Catherine Sudlow

Comparable Studies of the Incidence of Stroke and its Pathological Types Results From an International Collaboration

BACKGROUND AND PURPOSE Comparing stroke rates in different parts of the world may increase our understanding of both etiology and prevention. However, comparisons are meaningful only if studies use standard definitions and methods, with comparably presented data. We compared the incidence of stroke and its pathological types (cerebral infarction, primary intracerebral hemorrhage, and subarachnoid hemorrhage) in recent studies from around the world. METHODS Studies with a midyear of 1984 or later, fulfilling standard criteria for a comparable, community-based study, provided original data for comparative analyses. RESULTS By mid-1995, data were available from 11 studies in Europe, Russia, Australasia, and the United States, comprising approximately 3.5 million person-years and 5575 incident strokes. Age- and sex-standardized annual incidence rates for subjects aged 45 to 84 years were similar (between approximately 300/100,000) and 500/100,000) in most places but were significantly lower in Dijon, France (238/100,000), and higher in Novosibirsk, Russia (627/100,000). In subjects aged 75 to 84 years, however, Novosibirsk no longer ranked higher than the other studies. The distribution of pathological types, when these were reliably distinguished, did not differ significantly between studies. CONCLUSIONS The similarities in stroke incidence and pathological types are perhaps not surprising given that all the populations were westernized and mainly white. The higher rates in Novosibirsk, disappearing in the elderly, and the lower rates in Dijon have several potential explanations. These include methodological artifact and different patterns of population risk factors. Further work is needed to explore these possibilities and to extend our knowledge of stroke incidence to other parts of the world, especially developing countries.

Are Lacunar Strokes Really Different? A Systematic Review of Differences in Risk Factor Profiles Between Lacunar and Nonlacunar Infarcts

Background and Purpose— Differences in risk factors between lacunar and nonlacunar infarcts might support a distinct arterial pathological process underlying lacunar infarction. Methods— We did a systematic review of studies comparing risk factors in patients with lacunar versus nonlacunar infarction. For each risk factor, we calculated study-specific and pooled relative risks (RRs) for lacunar versus nonlacunar infarction. Results— A total of 16 of 28 studies included risk factors in their ischemic stroke subtype definitions. Hypertension and diabetes appeared commoner among patients with lacunar versus nonlacunar infarction. However, analyses confined to studies using risk factor–free ischemic subtype definitions found only a marginal excess of hypertension with lacunar versus nonlacunar infarction (RR, 1.11; 95% CI, 1.04 to 1.19) and no difference for diabetes (RR, 0.95; 95% CI, 0.83 to 1.09). Atrial fibrillation and carotid stenosis were associated more with nonlacunar than lacunar infarction but less so when only studies using risk factor–free classifications were considered. Otherwise, there was no evidence of differences in risk factor profiles. Conclusions— Risk factor–free ischemic stroke subtype classification methods should be used for comparing risk factor profiles between lacunar and nonlacunar subtypes.

Common variants at 6p21.1 are associated with large artery atherosclerotic stroke

Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR) = 1.62, P = 3.9 × 10−8) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR = 1.15, P = 3.9 × 10−4; discovery and replication combined OR = 1.21, P = 4.7 × 10−8). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.

Ischemic Stroke Is Associated with the ABO Locus: The EuroCLOT Study

Objective: End‐stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end‐stage coagulation in healthy REFVIDunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.

Comparison of Sociodemographic and Health-Related Characteristics of UK Biobank Participants With Those of the General Population.

Abstract The UK Biobank cohort is a population-based cohort of 500,000 participants recruited in the United Kingdom (UK) between 2006 and 2010. Approximately 9.2 million individuals aged 40–69 years who lived within 25 miles (40 km) of one of 22 assessment centers in England, Wales, and Scotland were invited to enter the cohort, and 5.5% participated in the baseline assessment. The representativeness of the UK Biobank cohort was investigated by comparing demographic characteristics between nonresponders and responders. Sociodemographic, physical, lifestyle, and health-related characteristics of the cohort were compared with nationally representative data sources. UK Biobank participants were more likely to be older, to be female, and to live in less socioeconomically deprived areas than nonparticipants. Compared with the general population, participants were less likely to be obese, to smoke, and to drink alcohol on a daily basis and had fewer self-reported health conditions. At age 70–74 years, rates of all-cause mortality and total cancer incidence were 46.2% and 11.8% lower, respectively, in men and 55.5% and 18.1% lower, respectively, in women than in the general population of the same age. UK Biobank is not representative of the sampling population; there is evidence of a “healthy volunteer” selection bias. Nonetheless, valid assessment of exposure-disease relationships may be widely generalizable and does not require participants to be representative of the population at large.

The Causative Classification of Stroke system: an international reliability and optimization study.

