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1.  Classification of Acute Decompensated Heart Failure (ADHF): An Automated Algorithm Compared to a Physician Reviewer Panel: The ARIC Study 
Circulation. Heart failure  2013;6(4):719-726.
Background
An algorithm to classify heart failure (HF) endpoints inclusive of contemporary measures of biomarkers and echocardiography was recently proposed by an international expert panel. Our objective was to assess agreement of HF classification by this contemporaneous algorithm with that by a standardized physician reviewer panel, when applied to data abstracted from community-based hospital records.
Methods and Results
During 2005-2007, all hospitalizations were identified from four U.S. communities under surveillance as part of the Atherosclerosis Risk in Communities (ARIC) study. Potential HF hospitalizations were sampled by ICD discharge codes and demographics from men and women aged 55 years and older. The HF classification algorithm was automated and applied to 2,729 (N=13,854 weighted hospitalizations) hospitalizations in which either BNP measures or ejection fraction were documented (mean age 75 years). There were 1,403 (54%, N=7,534 weighted) events classified as acute, decompensated HF (ADHF) by the automated algorithm, and 1,748 (68%, N=9,276 weighted) such events by the ARIC reviewer panel. The chance-corrected agreement between ADHF by physician reviewer panel and the automated algorithm was moderate (Kappa=0.39). Sensitivity and specificity of the automated algorithm with ARIC reviewer panel as the referent standard was 0.68 (95% CI, 0.67 - 0.69), and 0.75 (95% CI, 0.74 - 0.76), respectively.
Conclusions
Although the automated classification improved efficiency and decreased costs, its accuracy in classifying HF hospitalizations was modest compared to a standardized physician reviewer panel.
doi:10.1161/CIRCHEARTFAILURE.112.000195
PMCID: PMC3767124  PMID: 23650310
heart failure; classification; BNP; ejection fraction; ARIC
2.  Genetic Ancestry and the Relationship of Cigarette Smoking to Lung Function and Percent Emphysema in Four Race/Ethnic Groups: a Cross-sectional Study 
Thorax  2013;68(7):634-642.
Background
Cigarette smoking is the major cause of chronic obstructive pulmonary disease and emphysema. Recent studies suggest that susceptibility to cigarette smoke may vary by race/ethnicity; however, they were generally small and relied on self-reported race/ethnicity.
Objective
To test the hypothesis that relationships of smoking to lung function and percent emphysema differ by genetic ancestry and self-reported race/ethnicity among Whites, African-Americans, Hispanics and Chinese-Americans.
Design
Cross-sectional population-based study of adults age 45-84 years in the United States
Measurements
Principal components of genetic ancestry and continental ancestry estimated from one-million genome-wide single nucleotide polymorphisms. Pack-years calculated as years smoking cigarettes-per-day/20. Spirometry measured for 3,344 and percent emphysema on computed tomography for 8,224 participants.
Results
The prevalence of ever-smoking was: Whites, 57.6%; African-Americans, 56.4%; Hispanics, 46.7%; and Chinese-Americans, 26.8%. Every 10 pack-years was associated with −0.73% (95% CI −0.90%, −0.56%) decrement in the forced expiratory volume in one second to forced vital capacity (FEV1/FVC) and a 0.23% (95% CI 0.08%, 0.38%) increase in percent emphysema. There was no evidence that relationships of pack-years to the FEV1/FVC, airflow obstruction and percent emphysema varied by genetic ancestry (all p>0.10), self-reported race/ethnicity (all p>0.10) or, among African-Americans, African ancestry. There were small differences in relationships of pack-years to the FEV1 among male Chinese-Americans and to the FEV1/FVC with African and Native American ancestry among male Hispanics only.
Conclusions
In this large cohort, there was little-to-no evidence that the associations of smoking to lung function and percent emphysema differed by genetic ancestry or self-reported race/ethnicity.
doi:10.1136/thoraxjnl-2012-202116
PMCID: PMC4020409  PMID: 23585509
cigarette smoke; genetic ancestry; lung function; chronic obstructive pulmonary disease; COPD; emphysema; FVC; Forced Vital Capacity; FEV1; Forced Expiratory Volume in 1 second
3.  Associations of NINJ2 Sequence Variants with Incident Ischemic Stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) Consortium 
PLoS ONE  2014;9(6):e99798.
Background
Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk.
Methods and Results
We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026).
Conclusion
Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings.
doi:10.1371/journal.pone.0099798
PMCID: PMC4069013  PMID: 24959832
4.  Redistribution of heart failure as the cause of death: the Atherosclerosis Risk in Communities Study 
Background
Heart failure is sometimes incorrectly listed as the underlying cause of death (UCD) on death certificates, thus compromising the accuracy and comparability of mortality statistics. Statistical redistribution of the UCD has been used to examine the effect of misclassification of the UCD attributed to heart failure, but sex- and race-specific redistribution of deaths on coronary heart disease (CHD) mortality in the United States has not been examined.
