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1.  Age Differences in the Association of Obstructive Sleep Apnea Risk with Cognition and Quality of Life 
Journal of sleep research  2013;23(1):69-76.
Summary
Using a sample of 2925 stroke-free participants drawn from a national population-based study, we examined cross-sectional associations of obstructive sleep apnea risk (OSA) with cognition and quality of life and whether these vary with age, while controlling for demographics and co-morbidities. Included participants from the REasons for Geographic And Racial Differences in Stroke Study were aged 47-93. OSA risk was categorized as high or low based on responses to the Berlin Sleep Questionnaire. Cognitive function was assessed with standardized fluency and recall measures. Depressive symptoms were assessed with the four-item Center for Epidemiologic Studies Depression Scale. Health-related Quality of Life (HRQoL) was assessed with the Medical Outcomes Study Short Form-12 (SF-12). MANCOVA statistics were applied separately to the cognitive and quality of life dependent variables while accounting for potential confounders (demographics, co-morbidities). In fully adjusted models, those at high risk for OSA had significantly lower cognitive scores (Wilks’ Lambda = 0.996, F(3, 2786) = 3.31, p < .05) and lower quality of life (depressive symptoms and HRQoL) (Wilks’ Lambda = 0.989, F(3, 2786) = 10.02, p < .0001). However, some of the associations were age-dependent. Differences in cognition and quality of life between those at high and low obstructive sleep apnea risk were most pronounced during middle age, with attenuated effects after age 70.
doi:10.1111/jsr.12086
PMCID: PMC4147721  PMID: 24033751
Obstructive sleep apnea; Berlin Sleep Questionnaire; cognitive function; depression; health related quality life; age differences
2.  Testing for clustering at many ranges inflates family-wise error rate (FWE) 
Background
Testing for clustering at multiple ranges within a single dataset is a common practice in spatial epidemiology. It is not documented whether this approach has an impact on the type 1 error rate.
Methods
We estimated the family-wise error rate (FWE) for the difference in Ripley’s K functions test, when testing at an increasing number of ranges at an alpha-level of 0.05. Case and control locations were generated from a Cox process on a square area the size of the continental US (≈3,000,000 mi2). Two thousand Monte Carlo replicates were used to estimate the FWE with 95% confidence intervals when testing for clustering at one range, as well as 10, 50, and 100 equidistant ranges.
Results
The estimated FWE and 95% confidence intervals when testing 10, 50, and 100 ranges were 0.22 (0.20 - 0.24), 0.34 (0.31 - 0.36), and 0.36 (0.34 - 0.38), respectively.
Conclusions
Testing for clustering at multiple ranges within a single dataset inflated the FWE above the nominal level of 0.05. Investigators should construct simultaneous critical envelopes (available in spatstat package in R), or use a test statistic that integrates the test statistics from each range, as suggested by the creators of the difference in Ripley’s K functions test.
doi:10.1186/1476-072X-14-4
PMCID: PMC4326498  PMID: 25588612
Ripley’s K function; Overall clustering; Point process; Family wise error rate (FWE); Multiple testing
3.  Environmental Public Health Applications Using Remotely Sensed Data 
Geocarto international  2012;29(1):85-98.
We describe a remote sensing and GIS-based study that has three objectives: (1) characterize fine particulate matter (PM2.5), insolation and land surface temperature using NASA satellite observations, EPA ground-level monitor data and North American Land Data Assimilation System (NLDAS) data products on a national scale; (2) link these data with public health data from the REasons for Geographic And Racial Differences in Stroke (REGARDS) national cohort study to determine whether these environmental risk factors are related to cognitive decline, stroke and other health outcomes; and (3) disseminate the environmental datasets and public health linkage analyses to end users for decision-making through the Centers for Disease Control and Prevention (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER) system. This study directly addresses a public health focus of the NASA Applied Sciences Program, utilization of Earth Sciences products, by addressing issues of environmental health to enhance public health decision-making.
doi:10.1080/10106049.2012.715209
PMCID: PMC4044865  PMID: 24910505
remote sensing; GIS; fine particulates; insolation; heat; public health
4.  The Secondary Prevention of Small Subcortical Strokes (SPS3) study 
Background
Small subcortical strokes, also known as lacunar strokes, comprise more than 25% of brain infarcts, and the underlying vasculopathy is the most common cause of vascular cognitive impairment. How to optimally prevent stroke recurrence and cognitive decline in S3 patients is unclear. The aim of the Secondary Prevention of Small Subcortical Strokes study (Trial registration: NCT00059306) is to define strategies for reducing stroke recurrence, cognitive decline, and major vascular events.
Methods
Secondary Prevention of Small Subcortical Strokes is a randomised, multicentre clinical trial (n = 3000) being conducted in seven countries, and sponsored by the US NINDS/NIH. Patients with symptomatic small subcortical strokes in the six-months before and an eligible lesion on magnetic resonance imaging are simultaneously randomised, in a 2 × 2 factorial design, to antiplatelet therapy – 325 mg aspirin daily plus 75 mg clopidogrel daily, vs. 325 mg aspirin daily plus placebo, double-blind – and to one of two levels of systolic blood pressure targets –‘intensive’ (<130 mmHg) vs. ‘usual’ (130–149 mmHg). Participants are followed for an average of four-years. Time to recurrent stroke (ischaemic or haemorrhagic) is the primary outcome and will be analysed separately for each intervention. The secondary outcomes are the rate of cognitive decline and major vascular events. The primary and most secondary outcomes are adjudicated centrally by those unaware of treatment assignment.
