Search

Background and Purpose: The purpose of this study was to replicate the top loci associated with white matter hyperintensity (WMH) phenotypes identified by large genome-wide association studies and the loci identified from the previous candidate gene studies. Methods: A total of 946 Geisinger MyCode patients with acute ischemic stroke with validated European ancestry and magnetic resonance imaging data were included in this study. Log-transformed WMH volume, as a quantitative trait, was calculated by a fully automated quantification process. The genome-wide association studies was carried out by a linear mixed regression model (GEMMA). A candidate-single nucleotide polymorphism analysis by including known single nucleotide polymorphisms, reported from a meta-analysis and several large GWAS for WMH, was conducted in all cases and binary converted extreme cases. Results: No genome-wide significantly associated variants were identified. In a candidate-single nucleotide polymorphism study, rs9515201 ( COL4A2 ) and rs3744028 ( TRIM65 ), 2 known genetic loci, showed nominal or trend of association with the WMH volume (β=0.13 and P =0.001 for rs9515201; β=0.094 and P =0.094 for rs3744028), and replicated in a subset of extreme cases versus controls (odds ratio=1.78, P =7.74×10 − 4 for rs9515201; odds ratio=1.53, P =0.047 for rs3744028, respectively). MTHFR677 cytosine/thymine (rs1801133) also showed an association with the binary WMH with odds ratio=1.47 for T allele ( P =0.019). Conclusions: Replication of COL4A1/2 associated with WMH reassures that the genetic risk factors for monogenic and polygenic ischemic stroke are shared at gene level.

We aim to determine whether ischemic stroke(IS)-related PRSs are also associated with and further predict 3-year all-cause mortality. 1756 IS patients with European ancestry were randomly split into training (n = 1226) and testing (n = 530) groups with 3-year post-event observations. Univariate Cox proportional hazards regression model (CoxPH) was used for primary screening of individual prognostic PRSs. Only the significantly associated PRSs and clinical risk factors with the same direction for a causal relationship with IS were used to construct a multivariate CoxPH. Feature selection was conducted by the LASSO method. After feature selection, a prediction model with 11 disease-associated pathway-specific PRSs outperformed the base model, as demonstrated by a higher concordance index (0.751, 95%CI [0.693–0.809] versus 0.729, 95%CI [0.676–0.782]) in the testing sample. A PRS derived from endothelial cell apoptosis showed independent predictability in the multivariate CoxPH (Hazard Ratio = 1.193 [1.027–1.385], p = 0.021). These PRSs fine-tuned the model by better stratifying high, intermediate, and low-risk groups. Several pathway-specific PRSs were associated with clinical risk factors in an age-dependent manner and further confirmed some known etiologies of IS and all-cause mortality. In conclusion, Pathway-specific PRSs for IS are associated with all-cause mortality, and the integrated multivariate risk model provides prognostic value in this context.

Introduction: The rise of ischemic stroke among young adults has stressed the need to understand their risk profiles and outcomes better. This study aimed to examine the five-year ischemic stroke recurrence and survival probability among young patients in rural Pennsylvania. Methods: This retrospective cohort study included first-time ischemic stroke patients from the Geisinger Health System between September 2003 and May 2014. The outcomes included all-cause mortality and ischemic stroke recurrence at five years. Kaplan-Meier estimator, cumulative incidence function, Cox proportional hazards model, and Cause-specific hazard model were used to examine the association of independent variables with the outcomes. Results: A total of 4459 first-time ischemic stroke patients were included in the study, with 664 (14.9%) patients in the 18–55 age group and 3795 (85.1%) patients in the >55 age group. In the 18–55 age group, the five-year survival probability was 87.2%, and the cumulative incidence of recurrence was 8%. Patients in the 18–55 age group had significantly lower hazard for all-cause mortality (HR = 0.37, 95% CI 0.29–0.46, p < 0.001), and non-significant hazard for five-year recurrence (HR = 0.81, 95% CI 0.58–1.12, p = 0.193) compared to the >55 age group. Chronic kidney disease was found to be associated with increased mortality in the 18–55 age group. Conclusion: In our rural population, younger ischemic stroke patients were at the same risk of long-term ischemic stroke recurrence as the older ischemic stroke patients. Identifying the factors and optimizing adequate long-term secondary prevention may reduce the risk of poor outcomes among younger ischemic stroke patients.

Long-term mortality in ischemic stroke patients with concomitant COPD has been largely unexplored. This study aimed to compare long-term all-cause mortality in ischemic stroke patients with and without COPD.This was a retrospective cohort study of ischemic stroke patients with and without COPD in the Geisinger Neuroscience Ischemic Stroke database to examine all-cause mortality up to 3 years using Kaplan-Meier estimator and Cox proportional hazards model.Of the 6,589 ischemic stroke patients included in this study, 5,525 (83.9%) did not have COPD (group A). Group B (n=1,006) consisted of patients with COPD diagnosis by ICD-9/10-CM codes. COPD patients in Group C (n=233) were diagnosed by spirometry, and in Group D (n=175) by both ICD-9/10-CM codes and spirometry confirmation. The survival probabilities at three years in Group B, C, and D were significantly lower than in Group A. Group B (HR=1.262, 95% CI 1.122-1.42, p0.001) and group C (HR=1.251, 95% CI 1.01-1.55, p=0.041) had significantly lower hazard of mortality compared to group A. There was no significant difference in survival between COPD subtypes of chronic bronchitis and emphysema. Patients in Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 stage had an increased mortality hazard compared to the GOLD 1 stage.While ischemic stroke patients with preexisting COPD have worse long-term survival than those without COPD, the results largely depended on the definition of COPD used. These results suggest that ischemic stroke patients with COPD need more personalized medical care to decrease long-term mortality.