Methods
We used coarsened exact matching to infer the UCD of vital records with heart failure as the UCD from 1999 to 2010 for decedents 55 years old and older from states encompassing regions under surveillance by the Atherosclerosis Risk in Communities (ARIC) Study (Maryland, Minnesota, Mississippi, and North Carolina). Records with heart failure as the UCD were matched on decedent characteristics (five-year age groups, sex, race, education, year of death, and state) to records with heart failure listed among the multiple causes of death. Each heart failure death was then redistributed to plausible UCDs proportional to the frequency among matched records.
Results
After redistribution the proportion of deaths increased for CHD, chronic obstructive pulmonary disease, diabetes, hypertensive heart disease, and cardiomyopathy, P < 0.001. The percent increase in CHD mortality after redistribution was the highest in Mississippi (12%) and lowest in Maryland (1.6%), with variations by year, race, and sex. Redistribution proportions for CHD were similar to CHD death classification by a panel of expert reviewers in the ARIC study.
Conclusions
Redistribution of ill-defined UCD would improve the accuracy and comparability of mortality statistics used to allocate public health resources and monitor mortality trends.
doi:10.1186/1478-7954-12-10
PMCID: PMC4113199  PMID: 24716810
Cause of death; Coronary heart disease; Death certificates; Heart failure; Mortality; Vital statistics; Ill-defined causes of death
5.  Apnea-hypopnea index: time to wake up 
Despite the widespread use of the apnea-hypopnea index in research, its scientific and statistical properties have not been examined thoroughly. The index may be viewed either as a rate (number of events per hour of sleep) or as a ratio of two variables (number of events/number of hours of sleep). When considered as a rate, the apnea-hypopnea index may be modeled as the dependent variable, provided that researchers explicitly state which physical property they assume to be measuring. On the other hand, the index is rarely, if ever, the preferred model of exposure to sleep-disordered breathing (an independent variable), regardless of whether it is considered a rate or a ratio variable. Continued indiscriminate use of the apnea-hypopnea index in sleep research should be discouraged.
doi:10.2147/NSS.S61853
PMCID: PMC3982973  PMID: 24741336
apnea-hypopnea index; respiratory disturbance index; ratio variables; rates
6.  Association between physical activity and risk of stroke subtypes: The Atherosclerosis Risk in Communities (ARIC) Study 
Neuroepidemiology  2012;40(2):109-116.
Background
The relationship between stroke subtypes and physical activity is unclear.
Methods
Using data from 13,069 men and women aged 45-64 years who participated in the Atherosclerosis Risk in Communities (ARIC) Study, physical activity was assessed by self-report using the Baecke questionnaire at baseline (1987-1989). The American Heart Association’s (AHA) ideal cardiovascular health guidelines served as basis for the calculation of three physical activity categories: poor, intermediate, and ideal. Stroke and its subtypes were ascertained from physician review of medical records. Multivariable adjusted hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression models.
Results
During a median follow-up of 18.8 years, a total of 648 incident ischemic strokes occurred. Significant inverse associations were found between physical activity categories and total, total ischemic, and nonlacunar stroke in adjusted models (age, sex, race-center, education, cigarette-years). Compared with poor physical activity, the adjusted HR (95% CI) for ideal physical activity were 0.78 (0.62, 0.97) for total, 0.76 (0.59, 0.96) for total ischemic, 0.85 (0.51, 1.40) for lacunar, 0.77 (0.47, 1.27) for cardioembolic, and 0.71 (0.51, 0.99) for nonlacunar stroke. Additional adjustments for waist-to-hip ratio, systolic blood pressure, antihypertensive medication, diabetes, left ventricular hypertrophy and laboratory parameters attenuated the HR. Further sex- and race-specific analysis revealed that the association was predominantly observed among males and among African-Americans.
Conclusion
These data suggest a tendency toward a reduced risk of total, total ischemic, and nonlacunar stroke with higher levels of physical activity.
doi:10.1159/000342151
PMCID: PMC3641888  PMID: 23095721
cerebrovascular disease; stroke subtypes; exercise; epidemiology; prevention
7.  Causal diagrams, the placebo effect, and the expectation effect 
Using causal diagrams, a formal research methodology, we analyzed several definitions of placebo and the placebo effect. We conclude that placebo is an ambiguous, redundant term and that the so-called placebo effect conceals far more interesting effects that are attributed to the patient’s expectation. Biomedical research will benefit from abandoning the term placebo effect and focusing instead on a deeper understanding of the expectation variable, including its causes, effects, and effect modifiers. This avenue of research should be pursued by observational cohorts that are nested within clinical trials.
doi:10.2147/IJGM.S52209
PMCID: PMC3790888  PMID: 24101881
causal diagrams; effect modification; placebo; expectation
8.  Prediction of Incident Heart Failure in General Practice: The ARIC Study 
Circulation. Heart failure  2012;5(4):422-429.
