Determinants of social inequalities in stroke incidence across Europe: a collaborative analysis of 126 635 individuals from 48 cohort studies.

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.

Combined effect of educational status and cardiovascular risk factors on the incidence of coronary heart disease and stroke in European cohorts: Implications for prevention.

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.

Educational class inequalities in the incidence of coronary heart disease in Europe.

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.

Troponin T and N-terminal pro-B-type natriuretic peptide: a biomarker approach to predict heart failure risk--the atherosclerosis risk in communities study.

BACKGROUND: Among the various cardiovascular diseases, heart failure (HF) is projected to have the largest increases in incidence over the coming decades; therefore, improving HF prediction is of significant value. We evaluated whether cardiac troponin T (cTnT) measured with a high-sensitivity assay and N-terminal pro-B-type natriuretic peptide (NT-proBNP), biomarkers strongly associated with incident HF, improve HF risk prediction in the Atherosclerosis Risk in Communities (ARIC) study. METHODS: Using sex-specific models, we added cTnT and NT-proBNP to age and race ("laboratory report" model) and to the ARIC HF model (includes age, race, systolic blood pressure, antihypertensive medication use, current/former smoking, diabetes, body mass index, prevalent coronary heart disease, and heart rate) in 9868 participants without prevalent HF; area under the receiver operating characteristic curve (AUC), integrated discrimination improvement, net reclassification improvement (NRI), and model fit were described. RESULTS: Over a mean follow-up of 10.4 years, 970 participants developed incident HF. Adding cTnT and NT-proBNP to the ARIC HF model significantly improved all statistical parameters (AUCs increased by 0.040 and 0.057; the continuous NRIs were 50.7% and 54.7% in women and men, respectively). Interestingly, the simpler laboratory report model was statistically no different than the ARIC HF model. CONCLUSIONS: cTnT and NT-proBNP have significant value in HF risk prediction. A simple sex-specific model that includes age, race, cTnT, and NT-proBNP (which can be incorporated in a laboratory report) provides a good model, whereas adding cTnT and NT-proBNP to clinical characteristics results in an excellent HF prediction model.

Prediction of incident heart failure in general practice: the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: A simple and effective heart failure (HF) risk score would facilitate the primary prevention and early diagnosis of HF in general practice. We examined the external validity of existing HF risk scores, optimized a 10-year HF risk function, and examined the incremental value of several biomarkers, including N-terminal pro-brain natriuretic peptide. METHODS AND RESULTS: During 15.5 years (210 102 person-years of follow-up), 1487 HF events were recorded among 13 555 members of the biethnic Atherosclerosis Risk in Communities (ARIC) Study cohort. The area under curve from the Framingham-published, Framingham-recalibrated, Health ABC HF recalibrated, and ARIC risk scores were 0.610, 0.762, 0.783, and 0.797, respectively. On addition of N-terminal pro-brain natriuretic peptide, the optimism-corrected area under curve of the ARIC HF risk score increased from 0.773 (95% CI, 0.753-0.787) to 0.805 (95% CI, 0.792-0.820). Inclusion of N-terminal pro-brain natriuretic peptide improved the overall classification of recalibrated Framingham, recalibrated Health ABC, and ARIC risk scores by 18%, 12%, and 13%, respectively. In contrast, cystatin C or high-sensitivity C-reactive protein did not add toward incremental risk prediction. CONCLUSIONS: The ARIC HF risk score is more parsimonious yet performs slightly better than the extant risk scores in predicting 10-year risk of incident HF. The inclusion of N-terminal pro-brain natriuretic peptide markedly improves HF risk prediction. A simplified risk score restricted to a patient's age, race, sex, and N-terminal pro-brain natriuretic peptide performs comparably to the full score (area under curve, 0.745) and is suitable for automated reporting from laboratory panels and electronic medical records.

Airflow obstruction, lung function, and risk of incident heart failure: the Atherosclerosis Risk in Communities (ARIC) study.

