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1.  Secondhand Smoke Exposure and Stroke 
Stroke is a major public health concern worldwide given the associated morbidity and mortality. Smoking is a risk factor for stroke, but the relationship between secondhand smoke (SHS) exposure and stroke has been inconsistent to date. The aim of the current study was to examine the association of SHS exposure and risk of stroke and its subtypes (ischemic and hemorrhagic stroke) among nonsmokers.
Demographic and clinical characteristics were compared by SHS exposure status for black and white nonsmokers aged ≥45 years in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study in 2014. Hazard ratios (HRs) and corresponding 95% CIs were calculated by Cox proportional hazards models to assess the relationship between SHS exposure and stroke risk.
Of the 21,743 participants (38% African American, 45% male), SHS exposure in the past year was reported by 23%. Compared with those without SHS exposure, exposed participants were more likely to be female, white, younger, and reside with a smoker (all p<0.001). A total of 428 incident strokes were observed from April 2003 to March 2012 during a mean follow-up of 5.6 years. The risk of overall stroke was increased 30% among those with SHS exposure after adjustment for other stroke risk factors (95% CI=2%, 67%). This relationship appeared to be driven by ischemic strokes.
SHS exposure is independently associated with an increased risk of stroke. Future studies are needed to confirm these findings and examine the role of long-term effects of SHS exposure on stroke outcomes.
PMCID: PMC4656115  PMID: 26117341
2.  Environmental Tobacco Smoke and Atrial Fibrillation: The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study 
To examine the association between environmental tobacco smoke (ETS) exposure and atrial fibrillation.
We examined the cross-sectional association between ETS exposure and atrial fibrillation in 12,021 participants (mean age: 65 ± 9.9 years; 60% women; 40% blacks) from the REasons for Geographic And Racial Differences in Stroke study who self-identified as never smokers between 2003 and 2007.
A total of 2,503 (21%) participants reported ETS exposure. In a multivariate logistic regression model adjusted for socio-demographics and potential confounders, ETS exposure was significantly associated with atrial fibrillation (OR=1.27, 95%CI=1.08, 1.50).
Our findings suggest that the harmful effects of ETS exposure extend to sustained arrhythmias such as atrial fibrillation.
PMCID: PMC4636018  PMID: 26539762
environmental tobacco smoke; arrhythmia; epidemiology
3.  Validating laboratory results in a national observational cohort study without field centers: The Reasons for Geographic and Racial Differences in Stroke cohort 
Clinical biochemistry  2014;47(16-17):243-246.
The REasons for Geographic and Racial Differences in Stroke (REGARDS) study is a prospective cohort of 30,239 Americans in the contiguous United States; the first of this scale to use home visits to obtain, process, and ship biologic samples to a core laboratory. Pre-analytical factors resulting from this study design may affect the results of some laboratory assays. We investigated the impact of REGARDS processing on a variety of analytes.
Design and methods
In REGARDS, blood samples were processed in the field by technicians who were trained on standardized methods for phlebotomy and sample processing. Field processing included centrifugation using varying non-uniform equipment and shipping overnight on ice to the University of Vermont, where samples were re-centrifuged for 30,000 ×g-minutes and stored at −80 °C. We assessed the effects of REGARDS sample handling by processing split samples from 20 volunteers using either ideal procedures or simulated REGARDS procedures. Assays for 19 analytes for potential study in REGARDS were then run on both samples and results compared.
Spearman correlation coefficients for analytes measured in ideal versus REGARDS processed samples ranged from 0.11 to 1.0. Thirteen of 19 analytes were highly correlated (>0.75), but platelet proteins were more variable.
Simulation of non-optimal field processing and shipment to a central laboratory showed high variability in analytes released by platelets. The majority of other analytes produced valid results, but platelet contamination in REGARDS samples makes measurement of platelet proteins unadvisable in these samples. Future analytes considered by REGARDS or similar studies should undergo similar pilot testing.
PMCID: PMC5038129  PMID: 25130959
Quality control; Blood chemical analysis; Biological markers; Blood specimen collection; Cohort studies
4.  A Risk Algorithm for Assessing Short–Term Mortality for Obese Black and White Men and Women 
Obesity (Silver Spring, Md.)  2013;22(4):1142-1148.
To develop and validate a mortality risk algorithm for obese black and white men and women to elucidate risk factors prognostic of short-term mortality among obese persons.
Prospective cohort study. Reasons for geographic and racial differences in stroke (REGARDS) study, is a cohort of black and white men and women aged ≥45 years. Obese (≥30 kg m−2) participants in REGARDS (n = 11 288) were randomly assigned to the derivation data set or an independent validation set.