Background: Valid and reliable ischemic stroke subtype determination is crucial for well-powered multicenter studies. The Causative Classification of Stroke System (CCS, available at http://ccs.mgh.harvard.edu) is a computerized, evidence-based algorithm that provides both causative and phenotypic stroke subtypes in a rule-based manner. We determined whether CCS demonstrates high interrater reliability in order to be useful for international multicenter studies. Methods: Twenty members of the International Stroke Genetics Consortium from 13 centers in 8 countries, who were not involved in the design and development of the CCS, independently assessed the same 50 consecutive patients with acute ischemic stroke through reviews of abstracted case summaries. Agreement among ratings was measured by kappa statistic. Results: The κ value for causative classification was 0.80 (95% confidence interval [CI] 0.78–0.81) for the 5-subtype, 0.79 (95% CI 0.77–0.80) for the 8-subtype, and 0.70 (95% CI 0.69–0.71) for the 16-subtype CCS. Correction of a software-related factor that generated ambiguity improved agreement: κ = 0.81 (95% CI 0.79–0.82) for the 5-subtype, 0.79 (95% CI 0.77–0.80) for the 8-subtype, and 0.79 (95% CI 0.78–0.80) for the 16-subtype CCS. The κ value for phenotypic classification was 0.79 (95% CI 0.77–0.82) for supra-aortic large artery atherosclerosis, 0.95 (95% CI 0.93–0.98) for cardioembolism, 0.88 (95% CI 0.85–0.91) for small artery occlusion, and 0.79 (0.76–0.82) for other uncommon causes. Conclusions: CCS allows classification of stroke subtypes by multiple investigators with high reliability, supporting its potential for improving stroke classification in multicenter studies and ensuring accurate means of communication among different researchers, institutions, and eras.

Association of Circulating Inflammatory Markers With Recurrent Vascular Events After Stroke A Prospective Cohort Study

Background and Purpose— Inflammatory markers may be associated with recurrent vascular events after stroke. We aimed to determine the association between IL-6, C-reactive protein, fibrinogen and white cell count, with recurrent vascular events after stroke, and to compare the association between circulating inflammatory markers with the risk of death from vascular vs nonvascular causes. Methods— We prospectively recruited patients with acute stroke (n=817) and followed them for up to 4 years for the occurrence of fatal or nonfatal recurrent stroke, myocardial infarction or fatal vascular events, and death from any cause (n=159). Results— The delay to assessment was a median of 10 days. The adjusted incidence of the outcome cluster recurrent stroke, myocardial infarction or vascular death after stroke was significantly higher with higher levels of IL-6 (75th to 25th percentile hazard ratio, 1.56; 95% CI, 1.37–1.77), C-reactive protein (75th to 25th percentile hazard ratio, 1.08; 95% CI, 1.04–1.11), and fibrinogen (75th to 25th percentile hazard ratio, 1.45; 95% CI, 1.24–1.72). The associations between inflammatory markers and death were stronger than with recurrent vascular events. The associations of inflammatory markers with vascular and nonvascular deaths were similar. Conclusions— Although inflammatory markers were associated with an increased risk of recurrent vascular events and vascular death after stroke, they were also associated with nonvascular causes of death, suggesting that inflammatory markers do not play a causal role specifically in the generation of recurrent vascular events after stroke. Future studies of the prediction of recurrent vascular events after stroke should concentrate on clinical variables or different blood markers.

Genetic associations with brain microbleeds: Systematic review and meta-analyses

Objective: We performed a systematic review and meta-analyses to assess the evidence for genetic associations with brain microbleeds (BMBs). Methods: We sought all published studies of the association between any genetic polymorphism and BMBs studied in a total of >100 people. We critically appraised studies, and calculated pooled odds ratios (ORs) using the generic inverse variance fixed effects method. We used I2 and χ2 statistics to assess heterogeneity, and fail-safe N estimates to assess the robustness of our results. Results: Only the APOE ϵ2/3/4 polymorphism had been studied in >100 people (10 studies, 7,351 participants). Compared with people with the ϵ3/ϵ3 genotype, carriers of the ϵ4 allele (ϵ4+) were statistically significantly more likely to have BMBs in any location (ϵ4+ vs ϵ3/ϵ3: pooled OR 1.22, 95% confidence interval [CI] 1.05–1.41, p = 0.01). For strictly lobar BMBs, this association appeared slightly stronger (ϵ4+ vs ϵ3/ϵ3: pooled OR 1.35, 95% CI 1.10–1.66, p = 0.005). The association of ϵ4+ genotypes with strictly lobar BMBs was reasonably robust to potential publication and reporting biases. Conclusions: Given the known associations of APOE alleles with lobar intracerebral hemorrhage and cerebral amyloid angiopathy, these findings support the concept that strictly lobar BMBs may be an imaging biomarker of cerebral amyloid angiopathy.

Shared genetic basis for migraine and ischemic stroke A genome-wide analysis of common variants

Objective: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation. Methods: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping. Results: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 × 10−28 for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 × 10−20 for the CE score in MO). Conclusions: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.

Prognostic value of blood interleukin-6 in the prediction of functional outcome after stroke: A systematic review and meta-analysis

We aimed to quantify the association of blood interleukin-6 (IL-6) concentrations with poor outcome after stroke and its added predictive value over clinical information. Meta-analysis of 24 studies confirmed this association with a weighted mean difference of 3.443 (1.592-5.294) pg/mL, despite high heterogeneity and publication bias. Individual participant data including 4112 stroke patients showed standardized IL-6 levels in the 4th quartile were independently associated with poor outcome (OR=2.346 (1.814-3.033), p<0.0001). However, the additional predictive value of IL-6 was moderate (IDI=1.5%, NRI=5.35%). Overall these results indicate an unlikely translation of IL-6 into clinical practice for this purpose.