AIMS: We examined the relationship between forced expiratory volume in 1 s (FEV(1)), airflow obstruction, and incident heart failure (HF) in black and white, middle-aged men and women in four US communities. METHODS AND RESULTS: Lung volumes by standardized spirometry and information on covariates were collected on 15 792 Atherosclerosis Risk in Communities (ARIC) cohort participants in 1987-89. Incident HF was ascertained from hospital records and death certificates up to 2005 in 13 660 eligible participants. Over an average follow-up of 14.9 years, 1369 (10%) participants developed new-onset HF. The age- and height-adjusted hazard ratios (HRs) for HF increased monotonically over descending quartiles of FEV(1) for both genders, race groups, and smoking status. After multivariable adjustment for traditional cardiovascular risk factors and height, the HRs [95% confidence intervals (CIs)] of HF comparing the lowest with the highest quartile of FEV(1) were 3.91 (2.40-6.35) for white women, 3.03 (2.12-4.33) for white men, 2.11 (1.33-3.34) for black women, and 2.23 (1.37-3.59) for black men. The association weakened but remained statistically significant after additional adjustment for systemic markers of inflammation. The multivariable adjusted incidence of HF was higher in those with FEV(1)/forced vital capacity <70% vs. ≥70%: HR 1.44 (95% CI 1.20-1.74) among men and 1.40 (1.13-1.72) among women. A consistent and positive association with HF was seen for self-reported diagnosis of emphysema and chronic obstructive pulmonary disease, but not for asthma. CONCLUSIONS: In this large population-based cohort with long-term follow-up, low FEV(1) and an obstructive respiratory disease were strongly and independently associated with the risk of incident HF.

The contribution of major risk factors and job strain to occupational class differences in coronary heart disease incidence: the MONICA Brianza and PAMELA population-based cohorts.

OBJECTIVES: We investigated the contribution of major coronary heart disease (CHD) risk factors and job strain to occupational class differences in CHD incidence in a pooled-cohort prospective study in northern Italy. METHODS: 2964 men aged 25-74 from four northern Italian population-based cohorts were investigated at baseline and followed for first fatal or non-fatal CHD event (171 events). Standardised procedures were used for baseline risk factor measurements, follow-up and validation of CHD events. Four occupational classes were derived from the Erikson-Goldthorpe-Portocarero social class scheme: higher and lower professionals and administrators, non-manual workers, skilled and unskilled manual workers, and the self-employed. HRs were estimated with Cox models. RESULTS: Among CHD-free subjects, with non-manual workers as the reference group, age-adjusted excess risks were found for professionals and administrators (+84%, p=0.02), the self-employed (+72%, p=0.04) and manual workers (+63%, p=0.04). The relationship was consistent across different CHD diagnostic categories. Adjusting for major risk factors only slightly reduced the reported excess risks. In a sub-sample of currently employed subjects, adjusting for major risk factors, sport physical activity and job strain reduced the excess risk for manual workers (relative change = -71.4%) but did not substantially modify the excess risks of professionals and administrators and the self-employed. CONCLUSIONS: In our study, we found higher CHD incidence rates for manual workers, professionals and administrators, and the self-employed, compared to non-manual workers. When the entire spectrum of job categories is considered, the job strain model helped explain the CHD excess risk for manual workers but not for other occupational classes.

A clinical risk score for atrial fibrillation in a biracial prospective cohort (from the Atherosclerosis Risk in Communities [ARIC] study).

