No additional prognostic value of genetic information in the prediction of vascular events after cerebral ischemia of arterial origin

The PROMISe study

Sefanja Achterberg, L. Jaap Kappelle, Paul I W De Bakker, Matthew Traylor, Ale Algra, Y. Van Der Graaf, D. E. Grobbee, G. E H M Rutten, F. L J Visseren, F. L. Moll, W. P T M Mali, P. A. Doevendans, Farrall Martin, Elizabeth G. Holliday, Cathie Sudlow, Jemma C. Hopewell, Yu Ching Cheng, Myriam Fornage, M. Arfan Ikram, Rainer Malik & 20 others Steve Bevan, Unnur Thorsteinsdottir, Anita L. DeStefano, Bradford B. Worrall, Alex P. Reiner, Braxton D. Mitchell, Robert Clarke, Christopher Levi, Sudha Seshadri, Giorgio B. Boncoraglio, Pankaj Sharma, Joshua C. Bis, Solveig Gretarsdottir, Bruce M. Psaty, Peter M. Rothwell, Jonathan Rosand, James F. Meschia, Kari Stefansson, Martin Dichgans, Hugh S. Markus

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: Patients who have suffered from cerebral ischemia have a high risk of recurrent vascular events. Predictive models based on classical risk factors typically have limited prognostic value. Given that cerebral ischemia has a heritable component, genetic information might improve performance of these risk models. Our aim was to develop and compare two models: one containing traditional vascular risk factors, the other also including genetic information. Methods and Results: We studied 1020 patients with cerebral ischemia and genotyped them with the Illumina Immunochip. Median follow-up time was 6.5 years; the annual incidence of new ischemic events (primary outcome, n=198) was 3.0%. The prognostic model based on classical vascular risk factors had an area under the receiver operating characteristics curve (AUC-ROC) of 0.65 (95% confidence interval 0.61-0.69). When we added a genetic risk score based on prioritized SNPs from a genome-wide association study of ischemic stroke (using summary statistics from the METASTROKE study which included 12389 cases and 62004 controls), the AUC-ROC remained the same. Similar results were found for the secondary outcome ischemic stroke. Conclusions: We found no additional value of genetic information in a prognostic model for the risk of ischemic events in patients with cerebral ischemia of arterial origin. This is consistent with a complex, polygenic architecture, where many genes of weak effect likely act in concert to influence the heritable risk of an individual to develop (recurrent) vascular events. At present, genetic information cannot help clinicians to distinguish patients at high risk for recurrent vascular events.

Original languageEnglish
Article numbere0119203
JournalPLoS One
Volume10
Issue number4
DOIs
Publication statusPublished - Apr 23 2015

Fingerprint

ischemia
Brain Ischemia
blood vessels
Blood Vessels
prediction
risk factors
stroke
ROC Curve
Area Under Curve
Stroke
Genome-Wide Association Study
Genes
Single Nucleotide Polymorphism
confidence interval
statistics
Confidence Intervals
incidence
Incidence
Statistics
genes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Achterberg, S., Kappelle, L. J., De Bakker, P. I. W., Traylor, M., Algra, A., Van Der Graaf, Y., ... Markus, H. S. (2015). No additional prognostic value of genetic information in the prediction of vascular events after cerebral ischemia of arterial origin: The PROMISe study. PLoS One, 10(4), [e0119203]. https://doi.org/10.1371/journal.pone.0119203

No additional prognostic value of genetic information in the prediction of vascular events after cerebral ischemia of arterial origin : The PROMISe study. / Achterberg, Sefanja; Kappelle, L. Jaap; De Bakker, Paul I W; Traylor, Matthew; Algra, Ale; Van Der Graaf, Y.; Grobbee, D. E.; Rutten, G. E H M; Visseren, F. L J; Moll, F. L.; Mali, W. P T M; Doevendans, P. A.; Martin, Farrall; Holliday, Elizabeth G.; Sudlow, Cathie; Hopewell, Jemma C.; Cheng, Yu Ching; Fornage, Myriam; Ikram, M. Arfan; Malik, Rainer; Bevan, Steve; Thorsteinsdottir, Unnur; DeStefano, Anita L.; Worrall, Bradford B.; Reiner, Alex P.; Mitchell, Braxton D.; Clarke, Robert; Levi, Christopher; Seshadri, Sudha; Boncoraglio, Giorgio B.; Sharma, Pankaj; Bis, Joshua C.; Gretarsdottir, Solveig; Psaty, Bruce M.; Rothwell, Peter M.; Rosand, Jonathan; Meschia, James F.; Stefansson, Kari; Dichgans, Martin; Markus, Hugh S.

In: PLoS One, Vol. 10, No. 4, e0119203, 23.04.2015.