During the mean follow-up period of 4.9 years, 8.9% (n = 504) in the derivation cohort and 8.7% (n = 492) in the validation cohort died. The best-fitting model based on data from the derivation cohort included demographic (age, sex), coronary heart disease (CHD) conditions (diabetes, systolic blood pressure, history of CHD), health behaviors (smoking, physical activity, alcohol use), and socioeconomic variables (income, use of physician services). The C-statistic when the model was applied to the validation cohort was 0.80. Observed and predicted rates of mortality were similar across deciles of mortality risk by race.
A risk algorithm was established and validated to predict mortality among black and white obese subjects based on CHD risk factors, behavioral risk factors, and socioeconomic status.
PMCID: PMC5036400  PMID: 24115735
5.  Recurrent vascular events in lacunar stroke patients with metabolic syndrome and/or diabetes 
Neurology  2015;85(11):935-941.
We used a prospective clinical trial to examine the risks conferred by metabolic syndrome (METS) and diabetes mellitus (DM) to recurrent strokes in the Secondary Prevention of Small Subcortical Strokes (SPS3) study cohort.
The SPS3 trial enrolled 3,020 patients with lacunar strokes. Participants were stratified into groups of METS only, DM only, both, or neither using American Heart Association/National Heart, Lung, and Blood Institute and World Health Organization guidelines. Annualized event rates of strokes, myocardial infarction (MI), and all-cause mortality were calculated, and hazard ratios (HRs) referencing the “neither” group were computed, controlling for significantly associated baseline characteristics.
Among 2,999 participants, 25% had METS only, 6% had DM only, 32% had both conditions, and 37% had neither. Over a median of 3.8 years of follow-up, there were 274 recurrent strokes (240 ischemic, 34 hemorrhagic) and 74 MIs; among the 240 ischemic strokes, 134 (56%) were lacunar. The rates of any recurrent stroke (HR 1.7, 95% confidence interval [CI] 1.3–2.3) or lacunar stroke (HR 2.4, 95% CI 1.5–3.7) were significantly higher for those with concurrent METS and DM compared with those who had neither. Risk of incident MI was higher in participants with DM (HR 2.8, 95% CI 1.1–7.0) or concurrent DM and METS (HR 2.6, 95% CI 1.4–4.9).
METS and DM were significant comorbid conditions in lacunar stroke patients and they were associated with stroke recurrence. In patients with lacunar infarcts, a vigilant approach to prevent development of DM in those with METS may be a potential strategy to reduce recurrent strokes.
PMCID: PMC4567462  PMID: 26296518
7.  ABO Blood Type and Stroke Risk: The REasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
ABO blood type is an inherited trait associated with coagulation factor levels and vascular outcomes.
To assess the association of blood type with stroke and whether blood type contributes to racial disparities in stroke in the United States.
Patients and Methods
The REasons for Geographic and Racial Differences in Stroke (REGARDS) Study recruited 30,239 participants between 2003-07. Using a case-cohort design, blood type was genotyped in 646 participants with stroke and a 1,104 participant cohort random sample. Cox models adjusting for Framingham stroke risk factors assessed the association of blood type with stroke.
Over 5.8 years of follow-up, blood types A or B versus type O were not associated with stroke. Blood type AB versus O was associated with an increased risk of stroke (adjusted HR 1.83; 95% CI 1.01, 3.30). The association of blood type AB versus O was greater in those without diabetes (adjusted HR 3.33; 95% CI 1.61, 6.88) than those with diabetes (adjusted HR 0.49; 95% CI 0.17, 1.44) (p-interaction = 0.02). Factor VIII levels accounted for 60% (95% CI 11%, 98%) of the association of AB blood type and stroke risk.
Blood type AB is associated with an increased risk of stroke that is not attenuated by conventional stroke risk factors and factor VIII levels were associated with 60% of the association. While blood type AB is rare in the U.S. population, it is a significant stroke risk factor and may play an important role in stroke risk in these individuals.
PMCID: PMC4913462  PMID: 24444093
ABO Blood-Group System; Continental Population Groups; Risk Factors; Factor VIII; Stroke
8.  Cognitive performance following lacunar stroke in Spanish-speaking patients: Results from the SPS3 trial 
Cognitive impairment is frequent in lacunar stroke patients. The prevalence and pattern of among Spanish-speaking patients (SSP) are unknown and have not been compared across regions or to English-speaking patients (ESP).
To characterize cognitive impairment in SSP and compare to ESP.
The baseline neuropsychological test (NPT) performance and the prevalence of mild cognitive impairment (MCI), defined as a z score ≤ −1.5 on memory and/or non-memory tests, were evaluated in SSP in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial.