Introduction: The cut-point for defining the age of young ischemic stroke (IS) is clinically and epidemiologically important, yet it is arbitrary and differs across studies. In this study, we leveraged electronic health records (EHRs) and data science techniques to estimate an optimal cut-point for defining the age of young IS. Methods: Patient-level EHRs were extracted from 13 hospitals in Pennsylvania, and used in two parallel approaches. The first approach included ICD9/10, from IS patients to group comorbidities, and computed similarity scores between every patient pair. We determined the optimal age of young IS by analyzing the trend of patient similarity with respect to their clinical profile for different ages of index IS. The second approach used the IS cohort and control (without IS), and built three sets of machine-learning models—generalized linear regression (GLM), random forest (RF), and XGBoost (XGB)—to classify patients for seventeen age groups. After extracting feature importance from the models, we determined the optimal age of young IS by analyzing the pattern of comorbidity with respect to the age of index IS. Both approaches were completed separately for male and female patients. Results: The stroke cohort contained 7555 ISs, and the control included 31,067 patients. In the first approach, the optimal age of young stroke was 53.7 and 51.0 years in female and male patients, respectively. In the second approach, we created 102 models, based on three algorithms, 17 age brackets, and two sexes. The optimal age was 53 (GLM), 52 (RF), and 54 (XGB) for female, and 52 (GLM and RF) and 53 (RF) for male patients. Different age and sex groups exhibited different comorbidity patterns. Discussion: Using a data-driven approach, we determined the age of young stroke to be 54 years for women and 52 years for men in our mainly rural population, in central Pennsylvania. Future validation studies should include more diverse populations.

ObjectiveTo determine the contribution of common genetic variants to risk of early onset ischemic stroke (IS).MethodsWe performed a meta-analysis of genome-wide association studies of early onset IS, ages 18-59, using individual level data or summary statistics in 16,927 cases and 576,353 non-stroke controls from 48 different studies across North America, Europe, and Asia. We further compared effect sizes at our most genome-wide significant loci between early and late onset IS and compared polygenic risk scores for venous thromboembolism between early versus later onset IS.ResultsWe observed an association between early onset IS and ABO, a known stroke locus. The effect size of the peak ABO SNP, rs8176685, was significantly larger in early compared to late onset IS (OR 1.17 (95% C.I.: 1.11-1.22) vs 1.05 (0.99-1.12); p for interaction = 0.008). Analysis of genetically determined ABO blood groups revealed that early onset IS cases were more likely to have blood group A and less likely to have blood group O compared to both non-stroke controls and to late onset IS cases. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with early, compared to late, onset IS (p=0.008).ConclusionThe ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with early onset IS, compared with late onset IS, supporting a stronger role of prothrombotic factors in early onset IS.

Various studies on oral anticoagulants (OAC) use among atrial fibrillation (AF) patients have shown high rates of undertreatment and the presence of sex disparity. This study used the ‘Geisinger Neuroscience Ischemic Stroke’ (GNSIS) database to examine sex differences in OAC treatment among ischemic stroke patients with the pre-event diagnosis of AF in rural Pennsylvania between 2004 and 2019. We examined sex disparities in OAC undertreatment and associated risks based on age group and ischemic stroke year. A total of 1062 patients were included in the study and 1015 patients (96%) had CHA2DS2-VASc score ≥ 2, of which 549 (54.1%) were women. Undertreatment rates were not statistically significant between men and women in the overall cohort (50.0% vs. 54.5%, p = 0.18), and male sex was not found to be a significant factor in undertreatment (OR 0.82, 95% CI 0.62–1.09, p = 0.17). The result persisted even when patients were divided into four age groups and two groups based on the study time period. The undertreatment rates in both sex groups remained consistent following the introduction of novel oral anticoagulants. In conclusion, there was no evidence of sex disparity with respect to OAC treatment, even after stratifying the cohort by age and ischemic stroke year.

Laboratory data from Electronic Health Records (EHR) are often used in prediction models where estimation bias and model performance from missingness can be mitigated using imputation methods. We demonstrate the utility of imputation in two real-world EHR-derived cohorts of ischemic stroke from Geisinger and of heart failure from Sutter Health to: (1) characterize the patterns of missingness in laboratory variables; (2) simulate two missing mechanisms, arbitrary and monotone; (3) compare cross-sectional and multi-level multivariate missing imputation algorithms applied to laboratory data; (4) assess whether incorporation of latent information, derived from comorbidity data, can improve the performance of the algorithms. The latter was based on a case study of hemoglobin A1c under a univariate missing imputation framework. Overall, the pattern of missingness in EHR laboratory variables was not at random and was highly associated with patients’ comorbidity data; and the multi-level imputation algorithm showed smaller imputation error than the cross-sectional method.

Background Regularly updated data on stroke and its pathological types, including data on their incidence, prevalence, mortality, disability, risk factors, and epidemiological trends, are important for evidence-based stroke care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) aims to provide a standardised and comprehensive measurement of these metrics at global, regional, and national levels. Methods We applied GBD 2019 analytical tools to calculate stroke incidence, prevalence, mortality, disability-adjusted life-years (DALYs), and the population attributable fraction (PAF) of DALYs (with corresponding 95% uncertainty intervals [UIs]) associated with 19 risk factors, for 204 countries and territories from 1990 to 2019. These estimates were provided for ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and all strokes combined, and stratified by sex, age group, and World Bank country income level. Findings In 2019, there were 12·2 million (95% UI 11·0–13·6) incident cases of stroke, 101 million (93·2–111) prevalent cases of stroke, 143 million (133–153) DALYs due to stroke, and 6·55 million (6·00–7·02) deaths from stroke. Globally, stroke remained the second-leading cause of death (11·6% [10·8–12·2] of total deaths) and the third-leading cause of death and disability combined (5·7% [5·1–6·2] of total DALYs) in 2019. From 1990 to 2019, the absolute number of incident strokes increased by 70·0% (67·0–73·0), prevalent strokes increased by 85·0% (83·0–88·0), deaths from stroke increased by 43·0% (31·0–55·0), and DALYs due to stroke increased by 32·0% (22·0–42·0). During the same period, age-standardised rates of stroke incidence decreased by 17·0% (15·0–18·0), mortality decreased by 36·0% (31·0–42·0), prevalence decreased by 6·0% (5·0–7·0), and DALYs decreased by 36·0% (31·0–42·0). However, among people younger than 70 years, prevalence rates increased by 22·0% (21·0–24·0) and incidence rates increased by 15·0% (12·0–18·0). In 2019, the age-standardised stroke-related mortality rate was 3·6 (3·5–3·8) times higher in the World Bank low-income group than in the World Bank high-income group, and the age-standardised stroke-related DALY rate was 3·7 (3·5–3·9) times higher in the low-income group than the high-income group. Ischaemic stroke constituted 62·4% of all incident strokes in 2019 (7·63 million [6·57–8·96]), while intracerebral haemorrhage constituted 27·9% (3·41 million [2·97–3·91]) and subarachnoid haemorrhage constituted 9·7% (1·18 million [1·01–1·39]). In 2019, the five leading risk factors for stroke were high systolic blood pressure (contributing to 79·6 million [67·7–90·8] DALYs or 55·5% [48·2–62·0] of total stroke DALYs), high body-mass index (34·9 million [22·3–48·6] DALYs or 24·3% [15·7–33·2]), high fasting plasma glucose (28·9 million [19·8–41·5] DALYs or 20·2% [13·8–29·1]), ambient particulate matter pollution (28·7 million [23·4–33·4] DALYs or 20·1% [16·6–23·0]), and smoking (25·3 million [22·6–28·2] DALYs or 17·6% [16·4–19·0]). Interpretation The annual number of strokes and deaths due to stroke increased substantially from 1990 to 2019, despite substantial reductions in age-standardised rates, particularly among people older than 70 years. The highest age-standardised stroke-related mortality and DALY rates were in the World Bank low-income group. The fastest-growing risk factor for stroke between 1990 and 2019 was high body-mass index. Without urgent implementation of effective primary prevention strategies, the stroke burden will probably continue to grow across the world, particularly in low-income countries. Funding Bill & Melinda Gates Foundation.

