Temporal trends in validated ischaemic stroke hospitalizations in the USA.

BACKGROUND: Accurate assessment of the burden of stroke, a major cause of disability and death, is crucial. We aimed to estimate rates of validated ischaemic stroke hospitalizations in the USA during 1998-2011. METHODS: We used the Atherosclerosis Risk in Communities (ARIC) study cohort's adjudicated stroke data for participants aged ≥55 years, to construct validation models for each International Classification of Diseases (ICD)-code group and patient covariates. These models were applied to the Nationwide Inpatient Sample (NIS) data to estimate the probability of validated ischaemic stroke for each eligible hospitalization. Rates and trends in NIS using ICD codes vs estimates of validated ischaemic stroke were compared. RESULTS: After applying validation models, the estimated annual average rate of validated ischaemic stroke hospitalizations in the USA during 1998-2011 was 3.37 [95% confidence interval (CI): 3.31, 3.43) per 1000 person-years. Validated rates declined during 1998-2011 from 4.7/1000 to 2.9/1000; however, the decline was limited to 1998-2007, with no further decline subsequently through 2011. Validation models showed that the false-positive (∼23% of strokes) and false-negative rates of ICD-9-CM codes in primary position for ischaemic stroke approximately cancel. Therefore, estimates of ischaemic stroke hospitalizations did not substantially change after applying validation models. CONCLUSIONS: Overall, ischaemic stroke hospitalization rates in the USA have declined during 1998-2007, but no further decline was observed from 2007 to 2011. Validated ischaemic stroke hospitalizations estimates were similar to published estimates of hospitalizations with ischaemic stroke ICD codes in primary position. Validation of national discharge data using prospective chart review data is important to estimate the accuracy of reported burden of stroke.

Migraine Age of Onset and Association With Ischemic Stroke in Late Life: 20 Years Follow-Up in ARIC.

BACKGROUND AND PURPOSE: To evaluate the association between cumulative exposure to migraine and incidence of ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. METHODS: In this ongoing, prospective longitudinal community-based cohort, participants were interviewed to ascertain migraine history at the third visit (1993-1995), followed for ischemic stroke incidence over 20 years. We performed a post hoc analysis to evaluate the association between the age of migraine onset and ischemic stroke. RESULTS: We identified 447 migraineurs with aura (MA) and 1128 migraineurs without aura (MO) among 11,592 black and white participants. There was an association between the age of MA onset ≥50 years old (average duration = 4.75 years) and ischemic stroke when compared to no headache group (multivariable adjusted HR = 2.17, 95% CI [1.39-3.39], P < .001). MA onset <50 years old (average duration = 28.17 years) was not associated with stroke (multivariable adjusted HR = 1.31, 95% CI [0.86-2.02], P = .212). These results were consistent with our logistic regression model. MO was not associated with increased stroke regardless of the age of onset. The absolute risk for stroke in migraine with aura is 37/447 (8.27%) and migraine without aura is 48/1128 (4.25%). CONCLUSION: As compared to the no headache participants, increased stroke risk in late life was observed in participants with late onset of MA. In this cohort, longer cumulative exposure to migraine with visual aura, as would be expected with early onset of migraine, was not associated with increased risk of ischemic stroke in late life. This study underscores the importance of the age of onset of MA in assessing stroke risk in older migraineurs.

Trends in Hospitalizations and Survival of Acute Decompensated Heart Failure in Four US Communities (2005-2014): ARIC Study Community Surveillance.