Out of 3020 participants, 1,177 were SSP residing in Latin America (n=693), the US (n=121) and Spain (n=363). Low education (0-8 years) was frequent in SSP (49-57%). Latin American SSP had frequent post-stroke upper extremity motor impairment (83%). Compared to ESP, all SSP groups had smaller memory deficits and larger non-memory/motor deficits, with Latin American SSP showing the largest deficits (median z-score 0.6 to −1.3 for non-memory tests; ≥ −5.0 grooved pegboard; −0.4 to −0.7 memory tests). The prevalence of MCI was high and comparable to ESP in the US and Latin American SSP but not Spanish group: ESP=47%, Latin American SSP=51%, US SSP=40%, Spanish SSP=29%, with >50% characterized as non-amnestic in SSP groups. Older age (OR per 10-y =1.52, CI=1.35-1.71), lower education (OR 0-4-y=1.23, CI=0.90-1.67), being a Latin American resident (OR=1.31, CI=0.87-1.98), and post-stroke disability (OR Barthel Index<95=1.89, CI-1.43-2.50) were independently associated with MCI.
Mild cognitive impairment in SPS3 Spanish-speaking patients with recent lacunar stroke is highly prevalent but has a different pattern to that observed in English-speaking patients. A combination of socio-demographics, stroke biology, and stroke care may account for these differences.
PMCID: PMC4435833  PMID: 25973704
cognitive impairment; cognitive function; lacunar stroke; Spanish-speaking; Hispanic
9.  Geographic Region and Racial Variations in Polypharmacy in the United States 
Annals of epidemiology  2015;25(6):433-438.e1.
Medications can have unintended effects. High medication use populations may benefit from increased regimen oversight. Limited knowledge exists concerning racial and regional polypharmacy variation. We estimated total medication distributions (excluding supplements) of American black and white adults and assessed racial and regional polypharmacy variation.
REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort data (N=30,239 U.S. blacks/whites ages ≥45 years) were analyzed. Home pill-bottle inspections assessed the last two weeks’ medications. Polypharmacy (≥ 8 medications) was determined by summing prescription and/or OTC ingredients. Population-weighted logistic regression assessed polypharmacy’s association with census region, race, and gender.
The mean ingredient number was 4.12 (SE = 0.039), with 15.7% of REGARDS using ≥8 ingredients. In crude comparisons, women used more medications than men, and blacks and whites reported similar mean ingredients. A cross-sectional, logistic model adjusting for demographics, socioeconomics, and comorbidities showed increased polypharmacy prevalence in whites vs. blacks (OR, [95% CI]: 0.63, [0.55–0.72]), women (1.94, [1.68–2.23]), and Southerners {broadly Southeasterners and Texans} (1.48, [1.17–1.87]) vs. Northeasterners {broadly New England and upper Mid-Atlantic}. Possible limitations include polypharmacy misclassification and model mis-specification.
Polypharmacy is common. Race and geography are associated with polypharmacy variation. Further study of underlying factors explaining these differences is warranted.
PMCID: PMC4437208  PMID: 25908300
pharmacoepidemiology; medications; REGARDS; polypharmacy; geographic variations; and race
10.  Should Blood Pressure Targets After Lacunar Stroke Vary by Body Size? The SPS3 Trial 
American Journal of Hypertension  2014;28(6):756-764.
It is unknown whether the physiological impact of a given blood pressure (BP) varies by body size. We explored interactions between higher vs. lower systolic BP (SBP) targets and anthropometric measures (body mass index (BMI), body surface area (BSA), height, weight) and recurrent stroke and death in the Secondary Prevention of Small Subcortical Strokes (SPS3) Trial.
Patients with recent magnetic resonance imaging-proven lacunar infarcts were randomized to 2 BP targets (130–149mm Hg vs. <130) in a prospective, open-label, blinded end-point design. Time to outcome was evaluated with Cox proportional hazard models and compared between targets. We examined multiplicative interactions between each anthropometric measure and target and mean difference in achieved BP 1 year after randomization between BP groups by quartile. We also computed rates of recurrent stroke and death by quartiles of anthropometrics.
Three thousand and twenty patients were followed over a mean of 3.7 (SD 2.0) years. Mean age was 63; 63% were male. Mean height was 167 (SD 11) cm, weight 81 (18) kg, BMI 29 (5.9) kg/m2, and BSA 1.9 (0.25) m2. Achieved BP at 1 year was comparable between quartiles for each anthropometric measurement. We found no consistent interactions between BP target and anthropometrics for either outcome, nor were there any significant associations between hazard of stroke or death when assessed by BMI, BSA, height, or weight.