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 NT-proBNP.
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 bi-ethnic Atherosclerosis Risk in Communities (ARIC) Study cohort. The area under curve (AUC) 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. Upon addition of NT-pro-BNP, the optimism corrected AUC 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 NT-proBNP improved the overall classification of re-calibrated Framingham, re-calibrated Health ABC, and ARIC risk scores by 18%, 12%, and 13%, respectively. In contrast, Cystatin C or hs-CRP did not add towards 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 NT-proBNP markedly improves HF risk prediction. A simplified risk score restricted to a patient’s age, race, gender, and NT-proBNP performs comparably to the full score (AUC = 0.745), and is suitable for automated reporting from laboratory panels and electronic medical records.
doi:10.1161/CIRCHEARTFAILURE.111.964841
PMCID: PMC3412686  PMID: 22589298
heart failure; risk prediction; external validation; NT-proBNP; Cystatin C; hs-CRP; biomarkers
9.  ORTHOSTATIC HYPOTENSION AS A RISK FACTOR FOR INCIDENT HEART FAILURE: THE ATHEROSCLEROSIS RISK IN COMMUNITIES (ARIC) STUDY 
Hypertension  2012;59(5):913-918.
Heart failure causes significant morbidity and mortality. Distinguishing risk factors for incident heart failure can help identify at-risk individuals. Orthostatic hypotension may be a risk factor for incident heart failure; however, this association has not been fully explored, especially in non-white populations.
The Atherosclerosis Risk in Communities study included 12,363 adults free of prevalent heart failure with baseline orthostatic measurements. Orthostatic hypotension was defined as a decrease of systolic blood pressure ≥20 mm Hg or diastolic blood pressure ≥10 mm Hg with position change from supine to standing. Incident heart failure was identified from hospitalization or death certificate disease codes.
Over 17.5 years of follow up, orthostatic hypotension was associated with incident heart failure with multivariable adjustment (hazard ratio 1.54, 95% CI 1.30-1.82). This association was similar across race and gender groups. A stronger association was identified in younger individuals ≤55 years old (hazard ratio 1.90, 95% CI 1.41-2.55) than in older individuals >55 years old (hazard ratio 1.37, 95% CI 1.12-1.69, interaction p=0.034).
The association between orthostatic hypotension and incident heart failure persisted with exclusion of those with diabetes mellitus, coronary heart disease, and those on anti-hypertensives, psychiatric or Parkinson’s medications. However, exclusion of those with hypertension somewhat attenuated the association (hazard ratio 1.34, 95% CI 1.00-1.80).
We identified orthostatic hypotension as a predictor of incident heart failure among middle-aged individuals, particularly those 45-55 years of age. This association may be partially mediated through hypertension. Orthostatic measures may enhance risk stratification for future heart failure development.
doi:10.1161/HYPERTENSIONAHA.111.188151
PMCID: PMC3382984  PMID: 22431580
10.  Airflow obstruction, lung function, and risk of incident heart failure: the Atherosclerosis Risk in Communities (ARIC) study 
European Journal of Heart Failure  2012;14(4):414-422.
Aims
We examined the relationship between forced expiratory volume in 1 s (FEV1), 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 FEV1 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 FEV1 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 FEV1/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 FEV1 and an obstructive respiratory disease were strongly and independently associated with the risk of incident HF.
doi:10.1093/eurjhf/hfs016
PMCID: PMC3530346  PMID: 22366234
Lung function; COPD; Heart failure; Risk factors; Cohort study
11.  Causal diagrams and the cross-sectional study 
Clinical Epidemiology  2013;5:57-65.