BACKGROUND: Community trends of acute decompensated heart failure (ADHF) in diverse populations may differ by race and sex. METHODS: The ARIC study (Atherosclerosis Risk in Communities) sampled heart failure-related hospitalizations (≥55 years of age) in 4 US communities from 2005 to 2014 using International Classification of Diseases, Ninth Revision, Clinical Modification codes. ADHF hospitalizations were validated by standardized physician review and computer algorithm, yielding 40 173 events after accounting for sampling design (unweighted n=8746). RESULTS: Of the ADHF hospitalizations, 50% had reduced ejection fraction, and 39% had preserved EF (HFpEF). HF with reduced ejection fraction was more common in black men and white men, whereas HFpEF was most common in white women. Average age-adjusted rates of ADHF were highest in blacks (38.1 per 1000 black men, 30.5 per 1000 black women), with rates differing by HF type and sex. ADHF rates increased over the 10 years (average annual percentage change: black women +4.3%, black men +3.7%, white women +1.9%, white men +2.6%), mostly reflecting more acute HFpEF. Age-adjusted 28-day and 1-year case fatality proportions were ≈10% and 30%, respectively, similar across race-sex groups and HF types. Only blacks showed decreased 1-year mortality over time (average annual percentage change: black women -5.4%, black men -4.6%), with rates differing by HF type (average annual percentage change: black women HFpEF -7.1%, black men HF with reduced ejection fraction -4.7%). CONCLUSIONS: Between 2005 and 2014, trends in ADHF hospitalizations increased in 4 US communities, primarily driven by acute HFpEF. Survival at 1 year was poor regardless of EF but improved over time for black women and black men.

Sleep characteristics and risk of dementia and Alzheimer's disease: The Atherosclerosis Risk in Communities Study.

INTRODUCTION: This study tested the hypotheses that late-midlife obstructive sleep apnea (OSA) and short and long sleep duration are associated with dementia over 15 years of follow-up. METHODS: A total of 1667 Atherosclerosis Risk in Communities Study participants underwent in-home polysomnography (1996-1998) and were followed for dementia. Dementia was defined by (1) hospitalization diagnosis codes (1996-2012) and (2) a comprehensive neurocognitive examination (2011-2013) with adjudication. RESULTS: OSA and sleep duration were not associated with risk of incident dementia. When using adjudicated outcomes, severe OSA (≥30 vs. <5 apnea-hypopnea events/hour) was associated with higher risk of all-cause dementia (risk ratio [95% confidence interval], 2.35 [1.06-5.18]) and Alzheimer's disease dementia (1.66 [1.03-2.68]); associations were attenuated with cardiovascular risk factor adjustment. Sleeping <7 versus 8 to ≤9 hours was associated with higher risk of all-cause dementia (2.00 [1.03-3.86]). DISCUSSION: When adjudicated outcome definitions were used, late-midlife OSA and short sleep duration were associated with all-cause and Alzheimer's disease dementia in later life.

The association of lipoprotein(a) with incident heart failure hospitalization: Atherosclerosis Risk in Communities study.

BACKGROUND AND AIMS: Lipoprotein(a) [Lp(a)] is a proatherogenic lipoprotein associated with coronary heart disease, ischemic stroke, and more recently aortic stenosis and heart failure (HF). We examined the association of Lp(a) levels with incident HF hospitalization in the Atherosclerosis Risk in Communities (ARIC) study. We also assessed the relationship between Lp(a) levels and arterial stiffness as a potential mechanism for development of HF. METHODS: Lp(a) was measured in 14,154 ARIC participants without prevalent HF at ARIC visit 1 (1987-1989). The association of Lp(a) quintiles with incident HF hospitalization was assessed using Cox proportional-hazards models. Arterial stiffness parameters were stratified based on Lp(a) quintiles, and p-trend was calculated across ordered groups. RESULTS: At a median follow-up of 23.4 years, there were 2605 incident HF hospitalizations. Lp(a) levels were directly associated with incident HF hospitalization in models adjusted for age, race, gender, systolic blood pressure, history of hypertension, diabetes, smoking status, body mass index, heart rate, and high-density lipoprotein cholesterol (quintile 5 vs. quintile 1: hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.09-1.41; p-trend across increasing quintiles <0.01), but not after excluding prevalent and incident myocardial infarction cases (HR 1.07, 95% CI 0.91-1.27; p-trend = 0.70). When adjusted for age, gender, and race, Lp(a) quintiles were not significantly associated with arterial stiffness parameters. CONCLUSIONS: Increased Lp(a) levels were associated with increased risk of incident HF hospitalization. After excluding prevalent and incident myocardial infarction, the association was no longer significant. Lp(a) levels were not associated with arterial stiffness parameters.

