@neurIST : Informatique biomédicale intégrée Pour la Gestion Des anévrismes cérébraux
Conditions: Intracranial Aneurysm
Sponsor: University Hospital, Geneva

 
@neurIST : informatique biomédicale intégrée pour la 
gestion des anévrismes cérébraux 
 
 
 
 
Research legislation: 
 Ordinance on human research with the exception of Clinical trials 
(HRO) (1). 
 
 
Type of Research Project: 
Research project involving human subjects  
 
 
Risk Categorisation:  
Category A according to ordinance HRO Art.7 
 
 
Project Leader:                      Prof. Philippe Bijlenga, Médecin adjoint agrégé, 
                                               Neurosurgery, Department of Clinical Neurosciences 
                                               Hôpitaux Universitaire de Genève 
                                               4 rue Gabrielle-Perret-Gentil 
                                               1211 Genève 14 
                                               079 204 40 43 
                                               philippe.bijlenga@hcuge.ch 
 
 

 
 
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PROTOCOL SIGNATURE FORM  
 
Study Title 
@neurIST : informatique biomédicale intégrée pour la 
gestion des anévrismes cérébraux 
 
The project leader (main center) and the investigator (at the local center/site) have approved the 
protocol version [6 (dated 16.05.2022)], and confirm hereby to conduct the project according to 
the protocol, the Swiss legal requirements (1, 2), the current version of the World Medical 
Association Declaration of Helsinki (3) and the principles and procedures for integrity in scientific 
research involving human beings. 
 
Project leader (lead center/site) 
 
Site Geneva University Hospitals, Geneva 
 
Name: Philippe Bijlenga 
Date: 
 _________________________ 
Signature:  ___________________________  
 
 
 
 
 
 
Sponsor:  
 
Name: Hôpitaux Universitaire de Genève 
Date: 
 _________________________ 
Signature:  ___________________________  
 
 
 
 
 
 
 
 
 

 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS 
3 
GLOSSARY OF ABBREVATIONS 
4 
1 BACKGROUND AND PROJECT RATIONALE 
6 
1.1 
Legal requirements 
6 
1.2 
Scientific background 
7 
1.3 
Rational for the research project 
11 
2 PROJECT OBJECTIVES AND DESIGN 
14 
2.1 
Hypothesis and primary and secondary objectives 
14 
2.2 
Primary and secondary endpoints 
15 
2.3 
Project design 
19 
3 PROJECT POPULATION AND STUDY PROCEDURES 
19 
3.1 
Project population, inclusion and exclusion criteria 
19 
3.2 
Recruitment, screening and informed consent procedure 
21 
3.3 
Study procedures 
23 
3.4 
Withdrawal and discontinuation 
30 
4 STATISTICS AND METHODOLOGY 
31 
4.1 
Statistical analysis plan 
31 
4.2 
Handling of missing data 
33 
5 REGULATORY ASPECTS AND SAFETY 
33 
5.1 
Local regulations / Declaration of Helsinki 
33 
5.2 
Notification of safety and protective measures (HRO Art. 20) 
33 
5.3 
Serious events (HRO Art. 21) 
33 
5.4 
Procedure for investigations involving radiation sources 
34 
5.5 
Amendments 
34 
5.6 
End of project 
34 
5.7 
Insurance 
35 
6 FURTHER ASPECTS 
35 
6.1 
Overall ethical considerations 
35 
6.2 
Risk-Benefit Assessment 
35 
6.3 
Rationale for the inclusion of vulnerable participants 
36 
7 QUALITY CONTROL AND DATA PROTECTION 
36 
7.1 
Quality measures 
36 
7.2 
Data recording and source data 
37 
7.3 
Confidentiality and coding 
37 
7.4 
Retention and destruction of study data and biological material 
40 
8 FUNDING / PUBLICATION / DECLARATION OF INTEREST 
41 
8.1 
Funding 
41 
8.2 
Publications of results 
41 
8.3 
Declaration of interest 
41 
8.4 
Data sharing 
41 
9 REFERENCES 
42 
10 APPENDIX 
45 

 
 
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GLOSSARY OF ABBREVATIONS 
 
AUC 
Area Under the Curve 
CCU 
Critical Care Unit 
CFD 
Computational Flow Dynamics  
CI 
Confidence Interval 
CSF 
Cerebro-Spinal Fluid 
CT 
Computerized Tomography 
CTA 
Computed Tomography Angiography 
DAI 
Data Acquisition Identifier 
DALY 
Disability-Adjusted Life Year 
DoH 
Declaration of Helsinki 
DRA 
Digital Rotational Angiography 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EGEP 
Essentials of Good Epidemiological Practice 
E5Y 
Every 5 Years 
FOPH 
Federal Office for Public Health 
HRA 
Human Research Act 
HRO 
Human Research Ordinance 
GCP 
Good Clinical Practice 
IAs 
Intracranial Aneurysms 
ICU 
Intermediate Care Unit 
ISUIA 
International Study of Unruptured Intracranial Aneurysms 
ICP 
IntraCranial Pressure 
GCS 
Glasgow Coma Scale 
M3 
Month 3 
M6 
Month 6 
MMSE 
Mini-Mental State Examination 
MoCA 
Montreal Cognitive Assessment score 
MRA 
MRI 
mRS 
Magnetic Resonance Angiography 
Magnetic Resonance Imaging 
Modified Ranking Scale 
NIHS 
National Institute of Health Stroke 
OR 
Odds Ratio 
PKD 
Polycystic Kidney Disease 
rCBF 
regional Cerebral Blood Flow 
ROC 
Receiver Operating Characteristic 
SAH 
SubArachnoid Hemorrhage  
SE 
Serious Event 
ADB 
AneurysmDataBank 
UCAS 
Unruptured Cerebral AneurysmS 

 
 
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UIAT 
Unruptured Intracranial Aneurysm Treatment 
W6 
Week 6 
Y1 
Year 1 
Y2 
Year 2 
Y5 
Year 5 
YLL 
Years of Life Lost 
YLD 
Years Lost due to Disability 
 
 

 
 
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1 BACKGROUND AND PROJECT RATIONALE  
1.1 Legal requirements 
1) Ethical conduct of study: 
The research project will be carried out in accordance to the research plan and with 
principles enunciated in the current version of the Declaration of Helsinki (DoH) (3), the 
principles of Good Clinical Practice, the Human Research Act (HRA) (2) and the Human 
Research Ordinance (HRO) (1) as well as other locally relevant regulations. The Ethics 
Committee (EC) and regulatory authorities will be informed about project start and 
termination.  
 
2) Risk categorisation: 
According to HRO Art. 7, this project comes under Category A because the planned 
measures for sampling biological material or collecting personal data entail only minimal 
risks and burdens: 
- 
Biological samples taken for this project i.e. aneurysmal dome and cerebro-spinal 
fluid (CSF) are biological samples normally harvesting during surgery and are 
never used for diagnostics. 
- 
Clinical information and images used for this project are not collected especially 
for this project but come from the patient clinical folder. During routine visits, the 
evolution of the intracranial aneurysm is monitored and the outcome of the patient 
is evaluated. As patients suffering from intracranial aneurysm have to go regularly 
to the hospital for the follow-up of their disease, enrolled patients in our study will 
not have to go to the hospital specially for the current project.  
- 
Risk associated with this project are those associated with blood puncture i.e. low 
risk of infection and hematoma. 
- 
Saliva and stool collection are without danger for the participant. 
- 
Concerning data security, information will be transferred over networks and links 
will be made with electronic hospital patient records. It is a part of the project to 
control accesses, and comply to all clinical research good practice requirements 
(please see details on section 7) 
 
3) Participant information and informed consent: 
All participants will be informed about the research project by the clinician in charge of 
the patient or by research nurses or clinical researchers dedicated to the present project.  
Information letters and informed consents are the following: 
- 
General information letter and associated informed consent (Annex 1); 
- 
General information letter and associated informed consent for patient recruited in 
emergency (Annex 2) 
- 
General information letter and associated informed consent for patient incapable 
of discernment (Annex 3) 
- 
General information letter and associated informed consent for patient incapable 
of discernment and recruited in emergency (Annex 4) 
- 
Genetic information letter and associated informed consent (Annex 5); 
- 
Genetic information letter and associated informed consent for patient incapable 
of discernment (Annex 6); 
- 
Declaration of informed consent for the re-use of biological data and samples in 
coded form (Annex 7); 
- 
Declaration of informed consent for the re-use of biological data and samples in 
coded form for patient incapable of discernment (Annex 8); 

 
 
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- 
Declaration of Withdrawal of Consent (Annex 9); 
- 
Declaration of Withdrawal of Consent for patient incapable of discernment (Annex 
10). 
 
Vulnerable participants will be recruited in normal and emergency settings by involving 
the next of kin as soon as possible as the patient’s representative. The next of kin will be 
informed about the research project by the clinician in charge of the patient or by research 
nurses or clinical researchers dedicated to the present project. The next of kin will be 
invited to sign a temporary consent form. As soon as the patient recovers the ability to 
consent and within a delay of 3 months, a formal definitive consent will be obtained from 
the patient. All patients recruited before the age of 18 will be invited to confirm their 
consent within 3 months of their 18th birthday. 
Agreement or refusal of each participant will be recorded in the eCRF “AneuX_Données 
Légales” (Annex 11). 
 
4) Participant privacy and safety: 
The Project Leader affirms and upholds the principle of the participants’ right to dignity, 
privacy and health and that the project team shall comply with applicable privacy laws. 
Especially, anonymity of the participants shall be guaranteed when presenting the data 
at scientific meetings or publishing them in scientific journals.  
Individual participant medical information obtained as a result of this research project is 
considered confidential and disclosure to third parties is prohibited. Participant 
confidentiality will be further ensured by utilising identification code numbers to 
correspond to medical information in the computer files. 
For data verification purposes, authorised representatives of the Sponsor, a competent 
authority, or an ethics committee may require direct access to parts of the medical records 
relevant to the project, including participants’ medical history. 
 
1.2 Scientific background  
Aneurysm is a disease of the vessel wall resulting in the deformation and enlargement 
of the vascular lumen. If the process of deformation remains active, the vessel wall may 
rupture and produce a hemorrhage, or a thrombosis and an ischemia may occur. All 
vessels can be affected but we are more particularly interested by Intracranial 
Aneurysms (IAs) (4). IAs are mostly quiescent and asymptomatic but when rupturing, 
potentially induce severe brain damage and death. The prevalence of IAs is high (2 to 
5%) and affects young people (median at 50 years) (5). The major risk with IAs is their 
rupture, which results in a SubArachnoid Hemorrhage (SAH) (6). SAH occurs in 5 to 
10/100.000 inhabitants per year. In Switzerland, SAH results in 24% death, 11% 
severely disabled patients and 64% patients recovering to a more or less independent 
life. Only 24% of the patients recover with no residual symptoms (7). Most of the IAs are 
asymptomatic and are rather incidentally detected. As image-based diagnosis is 
increasingly prescribed, the proportion of patients diagnosed with incidental IAs is likely 
to grow.  Today, more and more patients face the extreme situation of taking a decision 
whether or not to risk an intervention (8-10). The complexity of decision-making 
regarding IA management has significantly increased since the last century. During the 
80’, all diagnosed aneurysms were considered at high risk and treated by microsurgical 
clipping. Nowadays, many technical innovations are regularly developed promoting less 
invasive interventions, but the risk associated with the surgery and the post-surgery 
disability for the patient are still elevated. 

 
 
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1) Current knowledge on IAs initiation, growth and rupture: 
IA is a heterogeneous disease that results from the combination of multiple factors over 
time. The general consensus is that IAs progress through different stages associated 
with specific predisposing factors, injuries, repair mechanisms, and treatments that all 
influence the balance between healing and progression (11, 12). 
 
A. Vessel conformations and IAs: 
Observations suggest that abnormal cerebral vasculogenesis and suboptimal 
geometrical conformation may favor aneurysm formation. Once an aneurysm appeared, 
the complexity of local flow conditions is increased and wall shear stress gradients in 
time and space are steeper. Observation of the aneurysm vessel wall shows that 
impairment of the endothelial surface and of the elastic lamina is early sign of vessel 
wall disease. These damages lead to the exposition of the muscle cells to the vascular 
lumen inducing platelet aggregation, inflammatory cell infiltration and finally progressive 
de-cellularisation of the vessel wall. 
As observed for many years, IAs develop on arterial feeders of arterio-venous 
malformations. In that specific situation, the treatment of the malformation is known to 
be sufficient to stabilize or shrink the aneurysms overtime (13-15). This observation 
leads to the hypothesis that aneurysm growth and rupture is driven by the vessel luminal 
hemodynamic. 
Shape of bifurcation influences also hemodynamic forces on the vessel wall and may 
play an important role for the initiation of aneurysm formation. Studies showed an 
association between sub-optimal bifurcation geometries and presence of aneurysms 
(16, 17). Presently, aneurysm location on specific artery segments or bifurcations is the 
strongest factor associated with the risk of aneurysm occurrence and risk of aneurysm 
rupture (8-10, 18). Those observations lead to the hypothesis that vessel shape may 
induce hemodynamic conditions prone to induce aneurysm formation. 
 
B. Aneurysm shape and risk of rupture: 
Aneurysm size is well recognized to be the second strongest factor used to assess the 
risk of aneurysm rupture (8-10, 18). Aneurysm shape may also influence luminal flow 
patterns and future progression of the disease. A study published in 2011 describes the 
importance and benefit of studying the blood flow in patient specific vessel geometries 
to understand the mechanism of the disease and evaluate the risk of aneurysm rupture. 
The authors report that qualitative hemodynamic analysis of cerebral aneurysms by 
using image-based patient-specific geometries showed that concentrated inflow jets, 
small impingement regions, complex flow patterns, and unstable flow patterns are 
correlated with a clinical history of prior aneurysm rupture (19). Studies report a 
signature aneurysm wall shear stress profile associated with aneurysm rupture (20-23). 
Very recently, we showed that irregular lumen shape carries significant information on 
the aneurysm's disease status (24). Such irregularity constitutes a continuous 
parameter showing a strong association with the rupture status. Those observations 
lead to the hypothesis that aneurysm shape may induce hemodynamic or mirror 
biological conditions prone to inducing aneurysm growth or rupture.  
 
