Intracranial Aneurysm Classifier Using Phenotypic Factors: An International Pooled Analysis

Sandrine Morel^{1

2}, Isabel C Hostettler^{3

4}, Georg R Spinner⁵, Romain Bourcier^{6

7}, Joanna Pera⁸, Torstein R Meling¹, Varinder S Alg³, Henry Houlden⁹, Mark K Bakker¹⁰, Femke Van't Hof¹⁰, Gabriel J E Rinkel¹⁰, Tatiana Foroud¹¹, Dongbing Lai¹¹, Charles J Moomaw¹², Bradford B Worrall¹³, Jildaz Caroff¹⁴, Pacôme Constant-Dits-Beaufils¹⁵, Matilde Karakachoff¹⁵, Antoine Rimbert⁶, Aymeric Rouchaud¹⁶, Emilia I Gaal-Paavola^{17

18}, Hanna Kaukovalta¹⁷, Riku Kivisaari¹⁷, Aki Laakso^{17

19}, Behnam Rezai Jahromi^{17

19}, Riikka Tulamo^{19

20}, Christoph M Friedrich^{21

22}, Jerome Dauvillier²³, Sven Hirsch⁵, Nathalie Isidor¹, Zolt Kulcsàr²⁴, Karl O Lövblad²⁴, Olivier Martin²³, Paolo Machi²⁴, Vitor Mendes Pereira²⁵, Daniel Rüfenacht²⁶, Karl Schaller¹, Sabine Schilling^{5

27}, Agnieszka Slowik⁸, Juha E Jaaskelainen^{28

29}, Mikael von Und Zu Fraunberg^{28

29}, Jordi Jiménez-Conde³⁰, Elisa Cuadrado-Godia³⁰, Carolina Soriano-Tárraga³⁰, Iona Y Millwood^{31

32}, Robin G Walters^{31

32}, The neurIST Project, The Ican Study Group, Genetics And Observational Subarachnoid Haemorrhage Gosh Study Investigators, International Stroke Genetics Consortium Isgc, Helen Kim^{33

34}, Richard Redon⁶, Nerissa U Ko³⁵, Guy A Rouleau³⁶, Antti Lindgren^{28

29

37}, Mika Niemelä^{17

19}, Hubert Desal⁷, Daniel Woo¹², Joseph P Broderick¹², David J Werring³, Ynte M Ruigrok¹⁰, Philippe Bijlenga¹

Affiliations

¹ Neurosurgery Division, Department of Clinical Neurosciences, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland.
² Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1205 Geneva, Switzerland.
³ Stroke Research Centre, University College London Queen Square Institute of Neurology, London WC1N 3BG, UK.
⁴ Department of Neurosurgery, Canton Hospital St. Gallen, 9000 St. Gallen, Switzerland.
⁵ ZHAW School of Life Sciences and Facility Management, 8820 Wädenswil, Switzerland.
⁶ Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), University Hospital Centre Nantes, University of Nantes, L'institut Du Thorax, 44007 Nantes, France.
⁷ Department of Neuroradiology, University Hospital of Nantes, 44000 Nantes, France.
⁸ Department of Neurology, Faculty of Medicine, Jagiellonian University Medical College, ul. Botaniczna 3, 31-503 Krakow, Poland.
⁹ Neurogenetics Laboratory, The National Hospital of Neurology and Neurosurgery, London WC1N 3BG, UK.
¹⁰ Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, 3584 CS Utrecht, The Netherlands.
¹¹ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
¹² Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
¹³ Departments of Neurology and Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
¹⁴ Department of Interventional Neuroradiology-NEURI Brain Vascular Center, Bicêtre Hospital, APHP, 94270 Le Kremlin Bicêtre, France.
¹⁵ Institut national de la santé et de la recherche médicale (INSERM), CIC 1413, Clinique des Données, University Hospital Centre Nantes, 44000 Nantes, France.
¹⁶ Department of Neuroradiology, Dupuytren University Hospital, 87000 Limoges, France.
¹⁷ Department of Neurosurgery, Helsinki University Hospital, University of Helsinki, 00260 Helsinki, Finland.
¹⁸ Clinical Neurosciences, University of Helsinki, Topeliuksenkatu 5, 00260 Helsinki, Finland.
¹⁹ Neurosurgery Research Group, Biomedicum, 00290 Helsinki, Finland.
²⁰ Department of Vascular Surgery, Helsinki University Hospital, University of Helsinki, 00290 Helsinki, Finland.
²¹ Department of Computer Science, University of Applied Science and Arts, 44139 Dortmund, Germany.
²² Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Hospital Essen, 45147 Essen, Germany.
²³ SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
²⁴ Diagnostic and Interventional, Department of Diagnostics, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland.
²⁵ Division of Neurosurgery, Department of Surgery, St Michael's Hospital, University of Toronto, Toronto, ON M5B 1W8, Canada.
²⁶ Swiss Neuroradiology Institute, 8002 Zurich, Switzerland.
²⁷ Lucerne School of Business, Lucerne University of Applied Sciences, 6002 Lucerne, Switzerland.
²⁸ Neurosurgery NeuroCenter Kuopio, University Hospital Kuopio, 70210 Kuopio, Finland.
²⁹ Institute of Clinical Medicine, Faculty of Health Sciences, University of Eastern Finland, 70210 Kuopio, Finland.
³⁰ Institut Hospital del Mar d'Investigacions Biomèdiques (IMIM) and Hospital del Mar, 08003 Barcelona, Spain.
³¹ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX1 2JD, UK.
³² MRC Population Health Research Unit, University of Oxford, Oxford OX1 2JD, UK.
³³ Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, CA 94143, USA.
³⁴ Department of Epidemiology and Biostatistics, Institute for Human Genetics, University of California, San Francisco, CA 94143, USA.
³⁵ Department of Neurology, University of California, San Francisco, CA 94143, USA.
³⁶ Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 0G4, Canada.
³⁷ Department of Clinical Radiology, Kuopio University Hospital, 70210 Kuopio, Finland.