Conclusions
Secondary Prevention of Small Subcortical Strokes will address several important clinical and scientific questions by testing two interventions in patients with recent magnetic resonance imaging-defined lacunar infarcts, which are likely due to small vessel disease. The results will inform the management of millions of patients with this common vascular disorder.
doi:10.1111/j.1747-4949.2010.00573.x
PMCID: PMC4214141  PMID: 21371282
antiplatelet therapy; hypertension; lacunar stroke; randomised clinical trial; SPS3
5.  Cognitive impairment in lacunar strokes: The Secondary Prevention of Small Subcortical Strokes (SPS3) Trial 
Annals of neurology  2012;72(3):351-362.
Objective
Lacunar strokes are a leading cause of cognitive impairment and vascular dementia. However, adequate characterization of cognitive impairment is lacking. The aim of this study was to estimate the prevalence and characterize the neuropsychological impairment in lacunar stroke patients.
Methods
All English-speaking participants in the SPS3 trial (NCT: 00059306) underwent neuropsychological testing at baseline. Raw scores were converted to z-scores using published norms. Those with impairment (z≤-1.5) in memory and/or non-memory domains were classified as having Mild Cognitive Impairment (MCI).
Results
Among the 1636 participants, average z scores on all tests were below zero with the largest deficits seen on tests of episodic memory (range of means -0.65 to -0.92), verbal fluency (mean -0.89), and motor dexterity (mean -2.5). Forty-seven percent were classified as having MCI: 36% amnestic, 37% amnestic multidomain, 28% non-amnestic. Of those with Rankin score 0-1 and Barthel score=100, 41% had MCI. Younger age [odds ratio (OR) per 10-yr increase=0.87], male sex (OR 1.3), less education (OR 0.13-0.66 compared to 0-4 yrs education), post-stroke disability (OR 1.4), and impaired activities of daily living (OR 1.8) were independently associated with MCI.
Conclusions
In this large, well characterized cohort of lacunar stroke patients, MCI was present in nearly half, including many with minimal or no physical disabilities. Cognitive dysfunction in lacunar stroke patients may commonly be overlooked in clinical practice but may be as important as motor and sensory sequelae.
doi:10.1002/ana.23733
PMCID: PMC4198173  PMID: 23034910
Small subcortical stroke; lacunar stroke; Vascular cognitive impairment; Neuropsychological tests; Mild Cognitive Impairment
6.  Stroke Genetics Network (SiGN) Study: Design and rationale for a genome-wide association study of ischemic stroke subtypes 
Background and Purpose
Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The NINDS Stroke Genetics Network (SiGN) contributes substantially to meta-analyses that focus on specific subtypes of stroke.
Methods
The NINDS Stroke Genetics Network (SiGN) includes ischemic stroke cases from 24 Genetic Research Centers (GRCs), 13 from the US and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the web-based Causative Classification of Stroke (CCS) system, with data entered by trained and certified adjudicators at participating GRCs. Through the Center for Inherited Diseases Research (CIDR), SiGN plans to genotype 10,296 carefully phenotyped stroke cases using genome-wide SNP arrays, and add to these another 4,253 previously genotyped cases for a total of 14,549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. CIDR-generated genotypes and corresponding phenotypic data will be shared with the scientific community through dbGaP, and brain MRI studies will be centrally archived.
Conclusions
The SiGN consortium, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.
doi:10.1161/STROKEAHA.113.001857
PMCID: PMC4056331  PMID: 24021684
ischemic stroke; genetics; genomics
7.  Clinical Features and Racial/Ethnic Differences among the 3020 Participants in the Secondary Prevention of Small Subcortical Strokes (SPS3) Trial 
AIM
To describe the baseline characteristics, racial/ethnic differences, and geographic differences among participants in the Secondary Prevention of Small Subcortical Strokes (SPS3) study.
METHODS
The SPS3 trial enrolled patients with a symptomatic small subcortical stroke (lacunar stroke) within the prior 6 months and an eligible lesion on MRI, who were randomized, in a factorial design, to antiplatelet therapy (aspirin 325 mg daily plus clopidogrel 75 mg daily vs. aspirin 325 mg daily plus placebo) and to one of two levels of systolic blood pressure targets (“intensive” (<130 mmHg) vs. “usual” (130–149 mmHg)).
RESULTS
Among the 3020 participants recruited from 81 clinical sites in 8 countries, the mean age was 63 years, 63% were men, 75% had a history of hypertension, and 37% were diabetic. Fifty-one percent were White, 30% Hispanic, and 16% Black. Black participants were younger (mean age 58 years vs. 64 years, p<0.001) and more often had hypertension (95% vs. 89%, p<0.001) than White participants. Hispanic and Black participants more often had diabetes than White participants (42%, 40% vs. 32% respectively, both p<0.001). Tobacco smoking at the time of qualifying stroke was much more frequent among Spanish participants (32%) than those from North America (22%) or Latin America (8%) (p<0.001); systolic blood pressure at study entry was 5 mmHg lower among Spanish vs. North American participants (p<0.01).
