Pathogenic ischemic stroke phenotypes in the NINDS-stroke genetics network

Abstract

Background and purpose: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

Keywords: classification; pathogenesis; phenotype.

Figure 1

Distribution of phenotypic and causative stroke subtypes: 1(a), phenotypic subtypes in the entire population; 1(b), phenotypic subtypes in the subset with complete vascular and cardiac investigation; 1(c), causative subtypes in the entire population; 1(d), causative subtypes in the subset with complete vascular and cardiac investigation. Please note that the term “incomplete evaluation” in Figures 1a and 1c designates an etiologic subgroup under “undetermined” category that is considered when diagnostic investigations are not performed in the absence of an identified etiology based on history and physical examination. According to this definition, a case with atrial fibrillation in history is not classified as incomplete evaluation when vascular and cardiac investigations are not done. The term “complete investigation” in Figures 1b and 1d, on the other hand, is solely based on availability of diagnostic tests indicating that brain imaging, vascular imaging, and cardiac evaluation are available. Hence, only 3,947 cases were classified as “incomplete evaluation”, while diagnostic investigations were not complete in 9,206 cases. Und: undetermined

Figure 2

Correlation between causative and phenotypic subtypes. Segments in each circle indicate proportion of causative subtypes in each major phenotypic category (circles).

Figure 3

The relationship between age and causative stroke subtypes.