The need to set explicit goals for human germline gene editing public dialogues.

Given the potentially large ethical and societal implications of human germline gene editing (HGGE) the urgent need for public and stakeholder engagement (PSE) has been repeatedly expressed. However, the explicit goals of such PSE efforts often remain poorly defined. In this program report, we outline the goals of our Dutch project called De DNA dialogen (The DNA dialogues). We believe that setting explicit goals in advance is essential to enable meaningful PSE efforts. Moreover, it enables the evaluation of our engagement efforts. The following four goals, which result from intensive consultations among the transdisciplinary projects' consortium members and based on the literature, form the foundation for how we will engage the public and stakeholders in deliberation about HGGE: 1) Enable publics and stakeholders to deliberate on "what if" questions, before considering "whether" and "how" questions regarding HGGE, 2) Investigate agreement and disagreement in values and beliefs regarding HGGE in order to agree and disagree more precisely, 3) Involve diverse publics with various perspectives, with a focus on those that are typically underrepresented in PSE, 4) Enable societally aligned policy making by providing policymakers, health care professionals and legal experts insight into how values are weighed and ascribed meaning in the context of HGGE by various publics, and how these values relate to the principles of democratic rule of law and fundamental rights. The effort to describe our goals in detail may serve as an example and can inform future initiatives striving for open science and open governance in the context of PSE.

"What if" should precede "whether" and "how" in the social conversation around human germline gene editing.

Given the potential large ethical and societal implications of human germline gene editing (HGGE) the urgent need for public and stakeholder engagement (PSE) has been repeatedly expressed. In this short communication, we aim to provide directions for broad and inclusive PSE by emphasizing the importance of futures literacy, which is a skill to imagine diverse and multiple futures and to use these as lenses to look at the present anew. By first addressing "what if" questions in PSE, different futures come into focus and limitations that arise when starting with the "whether" or "how" questions about HGGE can be avoided. Futures literacy can also aid in the goal of societal alignment, as "what if" questions can be answered in many different ways, thereby opening up the conversation to explore a multitude of values and needs of various publics. Broad and inclusive PSE on HGGE starts with asking the right questions.

Changes in opinions about human germline gene editing as a result of the Dutch DNA-dialogue project.

Public engagement for Human Germline Genome Editing (HGGE) has often been called for, for example by the WHO. However, the impact of public engagement remains largely unknown. This study reports on public engagement outcomes in the context of a public dialogue project about HGGE in the Netherlands; the DNA-dialogue. The aim was to inquire opinions and opinion change regarding HGGE. A questionnaire was distributed on a national level (n = 2381) and a dialogue level (n = 414). The results indicate that the majority of the Dutch population agrees with the use of HGGE to prevent severe genetic diseases (68.6%), unlike the use to protect against infectious diseases (39.7%), or for enhancement (8.5%). No indications of change in these acceptance rates as a result of dialogue participation were found. The results did provide a tentative indication that participation in dialogue may lead to less negative opinions about HGGE (χ2(1) = 5.14, p = 0.023, OR = 0.56, 95% CI [0.34, 0.93]). While it was not a goal of the project to make people more accepting towards HGGE, this might be the effect of exposure to opinions that are less often heard in the global debate. We conclude that dialogue may lead to different outcomes for different people, depending on their characteristics and their entrance attitude, but does not appear to systematically direct people towards a certain opinion. The self-reported, impacts of dialogue participation included no impact, strengthening of opinion, enabling of forming a first opinion, more insight into the potential implications of HGGE, and a better understanding of other people's perspectives.

Factors that impact on women's decision-making around prenatal genomic tests: An international discrete choice survey.