CONCLUSIONS
The SPS3 cohort is the largest MRI-defined series of patients with S3. Among the racially/ethnically diverse SPS3 participants, there are important differences in patient features and vascular risk factors could influence prognosis for recurrent stroke and response to interventions.
Clinical Trial Registration Information
The SPS3 study is registered on www.clinicaltrials.gov (NCT00059306).
doi:10.1016/j.jstrokecerebrovasdis.2012.03.002
PMCID: PMC3970545  PMID: 22516427
8.  Racial and Regional Differences in Venous Thromboembolism in the United States in Three Cohorts 
Circulation  2014;129(14):1502-1509.
Introduction
Blacks are thought to have a higher risk of venous thromboembolism (VTE) than whites however prior studies are limited to administrative databases that lack specific information on VTE risk factors or have limited geographic scope.
Methods and Results
We ascertained VTE from three prospective studies; the Atherosclerosis Risk in Communities study (ARIC), the Cardiovascular Health Study (CHS), and the REasons for Geographic and Racial Differences in Stroke study (REGARDS). We tested the association of race with VTE using Cox proportional hazard models adjusted for VTE risk factors. Over 438,090 person-years, 916 incident VTE events (302 in blacks) occurred in 51,149 individuals (17,318 blacks) followed. In risk factor-adjusted models, blacks had a higher rate of VTE than whites in CHS (HR 1.81; 95% CI 1.20, 2.73) but not ARIC (HR 1.21; 95% CI 0.96, 1.54). In REGARDS, there was a significant region by race interaction (p = 0.01); blacks in the southeast had a significantly higher rate of VTE than blacks in the rest of the US (HR 1.63; 95% CI 1.08, 2.48) which was not seen in whites (HR 0.83; 95% CI 0.61, 1.14).
Conclusions
The association of race with VTE differed in each cohort, which may reflect the different time periods of the studies and/or different regional rates of VTE. Further study of environmental and genetic risk factors for VTE are needed to determine which underlie racial and perhaps regional differences in VTE.
doi:10.1161/CIRCULATIONAHA.113.006472
PMCID: PMC4098668  PMID: 24508826
Venous Thrombosis; Epidemiology; Race
9.  Report of stroke-like symptoms predicts incident cognitive impairment in a stroke-free cohort 
Neurology  2013;81(2):113-118.
Objective:
The present study characterizes the relationship between report of stroke symptoms (SS) or TIA and incident cognitive impairment in the large biracial cohort of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study.
Methods:
The REGARDS Study is a population-based, biracial, longitudinal cohort study that has enrolled 30,239 participants from the United States. Exclusion of those with baseline cognitive impairment, stroke before enrollment, or incomplete data resulted in a sample size of 23,830. Participants reported SS/TIA on the Questionnaire for Verifying Stroke-free Status at baseline and every 6 months during follow-up. Incident cognitive impairment was detected using the Six-item Screener, which was administered annually.
Results:
Logistic regression found significant association between report of SS/TIA and subsequent incident cognitive impairment. Among white participants, the odds ratio for incident cognitive impairment was 2.08 (95% confidence interval: 1.81, 2.39) for those reporting at least one SS/TIA compared with those reporting no SS/TIA. Among black participants, the odds ratio was 1.66 (95% confidence interval: 1.45, 1.89) using the same modeling. The magnitude of impact was largest among those with fewer traditional stroke risk factors, particularly among white participants.
Conclusions:
Report of SS/TIA showed a strong association with incident cognitive impairment and supports the use of the Questionnaire for Verifying Stroke-free Status as a quick, low-cost instrument to screen for people at increased risk of cognitive decline.
doi:10.1212/WNL.0b013e31829a352e
PMCID: PMC3770175  PMID: 23783751
10.  IDENTIFYING A HIGH STROKE RISK SUBGROUP IN INDIVIDUALS WITH HEART FAILURE 
Heart failure (HF) is associated with an overall stroke rate that is too low to justify anticoagulation in all patients. This study was conducted to determine if vascular risk factors can identify a subgroup of individuals with heart failure with a stroke rate high enough to warrant anticoagulation. The REGARDS study is a population-based cohort of US adults aged ≥45 years. Participants are contacted every six months by telephone for self- or proxy-reported stroke and medical records are retrieved and adjudicated by physicians. Participants were characterized into three groups: HF without atrial fibrillation (AF), AF with or without HF, and neither HF nor AF. Cardiovascular risk factors at baseline were compared between participants with and without incident stroke in HF and AF. Stroke incidence was assessed in risk factor subgroups in HF participants. Of the 30,239 participants, those with missing/anomalous data were excluded. Of the remaining 28,832, 1,360 (5%) had HF without AF, 2,528 (9%) had AF, and 24,944 (86%) had neither. Prior stroke/TIA (p=0.0004), diabetes (DM) (p=0.03) and higher systolic blood pressure (p=0.046), were associated with increased stroke risk in participants with HF without AF. In participants with HF without AF, stroke incidence was highest in those with prior stroke/TIA and DM (2.4 [1.1, 4.0] per hundred personyears). The combination of prior stroke/TIA and DM increases the incidence of stroke in participants with HF without AF. No analyzed subgroup had a stroke rate high enough to make it likely that the benefits of warfarin would outweigh the risks.
doi:10.1016/j.jstrokecerebrovasdis.2011.10.012
PMCID: PMC3326204  PMID: 22142776
11.  Sunlight exposure and cardiovascular risk factors in the REGARDS study: a cross-sectional split-sample analysis 
BMC Neurology  2014;14:133.