C. Environmental and life style risk factors for IAs: 
A variety of risk factors have been identified and their respective individual impact on 
the disease and patient outcome not fully investigated. Women are more affected than 
men, smokers more than non-smokers and hypertensive patients more than 

 
 
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normotensive subjects (7, 25, 26). Oral and gut microbiota emerged as critical 
environmental factors contributing to human physiology and pathology. Recently, oral 
bacteria derived DNA has been found in both ruptured and unruptured IA walls in 
surgically treated Finnish patients (27, 28), suggesting that dental infection could be a 
part of the pathophysiology of IA disease. Moreover, a mouse model of induced IA 
formation showed the relevance of gut microbiota for IA formation, and showed that 
exposure to gut microbiota affects the remodeling of cerebral artery wall through 
modulation of local immune response without local bacterial infection (29). Interestingly, 
IA patients have used more antibiotics than their age and gender matched population, 
suggesting that dysbiosis of the microbiota might be relevant in IA formation also in 
humans (30). While it remains to be studied whether gastrointestinal tract microbiota is 
relevant for IA formation in humans, it is important to note that oral microbiota dysbiosis 
can affect also the microbiota of the gastrointestinal tract (31), thus generating yet 
another possible explanation how periodontitis may predispose to IA formation. Oral and 
intestinal microbiota are strongly influenced by the local environment and eating habits. 
The association of oral and gut microbiota would represent a new factor influencing IA 
disease that might explain the currently unpredictable evolution of this disease. 
Importantly, identification of specific forms of oral and gut microbiota would serve as risk 
biomarkers for IA disease and rupture, and as a target for medical treatment. The clinical 
alteration, the amount of bleeding and the optimal choice of treatment management all 
impact independently on the long-term the patient outcome. New evidence appears 
showing that effects of combined factors vary according to different patient groups and 
need complex modeling (18, 32-34). 
 
D. Genetics and IAs: 
Genetic mechanisms for IA may be either mono-factorial (one single gene with a very 
strong effect present in the person’s genome can cause the disease) or multi-factorial 
(multiple genes with mild effects present at the same time in the person’s genome can 
predispose to the disease). For example, studies of cases with a familial history of IAs 
reveal that patients affected by Polycystic Kidney Disease (PKD) are by far the most 
prone to suffer from IA with a penetrance of approximately 20% (5, 35, 36). Vascular 
consequences of PKD seem to be due to a dysfunction of the endothelial cells in 
response to the wall shear stress induced by the blood flow on the vessel wall (37). 
Studying the level of expression of a high number of different genes in circulating blood 
cells from healthy volunteers and patients affected with IAs lead to the identification of 
differentially expressed genes (38-40). The expression of forty-two genes is significantly 
modified in patients affected by non-ruptured IAs. Functional analysis shows immune 
system, inflammatory system and apoptosis to be the major biological processes 
implicated with aneurysm rupture whereas cell-cell communication and cytoskeleton 
seem to be implicated in aneurysm formation. Last year by performing a cross-ancestry, 
genome-wide association study in 10,754 cases and 306,882 controls of European and 
East Asian ancestry, we discovered 17 risk loci associated with IA disease, 11 of which 
are new (41). These results revealed a polygenic architecture and explained over half 
of the disease heritability. A high genetic correlation between ruptured and unruptured 
IAs has been shown. We also found a suggestive role for endothelial cells by using gene 
mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between 
IAs and antiepileptic and sex hormone drugs, providing insights into IA pathophysiology. 
Finally, genetic risks for smoking and high blood pressure, the two main clinical risk 
factors, play important roles in IA risk, and drive most of the genetic correlation between 
IA and other cerebrovascular traits. Such results suggest that the multifactorial effects 

 
 
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extend out of genetics and involve interactions between environmental and genetic 
factors to cause the disease. Schematically, mono-factorial inheritance is responsible 
for familial cases while multi-factorial inheritance is mainly responsible for sporadic 
cases. Because roughly 10% of patients with aneurysmal SAH have first or second-
degree relatives with SAH or non-ruptured IA aneurysms there is a likely genetic 
component to IA. 
 
2) Current management of non-ruptured IAs: 
Currently, the process of disease diagnosis, treatment planning and treatment 
development is compromised by the fragmentation of the underpinning data. Indeed, 
information is available from a wide range of sources at all levels from personal to 
population, and at all length scales from molecular through cellular and organ to system. 
Clinical decision making is usually performed by categorizing aneurysms as high or low 
risk of rupture considering: 
- 
Location in a high or low risk segment of the cerebrovascular tree; 
- 
Size smaller than 4 mm, 7 mm or larger; 
- 
Overall aneurysm shape as saccular or fusiform; 
- 
Already rupture status of the patient. 
 
From this categorization, clinicians decide to observe or secure the aneurysm by an 
intervention exposing patients to risks that are difficult to balance. It appears that 
aggressive clinical treatment is not justified in all cases incidentally diagnosed with IA. 
Today, an increasing number of patients are monitored instead of being treated (9, 42-
44). Clinicians have to extrapolate the individual risk of aneurysm rupture using 
observations made on cohorts of highly selected patients. Those cohorts are known to 
poorly represent the general population of subjects seeking medical advice for 
management of an IA. Due to the potential high impact of the decision, patients tend to 
refuse randomization regarding treatment, consequently, randomized controlled trials 
have failed to recruit (45-47). As a result, it appears very difficult to inform the patient on 
specific rupture versus treatment risks. Currently, the estimation of the aneurysm’s 
rupture is based on the PHASES score (Table 1) (9). This is the best available tool but 
it only estimates the risk of rupture without prediction of death or disability associated 
with the treatment, and without estimation of the quality of life of the patient following the 
discovery of the IA and after the treatment. 
 

 
 
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Table 1: PHASES aneurysm risk score (9) 
Regarding the treatment of non-ruptured IAs, better understanding of the nature 
of IAs, and of the interaction between multiple and complex risk factors 
associated with aneurysm formation, growth and rupture, will allow us to create 
a decision support tool to assist the management of IAs. 
 
1.3 Rational for the research project 
As can be estimated from the discrepancy between the high prevalence of IAs (2-5% of 
the population) and the low incidence of rupture (5-10/100.000 inhabitants/year), 50% 
of the patients diagnosed with an IA will never suffer from a bleeding (5). Treatment of 
non-ruptured IA is associated to risky interventions that may induces patient’s disability 
for several months and also death in the worst case. Financially, the average treatment 
and first year follow-up care costs for an IA patient is approximately CHF 40’000. 
Regarding the consequences of the treatment of non-ruptured IAs, better understanding 
of the nature of IAs, and of the interaction between multiple and complex risk factors 
relating to aneurysm formation, growth and rupture is needed to create a decision 
support tool for the management of IAs. To address this clinical challenge of obtaining 
a lifelong optimal patient health, we address to answer the following questions: 
1) Who in the population should be screened for IAs?  
2) Among patients diagnosed with IAs, whom should an intervention be offered? 
3) Among patients diagnosed with IAs and initially observed, when should an 
intervention be offered? 
4) Which intervention or management plan would offer the best outcome? 

 
 
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This project requires a holistic approach integrating information regarding: 
- 
Genetics 
- 
Environmental and life style factors, comorbidities and treatments  
- 
Congenital factors (i.e. cerebrovascular anatomical variants) 
- 
Shape of cerebral vessels and lesions 
- 
Hemodynamic conditions in the cerebral vessel lumen 
- 
Proteomic variants or profiles in blood, CSF or aneurysmal dome tissue 
- 
Blood bacterial infection and inflammation 
- 
Oral and gut microbiota 
- 
Risk of disability and/or death associated with intervention undertaken to secure 
IAs 
- 
Quality of life of the patient after discovery of the aneurysm and aneurysm surgery 
 
1) Rational for genetic investigations 
Several studies have highlighted genes that could be implicated in IAs initiation, growth 
or rupture but nowadays no definitive relationship has been demonstrated between one 
specific gene or a family of genes and IAs. Pursuing this research avenue more 
particularly in patients with a positive familial history of IAs would be a powerful 
complement because: 
- 
Finding genetic linkage for familial cases will help in reducing the complexity of 
the genetics of IA. 
- 
Genes responsible for familial cases may point out candidate genes for the 
sporadic forms of the disease. 
- 
Some sporadic cases may actually belong to the familial group if for instance 
some members died before the disease has developed, nothing is known about 
the early death of a family member or whether there is only a single child in the 
family. 
- 
Risk assessment in the context of a familial case may be substantially different 
as compared to sporadic cases. 
- 
We may find new loci that could be specific to each sub-population. 
- 
Screening for genetic markers of risk factors (like i.e. smoking or blood 
hypertension) may allow a better clustering of cases and associated with clinical 
information improve the precision of predictors. 
Finding a genetic profile predisposing to IA formation or favoring IA rupture could result 
in a blood-screening test allowing a cheap and efficient selection of a population at risk. 
 
2) Rational for information collection on environmental and life style factors, 
comorbidities and treatments 
Currently, IAs have been described to be more present in women, smokers and 
hypertensive people (5), but the effects of this factors for IAs growth and rupture are not 
yet established and need more investigations. Oral and intestinal microbiota are strongly 
influenced by the local environment and eating habits. Recent work suggests a 
connection between IA and oral and gut microbiota, but a direct linked has never been 
proved. As IAs is a multifactorial disease it appears crucial to integrate all factors 
influencing patient’s biology such as environmental and life style factors, co-morbidities 
and associated treatments. For details about all parameters that will be recorded, please 
see the electronic Case Report Forms (eCRFs) “AneuX_Antécédents“ (Annex 12), and 
“Aneux_Microbiote” (Annex 13). 

 
 
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3) Rational for evaluation of congenital cerebro-vascular anatomical variants 
People with arterio-venous malformations are known to be more prone for IAs formation 
as compared with people presenting a normal cerebro-vascular anatomy. As IAs growth 
and rupture seem to be influenced by hemodynamics flux in the parental artery and 
inside the aneurysm (22), presence of malformations could have additional effects on 
IAs growth and rupture (13, 14). In addition, existence of arterio-venous malformations 
increases risks during surgery (15). For these different reasons, more investigations are 
needed about the cerebro-vascular anatomy and IAs to better balance the risk between 
rupture and surgery. 
 
4) Rational for cerebral imagery 
As described above, aneurysm size and shape may induce hemodynamic or mirror 
biological conditions prone to induce aneurysm growth or rupture. Studying the 
differences between patients bearing anatomically stable lesion or in contrast lesions 
that do change in shape or size could provide information on the mechanism of disease 
activation or healing processes. Pursuing this avenue of research may allow the design 
of a better case classifier. 
 
5) Rational for Computational Fluid Dynamics analysis 
Increasing evidences allow researchers and neurosurgeons to consider that shear 
stress profile inside an aneurysm could define its growth and its risk of rupture (19-23). 
In this context, Computational Fluid Dynamics (CFD) analysis of Doppler, 3D-Digital 
Rotational Angiography (DRA) or 3D-Digital Subtracted Angiography (DSA) images 
performed during cerebro-vascular investigations for the characterizations of the IAs 
should provide qualitative measures aimed at assigning aneurysm risk of future rupture.  
 
6) Rational for proteomics analysis 
Following on the same track but one step down stream, differential protein expression 
and post-translational modification will be studied in blood, CSF and/or aneurysmal 
dome tissue. Searching for new biological markers of cerebral trauma and predictors of 
SAH complication such as vasospasm, will allow to identify markers for a better staging 
of the disease and hopefully to find prevention mechanisms or medications. 
 
7) Rational for quality of life and surgery risk evaluations  
Nowadays, the PHASES score is the best available tool for the prediction of IA risk of 
rupture (9), but it doesn’t consider the risk of death or disability associated with 
interventions, and the impact of IA discovery and surgery on the quality of life of the 
patient. The type of treatment (i.e. surgical clipping, endovascular coiling, stenting or 
combination) offered to patients is decided on the basis of aneurysm and patient specific 
factors balanced by a multidisciplinary team. The level of risk for death and disability 
associated with intervention is estimated on the basis of the team’s experience. There 
is currently a significant knowledge gap regarding the risk quantification as a function of 
aneurysm, patient and intervention factors. Intervention-related risk factors have been 
implemented in the Unruptured Intracranial Aneurysms Treatment (UIAT) score (Table 
2) but no distinction between the different type of treatment has been made (48). It is 
therefore expected to improve decision making by quantifying risks integrating 
aneurysm, patients and intervention risk factors in a statistical and mechanistic disease 
model. 

 
 
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Table 2: UIATS aneurysm risk score (48) 
 
2 PROJECT OBJECTIVES AND DESIGN  
2.1 Hypothesis and primary and secondary objectives  
Due to the multi-factorial nature of the disease, it is necessary to provide a holistic 
information platform covering all aspects of the vessel wall biology and clinical 
epidemiology to bridge between both worlds: biology and clinical epidemiology. In this 
context, the purpose of the AneurysmDataBank (ADB) (49) is to collect and harmonize 
information to allow more personalized and homogenous patient clustering associated 
with more refined disease management models to allow more accurate predictions 
according to all available options. 
Estimation of the yearly aneurysm rupture risk using tables provided by the PHASES 
score (Table 1) (9), the International Study of Unruptured Intracranial Aneurysms 
(ISUIA) study (Table 2) (18, 48) or the Unruptured Cerebral Aneurysm Study (UCAS) 
(10) remains inaccurate with predictive power of less than 80% (43). 
Risk associated with different treatment strategies is estimated on the basis of expert’s 
opinion or analysis of single center case series, observational studies of high-volume 
centers and a few multicentric, industry supported, single arm studies that have not yet 
been meta-analyzed. 