The cross-sectional study design is sometimes avoided by researchers or considered an undesired methodology. Possible reasons include incomplete understanding of the research design, fear of bias, and uncertainty about the measure of association. Using causal diagrams and certain premises, we compared a hypothetical cross-sectional study of the effect of a fertility drug on pregnancy with a hypothetical cohort study. A side-by-side analysis showed that both designs call for a tradeoff between information bias and variance and that neither offers immunity to sampling colliding bias (selection bias). Confounding bias does not discriminate between the two designs either. Uncertainty about the order of causation (ambiguous temporality) depends on the nature of the postulated cause and the measurement method. We conclude that a cross-sectional study is not inherently inferior to a cohort study. Rather than devaluing the cross-sectional design, threats of bias should be evaluated in the context of a concrete study, the causal question at hand, and a theoretical causal structure.
doi:10.2147/CLEP.S42843
PMCID: PMC3600935  PMID: 23516121
cross-sectional study; causal diagrams; colliding bias; information bias
12.  Classification of Heart Failure in the Atherosclerosis Risk in Communities (ARIC) Study: A Comparison of Diagnostic Criteria 
Circulation. Heart Failure  2012;5(2):152-159.
Background
Population-based research on heart failure (HF) is hindered by lack of consensus on diagnostic criteria. Framingham (FRM), National Health and Nutrition Examination Survey (NHANES), Modified Boston (MBS), Gothenburg (GTH), and International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) code criteria do not differentiate acute decompensated heart failure (ADHF) from chronic stable HF. We developed a new classification protocol for identifying ADHF in the Atherosclerosis Risk in Communities (ARIC) Study and compared it with these other schemes.
Methods and Results
A sample of 1180 hospitalizations with a patient address in four study communities and eligible discharge codes were selected. After assessing whether the chart contained evidence of possible HF signs, 705 were fully abstracted. Two independent reviewers classified each case as ADHF, chronic stable HF or no HF using ARIC classification guidelines. Fifty-nine percent of cases met ARIC criteria for ADHF and 13.9% and 27.1% were classified as chronic stable HF or no HF, respectively. Among events classified as HF by FRM criteria, 68.4% were validated as ADHF, 9.6% as chronic stable HF and 21.9% as no HF. However, 92.5% of hospitalizations with a primary ICD-9-CM 428 “heart failure” code were validated as ADHF. Sensitivities of comparison criteria to classify ADHF ranged from 38 to 95%, positive predictive values from 62 to 92%, and specificities from 19 to 96%.
Conclusions
Although comparison criteria for classifying HF were moderately sensitive in identifying ADHF, specificity varied when applied to a randomly selected set of suspected HF hospitalizations in the community.
doi:10.1161/CIRCHEARTFAILURE.111.963199
PMCID: PMC3326579  PMID: 22271752
heart failure; epidemiology
13.  Relationship of Ventricular Premature Complexes to Heart Failure (From the Atherosclerosis Risk in Communities [ARIC] Study) 
The American journal of cardiology  2011;109(1):105-109.
Analogous to rapid ventricular pacing, frequent ventricular premature complexes (VPCs) may predispose over time to cardiomyopathy and subsequent heart failure (HF). We examined the association of frequent VPCs with HF incidence in a population-based cohort, free of HF and coronary heart disease (CHD) at baseline. At study baseline (1987-89), at least one VPC on a 2-minute rhythm ECG strip was seen in 5.5% (739/13486) of the middle aged (45-64 years old at baseline), white and African-American, men and women of the ARIC cohort. Incident HF was defined as the first appearance of ICD code ‘428.x’ in hospital discharge record or death certificate through 2005. Over an average follow up of 15.6 years, incident HF was seen in 10% subjects (19.4% in those with VPCs vs. 9.4% in those without). The age, race, and gender adjusted hazard ratio (HR) of HF for VPCs was 1.89 (95% CI = 1.59, 2.24). After multivariable adjustment for potential confounders, HR (95% CI) of HF for those with any VPC vs. no VPCs was 1.63 (1.36, 1.96). After additional adjustment for incident CHD as a time-varying covariate, the HR (95% CI) was 1.71 (1.42, 2.08). Presence of higher frequency of VPCs or complex VPCs had similar rates of HF as compared to single VPC and all were higher than no VPC group. In conclusion, in this large population based cohort, presence of VPCs is associated with incident HF independent of incident CHD.
doi:10.1016/j.amjcard.2011.08.009
PMCID: PMC3242884  PMID: 21945138
Heart Failure; Ventricular premature complexes; arrhythmias; risk factors; cohort study
14.  Carotid Intima-Media Thickness, Electrocardiographic Left Ventricular Hypertrophy and Incidence of Intracerebral Hemorrhage 
Background and Purpose
Carotid intima-media thickness (IMT) and electrocardiographic left ventricular hypertrophy (ECG-LVH) are two subclinical cardiovascular disease measures associated with increased risk of total and ischemic strokes. Increased IMT and ECG-LVH also may reflect end-organ hypertensive effects. Information is scant on the associations of these subclinical measures with intracerebral hemorrhage (ICH). We hypothesized that greater carotid IMT and the presence of ECG-LVH would be independently associated with increased ICH incidence.