OBJECTIVE: We conducted a survey-based discrete-choice experiment (DCE) to understand the test features that drive women's preferences for prenatal genomic testing, and explore variation across countries. METHODS: Five test attributes were identified as being important for decision-making through a literature review, qualitative interviews and quantitative scoring exercise. Twelve scenarios were constructed in which respondents choose between two invasive tests or no test. Women from eight countries who delivered a baby in the previous 24 months completed a DCE presenting these scenarios. Choices were modeled using conditional logit regression analysis. RESULTS: Surveys from 1239 women (Australia: n = 178; China: n = 179; Denmark: n = 88; Netherlands: n = 177; Singapore: n = 90; Sweden: n = 178; UK: n = 174; USA: n = 175) were analyzed. The key attribute affecting preferences was a test with the highest diagnostic yield (p < 0.01). Women preferred tests with short turnaround times (p < 0.01), and tests reporting variants of uncertain significance (VUS; p < 0.01) and secondary findings (SFs; p < 0.01). Several country-specific differences were identified, including time to get a result, who explains the result, and the return of VUS and SFs. CONCLUSION: Most women want maximum information from prenatal genomic tests, but our findings highlight country-based differences. Global consensus on how to return uncertain results is not necessarily realistic or desirable.

Assessing women's preferences towards tests that may reveal uncertain results from prenatal genomic testing: Development of attributes for a discrete choice experiment, using a mixed-methods design.

Prenatal DNA tests, such as chromosomal microarray analysis or exome sequencing, increase the likelihood of receiving a diagnosis when fetal structural anomalies are identified. However, some parents will receive uncertain results such as variants of uncertain significance and secondary findings. We aimed to develop a set of attributes and associated levels for a discrete-choice experiment (DCE) that will examine parents' preferences for tests that may reveal uncertain test results. A two phase mixed-methods approach was used to develop attributes for the DCE. In Phase 1, a "long list" of candidate attributes were identified via two approaches: 1) a systematic review of the literature around parental experiences of uncertainty following prenatal testing; 2) 16 semi-structured interviews with parents who had experienced uncertainty during pregnancy and 25 health professionals who return uncertain prenatal results. In Phase 2, a quantitative scoring exercise with parents prioritised the candidate attributes. Clinically appropriate levels for each attribute were then developed. A final set of five attributes and levels were identified: likelihood of getting a result, reporting of variants of uncertain significance, reporting of secondary findings, time taken to receive results, and who tells you about your result. These attributes will be used in an international DCE study to investigate preferences and differences across countries. This research will inform best practice for professionals supporting parents to manage uncertainty in the prenatal setting.

The DNA-Dialogue: A Broad Societal Dialogue About Human Germline Genome Editing in the Netherlands.

For years, calls for public involvement in the debate concerning the acceptability of human germline genome editing (HGGE) have been made. A multidisciplinary consortium of 11 organizations in the Netherlands organized a broad societal dialogue to inquire about the views of Dutch society toward HGGE. The project aimed to reach a wide and diverse audience and to stimulate a collective process of deliberative opinion forming and reflection. To that end, several instruments and formats were developed and employed. We present the results of 27 moderated dialogues organized between October 2019 and October 2020. Overall, participants of the dialogues were capable of assessing and discussing the subject of HGGE in a nuanced way. Analysis of these dialogues shows that in general, participants had no fundamental and absolute objections toward HGGE technology. However, they only deemed HGGE to be acceptable when it is used to prevent serious heritable diseases and under strict conditions, without affecting important (societal) values. There was a small group of participants who found HGGE fundamentally unacceptable because it would cross natural, socio-ethical, or religious boundaries.

Experts in science communication: A shift from neutral encyclopedia to equal participant in dialogue.

Even if the predominant model of science communication with the public is now based on dialogue, many experts still adhere to the outdated deficit model of informing the public.

How to deal with uncertainty in prenatal genomics: A systematic review of guidelines and policies.

Exome sequencing (ES) enhanced the diagnostic yield of genetic testing, but has also increased the possibility of uncertain findings. Prenatal ES is increasingly being offered after a fetal abnormality is detected through ultrasound. It is important to know how to handle uncertainty in this particularly stressful period. This systematic review aimed to provide a comprehensive overview of guidelines available for addressing uncertainty related to prenatal chromosomal microarray (CMA) and ES. Ten uncertainty types associated with prenatal ES and CMA were identified and defined by an international multidisciplinary team. Medline (all) and Embase were systematically searched. Laboratory scientists, clinical geneticists, psychologists, and a fetal medicine specialist screened the papers and performed the data extraction. Nineteen papers were included. Recommendations generally emphasized the importance of trio analysis, clinical information, data sharing, validation and re-analysis, protocols, multidisciplinary teams, genetic counselling, whether to limit the possible scope of results, and when to report particular findings. This systematic review helps provide a vocabulary for uncertainties, and a compass to navigate uncertainties. Prenatal CMA and ES guidelines provide a strong starting point for determining how to handle uncertainty. Gaps in guidelines and recommendations were identified and discussed to provide direction for future research and policy making.