Research output: Contribution to journalArticle

Achterberg, S, Kappelle, LJ, De Bakker, PIW, Traylor, M, Algra, A, Van Der Graaf, Y, Grobbee, DE, Rutten, GEHM, Visseren, FLJ, Moll, FL, Mali, WPTM, Doevendans, PA, Martin, F, Holliday, EG, Sudlow, C, Hopewell, JC, Cheng, YC, Fornage, M, Ikram, MA, Malik, R, Bevan, S, Thorsteinsdottir, U, DeStefano, AL, Worrall, BB, Reiner, AP, Mitchell, BD, Clarke, R, Levi, C, Seshadri, S, Boncoraglio, GB, Sharma, P, Bis, JC, Gretarsdottir, S, Psaty, BM, Rothwell, PM, Rosand, J, Meschia, JF, Stefansson, K, Dichgans, M & Markus, HS 2015, 'No additional prognostic value of genetic information in the prediction of vascular events after cerebral ischemia of arterial origin: The PROMISe study', PLoS One, vol. 10, no. 4, e0119203. https://doi.org/10.1371/journal.pone.0119203
Achterberg, Sefanja ; Kappelle, L. Jaap ; De Bakker, Paul I W ; Traylor, Matthew ; Algra, Ale ; Van Der Graaf, Y. ; Grobbee, D. E. ; Rutten, G. E H M ; Visseren, F. L J ; Moll, F. L. ; Mali, W. P T M ; Doevendans, P. A. ; Martin, Farrall ; Holliday, Elizabeth G. ; Sudlow, Cathie ; Hopewell, Jemma C. ; Cheng, Yu Ching ; Fornage, Myriam ; Ikram, M. Arfan ; Malik, Rainer ; Bevan, Steve ; Thorsteinsdottir, Unnur ; DeStefano, Anita L. ; Worrall, Bradford B. ; Reiner, Alex P. ; Mitchell, Braxton D. ; Clarke, Robert ; Levi, Christopher ; Seshadri, Sudha ; Boncoraglio, Giorgio B. ; Sharma, Pankaj ; Bis, Joshua C. ; Gretarsdottir, Solveig ; Psaty, Bruce M. ; Rothwell, Peter M. ; Rosand, Jonathan ; Meschia, James F. ; Stefansson, Kari ; Dichgans, Martin ; Markus, Hugh S. / No additional prognostic value of genetic information in the prediction of vascular events after cerebral ischemia of arterial origin : The PROMISe study. In: PLoS One. 2015 ; Vol. 10, No. 4.
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abstract = "Background: Patients who have suffered from cerebral ischemia have a high risk of recurrent vascular events. Predictive models based on classical risk factors typically have limited prognostic value. Given that cerebral ischemia has a heritable component, genetic information might improve performance of these risk models. Our aim was to develop and compare two models: one containing traditional vascular risk factors, the other also including genetic information. Methods and Results: We studied 1020 patients with cerebral ischemia and genotyped them with the Illumina Immunochip. Median follow-up time was 6.5 years; the annual incidence of new ischemic events (primary outcome, n=198) was 3.0{\%}. The prognostic model based on classical vascular risk factors had an area under the receiver operating characteristics curve (AUC-ROC) of 0.65 (95{\%} confidence interval 0.61-0.69). When we added a genetic risk score based on prioritized SNPs from a genome-wide association study of ischemic stroke (using summary statistics from the METASTROKE study which included 12389 cases and 62004 controls), the AUC-ROC remained the same. Similar results were found for the secondary outcome ischemic stroke. Conclusions: We found no additional value of genetic information in a prognostic model for the risk of ischemic events in patients with cerebral ischemia of arterial origin. This is consistent with a complex, polygenic architecture, where many genes of weak effect likely act in concert to influence the heritable risk of an individual to develop (recurrent) vascular events. At present, genetic information cannot help clinicians to distinguish patients at high risk for recurrent vascular events.",
author = "Sefanja Achterberg and Kappelle, {L. Jaap} and {De Bakker}, {Paul I W} and Matthew Traylor and Ale Algra and {Van Der Graaf}, Y. and Grobbee, {D. E.} and Rutten, {G. E H M} and Visseren, {F. L J} and Moll, {F. L.} and Mali, {W. P T M} and Doevendans, {P. A.} and Farrall Martin and Holliday, {Elizabeth G.} and Cathie Sudlow and Hopewell, {Jemma C.} and Cheng, {Yu Ching} and Myriam Fornage and Ikram, {M. Arfan} and Rainer Malik and Steve Bevan and Unnur Thorsteinsdottir and DeStefano, {Anita L.} and Worrall, {Bradford B.} and Reiner, {Alex P.} and Mitchell, {Braxton D.} and Robert Clarke and Christopher Levi and Sudha Seshadri and Boncoraglio, {Giorgio B.} and Pankaj Sharma and Bis, {Joshua C.} and Solveig Gretarsdottir and Psaty, {Bruce M.} and Rothwell, {Peter M.} and Jonathan Rosand and Meschia, {James F.} and Kari Stefansson and Martin Dichgans and Markus, {Hugh S.}",
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T1 - No additional prognostic value of genetic information in the prediction of vascular events after cerebral ischemia of arterial origin

