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Stroke. 2014 Dec;45(12):3589-96. doi: 10.1161/STROKEAHA.114.007362. Epub 2014 Nov 6.

Pathogenic ischemic stroke phenotypes in the NINDS-stroke genetics network.

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From the Department of Radiology, AA Martinos Center for Biomedical Imaging (H.A., E.M.A., T.B.), Stroke Service, Department of Neurology (H.A., J.R.), and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Harvard Medical School, Boston; Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden (G.A., H.D., A.L., O.M., B.N.); Department of Neurology, Mayo Clinic Rochester, MN (R.D.B.); Department of Neurology (S.N.C., B.B.W.), Center for Public Health Genomics (S.S.R.), and Department of Public Health Sciences (B.B.W.), University of Virginia, Charlottesville; Department of Neurology (J.W.C., S.J.K.) and Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine (P.F.M.), University of Maryland School of Medicine, Baltimore; Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians-University, München, Germany (M.D., M.L.); Department of Clinical Science, Lund University, Malmö, Sweden (G.E., B.N.); Department of Neurology, Neurovascular Research Group, IMIM-Hospital del Mar, Universitat Autonoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Spain (E.G.-S., J.J.-C., J.R.); Neuroscience Institute, Saint Francis Medical Center, Trenton, NJ (R.P.G., L.R.P.); National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (K.G.); Institute of Biomedicine (C.J., A.P.) and Institute of Neuroscience and Physiology (K.J.), Sahlgrenska Academy at University of Gothenburg, Sweden; Department of Neurology, University of Miami Miller School of Medicine, FL (M.K., T.R., R.L.S.); Department of Neurology, University of Cincinnati College of Medicine, OH (B.K., D.O.K.); Department of Neurology, Stern Stroke Center, Albert Einstein College of Medicine, Bronx, NY (D.L.L.); Department of Neuroscience and Sensory Organs, Policlinico Hospital Foundation IRCCS Cà Granda, Milan, Italy (S.L.); Department of Neurology, Washington U

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NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium.


Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16 954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases.


The distribution of pathogenic categories varied by study, age, sex, and race (P<0.001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke pathogenesis (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (κ 0.72; 95% confidence interval, 0.69-0.75) and phenotypic classifications (κ 0.73; 95% confidence interval, 0.70-0.75).


This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke.


classification; pathogenesis; phenotype

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