Dealing with uncertain results from chromosomal microarray and exome sequencing in the prenatal setting: An international cross-sectional study with healthcare professionals.

OBJECTIVES: To conduct qualitative interviews with healthcare providers working in different countries to understand their experiences of dealing with uncertain results from prenatal chromosome microarray analysis (CMA) and exome sequencing (ES). METHODS: Semi-structured interviews with 31 healthcare providers who report or return prenatal CMA and/or ES results (clinicians, genetic counsellors and clinical scientists) in six countries with differing healthcare systems; Australia (4), Denmark (5), Netherlands (6), Singapore (4), Sweden (6) and United Kingdom (6). The topic guide explored the main sources of uncertainty and their management. RESULTS: There was variation in reporting practices both between and across countries for variants of uncertain significance, however, there was broad agreement on reporting practices for incidental findings. There was also variation in who decides what results are reported (clinical scientists or clinicians). Technical limitations and lack of knowledge (to classify variants and of prenatal phenotypes) were significant challenges, as were turnaround times and lack of guidelines. CONCLUSION: Health professionals around the globe are dealing with similar sources of uncertainty, but managing them in different ways, Continued dialogue with international colleagues on ways of managing uncertain results is important to compare and contrast the benefits and limitations of the different approaches.

In the Era of the Actionable Genome, Everyone is Responsible.

Genomics professionals and the general public have a responsibility to bridge the gap between science and society. The general public has a responsibility to deliberate, as their choices not only impact themselves but also shape society. Conversely, genomics professionals have a responsibility to enable the process of opinion formation.

Parental experiences of uncertainty following an abnormal fetal anomaly scan: Insights using Han's taxonomy of uncertainty.

For a number of prospective parents, uncertainty during pregnancy starts when an anomaly is found during a routine fetal anomaly scan. This may be followed by numerous tests to determine the etiology and nature of the anomaly. In this study, we aimed to understand how prospective parents perceive and manage uncertainty after being confronted with a structural anomaly during their routine ultrasound. Han's taxonomy of uncertainty was used as a framework to identify and understand the different types of uncertainty experienced. Interviews were held in the UK (n = 8 women and n = 1 male partner) and in the Netherlands (n = 7 women) with participants who had experienced uncertainty in their pregnancy after a fetal scan. Data were analyzed using thematic analysis, and the uncertainties experienced by parents were mapped against the dimensions of the Han taxonomy (sources, issues, and locus). Participants' experience of uncertainty was relevant to all dimensions and subcategories of the Han taxonomy, showing its applicability in the prenatal setting. Sources of uncertainty included receiving probabilistic or ambiguous information about the anomaly, or information that was complex and challenging to understand. Issues of uncertainty included were those that were scientific-such as a probable diagnosis with no further information, personal-such as the emotional impact of uncertainty, and practical-such as limited information about medical procedures and practical aspects of care. Additionally, participants described what helped them to manage uncertainty. This included active coping strategies such as searching for information on the Internet, external coping resources such as seeking social support, and internal coping resources such as using positivity and hope. Several recommendations for the healthcare professional to minimize uncertainty and help the patient deal with uncertainty have been proposed based on these findings.

Non-invasive prenatal testing (NIPT): societal pressure or freedom of choice? A vignette study of Dutch citizens' attitudes.

