for cerebrovascular-risk stratification in appropriate populations.

The study objective was to provide an example of how risk estimates might vary across studies of observational design, even when a causal association is present and to explore the possible sources of such variation. A meta-analysis of studies on the association between prone sleeping position and sudden infant death syndrome (SIDS) is used to illustrate how risk estimates might vary across studies. Data used were reported case-control studies of the association between sleeping position and SIDS that were published between 1970 and 1994. If the pooled odds ratio had been relied on to assess the association between sleeping position and SIDS without an accompanying examination of the reasons for heterogeneity, important insights into the causal significance of the relationship may have been lost. In meta-analyses of observational studies it is important to investigate the reasons for heterogeneity across studies.

Glutathione S-transferases M1 or T1 (GSTM1/GSTT1) affect the body's ability either to detoxify or to activate chemicals in cigarette smoke. Cigarette smoking increases the risk of lower extremity arterial disease (LEAD). We conducted a cross-sectional study to evaluate a hypothesized interaction of the genetic polymorphisms of GSTM1 and T1 with cigarette smoking in the risk of LEAD in the ARIC study. A stratified-random sample, including 212 LEAD cases (ankle-brachial index0.9 in men or0.85 in women) and 1277 non-cases, was selected from the ARIC cohort of 12041 middle-aged participants free of CHD, transient ischemic attack and stroke at baseline (1987-1989). Overall, the differences in the frequencies of GSTM1-0 and GSTT1-0 (the homozygous deletion genotype) were not statistically significant between cases and non-cases (44 vs. 41% and 28 vs. 18%). However, smoking was more prevalent among LEAD cases than non-cases. The results suggest that the non-deletion genotype GSTM1-1 interacts with smoking to increase the risk of LEAD, but this interaction was not statistically significant. The functional genotype GSTT1-1 was significantly associated with increased risk of LEAD given smoking after adjustment for other risk factors. In individuals with GSTT1-1, the odds ratios (ORs) (95% confidence intervals) of LEAD were 3.6 (1.4, 9.0) for current smoking and 5.0 (1.9, 13.0) for 20+ pack-years. However, in those with GSTT1-0, the ORs were 0.8 (0.2, 2.8) for current smoking and 0.6 (0.1, 2.1) for 20+ pack-years. The interaction was significant (P0.05) on the additive scale for current smoking and on both the additive and multiplicative scales for 20+ pack-years. Among non-smokers, GSTT1-1 was not associated with LEAD. The results suggest that the GSTT1-1 polymorphism may be a susceptibility factor modifying the risk of LEAD associated with cigarette smoking.

Purpose To examine the relation of early age-related macular degeneration (AMD) with cerebral magnetic resonance imaging (MRI) changes. Design Population-based, cross-sectional study. Methods A sample of 1,684 persons ages 51 to 72 years with no history of stroke had cerebral MRI and retinal photography. MRI scans were graded for severity of white matter lesions (WML), sulcal widening (SW), and ventricular enlargement (VE). AMD was graded from retinal photographs. Results After adjustment for age, gender, race, or center, early AMD (5.0% of participants) was not significantly associated with WML (odds ratio [OR] 1.0, 95% confidence intervals [CI], 0.6 to 1.6), SW (OR 0.6, 95% CI, 0.4 to 1.2), or VE (OR 1.0, 95% CI, 0.6 to 1.8). Conclusions These data showed no statistically significant association of early AMD with cerebral MRI changes, but the study was limited by a small number of cases with wide CIs. Further studies may clarify these associations.

The Pooled Cohort risk equations were developed to estimate 10-year ASCVD risk and guide prevention measures. Socio-economic (SES) factors such as education are known independent risk factors for ASCVD. We assessed the calibration of the Pooled Cohort risk equations across different education levels

Few population-based data support the hypothesis that hypertensive retinopathy is more common in African Americans than in whites. We examined racial differences in the prevalence of and risk factors for hypertensive retinopathy in a population-based sample of 1860 African Americans and 7874 white persons, aged 49 to 73 years, without diabetes. Retinal photographs were taken of one randomly selected eye and evaluated for the presence of retinopathy (flame and blot-shaped retinal hemorrhages, microaneurysms, and soft exudates) according to standardized protocols by graders masked to participant characteristics. The prevalence of retinopathy was 2 times higher in African Americans than in whites (7.7% versus 4.1%, age- and gender-adjusted odds ratio [OR] 2.03, 95% confidence intervals [CI] 1.65, 2.49). After controlling for 6-year mean arterial blood pressure, use of antihypertensive medications and left ventricular hypertrophy by ECG criteria, the excess prevalence of retinopathy in African Americans was reduced by 40% (adjusted OR 1.61, 95% CI 1.26, 2.06). Further adjustment for other vascular risk factors, common carotid artery intima-media thickness, and serum creatinine levels reduced the excess prevalence in African Americans by another 13% (adjusted OR 1.48, 95% CI 1.08, 2.03). We conclude that hypertensive retinopathy is twice as frequent in African Americans compared with whites without diabetes and that the excess prevalence of retinopathy in African Americans is associated with blood pressure and severity of hypertension.

Objective: To examine the relation of retinal microvascular abnormalities and MRI signs of cerebral atrophy in healthy middle-aged people. Methods: A population-based, cross-sectional study involved 1,684 persons aged 51 to 72 years who had cerebral MRI and retinal photography in 1993 to 1995. Sulcal and ventricular size were quantified from the MRI scans and coded as grades 0 to 9, with sulcal widening (SW) and ventricular enlargement (VE) defined as grades 3 or higher. The presence or absence of retinopathy, microaneurysms, hemorrhages, and other characteristics were defined from retinal photographs using a standardized protocol. Generalized arteriolar narrowing was defined from a computer-assisted measurement of arteriolar diameters from digitized photographs. Results: Persons with retinopathy had higher sulcal ( p = 0.001) and ventricular ( p = 0.03) grades than persons without retinopathy. After adjusting for age, gender, race, mean arterial blood pressure, diabetes, cigarette smoking, common carotid artery intima–media thickness, and other vascular risk factors, retinopathy was significantly associated with SW (odds ratio [OR], 1.9; 95% CI, 1.2, 3.0) and VE (OR, 1.5; 95% CI, 1.0, 2.3). These associations persisted even in people without diabetes or hypertension (OR 1.9, 95% CI, 0.8, 4.4 for SW; OR 2.7, 95% CI, 1.2, 6.5 for VE). Other retinal arteriolar characteristics (arteriovenous nicking, focal and generalized arteriolar narrowing) were not related to sulcal or ventricular grade. Conclusions: In healthy, middle-aged people, retinopathy is independently associated with sulcal and ventricular enlargement on MRI. This finding is compatible with the hypothesis that microvascular characteristics may influence the development of cerebral atrophic changes.