A risk score for atrial fibrillation (AF) has been developed by the Framingham Heart Study; however, the applicability of this risk score, derived using data from white patients, to predict new-onset AF in nonwhites is uncertain. Therefore, we developed a 10-year risk score for new-onset AF from risk factors commonly measured in clinical practice using 14,546 subjects from the Atherosclerosis Risk In Communities (ARIC) study, a prospective community-based cohort of blacks and whites in the United States. During 10 years of follow-up, 515 incident AF events occurred. The following variables were included in the AF risk score: age, race, height, smoking status, systolic blood pressure, hypertension medication use, precordial murmur, left ventricular hypertrophy, left atrial enlargement, diabetes, coronary heart disease, and heart failure. The area under the receiver operating characteristics curve (AUC) of a Cox regression model that included the previous variables was 0.78, suggesting moderately good discrimination. The point-based score developed from the coefficients in the Cox model had an AUC of 0.76. This clinical risk score for AF in the Atherosclerosis Risk In Communities cohort compared favorably with the Framingham Heart Study's AF (AUC 0.68), coronary heart disease (CHD) (AUC 0.63), and hard CHD (AUC 0.59) risk scores and the Atherosclerosis Risk In Communities CHD risk score (AUC 0.58). In conclusion, we have developed a risk score for AF and have shown that the different pathophysiologies of AF and CHD limit the usefulness of a CHD risk score in identifying subjects at greater risk of AF.

Gender differences in the association between education and the incidence of cardiovascular events in Northern Italy.

BACKGROUND: The educational differences in the incidence of major cardiovascular events are under-studied in Southern Europe and among women. METHODS: The study sample includes n = 5084 participants to 4 population-based Northern Italian cohorts, aged 35-74 at baseline and with no previous cardiovascular events. The follow-up to ascertain the first onset of coronary heart disease (CHD) or ischaemic stroke ended in 2002. At baseline, major cardiovascular risk factors were investigated adopting the standardized MONICA procedures. Two educational classes were obtained from years of schooling. Age- and risk factors-adjusted hazard ratios of first CHD or ischaemic stroke were estimated through sex-specific separate Cox models (high education as reference). RESULTS: Median follow-up time was 12 years. Event rates were 6.38 (CHD) and 2.12 (ischaemic stroke) per 1000 person-years in men; and 1.59 and 0.94 in women. In men, low education was associated with higher mean Body Mass Index and prevalence of diabetes and cigarette smokers; but also with higher HDL cholesterol and a more favourable alcohol intake pattern. Less-educated women had higher mean systolic blood pressure, Body Mass Index and HDL cholesterol and were more likely to have diabetes. Men and women in the low educational class had a 2-fold increase in ischaemic stroke and CHD incidence, respectively, after controlling for major risk factors. Education was not associated with CHD incidence in men. Higher ischaemic stroke rates were observed among more educated women. CONCLUSION: In this northern Italian population, the association between education and cardiovascular risk seems to vary by gender.

Association of circulating matrix metalloproteinases with carotid artery characteristics: the Atherosclerosis Risk in Communities Carotid MRI Study.

OBJECTIVE: To examine the relationship of plasma levels of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase 1 (TIMP-1) with carotid artery characteristics measured by MRI in a cross-sectional investigation among Atherosclerosis Risk in Communities Carotid MRI Study participants. METHODS AND RESULTS: A stratified random sample was recruited based on intima-media thickness from a previous ultrasonographic examination. A high-resolution gadolinium-enhanced MRI examination of the carotid artery was performed from 2004 to 2005 on 1901 Atherosclerosis Risk in Communities cohort participants. Multiple carotid wall characteristics, including wall thickness, lumen area, calcium area, lipid core, and fibrous cap measures, were evaluated for associations with plasma MMPs 1, 2, 3, 7, 8, and 9 and TIMP-1. Plasma MMPs 1, 3, and 7 were significantly higher among participants in the high intima-media thickness group compared with those in the low intima-media thickness group. The normalized wall index was independently associated with MMPs 3 and 7 and TIMP-1. MMP-7 was positively associated with carotid calcification. The mean fibrous cap thickness was significantly higher in individuals with elevated TIMP-1 levels. In addition, TIMP-1 was positively associated with measures of lipid core. CONCLUSION: Circulating levels of specific MMPs and TIMP-1 were associated with carotid wall remodeling and structural changes related to plaque burden in elderly participants.