Background
Previous research has suggested that vitamin D and sunlight are related to cardiovascular outcomes, but associations between sunlight and risk factors have not been investigated. We examined whether increased sunlight exposure was related to improved cardiovascular risk factor status.
Methods
Residential histories merged with satellite, ground monitor, and model reanalysis data were used to determine previous-year sunlight radiation exposure for 17,773 black and white participants aged 45+ from the US. Exploratory and confirmatory analyses were performed by randomly dividing the sample into halves. Logistic regression models were used to examine relationships with cardiovascular risk factors.
Results
The lowest, compared to the highest quartile of insolation exposure was associated with lower high-density lipoprotein levels in adjusted exploratory (−2.7 mg/dL [95% confidence interval: −4.2, −1.2]) and confirmatory (−1.5 mg/dL [95% confidence interval: −3.0, −0.1]) models. The lowest, compared to the highest quartile of insolation exposure was associated with higher systolic blood pressure levels in unadjusted exploratory and confirmatory, as well as the adjusted exploratory model (2.3 mmHg [95% confidence interval: 0.8, 3.8]), but not the adjusted confirmatory model (1.6 mg/dL [95% confidence interval: −0.5, 3.7]).
Conclusions
The results of this study suggest that lower long-term sunlight exposure has an association with lower high-density lipoprotein levels. However, all associations were weak, thus it is not known if insolation may affect cardiovascular outcomes through these risk factors.
doi:10.1186/1471-2377-14-133
PMCID: PMC4075775  PMID: 24946776
Sunlight; Temperature; Weather; Climate; Environment; Blood pressure; Lipids and lipoproteins
12.  The American Heart Association Life's Simple 7 and Incident Cognitive Impairment: The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study 
Background
Life's Simple 7 is a new metric based on modifiable health behaviors and factors that the American Heart Association uses to promote improvements to cardiovascular health (CVH). We hypothesized that better Life's Simple 7 scores are associated with lower incidence of cognitive impairment.
Methods and Results
For this prospective cohort study, we included REasons for Geographic And Racial Differences in Stroke (REGARDS) participants aged 45+ who had normal global cognitive status at baseline and no history of stroke (N=17 761). We calculated baseline Life's Simple 7 score (range, 0 to 14) based on smoking, diet, physical activity, body mass index, blood pressure, total cholesterol, and fasting glucose. We identified incident cognitive impairment using a 3‐test measure of verbal learning, memory, and fluency obtained a mean of 4 years after baseline. Relative to the lowest tertile of Life's Simple 7 score (0 to 6 points), odds ratios of incident cognitive impairment were 0.65 (0.52, 0.81) in the middle tertile (7 to 8 points) and 0.63 (0.51, 0.79) in the highest tertile (9 to 14 points). The association was similar in blacks and whites, as well as outside and within the Southeastern stroke belt region of the United States.
Conclusions
Compared with low CVH, intermediate and high CVH were both associated with substantially lower incidence of cognitive impairment. We did not observe a dose‐response pattern; people with intermediate and high levels of CVH had similar incidence of cognitive impairment. This suggests that even when high CVH is not achieved, intermediate levels of CVH are preferable to low CVH.
doi:10.1161/JAHA.113.000635
PMCID: PMC4309046  PMID: 24919926
cardiovascular disease prevention; cardiovascular disease risk factors; cognitive impairment; cognitive tests; lifestyle
13.  Effect of duration and age at exposure to the Stroke Belt on incident stroke in adulthood 
Neurology  2013;80(18):1655-1661.
Objective:
To assess whether there are differences in the strength of association with incident stroke for specific periods of life in the Stroke Belt (SB).
Methods:
The risk of stroke was studied in 24,544 black and white stroke-free participants, aged 45+, in the Reasons for Geographic and Racial Differences in Stroke study, a national population-based cohort enrolled 2003–2007. Incident stroke was defined as first occurrence of stroke over an average 5.8 years of follow-up. Residential histories (city/state) were obtained by questionnaire. SB exposure was quantified by combinations of SB birthplace and current residence and proportion of years in SB during discrete age categories (0–12, 13–18, 19–30, 31–45, last 20 years) and entire life. Proportional hazards models were used to establish association of incident stroke with indices of exposure to SB, adjusted for demographic, socioeconomic (SES), and stroke risk factors.
Results:
In the demographic and SES models, risk of stroke was significantly associated with proportion of life in the SB and with all other exposure periods except birth, ages 31–45, and current residence. The strongest association was for the proportion of the entire life in SB. After adjustment for risk factors, the risk of stroke remained significantly associated only with proportion of residence in SB in adolescence (hazard ratio 1.17, 95% confidence interval 1.00–1.37).
Conclusions:
Childhood emerged as the most important period of vulnerability to SB residence as a predictor of future stroke. Improvement in childhood health circumstances should be considered as part of long-term health improvement strategies in the SB.
doi:10.1212/WNL.0b013e3182904d59
PMCID: PMC3716470  PMID: 23616168
14.  Monitoring futility in a two-by-two factorial design: The SPS3 experience 
Clinical trials (London, England)  2013;10(2):250-256.
