Ethnic and Racial Variation in Intracerebral Hemorrhage Risk Factors and Risk Factor Burden

Kittner, Steven J.; Sekar, Padmini; Comeau, Mary E.; Anderson, Christopher; Parikh, Gunjan; Tavarez, Tachira; Flaherty, Matthew L.; Testai, Fernando D.; Frankel, Michael; James, Michael L.; Sung, Gene; Elkind, Mitchell S.V.; Worrall, Bradford B.; Kidwell, Chelsea S.; Gonzales, Nicole R.; Koch, Sebastian; Hall, Christiana E.; Birnbaum, Lee; Mayson, Douglas; Coull, Bruce M.; Malkoff, Marc; Sheth, Kevin N; McCauley, Jacob L.; Osborne, Jennifer; Morgan, Misty; Gilkerson, Lee; Behymer, Tyler P; Demel, Stacie L; Moomaw, Charles J.; Rosand, Jonathan; Langefeld, Carl D.; Woo, Daniel

doi:10.1001/jamanetworkopen.2021.21921

Cited by 30 publications

(24 citation statements)

References 38 publications

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“…Thus, future research should focus in particular on underserved populations that have higher burden and earlier onset of ICH. 38 Larger studies to better characterize the genetic architecture of ICH in diverse populations are underway. 39 Second, data on INR lability-an important determinant of ICH risk in anticoagulant users and a component of the HAS-BLED score-was not available, and its omission may have led to underperformance of the CRS and may limit generalizability of our findings, particularly in warfarin-exposed populations.…”

Section: Discussionmentioning

confidence: 99%

Genetic Risk Score Improves Risk Stratification for Anticoagulation-Related Intracerebral Hemorrhage

Mayerhofer

Parodi

Prapiadou

et al. 2023

Stroke

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Background: Intracerebral hemorrhage (ICH) is the most devastating adverse outcome for patients on anticoagulants. Clinical risk scores that quantify bleeding risk can guide decision-making in situations when indication or duration for anticoagulation is uncertain. We investigated whether integration of a genetic risk score into an existing risk factor–based CRS could improve risk stratification for anticoagulation-related ICH. Methods: We constructed 153 genetic risk scores from genome-wide association data of 1545 ICH cases and 1481 controls and validated them in 431 ICH cases and 431 matched controls from the population-based UK Biobank. The score that explained the largest variance in ICH risk was selected and tested for prediction of incident ICH in an independent cohort of 5530 anticoagulant users. A CRS for major anticoagulation-related hemorrhage, based on 8/9 components of the HAS-BLED score, was compared with a combined clinical and genetic risk score incorporating an additional point for high genetic risk for ICH. Results: Among anticoagulated individuals, 94 ICH occurred over a mean follow-up of 11.9 years. Compared with the lowest genetic risk score tertile, being in the highest tertile was associated with a two-fold increased risk for incident ICH (hazard ratio, 2.08 [95% CI, 1.22–3.56]). Although the CRS predicted incident ICH with a hazard ratio of 1.24 per 1-point increase (95% CI [1.01–1.53]), adding a point for high genetic ICH risk led to a stronger association (hazard ratio of 1.33 per 1-point increase [95% CI, 1.11–1.59]) with improved risk stratification (C index 0.57 versus 0.53) and maintained calibration (integrated calibration index 0.001 for both). The new clinical and genetic risk score showed 19% improvement in high-risk classification among individuals with ICH and a net reclassification improvement of 0.10. Conclusions: Among anticoagulant users, a prediction score incorporating genomic information is superior to a clinical risk score alone for ICH risk stratification and could serve in clinical decision-making.

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Section: Discussionmentioning

confidence: 99%

Genetic Risk Score Improves Risk Stratification for Anticoagulation-Related Intracerebral Hemorrhage

Mayerhofer

Parodi

Prapiadou

et al. 2023

Stroke

Self Cite

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“…Thus, future research should focus in particular on underserved populations that have higher burden and earlier onset of ICH. 41 Larger studies to better characterize the genetic architecture of ICH in diverse populations are underway. 42 Second, the vast majority (97%) of patients were on warfarin because that was the dominant oral anticoagulant at the time of recruitment into the UK Biobank, thus the findings cannot be translated to direct oral anticoagulants, some of which have lower reported hemorrhage risk.…”

Section: Discussionmentioning

confidence: 99%

A genetic risk score improves risk stratification for anticoagulation-related intracerebral hemorrhage