Background The role of genotype variants of HMGB1 and RAGE in susceptibility to acute ischemic stroke remains inconclusive. Methods Caucasian acute ischemic stroke patients admitted to three hospitals within a large healthcare system in the U.S. between 2009 and 2017 were reviewed. For each stroke case, three age and sex-matched non-stroke patients were identified as controls. Associations of phased-genotype data for RAGE (rs1035798, rs2070600, rs1800624, rs1800625) and HMGB1 (rs1360485, rs1045411, rs3742305, rs2249825, rs1412125) single-nucleotide-polymorphisms (SNPs) and haplotypes with stroke susceptibility were analyzed. The Benjamini-Hochberg procedure was performed. Results Collectively, 4,264 patients, 1,066 acute ischemic stroke and 3,198 controls were identified. Genotype distributions were in Hardy-Weinberg equilibrium. None of the SNPs alternate allele frequencies differed from the NCBI SNP database. No differences were found in the genotype distributions when analyzing each SNP and the two most common haplotypes in a covariate adjusted model. In a sex-specific stratification, males harboring the RAGE SNP rs1800625 AG or GG genotype had an independently increased risk for ischemic strokes compared to controls (adjusted OR = 1.27,95%CI 1.03–1.57, pa = 0.0276). After the Benjamini-Hochberg procedure, a trend towards this association remained (pBH = 0.1104). Conclusion No association of RAGE and HMGB1 genotypes variations with risk for overall ischemic stroke or specific stroke subtypes could be observed. Congruent with the literature, a sex-specific role of RAGE SNPs might associate with stroke susceptibility. The functional role of the HMGB1-RAGE axis in this context warrants further exploration.

Background and Purpose: Hospital readmissions impose a substantial burden on the healthcare system. Reducing readmissions after stroke could lead to improved quality of care especially since stroke is associated with a high rate of readmission. The goal of this study is to enhance our understanding of the predictors of 30-day readmission after ischemic stroke and develop models to identify high-risk individuals for targeted interventions. Methods: We used patient-level data from electronic health records (EHR), five machine learning algorithms (random forest, gradient boosting machine, extreme gradient boosting–XGBoost, support vector machine, and logistic regression-LR), data-driven feature selection strategy, and adaptive sampling to develop 15 models of 30-day readmission after ischemic stroke. We further identified important clinical variables. Results: We included 3,184 patients with ischemic stroke (mean age: 71 ± 13.90 years, men: 51.06%). Among the 61 clinical variables included in the model, the National Institutes of Health Stroke Scale score above 24, insert indwelling urinary catheter, hypercoagulable state, and percutaneous gastrostomy had the highest importance score. The Model’s AUC (area under the curve) for predicting 30-day readmission was 0.74 (95%CI: 0.64–0.78) with PPV of 0.43 when the XGBoost algorithm was used with ROSE-sampling. The balance between specificity and sensitivity improved through the sampling strategy. The best sensitivity was achieved with LR when optimized with feature selection and ROSE-sampling (AUC: 0.64, sensitivity: 0.53, specificity: 0.69). Conclusions: Machine learning-based models can be designed to predict 30-day readmission after stroke using structured data from EHR. Among the algorithms analyzed, XGBoost with ROSE-sampling had the best performance in terms of AUC while LR with ROSE-sampling and feature selection had the best sensitivity. Clinical variables highly associated with 30-day readmission could be targeted for personalized interventions. Depending on healthcare systems’ resources and criteria, models with optimized performance metrics can be implemented to improve outcomes. VA had financial research support from the National Institute of Health (NIH) grant no. R56HL116832 subawarded to Geisinger during the study period. RZ had financial research support from Bucknell University Initiative Program, Roche – Genentech Biotechnology Company, the Geisinger Health Plan Quality fund, and receives institutional support from Geisinger Health System during the study period. Published version

Introduction: Stroke hospitalization and mortality are influenced by various social determinants. This ecological study aimed to determine the associations between social determinants and stroke hospitalization and outcome at county-level in the United States. Methods: County-level data were recorded from the Centers for Disease Control and Prevention as of January 7, 2020. We considered four outcomes: all-age (1) Ischemic and (2) Hemorrhagic stroke Death rates per 100,000 individuals (ID and HD respectively), and (3) Ischemic and (4) Hemorrhagic stroke Hospitalization rate per 1,000 Medicare beneficiaries (IH and HH respectively). Results: Data of 3,225 counties showed IH (12.5 ± 3.4) and ID (22.2 ± 5.1) were more frequent than HH (2.0 ± 0.4) and HD (9.8 ± 2.1). Income inequality as expressed by Gini Index was found to be 44.6% ± 3.6% and unemployment rate was 4.3% ± 1.5%. Only 29.8% of the counties had at least one hospital with neurological services. The uninsured rate was 11.0% ± 4.7% and people living within half a mile of a park was only 18.7% ± 17.6%. Age-adjusted obesity rate was 32.0% ± 4.5%. In regression models, age-adjusted obesity (OR for IH: 1.11; HH: 1.04) and number of hospitals with neurological services (IH: 1.40; HH: 1.50) showed an association with IH and HH. Age-adjusted obesity (ID: 1.16; HD: 1.11), unemployment (ID: 1.21; HD: 1.18) and income inequality (ID: 1.09; HD: 1.11) showed an association with ID and HD. Park access showed inverse associations with all four outcomes. Additionally, population per primary-care physician was associated with HH while number of pharmacy and uninsured rate were associated with ID. All associations and OR had p ≤0.04. Conclusion: Unemployment and income inequality are significantly associated with increased stroke mortality rates.

