Combining Imaging and Genetics to Predict Recurrence of Anticoagulation-Associated Intracerebral Hemorrhage

Alessandro Biffi; Sebastian Urday; Patryk Kubiszewski; Lee Gilkerson; Padmini Sekar; Axana Rodriguez-Torres; Margaret Bettin; Andreas Charidimou; Marco Pasi; Christina Kourkoulis; Kristin Schwab; Zora DiPucchio; Tyler Behymer; Jennifer Osborne; Misty Morgan; Charles J Moomaw; Michael L James; Steven M Greenberg; Anand Viswanathan; M Edip Gurol; Bradford B Worrall; Fernando D Testai; Jacob L McCauley; Guido J Falcone; Carl D Langefeld; Christopher D Anderson; Hooman Kamel; Daniel Woo; Kevin N Sheth; Jonathan Rosand

doi:10.1161/STROKEAHA.120.028310

Combining Imaging and Genetics to Predict Recurrence of Anticoagulation-Associated Intracerebral Hemorrhage

Stroke. 2020 Jul;51(7):2153-2160. doi: 10.1161/STROKEAHA.120.028310. Epub 2020 Jun 10.

Authors

Alessandro Biffi^#^{1

2

3

4}, Sebastian Urday^#¹, Patryk Kubiszewski², Lee Gilkerson⁵, Padmini Sekar⁵, Axana Rodriguez-Torres^{1

3}, Margaret Bettin⁶, Andreas Charidimou^{1

3}, Marco Pasi^{1

3}, Christina Kourkoulis^{1

2

3

4}, Kristin Schwab³, Zora DiPucchio^{1

3}, Tyler Behymer⁵, Jennifer Osborne⁵, Misty Morgan⁵, Charles J Moomaw⁵, Michael L James⁷, Steven M Greenberg^{1

3}, Anand Viswanathan^{1

3}, M Edip Gurol^{1

3}, Bradford B Worrall⁶, Fernando D Testai⁸, Jacob L McCauley⁹, Guido J Falcone¹⁰, Carl D Langefeld¹¹, Christopher D Anderson^{1

2

3

4

12}, Hooman Kamel¹³, Daniel Woo⁵, Kevin N Sheth, Jonathan Rosand^{1

2

3

4

12}

Affiliations

¹ Department of Neurology (A.B., S.U., A.R.-T., A.C., M.P., C.K., K.S., Z.D., S.M.G., A.V., M.E.G., C.D.A., J.R.), Massachusetts General Hospital, Boston.
² Center for Genomic Medicine (A.B., P.K., C.K., C.D.A., J.R.), Massachusetts General Hospital, Boston.
³ Hemorrhagic Stroke Research Program (A.B., A.R.-T., A.C., M.P., C.K., K.S., Z.D., S.M.G., A.V., M.E.G., C.D.A, J.R.), Massachusetts General Hospital, Boston.
⁴ Henry and Allison McCance Center for Brain Health (A.B., C.K., C.D.A., J.R.), Massachusetts General Hospital, Boston.
⁵ Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, OH (L.G., P.S., T.B., J.O., M.M., C.J.M., D.W.).
⁶ Department of Neurology, University of Virginia Health System, Charlottesville (M.B., B.B.W.).
⁷ Department of Anesthesiology, Duke University, Durham, NC (M.L.J.).
⁸ Department of Neurology and Rehabilitation, University of Illinois at Chicago College of Medicine, Chicago (F.D.T.).
⁹ Center for Genome Technology and Biorepository Facility, University of Miami, Miller School of Medicine, FL (J.L.M.).
¹⁰ Department of Neurology, Yale University School of Medicine, New Haven, CT (G.J.F.).
¹¹ Department of Biostatistics and Data Sciences, Wake Forest University, Winston-Salem, NC (C.D.L.).
¹² Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge (C.D.A., J.R.).
¹³ Department of Neurology, Weill Cornell School of Medicine, New York, NY (H.K.).

^# Contributed equally.

Abstract

Background and purpose: For survivors of oral anticoagulation therapy (OAT)-associated intracerebral hemorrhage (OAT-ICH) who are at high risk for thromboembolism, the benefits of OAT resumption must be weighed against increased risk of recurrent hemorrhagic stroke. The ε2/ε4 alleles of the apolipoprotein E (APOE) gene, MRI-defined cortical superficial siderosis, and cerebral microbleeds are the most potent risk factors for recurrent ICH. We sought to determine whether combining MRI markers and APOE genotype could have clinical impact by identifying ICH survivors in whom the risks of OAT resumption are highest.

Methods: Joint analysis of data from 2 longitudinal cohort studies of OAT-ICH survivors: (1) MGH-ICH study (Massachusetts General Hospital ICH) and (2) longitudinal component of the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage). We evaluated whether MRI markers and APOE genotype predict ICH recurrence. We then developed and validated a combined APOE-MRI classification scheme to predict ICH recurrence, using Classification and Regression Tree analysis.

Results: Cortical superficial siderosis, cerebral microbleed, and APOE ε2/ε4 variants were independently associated with ICH recurrence after OAT-ICH (all P<0.05). Combining APOE genotype and MRI data resulted in improved prediction of ICH recurrence (Harrell C: 0.79 versus 0.55 for clinical data alone, P=0.033). In the MGH (training) data set, CSS, cerebral microbleed, and APOE ε2/ε4 stratified likelihood of ICH recurrence into high-, medium-, and low-risk categories. In the ERICH (validation) data set, yearly ICH recurrence rates for high-, medium-, and low-risk individuals were 6.6%, 2.5%, and 0.9%, respectively, with overall area under the curve of 0.91 for prediction of recurrent ICH.

Conclusions: Combining MRI and APOE genotype stratifies likelihood of ICH recurrence into high, medium, and low risk. If confirmed in prospective studies, this combined APOE-MRI classification scheme may prove useful for selecting individuals for OAT resumption after ICH.

Keywords: anticoagulants; apolipoprotein E; cohort studies; genetics; thromboembolism.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Anticoagulants / adverse effects*
Apolipoprotein E4 / genetics*
Cerebral Hemorrhage / chemically induced*
Cerebral Hemorrhage / diagnostic imaging*
Cerebral Hemorrhage / genetics*
Female
Humans
Magnetic Resonance Imaging / methods
Male
Middle Aged
Neuroimaging / methods
Recurrence

Substances

Anticoagulants
Apolipoprotein E4

Abstract

Publication types

MeSH terms

Substances

Grants and funding