Relationship between non-specific prescription pill adherence and ischemic stroke outcomes.

BACKGROUND: Adherence to non-specific prescription therapy may be associated with clinical outcomes beyond a given treatment effect. We assessed the association of blinded randomized pill prescription adherence with vascular outcomes after ischemic stroke. METHODS: We analyzed the Vitamin Intervention for Stroke Prevention (VISP) study database. VISP was a double-blind randomized trial, designed to determine whether high doses of vitamins (vs. low doses) would reduce recurrent stroke risk in 3,680 participants over a 2-year period. We examined the independent association of adherence with a composite endpoint (stroke, myocardial infarction, death). RESULTS: Among 3,357 (91%) subjects with complete data, women, non-White persons, current smokers, those not on statins and those without a history of coronary artery bypass surgery were significantly less likely to be optimally adherent. Over the trial, persons who adhered well to treatment were less likely to experience the combined outcome than those who adhered poorly (13.4 vs. 20.6%, p < 0.0001). After multivariable analysis using various adherence measures, there were no significant differences between >or=80% vs. <80% adherence, but compared to <65% adherence, pill adherence levels of >or=90 to <99% (HR 0.56, 95% CI = 0.34-0.91; p = 0.02) and >or=99% (HR 0.46, 95% CI = 0.29-0.73; p = 0.001) were associated with lower occurrence of the combined outcome at 18 months. CONCLUSIONS: Long-term excellent adherence to non-specific pill prescription among ischemic stroke patients is independently associated with lower vascular risk, and is likely a marker of overall healthy behavior that may be helpful in targeting stroke patients with unhealthy practices.

Absolute and attributable risks of heart failure incidence in relation to optimal risk factors.

BACKGROUND: Epidemiological studies have shown that a large proportion of coronary heart disease and stroke events are explained by borderline or elevated risk factors and that adults with optimal risk factors greatly avoid these events. The degree to which this applies to heart failure incidence is not well documented. METHODS AND RESULTS: We categorized baseline (1987-1989) risk factors in the Atherosclerosis Risk in Communities Study cohort (n=13,460, aged 45 to 64 years) into optimal, borderline, and elevated groups based on national guidelines, using a 4-factor score (blood pressure, plasma cholesterol, diabetes, and smoking) and a 5-factor score (which included body mass). Incidence of hospitalized heart failure (n=1344) was identified over a 16-year period. Only 4.9% of the cohort at baseline had all optimal risk factors based on the 4-factor score and 2.6% using the 5-factor score. Compared with participants with any elevated risk factor using the 4-factor score, the age-, sex-, and race-adjusted relative hazard for heart failure events was 0.18 (95% CI, 0.10 to 0.32) for those with all optimal risk factors and 0.35 (95% CI, 0.30 to 0.41) for those with only borderline risk factors. A population-attributable fraction estimate suggested that having at least 1 of the 4 risk factors, elevated or borderline, accounted for 77.1% of heart failure events. For the 5-factor score, that percentage was 88.8%. CONCLUSIONS: Middle-aged adults with optimal (low) risk factors have low incidence rates of heart failure, which supports redoubled efforts to prevent risk factor development in the first place.

Association of multiple anthropometrics of overweight and obesity with incident heart failure: the Atherosclerosis Risk in Communities study.