 
 
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The purpose of the development of the information platform and associated 
decision support tools is to reduce the risk of bias by collecting information on a 
population basis and offer more accurate and personalized estimation of risks to 
support the disease management. 
 
Recording of information concerning patients and aneurysms, and collection of blood, 
saliva, stool, CSF and aneurysmal dome tissue will allow interdisciplinary approaches 
to identify: 
- 
Factors associated with an increased risk of aneurysm formation, such as 
genetic, proteomics, bacteriomics, anatomical, environmental and life-style 
factors, co-morbidities and treatments. Quantification of their respective impact 
on disease initiation will be done by comparing characteristics of IA patients 
with healthy controls. 
- 
Factors associated with aneurysm growth or instability. Quantification of their 
respective impact on disease progression will be done by comparing 
characteristics of patients and aneurysms between patients presenting stable 
aneurysm and patients suffering of unstable aneurysms (i.e. new clinical 
symptoms, geometrical aneurysm dome modifications or vessel wall properties 
modifications). 
- 
Factors associated with aneurysm rupture. Quantification of their respective 
impact on rupture risk will be done by comparing characteristics of patients and 
aneurysms between patients presenting stable aneurysm and patients diagnosed 
with ruptured aneurysm. Particular care will be taken to study characteristics of 
patients with long term aneurysm stability as compared to the rare patients that 
suffered aneurysm rupture during follow-up. 
- 
Prognostic factors and to quantify their respective impact on outcome by 
comparing in groups of patients with similar initial characteristics, patients with 
the best outcomes to patients with the poorest outcome. 
 
The primary objective of the project is to determine the disease burden of the presence 
of an IA and associated disease management on patient's life. To this aim, the modified 
Rankin Scale (mRS) will be repetitively measured to assess patient’s survival time and 
disability during the post diagnostic life duration. 
 
The secondary objectives of the project are: 
- 
To assess differences in the rate of disease associated significant adverse events 
and death following the diagnosis of an IA between different types of disease 
managements (medical, surgical, interventional). 
- 
To evaluate the impact of the discovery of non-ruptured IAs and of the associated 
treatments and follow-up visits on the quality of life of the patients. 
- 
To create a specific data base and a specific biobank on IAs to improve 
knowledge on initiation, growth and rupture of IAs. 
- 
To create a decision-support tool for the management of non-ruptured IAs to 
reduce the risk associated with overtreatment of IAs, with poor treatment choices, 
with atypical follow-up of the patient, and to reduce significant clinical adverse 
events.  
- 
To evaluate the use of the ADB on care improvement, cost-effectiveness, 
knowledge discovery and new product development and market promotion. 
2.2 Primary and secondary endpoints 

 
 
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To determine the disease burden of the presence of an IA on patient's life, the initial 
primary outcome will be the disability and duration of disability after recruitment 
measured using the mRS. 
 
Disability is defined as a score higher than 2 on the mRS (50, 51) specified as:  
- 
0= No symptom at all 
- 
1= No significant disability despite symptoms; able to carry out all usual duties 
and activities 
- 
2= Slight disability; unable to carry out all previous activities, but able to look after 
own affairs without assistance 
- 
3= Moderate disability; requiring some help, but able to walk without assistance 
- 
4= Moderately severe disability; unable to walk without assistance and unable to 
attend to own bodily needs without assistance 
- 
5= Severe disability; bedridden, incontinent and requiring constant nursing care 
and attention 
- 
6= Dead 
 
The value of the mRS will be recorded initially assessing the disability prior to diagnosis 
and at diagnosis and later after treatment, discharge and at each follow-up according to 
the follow-up schedule (Table 4). mRS will be recorded using the following eCRFs: 
“AneuX_Antécédents”, eCRF “Aneux_Microbiote”, eCRF “Signes et Symptômes” 
(Annex 
14), 
eCRF 
“AneuX_Evaluation 
de 
traitement” 
(Annex 
15), 
eCRF 
“AneuX_Evaluation à la sortie” (Annex 16) and eCRF “AneuX_Suivi” (Annex 17). 
 
To determine the overall impact of the IA disease on patient's life, we need to compare 
patients to a reference population not affected by IA. To our knowledge, no 
epidemiological study measuring the mRS and involving healthy volunteers have yet 
been performed in Switzerland, forcing us to enroll healthy volunteers in our project as 
done in other studies (52, 53). In addition, we are highly interested to enroll also family 
members because they are usually exposed to similar environment factors and will allow 
the distinction between environmental and genetic factors. 
 
Ultimately the primary outcome will be Disability-Adjusted Life Year (DALY) for each 
relevant patient group. DALY will be the principal outcome factor to compare different 
management strategies. DALY is calculated as the sum of Years of Life Lost (YLL) due 
to premature mortality in the population and Years Lost due to Disability (YLD) for people 
living 
with 
the 
health 
condition 
or 
its 
consequences 
(54, 
55):  
 
DALY = YLL + YLD  
 
YLL is calculated according to: 
 
 
where K indicates age-weighting modulation factor; β, parameter from age-weighting 
function; r, discount rate; C, constant; a, age of death; L, life expectancy of general 
population at age a. Patient’s age-specific life expectancy without disease will be taken 
from the nation of residency life tables appropriate for gender. 
 
YLD is calculated according to: 

 
 
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where DW indicates disability weight; K, age-weighting modulation factor; β, parameter 
from age-weighting function; r, discount rate; C, constant; a, age at diagnosis; L, 
duration of disability. 
 
 
The secondary outcomes measured in this project will be separated in 4 categories to 
address to following points: 
1) Evaluation of the impact of the discovery of non-ruptured IAs and of the 
associated treatments and follow-up visits on the quality of life of the patients. 
The measured outcomes will be: 
o Quality of life: evaluated with the EQ-5D survey (Annex 18). 
o Neuropsychological performance: evaluated with the Mini-Mental State 
Examination (MMSE™) assessment. 
o Neurological status: evaluated with the National Institute of Health Stroke 
(NIHS) scale. 
o Cranial nerves function evaluation. 
 
2) Creation of a specific data base and a specific biobank on IAs to improve 
knowledge on formation, growth and rupture of IAs. The measured outcomes will 
be: 
o Aneurysm growth: Observation of the growth of an aneurysm after 
diagnosis: measurements are recorded in the eCRF “AneuX_Données 
d’imagerie” (Annex 19), the eCRF “AneuX_Anévrisme” (Annex 20) and in 
the eCRF “AneuX_Suivi”. 
o Comorbidities: for details, please see the eCRF “AneuX_Antécédents”. 
o Treatments: for details, please see the eCRF “AneuX_Antécédents”. 
o Positive familial history of IAs: for details, please see the eCRF 
“AneuX_Antécédents”. 
o Life 
style 
risk 
factors: 
for 
details, 
please 
see 
the 
eCRF 
“AneuX_Antécédents”. 
o Environmental risk factors: for details, please see the eCRF 
“AneuX_Antécédents”. 
o Food 
and 
drink 
habits: 
for 
details, 
please 
see 
the 
eCRF 
“AneuX_Microbiote”. 
 
3) Creation of a decision-making tool for the management of IAs to reduce the 
risk associated with overtreatment of IAs, with inadequate treatment choices, with 
inadequate follow-up of the patient, and with significant clinical events associated 
with IAs. The measured outcomes will be: 
o PHASES score: PHASES aneurysm risk score is described in table 1 (9). 
All data needed to calculate this score will be recorded in the eCRF 
“AneuX_Antécédents”, in the eCRF “AneuX_Données d’imagerie” and in 
the eCRF “AneuX_Anévrisme”. 
o Unruptured Intracranial Aneurysm Treatment Score (UIATS): UIATS is 
described in table 2 (48). All data needed to calculate this score will be 
recorded 
in 
the 
eCRF 
“AneuX_Antécédents”, 
in 
the 
eCRF 
“AneuX_Données d’imagerie”, in the eCRF “AneuX_Anévrisme” and in the 

 
 
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eCRF “AneuX_Signes et Symptômes”. 
o Ability to completely and permanently exclude the lesion with the 
treatment. 
o Recurrence or repermeabilisation of the aneurysm after treatment. 
o Neo-aneurysm formation: identification of new aneurysm during follow-up. 
o Number of significant adverse events observed after the diagnosis of an 
IA. Significant adverse events are defined as: 
 Rupture of IA after diagnosis leading to the death of the patient 
 Rupture of IA after diagnosis  
 Reintervention on a previously secured IA 
 New focal neurological deficits associated to the IA or intervention 
to secure the IA 
o Occurrence of hydrocephalus. 
o Occurrence of vasospasm. 
All of these points will be recorded in the eCRF “AneuX_Anévrisme”, in the eCRF 
“AneuX_Traitement” (Annex 21), in the eCRF “AneuX_Evaluation du traitement”, in the 
eCRF “AneuX_Evaluation à la sortie” and in the eCRF “AneuX_Suivi”.  
 
 
4) Evaluation of the use of the ADB on care improvement, cost-effectiveness, 
knowledge discovery and new product developments and commercialization. 
Measured outcomes will be: 
o Management cost per patient: number of imaging studies, type of 
interventions, numbers of hospital days in Critical and Intermediate Care 
Unit (CCU and ICU) needed to manage the patient due to IA disease. 
o Average disability pension per disease severity groups: national yearly 
costs in disability pension due to IA and aneurysmal SAH. 
o Number of scientific publications acknowledging the ADB. 
o Number of products or services provided by the ADB. 
o Number of products developed and sold by companies associated with 
the ADB. 
o Number of commercial entities having contracts with the ADB. 
 
To reduce the confounding influence of baseline factors and to adequately estimate 
risks associated with the disease, it is important that the clinical sites are meticulous in 
identifying individuals known to have any of the conditions identified in Table 3. Such 
information will be recorded in the eCRF “AneuX_Antécédents” and in the eCRF 
“AneuX_Signes et Symptômes”. 
Positive familial history for IA 
Hypercoagulable disorders 
Hypertension 
ArterioVenous Malformation 
Fear from IA 
Hypercholesterolemia 
Abdominal Aortic Aneurysm 
Multiple aneurysms 
Hypertriglyceridemia 
Ehlers-Danlos Syndrome type IV 
MoyaMoya disease 
Myocardial infarction 
Tuberous Sclerosis 
Neurofibromatosis type I 
Coronary Heart Disease 
Former Meningitis 
Pregnancy 
Stroke 
Cancer 
Oral contraception 
Carotid Stenosis 
Sickle Cell Anemia 
Hormone replacement therapy 
Neurocognitive disorder 
Atherosclerosis 
Polycystic Kidney Disease 
Psychiatric illness 
Diabetes Mellitus 
Coarctation of the Aorta 
Epilepsy 

 
 
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Table 3: Factors influencing decision making 
 
All factors are compliant with the NIH Common Data Elements defined by the 
International Working Group (56-63)  for patients suffering of SAH and patients diagnosed 
with IA, and with the proposed integrated disease model (49). 
2.3 Project design  
This project is an observational study where all decisions and interventions are taken 
according to international recommendations in the field and to the experience of the 
physician in charge and local multidisciplinary team. The observations made will serve 
as a baseline for the future evaluation of decision support tools, new management 
paradigms, treatments and interventions. 
 
All information reported in the CRF are information routinely obtained or measured by 
the clinician in the context of IA discovery, treatment and follow-up. 
Aneurysm dome removing is part of the surgical treatment process to safely exclude the 
aneurysm dome from the blood circulation. Aneurysm dome are removed to allow 
careful visual quality check of the clipping but have currently no relevant clinical value 
and are traditionally not analyzed. No intervention will be undertaken specifically for the 
purpose of this study.  
The only surveys that the patient will have to complete in addition of usual questions 
asked in the context of this pathology is the EQ-5D survey for the evaluation of the 
quality of life of the patient, and the CRF AneuX_Microbiote to know the food and drink 
habits of the patients. 
In addition, blood samples, saliva samples, stool samples and CSF will be harvested for 
genetics, proteomics or bacteriomics analysis. 
For comparison, healthy volunteers and family members will be interviewed as it will be 
done for patient suffering from IAs. Blood, saliva and stool samples will also be taken 
from these people. 
3 PROJECT POPULATION AND STUDY PROCEDURES 
3.1 Project population, inclusion and exclusion criteria  
1) Project population 
Information will be collected prospectively and consecutively about all patients affected 
by IA, selected family members when two or more directly genetically linked members 
are affected and healthy volunteers. The rational is to obtain a minimally biased 
understanding of the affected population and burden of the disease on society. Special 
Ethnicity 
(Caucasian/Japanese/Finnish) 
Fibromuscular Dysplasia 
Previous use of corticoids 
Smoking History 
Sturge-Weber Syndrome 
Marfan syndrome 
Alcohol History 
Former Vasculitis 
Recent brain ischemic lesion 
(less that 4 weeks) 
Drug History 
Alpha 1-antitrypsin Deficiency 
Delivery 
Migraine 
Valvular Heart Disease  
Infection disease 
Bleeding disorders 
Previous history of SAH 
Elastic pseudoxanthoma 

 
 
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care will be taken using information technologies to optimally select participants to 
screen (optimize prevention) and healthy volunteers to assess the reliability and 
representativeness of existing data to be used (subsidiarity). 
 
There is no defined number of patients to be recruited. The accuracy and refinement of 
models will progressively be improved with growing number of patients. Based on the 
recent Swiss Study on Subarachnoid Hemorrhage (Swiss SOS) (7) in which 1787 
patients suffering of SAH have been enrolled between 2009 and 2014, and based on the 
observation reported in the population based studies assessing the follow-up protocol 
and the PHASES score (43, 44), patients diagnosed with ruptured IA represent 1/3 of the 
patients affected by IAs. The expected number of patients to be enrolled every year in 
the HUG is estimated to be at least 150. Approximately 10% of patients are members of 
families affected by IAs and in each family usually 3 persons could be recruited as family 
members. Therefore, it is expected that 45 family members could be recruited each year 
in the HUG. To compare patients affected with IA with healthy controls and assess risk 
factors and the impact on patient’s quality of life with a type I error of 5% and a power of 
90%, setting the ratio between controls and patients at 0.7, it is calculated that 105 healthy 
volunteers should be recruited each year in the study. The relevance of recruiting healthy 
volunteers will be reassessed regularly (every 3 years). 
 