We found no interactions between BP target groups and quartiles of anthropometrics for rates of stroke and death in SPS3. There is no evidence at this time supporting body size-based modifications to current BP targets for secondary prevention after lacunar stroke.
Trial Number NCT00059306
PMCID: PMC4447819  PMID: 25452300
blood pressure; BMI; body size; BSA; height; hypertension; lacunar stroke; prognosis; secondary prevention; weight.
11.  Correlates of Incident Cognitive Impairment in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
The Clinical neuropsychologist  2015;29(4):466-486.
To identify approximately 500 cases of incident cognitive impairment (ICI) in a large, national sample adapting an existing cognitive test-based case definition and to examine relationships of vascular risk factors with ICI.
Participants were from the REGARDS study, a national sample of 30,239 African-American and white Americans. Participants included in this analysis had normal cognitive screening and no history of stroke at baseline, and at least one follow-up cognitive assessment with a three test battery (TTB). Regression-based norms were applied to TTB scores to identify cases of ICI. Logistic regression was used to model associations with baseline vascular risk factors.
We identified 495 participants with ICI out of 17,630 eligible participants. In multivariable modeling, income (OR 1.83 CI 1.27,2.62), stroke belt residence (OR 1.45 CI 1.18,1.78), history of transient ischemic attack (OR 1.90 CI 1.29,2.81), coronary artery disease(OR 1.32 CI 1.02,1.70), diabetes (OR 1.48 CI 1.17,1.87), obesity (OR 1.40 CI 1.05,1.86), and incident stroke (OR 2.73 CI 1.52,4.90) were associated with ICI.
We adapted a previously validated cognitive test-based case definition to identify cases of ICI. Many previously identified risk factors were associated with ICI, supporting the criterion-related validity of our definition.
PMCID: PMC4504009  PMID: 25978342
epidemiology; risk factors; methods; cognitive disorders; mild cognitive impairment; cognitive aging; stroke
12.  Long-term disability after lacunar stroke 
Neurology  2015;84(10):1002-1008.
To determine whether vascular and demographic factors predict worsening disability up to 8 years after lacunar stroke.
SPS3 (Secondary Prevention of Small Subcortical Strokes) was a clinical trial in lacunar stroke patients with annual assessment of disability using the Older Americans Resources and Survey instrumental activities of daily living (IADL) scale (range 0–14). Generalized estimating equations modeled the likelihood of disability (IADL <14) over time, adjusting for demographics, medical risk factors, cognition, mood, stroke location, and geographic region in univariate and multivariable models. IADL assessments after recurrent stroke were censored. We stratified by study region and age quartile.
Among 2,820 participants, mean age was 63.4 years (SD 10.8), 63% were male, 36% had diabetes, 90% hypertension, and 10% prior stroke. Mean follow-up was 3.7 years. In multivariable models, female sex, education, diabetes, nonregular alcohol use, prior stroke, Cognitive Abilities Screening Instrument score, depression, mild cognitive impairment, and stroke location were associated with disability. The youngest age quartile had decreased odds of disability over time (odds ratio 0.90 per year, 95% confidence interval 0.85–0.95), whereas the oldest age quartile had increased odds (2.20, 95% confidence interval 1.75–2.75). Americans and Latin Americans had >2-fold greater odds of disability per year compared with Spaniards (p < 0.0001).
In lacunar stroke patients, older age was associated with worsening long-term disability, even without recurrence. Worse long-term function was associated with diabetes, cognitive status, and prior stroke, and regional differences may be attributable to variations in health care delivery or scale interpretation.
PMCID: PMC4352098  PMID: 25663222
13.  Evaluating a Website to Teach Children Safety with Dogs 
Pediatric dog bites are a significant public health problem worldwide. Existing prevention programs focused on altering children’s risky behavior with pet dogs tend to be atheoretical and only moderately effective.
Test efficacy of a website to train young children in relevant cognitive skills to be safe with pet dogs in their home.
Birmingham, Alabama, USA.
A randomized trial will be conducted with an expected sample of two groups of 34 children ages 4-6 (total N = 68). One group will engage in the newly-designed website at home for two weeks and the other group will engage in a control website on transportation safety for an equivalent amount of time. All participants will complete a battery of laboratory-based tests to assess safety with dogs and cognitive functioning both at baseline and post-intervention.
Outcome Measures
Primary analyses will be conducted through linear mixed models testing change over time. Children’s cognitive functioning, knowledge about safety with dogs, and behavior with dogs in simulation and in vivo will serve as the primary outcomes.
Clinical Trial Registration
This study is exempt from registry at the US government website,, based on being a behavioral trial in the early phases of testing.