A Theorem at the Core of Colliding Bias.

Conditioning on a shared outcome of two variables can alter the association between these variables, possibly adding a bias component when estimating effects. In particular, if two causes are marginally independent, they might be dependent in strata of their common effect. Explanations of the phenomenon, however, do not explicitly state when dependence will be created and have been largely informal. We prove that two, marginally independent, causes will be dependent in a particular stratum of their shared outcome if and only if they modify each other's effects, on a probability ratio scale, on that value of the outcome variable. Using our result, we also qualify the claim that such causes will "almost certainly" be dependent in at least one stratum of the outcome: dependence must be created in one stratum of a binary outcome, and independence can be maintained in every stratum of a trinary outcome.

Obstructive sleep apnea and incident type 2 diabetes.

OBJECTIVES: To determine whether severity of obstructive sleep apnea is associated with incident diabetes in middle-aged and older adults. METHODS: A prospective analysis of 1453 non-diabetic participants of both the Atherosclerosis Risk in Communities Study and the Sleep Heart Health Study (mean age 63 years, 46% male) had in-home polysomnography (1996-1998) and was followed up for incident diabetes. Using the apnea-hypopnea index derived from home polysomnography, study participants were categorized as follows: <5.0 (normal), 5.0-14.9 (mild), 15.0-29.9 (moderate), and ≥30.0 events/h (severe). Incident diabetes was ascertained during annual follow-up telephone calls through 2013. RESULTS: During a median follow-up of 13 years, there were 285 incident diabetes cases among the 1453 participants. Participants with severe obstructive sleep apnea were at greater risk of incident diabetes compared to persons classified as normal after adjustment for confounders including body mass index and waist circumference (1.71 [1.08, 2.71]). The association between severe obstructive sleep apnea and incident diabetes was similar when analyses were restricted to obese individuals. CONCLUSIONS: Severe obstructive sleep apnea was associated with greater risk of incident diabetes, independent of adiposity in a community-based sample. Healthcare professionals should be cognizant of the high prevalence of OSA in the general population and the potential link to incident diabetes.

Association of sleep apnea and sleep duration with peripheral artery disease: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND AND AIMS: Numerous biological pathways linking sleep disturbances to atherosclerosis have been identified, such as insulin resistance, inflammation, hypertension, and endothelial dysfunction. Yet, the association of sleep apnea and sleep duration with peripheral artery disease (PAD) is not well characterized. METHODS: We evaluated the cross-sectional association between objectively measured sleep and prevalent PAD in 1844 participants (mean age 68 years) who in 2010-2013 had in-home polysomnography, 7-day wrist actigraphy and ankle-brachial index (ABI) measurements. We also evaluated the relation between self-reported diagnosed sleep apnea and PAD incidence in 5365 participants followed from 2000 to 2012. PAD was defined as ABI < 0.90. RESULTS: In cross-sectional analyses, severe sleep apnea [apnea-hypopnea index (AHI) ≥30 vs. AHI <5] was associated with greater prevalent PAD only among black participants [multivariate adjusted prevalence ratio (95% CI): 2.29 (1.07-4.89); p-interaction = 0.05]. Short and long sleep duration was also associated with a 2-fold higher prevalence of PAD as compared with those who slept 7 h/night, in the full sample. In longitudinal analyses, participants with self-reported diagnosed sleep apnea were at higher risk of incident PAD [multivariable adjusted hazard ratio (95% CI): 1.93 (1.05-3.53)], with no evidence of interaction by race/ethnicity. CONCLUSIONS: These findings support a significant association between sleep apnea and prevalent and incident PAD, with evidence for stronger associations with objectively measured sleep apnea and cross sectional PAD in blacks. In addition, short and long sleep duration was associated with PAD. These results identify sleep disturbances as a potential risk factor for PAD.

Sleep Apnea, Sleep Duration and Brain MRI Markers of Cerebral Vascular Disease and Alzheimer's Disease: The Atherosclerosis Risk in Communities Study (ARIC).