2) Inclusion criteria  
A participant is eligible as patient (IA or IA+SAH) if:  
- 
he/she has an IA identified on the basis of angiographic appearance (3D-DSA, 
3D-Magnetic Resonance Angiography (MRA), or 3D-Computed Tomography 
Angiography (CTA)) and of surgical documentation. SAH has to be verified by 
Computerized Tomography (CT) / magnetic resonance imaging (MRI) or by 
lumbar puncture; 
and  
- 
he/she is older than 14 years; 
and  
- 
he/she is able to provide consent. In the case of a patient incapable of providing 
consent, the consent has to be obtained from a person legally authorized to give 
it on behalf of the patient according to legal and ethical requirements of the 
country where the clinical center is located. 
 
Participant eligible as healthy volunteer:  
- 
any individual volunteering, responding to open advertisement or randomly 
selected in a defined population and accepting to be approached for recruitment; 
and 
- 
he/she is not eligible as a patient or a family member; 
and  
- 
he/she is older than 14 years; 
and  
- 
he/she is able to provide consent. 
 
A participant is eligible as family member if: 
- 
he/she is selected on review of a patient’s family tree where at least two directly 
linked members are affected by IA; 
and  
- 
he/she is contacted by the patient; 

 
 
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and  
- 
he/she is older than 14 years; 
and  
- 
he/she is able to provide consent. 
 
3) Exclusion criteria  
The presence of one of the following criteria will lead to the exclusion of the participant: 
- 
He/she is younger than 14 years 
- 
Refusal to provide informed consent 
- 
Failure of the candidate to contribute to clinical data 
- 
For patients only: Lack of angiographically proven IA on 3D-DSA, 3D-MRA or 3D-
CTA on at least one occasion or a second occasion performed 1 or more weeks 
later, and absence of confirmatory CT/MRI or lumbar puncture in case of 
suspected SAH. 
 
The verification that all inclusion and exclusion criteria are respected for all participant will 
be done automatically and documented on a recruitment form. At the moment of 
exportation of the data from the CRF to the data bank, the automated process will check 
the criteria and only export the data from participant filing all the criteria. If one of the 
criteria is not respected, the participant data will not be exported.  
3.2 Recruitment, screening and informed consent procedure 
 
The different participant groups are: 
1) IA: Patients with one or more identified IA, none of which are believed to have 
ruptured. 
2) IA+SAH: Patients with one or more identified IA, at least one of which has been 
radiologically or surgically determined to have ruptured.  
3) Healthy volunteers (Controls): Individuals, accompanying or contacted by a 
patient, or responding to open advertisement (Annex 22), or randomly selected 
in a defined population who agree to be approached for recruitment. 
4) Family Members: Individuals selected on review of a patient’s family tree and 
contacted by the patient, who agree to be approached for recruitment. In affected 
families, each member will be identified as proband, affected, unaffected, IA 
status unknown. Not genetically link family members may be recruited as healthy 
volunteers. 
 
Participants will be recruited from the following sources: 
1) Patients are people arriving at the clinical center either as newly diagnosed 
(incidental cases) or already known for the disease (prevalent cases). 
- 
Patient identification from medical records and ongoing practice has to be 
performed by the clinician responsible for clinical care of the patient, or a 
trained alternate who is a member of the patient’s clinical care team. 
- 
A member of the patient’s clinical care team, preferably one known by the 
patient, will introduce the project. The clinical care team member should 
screen the inclusion and exclusion criteria’s, provide the participant’s 
general information letter and the participant’s genetic information letter 
and if there is no basis for exclusion or no unwillingness to participate, the 
two associated informed consents will be signed by the patient. Sufficient 

 
 
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time has to be given to the patient between information and signature of 
the consent (usually 72 hours but at the best convenience of the patient). 
- 
The care team member performing this role must have received all 
information about the project and a training concerning the process of 
recruitment. 
- 
In case of patients diagnosed with a ruptured IA, as the microbiota can be 
affected by the medical care, saliva and blood (17 ml) needed for the 
microbiota project will be collected just before IA treatment. In such cases, 
the anesthesiologist involved in the care of the patient, but not involved in 
the research project, will be consulted before any samples collection to 
defend the patient’s interest. The patient or his/her representative will be 
informed about the project and will receive the informed consent for 
signature. If the patient or his/her representative refuses the sample to be 
used for this research, all the samples will be destroyed. 
- 
Self-presentation as a potential patient is not a recognized pathway for 
identification. 
- 
A patient cannot give consent to a care team member or a researcher on 
behalf of another. 
 
2) Healthy volunteers are people answering a call, randomly selected subjects 
from a known population that consent to participate or non-genetically linked 
family members of patients that consent to participate. The initiation of the 
recruitment pathway for candidate healthy volunteers has to be identification 
through one of the following pathways (in order of preference for matching to 
the index patient thus to minimize the environmental effects): 
- 
The patient identifies the candidate on the basis of requirements of age, 
and ethnicity matching or analysis of the family history with the assistance 
of a trained clinician. The patient then introduces the @neurIST project to 
the candidate, provides the participant’s general information letter and the 
participant’s genetic information letter and asks the candidate to initiate 
contact with the trained clinician. The signing of the consent by a healthy 
volunteer contacted by a patient will not be done in presence of the patient 
to respect his/her freedom to accept or refuse to participate. 
- 
The candidate is known by the clinical researchers at the clinical center 
through having accompanied a patient at the time of the patient’s 
recruitment, and is thus aware of the ADB, and is approached directly by 
the clinical researcher. 
- 
The candidate advances himself or herself in response to open 
advertisement or indirect publicity. 
- 
The candidate is randomly selected within a defined population and is 
directly approached by the clinical researcher. 
 
3) Family members are people identified with a familial history of IA: 
- 
Each patient identified as being a familial case (i.e. having at least one 
other known family member affected by IA) will be asked to assist the 
clinical researchers in identifying affected and linking family members for 
involvement in the study. It will also be asked to perform the initial 
approach to candidate family members for involvement in the study unless 
prohibited by local legal or ethical requirements. 

 
 
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- 
The family member will be recruited only after he/she has agreed to be 
contacted for recruitment. 
- 
The signing of the consent by a family member will not be done in 
presence of the patient to respect his/her freedom to accept or refuse to 
participate. 
 
No compensation or payment will be given to the project participants. 
3.3 Study procedures 
Information to be collected and definition of patient groups as well as information used 
to classify patients, compare groups and outcomes for each stage of the disease have 
been defined by the International Common Data Elements for Subarachnoid 
Hemorrhage and Unruptured Intracranial Aneurysms Working Group (56-63) and the 
integrated disease model proposed by the @neurIST investigators (49). 
 
The milestones for a participant recruited as “Patient” are: 
- 
Initial period: Period between the initial diagnosis and the first management 
decision. 
- 
Treatment: Period starting with the admission of the patient for the treatment of 
the IA and the end of the surgical or endovascular treatment (risk securing 
treatment of the IA). 
- 
Until 48h after treatment: Time of clinical evaluation between the risk securing 
treatment of the IA until 48h after the treatment of the IA. 
- 
Discharge: Time of clinical evaluation when patient is discharged from the 
specialized service to return home or to be transferred to rehabilitation or other 
secondary care institution. 
- 
Follow-up: Scheduled follow-up visits are fixed according to initial condition at 
week 6 (W6), month 3 (M3), month 6 (M6), year 1 (Y1), year 5 (Y5) after diagnosis 
or treatment, and every 5 years (E5Y) thereafter. 
 
The milestones for a participant recruited as “Family member” or “Healthy volunteer” 
are: 
- 
Initial period: Period until 3 months following the agreement to participate to the 
study. 
- 
Follow-up: every 5 years (E5Y). 
 
For each milestone and participant group, a set of assessments will be recorded and 
samples could be harvested as described in the Annex 23 “Schedule of assessments” 
and in more details below. 
Clinical history, imaging data, biological samples and information derived from are the 
main items to be captured to the ADB. No limits are set on the number of participants 
for whom data can be entered to the ADB. 
 
1) Initial period: 
A. Clinical evaluation: 
For all participants, the following information (for details of each items see eCRF 
“AneuX_Antécédents”, eCRF “Aneux_Microbiote” and eCRF “AneuX_Signes et 
symptômes”) will be collected either directly or with help of relatives: 
- Administrative information 

 
 
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- Demographic information 
- Disability based on the mRS (prior to ictus for IA+SAH) 
- Treatments 
- Epilepsy 
- Personal medical history 
- Comorbidities 
- Positive familial history for IA or SAH 
- Systematic screening for risk factors according to list 
- Quality of life using the EQ-5D survey 
- Food and drink habits 
 
For patients with IA and patients with IA+SAH, the following additional information will 
be collected: 
- Neuropsychological performance using the MMSE™ assessment 
- MMSE @neurIST scale 
- Montreal Cognitive Assessment score (MoCA) 
- Cranial nerve deficits evaluation 
- Focal signs evaluation 
- Type of IAs and characterization 
 
For patients with IA, the specific additional following information will be collected: 
- Fear of rupture 
 
For patients with IA+SAH, the specific additional following information will be collected: 
- WFNS and hWFNS scores 
- Consciousness level on Glasgow Coma Scale (GCS) 
 
The interview of the patient will be done by a clinician of the clinical care team via the 
use of computerized data entry of the hospital’s patient records interface at the sites 
with suitable informatics infrastructure. For healthy volunteers and family members, 
interviews will be performed by a clinical researcher who has completed training in the 
interpretation of the questions and the use of the software.  
The time to inform, answer questions and give the information sheets and consent forms 
is estimated to require 30 minutes. 
The time required for completion of the EQ-5D survey should be around 15 minutes. 
When possible, the data questionnaire should be administered prior to any planned or 
emergency treatment. 
Completion of the questionnaire will take place within the clinical care institution, in a 
consultation room or similar location for ensuing privacy during the process.  
 
B. Imaging data (for patients only): 
Patients with IA or with IA+SAH will be assessed for; 
- IA characterization by 3D-MRA, or 3D-CTA or 3D-DRA. Additional information 
consisting for example of bi-plane x-ray angiography, MR phase mapping flow maps, 
4D-Xray angiography, transcranial Doppler ultrasound, or intravascular pressure 
measurements may be included. 
- Hydrocephalus measuring ventricular size on imaging. 
 

 
 
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The imaging and angiographic data have to be derived from scans obtained in the 
course of routine clinical exams or from scans performed as part of other research 
projects.  
On the basis of the imaging examinations, general observations about the intra-cranial 
vessels will be recorded and the aneurysms will be classified as to location, size and 
morphological features, consistent with clinical practice. Hemorrhage will be classified 
according to location, volume and mass effect. Presence of hydrocephalus will be 
reported as well as observation of vasospasm. These details are to be recorded as part 
of the radiological report for the patient. All information will be recorded is the eCRF 
“AneuX_Données d’imagerie” and in the eCRF “AneuX_Anévrisme”.  
 
Imaging and angiographic datasets will be incorporated into the ADB from IA and 
IA+SAH patients agreeing to have such data included. Angiographic data are to be 
provided to the ADB in DICOM format. 
Acquisition parameters for routine angiographic studies are also known to vary between 
sites and changes over time are likely. To ensure the images obtained are optimal for 
both diagnostic and CFD modelling purposes, outline guidance on recommended 
parameters and practice are provided in the Annex 24: AneurysmDataBank regulation.  
 
No specific exams will be performed in healthy volunteers and in family members for the 
project.  
No requirement is made but it is routinely recommended that family members of IA or 
IA+SAH patients considered at risk undergo screening angiography for IA. However, 
these individuals should be asked whether they have had angiography, and if so, the 
angiogram findings should be verified, and consent requested to incorporate any 3D 
angiograms into the database. 
 
C. Blood samples: 
For all participants, a total of 56 mL of blood samples will be taken for: 
- Genetics (17 mL), PAXgene DNA tube (2x8.5 mL) (ref: 761125) 
- Gene expression profiling (5 mL), PAXgene RNA tube (2x2.5 mL) (ref: 762165) 
- Protein marker profiling (17 mL), BD Vacutainer ACD-A (2x8.5 mL) (ref: 366645) 
- Bacteriomic analyses on serum (6 mL), BD Vacutainer (ref: 367815) 
- Bacteriomic analyses on whole blood (8.5 mL), PAXgene DNA tube (ref: 
761125) 
- Bacteriomic analyses on whole blood (2.5 mL), PAXgene RNA tube (ref: 
762165) 
 
Blood samples will be collected for genetics, gene expression profiling and protein 
marker profiling (Maximal blood volume collection: 39 mL) or for bacteriomic analyses 
(Maximal blood volume collection: 17 mL). 
The time to take the blood sample is less than 20 minutes. 
 
D. Saliva sample: 
Saliva will be collected using the kit GeneFiX™ 2ml DNA/RNA Collector – GFX-02 
(Isohelix). 
Samples will be collected by rubbing saliva on the side of the back (molar) teeth with 
sheet swab and will be stored frozen until analysis.  
The time to take the saliva sample is less than 5 minutes. 
 

 
 
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E. Stool sample: 
Stool will be collected using the kit STF-S1/1/50, StoolFiX™ Tube Pre-Filled with 1ml 
Stabilization Buffer pk50 (Isohelix). 
The time to take the stool sample is less than 5 minutes. 
 
Collection of the samples have to be recorded in the eCRF “AneuX_Echantillons” 
(Annex 25). 
Biological samples collection has to follow the AneurysmDataBank regulation. 
Biological samples will be conserved in the Serotec of the Centre Médical Universitaire, 
Rue Michel-Servet 1, 1211 Geneva. 
 
