PLOS ONE RESEARCH ARTICLE Consent is a confounding factor in a prospective observational study of critically ill elderly patients Hans Flaatten ID1☯*, Bertrand Guidet2☯, Christian Jung3☯, Ariane Boumendil4☯, Susannah Leaver5☯, Wojciech Szczeklik6☯, Antonio Artigas7, Finn Andersen8, Rui Moreno ID9, Sten Walther ID10, Sandra Oeyen11, Joerg C. Schefold ID12, Brian Marsh13, Michael Joannidis14, Muhammed Elhadi ID15, Yuriy Nalapko ID16, Jesper Fjølner17☯, Dylan W. de Lange18☯ a1111111111 1 Department of Anaesthesia and Intensive Care, Haukeland University Hospital, Bergen, Norway, a1111111111 2 Sorbonne Université, INSERM, Institut Pierre Louis d’Epidémiologie et de Santé Publique, Saint Antoine a1111111111 Hospital, AP-HP, Hôpital Saint-Antoine, Service de Animation, F75012, Paris, France, 3 Division of a1111111111 Cardiology, Pulmonology and Vascular Medicine, University Hospital Düsseldorf, Heinrich-Heine-University, a1111111111 Düsseldorf, Germany, 4 AP-HP, Hôpital Saint-Antoine, service de réanimation, F75012, Paris, France, 5 Research Lead Critical Care Directorate St George’s Hospital, London, United Kingdom, 6 Intensive Care and Perioperative Medicine Division, Jagiellonian University Medical College, Kraków, Poland, 7 Intensive care Department, CIBER Enfermedades Respiratorias, Corporacion Sanitaria Universitaria Parc Tauli, Autonomous University of Barcelona, Sabadell, Spain, 8 Department of Anaesthesia and Intensive Care, NTNU, Dep of Circulation and Medical Imaging, Ålesund Hospital, Trondheim, Ålesund, Norway, OPEN ACCESS 9 Faculdade de Ciências Médicas de Lisboa (Nova Médical School), Unidade de Cuidados Intensivos Neurocrı́ticos e Trauma, Hospital de São José, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Citation: Flaatten H, Guidet B, Jung C, Boumendil Portugal, 10 Linkoping University Hospital, Linkoping, Sweden, 11 Department of Intensive Care 1K12IC A, Leaver S, Szczeklik W, et al. (2022) Consent is a Ghent University Hospital, Ghent, Belgium, 12 Department of Intensive Care Medicine, Inselspital, confounding factor in a prospective observational Universitätsspital, University of Bern, Bern, Switzerland, 13 Mater Misericordiae University Hospital, Dublin, study of critically ill elderly patients. PLoS ONE Ireland, 14 Division of Intensive Care and Emergency Medicine, Department of Internal Medicine, Medical 17(10): e0276386. https://doi.org/10.1371/journal. University Innsbruck, Innsbruck, Austria, 15 Faculty of Medicine, University of Tripili, Tripoli, Libya, pone.0276386 16 European Wellness International, ICU, Luhansk, Ukraine, 17 Department of Anaesthesia and Intensive Care, Viborg Regional Hospital, Viborg, Denmark, 18 Department of Intensive Care Medicine, University Editor: Giuseppe Vittorio De Socio, Azienda Medical Center, University Utrecht, Utrecht, The Netherlands Ospedaliera Universitaria di Perugia, ITALY ☯ These authors contributed equally to this work. Received: March 18, 2022 * Hans.flaatten@uib.no Accepted: September 21, 2022 Published: October 27, 2022 Peer Review History: PLOS recognizes the Abstract benefits of transparency in the peer review During analysis of a prospective multinational observation study of critically ill patients �80 process; therefore, we enable the publication of all of the content of peer review and author years of age, the VIP2 study, we also studied the effects of differences in country consent responses alongside final, published articles. The for study inclusion. This is a post hoc analysis where the ICUs were analyzed according to editorial history of this article is available here: requirement for study consent. Group A: ICUs in countries with no requirement for consent https://doi.org/10.1371/journal.pone.0276386 at admission but with deferred consent in survivors. Group B: ICUs where some form of Copyright: © 2022 Flaatten et al. This is an open active consent at admission was necessary either from the patient or surrogates. Patients’ access article distributed under the terms of the Creative Commons Attribution License, which characteristics, the severity of disease and outcome variables were compared. Totally 3098 permits unrestricted use, distribution, and patients were included from 21 countries. The median age was 84 years (IQR 81–87). reproduction in any medium, provided the original England was not included because of changing criteria for consent during the study period. author and source are credited. Group A (7 countries, 1200 patients), and group B (15 countries, 1898 patients) were com- Data Availability Statement: Our data contains parable with age and gender distribution. Cognition was better preserved prior to admission indirect possibilities to identify some patients since in group B. Group A suffered from more organ dysfunction at admission compared to group we have age, gender, country ID and ICU ID in our registry. Hence