PMCID: PMC4250438  PMID: 24871960
dogs; dog bite; safety; injury; children; website; internet training
15.  Measuring personal heat exposure in an urban and rural environment 
Environmental research  2015;137:410-418.
Previous studies have linked heat waves to adverse health outcomes using ambient temperature as a proxy for estimating exposure. The goal of the present study was to test a method for determining personal heat exposure. An occupationally exposed group (urban groundskeepers in Birmingham, AL, USA N=21), as well as urban and rural community members from Birmingham, AL (N=30) or west central AL (N=30) wore data logging temperature and light monitors clipped to the shoe for 7 days during the summer of 2012. We found that a temperature monitor clipped to the shoe provided a comfortable and feasible method for recording personal heat exposure. Ambient temperature (°C) recorded at the nearest weather station was significantly associated with personal heat exposure [β 0.37, 95%CI (0.35, 0.39)], particularly in groundskeepers who spent more of their total time outdoors [β 0.42, 95%CI (0.39, 0.46)]. Factors significantly associated with lower personal heat exposure include reported time indoors [β −2.02, 95%CI (−2.15, −1.89)], reported income > 20K [β −1.05, 95%CI (−1.79, −0.30)], and measured % body fat [β −0.07, 95%CI (−0.12, −0.02)]. There were significant associations between income and % body fat with lower indoor and nighttime exposures, but not with outdoor heat exposure, suggesting modifications of the home thermal environment play an important role in determining overall heat exposure. Further delineation of the effect of personal characteristics on heat exposure may help to develop targeted strategies for preventing heat-related illness.
PMCID: PMC4355189  PMID: 25617601
personal exposure; outdoor versus indoor exposure; sunlight exposure; heat exposure; occupational heat exposure
16.  Dietary patterns are associated with cognitive function in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort 
Identifying factors that contribute to the preservation of cognitive function is imperative to maintaining quality of life in advanced years. Of modifiable risk factors, diet quality has emerged as a promising candidate to make an impact on cognition. The objective of this study was to evaluate associations between empirically derived dietary patterns and cognitive function. This study included 18 080 black and white participants aged 45 years and older from the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. Principal component analysis on data from the Block98 FFQ yielded five dietary patterns: convenience, plant-based, sweets/fats, Southern, and alcohol/salads. Incident cognitive impairment was defined as shifting from intact cognitive status (score >4) at first assessment to impaired cognitive status (score ≤4) at latest assessment, measured by the Six-Item Screener. Learning, memory and executive function were evaluated with the Word List Learning, Word List Delayed Recall, and animal fluency assessments. In fully adjusted models, greater consumption of the alcohol/salads pattern was associated with lower odds of incident cognitive impairment (highest quintile (Q5) v. lowest quintile (Q1): OR 0·68; 95 % CI 0·56, 0·84; P for trend 0·0005). Greater consumption of the alcohol/salads pattern was associated with higher scores on all domain-specific assessments and greater consumption of the plant-based pattern was associated with higher scores in learning and memory. Greater consumption of the Southern pattern was associated with lower scores on each domain-specific assessment (all P < 0·05). In conclusion, dietary patterns including plant-based foods and alcohol intake were associated with higher cognitive scores, and a pattern including fried food and processed meat typical of a Southern diet was associated with lower scores.
PMCID: PMC5048188  PMID: 27752305
Dietary patterns; Cognition; Nutrition; Cognitive function; AFT, Animal Fluency Test; Block98 FFQ, Block98 food frequency questionnaire; Q1, lowest quintile; Q5, highest quintile; PCA, principal component analysis; REGARDS, REasons for Geographic And Racial Differences in Stroke; SIS, Six-Item Screener; WLDR, Word List Delayed Recall; WLL, Word List Learning
17.  Effects of long-term blood pressure lowering and dual antiplatelet therapy on cognition in patients with recent lacunar stroke: Secondary Prevention of Small Subcortical Strokes (SPS3) trial The SPS3 Investigators* 
The Lancet. Neurology  2014;13(12):1177-1185.
The primary outcome results for the Secondary Prevention of Small Subcortical Strokes (SPS3) trial suggested that a lower target blood pressure may be beneficial (19% nonsignificant reduction) for reducing risk of recurrent stroke but that addition of clopidogrel to aspirinwas not. Whether blood pressure (BP) reduction and dual antiplatelet therapy affectchanges in cognition over time in patients with cerebral small vessel disease is unclear.