T2 - The PROMISe study

AU - Achterberg, Sefanja

AU - Kappelle, L. Jaap

AU - De Bakker, Paul I W

AU - Traylor, Matthew

AU - Algra, Ale

AU - Van Der Graaf, Y.

AU - Grobbee, D. E.

AU - Rutten, G. E H M

AU - Visseren, F. L J

AU - Moll, F. L.

AU - Mali, W. P T M

AU - Doevendans, P. A.

AU - Martin, Farrall

AU - Holliday, Elizabeth G.

AU - Sudlow, Cathie

AU - Hopewell, Jemma C.

AU - Cheng, Yu Ching

AU - Fornage, Myriam

AU - Ikram, M. Arfan

AU - Malik, Rainer

AU - Bevan, Steve

AU - Thorsteinsdottir, Unnur

AU - DeStefano, Anita L.

AU - Worrall, Bradford B.

AU - Reiner, Alex P.

AU - Mitchell, Braxton D.

AU - Clarke, Robert

AU - Levi, Christopher

AU - Seshadri, Sudha

AU - Boncoraglio, Giorgio B.

AU - Sharma, Pankaj

AU - Bis, Joshua C.

AU - Gretarsdottir, Solveig

AU - Psaty, Bruce M.

AU - Rothwell, Peter M.

AU - Rosand, Jonathan

AU - Meschia, James F.

AU - Stefansson, Kari

AU - Dichgans, Martin

AU - Markus, Hugh S.

PY - 2015/4/23

Y1 - 2015/4/23

N2 - Background: Patients who have suffered from cerebral ischemia have a high risk of recurrent vascular events. Predictive models based on classical risk factors typically have limited prognostic value. Given that cerebral ischemia has a heritable component, genetic information might improve performance of these risk models. Our aim was to develop and compare two models: one containing traditional vascular risk factors, the other also including genetic information. Methods and Results: We studied 1020 patients with cerebral ischemia and genotyped them with the Illumina Immunochip. Median follow-up time was 6.5 years; the annual incidence of new ischemic events (primary outcome, n=198) was 3.0%. The prognostic model based on classical vascular risk factors had an area under the receiver operating characteristics curve (AUC-ROC) of 0.65 (95% confidence interval 0.61-0.69). When we added a genetic risk score based on prioritized SNPs from a genome-wide association study of ischemic stroke (using summary statistics from the METASTROKE study which included 12389 cases and 62004 controls), the AUC-ROC remained the same. Similar results were found for the secondary outcome ischemic stroke. Conclusions: We found no additional value of genetic information in a prognostic model for the risk of ischemic events in patients with cerebral ischemia of arterial origin. This is consistent with a complex, polygenic architecture, where many genes of weak effect likely act in concert to influence the heritable risk of an individual to develop (recurrent) vascular events. At present, genetic information cannot help clinicians to distinguish patients at high risk for recurrent vascular events.

AB - Background: Patients who have suffered from cerebral ischemia have a high risk of recurrent vascular events. Predictive models based on classical risk factors typically have limited prognostic value. Given that cerebral ischemia has a heritable component, genetic information might improve performance of these risk models. Our aim was to develop and compare two models: one containing traditional vascular risk factors, the other also including genetic information. Methods and Results: We studied 1020 patients with cerebral ischemia and genotyped them with the Illumina Immunochip. Median follow-up time was 6.5 years; the annual incidence of new ischemic events (primary outcome, n=198) was 3.0%. The prognostic model based on classical vascular risk factors had an area under the receiver operating characteristics curve (AUC-ROC) of 0.65 (95% confidence interval 0.61-0.69). When we added a genetic risk score based on prioritized SNPs from a genome-wide association study of ischemic stroke (using summary statistics from the METASTROKE study which included 12389 cases and 62004 controls), the AUC-ROC remained the same. Similar results were found for the secondary outcome ischemic stroke. Conclusions: We found no additional value of genetic information in a prognostic model for the risk of ischemic events in patients with cerebral ischemia of arterial origin. This is consistent with a complex, polygenic architecture, where many genes of weak effect likely act in concert to influence the heritable risk of an individual to develop (recurrent) vascular events. At present, genetic information cannot help clinicians to distinguish patients at high risk for recurrent vascular events.

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