we have removed all potentially ID B with Sequential Organ Failure Assessment score median 8 and 6 respectively. ICU PLOS ONE | https://doi.org/10.1371/journal.pone.0276386 October 27, 2022 1/9 PLOS ONE Consent is a confounding factor to patients and attached a file with data we hope survival was lower in group A, 66.2% compared to 78.4% in group B (p<0.001). We hence will serve the purpose of your request but not found profound effects on outcomes according to differences in obtaining consent for this putting anonymity in danger. These data is attached as a supplementary x-l file. study. It seems that the most severely ill elderly patients were less often recruited to the study in group B. Hence the outcome measured as survival was higher in this group. We Funding: This study was endorsed by the ESICM. Free support for running the electronic database therefore conclude that consent likely is an important confounding factor for outcome evalu- and was granted from the dep. of Epidemiology, ation in international studies focusing on old patients. University of Aarhus, Denmark. Financial support for creation of the e-CRF and maintenance of the database was possible from a grant (open project support) by Western Health region in Norway) 2018 project F-11487, who also funded the Introduction participating Norwegian ICUs. DRC Ile de France In a recently published, prospective, observational study of the acutely admitted very old inten- and URC Est helped conducting VIP2 in France. sive care patients (� 80 years old), the VIP2 study) conducted in 22 European countries, we The VIP2-study collaborators are listed in the ESM 1. found an overall 30-day survival of 61%. Factors predicting mortality were frailty at admission, ICU admission categories and degree of organ failure at admission [1]. During the study, we Competing interests: Joerg C. Schefold declares also noticed a considerable heterogeneity among European countries regarding the require- that the Dept. of Intensive Care Medicine Bern has/ had research and/or development/consulting ments for informed consent for this observational study. Some countries waived the need for contracts with (full disclosure): Orion Corporation, informed consent while others demanded consent prior to patient inclusion. Abbott Nutrition International, B. Braun Medical Previously we have reported problems with obtaining consent for a similar study with wait- AG, CSEM SA, Edwards Lifesciences Services ing time before decision up to one year for some countries [2]. GmbH/SA, Kenta Biotech Ltd, Maquet Critical Care In observational clinical research, the patients are typically not subjected to an intervention AB, Omnicare Clinical Research AG, and Nestlé. that can alter the course of the disease or illness. Only patient data that is already collected in Educational grants were received from Fresenius Kabi; GSK; MSD; Lilly; Baxter; Astellas; the daily clinical routine or collected for the purpose of that prospective observational research, AstraZeneca; B. Braun Medical AG, CSL Behring, are used. In general, patients should have the right to decide whether they want their data to Maquet, Novartis, Covidien, Nycomed, Pierre Fabre enter a research project, also in non-intervention studies. However, informed consent from Pharma (Roba Pharma); Pfizer, Orion Pharma. The patients is not always possible, particularly in acute care settings. When a patient is severely ill money went into departmental funds. No personal and admitted to an intensive care unit (ICU), they very often lack decisional capacity. In such financial gain applies. This does not alter our adherence to PLOS ONE policies on sharing data instances, the national or regional medical ethical committee might agree to use informed con- and materials All other authors do not have any sent from surrogate decision-makers or waive the need for informed consent at the time of conflict of interest to declare related to this admission, so-called deferred consent, and inform patient survivors about the study and their manuscript. right to withdraw their inclusion at a later stage. The introduction of the General Data Protec- tion Act (GDPR) in the European Union (EU) May 2018 necessitated in many countries an additional (written) informed consent for sharing privacy sensitive patent data even when deferred consent was allowed by the ethical committees. We started recruiting countries and ICUs to the VIP2 study in spring 2018, just before to the implementation of the European General Data Protection Regulation (GDPR). This resulted that some countries waived the need for informed consent while others, especially those who completed the ethical procedures after implementation of the GDPR, required written informed consent from either the criti- cally ill patient themselves, or, if not possible, from next-of-kin. During the preparation