BACKGROUND: The association of central adiposity with incident heart failure (HF) has yet to be studied in a large population-based study. METHODS AND RESULTS: The Atherosclerosis Risk in Communities study is an ongoing biracial population-based cohort of those aged 45 to 64 years from 4 US communities with 16 years' median follow-up for incident, hospitalized, or fatal HF. Waist-hip ratio, waist circumference, and body mass index (BMI) were measured at baseline (1987-1989). After exclusions, the sample size was 14 641. BMI was categorized as <25, 25 to 29.9, and >or=30 kg/m(2). Waist circumference and waist-hip ratio were divided into gender-specific tertiles. A first occurrence of International Classification of Diseases, 9th Revision, Clinical Modification, codes of HF, either hospital discharge (428.0 to 428.9; n=1451) or on a death certificate (428.0 to 428.9 or I50.0 to I50.9; n=77) was considered an HF event. Cox models were adjusted for alcohol use, smoking, age, center, and educational level. The adjusted hazard ratios for the highest category (obese) compared with the lowest were well above 1.0 for all 3 anthropometric measures (hazard ratio for 3rd versus 1st tertile of waist-hip ratio: 2.27 [1.71, 3.02] for white women; 3.24 [2.25, 4.65] for black women; 2.46 [1.95, 3.09] for white men; and 2.63 [1.90, 3.65] for black men). Hazard ratios for overweight were lower in magnitude, suggesting a graded response between body size and HF. CONCLUSIONS: Obesity and overweight, as measured by 3 different anthropometrics, were associated with incident HF in the Atherosclerosis Risk in Communities cohort. The current study does not support the superiority of waist-hip ratio and waist circumference over BMI for the prediction of incident HF.

Using the whole cohort in the analysis of case-cohort data.

Case-cohort data analyses often ignore valuable information on cohort members not sampled as cases or controls. The Atherosclerosis Risk in Communities (ARIC) study investigators, for example, typically report data for just the 10%-15% of subjects sampled for substudies of their cohort of 15,972 participants. Remaining subjects contribute to stratified sampling weights only. Analysis methods implemented in the freely available R statistical system (http://cran.r-project.org/) make better use of the data through adjustment of the sampling weights via calibration or estimation. By reanalyzing data from an ARIC study of coronary heart disease and simulations based on data from the National Wilms Tumor Study, the authors demonstrate that such adjustment can dramatically improve the precision of hazard ratios estimated for baseline covariates known for all subjects. Adjustment can also improve precision for partially missing covariates, those known for substudy participants only, when their values may be imputed with reasonable accuracy for the remaining cohort members. Links are provided to software, data sets, and tutorials showing in detail the steps needed to carry out the adjusted analyses. Epidemiologists are encouraged to consider use of these methods to enhance the accuracy of results reported from case-cohort analyses.

Repeatability and measurement error in the assessment of choline and betaine dietary intake: the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: The repeatability of a risk factor measurement affects the ability to accurately ascertain its association with a specific outcome. Choline is involved in methylation of homocysteine, a putative risk factor for cardiovascular disease, to methionine through a betaine-dependent pathway (one-carbon metabolism). It is unknown whether dietary intake of choline meets the recommended Adequate Intake (AI) proposed for choline (550 mg/day for men and 425 mg/day for women). The Estimated Average Requirement (EAR) remains to be established in population settings. Our objectives were to ascertain the reliability of choline and related nutrients (folate and methionine) intakes assessed with a brief food frequency questionnaire (FFQ) and to estimate dietary intake of choline and betaine in a bi-ethnic population. METHODS: We estimated the FFQ dietary instrument reliability for the Atherosclerosis Risk in Communities (ARIC) study and the measurement error for choline and related nutrients from a stratified random sample of the ARIC study participants at the second visit, 1990-92 (N = 1,004). In ARIC, a population-based cohort of 15,792 men and women aged 45-64 years (1987-89) recruited at four locales in the U.S., diet was assessed in 15,706 baseline study participants using a version of the Willett 61-item FFQ, expanded to include some ethnic foods. Intraindividual variability for choline, folate and methionine were estimated using mixed models regression. RESULTS: Measurement error was substantial for the nutrients considered. The reliability coefficients were 0.50 for choline (0.50 for choline plus betaine), 0.53 for folate, 0.48 for methionine and 0.43 for total energy intake. In the ARIC population, the median and the 75th percentile of dietary choline intake were 284 mg/day and 367 mg/day, respectively. 94% of men and 89% of women had an intake of choline below that proposed as AI. African Americans had a lower dietary intake of choline in both genders. CONCLUSION: The three-year reliability of reported dietary intake was similar for choline and related nutrients, in the range as that published in the literature for other micronutrients. Using a brief FFQ to estimate intake, the majority of individuals in the ARIC cohort had an intake of choline below the values proposed as AI.