2) Treatments (for operated patients only): 
A. Information about the treatment: 
The type of treatment (surgery, endovascular interventions and supportive 
interventions) and the date of the intervention will be recorded in the eCRF 
“AneuX_Traitements”. 
 
B. Biological samples harvested for therapeutics, but not used in diagnostics: 
For patients needing microsurgical clipping or the introduction of a cerebral ventricular 
catheter or intraparenchymal monitoring device, the CSF evacuated for treatment 
purposes will be stored. The patient will be asked for authorization of the storage and 
the use of CSF for research. 
For patients treated by microsurgical clipping of the aneurysm it is standard procedure 
to cut the aneurysmal dome out to properly verify the complete exclusion of the 
aneurysm and preservation of all neighboring small perforator vessels. The patient will 
be asked for authorization of the storage and the use of the aneurysmal dome tissue for 
research. 
For histological investigation, the aneurysmal dome will be conserved in formol. For 
bacteriomic analysis, the aneurysmal dome will be conserved in an RNA later solution 
(Merck R0901). 
 
C. Blood samples: 
For treated patient, four blood samples will be taken within the 48 hours following the 
treatment for gene (2x2.5 mL) and protein (2x8.5 mL) expression profiling analysis 
(Maximal blood volume collection: 22 mL). 
For treated patient, 3 blood samples will be taken before any antibiotic treatment for the 
bacteriomic analysis (Maximal blood volume collection: 17 mL). 
Blood samples will be collected for gene and protein expression profiling analysis or for 
bacteriomic analysis. 
 
D. Saliva sample: 
For treated patient, saliva will be collected before any antibiotic treatment following the 
same protocol as in the “Initial period” for the bacteriomic analysis. 
 
E. Stool sample: 
For treated patient, stool will be collected before any antibiotic treatment following the 
same protocol as in the “Initial period” for the bacteriomic analysis. 
 
For detailed protocols, please see the AneurysmDataBank regulation. 
Biological samples harvesting is not allowed to interfere with clinical care. 

 
 
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Collection of the samples will be recorded in the CRF “AneuX_Echantillons”. 
Biological samples will be conserved in the Serotec of the Centre Médical Universitaire, 
Rue Michel-Servet 1, 1211 Geneva. 
 
3) Until 48h after treatment (for operated patients only): 
During the 48h after securing the aneurysm the following information will be collected 
for all operated patients and reported in the eCRF “AneuX_Evaluation Traitement” and 
in the eCRF “AneuX_Anévrisme”: 
- Disability based on the mRS 
- Epilepsy 
- Neuropsychological performance using the MMSE™ assessment 
- MMSE @neurIST scale 
- Montreal Cognitive Assessment score (MoCA) 
- Cranial nerve deficits evaluation 
- Focal signs evaluation 
- Consciousness level on Glasgow Coma Scale (GCS) 
- Evaluation of IA treatment 
- Complications 
- New event 
- Death (review of death certificates and autopsy reports may be requested to 
ensure completeness of the clinical history report. Of special interest is the date 
of death, the primary and contributing cause of death) 
- Imaging data 
 
4) Discharge (for operated patients only): 
Before patients are discharged back home or to another institution or to a rehabilitation 
unit, the following information will be recorded in the eCRF “AneuX_Evaluation à la 
sortie” and in the eCRF “AneuX_Anévrisme”: 
- Disability based on the mRS 
- Treatments 
- Epilepsy 
- Neuropsychological performance using the MMSE™ assessment 
- MMSE @neurIST scale 
- Montreal Cognitive Assessment score (MoCA) 
- Cranial nerve deficits evaluation 
- Focal signs evaluation 
- Consciousness level on Glasgow Coma Scale (GCS) 
- Complications 
- Destination of patient 
- The number of days since admission 
- The number of days in CCU 
- The number of days ventilated 
- The number of days in ICU 
- Complains 
- Death 
- Imaging data (if not done at 48h post-treatment) 
 
5) Follow-up: 
On successive return clinical visits to the clinical care centre, a reduced version of the 
questionnaire will be used for clinical history follow-up data. The frequency of follow-up 

 
 
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visits recommended by the project varies with initial condition of recruitment (Table 4). 
 
Participant 
groups 
IA management status 
Follow-up milestones 
IA 
Observation 
Y1 / Y2 / Y5 / E5Y 
 
Treated by surgery 
W6 / Y1 / Y5 / E5Y 
 
Treated by 
endovascular 
intervention 
M6 / Y1 / Y5 / E5Y 
IA+SAH 
Treated by surgery 
W6 / M3 / Y1 / Y5 / E5Y 
 
Treated by 
endovascular 
intervention 
M3 / Y1 / Y5 / E5Y 
Family members 
Not applicable 
E5Y 
Healthy 
volunteers 
Not applicable 
E5Y 
Table 4: Times for follow-up visits 
 
To facilitate patient contacts, patients will be asked as part of the consent process to 
agree or disagree to being contacted on no more than an annual basis for follow-up 
purposes.  
Different strategies may be evaluated for obtaining follow-up data from patients who do 
not attend annual follow-up visits as part of their clinical routine. These include postal 
questionnaire, telephone interview and a possible web-questionnaire. 
The patients agreeing to participate in follow-up contact will be asked to provide the 
name and address of their primary care doctor and to sign a medical release form for 
use in the event that the patient cannot be contacted directly. 
 
A. Clinical evaluation: 
All patients will be evaluated regarding the following items and all of information will be 
collected in the eCRF “AneuX_Suivi” and in the eCRF “AneuX_Anévrisme”: 
- Disability based on the mRS 
- Treatments 
- Epilepsy 
- Comorbidities 
- Risk factors according to list 
- Neuropsychological performance using the MMSE™ assessment 
- MMSE @neurIST scale 
- Montreal Cognitive Assessment score (MoCA) 
- Cranial nerve deficits evaluation 
- Focal signs evaluation 
- Consciousness level on Glasgow Coma Scale (GCS) 
- Quality of life using the EQ-5D survey 
- Complications 
- New event 
- Complains 
- Death 
 
For patients with untreated IA, the specific additional following information will be 
collected: 

 
 
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- Fear of rupture 
 
For family members and healthy volunteers, only the following information will be 
collected: 
- Disability based on the mRS 
- Quality of life using the EQ-5D survey 
- Death 
 
B. Imaging data (for patients only): 
To follow the evolution or the recurrence of the disease, 3D-MRA, 3D-CTA or 3D-MRA 
will be performed in patients. All information will be collected in the eCRF 
“AneuX_Anévrisme”. 
Modalities are the same as for images obtained during the initial period (see above and 
in the AneurysmDataBank regulation. 
 
C. Blood samples (for treated patients only): 
For treated patient, four blood samples will be taken within the 48 hours following the 
treatment for gene (2x2.5 mL) and protein (2x8.5 mL) expression profiling analysis 
(Maximal blood volume collection: 22 mL). 
For treated patient, at least 6 months after the end of antibiotic treatment, 3 blood 
samples will be taken for the bacteriomic analysis (Maximal blood volume collection: 17 
mL). 
Blood samples will be collected for gene and protein expression profiling analysis or for 
bacteriomic analysis. 
 
For detailed protocols, please see the AneurysmDataBank regulation. 
Blood sample harvesting should not interfere with clinical care. 
Collection of the samples have to be recorded in the eCRF “AneuX_Echantillons”. 
Biological samples will be conserved in the Serotec of the Centre Médical Universitaire, 
Rue Michel-Servet 1, 1211 Geneva. 
 
D. Saliva sample: 
For treated patient, at least 6 months after the end of antibiotic treatment, saliva will be 
collected following the same protocol as in the “Initial period” for the bacteriomic analysis. 
 
E. Stool sample: 
For treated patient, at least 6 months after the end of antibiotic treatment, stool will be 
collected following the same protocol as in the “Initial period” for the bacteriomic analysis. 
 
 
 
5) Expected bias and taken measures: 
 
A. Recruitment bias: 
It is ethically and financially impossible to recruit all people affected by IA in Switzerland. 
It would need the screening of the full Swiss population and the risk/benefit balance has 
been shown beneficial only in specific subgroups of patients at high risk. Listing of 
recruited patients in the @neurIST project will be compared to listing of diagnostic and 
intervention codes in the HUG. All patients diagnosed with IA in the HUG should receive 
the information regarding the @neurIST project and should have the opportunity to be 

 
 
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enrolled in the project. Finally, particular efforts will be made concerning the recruitment 
of complex cases and deceased patients to reduce the risk of sample bias. Recruitment 
of deceased patient will be performed by the clinician who was in charge of the patient. 
One month following the death of the patient, the clinician contacts by phone a family 
member to find out about the family's experience of the tragic situation, to ensure that 
there is no outstanding issue, and to respond to concerns they could have. Then, the 
clinician will explain the study to the family member and will offer to send all the 
information about the project, and ask for consent.  
 
 
B. Missing data bias: 
To reduce the volume of missing data, CRF collecting data have been integrated within 
the Geneva University Hospital clinical information system and integrated to clinical 
practice and part of the necessary clinical documentation of cases. Such forms are part 
of the clinical patient files and are completed at each visit of the patients. Data extraction 
for the @neurIST project is performed automatically from these clinical forms limiting 
missing data and errors. Moreover, to favor the use of such forms in routine clinical 
practice, a clinical decision support tool will be added to the forms. To use such decision 
support tool, the forms have to be sufficiently documented reducing the quantity of 
missing data. At each follow-up visit, forms are checked and completed if data is missing. 
Once the data is extracted, presence of missing data will be inspected and information 
regarding missing data transferred to the clinician in charge for completion on the next 
patient visit. 
 
C. Data quality bias: 
The clinical file of each patients is discussed in multidisciplinary team meetings and 
signed by the clinician in charge of the patient limiting erroneous data. At each data 
extraction, outliers and incoherent data will be carefully inspected and if errors are 
identified after a careful file inspection and on a case by case basis corrected after 
discussion with the clinician in charge of the patient. The correction will be recorded in 
the case log. 
3.4 Withdrawal and discontinuation 
All participants retain the option of withdrawing from the study at any time. All 
participants are informed of the possibility to be withdrawn from the project and will be 
withdrawn on her/his demand. 
When a participant indicates its desire to withdraw from the study to its contact at the 
clinical center, the participant will be provided the “Declaration of Withdrawal of Consent” 
(Annexes 9 and 10). The participant does not have to state their reason for withdrawal. 
At withdrawal, two options are proposed to the patient: 1) All mechanisms for linking the 
information covered by the project to personal identifying information are removed and 
data are anonymized; or 2) Data and biological material are kept coded. Importantly, the 
collected data already recorded in the database will still be analyzed because once 
integrated into the database their destruction will become impossible. 
The participant has also to choose whether his/her biological samples could be 
conserved or not. 

 
 
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4 STATISTICS AND METHODOLOGY 
4.1 Statistical analysis plan 
Statisticians and methodologists from the @neurIST project and later the ZHAW Institute 
(ZHAW Life Sciences und Facility Management, Einsiedlerstrasse 31a, 8820 Wädenswil) 
as well as statisticians and methodologists from the different clinical research centres of 
the different centres involved were and are integrated in the study when joining the effort. 
 
1) Determination of Sample Size  
There is no limited number of patients to be recruited. The accuracy and refinement of 
models will progressively be improved with growing number of patients. Based on the 
recent Swiss Study on Subarachnoid Hemorrhage (Swiss SOS) (7) in which 1787 
patients suffering of SAH have been enrolled between 2009 and 2014, and based on the 
observation reported in the population based studies assessing the follow-up protocol 
and the PHASES score (43, 44), patients diagnosed with ruptured IA represent 1/3 of the 
patients affected by IAs. The expected number of patients to be enrolled every year in 
the HUG is estimated to be at least 150. Approximately 10% of patients are members of 
families affected by IAs and in each family usually 3 persons could be recruited as family 
members. Therefore, it is expected that 45 family members could be recruited each year 
in the HUG. To compare patients affected with IA with healthy controls and assess risk 
factors and the impact on patient’s quality of life with a type I error of 5% and a power of 
90%, setting the ratio between controls and patients at 0.7, it is calculated that 155 healthy 
volunteers should be recruited each year in the study. The relevance of recruiting healthy 
volunteers will be reassessed regularly (every 3 years). 
 
2) Data processing 
All clinicians involved in this project will be trained to adequately fill-up the eCRF. As data 
for this project will be collected in a multi-national clinical practice setting, it cannot be 
expected that the schedule of assessments will be respected accurately in all study sites. 
Therefore, for data to be analyzed by study visit, broad visit windows will be defined 
before database freezing, together with the definition of rules to determine the unique 
value to be used in case of multiple assessments within any given window.  
Other data manipulation procedures will be documented in the statistical report. 
 
3) Planned analysis 
Intracranial aneurysm disease is defined by different phases :1) IA initiation; 2) IA growth 
characterized by modification of the IA geometry and/or change in the vascular wall 
composition; 3) IA rupture; 4) Vasospasm; 5) Hydrocephalus; 6) Recurrence defined as 
IA repermeabilisation or new IA formation on the same artery or new IA formation on a 
different artery. 
 
For each stage, sets of factors and outcomes specific for each group of patients and 
stage transition have been determined in an integrated disease model proposed by the 
@neurIST investigators (49). 
 
A. Univariate analyses to compare basic characteristics of patient groups: 
a. Comparison of dichotomic variables. Proportion will be compared using 
Fischer’s exact test. 

 
 
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b. Comparison of categorical variables presented as median and quartiles or 
by absolute and relative frequencies. Comparison will be performed using 
Chi-Square or non-parametric Mann-Whitney U test. 
c. Comparison of continuous variables reported as mean ± Standard 
Deviation (SD). Comparison will be performed using Student‘s t-test. 
Two-sided P values of less than 0.05 will be considered as threshold for statistical 
significance and Bonferroni corrected for multiple testing if required. 
 