BACKGROUND: A growing body of literature has suggested that obstructive sleep apnea (OSA) and habitual short sleep duration are linked to poor cognitive function. Neuroimaging studies may provide insight into this relation. OBJECTIVE: We tested the hypotheses that OSA and habitual short sleep duration, measured at ages 54-73 years, would be associated with adverse brain morphology at ages 67-89 years. METHODS: Included in this analysis are 312 ARIC study participants who underwent in-home overnight polysomnography in 1996-1998 and brain MRI scans about 15 years later (2012-2013). Sleep apnea was quantified by the apnea-hypopnea index and categorized as moderate/severe (≥15.0 events/hour), mild (5.0-14.9 events/hour), or normal (<5.0 events/hour). Habitual sleep duration was categorized, in hours, as <7, 7 to <8, ≥8. MRI outcomes included number of infarcts (total, subcortical, and cortical) and white matter hyperintensity (WMH) and Alzheimer's disease signature region volumes. Multivariable adjusted logistic and linear regression models were used. All models incorporated inverse probability weighting, to adjust for potential selection bias. RESULTS: At the time of the sleep study participants were 61.7 (SD: 5.0) years old and 54% female; 19% had moderate/severe sleep apnea. MRI imaging took place 14.8 (SD: 1.0) years later, when participants were 76.5 (SD: 5.2) years old. In multivariable models which accounted for body mass index, neither OSA nor abnormal sleep duration were statistically significantly associated with odds of cerebral infarcts, WMH brain volumes or regional brain volumes. CONCLUSIONS: In this community-based sample, mid-life OSA and habitually short sleep duration were not associated with later-life cerebral markers of vascular dementia and Alzheimer's disease. However, selection bias may have influenced our results and the modest sample size led to relatively imprecise associations.

Forced Expiratory Volume in the First Second and Aldosterone as Mediators of Smoking Effect on Stroke in African Americans: The Jackson Heart Study.

BACKGROUND: Cigarette smoking is a risk factor for stroke, but the mechanisms by which smoking contributes to stroke are not well understood. This study aimed to evaluate the roles of lung function (represented by forced expiratory volume in the first second (FEV1)) and aldosterone as potential mediators of the association of smoking with stroke. METHODS AND RESULTS: The data were derived from 5010 Jackson Heart Study participants who had mean follow-up of 97.9 months. Using the Cox proportional hazards model, we estimated the hazard ratios of smoking for total stroke with and without adjustment for FEV1 and/or aldosterone at baseline after controlling for the confounders. The hazard ratio for current smoking (versus never smoking) was 2.70 (95% CI 1.71 to 4.25) for total stroke after adjustment for the confounders. Additional adjustment for FEV1 and aldosterone reduced the hazard ratio to 2.32 (95% CI 1.42 to 3.79), suggesting that 22.4% of the excess risk of current smoking for total stroke is mediated by these factors. FEV1 and aldosterone account for 13.1% and 12.1%, respectively, of the excess risk. The hazard ratio for FEV1 increased (0.61 versus 0.65) after including systemic inflammatory marker C-reactive protein, and the hazard ratios for aldosterone were comparable for the models that included all confounders and smoking status with or without different blood pressure measurements. CONCLUSIONS: Our findings suggest that the difference in stroke risk between current and never smokers may develop partially through pathways involving lung function and aldosterone and that the mediation effect through aldosterone is independent of blood pressure.

Obstructive Sleep Apnea and 15-Year Cognitive Decline: The Atherosclerosis Risk in Communities (ARIC) Study.