Objective: To determine whether Polygenic Risk Scores (PRS) derived from MEGASTROKE is associated with ischemic stroke (IS) and its subtypes in an independent tertiary healthcare system and to identify PRS derived from gene-sets of known biological pathways associated with IS and its outcomes (mortality and recurrent stroke). Methods: Controls(n=19806/7484, age≥69/79) and cases(n=1184/951 for discovery/replication) of acute IS with European ancestry and clinical risk factors identified by leveraging the Geisinger Electronic Health Record (EHR) and chart review confirmation. All Geisinger MyCode patients with age ≥69/79, without any stroke-related diagnostic codes as low-risk control. Genetic heritability and genetic correlation between Geisinger and MEGASTROKE(EUR) using the summary statistics of GWAS by LDSC. All PRS for any stroke — AS, any ischemic stroke — AIS, large artery stroke — LAS, cardioembolic stroke — CES, and small vessel stroke — SVS constructed by PRSice-2. PRS (top or bottom quantiles) derived from 7350 gene-sets of GO Biological Process was used to stratify the IS. Results: A moderate heritability (10-20%) for Geisinger sample as well as the genetic correlation between MEGASTROKE and the Geisinger cohort was identified. Gene sets analyses highlighted the association of PRS with Gene Ontology terms (vascular endothelial growth factor, amyloid precursor protein, and atherosclerosis). The PRS LAS , PRS CES , and PRS SVS explained the most variance of the corresponding subtypes of Geisinger IS suggesting shared etiologies and corroborated Geisinger TOAST subtyping. We further evaluate PRS derived from the gene-sets of which GO terms may best differentiate the survival in IS cases with the corresponding high or low genetic burden. The result from the Cox regression analysis showed simultaneously the effect of several risk factors including PRS on mortality and recurrent stroke probabilities. Conclusions: We provide the first evidence that PRSs derived from MEGASTROKE have value in identifying shared etiologies and determining stroke subtypes.

Introduction: Obesity is an established risk factor for ischemic stroke but the association of increased body mass index (BMI) with survival after ischemic stroke remains controversial. Many studies have shown that increased BMI has a “protective” effect on survival after stroke while other studies have debunked the obesity paradox. This study aimed at examining the relationship between BMI and all-cause mortality at one year in first-time ischemic stroke patients using data extracted from different resources including electronic health records. Methods: We analyzed consecutive ischemic stroke patients captured in the Geisinger NeuroScience Ischemic Stroke (GNSIS) database. Survival in first-time ischemic stroke patients was analyzed using Kaplan-Meier estimator, stratified by different BMI categories. The predictors of mortality at one-year were assessed using a multivariate Cox proportional hazards model. Results: Among 6,703 first-time adult ischemic stroke patients, mean age was 70.2 ±13.5 years and 52% were men. Of these patients, 24% patients were non-overweight (BMI < 25), 34% were overweight (BMI 25-29.9) and 41% were obese (BMI ≥ 30). One-year survival probability was significantly higher in overweight patients (87%, 95% CI: [85.6 - 88.4], p Conclusion: Our results support the obesity paradox in ischemic stroke patients as shown by a significantly decreased hazard ratio for one-year mortality among overweight and obese patients in comparison to non-overweight patients.

Objective: The long-term risk of recurrent ischemic stroke, estimated to be between 17%-30%, cannot be reliably assessed. Our goal was to study whether machine-learning can be trained to predict stroke recurrence and identify key clinical variables and assess whether performance metrics can be optimized. Methods: We used patient-level data from electronic health records, 6 algorithms (Logistic Regression, Extreme Gradient Boosting, Gradient Boosting Machine, Random Forest, Support Vector Machine, Decision Tree), 4 feature selection strategies, 5 prediction windows, and 2 sampling strategies to develop 288 models for up to 5-year stroke recurrence prediction. We further identified important clinical features and different optimization strategies. Results: We included 2,091 ischemic stroke patients for this study. Model AUROC was stable for prediction windows of 1,2,3,4 and 5 years, with the highest score for the 1-year (0.79) and the lowest score for the 5-year prediction window (0.69). A total of 21(7%) models reached an AUROC above 0.73 while 110(38%) models reached an AUROC greater than 0.7. Among the 53 features analyzed, age, body mass index, and laboratory-based features (such as high-density lipoprotein, hemoglobin A1C, and creatinine) had the highest overall importance scores. The balance between specificity and sensitivity improved through sampling strategies. Conclusion: All the selected six modeling algorithms could be trained to predict the long-term stroke recurrence and laboratory-based variables were highly associated with stroke recurrence. The latter could be targeted for personalized interventions. Model performance metrics could be optimized, and models can be implemented in the same healthcare system as intelligent decision support to improve outcomes.

Introduction: Several studies suggest women may be disproportionately affected by poorer stroke outcomes than men. This study aimed to investigate if women had a higher risk of all-cause mortality and recurrence after an ischemic stroke in a rural population in central Pennsylvania, United States. Methods: We analyzed consecutive ischemic stroke patients captured in our comprehensive research database from 2004 to 2019. Kaplan-Meier (KM) estimator curves stratified by gender and age were used to plot survival probabilities and Cox Proportional Hazards Ratios were used to analyze outcomes of all-cause mortality and the composite outcome of ischemic stroke recurrence or death. Fine-Gray Competing Risk models were used for the outcome of recurrent ischemic stroke, with death as the competing risk. Two models were generated; Model 1 was adjusted by data-driven associated health factors, and Model 2 was adjusted by traditional vascular risk factors. Results: Among 8,900 adult ischemic stroke patients (median age of 71.6 [IQR:61.1-81.2] years and 48% women), women had a higher crude all-cause mortality. The KM curves demonstrated a 63.3% survival in women compared to a 65.7% survival in men (p=0.003) at five years; however, the survival difference was not present after adjustment by the associated factors of age, atrial fibrillation or flutter, myocardial infarction, diabetes mellitus, dyslipidemia, heart failure, chronic lung diseases, rheumatic disease, chronic kidney disease, neoplasm, peripheral vascular disease, past ischemic stroke, past hemorrhagic stroke, and depression. There was no adjusted or unadjusted sex difference in terms of recurrent ischemic stroke or composite outcome. Conclusion: Sex was not an independent risk factor for all-cause mortality and ischemic stroke recurrence in the rural population in central Pennsylvania.