Pre-specified secondary endpoint analyses of the SPS3 trial involving 3020 patients, mean age 63 years, with recent symptomatic lacunar infarcts randomized 1:1 to two target levels of systolic BP (130-149 mm Hg vs. <130 mm Hg, open-label) and 1:1 to aonce-dailyantiplatelet therapy (75 mg clopidogrel plus 325 mg aspirin vs. 325 mg aspirin alone, double-blind) during 2003-2011 at 81 centers. The primary cognitive outcome was change in Cognitive Abilities Screening Instrument (CASI) during follow-up. Patients were tested annually (median 3 years of follow-up, maximum5)during which the mean difference in systolic BP averaged 11 mmHg between the two target (138 mm Hg vs 127 mm Hg at 1 year). This study is registered with, number NCT 00059306.
The 2916 participants with CASI scores at study entry are included in the analysis.Mean (SD) changes in CASI z-scores from study entry to assessment at years1 (n=2699), 2 (n=2251), 3 (n=1785), 4( n=1134) and 5 (n=803) were 0.11 (0.84), 0.15 (0.85), 0.15 (0.97), 0.19 (1.0), and 0.16 (1.2), respectively. Changes in CASI z-scores over time did not differ between assigned antiplatelet groups (p=0.9) or between assigned blood pressure control groups (p=0.5).There was no interaction between assigned antiplatelet groups and assigned blood pressure control groups and change over time. (p=0.2)
Cognitivefunctionis not influenced by short-term treatment with dual antiplatelet therapy or blood pressure reduction in relatively young patients with recent lacunar stroke. Future studies of the effects of blood pressure reduction on cognition should focus on patients with higher rates of cognitive decline.
PMCID: PMC4284947  PMID: 25453457
18.  Inflammation Markers and Incident Venous Thromboembolism: the REasons for Geographic And Racial Differences in Stroke (REGARDS) Cohort 
Inflammation biomarkers are associated with the venous thromboembolism (VTE) risk factors obesity and age, however the relationships of inflammation with VTE risk remain controversial.
To examine associations of four inflammation biomarkers, C-reactive protein (CRP), serum albumin, white blood cell count (WBC), and platelet count (PLTC), with incident VTE, and determine whether they mediate the association of age or obesity with VTE.
Hazards models adjusted for VTE risk factors were used to calculate prospective associations of each biomarker with incident VTE in 30,239 participants of the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Mediation of the associations of obesity and age with VTE were examined by bootstrapping. Over 4.6 years, there were 268 incident VTE events. Adjusting for VTE risk factors, the hazard ratio (HR) (95% confidence interval (CI)) was 1.25 (1.09, 1.43) per standard deviation (SD) higher log-CRP and 1.25 (1.06, 1.48) per SD lower albumin, with no associations for WBC or PLTC. The association of BMI, but not age, with VTE was partially mediated by CRP and albumin. In risk factor-adjusted models, the percent attenuation of the BMI HR for VTE by introducing CRP or albumin to the models was 15.4% (95% CI: 7.7%, 33.3%) and 41.0% (95% CI: 12.8%, 79.5%), respectively.
Higher CRP and lower serum albumin were associated with increased VTE risk, and statistically mediated part of the association of BMI with VTE. These data suggest inflammation may be a potential mechanism underlying the relationship of obesity and VTE risk.
PMCID: PMC4643856  PMID: 25292154
Biomarkers; C-reactive protein; Inflammation; Serum albumin; Venous Thromboembolism
19.  Dichotomizing partial compliance and increased participant burden in factorial designs: the performance of four noncompliance methods 
Trials  2015;16:523.
Noncompliance to treatment assignment is an inevitable occurrence in randomized clinical trials (RCTs). Intention to treat (ITT) is generally considered the best method for addressing noncompliance in RCTs. Alternatives to ITT exist, including per protocol (PP), as treated (AT), and instrumental variables (IV). These three methods define participant compliance dichotomously, but partial compliance is a common occurrence in RCTs. By defining a threshold, above which a participant is called a complier, PP, AT and IV can be used, but the resulting loss of information may affect their performance. Trials with factorial designs may experience higher rates of noncompliance due to the heavier burden that participants experience by being assigned to multiple experimental treatments.
Using simulations, we assessed the performance of ITT, PP, AT, and IV in both the partial compliance setting and in a 2-by-2 factorial design with increased participant burden for those randomized to both active treatments.
The bias, mean squared error, and type I error rates of the IV method after dichotomizing partial compliance were heavily inflated. The performance of all four methods depended on the level of noncompliance present, with higher average noncompliance leading to poorer performance. PP and AT showed improved bias and power relative to ITT without inflating the type I error beyond acceptable limits. However, the PP and AT heavily inflated the type I error rates when participant compliance was affected by the participants’ general health.