STUDY OBJECTIVES: Prospective data evaluating abnormal sleep quality and quantity with cognitive decline are limited because most studies used subjective data and/or had short follow-up. We hypothesized that, over 15 y of follow-up, participants with objectively measured obstructive sleep apnea (OSA) and other indices of poor sleep quantity and quality would experience greater decline in cognitive functioning than participants with normal sleep patterns. METHODS: ARIC participants (n = 966; mean age 61 y, 55% women) with in-home polysomnography (1996-1998) and repeated cognitive testing were followed for 15 y. Three cognitive tests (Delayed Word Recall, Word Fluency, and Digit Symbol Substitution) were administered at two time points (1996-1998 and 2011-2013). Ten additional cognitive tests were administered at the 2011-2013 neurocognitive examination. OSA was modeled using established clinical OSA severity categories. Multivariable linear regression was used to explore associations of OSA and other sleep indices with change in cognitive tests between the two assessments. RESULTS: A median of 14.9 y (max: 17.3) passed between the two cognitive assessments. OSA category and additional indices of sleep (other measures of hypoxemia and disordered breathing, sleep fragmentation, sleep duration) were not associated with change in any cognitive test. Analyses of OSA severity categories and 10 cognitive tests administered only in 2011-2013 also showed little evidence of an association. CONCLUSIONS: Overall, abnormal sleep quality and quantity at midlife was not related to cognitive decline and later-life cognition. The effect of adverse sleep quality and quantity on cognitive decline among the elderly remains to be determined.

Plasma d-Dimer and Incident Ischemic Stroke and Coronary Heart Disease: The Atherosclerosis Risk in Communities Study.

BACKGROUND AND PURPOSE: Epidemiological studies have documented that plasma d-dimer, a fibrin degradation product, is a risk marker for coronary heart disease, but there is limited prospective evidence for stroke. Given that thrombosis is a key mechanism for many strokes, we studied whether d-dimer is a risk marker for ischemic stroke incidence in the Atherosclerosis Risk in Communities (ARIC) Study. METHODS: We measured d-dimer in 11 415 ARIC participants free of stroke and coronary heart disease in 1992 to 1995. We followed them for stroke, stroke subtype, and coronary heart disease events through 2012. RESULTS: Over a median of 18 years of follow-up, 719 participants had incident strokes (628 ischemic and 91 hemorrhagic). d-dimer was associated positively with risk of total, ischemic, and cardioembolic strokes, with risk elevated primarily for the highest quintile of d-dimer. After adjustment for other cardiovascular risk factors, the hazard ratio for the highest versus lowest quintile of d-dimer was 1.30 (95% confidence interval, 1.02-1.67) for total stroke, 1.33 (95% confidence interval, 1.02-1.73) for ischemic stroke, and 1.79 (95% confidence interval, 1.08-2.95) for cardioembolic stroke. There was no association with hemorrhagic, lacunar, or nonlacunar stroke categories. d-dimer was positively but weakly associated with coronary heart disease incidence. CONCLUSIONS: A higher basal plasma d-dimer concentration in the general population is a risk marker for ischemic stroke, especially cardioembolic stroke.

Depressive Symptoms and Risk of Cardiovascular Events in Blacks: Findings From the Jackson Heart Study.

BACKGROUND: Most studies of depression and cardiovascular risk have been conducted in white populations. We investigated this association in a community-based cohort of blacks. METHODS AND RESULTS: We used data from the Jackson Heart Study to investigate associations of baseline depressive symptoms between 2000 and 2004 with incident stroke and coronary heart disease (CHD) during 10 years. We used Kaplan-Meier estimates and Cox proportional hazards models to assess cardiovascular event risk using 3 exposure variables: any depressive symptoms (Center for Epidemiological Studies Depression score ≥16); none (score <16), minor (score 16 to <21), and major depression (score≥21); and Center for Epidemiological Studies Depression score per 1-SD increase. Models were adjusted for a stroke or CHD risk score and behavioral risk factors. Of 3309 participants with no stroke history, 738 (22.3%) had baseline depressive symptoms. A similar proportion with no previous CHD had baseline depressive symptoms (21.8%). The unadjusted 10-year risk of stroke was similar among participants with any compared with no depressive symptoms (3.7% versus 2.6%; P=0.12). Unadjusted CHD rates were higher among participants with depressive symptoms (5.6% versus 3.6%; P=0.03), and differences persisted after adjustment for clinical and behavioral risk factors but not after adjustment for coping strategies. In adjusted models comparing major versus no depressive symptoms, patients with major depressive symptoms had a 2-fold greater hazard of stroke (hazard ratio, 1.95; 95% confidence interval, 1.02-3.71; P=0.04). In continuous models, a 1-SD increase in Center for Epidemiological Studies Depression score was associated with a 30% increase in adjusted incident stroke risk (P=0.04). Similar associations were observed for incident CHD in models adjusted for clinical and behavioral risk factors, but associations were not significant after adjustment for coping strategies. CONCLUSIONS: In a community-based cohort of blacks, major depressive symptoms were associated with greater risks of incident stroke and CHD after adjustment for clinical and behavioral risk factors.