Introduction: The stroke mortality rate has gradually declined due to improved interventions and controlled risk factors. We investigated the trends in stroke risk factors and outcomes among a rural population in the United States between 2004 and 2018. Methods: We built a comprehensive stroke database called “Geisinger NeuroScience Ischemic Stroke (GNSIS)” for this study. Clinical data were extracted from multiple sources, including electronic health records and quality data. Results: Our cohort comprised of 8,561 consecutive ischemic stroke patients (mean age: 70.1±13.9 years, men: 51.6%, 95.1% Caucasian). Hypertension was the most prevalent risk factor (75.2%). The rate of hypertension, diabetes, dyslipidemia, and history of stroke increased significantly over the fifteen years window. The one-year recurrence and mortality rates were 6.3% and 15.8%, respectively. Although the one-year stroke recurrence increased from 2004 to 2018 (Cochran-Armitage test Z = -3.66, p65 years, atrial fibrillation or flutter, heart failure, and prior ischemic stroke were independently associated with one-year all-cause mortality in stratified Cox proportional hazards model. In the Fine-Gray competing risk model, diabetes mellitus and age 65 years, atrial fibrillation or flutter, CKD, heart failure, prior hemorrhagic and ischemic stroke, history of neoplasm, myocardial infarction, and rheumatic diseases were predictors of one-year mortality. Conclusion: Although stroke mortality has decreased, stroke recurrence and several vascular risk factors have significantly increased in our rural population between 2004-2018. Older age, atrial fibrillation or flutter, heart failure, and prior ischemic stroke were independently associated with one-year all-cause mortality while diabetes mellitus and age less than 65 years were predictors of ischemic stroke recurrence.

Background and purpose Obesity is an established risk factor for ischemic stroke but the association of increased body mass index (BMI) with survival after ischemic stroke remains controversial. Many studies have shown that increased BMI has a "protective" effect on survival after stroke while other studies have debunked the "obesity paradox". This study aimed at examining the relationship between BMI and all-cause mortality at one year in first-time ischemic stroke patients using a large dataset extracted from different resources including electronic health records. Methods This was a retrospective cohort study of consecutive ischemic stroke patients captured in our Geisinger NeuroScience Ischemic Stroke (GNSIS) database. Survival in first-time ischemic stroke patients in different BMI categories was analyzed using Kaplan Meier survival curves. The predictors of mortality at one-year were assessed using a stratified Cox proportional hazards model. Results Among 6,703 first-time ischemic stroke patients, overweight and obese patients were found to have statistically decreased hazard ratio (HR) compared to the non-overweight patients (overweight patients- HR = 0.61 [95% CI, 0.52-0.72]; obese patients- HR = 0.56 [95% CI, 0.48-0.67]). Predictors with a significant increase in the hazard ratio for one-year mortality were age at the ischemic stroke event, history of neoplasm, atrial fibrillation/flutter, diabetes, myocardial infarction and heart failure. Conclusion Our study results support the obesity paradox in ischemic stroke patients as shown by a significantly decreased hazard ratio for one-year mortality among overweight and obese patients in comparison to non-overweight patients. Defense Threat Reduction Agency (DTRA) grant [HDTRA1-18-1-0008]; National Institute of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R56HL116832]; Bucknell University Initiative Program; Roche -Genentech Biotechnology Company; Geisinger Health Plan Quality fund This study had no specific funding. VA had financial research support from the Defense Threat Reduction Agency (DTRA) grant No. HDTRA1-18-1-0008 sub-awarded to Geisinger and funds from the National Institute of Health (NIH) grant No. R56HL116832 sub-awarded to Geisinger during the study period. RZ had financial research support from Bucknell University Initiative Program, Roche -Genentech Biotechnology Company, the Geisinger Health Plan Quality fund during the study period, and receives institutional support from Geisinger Health System. The funders had no role in study design, data collection and analysis, or preparation of the manuscript.

Background: The long-term risk of recurrent ischemic stroke, estimated to be between 17% and 30%, cannot be reliably assessed at an individual level. Our goal was to study whether machine-learning can be trained to predict stroke recurrence and identify key clinical variables and assess whether performance metrics can be optimized. Methods: We used patient-level data from electronic health records, six interpretable algorithms (Logistic Regression, Extreme Gradient Boosting, Gradient Boosting Machine, Random Forest, Support Vector Machine, Decision Tree), four feature selection strategies, five prediction windows, and two sampling strategies to develop 288 models for up to 5-year stroke recurrence prediction. We further identified important clinical features and different optimization strategies. Results: We included 2091 ischemic stroke patients. Model area under the receiver operating characteristic (AUROC) curve was stable for prediction windows of 1, 2, 3, 4, and 5 years, with the highest score for the 1-year (0.79) and the lowest score for the 5-year prediction window (0.69). A total of 21 (7%) models reached an AUROC above 0.73 while 110 (38%) models reached an AUROC greater than 0.7. Among the 53 features analyzed, age, body mass index, and laboratory-based features (such as high-density lipoprotein, hemoglobin A1c, and creatinine) had the highest overall importance scores. The balance between specificity and sensitivity improved through sampling strategies. Conclusion: All of the selected six algorithms could be trained to predict the long-term stroke recurrence and laboratory-based variables were highly associated with stroke recurrence. The latter could be targeted for personalized interventions. Model performance metrics could be optimized, and models can be implemented in the same healthcare system as intelligent decision support for targeted intervention.