PMID: 36143196
PMCID: PMC9501769
DOI: 10.3390/jpm12091410

Intracranial Aneurysm Classifier Using Phenotypic Factors: An International Pooled Analysis

Sandrine Morel et al. J Pers Med. 2022.

. 2022 Aug 30;12(9):1410.

doi: 10.3390/jpm12091410.

Authors

Affiliations

¹ Neurosurgery Division, Department of Clinical Neurosciences, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland.
² Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1205 Geneva, Switzerland.
³ Stroke Research Centre, University College London Queen Square Institute of Neurology, London WC1N 3BG, UK.
⁴ Department of Neurosurgery, Canton Hospital St. Gallen, 9000 St. Gallen, Switzerland.
⁵ ZHAW School of Life Sciences and Facility Management, 8820 Wädenswil, Switzerland.
⁶ Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), University Hospital Centre Nantes, University of Nantes, L'institut Du Thorax, 44007 Nantes, France.
⁷ Department of Neuroradiology, University Hospital of Nantes, 44000 Nantes, France.
⁸ Department of Neurology, Faculty of Medicine, Jagiellonian University Medical College, ul. Botaniczna 3, 31-503 Krakow, Poland.
⁹ Neurogenetics Laboratory, The National Hospital of Neurology and Neurosurgery, London WC1N 3BG, UK.
¹⁰ Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, 3584 CS Utrecht, The Netherlands.
¹¹ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
¹² Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
¹³ Departments of Neurology and Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
¹⁴ Department of Interventional Neuroradiology-NEURI Brain Vascular Center, Bicêtre Hospital, APHP, 94270 Le Kremlin Bicêtre, France.
¹⁵ Institut national de la santé et de la recherche médicale (INSERM), CIC 1413, Clinique des Données, University Hospital Centre Nantes, 44000 Nantes, France.
¹⁶ Department of Neuroradiology, Dupuytren University Hospital, 87000 Limoges, France.
¹⁷ Department of Neurosurgery, Helsinki University Hospital, University of Helsinki, 00260 Helsinki, Finland.
¹⁸ Clinical Neurosciences, University of Helsinki, Topeliuksenkatu 5, 00260 Helsinki, Finland.
¹⁹ Neurosurgery Research Group, Biomedicum, 00290 Helsinki, Finland.
²⁰ Department of Vascular Surgery, Helsinki University Hospital, University of Helsinki, 00290 Helsinki, Finland.
²¹ Department of Computer Science, University of Applied Science and Arts, 44139 Dortmund, Germany.
²² Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Hospital Essen, 45147 Essen, Germany.
²³ SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
²⁴ Diagnostic and Interventional, Department of Diagnostics, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland.
²⁵ Division of Neurosurgery, Department of Surgery, St Michael's Hospital, University of Toronto, Toronto, ON M5B 1W8, Canada.
²⁶ Swiss Neuroradiology Institute, 8002 Zurich, Switzerland.
²⁷ Lucerne School of Business, Lucerne University of Applied Sciences, 6002 Lucerne, Switzerland.
²⁸ Neurosurgery NeuroCenter Kuopio, University Hospital Kuopio, 70210 Kuopio, Finland.
²⁹ Institute of Clinical Medicine, Faculty of Health Sciences, University of Eastern Finland, 70210 Kuopio, Finland.
³⁰ Institut Hospital del Mar d'Investigacions Biomèdiques (IMIM) and Hospital del Mar, 08003 Barcelona, Spain.
³¹ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX1 2JD, UK.
³² MRC Population Health Research Unit, University of Oxford, Oxford OX1 2JD, UK.
³³ Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, CA 94143, USA.
³⁴ Department of Epidemiology and Biostatistics, Institute for Human Genetics, University of California, San Francisco, CA 94143, USA.
³⁵ Department of Neurology, University of California, San Francisco, CA 94143, USA.
³⁶ Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 0G4, Canada.
³⁷ Department of Clinical Radiology, Kuopio University Hospital, 70210 Kuopio, Finland.