The introduction of the accurate and procedurally easy non-invasive prenatal test (NIPT) raises ethical concerns that public attitudes towards prenatal screening may change, leading to societal pressure to participate in aneuploidy screening. This study examined Dutch citizens' attitudes towards a pregnant woman's decision to (1) decline NIPT in the context of two different funding policies and (2) to terminate or continue a pregnancy affected by different disorders. The attitudes of 1096 respondents were assessed with the contrastive vignette method, using two pairs of vignettes about declining NIPT and termination of pregnancy. Most respondents either agreed with a woman's decision to decline NIPT or were neutral about it, stating that this decision should be made independently by women, and does not warrant judgement by others. Interestingly, funding policies did influence respondents' attitudes: significantly more respondents disagreed with declining NIPT when it was fully reimbursed. Respondents had similar attitudes to the vignettes on termination and continuation of pregnancy in case of Down's syndrome. In case of Edwards' or Patau's syndrome, however, significantly more respondents disagreed with continuation, citing the severity of the disorder and the child's best interests. This study demonstrates broad acknowledgement of women's freedom of choice in Dutch society; a finding that may help to rebut existing concerns about societal pressure for pregnant women to participate in prenatal screening. As the reimbursement policy and the scope of NIPT may influence people's attitudes and elicit moral judgements, however, maintaining freedom of choice warrants sustained efforts by health professionals and policy makers.

"It's probably nothing, but " Couples' experiences of pregnancy following an uncertain prenatal genetic result.

INTRODUCTION: A common concern regarding the introduction of chromosomal microarray in prenatal testing is the concomitant identification of an uncertain copy number variant (CNV) where significance and clinical implication for the unborn child can be difficult or impossible to predict. Following the identification of an uncertain CNV, prospective parents may decide to continue the pregnancy. The aim of this study was to explore how prospective parents manage uncertainty and experience pregnancy in light of an uncertain CNV result. MATERIAL AND METHODS: Qualitative interviews with 16 women and 10 partners who had received a prenatally diagnosed, uncertain CNV. Participants were recruited from the Aarhus University Hospital, Denmark and most were interviewed in their homes 1-14 weeks after birth. Data were analyzed using thematic analysis. RESULTS: Following the CNV diagnosis, some couples focused on the severe syndromes ruled out by the result, whereas others were more concerned with the new potential risks, for example, learning disabilities. Most couples did not remember the actual diagnosis, but all described a number of attention points generated by the CNV result. During pregnancy, the couples used various strategies to limit worry and enjoy their pregnancy, such as limiting information seeking, reducing talk of the CNV, and deferring thoughts of potential consequences. Furthermore, ultrasound was considered a valuable resource for reducing worry as it provided reassurance about the development of the baby. Inherited CNVs caused relief on one hand, but also feelings of responsibility for the child's potential challenges. After birth, worry decreased considerably, but all couples paid some extra attention to the child's development, while also being alert to the risk of wrongfully interpreting the child's development in terms of the CNV. Eleven couples expressed satisfaction with knowing about the child's CNV, whereas five couples would rather not have known. CONCLUSIONS: The results indicate that health professionals should be mindful of terminology, remember to point out what has been ruled out by the CNV result, and discuss potential coping strategies with the couple. Furthermore, these couples may have a higher need for ultrasound during pregnancy to help reduce worry. More research is needed on the families' long-term coping.

Implementing non-invasive prenatal testing (NIPT) in the Netherlands: An interview study exploring opinions about and experiences with societal pressure, reimbursement, and an expanding scope.

The noninvasive prenatal test (NIPT) as the first trimester prenatal screening (FTS) for trisomies 21, 18, and 13 is offered to all pregnant women in the Netherlands. NIPT using genome sequencing allows for an expansion of the scope of FTS and the introduction of NIPT gives rise to ethical and societal concerns about deliberated decision-making, pressure to engage in screening, and possible lack of equal access due to the financial contribution (€175) to NIPT. We explored the opinions and experiences of pregnant women, who were offered FTS, about these concerns, and the possibility of a broadened scope. Nineteen pregnant women representing a diversity of backgrounds were interviewed using a semi-structured interview guide. Eight women did not opt for prenatal screening while 11 did (NIPT = 4, combined test = 7). Women experienced a free choice to accept or decline prenatal screening, despite sometimes receiving advice from others. Prior to pretest counseling, some women had already deliberated about what an abnormal test result would mean to them. Others accepted or declined FTS without deliberation. The current Dutch policy of requiring a co-payment was acceptable to some, who believed that it functioned as a threshold to think carefully about FTS. Others were concerned that a financial threshold would lead to unequal access to screening. Finally, pregnant women found it difficult to formulate opinions on the scope of FTS, because of lack of knowledge. Life expectancy, severity, and treatability were considered important criteria for the inclusion of a condition in NIPT.

