Knowledge, attitudes and decision regret: a longitudinal survey study of participants offered genome sequencing in the 100,000 Genomes Project.

We used cross-sectional surveys to compare the knowledge, attitudes, and decision regret of participants who had consented for genome sequencing (GS) for rare disease diagnosis in the 100,000 Genomes Project (100kGP) across two timepoints (at the time of consenting for GS (T1) and 12-18 months later (T2)). At T1, participants (n = 504) completed a survey that included measures of general knowledge of GS ("Knowledge of Genome Sequencing" (KOGS)), specific knowledge of GS and attitudes towards GS ("General attitudes" and "Specific attitudes"). At T2, participants (n = 296) completed these same assessments (apart from the specific knowledge scale) together with an assessment of decision regret towards GS ("Decisional Regret Scale"). At 12-18 months after consenting for GS, participants' basic knowledge of GS had remained stable. General knowledge of GS varied across topics; concepts underlying more general information about genetics were better understood than the technical details of genomic testing. Attitudes towards GS at T2 were generally positive, and feelings towards GS (both positive and negative) remained unchanged. However, those who were more positive about the test at the outset had greater specific knowledge (as opposed to general knowledge) of GS. Finally, although the majority of participants indicated feeling little regret towards undergoing GS, those with low positive attitude and high negative attitude about GS at T1 reported greater decision regret at T2. Careful assessment of patient knowledge about and attitudes towards GS at the time of offering testing is crucial for supporting informed decision making and mitigating later regret.

Participant experiences of genome sequencing for rare diseases in the 100,000 Genomes Project: a mixed methods study.

In this mixed methods study, a survey and in-depth interviews were used to explore whether decision regret and the psychological impact of receiving genome sequencing (GS) results differed between parents and patients, and between those who received a genetic diagnosis and those who did not. Participants (n = 77) completed a survey that included the Decisional Regret Scale (DRS) and an adaptation of the Multidimensional Impact of Cancer Risk Assessment (MICRA) at least 12 months after consenting for GS for rare disease diagnosis in the 100,000 Genomes Project. Survey participants were invited to take part in an interview and 39 agreed; 12 with a diagnosis, 5 with variants of uncertain significance, and 19 with no pathogenic findings identified. Both survey and interview findings indicated that decision regret was low. DRS scores revealed no differences in levels of regret between parents and patients, or between those with a diagnosis and those without. Though MICRA scores indicated minimal evidence of negative psychological impacts of receiving GS results, subscale analysis revealed greater distress and uncertainty for parents compared to patients. Receiving a diagnosis was found not to influence MICRA scores, supporting interview findings of both positive and negative emotional and psychological impacts irrespective of a genetic diagnosis. Our findings have implications for policy and practice as GS is integrated into the UK and worldwide; notably, that expectation-setting is critical when offering GS, and that post-test counselling is important regardless of the GS result received, with parents perhaps needing additional emotional support.

Optimising Exome Prenatal Sequencing Services (EXPRESS): a study protocol to evaluate rapid prenatal exome sequencing in the NHS Genomic Medicine Service.

Background: Prenatal exome sequencing (ES) for the diagnosis of fetal anomalies was implemented nationally in England in October 2020 by the NHS Genomic Medicine Service (GMS). is the GMS is based around seven regional Genomic Laboratory Hubs (GLHs). Prenatal ES has the potential to significantly improve NHS prenatal diagnostic services by increasing genetic diagnoses and informing prenatal decision-making. Prenatal ES has not previously been offered routinely in a national healthcare system and there are gaps in knowledge and guidance. Methods: Our mixed-methods evaluation commenced in October 2020, aligning with the start date of the NHS prenatal ES service . Study design draws on a framework developed in previous studies of major system innovation. There are five interrelated workstreams. Workstream-1 will use interviews and surveys with professionals, non-participant observations and documentary analysis to produce in-depth case studies across all GLHs. Data collection at multiple time points will track changes over time. In Workstream-2 qualitative interviews with parents offered prenatal ES will explore experiences and establish information and support needs. Workstream-3 will analyse data from all prenatal ES tests for nine-months to establish service outcomes (e.g. diagnostic yield, referral rates, referral sources). Comparisons between GLHs will identify factors (individual or service-related) associated with any variation in outcomes. Workstream-4 will identify and analyse practical ethical problems. Requirements for an effective ethics framework for an optimal and equitable service will be determined. Workstream-5 will assess costs and cost-effectiveness of prenatal ES versus standard tests and evaluate costs of implementing an optimal prenatal ES care pathway. Integration of findings will determine key features of an optimal care pathway from a service delivery, parent and professional perspective. Discussion: The proposed formative and summative evaluation will inform the evolving prenatal ES service to ensure equity of access, high standards of care and benefits for parents across England.

