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Attitudes towards Genetic Information Delivered by High-Throughput Sequencing among Molecular Geneticists, Genetic Counselors, Medical Advisors and Students in France
Journal Pre-proof Attitudes towards genetic information delivered by high-throughput sequencing among clinical molecular Geneticists, genetic counselors, medical advisors and students in France Vlad Titerlea, Doulaye Dembélé, Jean-Louis Mandel, Jocelyn Laporte PII:
S1769-7212(19)30309-X
DOI:
https://doi.org/10.1016/j.ejmg.2019.103770
Reference:
EJMG 103770
To appear in:
European Journal of Medical Genetics
Received Date: 7 May 2019 Revised Date:
10 August 2019
Accepted Date: 15 September 2019
Please cite this article as: V. Titerlea, D. Dembélé, J.-L. Mandel, J. Laporte, Attitudes towards genetic information delivered by high-throughput sequencing among clinical molecular Geneticists, genetic counselors, medical advisors and students in France, European Journal of Medical Genetics (2019), doi: https://doi.org/10.1016/j.ejmg.2019.103770. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Masson SAS.
Attitudes towards Genetic Information Delivered by HighThroughput Sequencing among Clinical Molecular Geneticists, Genetic Counselors, Medical Advisors and Students in France Vlad Titerleaa,b, Doulaye Dembéléb, Jean-Louis Mandelb,*,**, Jocelyn Laporteb,** a
Centre Européen d'Enseignement et de Recherche en Éthique (CEERE), University of Strasbourg, 67000 Strasbourg b Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258, CNRS UMR7104, University of Strasbourg, 67400 Illkirch France *Corresponding author: 1 rue Laurent Fries / BP 10142 / 67404 Illkirch CEDEX, France E-mail address: [email protected] (J-L. Mandel) **equal contributors
Keywords: Genetic Testing, Incidental Finding, Preconception Carrier Screening, HighThroughput Sequencing, Survey, Bioethics
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Abstract High-throughput sequencing technologies performed in the clinical setting have the potential to reveal diverse genetic information. Whether it is initially targeted or unsolicited, strictly medical or not, or even information on a carrier status as part of preconception screening, access to genetic information needs to be managed. The aim of the current study was to gather potential attitudes of various stakeholders towards the sharing of genetic information from next-generation sequencing, and more specifically towards secondary findings, predictive findings, non-medical information and carrier status. Answers from a total number of 1631 individuals belonging to four different groups (45 molecular geneticists, 65 genetic counselors, 56 medical advisors to the state insurance plan, and 1465 university students) were collected through online questionnaires. Overall, a preference for disclosure of genetic information, on both personal and reproductive risks, was observed regardless of the scenario. The importance of the perceived medical utility, both for disease prevention and treatment, was the main distinguishing feature. Attitudes from genetic health professionals were found more reluctant to receive a wide range of information. Hands-on experience with the practice of genetic testing is likely to influence perception of the utility of the genetic information that should be delivered. At the same time, perceptions of preconception genetic carrier screening brought out less differences between participants. Better understanding of the underlying interest in genomic information and thorough education on its value and usage are key elements to the adoption of future guidelines and policy that respect bioethical principles.
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Introduction Next-Generation Sequencing (NGS) technologies which enable the simultaneous sequencing of large regions of the human genome or transcriptome, have a major impact on the practice of genetic tests. They increase the likelihood of discovering incidental findings, generally defined as results that are outside the original purpose for which the test or procedure was conducted (Presidential Commission for the Study of Bioethical Issues, 2013). The conceptual variety of findings that can arise needs to be clarified. The term “incidental findings” can refer to unanticipated or unintended results, but also to findings that can be anticipated and even actively sought, in which case we prefer to use the term “secondary findings”. Access to new information that might not be initially targeted by a genetic analysis is one of the most challenging aspects of the return of information in the clinical setting for both genetic health professionals and subjects of genetic tests, as deliverers and recipients of genetic test results. NGS technologies also provide scope for significant expansion of carrier screening to include a universal type of test for many genetic disorders simultaneously (Kingsmore and Saunders, 2011). Preconception carrier screening can be defined as the detection of carrier status of recessive diseases in individuals before pregnancy. Couples can thus have access to data on hereditary pathologies before they conceive. Offering a preconception testing may increase available reproductive options, while giving more time to make an informed decision. Future parents could consider not having a child, choosing in-vitro fertilization followed by a preimplantation genetic diagnosis (PGD) on the embryo, pursuing a natural pregnancy with prenatal diagnosis or choosing another partner. The declared aim of the carrier screening offered by commercial companies is to enhance reproductive autonomy, not prevention. Some public health aspects may nevertheless consider the prevention aspect. Preconception genetic screening is already widely used in some countries or populations with a marked prevalence for certain inherited conditions, e.g., beta thalassemia in some Mediterranean countries, Tay-Sachs and up to 15 other recessive diseases in Ashkenazi Jews from North America and is developed as a state organized program in Israel (Zlotogora et al., 2015; Cao and Kan, 2013; Cousens et al., 2010; Scott et al., 2010). The potential risks associated to the delivery of genetic information in both contexts have encouraged numerous reflections, statements or ethical guidance from professional societies, especially in the United States (Berg et al., 2011; Edwards et al., 2015; Green et al., 2013). Discussions are also vivid in the United Kingdom where the 100,000 Genomes Project is underway (PHG Foundation, 2013). Although there is acknowledgement of advances in next-generation sequencing, France has traditionally taken a more cautious approach towards access to genetic test results. Ethical opinions delivered by the French National Consultative Ethics Committee have expressed reservations about expanding the scope of genetic testing (National Consultative Ethics Committee for Health and Life Sciences, 2016, 2009). In this context, we set out to explore the attitudes towards genetic information as part of a genetic test on an adult individual or a preconception genetic carrier testing for current or prospective parents, before they would engage in a parental project. We performed online 3
surveys to find out what would potential subjects with different backgrounds want to know if they were confronted to diverse genetic information delivered through next-generation sequencing.
Methods Content of the surveys The survey was validated by the Ethics Committee of the Faculty of Medicine within the University of Strasbourg on July 10, 2012 (Ref. JS/CJ/N° 2012-92). It comprised 22 questions on various issues related to next-generation sequencing divided in 6 different parts (including the profile of the participants to the survey and a last section for comments), generally introduced by short informative texts briefly summarizing the pending issues raised by NGS technologies (Supplementary information for the full questionnaire in French and the translation of the main questions into English). We addressed the online questionnaire to students and genetic counselors. Prior to this study we conducted another quasi-identical online survey among smaller sets of health professionals for which prior ethical approval had not been sought. This first survey from a chronological perspective contained 19 similar questions and was addressed to molecular geneticists and to medical advisors. This paper only presents the answers to four questions on NGS related to the parts titled “Results of a Genetic Test” and “Predictive Genetic Tests & Family”. The aim of the questions was to seek the interest of participants in their own genetic information or in hereditary information they might transfer to their children. The other questions dealt with the management of genetic data in a broader context. These questions are not discussed here, although the adoption of any new technology largely depends on addressing other numerous issues that go beyond access to genetic information (e.g., implementation costs, privacy). Participants The identification of different, but relatively homogenous and relevant stakeholder groups was done in consideration of the impact that next-generation sequencing might have on these groups. Thus the survey was addressed to genetic health professionals, as well as non-professionals of genetic health, whether they were medical professionals or a specific group of the general public. Four groups were considered: • • • •
Clinical Molecular Geneticists Genetic Counselors Medical Advisors Students
The first survey from a chronological perspective was sent to molecular geneticists and to medical advisors (praticiens-conseils in French). Molecular geneticists are practitioners involved in the molecular diagnostics of genetic disorders and more recently in the field of pharmacogenetics. They were all members of the French National Society of Practitioners in Molecular Genetics - the ANPGM (Association Nationale des Praticiens de Génétique Moléculaire). Medical advisors are non-genetic health professionals, most of them being 4
medical doctors. They were all working for the Regional Public Health Agency (Agence Régionale de Santé) in north-eastern France (Alsace-Moselle). The second survey was sent to genetic counselors, all members of the French national professional society of genetic counselors, the AFCG (Association Française des Conseillers en Génétique), a relatively new profession in the field of genetic health. The last group was made of students enrolled at the University of Strasbourg, from different disciplines encompassing Humanities related disciplines (Law, Social Sciences, Liberal Arts…), natural sciences (Chemistry, Physics…) and health-related disciplines (Medicine, Pharmacy…). The degrees they attended were not known. For a summarized profile of the participants, see Tables 1-2 and Supplementary information. Recruitment Participants were recruited via direct e-mail invitation. Data were collected anonymously, online, as electronic form questionnaires seemed the most effective way to reach a large public (Bälter et al., 2005; Kongsved et al., 2007). The first survey was used to collect answers from molecular geneticists and medical advisors over the months of May to July 2011. Data from genetic counselors and students were collected through the second survey between the end of November 2012 and beginning of January 2013. For genetics practitioners and medical advisors we used Google Docs® to collect the information. Answers from students and genetic counselors were collected through a Limesurvey® platform provided by the University of Strasbourg. Data were collected separately for each group. Every respondent participated on a voluntary basis. Consent was deemed implicit once the survey was accepted and made available by the institution to their members. Participants accessed the link in the email address given to the institution they were affiliated to. No reminder was sent to any of the surveyed groups. The language of the surveys was French. We should stress that the study was done at a time when policy and bioethical issues regarding NGS were just beginning to be considered. Statistical analysis We used the R environment (version 3.4.3) to analyze the survey data. Only complete answers to the surveys were considered for the analysis. Results of participants who accessed the survey without completing it were not taken into account. Categorical variables were examined through Chi-square tests. Binary logistic regression was used to provide estimates of these associations adjusted for the following covariates: gender, parenthood, self-reported knowledge of genetics, self-reported presence or absence in the family of a relative with a genetic disease and field of study for students. The analysis of variance (ANOVA) was used to test the significance of the regression parameters. We employed the Bonferroni correction for multiple testing to adjust probability values (significant p-values set at 0.05). Responses of participants to the survey were summarized as percentages calculated for each stakeholder group (Figures. 1-4).