B. Multivariate analyses to compare predictors of outcomes: 
Multivariate analysis will be performed to determine the predictor factors of the different 
phases of the disease. For this purpose, parameters found to be significant (P < 0.05) in 
the univariate analysis will be analyzed using multivariate logistic regression to identify 
those parameters that retained significance when accounting for all relevant variables. 
Odds Ratios (ORs) will be reported with a 95% Confidence Interval (CI). Receiver 
Operating Characteristic (ROC) analysis will also be performed for all relevant 
parameters. The ROC curves will be plotted, and Area Under the Curve (AUC) values for 
each relevant parameter will be calculated and compared. The ROC curves and the AUC 
indicate the limits of a parameter's ability to discriminate between the subgroups. 
Thresholds for optimal sensitivity and specificity will also be calculated for parameters 
that were found to be significant. 
Currently, some set of predictors are described in the literature but need to be confirmed 
such as cerebro-vascular shape, hypertension, and smoking for IA initiation; IA location, 
IA size, hypertension and gender for IA growth; IA location, IA size, IA shape, gender and 
age for IA rupture; Fisher grade or automated blood quantity assessment for vasospasm; 
Fisher grade, presence of acute hydrocephalus, atrophy and age for hydrocephalus.  
As illustrated in recent publications involving investigators of the study, new advanced 
analysis tools based on statistical learning will be used to refine models specific to each 
stage of the disease (22, 23, 64-67). 
As described previously, IA disease in a complex disease evolving through different 
stages and influenced by a lot of factors. To increase the clinical relevance and evolution 
of the models, Bayesian statistics will be used considering a priori predictor factors 
determined from our initial study and from the literature. The Bayesian’s model that will 
emerge will be continuously updated by inferences of parameters or hypotheses as 
evidences will accumulate. 
All statistical analysis will be performed using the statistical software R (68). To avoid or 
reduce data protection issues and accidental patient re-identification, analysis codes 
written in R will be developed on mock data sets. The R codes will be cross-checked by 
trusted parties before being run on the real data set and results based on less than 5 
patients sensored. Only aggregated data will be provided back as results. 
Datasets to be analyzed 
Univariate analysis will include all patients who fulfill the selection criteria. 
For the multivariate analysis, two-third of the patients who fulfill the selection criteria will 
be used to develop the model of each disease stage and one-third of the patients will be 
used to validate the model. 
 
Ancillary analysis 
Sensitivity analyses will be performed as described in the paragraph “Planned analysis”.  

 
 
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Deviations from the original statistical plan 
Deviations from the original statistical plan will be justified and documented in the 
statistical report. 
4.2 Handling of missing data  
To reduce the volume of missing data, CRF collecting data have been integrated within 
the Geneva University Hospital clinical information system and integrated to clinical 
practice and part of the necessary clinical documentation of cases. Such forms are part 
of the clinical patient files and are completed at each visit of the patients. Data extraction 
for the @neurIST project is performed automatically from these clinical forms limiting 
missing data and errors. Moreover, to favor the use of such forms in routine clinical 
practice, a clinical decision support tool will be added to the forms. To use such decision 
support tool, the forms have to be sufficiently documented reducing the quantity of 
missing data. At each follow-up visit, forms are checked and completed if data is missing. 
Once the data is extracted, presence of missing data will be inspected and information 
regarding missing data transferred to the clinician in charge for completion on the next 
patient visit. 
 
In addition to the efforts for limiting missing data during data collection, standard inferring 
methods will be used to reduce missing data. However, data manipulation will be reduced 
as much as possible and most probably not necessary. It is expected that by promoting 
the interaction between patients and clinicians with the decision support tool, data 
collection of the most relevant information will progressively improve in quantity and 
quality avoiding the need of missing data handling. 
 
5 REGULATORY ASPECTS AND SAFETY 
5.1 Local regulations / Declaration of Helsinki 
This research project will be conducted in accordance with the protocol, the Declaration 
of Helsinki (3), the principles of Good Clinical Practice, the Human Research Act (HRA) 
(2) and the Human Research Ordinance (HRO) (1) as well as other locally relevant 
regulations. The Sponsor and the Project Leader acknowledge their responsibilities. 
5.2 Notification of safety and protective measures (HRO Art. 20) 
The project leader is promptly notified (within 24 hours) if immediate safety and protective 
measures have to be taken during the conduct of the research project. The Ethics 
Committee will be notified via BASEC of these measures and of the circumstances 
necessitating them within 7 days. 
5.3 Serious events (HRO Art. 21) 
The risks associated with this study are those related to a blood test (low infectious risk, 
hematoma) and the use of a computer network for the transfer of data whose safety can 
never be fully guaranteed. 

 
 
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We will endeavor to make the blood tests as painless as possible and will put in place 
security measures for all our coded data transfers. 
 
Assessment and documentation of unrelated and related serious events (SEs) will be 
done by expert clinicians. All SEs will be documented in the participant’s file and on the 
SE report (Annex 26). 
If a serious event occurs, the research project will be interrupted and the Ethics 
Committee notified on the circumstances via BASEC within 7 days according to HRO Art. 
211. 
The project leader will report any occurring SE to the responsible EC within 7 days. He 
will also submit a report which will evaluate the relationship between the event reported 
and the methods of collecting health related personal data or sampling of biological 
material within the project. 
The project leader will notify the EC within 7 days of any immediate other safety and 
protective measures, which have to be taken during the conduct of the research project. 
In addition, the project leader will explain the circumstances, which necessitated the 
safety and protective measures.  
5.4 Procedure for investigations involving radiation sources 
NA 
5.5 Amendments 
Substantial changes to the project set-up, the protocol and relevant project documents 
will be submitted to the Ethics Committee for approval according to HRO Art. 18 before 
implementation. Exceptions are measures that have to be taken immediately in order to 
protect the participants. 
5.6 End of project 
This project is an observational study about a chronic disease whose purpose is to create 
a decision support tool for the management of intracranial aneurysms. The criteria for the 
termination of the project will be the creation of such a reliable tool. However, such a tool 
is a dynamic tool most probably requiring a constant evolution, in consequence the 
probability to terminate this project is quite low. 
 
The Sponsor or the Project Leader may terminate the study prematurely according to 
certain circumstances, for example:  
- 
Ethical concerns; 
- 
Insufficient participant recruitment; 
- 
When the safety of the participants is doubtful or at risk; 
- 
Alterations in accepted clinical practice that make the continuation of a project 
unwise. 
- 
Lack of funding or resources to continue the project. 
                                                        
1 A serious event is defined as any adverse event where it cannot be excluded, that the event is attributable to the 
sampling of biological material or the collection of health-related personal data, and which: 
a. requires inpatient treatment not envisaged in the protocol or extends a current hospital stay; 
b. results in permanent or significant incapacity or disability; or 
c. is life-threatening or results in death. 

 
 
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The premature end or interruption of the research project will be reported to the EC within 
90 days upon completion of the project (HRO Art. 22). 
5.7 Insurance 
In the event of project-related damage or injuries, the Sponsor will be liable, except for 
damages that are only slight and temporary; and for which the extent of the damage is 
no greater than would be expected in the current state of scientific knowledge (Art. 12 
HRO). 
6 FURTHER ASPECTS 
6.1 Overall ethical considerations 
IAs which have a prevalence between 2 to 5% of the general population are mostly 
quiescent and asymptomatic, but once diagnosed they induce patient’s fear to be the 
victim of SAH. In Switzerland, SAH results in 24% death, 11% severely disabled patients 
and 64% patients recovering to a more or less independent life. Only 24% of the patients 
recover with no residual symptoms (7). However, treatment of non-ruptured IA is a risky 
intervention inducing patient’s disability for several months and death in the worst case. 
Today, more and more patients face the extreme situation to take the decision to live 
with their IA or to treat it. Regarding the consequences of SAH and of the treatment of 
non-ruptured IAs, better understanding of the nature of IAs, and of the interaction 
between multiple and complex risk factors relating to aneurysm initiation, growth and 
rupture is needed to create a decision support tool for the management of IAs. 
This project is an observational study where all decisions and interventions are taken 
according to international recommendations in the field and to the experience of the 
physician in charge and local multidisciplinary teams. All participants will be informed 
about the research project by the clinician in charge of the patient or by research nurses 
or clinical researchers dedicated to the present project. This project is of minimal 
physical risk for the patient, indeed, all investigations that will be performed will be those 
routinely done to characterize and follow IAs or to follow the behavior of a ruptured IA 
with the exception of blood, saliva and stool samples for genetics, proteomics and 
bacteriomics. 
The end result of the ADB is to provide a detailed assessment tool to monitor the 
aneurysmal disease burden and optimize patient care by developing and continuously 
up-dating a decision-support tool. It will support the collection of information and 
biological material to be investigated to better understand the patho-physiological 
processes involved in the disease. This databank and associated biobank will be 
beneficial to the overall aneurysm patient population. The original patient group will also 
profit from the study because IA is a life-long chronic disease that requires periodical re-
evaluation. Decision making could be influenced in the future by the currently acquired 
information and biological samples. 
6.2 Risk-Benefit Assessment  
Presently, no precise and validated tool exists to balance the risk of rupture of an 
aneurysm with the risk of complications associated with the treatment option of this 
aneurysm. The end result of the ADB (49) is to provide a decision-support tool for the 

 
 
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management of IAs. 
 
This project is of minimal physical risk for the patient. Indeed, all exams that will be 
performed will be those routinely done to characterize and follow the patients with IAs 
or to follow the behaviour of a ruptured IA with the exception of blood, saliva and stool 
sample collected for genetics, proteomics and bacteriomics investigations. 
Concerning data security, information will be transferred over secured networks and 
links will be made with electronic hospital patient records (for details, please see section 
7). It is part of the project to control data accesses, and comply to all clinical research 
good practice requirements as well as with EU General Data Protection Rules 2016/679. 
Despite the best use of methods for improving medical research using the latest 
information technologies, perfect data protection cannot be absolutely guaranteed, but 
all measures will be taken to ensure data protection. Data protection breaches will be 
reported and measures taken immediately to reduce the potential harm as much as 
possible. 
 
A third risk lays in the return of clinically relevant details. The participants may receive 
individual research results, which could aid disease treatment and diagnosis. 
Participants will, as part of the informed consent process, have to choose whether or 
not they want to be contacted about any results relevant to their health. The return of 
individual research results will be reviewed by the Ethic and Legal Advisory Board, an 
internal ADB committee, which will consider whether results should be returned, the 
method of return, and whether counselling may be needed. In case of concerns caused 
by the study, psychological support will be offered to patients if wishes. 
 
This database will be beneficial to the overall aneurysm patient population. The original 
patient group will also profit from the study because IA is a life-long chronic disease that 
requires periodical re-evaluation. Decision making could be influenced in the future by 
the currently acquired information and biological samples. 
6.3 Rationale for the inclusion of vulnerable participants  
Vulnerable participants are included in the present study. Rational for the inclusion of 
vulnerable participants is that the disease itself affects consciousness and judgement 
capacity in a high proportion of patients and exclusion would highly bias observations and 
result in clinically dangerously overoptimistic conclusions. Teenagers are rarely affected 
and medical management and treatments cannot be extrapolated from the adult 
population. It would be a discrimination to exclude this population from the project. 
Procedure to recruit and consent vulnerable participants in normal and emergency 
situations (incapable of judgment, under tutelage and capable of judgement, minor) is 
described in section 1.1. Legal requirements. 
 
7 QUALITY CONTROL AND DATA PROTECTION 
7.1 Quality measures  
The interview of the patient will be done by a clinician of the clinical care team via the 
use of computerized data entry of the hospital’s patient records interface. 

 
 
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For healthy volunteers and family members, interviews will be performed by a research 
nurse or a clinical researcher who has completed training in the interpretation of the 
questions and the use of the software. 
The expert clinicians, research nurses and clinical researchers will only get access to the 
eCRF after specific training by the trial management. Information collected in these eCRF 
will permit the review of each particular case to check for data accuracy. The clinicians 
will have to sign a summary report that will be stored as a legally binding medical reports 
in the hospital archives. All this process should allow high data quality recording. 
Health-related personal data captured during this project are strictly confidential. Data 
generation, storage and analyses of health-related personal data within this project will 
strictly follow the current Swiss legal requirements for data protection and will be 
performed according to the Ordinance HRO Art. 5. Only authorized personnel will have 
access to health-related data. Information about study subjects will be kept confidential 
and managed according to the requirements of the Authorities. For quality assurance, the 
Ethics Committee may visit the research sites. Direct access to the source data and all 
project related files and documents must be granted on such occasions. 
7.2 Data recording and source data 
All data will be recording in electronic CRF.  
The eCRF “AneuX_Données Légales”, “AneuX_Antécédents”, “AneuX_Signes et 
Symptômes”, “AneuX_Evaluation de traitement”, “AneuX_Evaluation à la sortie”, 
“AneuX_Suivi”, 
“AneuX_Données 
d’imagerie”, 
“AneuX_Anévrisme”, 
“AneuX_Traitement”, “AneuX_Echantillons” are part of the « Dossier Patient Intégré » 
(DPI) system of the HUG. 
The eCRF « AneuX_Microbiote » will be a Redcap® form. 
To optimize resources and data collection quality, all information (primary and secondary 
outcomes) will be directly captured from expert clinicians during patient evaluation using 
eCRF adjusted to the clinical work flow. These expert clinicians will only get access to the 
eCRF after specific training by the trial management. Information collected in these eCRF 
will permit the review of each particular case to check for data accuracy. The clinicians 
will have to sign a summary report that will be stored as medical reports in the hospital 
archives. All this process should allow high data quality recording. 
Only validated scores, scales and surveys commonly used for patients affected by IA will 
be recorded. 
Source data collected in this project (with the exception of the data collected for the eCRF 
“AneuX_Microbiote”) are data routinely collected during the daily practice. 
Source data collected in the eCRF “AneuX_Microbiote” are collected specifically for the 
project. 
7.3 Confidentiality and coding 
 
1) Confidentiality 
Data generation, transmission, storage and analysis of health-related personal data, and 
the storage of biological samples within this project will strictly follow the current Swiss 

 
 
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legal requirements for data protection and will be performed according to the Ordinance 
HRO Art. 5. 
Health-related personal data captured during this project and biological samples from 
participants are strictly confidential and disclosure to third parties is prohibited; coding will 
safeguard participants' confidentiality. 
Project data will be handled with uttermost discretion and only be accessible to authorized 
personnel. 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Authorities. Direct access to source documents will be permitted for 
purposes of audits or inspections. 
 