Background
For studies with two-by-two factorial designs, the complexity of determining an appropriate futility analysis plan is increased as compared to studies where patients are randomized to one treatment. Issues that must be addressed include the possibility of a significant interaction and the need to determine how to proceed given evidence of futility in one arm. Suggested approaches include a two-stage plan, which first assesses futility of the interaction term and proceeds to examine the main effects, given sufficient evidence that no interaction is present, and variations on one-stage plans, which assume the trial will not be stopped for futility in the interaction.
Purpose
To discuss different approaches to monitoring futility in two-by-two factorial clinical trials and compare their properties.
Methods
We utilized a simulation study, designed to mimic the Secondary Prevention of Small Subcortical Strokes (SPS3) Study, to determine which approach to monitoring futility in two-by-two factorial studies had the most desirable statistical properties.
Results
We found that in most scenarios typical of clinical trials, monitoring futility in each arm simultaneously was superior to or as good as monitoring the interaction and then assessing futility in each arm only when the interaction was deemed futile. Monitoring each arm simultaneously lead to early stopping more often when no treatment effect was present, and lower average sample numbers (ASNs). The exception to this was the unlikely case when a qualitative interaction was present.
Limitations
We assumed that one-sided tests were to be performed, and only assessed some of the possible methods for monitoring futility under the study design.
Conclusions
Futility monitoring in two-by-two factorial studies should proceed by assessing each arm simultaneously, rather than monitoring the interaction first. If sizeable interactions are anticipated, study design, rather than study monitoring, should account for this.
doi:10.1177/1740774512474374
PMCID: PMC3731445  PMID: 23378483
15.  Heat Waves and Health Outcomes in Alabama (USA): The Importance of Heat Wave Definition 
Environmental Health Perspectives  2013;122(2):151-158.
Background: A deeper understanding of how heat wave definition affects the relationship between heat exposure and health, especially as a function of rurality, will be useful in developing effective heat wave warning systems.
Objective: We compared the relationships between different heat wave index (HI) definitions and preterm birth (PTB) and nonaccidental death (NAD) across urban and rural areas.
Methods: We used a time-stratified case-crossover design to estimate associations of PTB and NAD with heat wave days (defined using 15 HIs) relative to non–heat wave control days in Alabama, USA (1990–2010). ZIP code–level HIs were derived using data from the North American Land Data Assimilation System. Associations with heat wave days defined using different HIs were compared by bootstrapping. We also examined interactions with rurality.
Results: Associations varied depending on the HI used to define heat wave days. Heat waves defined as having at least 2 consecutive days with mean daily temperatures above the 98th percentile were associated with 32.4% (95% CI: 3.7, 69.1%) higher PTB, and heat waves defined as at least 2 consecutive days with mean daily temperatures above the 90th percentile were associated with 3.7% (95% CI: 1.1, 6.3%) higher NAD. Results suggest that significant positive associations were more common when relative—compared with absolute—HIs were used to define exposure. Both positive and negative associations were found in each rurality stratum. However, all stratum-specific significant associations were positive, and NAD associations with heat waves were consistently positive in urban strata but not in middle or rural strata.
Conclusions: Based on our findings, we conclude that a relative mean-temperature-only heat wave definition may be the most effective metric for heat wave warning systems in Alabama.
Citation: Kent ST, McClure LA, Zaitchik BF, Smith TT, Gohlke JM. 2014. Heat waves and health outcomes in Alabama (USA): the importance of heat wave definition. Environ Health Perspect 122:151–158; http://dx.doi.org/10.1289/ehp.1307262
doi:10.1289/ehp.1307262
PMCID: PMC3914868  PMID: 24273236
16.  Self-report of stroke, transient ischemic attack, or stroke symptoms and risk of future stroke in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
Background and Purpose
History of stroke and Transient Ischemic Attack (TIA) are documented risk factors for subsequent stroke and all-cause mortality. Recent reports suggest increased risk among those reporting stroke symptoms absent stroke or TIA. However, the relative magnitude of increased stroke risk has not been described across the symptomatic spectrum: 1) asymptomatic (Asx), 2) stroke symptoms only (SS), 3) TIA, 4) stroke in the distant past (DS), and 5) recent stroke (RS).
Methods
Between 2003–2007 the REasons for Geographic And Racial Differences in Stroke (REGARDS) study enrolled 30,239 black and white Americans aged 45+. DS and RS were defined as self-report of physician diagnosis of stroke >5 or <5 years before baseline, respectively. SS was defined as a history of any of six sudden onset stroke symptoms absent TIA/stroke diagnosis. Kaplan-Meier and proportional hazards analysis were used to contrast stroke risk differences.
Results
Over 5.0 ± 1.72 years of follow up, 737 strokes were validated. Compared to Asx persons, those with SS, TIA, DS and RS all had increased risk of future stroke. After adjustment for age, race, sex, income, education, alcohol intake, current smoking, and a history of diabetes, hypertension, myocardial infarction, atrial fibrillation, and dyslipidemia, there was 1.20-fold (not statistically significant) increased stroke risk for SS (95% CI 0.96, 1.51), 1.73-fold for TIA (95% CI 1.27, 2.36), 2.23-fold for DS (95% CI 1.61, 3.09) and 2.85-fold for RS (95% CI 2.16, 3.76).