Mayerhofer

Parodi

Prapiadou

et al. 2022

Preprint

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Background: Intracerebral hemorrhage (ICH) is the most devastating adverse outcome for patients on anticoagulants. Clinical risk scores (CRS) that quantify bleeding risk can guide decision making in situations when indication or duration for anticoagulation is uncertain. We investigated whether integration of a genetic risk score (GRS) into an existing risk factor-based CRS could improve risk stratification for anticoagulation-related ICH. Methods: We constructed 153 GRS from genome-wide association data of 1,545 ICH cases and 1,481 controls and validated them in 431 ICH cases and 431 matched controls from the population-based UK Biobank. The score that explained the largest variance in ICH risk was selected and tested for prediction of incident ICH in an independent cohort of 5,530 anticoagulant users. A CRS for major anticoagulation-related hemorrhage, based on 8/9 components of the HAS-BLED score, was compared with an enhanced score incorporating an additional point for high genetic risk for ICH (CRS+G). Results: Among anticoagulated individuals, 94 ICH occurred over a mean follow-up of 11.9 years. Compared to the lowest GRS tertile, being in the highest tertile was associated with a two-fold increased risk for incident ICH (HR: 2.08 [95% CI 1.22, 3.56]). While the CRS predicted incident ICH with a HR of 1.24 per one point increase (95% CI [1.01, 1.53]), adding a point for high genetic ICH risk led to a stronger association (HR of 1.33 per one point increase, 95% CI [1.11, 1.59]) with improved risk stratification (C-index 0.58 vs. 0.53) and maintained calibration (integrated calibration index 0.001 for both). The new score (CRS+G) showed 20% improvement of high-risk classification among individuals with ICH and a net reclassification improvement of 0.10. Conclusions: Among anticoagulant users, a prediction score incorporating genomic information is superior to a clinical risk score alone for ICH risk stratification and could serve in clinical decision making.

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“…In order to evaluate the potential clinical utility of the metaGRS, we first assessed whether the metaGRS is independently associated with ICH risk in a multivariable logistic regression model controlling for established clinical risk factors for ICH (BMI, history of ischemic stroke, hypertension, diabetes, high cholesterol, smoking history, alcohol use, anticoagulant medication use). 56, 57 Four cases were excluded from this analysis – three had a previous ICH and one ICH case was a cavernoma. To restrict our clinical variables to those most strongly associated with ICH, we performed backward elimination on the logistic regression model containing the clinical risk factors alone.…”

Section: Methodsmentioning

confidence: 99%

A Genomic Risk Score Identifies Individuals at High Risk for Intracerebral Hemorrhage

Myserlis

Georgakis

Demel

et al. 2022

Preprint

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BackgroundIntracerebral hemorrhage (ICH), the most fatal form of stroke, has an estimated heritability of 29%. Applying a meta-scoring approach, we developed a genomic risk score for ICH and determined its predictive power in comparison to standard clinical risk factors.MethodsUsing a meta-analytic approach, we combined genome-wide association data from individuals of European ancestry for ICH and ICH-related traits in a meta-genomic risk score (metaGRS) consisting of 2.6 million variants. We tested associations with ICH and the predictive performance of the metaGRS in addition to clinical risk factors in a held-out validation dataset (842 cases and 796 controls). Furthermore, we tested associations with risk of incident ICH in the population-based UK Biobank cohort (486,784 individuals, 1,526 events, median follow-up 11.3 years).ResultsOne SD increment in the metaGRS was significantly associated with 45% higher odds for ICH (OR 1.45; 95%CI: 1.30-1.63) in age- and sex-adjusted models and 31% higher odds for ICH (OR: 1.31, 95%CI: 1.16-1.48) in models further adjusted for clinical risk factors. The metaGRS identified individuals with almost 5-fold higher odds for ICH in the top score percentile (OR: 4.83, 95%CI: 1.56-21.2). Predictive models for ICH incorporating the metaGRS in addition to clinical predictors showed superior performance compared with clinical risk factors alone (c-index: 0.695 vs. 0.686). The metaGRS showed similar associations for both lobar and non-lobar ICH, which were independent of the known APOE risk locus for lobar ICH. In the UK Biobank, the metaGRS was associated with higher risk of incident ICH (HR: 1.15, 95%CI: 1.09-1.21). The associations were significant within both a relatively high-risk population of users of antithrombotic medications, as well as among a relatively low-risk population with a good control of vascular risk factors and no use of anticoagulants.ConclusionsWe developed and validated a genomic risk score that predicts lifetime risk of ICH beyond established clinical risk factors among individuals of European ancestry. Whether implementation of the score in risk prognostication models for high-risk populations, such as patients under antithrombotic treatment, could improve clinical decision making should be explored in future studies.

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Ethnic and Racial Variation in Intracerebral Hemorrhage Risk Factors and Risk Factor Burden

Cited by 30 publications

References 38 publications

Genetic Risk Score Improves Risk Stratification for Anticoagulation-Related Intracerebral Hemorrhage

Genetic Risk Score Improves Risk Stratification for Anticoagulation-Related Intracerebral Hemorrhage

A genetic risk score improves risk stratification for anticoagulation-related intracerebral hemorrhage

A Genomic Risk Score Identifies Individuals at High Risk for Intracerebral Hemorrhage

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