Midlife Alcohol Consumption and the Risk of Stroke in the Atherosclerosis Risk in Communities Study.

BACKGROUND AND PURPOSE: Alcohol consumption is common in the United States and may confer beneficial cardiovascular effects at light-to-moderate doses. The alcohol-stroke relationship remains debated. We estimated the relationship between midlife, self-reported alcohol consumption and ischemic stroke and intracerebral hemorrhage (ICH) in a biracial cohort. METHODS: We examined 12,433 never and current drinkers in the Atherosclerosis Risk in Communities study, aged 45 to 64 years at baseline. Participants self-reported usual drinks per week of beer, wine, and liquor at baseline. We used multivariate Cox proportional hazards regression to assess the association of current alcohol consumption relative to lifetime abstention with incident ischemic stroke and ICH and modification by sex-race group. We modeled alcohol intake with quadratic splines to further assess dose-response relationships. RESULTS: One third of participants self-reported abstention, 39% and 24%, respectively, consumed ≤3 and 4 to 17 drinks/wk, and only 5% reported heavier drinking. There were 773 ischemic strokes and 81 ICH over follow-up (median≈22.6 years). For ischemic stroke, light and moderate alcohol consumption were not associated with incidence (hazard ratios, 0.98; 95% CI, 0.79-1.21; 1.06, 0.84-1.34), whereas heavier drinking was associated with a 31% increased rate relative to abstention (hazard ratios, 1.31; 95% CI, 0.92-1.86). For ICH, moderate-to-heavy (hazard ratios, 1.99; 95% CI, 1.07-3.70), but not light, consumption increased incidence. CONCLUSIONS: Self-reported light-to-moderate alcohol consumption at midlife was not associated with reduced stroke risk compared with abstention over 20 years of follow-up in the Atherosclerosis Risk in Communities study. Heavier consumption increased the risk for both outcomes as did moderate intake for ICH.

Objectively measured sleep characteristics and prevalence of coronary artery calcification: the Multi-Ethnic Study of Atherosclerosis Sleep study.

BACKGROUND: We tested whether objectively measured indices of obstructive sleep apnoea (OSA) and sleep quality are associated with coronary artery calcification (CAC) prevalence independent of obesity, a classic confounder. METHODS: 1465 Multi-Ethnic Study of Atherosclerosis participants (mean age 68 years), who were free of clinical cardiovascular disease, had both coronary CT and in-home polysomnography and actigraphy performed. OSA categories were defined by the Apnea-Hypopnea Index (AHI). Prevalence ratios (PRs) for CAC >0 and >400 (high burden) were calculated. RESULTS: Participants with severe OSA (AHI ≥30; 14.6%) were more likely to have prevalent CAC, relative to those with no evidence of OSA, after adjustment for demographics and smoking status (PR 1.16; 95% CI 1.06 to 1.26), body mass index (1.11; 1.02 to 1.21) and traditional cardiovascular risk factors (1.10; 1.01 to 1.19). Other markers of hypoxaemia tended to be associated with a higher prevalence of CAC >0. For CAC >400, a higher prevalence was observed with both a higher arousal index and less slow-wave sleep. Overall, associations were somewhat stronger among younger participants, but did not vary by sex or race/ethnicity. CONCLUSIONS: In this population-based multi-ethnic sample, severe OSA was associated with subclinical coronary artery disease (CAC >0), independent of obesity and traditional cardiovascular risk factors. Furthermore, the associations of the arousal index and slow-wave sleep with high CAC burden suggest that higher nightly sympathetic nervous system activation is also a risk factor. These findings highlight the potential importance of measuring disturbances in OSA as well as sleep fragmentation as possible risk factors for coronary artery disease.

Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans.

BACKGROUND AND PURPOSE: The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African Americans, despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations. METHODS: Using METAL, we conducted meta-analyses of GWAS in 14 746 African Americans (1365 ischemic and 1592 total stroke cases) from COMPASS, and tested genetic variants with P<10(-6) for validation in METASTROKE, a consortium of ischemic stroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations. RESULTS: The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613; P=3.9×10(-8)) in African Americans. Nominal associations (P<10(-6)) for total or ischemic stroke were observed for 18 variants in or near genes implicated in cell cycle/mRNA presplicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, and IL1F10-IL1RN), and histone modification (HDAC9). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 (P=0.03), and 1p31.1 (P=0.018). Four of 7 previously reported ischemic stroke loci (PITX2, HDAC9, CDKN2A/CDKN2B, and ZFHX3) were nominally associated (P<0.05) with stroke in COMPASS. CONCLUSIONS: We identified a novel genetic variant associated with total stroke in African Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations.

Obstructive sleep apnea and progression of coronary artery calcium: the multi-ethnic study of atherosclerosis study.

BACKGROUND: Obstructive sleep apnea (OSA) is a common condition associated with cardiovascular disease. Its potential effect on progression of subclinical atherosclerosis is not well understood. We tested the hypothesis that self-reported OSA is associated with progression of coronary artery calcium (CAC). We also evaluated whether traditional cardiovascular risk factors accounted for the association. METHODS AND RESULTS: In the Multi-Ethnic Study of Atherosclerosis (MESA) prospective cohort, we studied 2603 participants who at baseline (2002-2004) completed a sleep questionnaire and underwent coronary computed tomography (CT) and, then 8 years later (2010-2011), a repeat coronary CT. Participants were categorized by symptoms of habitual snoring or reported physician diagnosis of OSA. At baseline, 102 (3.9%) reported diagnosed OSA; 666 (25.6%) reported diagnosed habitual snoring; and 1835 (70.5%) reported neither habitual snoring nor OSA ("normal"). At baseline, CAC prevalence was highest among those with OSA but similar for those with and without habitual snoring. During 8 years of follow-up, greater progression of CAC was observed among those with OSA versus normal (mean increase of 204.2 versus 135.5 Agatston units; P=0.01), after accounting for demographics, behaviors, and body habitus. Modest attenuation was observed after adjustment for cardiovascular risk factors (188.7 versus 138.8; P=0.06). CAC progression among habitual snorers was similar to that observed in the normal group. CONCLUSIONS: OSA was associated with CAC score progression after adjustment for demographics, behaviors, and body mass index. However, the association was not significant after accounting for cardiovascular risk factors, which may mediate the association between OSA and CAC.

Validity of hospital discharge diagnosis codes for stroke: the Atherosclerosis Risk in Communities Study.

BACKGROUND AND PURPOSE: Characterizing International Classification of Disease 9th Revision, Clinical Modification (ICD-9-CM) code validity is essential given widespread use of hospital discharge databases in research. Using the Atherosclerosis Risk in Communities (ARIC) Study, we estimated the accuracy of ICD-9-CM stroke codes. METHODS: Hospitalizations with ICD-9-CM codes 430 to 438 or stroke keywords in the discharge summary were abstracted for ARIC cohort members (1987-2010). A computer algorithm and physician reviewer classified definite and probable ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Using ARIC classification as a gold standard, we calculated the positive predictive value (PPV) and sensitivity of ICD-9-CM codes grouped according to the American Heart Association/American Stroke Association (AHA/ASA) 2013 categories and an alternative code grouping for comparison. RESULTS: Thirty-three percent of 4260 hospitalizations were validated as strokes (1251 ischemic, 120 intracerebral hemorrhage, 46 subarachnoid hemorrhage). The AHA/ASA code groups had PPV 76% and 68% sensitivity compared with PPV 72% and 83% sensitivity for the alternative code groups. The PPV of the AHA/ASA code group for ischemic stroke was slightly higher among blacks, individuals <65 years, and at teaching hospitals. Sensitivity was higher among older individuals and increased over time. The PPV of the AHA/ASA code group for intracerebral hemorrhage was higher among blacks, women, and younger individuals. PPV and sensitivity varied across study sites. CONCLUSIONS: A new AHA/ASA discharge code grouping to identify stroke had similar PPV and lower sensitivity compared with an alternative code grouping. Accuracy varied by patient characteristics and study sites.