Social and medical need for whole genome high resolution NIPT.

BACKGROUND: Two technological innovations in the last decade significantly influenced the diagnostic yield of prenatal cytogenetic testing: genomic microarray allowing high resolution analysis and noninvasive prenatal testing (NIPT) focusing on aneuploidy. To anticipate future trends in prenatal screening and diagnosis, we evaluated the number of invasive tests in our center and the number of aberrant cases diagnosed in the last decade. METHODS: We retrospectively analyzed fetal chromosomal aberrations diagnosed in 2009-2018 in 8,608 pregnancies without ultrasound anomalies. RESULTS: The introduction of NIPT as the first-tier test led to a substantial decrease in the number of invasive tests and a substantially increased diagnostic yield of aneuploidies in the first trimester. However, we have also noted a decreased detection of submicroscopic aberrations, since the number of invasive tests substantially decreased. We have observed that pregnant women were interested in broader scope of prenatal screening and diagnosis than detection of common trisomies. CONCLUSION: Since the frequency of syndromic disorders caused by microdeletions/microduplications is substantial and current routine NIPT and ultrasound investigations are not able to detect them, we suggest that a noninvasive test with resolution comparable to microarrays should be developed, which will also meet patient's needs.

Offering a choice between NIPT and invasive PND in prenatal genetic counseling: the impact of clinician characteristics on patients' test uptake.

Testing options for pregnant women at increased risk of common aneuploidies are non-invasive prenatal testing (NIPT) and invasive prenatal diagnosis (PND). Clinicians are challenged to comprehensively discuss the complex information in a patient-centered and non-directive manner, to allow for patients' informed decision-making. This study explored the information-centeredness, patient-centeredness, and level of non-directivity of different clinicians and examined group differences between their patients. First, semi-structured interviews with four senior obstetricians and one senior nurse were held regarding their information provision, their adaptation of a patient-centered attitude, and their practice of non-directivity. Interviews were transcribed verbatim and rated by four independent researchers. Secondly, 181 pregnant women were included in the study, of whom 82% opted for NIPT and 18% chose PND. Between clinicians, we assessed the distribution of choice ratios, patients' impression of clinicians' test preferences, and patients' knowledge scores. The results indicate that clinicians do not differ in their information-centeredness, but do differ in their patient-centeredness and their level of non-directivity. Significant differences in patients' NIPT/PND ratios were observed between clinicians, with the largest difference being 35 vs. 4% opting for invasive PND. Between 9 and 22% of the patients had an impression of their clinician's preference and chose in accordance with this preference. Patients' overall knowledge scores did not differ across clinicians. In conclusion, the differences in NIPT/PND ratios between clinicians indicate that clinicians' differing counseling approaches affect the choices their patients make. The interviews indicate a possible framing effect which may unintentionally steer the decision-making process.

Prenatal diagnosis of susceptibility loci for neurodevelopmental disorders - genetic counseling and pregnancy outcome in 57 cases.

BACKGROUND: Whole genome array testing not only provides an increased diagnostic yield of pathogenic causative findings, but it may also reveal so called susceptibility loci (SL) for neurodevelopmental disorders. The goal of this study was to evaluate the pregnancy outcomes in SL cases and to establish a protocol for pregnancy management, follow-up and additional investigations. METHODS: Fifty seven cases were evaluated: 34 with and 23 without ultrasound anomalies at referral. Each pregnant couple received pretest counseling and extensive posttest genetic counseling. RESULTS: After diagnosis of SL, parental testing and an additional ultrasound examination were offered. The severity of the ultrasound anomalies and not the diagnosis of SL was the most important factor contributing to the decision on pregnancy continuation. In the majority of cases with milder or no ultrasound anomalies, the pregnancy was continued and a normal outcome after birth was observed. CONCLUSIONS: The diagnosis of a SL did not seem to be a reason for termination of pregnancy. Most patients were able to cope with the uncertainty and were interested in both prenatal and postnatal actionability of SL. Long-term follow-up is crucial to assess the actual risks for neurodevelopmental disorders, especially in families with unremarkable history. © 2016 John Wiley & Sons, Ltd.