There are consequences for dichotomizing compliance information to make it fit into well-known methods. The results suggest the need for a method of estimating treatment effects that can utilize partial compliance information.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-1044-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4647702  PMID: 26573840
20.  Clinical Correlates of Infarct Shape and Volume in Lacunar Strokes The SPS3 Trial 
Background and Purpose
Infarct size and location are thought to correlate with different mechanisms of lacunar infarcts. We examined the relationship between the size and shape of lacunar infarcts and vascular risk factors and outcomes.
We studied 1679 participants in the Secondary Prevention of Small Subcortical Stroke trial with a lacunar infarct visualized on DWI. Infarct volume was measured planimetrically, and shape was classified based on visual analysis after 3D reconstruction of axial MRI slices.
Infarct shape was ovoid/spheroid in 63%, slab 12%, stick 7%, and multi- component 17%. Median infarct volume was smallest in ovoid/spheroid relative to other shapes: 0.46, 0.65, 0.54, and 0.90 ml respectively, p< 0.001. Distributions of vascular risk factors were similar across the four groups except that patients in the ovoid/spheroid and stick groups were more often diabetic and those with multi-component had significantly higher blood pressure at study entry. Intracranial stenosis did not differ among groups (p=0.2). Infarct volume was not associated with vascular risk factors. Increased volume was associated with worse functional status at baseline and 3 months. Overall, 162 recurrent strokes occurred over an average of 3.4 years of follow-up with no difference in recurrent ischemic stroke rate by shape or volume.
In patients with recent lacunar stroke, vascular risk factor profile was similar amongst the different infarct shapes and sizes. Infarct size correlated with worse short- term functional outcome. Neither shape nor volume was predictive of stroke recurrence.
PMCID: PMC4198938  PMID: 25190442
Small subcortical infarcts; Lacunar infarcts; Infarct shape; Infarct size; Diffusion weighted imaging; Lacunar stroke
21.  ABO blood type, factor VIII, and incident cognitive impairment in the REGARDS cohort 
Neurology  2014;83(14):1271-1276.
To assess the relationships among ABO group, factor VIII (FVIII), and incident cognitive impairment in a large, prospective cohort study of black and white adults in the United States using a nested case-control design.
Incident cognitive impairment was defined using cognitive domain tests over a mean follow-up of 3.4 years. ABO blood group was measured by genotyping in a nested case-control sample of 495 cases with cognitive impairment and 587 controls.
Those with blood group AB and those with higher FVIII had an increased risk of cognitive impairment, adjusting for age, race, region, and sex (respective odds ratios 1.82, 95% confidence interval [CI] 1.15–2.90; and 1.24, 95% CI 1.10–1.38 for 40 IU/dL higher FVIII). Mean FVIII was higher in those with blood type AB (142 IU/dL; 95% CI 119–165) compared with O (104 IU/dL; 95% CI 101–107), and FVIII mediated 18% of the association between AB group and incident cognitive impairment (95% CI for mediation −30% to 68%).
Blood group AB and higher FVIII were associated with increased incidence of cognitive impairment in this prospective study. The association of blood group AB with incident cognitive impairment was not significantly mediated by FVIII levels.
PMCID: PMC4180487  PMID: 25209581
22.  Children's Pedestrian Route Selection: Efficacy of a Video and Internet Training Protocol 
This randomized controlled trial examined one aspect of child pedestrian behavior, route selection across intersections, to evaluate whether a combination of widely-available videos and websites effectively train children in safe pedestrian route selection compared to active pedestrian safety control training and a no-contact control group.
A sample of 231 seven- and eight-year-olds were randomly assigned to one of four groups: training with videos and internet websites, active control groups of individualized streetside training or training within a virtual pedestrian environment, or a no-contact control group. All training groups received six 30-minute training sessions. Pedestrian route selection was assessed using two strategies, vignettes accompanied by illustrations and tabletop models of intersections, on three occasions: prior to intervention group assignment, immediately post-training, and six months after training.
Although there were differences in route selection over time, no time by condition interaction effects were significant (ps > .05), suggesting children in the video/internet training group did not learn pedestrian route selection skills at a rate different from those in the other training groups or those in the no-contact control group.
Safe route selection is a critical component of pedestrian safety. Our results suggest children may not learn route selection from widely-available videos or websites. Explanations for the null finding and implications for both research and future practice are discussed.
PMCID: PMC4142561  PMID: 25170289
pedestrian; route selection; injury; safety; randomized controlled trial
23.  Lacunar strokes in patients with diabetes: Risk factors, infarct location, and prognosis: The SPS3 Study 
Background and Purpose
Diabetes is an independent risk factor for lacunar strokes. Few data are available regarding patient features, infarct location, and recurrent vascular events for diabetic patients with lacunar stroke.