and analysis of the main publication from the VIP2 study, we were concerned about any effect from these two different approaches regarding consent or no con- sent with potential bias on the recruitment to the study. In this paper, our aim was to reveal any effect from consent on patient demographics, in par- ticular about presence of organ failure at admission and later mortality of the enrolled patients. Materials and methods The methods specific for this post-hoc study are described below, and the detailed overview of the whole study can be found in the recent publication from the VIP-2 study [1]. The main aim of the VIP2 study was to investigate the influence of four common geriatric syndromes; PLOS ONE | https://doi.org/10.1371/journal.pone.0276386 October 27, 2022 2/9 PLOS ONE Consent is a confounding factor frailty, cognitive decline, activity of daily life and comorbidity/polypharmacy on various out- come measures, mainly ICU resource use and mortality. The severity of the critical illness was assessed by using the sequential organ dysfunction score (SOFA) [3] at admission. To analyze potential effects from different requirements for ethical approval, we divided the countries in two groups, those allowed to include patients without consent at ICU admission (group A) and countries that needed patient or legal proxy consent at admission, be it from the patient, caregivers or independent physicians (Group B). In group A most countries required deferred consent in hospital survivors. To illustrate the effects, we analyzed the pres- ence of geriatric syndromes clinical frailty scale (CFS), Katz activity of daily life, Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) and SOFA score at admission. The reason for admission to the ICU was grouped using a description of the main direct cause of admission as used previously. For outcomes, we used ICU length of stay (LOS), use of inten- sive care procedures like mechanical ventilation (MV) and use of vasoactive drugs (VAD) for organ support, use of limitation of care and ICU survival. Statistical methods Baseline characteristics of patients were analysed as frequencies and percentages for categorical variables and as medians and interquartile ranges for continuous variables. Comparisons between consent and no consent group were evaluated using the Wilcoxon test for continuous variables and the χ2 or Fisher exact test for categorical variables as appropriate. The crude overall survival up to 90 days after ICU admission was estimated by the Kaplan-Meier method and compared between groups using a log-rank test. Incidence of organ support and treatment limitations were estimated using cumulative incidence analysis considering ICU death and ICU discharge as competing risks. Univariate comparisons were performed using Gray’s test. In order to adjust comparison of outcomes for patients’ characteristics Cox model was used for survival and cause-specific Cox models were used for organ support and treatment limitations. The following factors were used for adjustment: age, sex, SOFA, reason for ICU admission, frailty and habitat. Adjusted survival curves were produced using an Inverse Probability Weighted (IPW) Kaplan-Meier estimation. Significance was tested using a Cox regression model weighted by the same weights (inverse probability-weighted Cox). We then used propensity score (PS) weighting to control for imbalances on observed vari- ables between groups for all outcomes. The PS model included the same covariates namely: age, sex, SOFA, reason for ICU admis- sion, frailty and habitat. Generalized boosted regression were used to estimate the propensity score and cases were then weighted to estimate the average effect of consent on the population. Two sensitivity analysis were conducted, first including all patients from England in the consent group, second including all patients from England in the no-consent group. All tests were two-sided. The type-I error rate was fixed at 0.05. Analyses were performed using the R statistical software version 3.4.2 (R Foundation for Statistical Computing, Vienna, Austria [https://www.R-project.org/]); IPW analysis were performed using the ipwpoint func- tion of the IPW package. PS analysis were performed using the PS function of the Twang pack- age and weighted analyses used the survey package. Ethical statement All 22 participating countries obtained ethical consent for conducting this study, although as the study shows the consent to participate varies from country to country. Of note is that 15 PLOS ONE | https://doi.org/10.1371/journal.pone.0276386 October 27, 2022 3/9 PLOS ONE Consent is a confounding factor countries required informed consent from patient or proxy while 7 countries accepted deferred consent, that is consent after the patient had recovered. In Norway where the princi- pal investigator (HF) works, the