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Results The aim of the study was to determine which of the following demographics affects attitudes toward genetic information among: gender, parenthood, relation to a genetic disease (selfreported presence or absence in the family of a relative with a genetic disease), self-reported knowledge of genetics and field of study for students. The four questions related to the return of genetic information presented in this article each correspond to four different scenarios. The first question focused on the possible interest in secondary findings, once the participant would have undergone a diagnostic test for a likely genetic condition and in case the test would reveal information unrelated to the initial purpose of the test. The second question dealt with preferences concerning a predictive genetic test in a participant apparently healthy. The third question probed the attitudes towards information that is not strictly medical, but that might be delivered when a genetic test is performed. The last question dealt with potential support for information delivered by a preconception genetic testing for determining carrier status. In an attempt to avoid bias based on personal history, no specific genetic conditions were mentioned, except otherwise stated (e.g., colon or breast cancer). For most scenarios participants could answer based on estimated severity, probable onset, likelihood of developing the disease and availability of potential treatment. The possible choices did not cover irrelevant or impossible to interpret variants. For all questions, participants were asked to choose from genetic information that would already be interpreted and considered as robust. Respondents also had the “right not to know” any genetic test result. Participation to the survey There were 45 molecular geneticists, 65 genetic counselors, 56 medical advisors and 1465 students who completed the survey. As far as members of a genetic-health professional society are concerned we obtained a 21.5% response rate for geneticists, as the email was sent to the 209 members of the ANPGM and a 47.4% participation rate for genetic counselors as, at the time, the AFCG had 137 members. Medical advisors were contacted in the context of a regular training program organized on May 26 and 27, 2011. About 110 participants to the training received the link, with a 50.9% response rate. As for students, the link was sent to the institutional e-mail address of about 40,000 students enrolled at the time at the University of Strasbourg. Response rate would thus account for approximately 3.7% of the students, but we cannot precisely determine the number of people who actually accessed their institutional email. The proportion of students enrolled in Humanities related disciplines at the University of Strasbourg was around 65%. Students studying natural science or health-related disciplines both accounted for about 35%. The participation rate was as follows: 41.4% of students enrolled in Humanities related disciplines (n=607), 54% of students studying natural science or health-related disciplines (n=791) and 4.6% for whom we could not determine the field of study (n=67). This suggests that the group of students enrolled in natural sciences or health-related disciplines was more interested in the topic. 6
The precise number of participants was impossible to investigate as this was an anonymous survey. Considering the amount of time it took to complete the numerous questions of the survey on a topic that is not accessible to everyone and the fact that no reminder was sent, participation with regard to the number of the estimated people to whom the survey was addressed was deemed overall satisfactory. Many positive remarks were made in the comments section at the end of the survey. Attitudes towards secondary findings from genetic diagnostic testing In the first scenario, respondents were asked to imagine that they were experiencing symptoms possibly related to a genetic condition and that their doctor ordered a “nextgeneration” sequencing test to confirm the diagnosis. They were informed that beyond the confirmation of the diagnosis, it was possible that the test reveals the risk to develop a second condition. The results of the survey suggested an interest in secondary findings, i.e., genetic information that are unsolicited at the beginning of the test. More than 90% of participants wanted to be informed of at least one second genetic condition: 97.8% of molecular geneticists (n=44), 96.9% of genetic counselors (n=63), 96.4 % of medical advisors (n=54) and 93.1% of students (n=1364)(Fig. 1). All groups seemed to favor disclosure of a specific genetic condition with a rather high risk (i.e., colon or breast cancer with a high probability of the disease appearing; personal risk would be of 50%), or when the disease was serious with available prevention and/or effective care (almost certain onset in the next 10 years) (items c and e in Fig.1). For the other answers mainly related to untreatable serious diseases (items a, b and d), most significant differences were found between genetic-health professionals (molecular geneticists and genetic counselors) who were more reluctant and students who were generally more favorable to disclosure of such information (χ² > 28.65; df=1; p < 4.32e-8). No significant differences existed in attitudes between genetic-health professionals and non-genetic health professionals (χ² = 1.29, df=1, p = 0.13). Overall students’ preferences to access genetic information appeared to be affected by demographics such as gender, parenthood and self-reported literacy. Female students appeared to be less eager to receive information on life-threatening conditions with no or uncertain available treatment (items a, b and d) (logistic regression: z < -2.16; p < 0.031) (Supplementary Fig. 1). Furthermore, parenthood was also found to have an influence on all answers. Although the number of students who were parents was low (n=43), they expressed a preference towards non-disclosure of secondary findings (logistic regression: z = 2.157; p = 0.031). Finally, students with a good and very good self-reported genetic literacy were less interested in information related to a higher than average risk to a serious condition involving heavy treatment with uncertain outcome (item d) than students with a lower selfreported knowledge of genetics (logistic regression: z = -2.611; p = 0.00902). Attitudes towards findings from predictive genetic testing In the second scenario, respondents had to imagine that they would undergo a predictive genetic test while being apparently healthy. Compared to the low number of participants who would not be interested in any secondary finding in the previous scenario (less than 10%), the proportion of respondents who would decline a predictive genetic test was much higher: 7
48.9% of molecular geneticists (n=22), 35.4% of genetic counselors (n=23), 21.4% of medical advisors (n=12) and 28.7% of students (n=421)(Fig. 2; supplementary Fig. 2). Nevertheless, more than half of participants of each group expressed an interest in communication of predictive findings. Once they accepted to receive information delivered by a predictive genetic test, we found the same patterns in responses concerning the different items as for the previous scenario, although in a lower proportion (Fig. 2). As in the case of secondary findings, preferences towards reporting predictive findings seemed motivated by the presence of actionable genes. In addition, no statistical difference could be observed in attitudes between molecular geneticists and genetic counselors. Most significant differences were found between genetichealth professionals and students with regard to life-threatening diseases with no or partially effective treatment (items a, b and d), as students showed a stronger interest in such information (χ² > 12.5; df = 1; p < 0.0002). Attitudes towards information unrelated to genetic diseases The interest in information which is not related to the diagnosis of genetic conditions, including non-medical information, was collected only for students and genetic counselors. If most respondents seemed interested in pharmacogenetics information (i.e., efficacy or side effects of drugs), regardless of the group they belonged to (66.2% of genetic counselors (n=43) and 72.4% of students (n=1061)), differences between groups could be observed when it came to genetic information that was not strictly medical (Fig. 3). Indeed, only 13.9% of genetic counselors (n=9) wanted to have access to information concerning phenotypic traits (e.g., baldness) compared to 53.99% of the students (n=791). A similar trend could be observed for genealogical information for which 29.2% of genetic counselors (n=19) and 56.2% of students (n=824) shared a common interest. The proportion of genetic counselors who did not want to know a more recreational type of genetic information was higher than the proportion of students. It might be worth mentioning that genetic counselors were slightly older on average than students (most represented age ranges were 25-34 and 18-24 respectively) (Table 2). Both groups also had the possibility to choose the option “Don’t know”, in case they did not know what kind of information they would be interested in. We could observe that only a small proportion checked this box: 4.6% of genetic counselors (n=3) and 5.9% of students from the University of Strasbourg (n=87), which might suggest that respondents were willing to express a choice. Compared to male students, we observed that female students generally preferred not to know information related to pharmacogenetics, phenotypic traits or ancestry (logistic regression: z < -2.61; p < 0.01) (Supplementary Fig. 3). Attitudes towards disclosure of phenotypic traits also seemed to be influenced by the parenthood status, as students and genetic counselors that were parents were less interested in this type of findings (ANOVA: F = 5.459; p = 0.0197 and F = 5.063; p = 0.0281 respectively). Other demographics like the self-reported knowledge of genetics or the field of study were not found to have a significant influence.