Methods
Among 18,155 participants initially free of stroke in the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS), we assessed carotid IMT, carotid plaque, and ECG-LVH. Over a median of 18 years of follow-up, 162 incident ICH events occurred.
Results
After adjustment for other ICH risk factors, carotid IMT was associated positively with incidence of ICH in both ARIC and CHS. The risk was lowest in study-specific quartile 1, elevated 1.6 to 2.6-fold in quartiles 2–3, and elevated 2.5 to 3.7-fold in quartile 4 (p<0.05 for both studies). In CHS, having a carotid plaque was associated with a 2-fold (95% CI = 1.1–3.4) greater ICH risk than having no plaque, but only 1.2-fold (95% CI = 0.76–2.0) greater ICH risk in ARIC. ECG-LVH carried a hazard ratio of ICH of 1.7 (95% CI = 0.77–3.7) in CHS and 2.8 (95% CI = 1.2–6.4) in ARIC.
Conclusions
Our data suggest that people with carotid atherosclerosis and possibly LVH are at increased risk not only of ischemic stroke but also of ICH.
doi:10.1161/STROKEAHA.111.623157
PMCID: PMC3202073  PMID: 21940954
atherosclerosis; left ventricular hypertrophy; intracerebral hemorrhage; prospective study; risk factors
15.  Causal diagrams and the logic of matched case-control studies 
Clinical Epidemiology  2012;4:137-144.
It is tempting to assume that confounding bias is eliminated by choosing controls that are identical to the cases on the matched confounder(s). We used causal diagrams to explain why such matching not only fails to remove confounding bias, but also adds colliding bias, and why both types of bias are removed by conditioning on the matched confounder(s). As in some publications, we trace the logic of matching to a possible tradeoff between effort and variance, not between effort and bias. Lastly, we explain why the analysis of a matched case-control study – regardless of the method of matching – is not conceptually different from that of an unmatched study.
doi:10.2147/CLEP.S31271
PMCID: PMC3373198  PMID: 22701093
causal diagrams; directed acyclic graphs; case-control study; matching; confounding bias; colliding bias; variance
16.  Carotid Artery Wall Thickness and Risk of Stroke Subtypes. The Atherosclerosis Risk in Communities (ARIC) Study 
Background and Purpose
Understanding associations of carotid atherosclerosis with stroke subtypes may contribute to more effective prevention of stroke.
Methods
Between 1987 and 1989, 13,560 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. Incident strokes were ascertained by hospital surveillance.
Results
During an average follow up of 15.7-years, 82 incident hemorrhagic and 621 incident ischemic strokes (131 lacunar, 358 nonlacunar, and 132 cardioembolic strokes) occurred. The incidence rates of hemorrhagic and ischemic strokes were greater across higher carotid intima-media thickness (IMT) levels. Although this positive association was observed for all stroke subtypes, the age-, sex-, and race-adjusted risk ratios (RR) were higher for cardioembolic and nonlacunar strokes than for hemorrhagic and lacunar strokes. Compared with participants in the lowest quintile (<0.61mm), the adjusted RRs for those in the highest quintile (≥0.85mm) of IMT were 2.55 (95%CI, 1.09 to 5.94) for hemorrhagic, 2.89 (95%CI, 1.50 to 5.54) for lacunar, 3.61 (95%CI, 2.33 to 5.99) for nonlacunar, and 6.12 (95%CI, 2.71 to 13.9) for cardioembolic stroke. The RRs were attenuated by additional adjustment for covariates, but remained statistically significant for nonlacunar and cardioembolic strokes (p for trend <0.001, respectively). The association between carotid IMT and lacunar stroke was somewhat stronger in African Americans than in whites (P for interaction = 0.07).
Conclusions
Carotid atherosclerosis was associated with increased risk of all stroke subtypes, but the association of carotid atherosclerosis with stroke may vary by subtypes.
doi:10.1161/STROKEAHA.110.592261
PMCID: PMC3026889  PMID: 21164133
Brain Infarction; Carotid artery; Epidemiology; Intima-media thickness; Stroke subtypes
17.  Cross-cultural comparison of the sleep-disordered breathing prevalence among Americans and Japanese 
To compare the sleep-disordered breathing prevalence among Hispanic and white Americans and Japanese, we performed a one-night sleep study with a single channel airflow monitor on 211 Hispanics and 246 whites from the Minnesota Field Center of the Multi-Ethnic Study of Atherosclerosis (MESA), and 978 Japanese from three community-based cohorts of the Circulatory Risk in Communities Study (CIRCS) in Japan.