Improved Horvitz-Thompson Estimation of Model Parameters from Two-phase Stratified Samples: Applications in Epidemiology.

The case-cohort study involves two-phase sampling: simple random sampling from an infinite super-population at phase one and stratified random sampling from a finite cohort at phase two. Standard analyses of case-cohort data involve solution of inverse probability weighted (IPW) estimating equations, with weights determined by the known phase two sampling fractions. The variance of parameter estimates in (semi)parametric models, including the Cox model, is the sum of two terms: (i) the model based variance of the usual estimates that would be calculated if full data were available for the entire cohort; and (ii) the design based variance from IPW estimation of the unknown cohort total of the efficient influence function (IF) contributions. This second variance component may be reduced by adjusting the sampling weights, either by calibration to known cohort totals of auxiliary variables correlated with the IF contributions or by their estimation using these same auxiliary variables. Both adjustment methods are implemented in the R survey package. We derive the limit laws of coefficients estimated using adjusted weights. The asymptotic results suggest practical methods for construction of auxiliary variables that are evaluated by simulation of case-cohort samples from the National Wilms Tumor Study and by log-linear modeling of case-cohort data from the Atherosclerosis Risk in Communities Study. Although not semiparametric efficient, estimators based on adjusted weights may come close to achieving full efficiency within the class of augmented IPW estimators.

Usual choline and betaine dietary intake and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Low dietary intake of the essential nutrient choline and its metabolite betaine may increase atherogenesis both through effects on homocysteine methylation pathways as well as through choline's antioxidants properties. Nutrient values for many common foods for choline and betaine have recently become available in the U.S. nutrient composition database. Our objective was to assess the association of dietary intake of choline and betaine with incident coronary heart disease (CHD), adjusting for dietary intake measurement error. METHODS: We conducted a prospective investigation of the relation between usual intake of choline and betaine with the risk of CHD in 14,430 middle-aged men and women of the biethnic Atherosclerosis Risk in Communities study. A semi-quantitative food frequency questionnaire was used to assess nutrient intake. Proportional hazard regression models were used to calculate the risk of incident CHD. A regression calibration method was used to adjust for measurement error. RESULTS: During an average 14 years of follow-up (1987-2002), 1,072 incident CHD events were documented. Compared with the lowest quartile of intake, incident CHD risk was slightly and non-significantly higher in the highest quartile of choline and choline plus betaine, HR = 1.22 (0.91, 1.64) and HR = 1.14 (0.85, 1.53), controlling for age, sex, education, total energy intake, dietary intakes of folate, methionine and vitamin B6. No association was found between dietary choline intake and incident CHD when correcting for measurement error. CONCLUSION: Higher intakes of choline and betaine were not protective for incident CHD. Similar investigations in other populations are of interest.

Absolute and attributable risks of cardiovascular disease incidence in relation to optimal and borderline risk factors: comparison of African American with white subjects--Atherosclerosis Risk in Communities Study.