BACKGROUND: Prenatal exome sequencing is a new test that is offered through the NHS Genomic Medicine Service. Prenatal exome sequencing is offered to pregnant women when ultrasound scans suggest that their baby may have a genetic condition that cannot be diagnosed using standard tests. If a genetic condition is diagnosed this can give parents important information about the outlook for their baby. It can also help with their decisions about whether to continue or end the pregnancy, pregnancy management, post-birth care and future pregnancies. STUDY METHODS: The aim of this study is to evaluate the prenatal exome sequencing service. To do this we will; 1. Study how prenatal exome sequencing is delivered across England using surveys and interviews with professionals.2. Interview parents to ask what they think of prenatal exome sequencing and how support and information could be improved3. Look at how many parents have prenatal exome sequencing and the test results. We will look carefully at who has access to the test and whether any particular groups are less likely to be offered testing.4. Conduct workshops with health professionals and parents to identify any practical or ethical problems that arise when prenatal exome sequencing is offered.5. Look at the cost of prenatal exome sequencing and compare it to the cost of other tests that are offered to diagnose genetic conditions in pregnancy.6. Gather our findings together to make recommendations for best practice. Patient and Public Involvement: A patient and public Involvement, engagement and participation (PPIEP) advisory group will work closely with the research team to design the study and develop study materials. They will also help us understand our findings to make sure the information and recommendations that come out of our research will be helpful to parents and the NHS.

Decision-making, attitudes, and understanding among patients and relatives invited to undergo genome sequencing in the 100,000 Genomes Project: A multisite survey study.

PURPOSE: The purpose of this study was to assess decisions, attitudes, and understanding of participants (patients, parents, relatives) having genome sequencing for rare disease diagnosis. METHODS: This study involved a cross-sectional observational survey with participants in the 100,000 Genomes Project. RESULTS: Survey response rate was 51% (504/978). Most participants self-reported that they had decided to undergo genome sequencing (94%) and that this was an informed decision (84%) with low decisional conflict (95%). Most self-reported that they had chosen to receive additional findings (88%) and that this was an informed decision (89%) with low decisional conflict (95%). Participants were motivated more by the desire to help others via research than by the belief it would help them obtain a diagnosis (Z = 14.23, P = 5.75 × 10-46), although both motivations were high. Concerns were relatively few but, where expressed, were more about the potential psychological impact of results than data sharing/access (Z = 9.61, P = 7.65 × 10-22). Concerns were higher among male, Asian or Asian British, and more religious participants. General and context-specific understanding of genome sequencing were both moderately high (means 5.2/9.0 and 22.5/28.0, respectively). CONCLUSION: These findings are useful to inform consent guidelines and clinical implementation of genome sequencing.

Animation or leaflet: Does it make a difference when educating young people about genome sequencing?

OBJECTIVE: To compare the effectiveness of an animation against two leaflets with and without images, in educating young people about genome sequencing (GS). METHODS: An experimental survey with three assessment points (pre- intervention [T1], post - intervention [T2], 6-week follow-up [T3]). Participants (N = 606) were randomly assigned to receive one of three educational interventions; animation (n = 212); leaflet with images (n = 197); or leaflet with text only (n = 197). Measures of objective and subjective knowledge were completed at T1 (N = 606), T2 (N = 606) and T3 (N = 459). Measures of attitudes, intentions and beliefs towards GS and satisfaction with intervention were completed at T2 only. RESULTS: The type of educational intervention young people received had no significant impact on their objective or subjective knowledge at both T2 and T3 (all p > .05), nor did the educational intervention type affect their attitudes, intentions and beliefs towards GS at T2 (p > .05). However, participant satisfaction was significantly higher in the animation group than the leaflet groups (p < .001). CONCLUSION: Animations and leaflets are both effective ways to deliver genomic education to young people, but the animations lead to higher satisfaction. PRACTICE IMPLICATIONS: Different individuals may find different modes of educational resources more accessible than others. Therefore a range of resources should ideally be made available to patients.