Stroke incidence and mortality trends in US communities, 1987 to 2011.

IMPORTANCE: Prior studies have shown decreases in stroke mortality over time, but data on validated stroke incidence and long-term trends by race are limited. OBJECTIVE: To study trends in stroke incidence and subsequent mortality among black and white adults in the Atherosclerosis Risk in Communities (ARIC) cohort from 1987 to 2011. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 14,357 participants (282,097 person-years) free of stroke at baseline was facilitated in 4 different US communities. Participants were recruited for the purpose of studying all stroke hospitalizations and deaths and for collection of baseline information on cardiovascular risk factors (via interviews and physical examinations) in 1987-1989. Participants were followed up (via examinations, annual phone interviews, active surveillance of discharges from local hospitals, and linkage with the National Death Index) through December 31, 2011. The study physician reviewers adjudicated all possible strokes and classified them as definite or probable ischemic or hemorrhagic events. MAIN OUTCOMES AND MEASURES: Trends in rates of first-ever stroke per 10 years of calendar time were estimated using Poisson regression incidence rate ratios (IRRs), with subsequent mortality analyzed using Cox proportional hazards regression models and hazard ratios (HRs) overall and by race, sex, and age divided at 65 years. RESULTS: Among 1051 (7%) participants with incident stroke, there were 929 with incident ischemic stroke and 140 with incident hemorrhagic stroke (18 participants had both during the study period). Crude incidence rates were 3.73 (95% CI, 3.51-3.96) per 1000 person-years for total stroke, 3.29 (95% CI, 3.08-3.50) per 1000 person-years for ischemic stroke, and 0.49 (95% CI, 0.41-0.57) per 1000 person-years for hemorrhagic stroke. Stroke incidence decreased over time in white and black participants (age-adjusted IRRs per 10-year period, 0.76 [95% CI, 0.66-0.87]; absolute decrease of 0.93 per 1000 person-years overall). The decrease in age-adjusted incidence was evident in participants age 65 years and older (age-adjusted IRR per 10-year period, 0.69 [95% CI, 0.59-0.81]; absolute decrease of 1.35 per 1000 person-years) but not evident in participants younger than 65 years (age-adjusted IRR per 10-year period, 0.97 [95% CI, 0.76-1.25]; absolute decrease of 0.09 per 1000 person-years) (P = .02 for interaction). The decrease in incidence was similar by sex. Of participants with incident stroke, 614 (58%) died through 2011. The mortality rate was higher for hemorrhagic stroke (68%) than for ischemic stroke (57%). Overall, mortality after stroke decreased over time (hazard ratio [HR], 0.80 [95% CI, 0.66-0.98]; absolute decrease of 8.09 per 100 strokes after 10 years [per 10-year period]). The decrease in mortality was mostly accounted for by the decrease at younger than age 65 years (HR, 0.65 [95% CI, 0.46-0.93]; absolute decrease of 14.19 per 100 strokes after 10 years [per 10-year period]), but was similar across race and sex. CONCLUSIONS AND RELEVANCE: In a multicenter cohort of black and white adults in US communities, stroke incidence and mortality rates decreased from 1987 to 2011. The decreases varied across age groups, but were similar across sex and race, showing that improvements in stroke incidence and outcome continued to 2011.