We compared features at study entry and prognosis during 3.6 years of follow-up of diabetic vs. non-diabetic patients with recent lacunar stroke participating in the Secondary Prevention of Small Subcortical Strokes (SPS3) randomized trial.
Among the 3020 participants, the prevalence of diabetes was 37% with a mean duration of 11 years. Diabetes was independently associated with slightly younger age (63 years vs. 64 years, p<0·001), Hispanic ethnicity (36% vs. 28%, p<0·0001), ischemic heart disease (11% vs. 6%, p=0·002), and peripheral vascular disease (5% vs. 2%, p<0·001). Diabetic patients more frequently had intracranial stenosis ≥50% (p<0·001), infarcts involving the brainstem or cerebellum (p<0·001), and more extensive white matter abnormalities (p<0·001). Diabetic patients were almost twice as likely to have a recurrent stroke (HR 1·8; 95% CI 1·4–2·3), recurrent ischemic stroke (HR 1·8; 95% CI 1·4–2·4), disabling/fatal stroke (HR 1·8; 95% CI 1·2–2·9), myocardial infarction (HR 1·7; 95% CI 1·0–2·8) and death (HR 2·1 (95% CI 1·6–2·8) compared with non-diabetics.
Diabetic patients with lacunar stroke have a distinctive clinical profile that includes double the prevalence of systemic and intracranial atherosclerosis, preferential involvement of the posterior circulation, and a poor prognosis for recurrent stroke and death.
PMCID: PMC4146755  PMID: 25034716
stroke; diabetes; lacunar stroke; small artery disease
24.  Teaching Children to Cross Streets Safely: A Randomized Controlled Trial 
Child pedestrian injury is a global public health challenge. This randomized controlled trial considered comparative efficacy of individualized streetside training, training in a virtual pedestrian environment, training using videos and websites, plus no-training control, to improve children’s street-crossing ability.
Pedestrian safety was evaluated among 231 seven- and eight-year-olds using both streetside (field) and laboratory-based (virtual environment) trials prior to intervention group assignment, immediately post-training, and six months post-training. All training groups received six 30-minute sessions. Four outcomes assessed pedestrian safety: start delay (temporal lag before initiating crossing), hits/close calls (collisions/near-misses with vehicles in simulated crossings), attention to traffic (looks left and right, controlled for time), and missed opportunities (safe crossing opportunities that were missed).
Results showed training in the virtual pedestrian environment and especially individualized streetside training resulted in safer pedestrian behavior post-intervention and at follow-up. As examples, children trained streetside entered safe traffic gaps more quickly post-training than control group children and children trained streetside or in the virtual environment had somewhat fewer hits/close calls in post-intervention VR trials. Children showed minimal change in attention to traffic post-training. Children trained with videos/websites showed minimal learning.
Both individualized streetside training and training within virtual pedestrian environments may improve 7- and 8-year-olds’ street-crossing safety. Individualized training has limitations of adult time and labor. Virtual environment training has limitations of accessibility and cost. Given the public health burden of child pedestrian injuries, future research should explore innovative strategies for effective training that can be broadly disseminated.
PMCID: PMC4101996  PMID: 24447187
pedestrian; street-crossing; injury; safety; randomized controlled trial
25.  Performance of the NINDS-CSN 5-Minute Protocol in a National Population-Based Sample 
In 2006, the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network (NINDS-CSN) Vascular Cognitive Impairment Harmonization Standards recommended a 5-Minute Protocol as a brief screening instrument for vascular cognitive impairment (VCI). We report demographically adjusted norms for the 5-Minute Protocol and its relation to other measures of cognitive function and cerebrovascular risk factors.
Cross-sectional analysis of 7,199 stroke-free adults in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study on the NINDS-CSN 5-Minute Protocol score.
Total scores on the 5-Minute Protocol were inversely correlated with age and positively correlated with years of education, and performance on the Six-Item Screener, Word List Learning, and Animal Fluency (all p-values<0.001). Higher cerebrovascular risk on the Framingham Stroke Risk Profile (FSRP) was associated with lower total 5-Minute Protocol scores (p<0.001). The 5-Minute Protocol also differentiated between participants with and without confirmed stroke and with and without stroke symptom histories (p<0.001).
The NINDS-CSN 5-Minute Protocol is a brief, easily administered screening measure that is sensitive to cerebrovascular risk and offers a valid method of screening for cognitive impairment in populations at risk for VCI.
PMCID: PMC4452126  PMID: 25166350
screening; cerebrovascular disorders; epidemiology; memory; semantic fluency; depression

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