PMID: 36143196
PMCID: PMC9501769
DOI: 10.3390/jpm12091410

Abstract

Intracranial aneurysms (IAs) are usually asymptomatic with a low risk of rupture, but consequences of aneurysmal subarachnoid hemorrhage (aSAH) are severe. Identifying IAs at risk of rupture has important clinical and socio-economic consequences. The goal of this study was to assess the effect of patient and IA characteristics on the likelihood of IA being diagnosed incidentally versus ruptured. Patients were recruited at 21 international centers. Seven phenotypic patient characteristics and three IA characteristics were recorded. The analyzed cohort included 7992 patients. Multivariate analysis demonstrated that: (1) IA location is the strongest factor associated with IA rupture status at diagnosis; (2) Risk factor awareness (hypertension, smoking) increases the likelihood of being diagnosed with unruptured IA; (3) Patients with ruptured IAs in high-risk locations tend to be older, and their IAs are smaller; (4) Smokers with ruptured IAs tend to be younger, and their IAs are larger; (5) Female patients with ruptured IAs tend to be older, and their IAs are smaller; (6) IA size and age at rupture correlate. The assessment of associations regarding patient and IA characteristics with IA rupture allows us to refine IA disease models and provide data to develop risk instruments for clinicians to support personalized decision-making.

Keywords: hypertension; intracranial aneurysm; location; risk factors; smoking; subarachnoid hemorrhage.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Cohort characteristics. Distribution of patients by sex (A), family history of IA (B), IA number (C,D), blood pressure (E), and smoking status (F). In panels (B–D), light blue represents participants with known IA location, and dark blue represents participants with missing or conflicting information. In panels (A,E,F), counts in parentheses correspond to the number of patients enrolled with known IA location. IA: Intracranial aneurysm; NBP: Normal Blood Pressure. Self-r. HBP: self-reported High Blood Pressure in the reference population, HBP prev.: HBP prevalence.

**Figure 2**
Patient characteristics and diagnosis of aSAH. Effect of family history of IA (A), blood pressure (B), smoking status (C), patient geographic location (D), sex (E), and IA multiplicity (F) on IA rupture status at diagnosis.

**Figure 3**
Intracranial aneurysm locations and risk of rupture. (A) Number of ruptured (dark blue) and unruptured (light blue) aneurysms for each IA location. (B) Relative risk for IA rupture, by IA location. The solid vertical line represents the relative risk for MCA. The dashed lines separate low-risk locations (left side) and high-risk locations (right side) from medium-risk locations (middle). (C) Distribution of IA size at rupture in high-risk (Acom, Pcom, VB, A2, and PCA, in red), medium-risk (MCA, ICA, basilar, A1, and other locations, in blue) and low-risk (Opht-ICA and Cav-ICA, in green) locations for rupture. (D) Distribution of patient’s age at rupture in high-risk (red), medium-risk (blue), and low-risk (green) IA locations for rupture. Acom: anterior communicating artery; MCA: middle cerebral artery; Pcom: posterior communicating artery; ICA: internal carotid artery; VB: vertebra-basilar artery, ophtl-ICA: ophthalmic segment of ICA, A2: anterior cerebral artery distal to Acom, cav-ICA: carotid-cavernous ICA, PCA: other posterior circulation arteries, A1: A1 anterior segment.

**Figure 4**
Patient’s age at time of rupture and risk factors for rupture. Patient’s age at IA rupture by sex (A), family history of IA (B), IA multiplicity (C), blood pressure (D), and smoking status (E).

**Figure 5**
Intracranial aneurysm size at rupture and risk factors for rupture. IA size at rupture by sex (A), family history of IA (B), IA multiplicity (C), blood pressure (D), and smoking status (E).

**Figure 6**
Importance of phenotypic markers for the likelihood of being diagnosed with a ruptured IA. (A) MLoR for diagnosis of aSAH. (B) MLiR for patient’s age at rupture and (C) MLiR for IA size at rupture. * p < 0.05, **p < 0.01, *** p < 0.001. (D) ROC curve of the MLoR.

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Intracranial Aneurysm Classifier Using Phenotypic Factors: An International Pooled Analysis

Affiliations

Intracranial Aneurysm Classifier Using Phenotypic Factors: An International Pooled Analysis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Medical