The respiratory disturbance index and sleep-disordered breathing, defined as respiratory disturbance index ≥ 15 disturbances/hr, were estimated. The sleep-disordered breathing prevalence was higher in men (34.2%) than women (14.8%), and higher among Hispanics (36.5%) and whites (33.3%) than among Japanese (18.4%), corresponding to differences in body mass index. Within body mass index strata, the race difference in sleep-disordered breathing was attenuated. This was also true when we adjusted for body mass index instead of stratification. The strong association between body mass index and sleep-disordered breathing was similar in Japanese and Americans.
The sleep-disordered breathing prevalence was lower among Japanese than the Americans. However, the association of body mass index with sleep-disordered breathing was strong, and similar among the race/ethnic groups studied. The majority of the race/ethnic difference in sleep-disordered breathing prevalence was explained by a difference in body mass index distribution.
doi:10.1183/09031936.00118609
PMCID: PMC2895689  PMID: 20110399
cross-sectional study; epidemiology; prevalence; sleep apnea
18.  A Prospective Study of Obstructive Sleep Apnea and Incident Coronary Heart Disease and Heart Failure: The Sleep Heart Health Study 
Circulation  2010;122(4):352-360.
Background
Clinic-based observational studies in men have reported that obstructive sleep apnea (OSA) is associated with an increased incidence of coronary heart disease. The objective of this study was to assess the relation of OSA to incident coronary heart disease and heart failure in a general community sample of adult men and women.
Methods and Results
A prospective, longitudinal epidemiologic study of 1927 men and 2495 women aged ≥ 40 years and free of coronary heart disease and heart failure at the time of baseline polysomnography were followed for a median of 8.7 years. After adjustment for multiple risk factors, OSA was a significant predictor of incident coronary heart disease (myocardial infarction, revascularization procedure, or coronary heart disease death) only in men age ≤70 years (adjusted hazard ratio 1.10 [95% CI 1.00, 1.21] per 10-unit increase in apnea-hypopnea index [AHI]), but not in older men or in women of any age. Among men age 40–70 years, those with AHI ≥30 were 68% more likely to develop coronary heart disease than those with AHI <5. OSA predicted incident heart failure in men but not in women (adjusted hazard ratio 1.13 [95% CI 1.02, 1.26] per 10-unit increase in AHI). Men with AHI ≥30 were 58% more likely to develop heart failure than those with AHI <5.
Conclusion
OSA is associated with increased risk of incident heart failure in community-dwelling middle-aged and older men; its association with incident coronary heart disease in this sample is equivocal.
doi:10.1161/CIRCULATIONAHA.109.901801
PMCID: PMC3117288  PMID: 20625114
epidemiology; sleep apnea; coronary disease; heart failure
19.  Obstructive Sleep Apnea–Hypopnea and Incident Stroke 
Rationale: Although obstructive sleep apnea is associated with physiological perturbations that increase risk of hypertension and are proatherogenic, it is uncertain whether sleep apnea is associated with increased stroke risk in the general population.
Objectives: To quantify the incidence of ischemic stroke with sleep apnea in a community-based sample of men and women across a wide range of sleep apnea.
Methods: Baseline polysomnography was performed between 1995 and 1998 in a longitudinal cohort study. The primary exposure was the obstructive apnea–hypopnea index (OAHI) and outcome was incident ischemic stroke.
Measurements and Main Results: A total of 5,422 participants without a history of stroke at the baseline examination and untreated for sleep apnea were followed for a median of 8.7 years. One hundred ninety-three ischemic strokes were observed. In covariate-adjusted Cox proportional hazard models, a significant positive association between ischemic stroke and OAHI was observed in men (P value for linear trend: P = 0.016). Men in the highest OAHI quartile (>19) had an adjusted hazard ratio of 2.86 (95% confidence interval, 1.1–7.4). In the mild to moderate range (OAHI, 5–25), each one-unit increase in OAHI in men was estimated to increase stroke risk by 6% (95% confidence interval, 2–10%). In women, stroke was not significantly associated with OAHI quartiles, but increased risk was observed at an OAHI greater than 25.
Conclusions: The strong adjusted association between ischemic stroke and OAHI in community-dwelling men with mild to moderate sleep apnea suggests that this is an appropriate target for future stroke prevention trials.
doi:10.1164/rccm.200911-1746OC
PMCID: PMC2913239  PMID: 20339144
sleep apnea; stroke; epidemiology
20.  Stroke Mortality, Clinical Presentation and Day of Arrival: The Atherosclerosis Risk in Communities (ARIC) Study 
Stroke Research and Treatment  2011;2011:383012.