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Attitudes towards carrier status information in preconception screening The fourth scenario dealt with disclosure of carrier status in the context of preconception screening. The majority of respondents opted to receive information on their carrier status and the genetic information they might transmit to their offspring (Fig. 4). No significant differences appeared in attitudes between the four groups towards information on carrier status for mutations involved in a serious disease leading to infant mortality and/or motor or mental handicap (potentially leading to voluntary medical termination of pregnancy). Similarly, there was no statistical difference between respondents who did not want a preconception test. Significant differences arose with respect to information about conditions that are not lifethreatening. Genetic counselors appeared to be more interested than clinical geneticists in knowing if they were carriers of mutations involved in a serious condition that can be treated (67% of genetic counselors compared to 38% of molecular geneticists; χ² = 8.46; df = 1; p = 0.018). The same patterns could be observed for medical advisors (77%; χ² = 14.167; df = 1, p = 8.36e-5) and students (60%; χ² = 8.791; df = 1; p = 0.0154). As far as preferences with regard to conditions impacting the quality of life (e.g., deafness at birth) are concerned, both groups of genetic health professionals (molecular geneticists and genetic counselors) were more reluctant to receive this type of information than medical advisors (35.5% and 62.5% respectively; χ² = 9.919; df = 1; p = 0.00082) and students (55.9%; χ² = 16.439; df = 1; p = 2.512e-05). On the whole, medical advisors were the most interested to receive information related to their carrier status. We found that the few students who were parents (n= 43) had a more reluctant attitude towards preconception genetic carrier test and the subsequent delivered information (logistic regression: z = 2.163; p = 0.0305) (Supplementary Fig. 4). Students that reported a good literacy in genetics (48.3%) appeared less interested in knowing their carrier status for conditions impacting the quality of life (logistic regression: z = -2.590; p = 0.0096). Other demographics, such as the field of study and the health status or being related to a patient were not found to play a significant role in those answers.
Discussion Favorable attitudes to the return of genetic information are influenced by hands-on experience in genetics All surveyed groups were in favor of the receipt of some kind of genetic information from next-generation sequencing when put in hypothetical scenarios. The interest in secondary findings delivered by genetic diagnostic testing on subjects that would already suffer from a genetic condition was higher than the interest in findings from predictive genetic testing on apparently healthy individuals. Once respondents accepted to receive some kind of genetic information, they generally favored access to more than one medical condition. Some demographics like the self-reported knowledge of genetics, gender and parenthood status appeared to have an influence among students. Indeed, female students and students who were parents seemed less inclined to receive genetic information related to conditions without available care or to non-medical genetic information. A stronger educational background in genetics, as well as parenthood experiences might be underlying a more cautious attitude and a different perception of benefits and risks of genetic information. 9
Attitudes towards the disclosure of genetic information seemed to be influenced by handson experience in genetics. Molecular geneticists and genetic counselors were generally the most reluctant to know information related to secondary and predictive findings, while students and medical advisors expressed more preferences in this respect. Participants with an established expertise in the field of genetics chose less to receive information related to life-threatening conditions with no available effective treatment and genetic counselors were less curious about non-medical information. Even students who reported a higher genetic literacy showed a lower interest in secondary findings and carrier status for some diseases. This suggests that genetic health professionals might favor genetic information with an unambiguous and beneficial medical impact, whereas other respondents without on-hands experience might appreciate that genetic information has a utility per se, as also observed in other studies (Middleton et al., 2016). Genetic health professionals appear to have a more cautious approach to genetic test results or to genetic testing than the lay public. There might be a cleavage between the preferences expressed by participants educated in other fields than genetics and the information deemed appropriate to be disclosed by the professionals performing the test. An adequate education of the general population concerning the accuracy and utility of genetic tests and information would be warranted. Considering the medical utility and scientific value of genetic information The perceived medical utility seemed to be the most important aspect that affected attitudes of the four groups towards genetic information. The availability of both prevention and successful prophylaxis appeared to be the main criterion that encouraged participants to receive genetic test results. Interest in pharmacogenomics data and in carrier status information can also be put in the context of prevention. For students, preferences extended to life-threatening conditions with no available care and to non-medical genetic information (phenotypical or genealogical information). This non-medical information is not part of the current routine clinical practice, as genetic tests may only be undertaken for medical or scientific research purposes. The observed curiosity may suggest a more consumerist attitude towards genetic testing in general, which is an aspect that should not be disregarded by policy-makers. All possible choices referred to conditions that were considered clinically valid and pertinent. There were neither variants with uncertain significance, nor variants with incomplete penetrance (except item c) for the first two scenarios). The interpretation that the majority of stakeholders is interested in genetic information with potential medical consequences is based on the assumption of a clear scientific significance of the genetic data. Clarifying the medical significance of the genomic data is the main challenge for genetic diagnosis in the future. There is currently no right for a person to choose useful findings they would want to know, nor a duty for a clinician to return such unsolicited information. The legal framework was initially tailored for targeted genetic tests and did not explicitly address the issue of additional findings. This legal uncertainty seems to be partly remedied by the report issued by the Government’s advisor in matters concerning the preparation of draft legislation (Conseil d’Etat) in the context of the adoption of a new French law of bioethics (Conseil d’Etat, 2018). It considers that there is no legal obstacle to disclose incidental findings on a case-by-case basis, as long as the findings are related to a serious risk that would benefit from effective care. However, anticipating and communicating genetic results which might be clinically 10
actionable, but are not related to the primary purpose of the test, is challenging in the absence of a more thorough normative framework. The possibility to communicate additional findings that might be relevant to a patient’s health or lifestyle can be daunting. Existing guidelines setting out good practices for genetic testing are likely to be updated on a regular basis to address the issue of incidental findings. Providing reproductive options through preconception carrier screening Our data suggest that attitudes are generally positive towards carrier status information delivered as part of a hypothetical parental project. Similar responses between all stakeholder groups were gathered with regard to disclosure of information related to a serious disease leading to infant mortality and/or motor or mental handicap (possibility of voluntary termination of pregnancy). Interest in less severe disorders appeared higher among non-genetic health professionals and students. Other studies have found similar results (Poppelaars et al., 2004) and the 2018 debates on the French bioethics law have shown population support for increasing reproductive options. There is growing accessibility of preconception screening in some countries where it is recommended or mandatory for targeted conditions, or as commercial services provided by companies (e.g., Counsyl (www.counsyl.com) in the US or bio.logis (https://pgsbox.de/dna/familienplanung-schwangerschaft-thrombose) in Germany) (Borry et al., 2011). At a European level, the European Society of Human Genetics has positioned itself in favor of responsible implementation of expanded carrier screening (Henneman et al., 2016). Ethical opinions in some European countries have also become favorable to its extension (Health Council of the Netherlands, 2007; Human Genetics Commission, 2011). In France, the current standard practice is to offer the screening only to couples who present a higher risk of a monogenic recessive disease, because there is an index case to whom they are closely related (for instance cascade screening for cystic fibrosis, spinal muscular atrophy or for X linked recessive diseases) (National Consultative Ethics Committee for Health and Life Sciences, 2016). The possibility to expand carrier screening to persons who do not have an a priori risk of being a carrier based on their personal or family history has not yet found a favorable legal outcome. Previous ethical opinions have put an emphasis on potential harmful effects carrier screening might have on couples and the risks of stigmatization and discrimination. Concerns of stigma have been documented in the past for early mass screening programs (Markel, 1992), but the link with current expanded carrier screening has yet to be established. Increased levels of anxiety, albeit relatively low and temporary, have also been observed (Lakeman et al., 2008). Those potential psychological ramifications and social risks need to be addressed by the French legislator through a balance between the benefits of an increasing available technology and the associated risks. The French National Ethics Consultative Committee has recently issued a report in favor of responsible expansion of preconception testing (National Consultative Ethics Committee for Health and Life Sciences, 2018). It is likely that considerations related to responsible implementation of preconception carrier screening will be a subject of debate in the near future.
Limits None of the surveyed groups can be considered as representative, as no criteria for representativeness have been established beforehand. The majority of participants 11
presented a specific profile that prevents us from generalizing conclusions to a wider public. There were some commonalities between all those groups, as most participants were educated, women which corresponds to the trends with regard to who generally responds to surveys (Smith, 2008). Other demographics like the socio-economic status, the marital status, the culture, the religious beliefs or ethnic origin were not taken into account. The large amount of comparisons which were done in this study and some of the differences found significant may have occurred by chance. Some of the beliefs and choices expressed in this survey may also have shifted over time. In an attempt to avoid very specific answers, no genetic conditions were mentioned as a general rule. The answers might have been different if participants had to choose from clearly identified genetic conditions. Furthermore, for three of the four scenarios, respondents did not directly have the possibility to check a “Don’t know” box, but they had a field where they could leave comments. Only a small proportion wrote that they did not know if they wanted to get tested or receive results from a high-throughput sequencing test. The questions the respondents answered were hypothetical ones, asked outside a medical setting. As the majority of the participants had to imagine being subject of a “nextgeneration” genetic test, the survey had a recreational dimension. Expressing preferences in the context of an online survey does not imply consent to genetic testing or to the information that should be delivered. Our questions were labeled around an autonomous-patient model in which respondents had full choice of the returned information. However, this approach is not part of routine genetic diagnosis where decision making is a shared process and takes into account particular situations, the clinical profile of subjects and the practical burdens that might arise when a genetic test is performed. Ethical or legal issues were not directly questioned in the survey, nor has the participants’ knowledge of the legal framework surrounding genetic tests. It is therefore difficult to draw conclusions with regard to changes in current policies and practices. Increased access to genetic information on a larger scale requires addressing a variety of issues that are not only scientific.