The ADB infrastructure (Figure 1) is divided in three zones as described by Kuchinke et 
al. (69, 70). 
 
 
Figure 1: AneurysmDataBase (ADB) infrastructure 
 
Although tools and services are provided to clinicians by the sponsor or other partners, 
the “Care Zone” is under the full responsibility of the clinical institution and principal 
investigator and comply with local medical practice and documentation regulations. Data 
stripped of all identifiable information and coded with a global unique pseudonym for 
each patient and transferred to the “Non-care Zone” managed by the ADB. The “Non-
care Zone” is under the responsibility of the sponsor Geneva University Hospitals. The 
“Research Zone” contains different extractions (Bx) of the ADB where each case 
receives a new pseudonym for each extraction. Each extraction is limited to the 
necessary information required to answer the question addressed by the researcher. 
Researchers will be granted access to a mock of her/his requested Bx to code her/his 
analysis in R. The analysis code will be reviewed by the third party in charge of the “Non-
care Zone” of the ADB to check it complies with the research agreement and sensors 
all results based on less than 5 patients to reduce the risk of accidental participant re-
ADB
Physician
Patient
Clinical
evaluation
Data 
collection
CARE ZONE
Clinical institution and PI
ADB Ethics and
Legal Advisory Board
NON-CARE ZONE
Privacy
Filter
B3
B2
B1
RESEARCH ZONE
ADB Scientific Advisory Board
and PIs
Privacy
Filter
Privacy
Filter
Privacy
Filter

 
 
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identification. Only aggregated results are delivered to the researchers. It is not allowed 
and technically made extremely difficult to merged different extractions to avoid 
uncontrolled reconstruction of the original database. The “Research zone” is under the 
responsibility of principal investigators of each research project.  
If relevant discoveries or errors are found by researchers, the information is transmitted 
to the Data controller of the ADB Management Office. After review and approval by the 
local ethics committees in clinical centers, information is re-identified and provided to 
physicians that inform patients according to what was agreed during the consent to 
participate to the project. 
 
2) Coding 
Project data will be handled with uttermost discretion and is only accessible to authorized 
personnel who require the data to fulfil their duties within the scope of the research 
project. On the CRFs and other project specific documents, participants are only identified 
by a unique participant number.  
 
Biological material in this project is not identified by participant name but by a unique 
participant number. Biological material is appropriately stored in a restricted area only 
accessible to authorized personnel. For more details, please see the AneurysmDataBank 
regulation. 
 
The measures to be taken to ensure patient privacy of digital data are: 
1) Depersonalisation and Pseudonymization 
The clinical data collection software generates a unique identifier, termed the Data 
Acquisition Identifier (DAI), for each individual participating in the Project. Before 
transfer to the ADB all the files are depersonalised by removing Identifying details except 
the DAI. The DAI is replaced by a pseudonym automatically generated by the system 
and information transferred to the ADB. 
Data stored will be pseudonymized a second time with a new unique identifier different 
from the original one when a new data set is generated for the purpose of “in silico” 
research. The original pseudonym will be discarded from the new data set. This is done 
to avoid uncontrolled combination of multiple data sets. 
 
2) Secure access, and defined access criteria 
Data entry and access to the any ADB tools will require a non-repudiable means of 
access for each user as part of an end-to-end communication and information security.  
There is a separation of research and clinical accesses. From within a clinical centre, 
there will be no access to pseudonyms, or to any research findings attributed to an 
individual, or to results from other clinical centres. 
From outside of the clinical centre, researchers will only be able access data 
depersonalised and pseudonymized. 
 
3) Confidentiality, integrity and authenticity of communicated transmissions 
All communications of data performed in the system will be encrypted, integrity-
protected and authenticated, and all entities will have secure certificates. 
 
4) Limitations on search criteria  
Any tools developed or service provided by ADB will not support queries based on name, 
date of birth, address, or other possible identifiable details. 
 

 
 
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5) Logging of search requests and data entry 
The identity of any person adding data to or requesting data from the ADB database will 
be logged together with the query expression. 
 
6) Non-repudiation of search requests and data entry 
The data collection and data query expression log will be protected at the hospital level 
and “Non-care zone” level. 
 
7) Filter checking of response data 
As a means of protecting against failure of the depersonalization processes, and to 
ensure uniformity between hospitals depersonalization processes data being 
transferred in response to queries will be filtered for information in the strip list of 
potentially identifiable information. No query result will be provided if representing less 
than 5 patients. 
 
8) Monitoring and alerts 
The completeness of data in the ADB databases will be checked, individual participant 
consent options will be recorded and followed in relation to participation and re-contact, 
and the system will be monitored for any attacks made on the data, and an appropriate 
notification mechanism for such an eventuality will be implemented.  
 
9)  Data origin authentication and provenance 
Mechanisms are in place to ensure the information is verifiable and traceable including 
means to unambiguously identify the origin of a data set and of subsequent updates.  
 
10) Confidentiality agreements 
Confidentiality provisions are built into ADB project documentation. External 
collaborators on the project will be asked to sign a specific confidentiality agreement, as 
any other parties accessing the ADB data sources. 
 
11) Removal of identifying facial features (imaging data) 
Where 3D MRI imaging data encompasses more than 5 cm of the head in the three-
orthogonal axis, a required step is that a bounding box is defined that contains the 
intracranial compartment, but excludes the nose and eyes. This bounding box has to be 
applied before imaging transfer. An automated facial features remover will be used for 
all radiological imaging before transfer to the ADB. 
7.4 Retention and destruction of study data and biological material 
At final analyses, data files will be extracted from the database into statistical packages 
to be analyzed. The status of the database at this time will be recorded in special archive 
tables. The study database with all archive tables will be securely stored by the Swiss 
Institute of Bioinformatics for at least 10 years. The sponsor will also keep the Trial Master 
File and interim and final reports both in electronic and in hard copy form for at least 10 
years.  
Destruction is not envisaged. 

 
 
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8 FUNDING / PUBLICATION / DECLARATION OF INTEREST 
8.1 Funding 
The ADB infrastructure is proposed to be maintained indefinitely.  
The Sponsor Geneva University Hospitals will raise funds from all possible sources as 
well as from commercial exploitation of the ADB and services offered to different 
stakeholders. 
Currently the project is funded by the “Fond de Service de Neurochirurgie (HUG)”, and 
financial support are regularly submitted to private foundations and public funding 
agencies. 
8.2 Publications of results 
Results will be disseminated via several ways:  
- Research reports for the financial supporting foundations 
  
- National and international community meetings 
  
- Peer-reviewed articles 
  
- Hospitals website 
 
All data or biological samples collected from patients in this study are public but remain 
protected and access gated under the responsibility of the Geneva University Hospital 
and the project leader. All data resulting from the processing of information remains the 
intellectual property of the individual or group of individuals that developed the data 
processing method and remain under the responsibility of the individual or group of 
individuals that generated the processed data. Commercial use of processed data or 
services processing data is authorized if complying with Swiss ethical and legal 
requirements or any country where the processed data or service processing data is to 
be sold. Patients and collaborators not involved in the development of the data processing 
or service processing data cannot claim any financial reward regarding the commercial 
use of processed data or services processing data involving their data or biological 
sample. 
8.3 Declaration of interest 
The sponsor and the investigators have no conflict of interest to declare. 
8.4 Data sharing 
Eventual queries regarding access to study data will be addressed to the project leader. 
Access will only be provided to third parties fulfilling Swiss Federal Data Protection Act, 
Swiss Human Research Act and EU data protection standards according to EU GDPR 
2016/679 and performing research in the field of medicine complying with ethical and 
legal standards. 
 
 

 
 
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9 
REFERENCES 
1. 
Ordinance on Human Research with the Exception of Clinical trials (HRO) 
https://www.admin.ch/opc/en/classified-compilation/20121177/index.html. 
2. 
Human Research Act (HRA) http://www.admin.ch/opc/en/classified-
compilation/20121176/201401010000/810.305.pdf. 
3. 
Declaration of Helsinki (https://www.wma.net/policies-post/wma-declaration-of-
helsinki-ethical-principles-for-medical-research-involving-human-subjects ). 
4. 
Portegies ML, Koudstaal PJ, Ikram MA. Cerebrovascular disease. Handb Clin Neurol. 2016;138:239-61. 
5. 
Vlak MH, Algra A, Brandenburg R, Rinkel GJ. Prevalence of unruptured intracranial aneurysms, with 
emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet 
neurology. 2011;10(7):626-36. 
6. 
van Donkelaar CE, Bakker NA, Veeger NJ, Uyttenboogaart M, Metzemaekers JD, Eshghi O, et al. Prediction 
of outcome after subarachnoid hemorrhage: timing of clinical assessment. J Neurosurg. 2016:1-8. 
7. 
Schatlo B, Fung C, Stienen MN, Fathi AR, Fandino J, Smoll NR, et al. Incidence and Outcome of 
Aneurysmal Subarachnoid Hemorrhage: The Swiss Study on Subarachnoid Hemorrhage (Swiss SOS). Stroke. 
2021;52(1):344-7. 
8. 
Bijlenga P, Ebeling C, Jaegersberg M, Summers P, Rogers A, Waterworth A, et al. Risk of rupture of small 
anterior communicating artery aneurysms is similar to posterior circulation aneurysms. Stroke; a journal of cerebral 
circulation. 2013;44(11):3018-26. 
9. 
Greving JP, Wermer MJ, Brown RD, Jr., Morita A, Juvela S, Yonekura M, et al. Development of the 
PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort 
studies. Lancet Neurol. 2014;13(1):59-66. 
10. 
Investigators UJ, Morita A, Kirino T, Hashi K, Aoki N, Fukuhara S, et al. The natural course of unruptured 
cerebral aneurysms in a Japanese cohort. The New England journal of medicine. 2012;366(26):2474-82. 
11. 
Meng H, Tutino VM, Xiang J, Siddiqui A. High WSS or low WSS? Complex interactions of hemodynamics 
with intracranial aneurysm initiation, growth, and rupture: toward a unifying hypothesis. AJNR Am J Neuroradiol. 
2014;35(7):1254-62. 
12. 
Etminan N, Rinkel GJ. Unruptured intracranial aneurysms: development, rupture and preventive 
management. Nat Rev Neurol. 2016;12(12):699-713. 
13. 
Brown RD, Jr., Wiebers DO, Forbes GS. Unruptured intracranial aneurysms and arteriovenous 
malformations: frequency of intracranial hemorrhage and relationship of lesions. J Neurosurg. 1990;73(6):859-63. 
14. 
Meisel HJ, Mansmann U, Alvarez H, Rodesch G, Brock M, Lasjaunias P. Cerebral arteriovenous 
malformations and associated aneurysms: analysis of 305 cases from a series of 662 patients. Neurosurgery. 
2000;46(4):793-800; discussion -2. 
15. 
Cagnazzo F, Brinjikji W, Lanzino G. Arterial aneurysms associated with arteriovenous malformations of the 
brain: classification, incidence, risk of hemorrhage, and treatment-a systematic review. Acta Neurochir (Wien). 
2016;158(11):2095-104. 
16. 
Ingebrigtsen T, Morgan MK, Faulder K, Ingebrigtsen L, Sparr T, Schirmer H. Bifurcation geometry and the 
presence of cerebral artery aneurysms. Journal of neurosurgery. 2004;101(1):108-13. 
17. 
Alfano JM, Kolega J, Natarajan SK, Xiang J, Paluch RA, Levy EI, et al. Intracranial aneurysms occur more 
frequently at bifurcation sites that typically experience higher hemodynamic stresses. Neurosurgery. 2013;73(3):497-
505. 
18. 
Wiebers DO, Whisnant JP, Huston J, 3rd, Meissner I, Brown RD, Jr., Piepgras DG, et al. Unruptured 
intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet. 
2003;362(9378):103-10. 
19. 
Cebral JR, Mut F, Weir J, Putman CM. Association of hemodynamic characteristics and cerebral aneurysm 
rupture. AJNR American journal of neuroradiology. 2011;32(2):264-70. 
20. 
Pereira VM, Brina O, Bijlenga P, Bouillot P, Narata AP, Schaller K, et al. Wall shear stress distribution of 
small aneurysms prone to rupture: a case-control study. Stroke; a journal of cerebral circulation. 2014;45(1):261-4. 
21. 
Cebral J, Ollikainen E, Chung BJ, Mut F, Sippola V, Jahromi BR, et al. Flow Conditions in the Intracranial 
Aneurysm Lumen Are Associated with Inflammation and Degenerative Changes of the Aneurysm Wall. AJNR Am J 
Neuroradiol. 2016. 
22. 
Detmer FJ, Mut F, Slawski M, Hirsch S, Bijlenga P, Cebral JR. Incorporating variability of patient inflow 
conditions into statistical models for aneurysm rupture assessment. Acta Neurochir (Wien). 2020;162(3):553-66. 
23. 
Detmer FJ, Hadad S, Chung BJ, Mut F, Slawski M, Juchler N, et al. Extending statistical learning for 
aneurysm rupture assessment to Finnish and Japanese populations using morphology, hemodynamics, and patient 
characteristics. Neurosurg Focus. 2019;47(1):E16. 
24. 
Juchler N, Schilling S, Bijlenga P, Morel S, Rufenacht D, Kurtcuoglu V, et al. Shape irregularity of the 
intracranial aneurysm lumen exhibits diagnostic value. Acta Neurochir (Wien). 2020;162(9):2261-70. 
25. 
Schatlo B, Gautschi OP, Friedrich CM, Ebeling C, Jagersberg M, Kulcsar Z, et al. Association of single and 
multiple aneurysms with tobacco abuse: an @neurIST risk analysis. Neurosurg Focus. 2019;47(1):E9. 