Discussion
Results suggest a spectrum of risk from stroke symptoms to TIA, distant stroke, and recent stroke, and imply a need for establishing these categories in health screenings to manage risk for future stroke, reinforcing the clinical importance of stroke history including the presence of stroke symptoms.
doi:10.1161/STROKEAHA.112.675033
PMCID: PMC3558975  PMID: 23233382
stroke; TIA; stroke symptoms; mortality
17.  Short and Long-Term Sunlight Radiation and Stroke Incidence 
Annals of neurology  2012;73(1):32-37.
OBJECTIVE
Examine whether long and short-term sunlight radiation is related to stroke incidence.
METHODS
Fifteen-year residential histories merged with satellite, ground monitor, and model reanalysis data were used to determine sunlight radiation (insolation) and temperature exposure for a cohort of 16,606 stroke and coronary artery disease free black and white participants aged 45+ from the 48 contiguous United States. Fifteen, ten, five, two and one-year exposures were used to predict stroke incidence during follow-up in Cox proportional hazard models. Potential confounders and mediators were included during model-building.
RESULTS
Shorter exposure periods exhibited similar, but slightly stronger relationships than longer exposure periods. After adjustment for other covariates, the previous year’s monthly average insolation exposure below the median gave an HR=1.61 (95% CI: 1.15, 2.26) and the previous year’s highest compared to the second highest quartile of monthly average maximum temperature exposure gave an HR=1.92 (1.27, 2.92).
INTERPRETATION
These results indicate a relationship between lower levels of sunlight radiation and higher stroke incidence. The biological pathway of this relationship is not clear. Future research will show whether this finding stands, the pathway for this relationship, and if it is due to short or long-term exposures.
doi:10.1002/ana.23737
PMCID: PMC3563869  PMID: 23225379
18.  Can a school-based hand hygiene program reduce asthma exacerbations among elementary school children? 
Background
Viral upper respiratory infections have been implicated as a major cause of asthma exacerbations among school age children. Regular hand washing is the most effective method to prevent the spread of viral respiratory infections but, effective hand washing practices are difficult to establish in schools.
Objectives
This randomized controlled trial evaluated whether a standardized regimen of hand washing plus alcohol-based hand sanitizer could reduce asthma exacerbations more than schools’ usual hand hygiene practices.
Methods
This was a two year, community-based, randomized controlled crossover trial. Schools were randomized to usual care then intervention (Sequence 1) or intervention then usual care (Sequence 2). Intervention schools were provided with alcohol-based hand sanitizer, hand soap, and hand hygiene education. The primary outcome was the proportion of students experiencing an asthma exacerbation each month. Generalized estimating equations were used to model the difference in the marginal rate of exacerbations between sequences while controlling for individual demographic factors and the correlation within each student and between students within each school.
Results
527 students with asthma were enrolled among 31 schools. The hand hygiene intervention did not reduce the number of asthma exacerbations as compared to the schools’ usual hand hygiene practices (p=0.132). There was a strong temporal trend as both sequences experienced fewer exacerbations during Year 2 as compared to Year 1 (p<0.001).
Conclusions
While the intervention was not found to be effective, the results were confounded by the H1N1 influenza pandemic that resulted in substantially increased hand hygiene behaviors and resources in usual care schools. Therefore, these results should be viewed cautiously.
doi:10.1016/j.jaci.2012.08.031
PMCID: PMC3511646  PMID: 23069487
asthma; schools; children; hand hygiene; hand sanitizer
19.  Association between Family Risk of Stroke and Myocardial Infarction with Prevalent Risk Factors and Coexisting Diseases 
Background
Familial transmission of stroke and myocardial infarction (MI) is partially mediated by transmission of cerebrovascular and cardiovascular risk factors. We examined relationships between family risk of stroke and MI with risk factors for these phenotypes.
Methods
Cross-sectional association between the stratified log-rank family score (SLFS) for stroke and MI with prevalent risk factors was assessed in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort.
Results
Individuals in the 4th quartile of SLFS scores for stroke were more likely to have prevalent risk factors including hypertension (OR: 1.43; 95% CI: [1.30, 1.58]), left ventricular hypertrophy (OR 1.42; 95% CI: [1.16, 1.42]), diabetes (OR: 1.26; 95% CI: [1.12, 1.43]) and atrial fibrillation (OR 1.23; 95% CI: [1.03, 1.45]) compared to individuals in the 1st quartile. Likewise, individuals in the 4th quartile of SLFS scores for MI were more likely to have prevalent risk factors including hypertension (OR 1.57; 95% CI: [1.27, 1.94]) and diabetes (OR 1.29; 95% CI: [1.12, 1.43]) than the 1st quartile. In contrast to stroke, the family risk score for MI was associated with dyslipidemia (OR 1.38; 95% CI: [1.23, 1.55]) and overweight/obesity (OR 1.22; 95% CI: [1.10, 1.37]).
Conclusions
Family risk of stroke and MI are strongly associated with the majority of risk factors associated with each disease. Family history and genetic studies separating nonspecific contributions of intermediate phenotypes from specific contributions to the disease phenotype may lead to more thorough understanding of transmission for these complex disorders.
doi:10.1161/STROKEAHA.111.645044
PMCID: PMC3805250  PMID: 22328552
stroke; myocardial infarction; cohort studies; family risk; REGARDS
20.  Fine Particulate Matter and Incident Cognitive Impairment in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Cohort 
PLoS ONE  2013;8(9):e75001.