Conclusion The majority of participants showed an interest in genetic information that NGS testing would provide, whether the findings were secondary, predictive, non-medical or information on a carrier status. Most respondents expressed higher preference for actionable conditions when discovered. Significant differences were found between genetic health professionals on the one hand and medical advisors and students on the other. Stakeholders should pool their efforts to ensure better understanding of patients’ choices and possible support for the return of genetic findings. Educating stakeholders adequately on issues related to genetics might influence beliefs on NGS. In the case of next-generation sequencing for health or reproductive purposes, ethical or legal guidelines should focus on better anticipation and reporting of findings with established medical value. Proper information and consent should also be addressed before the start of any procedure. Additional empirical evidence, interdisciplinary debates and anything that can raise awareness would help realize the full and accurate potential of genomic medicine.
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Ethical Statement Conflict of interest The authors declare no conflict of interest. Funding This study was supported by INSERM, CNRS, University of Strasbourg, ANR-10-LABX0030-INRT, a French State fund managed by the ANR under the frame program Investissements d’Avenir (10-IDEX-0002) and a prize from the French Paediatric Pathology Society.
Acknowledgements We would like to thank all the participants to the survey. We are thankful to the University of Strasbourg for allowing us to contact the students and for providing the infrastructure to gather the data. This work was partially done while VT was doing an internship at the IGBMC for his Master’s Degree in Ethics.
References Bälter, K.A., Bälter, O., Fondell, E., Lagerros, Y.T., 2005. Web-based and mailed questionnaires: a comparison of response rates and compliance. Epidemiol. Camb. Mass 16, 577–579. Berg, J.S., Khoury, M.J., Evans, J.P., 2011. Deploying whole genome sequencing in clinical practice and public health: Meeting the challenge one bin at a time. Genet. Med. 13, 499–504. https://doi.org/10.1097/GIM.0b013e318220aaba Borry, P., Henneman, L., Lakeman, P., ten Kate, L.P., Cornel, M.C., Howard, H.C., 2011. Preconceptional genetic carrier testing and the commercial offer directly-toconsumers. Hum. Reprod. Oxf. Engl. 26, 972–977. https://doi.org/10.1093/humrep/der042 Cao, A., Kan, Y.W., 2013. The Prevention of Thalassemia. Cold Spring Harb. Perspect. Med. 3. https://doi.org/10.1101/cshperspect.a011775 Conseil d’Etat, 2018. Révision de la loi de bioéthique : quelles options pour demain ? Cousens, N.E., Gaff, C.L., Metcalfe, S.A., Delatycki, M.B., 2010. Carrier screening for betathalassaemia: a review of international practice. Eur. J. Hum. Genet. EJHG 18, 1077– 1083. https://doi.org/10.1038/ejhg.2010.90 Edwards, J.G., Feldman, G., Goldberg, J., Gregg, A.R., Norton, M.E., Rose, N.C., Schneider, A., Stoll, K., Wapner, R., Watson, M.S., 2015. Expanded Carrier Screening in Reproductive Medicine—Points to Consider: A Joint Statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine. Obstet. Gynecol. 125, 653. https://doi.org/10.1097/AOG.0000000000000666 Green, R.C., Berg, J.S., Grody, W.W., Kalia, S.S., Korf, B.R., Martin, C.L., McGuire, A.L., Nussbaum, R.L., O’Daniel, J.M., Ormond, K.E., Rehm, H.L., Watson, M.S., Williams, M.S., Biesecker, L.G., 2013. ACMG recommendations for reporting of incidental 13
findings in clinical exome and genome sequencing. Genet. Med. 15, 565–574. https://doi.org/10.1038/gim.2013.73 Health Council of the Netherlands, 2007. Preconception care: a good beginning. Henneman, L., Borry, P., Chokoshvili, D., Cornel, M.C., van El, C.G., Forzano, F., Hall, A., Howard, H.C., Janssens, S., Kayserili, H., Lakeman, P., Lucassen, A., Metcalfe, S.A., Vidmar, L., de Wert, G., Dondorp, W.J., Peterlin, B., 2016. Responsible implementation of expanded carrier screening. Eur. J. Hum. Genet. 24, e1–e12. https://doi.org/10.1038/ejhg.2015.271 Human Genetics Commission, 2011. Increasing Options, Informing Choice: A Report on Preconception Genetic Testing and Screening. Kingsmore, S.F., Saunders, C.J., 2011. Deep sequencing of patient genomes for disease diagnosis: when will it become routine? Sci. Transl. Med. 3, 87ps23. https://doi.org/10.1126/scitranslmed.3002695 Kongsved, S.M., Basnov, M., Holm-Christensen, K., Hjollund, N.H., 2007. Response rate and completeness of questionnaires: a randomized study of Internet versus paper-andpencil versions. J. Med. Internet Res. 9, e25. https://doi.org/10.2196/jmir.9.3.e25 Lakeman, P., Plass, A.M.C., Henneman, L., Bezemer, P.D., Cornel, M.C., ten Kate, L.P., 2008. Three-month follow-up of Western and non-Western participants in a study on preconceptional ancestry-based carrier couple screening for cystic fibrosis and hemoglobinopathies in the Netherlands. Genet. Med. Off. J. Am. Coll. Med. Genet. 10, 820–830. https://doi.org/10.1097/GIM.0b013e318188d04c Markel, H., 1992. The stigma of disease: implications of genetic screening. Am. J. Med. 93, 209–215. Middleton, A., Morley, K.I., Bragin, E., Firth, H.V., Hurles, M.E., Wright, C.F., Parker, M., 2016. Attitudes of nearly 7000 health professionals, genomic researchers and publics toward the return of incidental results from sequencing research. Eur. J. Hum. Genet. 24, 21–29. https://doi.org/10.1038/ejhg.2015.58 National Consultative Ethics Committee for Health and Life Sciences, 2018. Contribution to the French Bioethics Law, 2018-2019. National Consultative Ethics Committee for Health and Life Sciences, 2016. Ethical Reflection on Development inn Genetic Testing in Connection with Very High Throughput Human DNA Sequencing (Opinion No. 124). National Consultative Ethics Committee for Health and Life Sciences, 2009. Ethical Issues in Connection with Antenatal Diagnosis: Prenatal Diagnosis (PND) and Preimplantation Genetic Diagnosis (PGD) (Opinion No. 107). PHG Foundation, 2013. Managing Incidental and Pertinent Findings from WGS in the 100,000 Genomes Project. Poppelaars, F.A.M., Henneman, L., Adèr, H.J., Cornel, M.C., Hermens, R.P.M.G., van der Wal, G., ten Kate, L.P., 2004. Preconceptional cystic fibrosis carrier screening: attitudes and intentions of the target population. Genet. Test. 8, 80–89. https://doi.org/10.1089/gte.2004.8.80 Presidential Commission for the Study of Bioethical Issues, 2013. Anticipate and Communicate Ethical Management of Incidental and Secondary Findings in the Clinical, Research, and Direct-to- Consumer Contexts. United States Government, Washington, DC. Scott, S.A., Edelmann, L., Liu, L., Luo, M., Desnick, R.J., Kornreich, R., 2010. Experience with carrier screening and prenatal diagnosis for 16 Ashkenazi Jewish genetic diseases. Hum. Mutat. 31, 1240–1250. https://doi.org/10.1002/humu.21327 Smith, W.G., 2008. Does Gender Influence Online Survey Participation? A Record-Linkage Analysis of University Faculty Online Survey Response Behavior. Zlotogora, J., Grotto, I., Kaliner, E., Gamzu, R., 2015. The Israeli national population program of genetic carrier screening for reproductive purposes. Genet. Med. 18, 203–206. https://doi.org/10.1038/gim.2015.55
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Table 1 Profiles of molecular geneticists and medical advisors
Total Age range 25 – 29 30 – 39 40 – 49 50 – 59 60 – 69 Gender Female Male Parenthood Yes No Self-reported Knowledge of Genetics Very good, I understand most notions in genetics Average, I understand main notions in genetics Poor, I understand few notions in genetics No knowledge
Molecular Geneticists 45
Medical Advisors 56
1 (2.2%) 10 (22.2%) 17 (37.8%) 16 (35.6%) 1 (2.2%)
1 (1.8%) 1 (1.8%) 19 (33.9%) 28 (50.0%) 7 (12.5%)
31 (68.9%) 14 (31.1%)
30 (53.6%) 26 (46.4%)
35 (77.8%) 10 (22.2%)
47 (83.9%) 9 (16.1%)
42 (93.5%) 3 (6.7%)
2 (3.6%) 53 (94.6%) 1 (1.8%)
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Table 2 Profiles of genetic counselors and students
Total Age range under 18 18 – 24 25 – 34 35 – 44 45 – 54 55 – 64 65 and above Gender Female Male Parenthood Yes No Self-reported Knowledge of Genetics Very good, I understand most notions in genetics Good, I understand main notions in genetics Average, I understand certain notions genetics Poor, I understand few notions in genetics No knowledge Patient or Family of a Patient No, I am not a patient, nor related to a patient Yes, I am a patient Yes, I am related to a patient I don’t know
Genetic Counselors 65
Students 1465
0 (0.0%) 10 (15.4%) 43 (66.1%) 7 (10.8%) 2 (3.1%) 3 (4.6%) 0 (0.0%)
31 (2.1%) 1203 (82.1%) 193 (13.2%) 16 (1.1%) 14 (1.0%) 6 (0.4%) 2 (0.1%)
55 (84.6%) 10 (15.4%)
984 (67.2%) 481 (32.8%)
19 (29.2%) 46 (70.8%)
50 (3.4%) 1415 (96.6%)
47 (72.3%) 18 (27.7%)
190 (13.2%) 518 (35.3%) 448 (30.5%) 242 (16.5%) 67 (4.5%)
54 (83.1%) 3 (4.6%) 8 (12.3%)
1087 (74%) 39 (2.7%) 187 (13%) 152 (10.3%)
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Figure Legends
Fig. 1. Attitudes towards receiving secondary findings from diagnostic genetic testing. (a) Serious and incurable condition with an almost certain onset in the next 10 years; (b) Serious and incurable condition with an almost certain onset later in the future; (c) Colon or breast cancer with a high probability of the disease appearing ; your risk would be of 50%; (d) Serious condition requiring extensive treatment with uncertain or partial efficacy: your risk for this disease would be of 10% compared to an average of 2% in the general population; (e) Serious condition with effective prevention and/or care (almost certain onset in the next 10 years); (f) I wouldn’t want to be informed of a second condition; (g) Other.