Young people's understanding, attitudes and involvement in decision-making about genome sequencing for rare diseases: A qualitative study with participants in the UK 100, 000 Genomes Project.

Genome sequencing (GS) will have a profound impact on the diagnosis of rare and inherited diseases in children and young people. We conducted 27 semi-structured interviews with young people aged 11-19 having GS through the UK 100, 000 Genomes Project. Participants demonstrated an understanding of the role and function of genes and DNA, however the terms 'genome' and 'genome sequencing' were less well understood. Participants were primarily motivated to take part to get a diagnosis or identify the gene causing their condition. The majority of participants understood they might not receive a diagnostic result. Most were unconcerned about data security or access, however anxieties existed around what the results might show and the potential for disappointment if the result was negative. Signing an assent form empowered young people, formalised the process and instilled a sense of responsibility for their choice to participate. Most young people (≥16 years) had consented to receive secondary findings and had come to that decision without parental influence. Our research suggests that at least some young people are capable of making informed decisions about taking part in GS, and that involving them in discussions about testing can empower them to take responsibility over healthcare decisions that affect them.

Parents' motivations, concerns and understanding of genome sequencing: a qualitative interview study.

The 100,000 Genomes Project is a hybrid clinical and research project in which patients and parents are offered genome sequencing for cancer and rare and inherited disease diagnosis; all participants receive their main findings and contribute their data for research, and are offered optional secondary findings. Our aim was to explore participating parents' attitudes towards and understanding of genome sequencing in this hybrid context. We conducted in-depth telephone interviews with 20 parents of children with rare diseases participating in the 100,000 Genomes Project. Parents were positive about contributing to research, although some had needed reassurance about data protections. Although most felt positive about secondary findings, some could not recall or misunderstood key aspects. Some were also concerned about potential emotional impact of results and a few raised concerns about life insurance implications, and the impact of future legal changes. Participants were generally positive about consent appointments, but several raised concerns about 'information overload' because of deciding about secondary findings at the same time as about the main diagnostic genome sequencing and data contribution. Additional information resources, particularly online tools, were highlighted as potentially useful ways of supporting the consent process. We conclude that parents offered genome sequencing as part of a national hybrid clinical and research project report many positive attitudes and experiences, but also concerns and misunderstandings. Further research is needed on how best to support informed consent, particularly about secondary findings. Additional resources such as online tools might usefully support future genome sequencing consent processes.

Development and mixed-methods evaluation of an online animation for young people about genome sequencing.

Children and young people with rare and inherited diseases will be significant beneficiaries of genome sequencing. However, most educational resources are developed for adults. To address this gap in informational resources, we have co-designed, developed and evaluated an educational resource about genome sequencing for young people. The first animation explains what a genome is, genomic variation and genome sequencing ("My Genome Sequence": http://bit.ly/mygenomesequence), the second focuses on the limitations and uncertainties of genome sequencing ("My Genome Sequence part 2": http://bit.ly/mygenomesequence2). In total, 554 school pupils (11-15 years) took part in the quantitative evaluation. Mean objective knowledge increased from before to after watching one or both animations (4.24 vs 7.60 respectively; t = 32.16, p < 0.001). Self-rated awareness and understanding of the words 'genome' and 'genome sequencing' increased significantly after watching the animation. Most pupils felt they understood the benefits of sequencing after watching one (75.4%) or both animations (76.6%). Only 17.3% felt they understood the limitations and uncertainties after watching the first, however this was higher among those watching both (58.5%, p < 0.001). Twelve young people, 14 parents and 3 health professionals consenting in the 100,000 Genomes Project reported that the animation was clear and engaging, eased concerns about the process and empowered young people to take an active role in decision-making. To increase accessibility, subtitles in other languages could be added, and the script could be made available in a leaflet format for those that do not have internet access. Future research could focus on formally evaluating the animations in a clinical setting.

Delivering genome sequencing in clinical practice: an interview study with healthcare professionals involved in the 100 000 Genomes Project.