Background. Recent studies report that acute stroke patients who present to the hospital on weekends have higher rates of 28-day mortality than similar patients who arrive during the week. However, how this association is related to clinical presentation and stroke type has not been systematically investigated. Methods and Results. We examined the association between day of arrival and 28-day mortality in 929 validated stroke events in the ARIC cohort from 1987–2004. Weekend arrival was defined as any arrival time from midnight Friday until midnight Sunday. Mortality was defined as all-cause fatal events from the day of arrival through the 28th day of followup. The presence or absence of thirteen stroke signs and symptoms were obtained through medical record review for each event. Binomial logistic regression was used to estimate odds ratios and 95% confidence intervals (OR; 95% CI) for the association between weekend arrival and 28-day mortality for all stroke events and for stroke subtypes. The overall risk of 28-day mortality was 9.6% for weekday strokes and 10.1% for weekend strokes. In models controlling for patient demographics, clinical risk factors, and event year, weekend arrival was not associated with 28-day mortality (0.87; 0.51, 1.50). When stratified by stroke type, weekend arrival was not associated with increased odds of mortality for ischemic (1.17, 0.62, 2.23) or hemorrhagic (0.37; 0.11, 1.26) stroke patients. Conclusions. Presence or absence of thirteen signs and symptoms was similar for weekday patients and weekend patients when stratified by stroke type. Weekend arrival was not associated with 28-day all-cause mortality or differences in symptom presentation for strokes in this cohort.
doi:10.4061/2011/383012
PMCID: PMC3137964  PMID: 21772968
21.  Premature ventricular complexes & risk of incident stroke: The Atherosclerosis Risk In Communities (ARIC) study 
Background
Ventricular premature complexes (PVCs) on a 2-minute electrocardiogram (ECG) are a common, largely asymptomatic finding, associated with increased risk of coronary heart disease (CHD) and death. They may reflect atherosclerosis or other pathogenic pathways that predispose to arrhythmias and stroke.
Methods/Results
We conducted a prospective evaluation of the Atherosclerosis Risk In Communities Study cohort (n=14,783) of middle aged men and women to assess whether the presence of PVCs at study baseline (1987-89) influenced the risk of incident stroke through 31st December 2004. PVCs were seen in 6.1% of the participants at baseline, and 729 (4.9%) had incident stroke. The unadjusted cumulative proportion of incident stroke in individuals with any PVC was 6.6% compared to 4.1% in those without PVC. The unadjusted hazard ratio (HR) of incident stroke in individuals with any PVC compared to those without any PVCs was 1.71 (95% Confidence Interval (CI) 1.33, 2.20).
Among individuals without hypertension and diabetes at baseline, PVCs were independently associated with incident stroke (HR: 1.72 (1.14, 2.59)). Among those with either diabetes or hypertension the presence of any PVCs did not increase the risk of stroke. The association was stronger for non-carotid embolic stroke than for thrombotic stroke and its magnitude increased with higher frequency of PVCs.
Conclusions
Frequent PVCs are associated with risk of incident stroke in participants free of hypertension and diabetes. This suggests that PVCs may contribute to atrio-ventricular remodeling or may be risk marker for incident stroke, particularly embolic stroke.
doi:10.1161/STROKEAHA.109.567800
PMCID: PMC2866170  PMID: 20167922
Stroke; Risk factors; Arrhythmia; Ventricular premature complexes; Atrial Fibrillation
22.  TRIGGERING OF NOCTURNAL ARRHYTHMIAS BY SLEEP DISORDERED BREATHING EVENTS 
Objectives
This study sought to evaluate respiratory disturbances as potential triggers for arrhythmia in those with sleep-disordered breathing (SDB).
Background
SDB is associated with increased risk of atrial fibrillation (AF) and non-sustained ventricular tachycardia (NSVT) as well as a predilection for sudden cardiac death during nocturnal sleeping hours. However, prior research has not established whether respiratory disturbances operate as triggers for nocturnal arrhythmias.
Methods
Overnight polysomnograms (PSGs) from the Sleep Heart Health Study (n = 2816) were screened for paroxysmal atrial fibrillation (PAF) and NSVT. We used the case-crossover design to determine whether apneas and/or hypopneas are temporally associated with episodes of PAF or NSVT. For each arrhythmia, 3 periods of sinus rhythm were identified as control intervals. PSGs were examined for the presence of respiratory disturbances, oxygen desaturations, and cortical arousals within a 90-second hazard period preceding each arrhythmia or control period.
Results
Fifty-seven participants with a wide range of SDB contributed 62 arrhythmias (76% NSVT). The odds of an arrhythmia following a respiratory disturbance were nearly 18-times (OR 17.5; 95% CI 5.3–58.4) the odds of an arrhythmia occurring following normal breathing. The absolute rate of arrhythmia associated with respiratory disturbances was low (1 excess arrhythmia/40000 respiratory disturbances). Neither hypoxia nor EEG-defined arousals alone increased arrhythmia risk.