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Fig. 2. Attitudes towards receiving findings from predictive genetic testing. (a) Serious and incurable condition with an almost certain onset in the next 10 years; (b) Serious and incurable condition with an almost certain onset later in the future; (c) Colon or breast cancer with a high probability of the disease appearing ; your risk would be of 50%; (d) Serious condition requiring extensive treatment with uncertain or partial efficacy: your risk for this disease would be of 10% compared to an average of 2% in the general population; (e) Serious condition with effective prevention and/or care (almost certain onset in the next 10 years); (f) I would refuse the testing; (g) Other.
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Fig. 3. Attitudes towards receiving information unrelated to the diagnosis of a genetic disease or without medical implication. (a) The response to a drug (efficacy or side effects of a drug); (b) Physical traits (predisposition to balding); (c) Genealogical Information; (d) I’m not interested in this type of information; (e) I don’t know; (f) Other.
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Fig. 4. Attitudes towards carrier status from preconception screening. (a) A serious condition leading to infant mortality and/or motor or mental handicap (with possibility of voluntary termination of pregnancy). (b) A serious condition with effective treatment. (c) Conditions that affect the quality of life (e.g., deafness at birth). (d) Do not want predictive genetic testing as part of a parental project.
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Supplementary materials • • • • •
Ethics committee approval Complete questionnaire in French Questions translated into English Additional demographic data: Distribution of students Additional figures : answers based on the gender of students
21
S1769-7212(19)30309-X
DOI:
https://doi.org/10.1016/j.ejmg.2019.103770
Reference:
EJMG 103770
To appear in:
European Journal of Medical Genetics
Received Date: 7 May 2019 Revised Date:
10 August 2019
Accepted Date: 15 September 2019
Please cite this article as: V. Titerlea, D. Dembélé, J.-L. Mandel, J. Laporte, Attitudes towards genetic information delivered by high-throughput sequencing among clinical molecular Geneticists, genetic counselors, medical advisors and students in France, European Journal of Medical Genetics (2019), doi: https://doi.org/10.1016/j.ejmg.2019.103770. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Masson SAS.
Attitudes towards Genetic Information Delivered by HighThroughput Sequencing among Clinical Molecular Geneticists, Genetic Counselors, Medical Advisors and Students in France Vlad Titerleaa,b, Doulaye Dembéléb, Jean-Louis Mandelb,*,**, Jocelyn Laporteb,** a
Centre Européen d'Enseignement et de Recherche en Éthique (CEERE), University of Strasbourg, 67000 Strasbourg b Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258, CNRS UMR7104, University of Strasbourg, 67400 Illkirch France *Corresponding author: 1 rue Laurent Fries / BP 10142 / 67404 Illkirch CEDEX, France E-mail address: [email protected] (J-L. Mandel) **equal contributors
Keywords: Genetic Testing, Incidental Finding, Preconception Carrier Screening, HighThroughput Sequencing, Survey, Bioethics
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Abstract High-throughput sequencing technologies performed in the clinical setting have the potential to reveal diverse genetic information. Whether it is initially targeted or unsolicited, strictly medical or not, or even information on a carrier status as part of preconception screening, access to genetic information needs to be managed. The aim of the current study was to gather potential attitudes of various stakeholders towards the sharing of genetic information from next-generation sequencing, and more specifically towards secondary findings, predictive findings, non-medical information and carrier status. Answers from a total number of 1631 individuals belonging to four different groups (45 molecular geneticists, 65 genetic counselors, 56 medical advisors to the state insurance plan, and 1465 university students) were collected through online questionnaires. Overall, a preference for disclosure of genetic information, on both personal and reproductive risks, was observed regardless of the scenario. The importance of the perceived medical utility, both for disease prevention and treatment, was the main distinguishing feature. Attitudes from genetic health professionals were found more reluctant to receive a wide range of information. Hands-on experience with the practice of genetic testing is likely to influence perception of the utility of the genetic information that should be delivered. At the same time, perceptions of preconception genetic carrier screening brought out less differences between participants. Better understanding of the underlying interest in genomic information and thorough education on its value and usage are key elements to the adoption of future guidelines and policy that respect bioethical principles.
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Introduction Next-Generation Sequencing (NGS) technologies which enable the simultaneous sequencing of large regions of the human genome or transcriptome, have a major impact on the practice of genetic tests. They increase the likelihood of discovering incidental findings, generally defined as results that are outside the original purpose for which the test or procedure was conducted (Presidential Commission for the Study of Bioethical Issues, 2013). The conceptual variety of findings that can arise needs to be clarified. The term “incidental findings” can refer to unanticipated or unintended results, but also to findings that can be anticipated and even actively sought, in which case we prefer to use the term “secondary findings”. Access to new information that might not be initially targeted by a genetic analysis is one of the most challenging aspects of the return of information in the clinical setting for both genetic health professionals and subjects of genetic tests, as deliverers and recipients of genetic test results. NGS technologies also provide scope for significant expansion of carrier screening to include a universal type of test for many genetic disorders simultaneously (Kingsmore and Saunders, 2011). Preconception carrier screening can be defined as the detection of carrier status of recessive diseases in individuals before pregnancy. Couples can thus have access to data on hereditary pathologies before they conceive. Offering a preconception testing may increase available reproductive options, while giving more time to make an informed decision. Future parents could consider not having a child, choosing in-vitro fertilization followed by a preimplantation genetic diagnosis (PGD) on the embryo, pursuing a natural pregnancy with prenatal diagnosis or choosing another partner. The declared aim of the carrier screening offered by commercial companies is to enhance reproductive autonomy, not prevention. Some public health aspects may nevertheless consider the prevention aspect. Preconception genetic screening is already widely used in some countries or populations with a marked prevalence for certain inherited conditions, e.g., beta thalassemia in some Mediterranean countries, Tay-Sachs and up to 15 other recessive diseases in Ashkenazi Jews from North America and is developed as a state organized program in Israel (Zlotogora et al., 2015; Cao and Kan, 2013; Cousens et al., 2010; Scott et al., 2010). The potential risks associated to the delivery of genetic information in both contexts have encouraged numerous reflections, statements or ethical guidance from professional societies, especially in the United States (Berg et al., 2011; Edwards et al., 2015; Green et al., 2013). Discussions are also vivid in the United Kingdom where the 100,000 Genomes Project is underway (PHG Foundation, 2013). Although there is acknowledgement of advances in next-generation sequencing, France has traditionally taken a more cautious approach towards access to genetic test results. Ethical opinions delivered by the French National Consultative Ethics Committee have expressed reservations about expanding the scope of genetic testing (National Consultative Ethics Committee for Health and Life Sciences, 2016, 2009). In this context, we set out to explore the attitudes towards genetic information as part of a genetic test on an adult individual or a preconception genetic carrier testing for current or prospective parents, before they would engage in a parental project. We performed online 3
surveys to find out what would potential subjects with different backgrounds want to know if they were confronted to diverse genetic information delivered through next-generation sequencing.