OBJECTIVES: Genome sequencing is poised to be incorporated into clinical care for diagnoses of rare diseases and some cancers in many parts of the world. Healthcare professionals are key stakeholders in the clinical delivery of genome sequencing-based services. Our aim was to explore views of healthcare professionals with experience of offering genome sequencing via the 100 000 Genomes Project. DESIGN: Interview study using thematic analysis. SETTING: Four National Health Service hospitals in London. PARTICIPANTS: Twenty-three healthcare professionals (five genetic clinicians and eight non-genetic clinicians (all consultants), and 10 'consenters' from a range of backgrounds) involved in identifying or consenting patients for the 100 000 Genomes Project. RESULTS: Most participants expressed positive attitudes towards genome sequencing in terms of improved ability to diagnose rare diseases, but many also expressed concerns, with some believing its superiority over exome sequencing had not yet been demonstrated, or worrying that non-genetic clinicians are inadequately prepared to discuss genome sequencing results with patients. Several emphasised additional evidence about utility of genome sequencing in terms of both main and secondary findings is needed. Most felt non-genetic clinicians could support patients during consent, as long as they have appropriate training and support from genetic teams. Many stated genetics experts will play a vital role in training and supporting non-genetic clinicians in variant interpretation and results delivery, particularly for more complex cases. CONCLUSIONS: Healthcare professionals responsible for delivering clinical genome sequencing have largely positive views about the potential for genome sequencing to improve diagnostic yield, but also significant concerns about practical aspects of offering these tests. Non-genetic clinicians delivering genome sequencing require guidance and support. Additional empirical evidence is needed to inform policy and practice, including how genome compares to exome sequencing; utility of secondary findings; training, in particular of non-genetic health professionals; and mechanisms whereby genetics teams can offer appropriate support to their non-genetics colleagues.

Growth Hormone Improves Short-Term Growth in Patients with Temple Syndrome.

BACKGROUND/AIMS: Temple syndrome is an imprinting disorder caused by maternal uniparental disomy of chromosome 14 (mat UPD14), paternal deletion of 14q32 or paternal hypomethylation of the intergenic differentially methylated region (MEG3/DLK1 IG-DMR). Patients with Temple syndrome have pre- and postnatal growth restriction, short stature, hypotonia, small hands and feet and precocious puberty. We sought to determine whether treatment with growth hormone improves growth outcomes in patients with Temple syndrome. METHODS: This was a retrospective observational study reviewing the medical records of 14 patients with Temple syndrome, 7 of whom were treated with growth hormone. RESULTS: After 1 year of growth hormone treatment, the height standard deviation score (SDS) increased a median of 1.31 SDS with a median increased height velocity of 5.30 cm/year. CONCLUSIONS: These results suggest short-term improvement in height SDS with growth hormone treatment similar to the response in patients treated under the small for gestational age indication. We recommend considering growth hormone therapy in all patients with Temple syndrome who have short stature.

Towards a European consensus for reporting incidental findings during clinical NGS testing.

In 2013, the American College of Medical Genetics (ACMG) examined the issue of incidental findings in whole exome and whole genome sequencing, and introduced recommendations to search for, evaluate and report medically actionable variants in a set of 56 genes. At a debate held during the 2014 European Society for Human Genetics Conference (ESHG) in Milan, Italy, the first author of that paper presented this view in a debate session that did not end with a conclusive vote from the mainly European audience for or against reporting back actionable incidental findings. In this meeting report, we elaborate on the discussions held during a special meeting hosted at the ESHG in 2013 from posing the question 'How to reach a (European) consensus on reporting incidental findings and unclassified variants in diagnostic next generation sequencing'. We ask whether an European consensus exists on the reporting of incidental findings in genome diagnostics, and present a series of key issues that require discussion at both a national and European level in order to develop recommendations for handling incidental findings and unclassified variants in line with the legal and cultural particularities of individual European member states.

Getting ready for the Human Phenome Project: the 2012 forum of the Human Variome Project.

A forum of the Human Variome Project (HVP) was held as a satellite to the 2012 Annual Meeting of the American Society of Human Genetics in San Francisco, California. The theme of this meeting was "Getting Ready for the Human Phenome Project." Understanding the genetic contribution to both rare single-gene "Mendelian" disorders and more complex common diseases will require integration of research efforts among many fields and better defined phenotypes. The HVP is dedicated to bringing together researchers and research populations throughout the world to provide the resources to investigate the impact of genetic variation on disease. To this end, there needs to be a greater sharing of phenotype and genotype data. For this to occur, many databases that currently exist will need to become interoperable to allow for the combining of cohorts with similar phenotypes to increase statistical power for studies attempting to identify novel disease genes or causative genetic variants. Improved systems and tools that enhance the collection of phenotype data from clinicians are urgently needed. This meeting begins the HVP's effort toward this important goal.