Background and Purpose: Stroke is reported as a consequence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in several reports. However, data are sparse regarding the details of these patients in a multinational and large scale. Methods: We conducted a multinational observational study on features of consecutive acute ischemic stroke, intracranial hemorrhage, and cerebral venous or sinus thrombosis among SARS-CoV-2–infected patients. We further investigated the risk of large vessel occlusion, stroke severity as measured by the National Institutes of Health Stroke Scale, and stroke subtype as measured by the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria among patients with acute ischemic stroke. In addition, we explored the neuroimaging findings, features of patients who were asymptomatic for SARS-CoV-2 infection at stroke onset, and the impact of geographic regions and countries’ health expenditure on outcomes. Results: Among the 136 tertiary centers of 32 countries who participated in this study, 71 centers from 17 countries had at least 1 eligible stroke patient. Of 432 patients included, 323 (74.8%) had acute ischemic stroke, 91 (21.1%) intracranial hemorrhage, and 18 (4.2%) cerebral venous or sinus thrombosis. A total of 183 (42.4%) patients were women, 104 (24.1%) patients were P =0.02) and higher rate of mechanical thrombectomy (12.4% versus 2%; P Conclusions: We observed a considerably higher rate of large vessel occlusions, a much lower rate of small vessel occlusion and lacunar infarction, and a considerable number of young stroke when compared with the population studies before the pandemic. The rate of mechanical thrombectomy was significantly lower in countries with lower health expenditures.

Background: Several studies suggest women may be disproportionately affected by poorer stroke outcomes than men. This study aims to investigate whether women have a higher risk of all-cause mortality and recurrence after an ischemic stroke than men in a rural population in central Pennsylvania, United States. Methods: We analyzed consecutive ischemic stroke patients captured in the Geisinger NeuroScience Ischemic Stroke research database from 2004 to 2019. Kaplan–Meier (KM) estimator curves stratified by gender and age were used to plot survival probabilities and Cox Proportional Hazards Ratios were used to analyze outcomes of all-cause mortality and the composite outcome of ischemic stroke recurrence or death. Fine–Gray Competing Risk models were used for the outcome of recurrent ischemic stroke, with death as the competing risk. Two models were generated; Model 1 was adjusted by data-driven associated health factors, and Model 2 was adjusted by traditional vascular risk factors. Results: Among 8900 adult ischemic stroke patients [median age of 71.6 (interquartile range: 61.1–81.2) years and 48% women], women had a higher crude all-cause mortality. The KM curves demonstrated a 63.3% survival in women compared with a 65.7% survival in men ( p = 0.003) at 5 years; however, the survival difference was not present after controlling for covariates, including age, atrial fibrillation or flutter, myocardial infarction, diabetes mellitus, dyslipidemia, heart failure, chronic lung diseases, rheumatic disease, chronic kidney disease, neoplasm, peripheral vascular disease, past ischemic stroke, past hemorrhagic stroke, and depression. There was no adjusted or unadjusted sex difference in terms of recurrent ischemic stroke or composite outcome. Conclusion: Sex was not an independent risk factor for all-cause mortality and ischemic stroke recurrence in the rural population in central Pennsylvania.

The stroke mortality rate has gradually declined due to improved interventions and controlled risk factors. We investigated the associated factors and trends in recurrence and all-cause mortality in ischemic stroke patients from a rural population in the United States between 2004 and 2018.This was a retrospective cohort study based on electronic health records (EHR) data. A comprehensive stroke database called "Geisinger NeuroScience Ischemic Stroke (GNSIS)" was built for this study. Clinical data were extracted from multiple sources, including EHR and quality data.The cohort included in the study comprised of 8561 consecutive ischemic stroke patients (mean age: 70.1 ± 13.9 years, men: 51.6%, 95.1% Caucasian). Hypertension was the most prevalent risk factor (75.2%). The one-year recurrence and all-cause mortality rates were 6.3% and 16.1%, respectively. Although the one-year stroke recurrence increased during the study period, the one-year stroke mortality rate decreased significantly. Age 65 years, atrial fibrillation or flutter, heart failure, and prior ischemic stroke were independently associated with one-year all-cause mortality in stratified Cox proportional hazards model. In the Cause-specific hazard model, diabetes, chronic kidney disease and age 65 years were found to be associated with one-year ischemic stroke recurrence.Although all-cause mortality after stroke has decreased, stroke recurrence has significantly increased in stroke patients from rural population between 2004 and 2018. Older age, atrial fibrillation or flutter, heart failure, and prior ischemic stroke were independently associated with one-year all-cause mortality while diabetes, chronic kidney disease and age less than 65 years were predictors of ischemic stroke recurrence.

Importance Management of transient ischemic attack (TIA) has gained significant attention during the past 25 years after several landmark studies indicated the high incidence of a subsequent stroke. Objective To calculate the pooled event rate of subsequent ischemic stroke within 2, 7, 30, and 90 days of a TIA and compare this incidence among the population with TIA recruited before 1999 (group A), from 1999 to 2007 (group B), and after 2007 (group C). Data Sources All published studies of TIA outcomes were obtained by searching PubMed from 1996, to the last update on January 31, 2020, irrespective of the study design, document type, or language. Study Selection Of 11 516 identified citations, 175 articles were relevant to this review. Both the classic time-based definition of TIA and the new tissue-based definition were accepted. Studies with a combined record of patients with TIA and ischemic stroke, without clinical evaluation for the index TIA, with diagnosis of index TIA event after ischemic stroke occurrence, with low suspicion for TIA, or duplicate reports of the same database were excluded. Data Extraction and Synthesis The study was conducted and reported according to the PRISMA, MOOSE, and EQUATOR guidelines. Critical appraisal and methodological quality assessment used the Quality in Prognosis Studies tool. Publication bias was visualized by funnel plots and measured by the Begg-Mazumdar rank correlation Kendall τ2statistic and Egger bias test. Data were pooled using double arcsine transformations, DerSimonian-Laird estimator, and random-effects models. Main Outcomes and Measures The proportion of the early ischemic stroke after TIA within 4 evaluation intervals (2, 7, 30, and 90 days) was considered as effect size. Results Systematic review yielded 68 unique studies with 223 866 unique patients from 1971 to 2019. The meta-analysis included 206 455 patients (58% women) during a span of 4 decades. The overall subsequent ischemic stroke incidence rates were estimated as 2.4% (95% CI, 1.8%-3.2%) within 2 days, 3.8% (95% CI, 2.5%-5.4%) within 7 days, 4.1% (95% CI, 2.4%-6.3%) within 30 days, and 4.7% (95% CI, 3.3%-6.4%) within 90 days. There was a recurrence risk of 3.4% among group A in comparison with 2.1% in group B or 2.1% in group C within 2 days; 5.5% in group A vs 2.9% in group B or 3.2% in group C within 7 days; 6.3% in group A vs 2.9% in group B or 3.4% in group C within 30 days, and 7.4% in group A vs 3.9% in group B or 3.9% in group C within 90 days. Conclusions and Relevance These findings suggest that TIA continues to be associated with a high risk of early stroke; however, the rate of post-TIA stroke might have decreased slightly during the past 2 decades.