Methods Content of the surveys The survey was validated by the Ethics Committee of the Faculty of Medicine within the University of Strasbourg on July 10, 2012 (Ref. JS/CJ/N° 2012-92). It comprised 22 questions on various issues related to next-generation sequencing divided in 6 different parts (including the profile of the participants to the survey and a last section for comments), generally introduced by short informative texts briefly summarizing the pending issues raised by NGS technologies (Supplementary information for the full questionnaire in French and the translation of the main questions into English). We addressed the online questionnaire to students and genetic counselors. Prior to this study we conducted another quasi-identical online survey among smaller sets of health professionals for which prior ethical approval had not been sought. This first survey from a chronological perspective contained 19 similar questions and was addressed to molecular geneticists and to medical advisors. This paper only presents the answers to four questions on NGS related to the parts titled “Results of a Genetic Test” and “Predictive Genetic Tests & Family”. The aim of the questions was to seek the interest of participants in their own genetic information or in hereditary information they might transfer to their children. The other questions dealt with the management of genetic data in a broader context. These questions are not discussed here, although the adoption of any new technology largely depends on addressing other numerous issues that go beyond access to genetic information (e.g., implementation costs, privacy). Participants The identification of different, but relatively homogenous and relevant stakeholder groups was done in consideration of the impact that next-generation sequencing might have on these groups. Thus the survey was addressed to genetic health professionals, as well as non-professionals of genetic health, whether they were medical professionals or a specific group of the general public. Four groups were considered: • • • •
Clinical Molecular Geneticists Genetic Counselors Medical Advisors Students
The first survey from a chronological perspective was sent to molecular geneticists and to medical advisors (praticiens-conseils in French). Molecular geneticists are practitioners involved in the molecular diagnostics of genetic disorders and more recently in the field of pharmacogenetics. They were all members of the French National Society of Practitioners in Molecular Genetics - the ANPGM (Association Nationale des Praticiens de Génétique Moléculaire). Medical advisors are non-genetic health professionals, most of them being 4
medical doctors. They were all working for the Regional Public Health Agency (Agence Régionale de Santé) in north-eastern France (Alsace-Moselle). The second survey was sent to genetic counselors, all members of the French national professional society of genetic counselors, the AFCG (Association Française des Conseillers en Génétique), a relatively new profession in the field of genetic health. The last group was made of students enrolled at the University of Strasbourg, from different disciplines encompassing Humanities related disciplines (Law, Social Sciences, Liberal Arts…), natural sciences (Chemistry, Physics…) and health-related disciplines (Medicine, Pharmacy…). The degrees they attended were not known. For a summarized profile of the participants, see Tables 1-2 and Supplementary information. Recruitment Participants were recruited via direct e-mail invitation. Data were collected anonymously, online, as electronic form questionnaires seemed the most effective way to reach a large public (Bälter et al., 2005; Kongsved et al., 2007). The first survey was used to collect answers from molecular geneticists and medical advisors over the months of May to July 2011. Data from genetic counselors and students were collected through the second survey between the end of November 2012 and beginning of January 2013. For genetics practitioners and medical advisors we used Google Docs® to collect the information. Answers from students and genetic counselors were collected through a Limesurvey® platform provided by the University of Strasbourg. Data were collected separately for each group. Every respondent participated on a voluntary basis. Consent was deemed implicit once the survey was accepted and made available by the institution to their members. Participants accessed the link in the email address given to the institution they were affiliated to. No reminder was sent to any of the surveyed groups. The language of the surveys was French. We should stress that the study was done at a time when policy and bioethical issues regarding NGS were just beginning to be considered. Statistical analysis We used the R environment (version 3.4.3) to analyze the survey data. Only complete answers to the surveys were considered for the analysis. Results of participants who accessed the survey without completing it were not taken into account. Categorical variables were examined through Chi-square tests. Binary logistic regression was used to provide estimates of these associations adjusted for the following covariates: gender, parenthood, self-reported knowledge of genetics, self-reported presence or absence in the family of a relative with a genetic disease and field of study for students. The analysis of variance (ANOVA) was used to test the significance of the regression parameters. We employed the Bonferroni correction for multiple testing to adjust probability values (significant p-values set at 0.05). Responses of participants to the survey were summarized as percentages calculated for each stakeholder group (Figures. 1-4).
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Results The aim of the study was to determine which of the following demographics affects attitudes toward genetic information among: gender, parenthood, relation to a genetic disease (selfreported presence or absence in the family of a relative with a genetic disease), self-reported knowledge of genetics and field of study for students. The four questions related to the return of genetic information presented in this article each correspond to four different scenarios. The first question focused on the possible interest in secondary findings, once the participant would have undergone a diagnostic test for a likely genetic condition and in case the test would reveal information unrelated to the initial purpose of the test. The second question dealt with preferences concerning a predictive genetic test in a participant apparently healthy. The third question probed the attitudes towards information that is not strictly medical, but that might be delivered when a genetic test is performed. The last question dealt with potential support for information delivered by a preconception genetic testing for determining carrier status. In an attempt to avoid bias based on personal history, no specific genetic conditions were mentioned, except otherwise stated (e.g., colon or breast cancer). For most scenarios participants could answer based on estimated severity, probable onset, likelihood of developing the disease and availability of potential treatment. The possible choices did not cover irrelevant or impossible to interpret variants. For all questions, participants were asked to choose from genetic information that would already be interpreted and considered as robust. Respondents also had the “right not to know” any genetic test result. Participation to the survey There were 45 molecular geneticists, 65 genetic counselors, 56 medical advisors and 1465 students who completed the survey. As far as members of a genetic-health professional society are concerned we obtained a 21.5% response rate for geneticists, as the email was sent to the 209 members of the ANPGM and a 47.4% participation rate for genetic counselors as, at the time, the AFCG had 137 members. Medical advisors were contacted in the context of a regular training program organized on May 26 and 27, 2011. About 110 participants to the training received the link, with a 50.9% response rate. As for students, the link was sent to the institutional e-mail address of about 40,000 students enrolled at the time at the University of Strasbourg. Response rate would thus account for approximately 3.7% of the students, but we cannot precisely determine the number of people who actually accessed their institutional email. The proportion of students enrolled in Humanities related disciplines at the University of Strasbourg was around 65%. Students studying natural science or health-related disciplines both accounted for about 35%. The participation rate was as follows: 41.4% of students enrolled in Humanities related disciplines (n=607), 54% of students studying natural science or health-related disciplines (n=791) and 4.6% for whom we could not determine the field of study (n=67). This suggests that the group of students enrolled in natural sciences or health-related disciplines was more interested in the topic. 6
The precise number of participants was impossible to investigate as this was an anonymous survey. Considering the amount of time it took to complete the numerous questions of the survey on a topic that is not accessible to everyone and the fact that no reminder was sent, participation with regard to the number of the estimated people to whom the survey was addressed was deemed overall satisfactory. Many positive remarks were made in the comments section at the end of the survey. Attitudes towards secondary findings from genetic diagnostic testing In the first scenario, respondents were asked to imagine that they were experiencing symptoms possibly related to a genetic condition and that their doctor ordered a “nextgeneration” sequencing test to confirm the diagnosis. They were informed that beyond the confirmation of the diagnosis, it was possible that the test reveals the risk to develop a second condition. The results of the survey suggested an interest in secondary findings, i.e., genetic information that are unsolicited at the beginning of the test. More than 90% of participants wanted to be informed of at least one second genetic condition: 97.8% of molecular geneticists (n=44), 96.9% of genetic counselors (n=63), 96.4 % of medical advisors (n=54) and 93.1% of students (n=1364)(Fig. 1). All groups seemed to favor disclosure of a specific genetic condition with a rather high risk (i.e., colon or breast cancer with a high probability of the disease appearing; personal risk would be of 50%), or when the disease was serious with available prevention and/or effective care (almost certain onset in the next 10 years) (items c and e in Fig.1). For the other answers mainly related to untreatable serious diseases (items a, b and d), most significant differences were found between genetic-health professionals (molecular geneticists and genetic counselors) who were more reluctant and students who were generally more favorable to disclosure of such information (χ² > 28.65; df=1; p < 4.32e-8). No significant differences existed in attitudes between genetic-health professionals and non-genetic health professionals (χ² = 1.29, df=1, p = 0.13). Overall students’ preferences to access genetic information appeared to be affected by demographics such as gender, parenthood and self-reported literacy. Female students appeared to be less eager to receive information on life-threatening conditions with no or uncertain available treatment (items a, b and d) (logistic regression: z < -2.16; p < 0.031) (Supplementary Fig. 1). Furthermore, parenthood was also found to have an influence on all answers. Although the number of students who were parents was low (n=43), they expressed a preference towards non-disclosure of secondary findings (logistic regression: z = 2.157; p = 0.031). Finally, students with a good and very good self-reported genetic literacy were less interested in information related to a higher than average risk to a serious condition involving heavy treatment with uncertain outcome (item d) than students with a lower selfreported knowledge of genetics (logistic regression: z = -2.611; p = 0.00902). Attitudes towards findings from predictive genetic testing In the second scenario, respondents had to imagine that they would undergo a predictive genetic test while being apparently healthy. Compared to the low number of participants who would not be interested in any secondary finding in the previous scenario (less than 10%), the proportion of respondents who would decline a predictive genetic test was much higher: 7