Studies of the effect of air pollution on cognitive health are often limited to populations living near cities that have air monitoring stations. Little is known about whether the estimates from such studies can be generalized to the U.S. population, or whether the relationship differs between urban and rural areas. To address these questions, we used a satellite-derived estimate of fine particulate matter (PM2.5) concentration to determine whether PM2.5 was associated with incident cognitive impairment in a geographically diverse, biracial US cohort of men and women (n = 20,150). A 1-year mean baseline PM2.5 concentration was estimated for each participant, and cognitive status at the most recent follow-up was assessed over the telephone using the Six-Item Screener (SIS) in a subsample that was cognitively intact at baseline. Logistic regression was used to determine whether PM2.5 was related to the odds of incident cognitive impairment. A 10 µg/m3 increase in PM2.5 concentration was not reliably associated with an increased odds of incident impairment, after adjusting for temperature, season, incident stroke, and length of follow-up [OR (95% CI): 1.26 (0.97, 1.64)]. The odds ratio was attenuated towards 1 after adding demographic covariates, behavioral factors, and known comorbidities of cognitive impairment. A 10 µg/m3 increase in PM2.5 concentration was slightly associated with incident impairment in urban areas (1.40 [1.06–1.85]), but this relationship was also attenuated after including additional covariates in the model. Evidence is lacking that the effect of PM2.5 on incident cognitive impairment is robust in a heterogeneous US cohort, even in urban areas.
doi:10.1371/journal.pone.0075001
PMCID: PMC3783452  PMID: 24086422
21.  Sample Size Re-Estimation in an On-going NIH-Sponsored Clinical Trial: The Secondary Prevention of Small Subcortical Stroke Experience 
Contemporary clinical trials  2012;33(5):1088-1093.
Background and Purpose
When planning clinical trials, decisions regarding sample size are often based on educated guesses of parameters, that may in fact prove to be over- or underestimates. For example, after initiation of the SPS3 study, published data indicated that the recurrent stroke rates might be lower than initially planned for the study. Failure to account for this could result in an under-powered study. Thus, we performed a sample size re-estimation, and describe the experience herein.
Methods
We evaluated different scenarios based on a re-estimated overall event rate, including increasing the sample size and increasing the follow-up time, to determine their impact on both Type I error and the power to detect the initially planned treatment difference.
Results
We found that by increasing the sample size from 2500 to 3000 and by following the patients for one year after the end of recruitment, we would maintain our planned Type I error rate, and increase the power to detect the prespecified clinically meaningful difference to between 67% and 87%, depending on the rate of recruitment.
Conclusions
We successfully implemented this unplanned design modification in the SPS3 study, in order to allow for sufficient power to detect the planned treatment differences.
Clinical Trials Registration Information
Clinical Trials Registration - http://clinicaltrials.gov/show/NCT00059306. Unique identifier: NCT00059306
doi:10.1016/j.cct.2012.06.007
PMCID: PMC3408857  PMID: 22750086
sample size re-estimation; SPS3; randomized clinical trial
22.  Care Seeking after Stroke Symptoms 
Annals of neurology  2008;63(4):466-472.
Objective
To assess risk factors associated with seeking care for stroke symptoms.
Methods
Using data from the population-based national cohort study (REasons for Geographic And Racial Differences in Stroke) conducted January 25, 2003–February 28, 2007 (N = 23,664), we assessed care-seeking behavior among 3,668 participants who reported a physician diagnosis of stroke/transient ischemic attack (n = 647) or stroke symptoms (n = 3,021) during follow-up. Care seeking was defined as seeking medical attention after stroke symptoms or a physician diagnosis.
Results
Overall, 58.5% of participants (2,146/3,668) sought medical care. In multivariable models, higher income was associated with greater likelihood of seeking care ( p = 0.02): participants with income of ≥$75,000 had odds 1.43 times (95% confidence interval [CI], 1.02–2.02) greater than those with income of less than $20,000. Diabetes and previous heart disease were associated with increased care seeking: odds ratio (OR) of 1.23 (95% CI, 1.04 –1.47) and OR of 1.26 (95% CI, 1.06– 1.49), respectively. Participants with previous stroke symptoms but no stroke history were less likely to seek care than those with stroke history or without previous symptoms (OR, 0.80; 95% CI, 0.67– 0.96). Past smoking was associated with lower likelihood (OR, 0.71; 95% CI, 0.59–0.85; p = 0.0003) of seeking care relative to nonsmokers.
Interpretation
Only approximately half of participants with stroke symptoms sought care. This is despite the encouragement of advocacy groups to seek prompt attention for stroke symptoms. Our results highlight the importance of identifying characteristics associated with care-seeking behavior. Recognizing factors that contribute to delays provides opportunities to enhance education on the importance of seeking care for stroke symptoms.
doi:10.1002/ana.21357
PMCID: PMC3727632  PMID: 18360830
23.  Regional Differences in Diabetes as a Possible Contributor to the Geographic Disparity in Stroke Mortality 
Background and Purpose
Diabetes and hypertension impart approximately the same increased relative risk for stroke, although hypertension has a larger population-attributable risk because of its higher population prevalence. With a growing epidemic of obesity and associated increasing prevalence of diabetes that disproportionately impacts the southeastern Stroke Belt states, any potential contribution of diabetes to the geographic disparity in stroke mortality will only increase.