Introduction: There is an unmet need to understand the genetic factors associated with stroke outcome. The purpose of this study is to identify the common genetic variants, if any, associated with incident of ischemic stroke in a community-based population and to determine if any genetic risk can be enriched in fatal stroke patients. Methods: Cases and controls of ischemic stroke were identified by leveraging the comprehensive Electronic Health Record, and endophenotypes, e.g. the fatal or nonfatal stroke was defined by those dying within one month (fatal incidence) or surviving to 12 months (nonfatal incidence) of their first-ever stroke incident. The GWAS was carried out in a nested case-control design by considering all patients with age >79 and without any stroke-related diagnostic codes as low-risk control. A linear mixed regression model (SAIGE) with saddlepoint approximation, adjusted for covariates was conducted to account for the relatedness and case-control imbalance. Results: No genome-wide significant association was identified for ischemic stroke (n=1,179) versus control (n=7,489). When stratifying stroke patients by the fatality (n=61/1,118), rs80094021 (MAF = 0.038; OR=3.332±0.635; p=9.04E-11) and SNPs in LD with, located at an intronic region of TIAM1, were the top associated signal. All these SNPs served as eQTL for TIAM1(β=0.144, p=5.8E-13, eQTLGen). Rs79694970, the second top SNP (MAF = 0.020; OR=4.179±0.931; p=9.27E-09), is located near GPD1L and functions as eQTL for GPD1L(β=-0.279, p=6.1E-28). GPD1L plays a role in the DPD1L-dependent SCN5A phosphorylation pathway, thereby regulating cardiac sodium current. Dysfunction of sodium current can cause fatal ventricular arrhythmia. According to PheWAS data from UK Biobank, rs80094021 showed a moderate association with high cholesterol (p=0.0045), coronary atherosclerosis (p=0.0075), and angina (p=0.012), with the same direction for the minor allele which increased the risk for fatal stroke. rs79694970 were associated with ischemic stroke (large artery atherosclerosis) with p=0.0016. Conclusion: Through stratification of ischemic stroke by fatality some genetic risk factors and genes with biological relevant to the pathogenesis of stroke could be identified.

Introduction: Although white matter hyperintensities (WMH) have been linked to cerebrovascular disease, the exact pathogenesis is not known. The purpose of this study was to identify common variants associated with WMH burden among patients with an acute ischemic stroke (AIS) through a genome-wide association study (GWAS). Methods: A total of 946 AIS patients with validated European ancestry and MRI data were included in this study. WMH volume (WMHv), as a quantitative trait, was calculated by a fully-automated quantification process, which integrates the automated brain extraction, intensity normalization, and WMH segmentation using spatial priors. The GWAS was carried out by a linear mixed regression model (GEMMA), adjusted for covariates, to account for the potential population structure and relatedness. The WMHv ranked in top and bottom quantile were converted to a binary trait which represent high and low WMHv subgroups. Results: The rs10815506 (MAF = 0.043; β=3.89; p=6.66E-09), at an intronic region of KDM4C , which encodes Lysine-specific demethylase 4C , was the top signal associated with WMHv. This SNP is in high linkage disequilibrium (LD) (R 2 = 0.79; D’ = 0.93) with rs35389625, a nonsynonymous variant (Asn>Ser), predicted to be pathogenic by SIFT and Polyphen. The rs35389625 was also associated with WMHv but at a lower significance level (MAF=0.040; β=3.19; p=3.21E-06). Patients with homozygous mutant alleles (GG) of rs35389625 showed significantly increased WMHv (14.93±10.15) than GA (7.94±8.48) and AA (5.09±5.85) carriers. Both rs10815506 and rs35389625 also predicted a subset of high and low WMHv group (OR=2.81, p=0.005; OR=2.42, p=0.016, respectively). No significant interaction between the top SNPs at KDM4C and other risk factors was identified in their association with WMHv. We also conducted a candidate-gene analysis by including several known SNPs, gathered from a reported meta-analysis for WMH. The frequency of MTHFR677 cytosine/thymine (rs1801133) showed difference between lower and upper quantile groups with OR=2.18 for T allele (p=0.030), the direction of which was consistent with previous studies. Conclusion: This study provides the first evidence that genetic variants at KDM4C are associated with WMH in AIS patients.

Background: The history of intracranial hemorrhage (ICrH) is considered a contraindication for intravenous thrombolysis (IVT) among patients with acute ischemic stroke (AIS). Objective: This study aimed at comparing the safety of IVT among patients with and without a history of ICrH. Methods: We performed a systematic review of the literature. Data regarding all AIS patients with prior ICrH who received IVT were retrieved. Meta-analysis was performed to compare the rate of symptomatic hemorrhagic transformation (sHT), death within 90 days, and favorable and unfavorable 90-day functional outcomes based on modified Rankin Scale (mRS) among stroke patients with and without prior ICrH. Results: Out of 13,032 reviewed records, 7 studies were included in the systematic review and meta-analysis. Quantitative synthesis of data regarding the rate of sHT (5068 patients) revealed no significant difference between the two groups [odds ratio, OR: 1.55 (0.77, 3.12); p = 0.22]. However, a significantly higher risk of death within 90 days [OR: 3.91 (2.16, 7.08); p < 0.00001] and a significantly higher 90-day poor functional outcomes (mRS, 4–6) [OR: 1.57 (1.07, 2.30); p = 0.02] were observed among patients with prior ICrH. Likewise, the percentage of 90-day good functional outcomes (mRS, 0–1) was lower in the prior ICrH group [OR: 0.54 (0.35, 0.84); p = 0.06]. Subgroup analyses in patients with a history of ICrH (based on both patients’ medical history and imaging confirmation) revealed no significant between-group differences in rates of sHT. Also, sensitivity analysis consisting of only studies using standard-dose IVT showed no difference in sHT rates and 90-day outcomes between the two groups. There was no evidence of heterogeneity ( I2 >50%) among included studies. Conclusion: The results of this study indicated that prior history of ICrH does not increase the risk of sHT post-IVT, but it is associated with a higher risk of death and poor functional outcomes in 90 days.