reference from the National Regional Board in Helse Sør-Øst is: 2018/87 (www.etikkom.no). The main study was registered at ClinicalTrials.gov (ID: NCT03370692). Results and discussion The main study (VIP2) recruited 3920 patients with a mean age of 84 years (95% CI 84–85 years) from 242 ICUs in 22 countries. The median duration of patient recruitment in an ICU was 64 days with no differences in outcomes in the ICUs below or above the median duration of recruitment. One country, England, initially required full consent but later accepted inclusion without consent for patients who died prior to consent. Since we have no information from individual ICUs the UK data is excluded from primary analysis leaving 3098 patients in this substudy. Hence, this country was excluded from the main analysis but included in a sensitivity analysis since they were the largest contributing country with 822 recruited patients. Another country, the Netherlands, initially approved to include patients without consent, but after the introduction of GDPR, 5 hospitals changed this to informed consent. Hence this country appears with ICUs in both groups. The group A consisted of 7 countries with 1200 patients included and group B of 15 countries with 1898 patients. Table 1 shows the baseline demographic and clinical data in the two groups, and Table 2 shows the differences in the six SOFA sub-scores. The groups were comparable at admission with regards to age and gender. SOFA score was higher in group A. Also, the cognitive decline score, IQCODE, was also increased, suggesting worse cognition in this group. With regards to outcomes, the groups differ. Patients in group A with higher degree of organ dysfunction were more often mechanically ventilated and given vasoactive drugs at day 1 and ICU survival was lower than in group B (66.2% vs 78.4%). Table 1. Demographic and clinical data in all patients. Data given as median and IQR. Consent (Group B)b No consent (group A)a Patients 1898 1200 Countries 15 7 Age in years, median (IQR) 84 (81–87) 84 (81–86) Gender (female) n (%) 872 (45.9%) 567 (47.2%) SOFA, median (IQR) 1 6 (3–9) 8 (5–10) CFS, median (IQR) 4 (1–9) 4 (1–9) IQCODE, median (IQR)1 3.19 (3–3.62) 3,31 (3.06–4.0) Katz ADL, median (IQR)1 6 (4–6) 6 (3–6) Mechanical ventilation n (%) 1 907 (47.7%) 738 (61.6%) Vasoactive drugs1 993(52.4%) 894 (74.7%) Withdrawal 231 (12.3%) 122 (10.3%) 1 ICU survival 1484 (78.4%) 787 (66.2%) 1 p<0.0001. SOFA = Sequential Organ Failure Assessment; CFS = Clinical Frailty Scale; IQCODE = Informant Questionnaire on Cognitive Decline in the Elderly; ADL = Activity of Daily Life. a Norway, Sweden, Poland, Greece, Libya, Austria and Netherland (partially) b Denmark, Ireland, Wales, Germany, Belgium, France, Switzerland, Spain, Italy, Portugal, Ukraine, Russia, Turkey, Croatia, Netherlands (partially). https://doi.org/10.1371/journal.pone.0276386.t001 PLOS ONE | https://doi.org/10.1371/journal.pone.0276386 October 27, 2022 4/9 PLOS ONE Consent is a confounding factor Table 2. SOFA sub-score in the two groups. Data given as median and IQR. SOFA sub-score Consent (group B) No consent (group A) SOFA resp 2 (1–3) 2 (1–3) 1 SOFA circ 0 (0–2) 1 (0–3) 1 SOFA neuro 0 (0–4) 1 (0–4) 1 SOFA liver 0 (0–0) 0 (0–0) SOFA coag 0 (0–0) 0 (0–1) 1 SOFA renal 1 (0–2) 1 (0–2) 1 p<0.0001. https://doi.org/10.1371/journal.pone.0276386.t002 There were differences in admission categories as can be seen from Table 3 with more sin- gle respiratory failure in group B while there was more combined respiratory and circulatory failure in group A. No clinical differences in end-of-life decisions between the groups were found. In Table 4 the unadjusted and adjusted HR for outcomes in the consent and no consent group are given. Both models confirm significantly higher risk of death in the no-consent group. Also, the propensity score weighting yield the same results. The table also shows that common ICU procedures like mechanical ventilation and vasoactive drugs support were more frequently used in the non-consent group. The adjusted cumulative survival curves between the two groups are illustrated in Fig 1 and clearly demonstrate the continuing difference up to 180 days. In the sensitivity analysis, we included England sequentially to either group A or B. If included in the non-consent group the results were not altered, but if all were included in the consent group the differences were no longer significant (Table 1a and 1b in S1 Table). In this secondary analysis of data from the VIP2 study, we found large differences in the patient cohorts and hence outcomes when countries were compared with versus without required upfront consent for study inclusion. Despite similar age, they have more cognitive dysfunction and reduced activity of daily life. The most striking difference is the increased SOFA score indicating more severe organ dysfunctions