Pathogenic Ischemic Stroke Phenotypes in the NINDS-Stroke Genetics Network

Abstract

Background and Purpose NINDS Stroke Genetics Network (SiGN) is an international consortium of ischemic stroke studies that aims to generate high quality phenotype data to identify the genetic basis of etiologic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. Methods Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major etiologic groups without weighting towards 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 re-adjudication of 1509 randomly selected cases. Results The distribution of etiologic 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 etiology (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (kappa 0.72, 95%CI:0.69-0.75) and phenotypic classifications (kappa 0.73, 95%CI:0.70-0.75). Conclusions This study demonstrates that etiologic 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 stroke patient does not necessarily mean that it is the cause of stroke.

Pharmacogenetic Associations of β1-Adrenergic Receptor Polymorphisms With Cardiovascular Outcomes in the SPS3 Trial (Secondary Prevention of Small Subcortical Strokes)

“…SiGN participants have been described elsewhere 21, 24 . Briefly, their mean age was 67 years, half (49%) were women, and White participants comprised 79%.…”

“…Briefly, their mean age was 67 years, half (49%) were women, and White participants comprised 79%. Twenty-five percent had diabetes, 68% had hypertension, and 23% had coronary artery disease 24 .…”

Acute stroke therapy: A review

“…) or interfere with the vascular risk factors. But apart from the above mentioned monogenic disorders, the current genomic technology is unlikely to improve assessment of stroke risk profile (7).…”

Study of the Outcome Differences among the Ischemic Stroke Subtypes basedon TOAST Classificationat Tribhuvan University Teaching Hospital, Nepal

“…The use of subtype classifi cation system helps to understand the differences in frequency of various stroke risk factors, incidence, strokeprognosis, chancesof recurrence, and long-termsurvival among different is chemic stroke subtypes. 2 The TOAS Tinvestigatorsdevised aseries of defi nitions to classify patients with is chemic stroke into 5 coreetiologic groupings:(1) Largeartery atherosclerosis, (2) Small artery occlusion(lacune), (3) Cardioembolism, (4) Stroke of other determined etiology, (5) Stroke of undetermined etiology, based on clinical impression and diagnostic fi ndings. 1 Studies of survival and recurrence after stroke have been reported throughout the world, 4,5,11,15,16 but there is limited data from Nepal on outcomes for individual subtypes of ischemic stroke.…”