48.9% of molecular geneticists (n=22), 35.4% of genetic counselors (n=23), 21.4% of medical advisors (n=12) and 28.7% of students (n=421)(Fig. 2; supplementary Fig. 2). Nevertheless, more than half of participants of each group expressed an interest in communication of predictive findings. Once they accepted to receive information delivered by a predictive genetic test, we found the same patterns in responses concerning the different items as for the previous scenario, although in a lower proportion (Fig. 2). As in the case of secondary findings, preferences towards reporting predictive findings seemed motivated by the presence of actionable genes. In addition, no statistical difference could be observed in attitudes between molecular geneticists and genetic counselors. Most significant differences were found between genetichealth professionals and students with regard to life-threatening diseases with no or partially effective treatment (items a, b and d), as students showed a stronger interest in such information (χ² > 12.5; df = 1; p < 0.0002). Attitudes towards information unrelated to genetic diseases The interest in information which is not related to the diagnosis of genetic conditions, including non-medical information, was collected only for students and genetic counselors. If most respondents seemed interested in pharmacogenetics information (i.e., efficacy or side effects of drugs), regardless of the group they belonged to (66.2% of genetic counselors (n=43) and 72.4% of students (n=1061)), differences between groups could be observed when it came to genetic information that was not strictly medical (Fig. 3). Indeed, only 13.9% of genetic counselors (n=9) wanted to have access to information concerning phenotypic traits (e.g., baldness) compared to 53.99% of the students (n=791). A similar trend could be observed for genealogical information for which 29.2% of genetic counselors (n=19) and 56.2% of students (n=824) shared a common interest. The proportion of genetic counselors who did not want to know a more recreational type of genetic information was higher than the proportion of students. It might be worth mentioning that genetic counselors were slightly older on average than students (most represented age ranges were 25-34 and 18-24 respectively) (Table 2). Both groups also had the possibility to choose the option “Don’t know”, in case they did not know what kind of information they would be interested in. We could observe that only a small proportion checked this box: 4.6% of genetic counselors (n=3) and 5.9% of students from the University of Strasbourg (n=87), which might suggest that respondents were willing to express a choice. Compared to male students, we observed that female students generally preferred not to know information related to pharmacogenetics, phenotypic traits or ancestry (logistic regression: z < -2.61; p < 0.01) (Supplementary Fig. 3). Attitudes towards disclosure of phenotypic traits also seemed to be influenced by the parenthood status, as students and genetic counselors that were parents were less interested in this type of findings (ANOVA: F = 5.459; p = 0.0197 and F = 5.063; p = 0.0281 respectively). Other demographics like the self-reported knowledge of genetics or the field of study were not found to have a significant influence.
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Attitudes towards carrier status information in preconception screening The fourth scenario dealt with disclosure of carrier status in the context of preconception screening. The majority of respondents opted to receive information on their carrier status and the genetic information they might transmit to their offspring (Fig. 4). No significant differences appeared in attitudes between the four groups towards information on carrier status for mutations involved in a serious disease leading to infant mortality and/or motor or mental handicap (potentially leading to voluntary medical termination of pregnancy). Similarly, there was no statistical difference between respondents who did not want a preconception test. Significant differences arose with respect to information about conditions that are not lifethreatening. Genetic counselors appeared to be more interested than clinical geneticists in knowing if they were carriers of mutations involved in a serious condition that can be treated (67% of genetic counselors compared to 38% of molecular geneticists; χ² = 8.46; df = 1; p = 0.018). The same patterns could be observed for medical advisors (77%; χ² = 14.167; df = 1, p = 8.36e-5) and students (60%; χ² = 8.791; df = 1; p = 0.0154). As far as preferences with regard to conditions impacting the quality of life (e.g., deafness at birth) are concerned, both groups of genetic health professionals (molecular geneticists and genetic counselors) were more reluctant to receive this type of information than medical advisors (35.5% and 62.5% respectively; χ² = 9.919; df = 1; p = 0.00082) and students (55.9%; χ² = 16.439; df = 1; p = 2.512e-05). On the whole, medical advisors were the most interested to receive information related to their carrier status. We found that the few students who were parents (n= 43) had a more reluctant attitude towards preconception genetic carrier test and the subsequent delivered information (logistic regression: z = 2.163; p = 0.0305) (Supplementary Fig. 4). Students that reported a good literacy in genetics (48.3%) appeared less interested in knowing their carrier status for conditions impacting the quality of life (logistic regression: z = -2.590; p = 0.0096). Other demographics, such as the field of study and the health status or being related to a patient were not found to play a significant role in those answers.
Discussion Favorable attitudes to the return of genetic information are influenced by hands-on experience in genetics All surveyed groups were in favor of the receipt of some kind of genetic information from next-generation sequencing when put in hypothetical scenarios. The interest in secondary findings delivered by genetic diagnostic testing on subjects that would already suffer from a genetic condition was higher than the interest in findings from predictive genetic testing on apparently healthy individuals. Once respondents accepted to receive some kind of genetic information, they generally favored access to more than one medical condition. Some demographics like the self-reported knowledge of genetics, gender and parenthood status appeared to have an influence among students. Indeed, female students and students who were parents seemed less inclined to receive genetic information related to conditions without available care or to non-medical genetic information. A stronger educational background in genetics, as well as parenthood experiences might be underlying a more cautious attitude and a different perception of benefits and risks of genetic information. 9
Attitudes towards the disclosure of genetic information seemed to be influenced by handson experience in genetics. Molecular geneticists and genetic counselors were generally the most reluctant to know information related to secondary and predictive findings, while students and medical advisors expressed more preferences in this respect. Participants with an established expertise in the field of genetics chose less to receive information related to life-threatening conditions with no available effective treatment and genetic counselors were less curious about non-medical information. Even students who reported a higher genetic literacy showed a lower interest in secondary findings and carrier status for some diseases. This suggests that genetic health professionals might favor genetic information with an unambiguous and beneficial medical impact, whereas other respondents without on-hands experience might appreciate that genetic information has a utility per se, as also observed in other studies (Middleton et al., 2016). Genetic health professionals appear to have a more cautious approach to genetic test results or to genetic testing than the lay public. There might be a cleavage between the preferences expressed by participants educated in other fields than genetics and the information deemed appropriate to be disclosed by the professionals performing the test. An adequate education of the general population concerning the accuracy and utility of genetic tests and information would be warranted. Considering the medical utility and scientific value of genetic information The perceived medical utility seemed to be the most important aspect that affected attitudes of the four groups towards genetic information. The availability of both prevention and successful prophylaxis appeared to be the main criterion that encouraged participants to receive genetic test results. Interest in pharmacogenomics data and in carrier status information can also be put in the context of prevention. For students, preferences extended to life-threatening conditions with no available care and to non-medical genetic information (phenotypical or genealogical information). This non-medical information is not part of the current routine clinical practice, as genetic tests may only be undertaken for medical or scientific research purposes. The observed curiosity may suggest a more consumerist attitude towards genetic testing in general, which is an aspect that should not be disregarded by policy-makers. All possible choices referred to conditions that were considered clinically valid and pertinent. There were neither variants with uncertain significance, nor variants with incomplete penetrance (except item c) for the first two scenarios). The interpretation that the majority of stakeholders is interested in genetic information with potential medical consequences is based on the assumption of a clear scientific significance of the genetic data. Clarifying the medical significance of the genomic data is the main challenge for genetic diagnosis in the future. There is currently no right for a person to choose useful findings they would want to know, nor a duty for a clinician to return such unsolicited information. The legal framework was initially tailored for targeted genetic tests and did not explicitly address the issue of additional findings. This legal uncertainty seems to be partly remedied by the report issued by the Government’s advisor in matters concerning the preparation of draft legislation (Conseil d’Etat) in the context of the adoption of a new French law of bioethics (Conseil d’Etat, 2018). It considers that there is no legal obstacle to disclose incidental findings on a case-by-case basis, as long as the findings are related to a serious risk that would benefit from effective care. However, anticipating and communicating genetic results which might be clinically 10
actionable, but are not related to the primary purpose of the test, is challenging in the absence of a more thorough normative framework. The possibility to communicate additional findings that might be relevant to a patient’s health or lifestyle can be daunting. Existing guidelines setting out good practices for genetic testing are likely to be updated on a regular basis to address the issue of incidental findings. Providing reproductive options through preconception carrier screening Our data suggest that attitudes are generally positive towards carrier status information delivered as part of a hypothetical parental project. Similar responses between all stakeholder groups were gathered with regard to disclosure of information related to a serious disease leading to infant mortality and/or motor or mental handicap (possibility of voluntary termination of pregnancy). Interest in less severe disorders appeared higher among non-genetic health professionals and students. Other studies have found similar results (Poppelaars et al., 2004) and the 2018 debates on the French bioethics law have shown population support for increasing reproductive options. There is growing accessibility of preconception screening in some countries where it is recommended or mandatory for targeted conditions, or as commercial services provided by companies (e.g., Counsyl (www.counsyl.com) in the US or bio.logis (https://pgsbox.de/dna/familienplanung-schwangerschaft-thrombose) in Germany) (Borry et al., 2011). At a European level, the European Society of Human Genetics has positioned itself in favor of responsible implementation of expanded carrier screening (Henneman et al., 2016). Ethical opinions in some European countries have also become favorable to its extension (Health Council of the Netherlands, 2007; Human Genetics Commission, 2011). In France, the current standard practice is to offer the screening only to couples who present a higher risk of a monogenic recessive disease, because there is an index case to whom they are closely related (for instance cascade screening for cystic fibrosis, spinal muscular atrophy or for X linked recessive diseases) (National Consultative Ethics Committee for Health and Life Sciences, 2016). The possibility to expand carrier screening to persons who do not have an a priori risk of being a carrier based on their personal or family history has not yet found a favorable legal outcome. Previous ethical opinions have put an emphasis on potential harmful effects carrier screening might have on couples and the risks of stigmatization and discrimination. Concerns of stigma have been documented in the past for early mass screening programs (Markel, 1992), but the link with current expanded carrier screening has yet to be established. Increased levels of anxiety, albeit relatively low and temporary, have also been observed (Lakeman et al., 2008). Those potential psychological ramifications and social risks need to be addressed by the French legislator through a balance between the benefits of an increasing available technology and the associated risks. The French National Ethics Consultative Committee has recently issued a report in favor of responsible expansion of preconception testing (National Consultative Ethics Committee for Health and Life Sciences, 2018). It is likely that considerations related to responsible implementation of preconception carrier screening will be a subject of debate in the near future.