in this group. We also found differences in the specter of admission groups where more patients with isolated respiratory failure was admitted in group B but more combined respiratory and circulatory failure in group A. The combined admission group is usually more critical ill and in need of ventilatory support and vasoactive drugs. As a consequence, also after correction for the known confounding factors, survival in the two groups is significantly different, with 66.2% survivors when no informed consent was requested necessary compared to 78.4% in the consent group, an absolute difference in mortal- ity of 12.2%. Table 3. Admission categories in the two groups (n and % within the group). Reason for admission Consent (group B) Non-consent (group A) Respiratory failure 520 (27.4%) 252 (21%) Circulatory failure 256 (13.5%) 179 (14.9%) Combined Resp&Circ failure 181 (9.5%) 200 (16.7%) Sepsis (Sepsis 3) 270 (14.2%) 188 (15.7%) Trauma 94 (5.1%) 89 (7.5%) Intoxication 20 (1.1%) 1 (0.1%) Non-trauma CNS disease 120 (6.3%) 50 (4.2%) Emergency surgery 191 (10.1%) 136 (11.3%) https://doi.org/10.1371/journal.pone.0276386.t003 PLOS ONE | https://doi.org/10.1371/journal.pone.0276386 October 27, 2022 5/9 PLOS ONE Consent is a confounding factor Table 4. Results from the Cox analysis and propensity score weighting in the consent versus non-consent groups. UNADJUSTED HR consent vs no consent 95% CI P-value Overall survival 0.66 0.59–0.73 <0.0001 ADJUSTED Cox 1 HR consent vs no consent 95% CI P-value Overall survival 0.82 0.74–0.91 0.0027 IPW weighted Cox model 1 HR consent vs no consent 95% CI P-value Overall survival 0.84 0.74–0.94 0.0023 Propensity score weighting 1 HR consent vs no consent 95% CI P-value Overall survival 0.81 0.72–0.90 0.0002 Mechanical ventilation 0.84 0.76–0.93 0.0004 Vasoactive drugs 0.71 0.65–0.79 <0.0001 Renal replacement 0.89 0.71–1.10 0.257 Limitation of care 1.05 0.91–1.2 0.472 1 including variables age, gender, habitat, frailty, reason for ICU admission and SOFA score. https://doi.org/10.1371/journal.pone.0276386.t004 One likely explanation for this finding is difficulties in recruiting the most unstable patients when informed consent was required at ICU admission. This seems logical for several reasons. When a critically ill patient is admitted to the ICU, the focus is on the acute treatment and stabi- lization of the disease process. Confronting patients or caregivers/family in this phase with information and explanation about a clinical study, although an observational study with no intervention, often has low priority. If directly asked, many patients are unconscious or with severely reduced mental capacity and caregivers are often too stressed to digest and understand information when asked for surrogate consent. Additionally, in many tertiary centers, family and caregivers may arrive in the ICU after the inclusion window, precluding participation in the study. Hence, sometimes the simplest way to respond is not to give consent. However, this Fig 1. Adjusted survival curve in the consent and no consent groups. (Fig 1 OS-adjusted-consent.tiff). https://doi.org/10.1371/journal.pone.0276386.g001 PLOS ONE | https://doi.org/10.1371/journal.pone.0276386 October 27, 2022 6/9 PLOS ONE Consent is a confounding factor does not mean that such an ICU has equally sick patients, but for the abovementioned reasons, they are just not recruited into the study, resulting in a selection bias of less severely ill patients. As we have demonstrated, the way consent is handled seems to be an important and inde- pendent confounding factor with considerable implication for the composition of the recruited cohort and hence affecting the primary study endpoint: survival. If the most critically ill unstable patients more often are left out from inclusion in the study and further analysis this may give a false impression of a better outcome. Consent has been the focus in several publications [4], but not discussed in clinical studies involving critically ill old patients. In a study about consent rates documented in clinical stud- ies involving critically ill patients, the researchers found that, particularly in non-randomized studies, information on how consent was handled was lacking in most studies (81%). This was considered a potential source of bias and validity of the studies [5]. The use of surrogates for informed consent in patients on mechanical ventilation has recently been discussed and was associated with difficulties and was not always consistent with the patients’ view [6]. In an interesting discussion about implication of the Food and Drug Administration guideline for informed consent, the authors conclude that inclusion without patient consent should be feasi- ble with the current guideline when patients cannot consent [7]. In some countries, like in Norway, there is a special document dealing with inclusion of patients in studies concerning emergency medical conditions [7]. Research, even intervention trials, may be conducted if: 1. The patient is unable to consent (unconscious, unable to com- prehend information). 