Conclusions
Although the absolute arrhythmia rate is low, the relative risk of PAF and NSVT during sleep is markedly increased shortly after a respiratory disturbance. These results support a direct temporal link between SDB events and the development of these arrhythmias.
doi:10.1016/j.jacc.2009.06.038
PMCID: PMC2814244  PMID: 19874994
sleep; arrhythmia; obesity
23.  Percent Emphysema, Airflow Obstruction, and Impaired Left Ventricular Filling 
The New England journal of medicine  2010;362(3):217-227.
BACKGROUND
Very severe chronic obstructive pulmonary disease causes cor pulmonale with elevated pulmonary vascular resistance and secondary reductions in left ventricular filling, stroke volume, and cardiac output. We hypothesized that emphysema, as detected on computed tomography (CT), and airflow obstruction are inversely related to left ventricular end-diastolic volume, stroke volume, and cardiac output among persons without very severe lung disease.
METHODS
We measured left ventricular structure and function with the use of magnetic resonance imaging in 2816 persons who were 45 to 84 years of age. The extent of emphysema (expressed as percent emphysema) was defined as the percentage of voxels below −910 Hounsfield units in the lung windows on cardiac computed tomographic scans. Spirometry was performed according to American Thoracic Society guidelines. Generalized additive models were used to test for threshold effects.
RESULTS
Of the study participants, 13% were current smokers, 38% were former smokers, and 49% had never smoked. A 10-point increase in percent emphysema was linearly related to reductions in left ventricular end-diastolic volume (−4.1 ml; 95% confidence interval [CI], −3.3 to −4.9; P<0.001), stroke volume (−2.7 ml; 95% CI, −2.2 to −3.3; P<0.001), and cardiac output (−0.19 liters per minute; 95% CI, −0.14 to −0.23; P<0.001). These associations were of greater magnitude among current smokers than among former smokers and those who had never smoked. The extent of airflow obstruction was similarly associated with left ventricular structure and function, and smoking status had similar modifying effects on these associations. Percent emphysema and airflow obstruction were not associated with the left ventricular ejection fraction.
CONCLUSIONS
In a population-based study, a greater extent of emphysema on CT scanning and more severe airflow obstruction were linearly related to impaired left ventricular filling, reduced stroke volume, and lower cardiac output without changes in the ejection fraction.
doi:10.1056/NEJMoa0808836
PMCID: PMC2887729  PMID: 20089972
24.  Prospective Study of Sleep-disordered Breathing and Hypertension 
Rationale: Cross-sectional epidemiologic studies show an association between sleep-disordered breathing and hypertension, but only one cohort study has examined sleep-disordered breathing as a risk factor for incident hypertension.
Objectives: To examine whether sleep-disordered breathing increases the risk of incident hypertension among persons 40 years of age and older.
Methods: In a prospective cohort study, we analyzed data from 2,470 participants who at baseline did not have hypertension, defined as blood pressure of at least 140/90 mm Hg or taking antihypertensive medication. The apnea-hypopnea index (AHI), the number of apneas plus hypopneas per hour of sleep, was measured by overnight in-home polysomnography. We estimated odds ratios for developing hypertension during 5 years of follow-up according to baseline AHI.
Measurements and Main Results: The odds ratios for incident hypertension increased with increasing baseline AHI; however, this relationship was attenuated and not statistically significant after adjustment for baseline body-mass index. Although not statistically significant, the observed association between a baseline AHI greater than 30 and future hypertension (odds ratio, 1.51; 95% confidence interval, 0.93–2.47) does not exclude the possibility of a modest association.
Conclusions: Among middle-aged and older persons without hypertension, much of the relationship between AHI and risk of incident hypertension was accounted for by obesity. After adjustment for body mass index, the AHI was not a significant predictor of future hypertension, although a modest influence of an AHI greater than 30 on hypertension could not be excluded.
doi:10.1164/rccm.200712-1809OC
PMCID: PMC2695498  PMID: 19264976
sleep apnea; sleep-disordered breathing; hypertension; cohort study
25.  Genomewide Association Studies of Stroke 
The New England journal of medicine  2009;360(17):1718-1728.
BACKGROUND
The genes underlying the risk of stroke in the general population remain undetermined.
METHODS
We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [±SD] age, 63±8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons.
RESULTS
Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5×10−8). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P = 0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P = 0.03) and 1.19 (95% CI, 1.01 to 1.41; P = 0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant.
CONCLUSIONS
A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.
doi:10.1056/NEJMoa0900094
PMCID: PMC2768348  PMID: 19369658

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