 
 
Version 6, 16.05.2022 
 
 
43/45 
26. 
Morel S, Diagbouga MR, Dupuy N, Sutter E, Braunersreuther V, Pelli G, et al. Correlating Clinical Risk 
Factors and Histological Features in Ruptured and Unruptured Human Intracranial Aneurysms: The Swiss AneuX 
Study. J Neuropathol Exp Neurol. 2018;77(7):555-66. 
27. 
Pyysalo MJ, Pyysalo LM, Pessi T, Karhunen PJ, Lehtimaki T, Oksala N, et al. Bacterial DNA findings in 
ruptured and unruptured intracranial aneurysms. Acta Odontol Scand. 2016;74(4):315-20. 
28. 
Pyysalo MJ, Pyysalo LM, Pessi T, Karhunen PJ, Ohman JE. The connection between ruptured cerebral 
aneurysms and odontogenic bacteria. Journal of neurology, neurosurgery, and psychiatry. 2013;84(11):1214-8. 
29. 
Shikata F, Shimada K, Sato H, Ikedo T, Kuwabara A, Furukawa H, et al. Potential Influences of Gut 
Microbiota on the Formation of Intracranial Aneurysm. Hypertension. 2019;73(2):491-6. 
30. 
Hallikainen J, Lindgren A, Savolainen J, Selander T, Jula A, Narhi M, et al. Periodontitis and gingival 
bleeding associate with intracranial aneurysms and risk of aneurysmal subarachnoid hemorrhage. Neurosurg Rev. 
2020;43(2):669-79. 
31. 
Olsen I, Yamazaki K. Can oral bacteria affect the microbiome of the gut? J Oral Microbiol. 
2019;11(1):1586422. 
32. 
Etminan N, Beseoglu K, Barrow DL, Bederson J, Brown RD, Jr., Connolly ES, Jr., et al. Multidisciplinary 
consensus on assessment of unruptured intracranial aneurysms: proposal of an international research group. Stroke; 
a journal of cerebral circulation. 2014;45(5):1523-30. 
33. 
Ishibashi T, Murayama Y, Urashima M, Saguchi T, Ebara M, Arakawa H, et al. Unruptured intracranial 
aneurysms: incidence of rupture and risk factors. Stroke; a journal of cerebral circulation. 2009;40(1):313-6. 
34. 
Juvela S, Poussa K, Lehto H, Porras M. Natural history of unruptured intracranial aneurysms: a long-term 
follow-up study. Stroke; a journal of cerebral circulation. 2013;44(9):2414-21. 
35. 
Kathem SH, Mohieldin AM, Nauli SM. The Roles of Primary cilia in Polycystic Kidney Disease. AIMS Mol 
Sci. 2014;1(1):27-46. 
36. 
Cagnazzo F, Gambacciani C, Morganti R, Perrini P. Intracranial aneurysms in patients with autosomal 
dominant polycystic kidney disease: prevalence, risk of rupture, and management. A systematic review. Acta 
neurochirurgica. 2017;159(5):811-21. 
37. 
Egorova AD, van der Heiden K, Poelmann RE, Hierck BP. Primary cilia as biomechanical sensors in 
regulating endothelial function. Differentiation. 2012;83(2):S56-61. 
38. 
Alg VS, Sofat R, Houlden H, Werring DJ. Genetic risk factors for intracranial aneurysms: a meta-analysis in 
more than 116,000 individuals. Neurology. 2013;80(23):2154-65. 
39. 
Yasuno K, Bilguvar K, Bijlenga P, Low SK, Krischek B, Auburger G, et al. Genome-wide association study of 
intracranial aneurysm identifies three new risk loci. Nature genetics. 2010;42(5):420-5. 
40. 
Kleinloog R, Verweij BH, van der Vlies P, Deelen P, Swertz MA, de Muynck L, et al. RNA Sequencing 
Analysis of Intracranial Aneurysm Walls Reveals Involvement of Lysosomes and Immunoglobulins in Rupture. 
Stroke; a journal of cerebral circulation. 2016;47(5):1286-93. 
41. 
Bakker MK, van der Spek RAA, van Rheenen W, Morel S, Bourcier R, Hostettler IC, et al. Genome-wide 
association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors. Nat 
Genet. 2020;52(12):1303-13. 
42. 
Sonobe M, Yamazaki T, Yonekura M, Kikuchi H. Small unruptured intracranial aneurysm verification study: 
SUAVe study, Japan. Stroke; a journal of cerebral circulation. 2010;41(9):1969-77. 
43. 
Bijlenga P, Gondar R, Schilling S, Morel S, Hirsch S, Cuony J, et al. PHASES Score for the Management of 
Intracranial Aneurysm: A Cross-Sectional Population-Based Retrospective Study. Stroke. 2017;48(8):2105-12. 
44. 
Gondar R, Gautschi OP, Cuony J, Perren F, Jagersberg M, Corniola MV, et al. Unruptured intracranial 
aneurysm follow-up and treatment after morphological change is safe: observational study and systematic review. J 
Neurol Neurosurg Psychiatry. 2016;87(12):1277-82. 
45. 
Naggara O, Darsaut T, Trystram D, Tselikas L, Raymond J. Unruptured intracranial aneurysms: why we 
must not perpetuate the impasse for another 25 years. Lancet Neurol. 2014;13(6):537-8. 
46. 
Greving JP, Wermer MJ, Rinkel GJ, Algra A. Unruptured intracranial aneurysms: why we must not 
perpetuate the impasse for another 25 years - authors' reply. Lancet neurology. 2014;13(6):538. 
47. 
Raymond J, Darsaut TE, Molyneux AJ, Group Tc. A trial on unruptured intracranial aneurysms (the TEAM 
trial): results, lessons from a failure and the necessity for clinical care trials. Trials. 2011;12:64. 
48. 
Etminan N, Brown RD, Jr., Beseoglu K, Juvela S, Raymond J, Morita A, et al. The unruptured intracranial 
aneurysm treatment score: a multidisciplinary consensus. Neurology. 2015;85(10):881-9. 
49. 
Bijlenga P, Morel S, Hirsch S, Schaller K, Rufenacht D. Plea for an international Aneurysm Data Bank: 
description and perspectives. Neurosurg Focus. 2019;47(1):E17. 
50. 
Hong KS, Saver JL. Years of disability-adjusted life gained as a result of thrombolytic therapy for acute 
ischemic stroke. Stroke. 2010;41(3):471-7. 
51. 
Hong KS, Saver JL. Quantifying the value of stroke disability outcomes: WHO global burden of disease 
project disability weights for each level of the modified Rankin Scale. Stroke. 2009;40(12):3828-33. 
52. 
Yamashiro S, Nishi T, Koga K, Goto T, Kaji M, Muta D, et al. Improvement of quality of life in patients 
surgically treated for asymptomatic unruptured intracranial aneurysms. J Neurol Neurosurg Psychiatry. 
2007;78(5):497-500. 
53. 
van der Schaaf IC, Brilstra EH, Rinkel GJ, Bossuyt PM, van Gijn J. Quality of life, anxiety, and depression in 
patients with an untreated intracranial aneurysm or arteriovenous malformation. Stroke. 2002;33(2):440-3. 
54. 
Murray CJ. Quantifying the burden of disease: the technical basis for disability-adjusted life years. Bull World 
Health Organ. 1994;72(3):429-45. 

 
 
Version 6, 16.05.2022 
 
 
44/45 
55. 
Murray CJ, Acharya AK. Understanding DALYs (disability-adjusted life years). J Health Econ. 
1997;16(6):703-30. 
56. 
Bijlenga P, Morita A, Ko NU, Mocco J, Morel S, Murayama Y, et al. Common Data Elements for 
Subarachnoid Hemorrhage and Unruptured Intracranial Aneurysms: Recommendations from the Working Group on 
Subject Characteristics. Neurocritical care. 2019;30(Suppl 1):20-7. 
57. 
Suarez JI, Macdonald RL. The End of the Tower of Babel in Subarachnoid Hemorrhage: Common Data 
Elements at Last. Neurocritical care. 2019;30:1-3. 
58. 
Hackenberg KAM, Etminan N, Wintermark M, Meyers PM, Lanzino G, Rufenacht D, et al. Common Data 
Elements for Radiological Imaging of Patients with Subarachnoid Hemorrhage: Proposal of a Multidisciplinary 
Research Group. Neurocritical care. 2019;30:60-78. 
59. 
Chou SHY, Macdonald RL, Keller E, Suarez JI, Macdonald RL, Amin-Hanjani S, et al. Biospecimens and 
Molecular and Cellular Biomarkers in Aneurysmal Subarachnoid Hemorrhage Studies: Common Data Elements and 
Standard Reporting Recommendations. Neurocritical care. 2019;30:46-59. 
60. 
Damani R, Mayer S, Dhar R, Martin RH, Nyquist P, Olson DM, et al. Common Data Element for Unruptured 
Intracranial Aneurysm and Subarachnoid Hemorrhage: Recommendations from Assessments and Clinical 
Examination Workgroup/Subcommittee. Neurocritical care. 2019;30:28-35. 
61. 
Wong GKC, Daly JJ, Rhoney DH, Broderick J, Ogilvy C, Roos YB, et al. Common Data Elements for 
Unruptured Intracranial Aneurysm and Subarachnoid Hemorrhage Clinical Research: Recommendations from the 
Working Group on Long-Term Therapies. Neurocritical care. 2019;30:79-86. 
62. 
Suarez JI, Sheikh MK, Macdonald RL, Amin-Hanjani S, Brown RD, Manoel ALD, et al. Common Data 
Elements for Unruptured Intracranial Aneurysms and Subarachnoid Hemorrhage Clinical Research: A National 
Institute for Neurological Disorders and Stroke and National Library of Medicine Project. Neurocritical care. 
2019;30:4-19. 
63. 
Manoel ALD, van der Jagt M, Amin-Hanjani S, Bambakidis NC, Brophy GM, Bulsara K, et al. Common Data 
Elements for Unruptured Intracranial Aneurysms and Aneurysmal Subarachnoid Hemorrhage: Recommendations 
from the Working Group on Hospital Course and Acute TherapiesProposal of a Multidisciplinary Research Group. 
Neurocritical care. 2019;30:36-45. 
64. 
Rousseau O, Karakachoff M, Gaignard A, Bellanger L, Bijlenga P, Constant Dit Beaufils P, et al. Location of 
intracranial aneurysms is the main factor associated with rupture in the ICAN population. Journal of neurology, 
neurosurgery, and psychiatry. 2021;92(2):122-8. 
65. 
Maldaner N, Zeitlberger AM, Sosnova M, Goldberg J, Fung C, Bervini D, et al. Development of a 
Complication- and Treatment-Aware Prediction Model for Favorable Functional Outcome in Aneurysmal 
Subarachnoid Hemorrhage Based on Machine Learning. Neurosurgery. 2021;88(2):E150-E6. 
66. 
Detmer FJ, Luckehe D, Mut F, Slawski M, Hirsch S, Bijlenga P, et al. Comparison of statistical learning 
approaches for cerebral aneurysm rupture assessment. Int J Comput Assist Radiol Surg. 2020;15(1):141-50. 
67. 
Detmer FJ, Luckehe D, Mut F, Slawski M, Hirsch S, Bijlenga P, et al. Comparison of statistical learning 
approaches for cerebral aneurysm rupture assessment. Int J Comput Assist Radiol Surg. 2019. 
68. 
Team R. R: A lamguage and envirobment for statistical computing. 2016. 
69. 
Kuchinke W, Karakoyun T, Ohmann C, Arvanitis TN, Taweel A, Delaney BC, et al. Extension of the primary 
care research object model (PCROM) as clinical research information model (CRIM) for the "learning healthcare 
system". BMC Med Inform Decis Mak. 2014;14:118. 
70. 
Kuchinke W, Ohmann C, Verheij RA, van Veen EB, Arvanitis TN, Taweel A, et al. A standardised graphic 
method for describing data privacy frameworks in primary care research using a flexible zone model. Int J Med 
Inform. 2014;83(12):941-57. 
 
 
 

 
 
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10 APPENDIX 
- 
Annex 1: General information letter and associated informed consent 
- 
Annex 2: General information letter and associated informed consent for patient 
recruited in emergency 
- 
Annex 3: General information letter and associated informed consent for patient 
incapable of discernment 
- 
Annex 4: General information letter and associated informed consent for patient 
incapable of discernment and recruited in emergency 
- 
Annex 5: Genetic information letter and associated informed consent 
- 
Annex 6: Genetic information letter and associated informed consent for patient 
incapable of discernment 
- 
Annex 7: Declaration of informed consent for the re-use of biological data and 
samples in coded form 
- 
Annex 8: Declaration of informed consent for the re-use of biological data and 
samples in coded form for patient incapable of discernment 
- 
Annex 9: Declaration of Withdrawal of Consent 
- 
Annex 10: Declaration of Withdrawal of Consent for patient incapable of 
discernment 
- 
Annex 11: eCRF “AneuX_Données Légales” 
- 
Annex 12: eCRF “AneuX_Antécédents” 
- 
Annex 13: eCRF « AneuX_Microbiote » 
- 
Annex 14: eCRF “AneuX_Signes et Symptômes” 
- 
Annex 15: eCRF “AneuX_Evaluation de traitement” 
- 
Annex 16: eCRF “AneuX_Evaluation à la sortie”   
- 
Annex 17: eCRF “AneuX_Suivi” 
- 
Annex 18: EQ-5D Survey 
- 
Annex 19: eCRF “AneuX_Données d’imagerie”  
- 
Annex 20: eCRF “AneuX_Anévrisme” 
- 
Annex 21: eCRF “AneuX_Traitement” 
- 
Annex 22: Advertisement for healthy volunteers 
- 
Annex 23: Schedule of Assessments 
- 
Annex 24: AneurysmDataBank regulation 
- 
Annex 25: eCRF “AneuX_Echantillons” 
- 
Annex 26: Serious Event Report