2. Similar research cannot be done in non-emergency situations; and that the project has been approved from the independent local ethical committee. 3. Research should be beneficial for the patient or should be of potential benefit for others and impose minimal extra risks for included patients. 4. If the patient recovers, he/she must be given infor- mation about the study at that time and the option to consent or not (deferred consent). How- ever, as our study reveals, in most European countries observational research cannot be performed today without written informed consent at admission. The fact that this is obstruct- ing observational research has been discussed previously [8,9] Our study was a purely observational study with no interventions outside standardizing information about geriatric syndromes. Although not potentially beneficial or detrimental for the individual patient, our study´s information may have huge implication for the group of very old patients who are acutely admitted to the ICU. If, as our results may indicate, survival in unselected patients is nearly halved within 30 days, we have the obligation to find ways to reduce unnecessary and futile therapy that is a huge burden on patients as well as caregivers, and to provide such care to those that most likely will profit from such treatment. Moreover, if the external validity of future observational studies is so low that we cannot trust such informa- tion, then our research becomes useless or even dangerous. This study has its strength being a prospective study with a high number of patients from many different countries in Europe, and patients were followed for 30 days. However, a weak- ness is the post-hoc design of this sub-study, which was not planned for during the pre-study phase. Another weakness is that in some countries with no national guidelines for research Ethical boards, the rules for inclusion could vary from region to region, and this variation have not been possible to capture in this analysis. Conclusions In this study we document the effects on how to receive informed consent in two patient groups within the same prospective study. If consent was necessary at admission (compared to deferred consent patients), patients were less severely ill and with a higher 30-day survival. PLOS ONE | https://doi.org/10.1371/journal.pone.0276386 October 27, 2022 7/9 PLOS ONE Consent is a confounding factor We hope that the EU will engage in the harmonization of inclusion rules in prospective observational studies where patients are unable to understand and/or make their own judg- ment regarding study participation. The unfortunate alternative would be significant biased data obtained from critically ill patients in Europe. Supporting information S1 Table. Table 1 Showing results from the Cox analysis and propensity score weighting in the consent versus non-consent groups when England was added to consent or non-con- sent group. (DOCX) S1 Dataset. A file with de-identified data performed in the analysis (minimal underlying dataset.xls). (XLS) Author Contributions Conceptualization: Hans Flaatten, Bertrand Guidet, Dylan W. de Lange. Data curation: Hans Flaatten, Christian Jung, Antonio Artigas, Finn Andersen, Jesper Fjølner. Formal analysis: Hans Flaatten, Bertrand Guidet, Ariane Boumendil. Funding acquisition: Hans Flaatten, Bertrand Guidet. Investigation: Bertrand Guidet, Christian Jung, Jesper Fjølner. Methodology: Hans Flaatten, Christian Jung, Ariane Boumendil, Jesper Fjølner, Dylan W. de Lange. Project administration: Hans Flaatten, Bertrand Guidet, Christian Jung, Susannah Leaver, Wojciech Szczeklik, Finn Andersen, Rui Moreno, Sten Walther, Joerg C. Schefold, Brian Marsh, Michael Joannidis, Muhammed Elhadi, Yuriy Nalapko, Jesper Fjølner, Dylan W. de Lange. Resources: Hans Flaatten, Bertrand Guidet. Software: Ariane Boumendil. Supervision: Hans Flaatten, Christian Jung, Wojciech Szczeklik, Antonio Artigas, Finn Ander- sen, Rui Moreno, Sten Walther, Sandra Oeyen, Joerg C. Schefold, Brian Marsh, Michael Joannidis, Muhammed Elhadi, Yuriy Nalapko, Jesper Fjølner. Validation: Hans Flaatten, Bertrand Guidet, Susannah Leaver, Wojciech Szczeklik, Antonio Artigas, Rui Moreno, Dylan W. de Lange. Visualization: Hans Flaatten. Writing – original draft: Hans Flaatten. Writing – review & editing: Bertrand Guidet, Christian Jung, Ariane Boumendil, Susannah Leaver, Wojciech Szczeklik, Antonio Artigas, Finn Andersen, Rui Moreno, Sten Walther, Sandra Oeyen, Joerg C. Schefold, Brian Marsh, Michael Joannidis, Muhammed Elhadi, Yuriy Nalapko, Jesper Fjølner, Dylan W. de Lange. 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