Investigation of genetic susceptibility to cerebrovascular disease has been of growing interest. A systematic review of human studies assessing neurogenomic aspects of cerebrovascular disease was performed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. Any association study exploring genetic variants located in the exome associated with one of the major cerebrovascular diseases with at least 500 subjects was eligible for inclusion. Of 6874 manuscripts identified, 35 studies met the inclusion criteria. Most studies of interest focused on ischemic stroke and cerebrovascular occlusive disease. Large cohort genetic association studies on hemorrhagic cerebrovascular disease were less common. In addition to rare, well-established monogenic conditions with significant risk for cerebrovascular disease, a number of genetic variants are also relevant to cerebrovascular pathogenesis as part of a multifactorial process. The 45 polymorphisms identified were located in genes involved in processes related to endothelial and vascular health (15 (33.4%) variants), plasma lipid metabolism (10 (22.2%) variants), inflammation (9 (20%) variants), coagulation (3 (6.7%) variants), and blood pressure modulation (2 (4.4%) variants), and other (6 (13.3%) variants). This work represents a comprehensive overview of genetic variants in the exome relevant to ischemic and hemorrhagic stroke pathophysiology.

Objective Despite improvements in treatment, stroke remains a leading cause of mortality and long-term disability. In this study, we leveraged administrative data to build predictive models of short- and long-term post-stroke all-cause-mortality. Methods The study was conducted and reported according to the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guideline. We used patient-level data from electronic health records, three algorithms, and six prediction windows to develop models for post-stroke mortality. Results We included 7144 patients from which 5347 had survived their ischemic stroke after two years. The proportion of mortality was between 8%(605/7144) within 1-month, to 25%(1797/7144) for the 2-years window. The three most common comorbidities were hypertension, dyslipidemia, and diabetes. The best Area Under the ROC curve(AUROC) was reached with the Random Forest model at 0.82 for the 1-month prediction window. The negative predictive value (NPV) was highest for the shorter prediction windows – 0.91 for the 1-month – and the best positive predictive value (PPV) was reached for the 6-months prediction window at 0.92. Age, hemoglobin levels, and body mass index were the top associated factors. Laboratory variables had higher importance when compared to past medical history and comorbidities. Hypercoagulation state, smoking, and end-stage renal disease were more strongly associated with long-term mortality. Conclusion All the selected algorithms could be trained to predict the short and long-term mortality after stroke. The factors associated with mortality differed depending on the prediction window. Our classifier highlighted the importance of controlling risk factors, as indicated by laboratory measures.

Introduction: Recurrent stroke has a higher rate of death and disability. A number of risk scores have been developed to predict short-term and long-term risk of stroke following an initial episode of stroke or transient ischemic attack (TIA) with limited clinical utilities. In this paper, we review different risk score models and discuss their validity and clinical utilities. Methods: The PubMed bibliographic database was searched for original research articles on the various risk scores for risk of stroke following an initial episode of stroke or TIA. The validation of the models was evaluated by examining the internal and external validation process as well as statistical methodology, the study power, as well as the accuracy and metrics such as sensitivity and specificity. Results: Different risk score models have been derived from different study populations. Validation studies for these risk scores have produced conflicting results. Currently, ABCD(2) score with diffusion weighted imaging (DWI) and Recurrence Risk Estimator at 90 days (RRE-90) are the two acceptable models for short-term risk prediction whereas Essen Stroke Risk Score (ESRS) and Stroke Prognosis Instrument-II (SPI-II) can be useful for prediction of long-term risk. Conclusion: The clinical risk scores that currently exist for predicting short-term and long-term risk of recurrent cerebral ischemia are limited in their performance and clinical utilities. There is a need for a better predictive tool which can overcome the limitations of current predictive models. Application of machine learning methods in combination with electronic health records may provide platform for development of new-generation predictive tools. Geisinger Health Plan Quality; National Institute of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R56HL116832]; Defense Threat Reduction Agency (DTRA)United States Department of DefenseDefense Threat Reduction Agency [HDTRA118-1-0008, 450557-19D03] This study was partially funded by Geisinger Health Plan Quality awarded to RZ. VA was partly supported by the National Institute of Health (NIH) Grant No. R56HL116832 to Sutter Health and sub-awarded to VA (Sub-PI, Geisinger) as well as funds from the Defense Threat Reduction Agency (DTRA) Grant No. HDTRA118-1-0008 to Virginia Tech and sub-awarded to VA (Sub-PI, Geisinger, sub-award No. 450557-19D03). The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication.

Stroke is the fifth leading cause of death in the United States and a major cause of severe disability worldwide. Yet, recognizing the signs of stroke in an acute setting is still challenging and leads to loss of opportunity to intervene, given the narrow therapeutic window. A decision support system using artificial intelligence (AI) and clinical data from electronic health records combined with patients' presenting symptoms can be designed to support emergency department providers in stroke diagnosis and subsequently reduce the treatment delay. In this article, we present a practical framework to develop a decision support system using AI by reflecting on the various stages, which could eventually improve patient care and outcome. We also discuss the technical, operational, and ethical challenges of the process. Geisinger Health Plan Quality Fund; National Institute of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R56HL116832] This work was sponsored in part by funds from the Geisinger Health Plan Quality Fund and National Institute of Health R56HL116832 (subaward) to VA and RZ. The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication.

Background: Current ischemic stroke (IS) subtyping systems are very labor-intensive and costly to implement in large samples. There is a need to develop phenotyping approaches for genetic and other studies that can be implemented using generally available items captured in electronic medical records. Objective: In this report, we seek to validate a simplified approach using results from a genetic association study. Specifically, the strength of association for known genetic signals in the NINDS Stroke Genetics Network study (SiGN) is compared between the established IS subtyping systems (TOAST and Causative Classification System (CCS) subtypes) and phenotyping based on a single item within the CCS. Methods: Non-mutually exclusive “Simple” IS subtypes were defined from single CCS items as follows: 1) Small vessel stroke- lacunar infarct on imaging (with no other imaging or other requirements); 2) large artery stroke - vascular imaging showing > 50% stenosis or Results: The Table shows that, for loci significant in SiGN GWAS study, the “Simple” IS subtypes had similar strengths of association and p-values compared to results from TOAST and the causative and phenotypic CCS subtypes. Conclusions: “Simple” IS subtypes perform as well in GWAS analyses as more complex phenotyping systems and could potentially be derived through automated or semi-automated methods applied to electronic medical record systems. Since the ‘Simple” phenotypes were based on high quality CCS data, the current findings reflect optimal performance. Additional validation studies will be required for implementation in other settings.