Methods
Racial and geographic differences in diabetes prevalence and diabetes awareness, treatment, and control were assessed in the REasons for Geographic And Racial Differences in Stroke study, a national population-based cohort of black and white participants older than 45 years of age. At the time of this report, 21 959 had been enrolled.
Results
The odds of diabetes were significantly increased in both white and black residents of the stroke buckle (OR, 1.26; [1.10, 1.44]; OR, 1.45 [1.26, 1.66], respectively) and Stroke Belt (OR, 1.22; [1.09, 1.36]; OR, 1.13 [1.02, 1.26]) compared to the rest of the United States. In the buckle, regional differences were not fully mediated and remained significant when controlling for socioeconomic status and risk factors. Addition of hypertension to the models did not reduce the magnitude of the associations. There were no significant differences by region with regard to awareness, treatment, or control for either race.
Conclusions
These analyses support a possible role of regional variation in the prevalence of diabetes as, in part, an explanation for the regional variation in stroke mortality but fail to support the potential for a contribution of regional differences in diabetes management.
doi:10.1161/STROKEAHA.107.507053
PMCID: PMC3725822  PMID: 18388336
diabetes; geography; racial differences
24.  Association of Family History of ESRD, Prevalent Albuminuria, and Reduced GFR With Incident ESRD 
Background
The contribution of albuminuria to the increased risk of incident end-stage renal disease (ESRD) in individuals with a family history of ESRD has not been well studied.
Study Design
Prospective cohort study.
Study Setting & Participants
We analyzed data for family history of ESRD collected from 19,409 participants of the Renal REGARDS (Reasons for Geographic and Racial Differences in Stroke) cohort study.
Predictor
Family history of ESRD was ascertained by asking “Has anyone in your immediate family ever been told that he or she had kidney failure? This would be someone who is on or had been on dialysis or someone who had a kidney transplant.”
Study Outcomes
Incidence rate for ESRD.
Measurements
Morning urine albumin-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). Incident cases of ESRD were identified through the US Renal Data System.
Results
A family history of ESRD was reported by 11.1% of participants. Mean eGFRs for those with and without a family history of ESRD were 87.5 ± 22.2 (SD) and 86.5 ± 19.3 mL/min/1.73 m2, respectively (P = 0.05) and the respective geometric mean ACRs were 12.2 and 9.7 mg/g (P < 0.001). ESRD incidence rates for those with and without a family history of ESRD were 244.3 and 106.1/100,000 person-years, respectively. After adjusting for age, sex, and race, the ESRD HR for those with versus those without a family history of ESRD was 2.13 (95% CI, 1.18-3.83). Adjustment for comorbid conditions and socioeconomic status attenuated this association (HR, 1.82; 95% CI, 1.00-3.28), and further adjustment for baseline eGFR and ACR completely attenuated the association between family history of ESRD and incident ESRD (HR, 1.12; 95% CI, 0.69-1.80).
Limitations
The report of a family history of ESRD was not validated.
Conclusion
Family history of ESRD is common in older Americans and the increased risk of ESRD associated with a family history reflects lower GFR, higher albuminuria, and comorbid conditions.
doi:10.1053/j.ajkd.2011.09.018
PMCID: PMC3725825  PMID: 22078058
Race; albuminuria; end-stage renal disease; chronic kidney disease
25.  What Stroke Symptoms Tell Us: Association of Risk Factors and Individual Stroke Symptoms in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study 
Background
Stroke symptoms are common among people without a history of stroke or transient ischemic attack; however, it is unknown if particular attention should be focused on specific symptoms for subgroups of patients.
Methods
Using baseline data from 26,792 REasons for Geographic and Racial Differences in Stroke (REGARDS) participants without a history of transient ischemic attack or stroke, we assessed the association between age, sex, race, current smoking, hypertension and diabetes and the six stroke symptoms in the Questionnaire for Verifying Stroke-Free Status.
Results
The mean age of participants was 64.4 ± 9.4 years, 40.7% were black and 55.2% women. After multivariable adjustment, older persons more often reported an inability to understand (odds ratio [OR] = 1.16 per 10 years older age, 95% confidence interval [CI]: 1.07–1.25) and unilateral vision loss (OR=1.09, 95% CI: 1.01–1.18) and less often reported numbness (OR=0.83, 95% CI: 0.79–0.87) and weakness (OR=0.85, 95% CI: 0.80–0.90). Women reported difficulty communicating more often than men (OR=1.36, 95% CI: 1.19–1.56). The OR for blacks compared to whites for each of the six stroke symptoms was increased, markedly so for unilateral numbness (OR=1.97, 95% CI: 1.81–2.16), unilateral weakness (OR=1.96, 95% CI: 1.76–2.18) and inability to understand (OR=1.87, 95% CI: 1.61–2.18). Current smoking, hypertension, and diabetes were associated with higher ORs for each stroke symptom.
Conclusion
The association of risk factors with six individual stroke symptoms studied was not uniform, suggesting the need to emphasize individual stroke symptoms in stroke awareness campaigns when targeting populations defined by risk.
doi:10.1016/j.jstrokecerebrovasdis.2012.04.009
PMCID: PMC3383611  PMID: 22726606
individual stroke symptoms; stroke symptoms; risk factors

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