Addressing the heterogeneity of the ischemic stroke phenotype in human genetics research

Many investigators have approached ischemic stroke as a complex phenotype by dividing the ischemic stroke population into distinct subtypes. The purpose of this study was to review systematically the methods used to subtype ischemic stroke in recent genetic studies.

The MEDLINE database was searched for articles pertaining to research on the genetics of human ischemic stroke published from January 2000 through January 2002. Abstracts and full-length reports were then sequentially screened to select articles pertaining to original case-control or cohort studies.

The initial search yielded 153 publications. Of 41 relevant articles, ischemic stroke was subtyped in 25 (61%). The most common standard subtyping system was the Cerebrovascular Classification of Diseases III system (9 articles). Of the subtyping systems used, 3 had previously published interrater reliability. The subtyping system was reported to have been prespecified in 1 study. Four articles reported using central adjudication. Two articles reported that the person doing the subtyping was blinded to genotype, and 2 reported that the person doing the genotyping was blinded to the patient's subtype status.

When investigators subtyped ischemic stroke, they typically used either nonstandard classification systems or systems of undetermined reliability. Important methodological issues, including blinding and prespecification of the classification system, were rarely reported. Advances in methodology and scientific reporting standards would foster identification of subtype-specific genetic risk factors.