BACKGROUND: Among white Americans, a large proportion of cardiovascular disease (CVD) events is explained by borderline or any elevated CVD risk factor levels. The degree to which this is true among African American subjects is unclear. METHODS: The Atherosclerosis Risk in Communities Study included 14 162 middle-aged adults who were free of recognized stroke or coronary heart disease and had baseline information on risk factors. Based on national guidelines, we categorized risk factors (blood pressure, cholesterol levels, diabetes, and smoking) into 3 categories, ie, optimal, borderline, and elevated. Incidence of CVD (composite of stroke and coronary heart disease) (n = 1492) and CVD mortality (n = 612) were identified for a 13-year period. RESULTS: The proportion of subjects with all optimal risk factor levels was lower in African American (3.8%) than in white (7.5%) subjects. Conversely, the proportion of subjects with at least 1 elevated risk factor was higher in African American (approximately 80%) than in white (approximately 60%) subjects. After adjustment for these risk factor differences and education level, African American and white subjects had virtually identical rates of CVD (relative hazard for African American subjects, 1.01; 95% confidence interval, 0.90-1.14). The proportion of CVD events explained by elevated risk factors was high in African American subjects (approximately 90%) compared with approximately 65% in white subjects. CONCLUSIONS: The higher CVD incidence rate in African American than in white subjects seems largely attributable to a high frequency of elevated CVD risk factors in African American subjects. Primary prevention of elevated CVD risk factors in African American subjects might greatly reduce CVD occurrence as much as it has for white subjects.

Risk factors for ischemic stroke subtypes: the Atherosclerosis Risk in Communities study.

BACKGROUND AND PURPOSE: To evaluate risk factors for ischemic stroke by its subtypes may contribute to more effective prevention of ischemic stroke, but few prospective studies have characterized risk factors for specific subtypes of ischemic stroke. METHODS: Between 1987 and 1989, 14,448 men and women aged 45 to 64 years and free of clinical stroke took part in the first examination of the Atherosclerosis Risk in Communities study. The incidence of stroke was ascertained from hospital surveillance records. RESULTS: During an average follow-up of 13.4-years, 531 incident ischemic strokes occurred (105 lacunar, 326 nonlacunar, and 100 cardioembolic). Blacks had a 3-fold higher multivariate-adjusted risk ratio of lacunar stroke compared with whites. No racial difference in nonlacunar or cardioembolic strokes was found after adjusting for prevalent risk factors. In addition to traditional risk factors, nontraditional risk factors, such as waist-to-hip ratio, history of coronary heart disease, left ventricular hypertrophy, lipoprotein(a), and von Willebrand factor, were associated with increased risk for nonlacunar stroke, whereas lacunar stroke was related to only 1 nontraditional risk factor, white blood cell count. The population-attributable fraction (PAF) for hypertension was approximately 35% for all ischemic stroke subtypes. The respective PAFs for diabetes and current smoking were 26.3% and 22.0% for lacunar versus 11.3% and 11.4% for nonlacunar stroke. The PAF for elevated von Willebrand factor was greater than that for current smoking for cardioembolic stroke. CONCLUSIONS: The impact of traditional and nontraditional risk factors other than hypertension on the incidence of ischemic stroke varied according to its subtype.

Does the impact of smoking on coronary heart disease differ by low-density lipoprotein cholesterol level?: the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: The association of smoking with coronary heart disease (CHD) occurrence has been reported to be weaker for populations with lower plasma cholesterol levels. Recent studies suggest that low-density lipoprotein cholesterol (LDL-C) and smoking contribute to different stages of atherosclerosis, so the present study was designed to test the hypothesis that smoking is a stronger risk factor for CHD when LDL-C is high. METHODS AND RESULTS: The study group of 13,410 middle-aged adults who were initially free of stroke and CHD were followed and over 13.3 years there were 932 incident CHD events. Tests for multiplicative interaction were performed using proportional hazards models. Both smoking and increased LDL-C were risk factors for CHD incidence. The relative hazard (RH) of CHD in relation to smoking tended to be larger among higher LDL-C categories compared with lower LDL-C categories. For example, when the participants were dichotomized into 4 categories, using smoking >or=15 cigarettes per day and LDL-C >or=130 mg/dl as cutoffs, those with high LDL-C and heavier cigarette smoking showed a very high RH of CHD (RH =2.81) compared with that expected from the product of the RHs of high LDL-C (RH =1.15) only x heavy smoking only (RH =1.71) (p for interaction =0.04). CONCLUSIONS: These results suggest positive multiplicative interactions between smoking and LDL-C for CHD incidence.