Limits None of the surveyed groups can be considered as representative, as no criteria for representativeness have been established beforehand. The majority of participants 11
presented a specific profile that prevents us from generalizing conclusions to a wider public. There were some commonalities between all those groups, as most participants were educated, women which corresponds to the trends with regard to who generally responds to surveys (Smith, 2008). Other demographics like the socio-economic status, the marital status, the culture, the religious beliefs or ethnic origin were not taken into account. The large amount of comparisons which were done in this study and some of the differences found significant may have occurred by chance. Some of the beliefs and choices expressed in this survey may also have shifted over time. In an attempt to avoid very specific answers, no genetic conditions were mentioned as a general rule. The answers might have been different if participants had to choose from clearly identified genetic conditions. Furthermore, for three of the four scenarios, respondents did not directly have the possibility to check a “Don’t know” box, but they had a field where they could leave comments. Only a small proportion wrote that they did not know if they wanted to get tested or receive results from a high-throughput sequencing test. The questions the respondents answered were hypothetical ones, asked outside a medical setting. As the majority of the participants had to imagine being subject of a “nextgeneration” genetic test, the survey had a recreational dimension. Expressing preferences in the context of an online survey does not imply consent to genetic testing or to the information that should be delivered. Our questions were labeled around an autonomous-patient model in which respondents had full choice of the returned information. However, this approach is not part of routine genetic diagnosis where decision making is a shared process and takes into account particular situations, the clinical profile of subjects and the practical burdens that might arise when a genetic test is performed. Ethical or legal issues were not directly questioned in the survey, nor has the participants’ knowledge of the legal framework surrounding genetic tests. It is therefore difficult to draw conclusions with regard to changes in current policies and practices. Increased access to genetic information on a larger scale requires addressing a variety of issues that are not only scientific.
Conclusion The majority of participants showed an interest in genetic information that NGS testing would provide, whether the findings were secondary, predictive, non-medical or information on a carrier status. Most respondents expressed higher preference for actionable conditions when discovered. Significant differences were found between genetic health professionals on the one hand and medical advisors and students on the other. Stakeholders should pool their efforts to ensure better understanding of patients’ choices and possible support for the return of genetic findings. Educating stakeholders adequately on issues related to genetics might influence beliefs on NGS. In the case of next-generation sequencing for health or reproductive purposes, ethical or legal guidelines should focus on better anticipation and reporting of findings with established medical value. Proper information and consent should also be addressed before the start of any procedure. Additional empirical evidence, interdisciplinary debates and anything that can raise awareness would help realize the full and accurate potential of genomic medicine.
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Ethical Statement Conflict of interest The authors declare no conflict of interest. Funding This study was supported by INSERM, CNRS, University of Strasbourg, ANR-10-LABX0030-INRT, a French State fund managed by the ANR under the frame program Investissements d’Avenir (10-IDEX-0002) and a prize from the French Paediatric Pathology Society.
Acknowledgements We would like to thank all the participants to the survey. We are thankful to the University of Strasbourg for allowing us to contact the students and for providing the infrastructure to gather the data. This work was partially done while VT was doing an internship at the IGBMC for his Master’s Degree in Ethics.
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Table 1 Profiles of molecular geneticists and medical advisors
Total Age range 25 – 29 30 – 39 40 – 49 50 – 59 60 – 69 Gender Female Male Parenthood Yes No Self-reported Knowledge of Genetics Very good, I understand most notions in genetics Average, I understand main notions in genetics Poor, I understand few notions in genetics No knowledge
Molecular Geneticists 45
Medical Advisors 56
1 (2.2%) 10 (22.2%) 17 (37.8%) 16 (35.6%) 1 (2.2%)
1 (1.8%) 1 (1.8%) 19 (33.9%) 28 (50.0%) 7 (12.5%)
31 (68.9%) 14 (31.1%)
30 (53.6%) 26 (46.4%)
35 (77.8%) 10 (22.2%)
47 (83.9%) 9 (16.1%)
42 (93.5%) 3 (6.7%)
2 (3.6%) 53 (94.6%) 1 (1.8%)
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Table 2 Profiles of genetic counselors and students
Total Age range under 18 18 – 24 25 – 34 35 – 44 45 – 54 55 – 64 65 and above Gender Female Male Parenthood Yes No Self-reported Knowledge of Genetics Very good, I understand most notions in genetics Good, I understand main notions in genetics Average, I understand certain notions genetics Poor, I understand few notions in genetics No knowledge Patient or Family of a Patient No, I am not a patient, nor related to a patient Yes, I am a patient Yes, I am related to a patient I don’t know
Genetic Counselors 65
Students 1465
0 (0.0%) 10 (15.4%) 43 (66.1%) 7 (10.8%) 2 (3.1%) 3 (4.6%) 0 (0.0%)
31 (2.1%) 1203 (82.1%) 193 (13.2%) 16 (1.1%) 14 (1.0%) 6 (0.4%) 2 (0.1%)
55 (84.6%) 10 (15.4%)
984 (67.2%) 481 (32.8%)
19 (29.2%) 46 (70.8%)
50 (3.4%) 1415 (96.6%)
47 (72.3%) 18 (27.7%)
190 (13.2%) 518 (35.3%) 448 (30.5%) 242 (16.5%) 67 (4.5%)
54 (83.1%) 3 (4.6%) 8 (12.3%)
1087 (74%) 39 (2.7%) 187 (13%) 152 (10.3%)
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Figure Legends
Fig. 1. Attitudes towards receiving secondary findings from diagnostic genetic testing. (a) Serious and incurable condition with an almost certain onset in the next 10 years; (b) Serious and incurable condition with an almost certain onset later in the future; (c) Colon or breast cancer with a high probability of the disease appearing ; your risk would be of 50%; (d) Serious condition requiring extensive treatment with uncertain or partial efficacy: your risk for this disease would be of 10% compared to an average of 2% in the general population; (e) Serious condition with effective prevention and/or care (almost certain onset in the next 10 years); (f) I wouldn’t want to be informed of a second condition; (g) Other.
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Fig. 2. Attitudes towards receiving findings from predictive genetic testing. (a) Serious and incurable condition with an almost certain onset in the next 10 years; (b) Serious and incurable condition with an almost certain onset later in the future; (c) Colon or breast cancer with a high probability of the disease appearing ; your risk would be of 50%; (d) Serious condition requiring extensive treatment with uncertain or partial efficacy: your risk for this disease would be of 10% compared to an average of 2% in the general population; (e) Serious condition with effective prevention and/or care (almost certain onset in the next 10 years); (f) I would refuse the testing; (g) Other.
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Fig. 3. Attitudes towards receiving information unrelated to the diagnosis of a genetic disease or without medical implication. (a) The response to a drug (efficacy or side effects of a drug); (b) Physical traits (predisposition to balding); (c) Genealogical Information; (d) I’m not interested in this type of information; (e) I don’t know; (f) Other.
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Fig. 4. Attitudes towards carrier status from preconception screening. (a) A serious condition leading to infant mortality and/or motor or mental handicap (with possibility of voluntary termination of pregnancy). (b) A serious condition with effective treatment. (c) Conditions that affect the quality of life (e.g., deafness at birth). (d) Do not want predictive genetic testing as part of a parental project.
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Supplementary materials • • • • •
Ethics committee approval Complete questionnaire in French Questions translated into English Additional demographic data: Distribution of students Additional figures : answers based on the gender of students
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