How should severity be understood in the context of reproductive genetic carrier screening?

Reproductive genetic carrier screening provides information about people's chance of having children with certain genetic conditions. Severity of genetic conditions is an important criterion for their inclusion in carrier screening programmes. However, the concept of severity is conceptually complex and underspecified. We analyse why severity is an important concept in carrier screening and for reproductive decision-making and show that assessments of severity can also have normative societal implications. While some genetic conditions are unambiguously associated with a high degree of suffering, there are many factors that contribute to how severe a condition is perceived to be, and perspectives will vary. Attempts to classify genetic conditions according to their severity tend to prioritise biomedical information at the expense of incorporating qualitative aspects of the impact of genetic conditions on people's lives. Further complexity arises because some genotypes can present with variable phenotypes and because some conditions are not always experienced in the same way by all people who have them. To acknowledge this complexity, we argue that an understanding of severity needs to distinguish between the severity of a genetic condition-requiring a generalised approach for purposes of policy development and programme design-and the severity of an instance of a genetic condition in a particular person. Families making reproductive decisions also require access to diverse experiences of the qualitative aspects of living with genetic conditions. As a result, reproductive carrier screening programmes must recognise and respond to the complexity inherent in determining the severity of genetic conditions.

Should genes for non-syndromic hearing loss be included in reproductive genetic carrier screening: Views of people with a personal or family experience of deafness.

Many commercial reproductive genetic carrier screening (RGCS) panels include genes associated with non-syndromic hearing loss (NSHL), however little is known about the general acceptability of their inclusion. Although some couples wish to avoid having a deaf child, there are effective interventions and supports available for deafness, and no consensus on whether it is appropriate to reproductively screen NSHL genes. This study explored views of people with personal experience of deafness regarding carrier screening for genes associated with NSHL. We interviewed 27 participants; 14 who identified as deaf and 13 hearing parents of a deaf child. Thematic analysis was undertaken on transcripts of interviews. The findings reveal the complexity of attitudes within these groups. Some vacillated between the wish to support prospective parents' reproductive autonomy and concerns about potential harms, especially the expression of negative messages about deafness and the potential loss of acceptance in society. While some participants felt carrier screening could help prospective parents to prepare for a deaf child, there was little support for reproductive screening and termination of pregnancy. Participants emphasized the need for accurate information about the lived experience of deafness. The majority felt deafness is not as severe as other conditions included in RGCS, and most do not consider deafness as a disability. People with personal experience of deafness have diverse attitudes towards RGCS for deafness informed by their own identify and experience, and many have concerns about how it should be discussed and implemented in a population wide RGCS program.

The views of people with a lived experience of deafness and the general public regarding genetic testing for deafness in the reproductive setting: A systematic review.

PURPOSE: Genes associated with nonsyndromic hearing loss are commonly included in reproductive carrier screening panels, which are now routinely offered in preconception and prenatal care in many countries. However, there is debate whether hearing loss should be considered a medical condition appropriate for screening. This systematic review assessed research on opinions of those with a lived experience of deafness and the general public regarding genetic testing for deafness in the reproductive setting. METHODS: Search of 5 online databases yielded 423 articles, 20 of which met inclusion criteria. We assessed the quality of each study, extracted data, and performed thematic analysis on qualitative studies. RESULTS: Most studies indicated interest in the use of prenatal diagnosis for deafness. However, there were mixed views, and sometimes strongly held views, expressed regarding the reproductive options that should be available to those with an increased chance of having a child with deafness. Studies were small, from a limited number of countries, and most were too old to include views regarding preimplantation genetic testing. CONCLUSION: There is a broad range of views regarding the use of reproductive options for deafness. Further research is essential to explore the benefits and harms of including nonsyndromic hearing loss genes in carrier screening.

Views of reproductive genetic carrier screening participants regarding screening for genes associated with non-syndromic hearing loss.

OBJECTIVE: Reproductive genetic carrier screening (RGCS) panels often include genes associated with non-syndromic hearing loss (NSHL) despite a lack of evidence of acceptability. Although some couples take steps to avoid having a child who is deaf, there are effective interventions for children who are deaf. There is no consensus whether deafness is considered a disabling condition. METHOD: This study explored views of people who had RGCS, without genes for NSHL, about this topic. Online surveys were sent to 2186 people who had a low chance RGCS result and 655 completed the survey (participation rate 30%). RESULTS: Sixty-three percent (N = 412) think deafness is a serious health condition. The majority agreed (60%, N = 391) that with support (i.e. hearing aids/cochlear implants) deafness is a minor condition in children. Most (84%, N = 545) agreed genes for NSHL should be included in RGCS. Thirty-five percent (N = 231) indicated they would make different reproductive decisions if they had an increased chance of having a child born deaf; 31% would not change their reproductive plans and 34% were unsure what they would do. CONCLUSION: While the majority support inclusion of genes associated with NSHL in RGCS, there was uncertainty about the severity of deafness as a health condition and there was no consensus on whether it is a health condition that warrants changing reproductive decisions.

Clinician views and experiences of non-invasive prenatal genetic screening tests in Australia.

BACKGROUND: Non-invasive prenatal screening (NIPS) is being increasingly used by expectant parents. Much provision of this test in Australia is occurring in clinical settings where specialised genetic counselling is unavailable, such as general practice. Potential psychosocial consequences from this kind of prenatal genetic screening remain largely unexplored. AIMS: To explore clinicians' experiences with NIPS for aneuploidy, their perspectives of the benefits and harms of NIPS, clinicians' information needs, and their perceptions of the needs of expectant parents. MATERIALS AND METHODS: Qualitative, semi-structured interviews with 17 health professionals (clinical geneticists, obstetricians, genetic counsellors and general practitioners) who request and counsel for NIPS in Australian hospital and private practice settings, conducted between June 2019 and February 2020. RESULTS: Five themes were identified relating to clinicians' perceptions and experiences of NIPS in their practice: perceived benefits of NIPS, perceived harms of NIPS (with two subthemes: clinical harms and psychosocial harms), financial and equity-related concerns, counselling as a protective buffer against perceived harms, and clinicians' unmet education needs. While clinicians view NIPS as a useful and high-quality screening test, especially for detection of common trisomies, many participants had concerns about how NIPS has been implemented in practice, particularly the quality (and often absence) of pre-/post-test counselling and the routinisation of testing for sex chromosome aneuploidies, microdeletion and microduplication syndromes. CONCLUSION: These findings support the need for targeted clinician training around NIPS, and for a shared decision-making approach to support expectant parents' autonomous decisions about NIPS.

Health practitioners' perceptions of the barriers and enablers to the implementation of reproductive genetic carrier screening: A systematic review.

BACKGROUND: As interest in reproductive genetic carrier screening rises, with increased availability, the role of healthcare practitioners is central in guiding uptake aligned with a couples' values and beliefs. Therefore, practitioners' views on implementation are critical to the success of any reproductive genetic carrier screening programme. AIM: To explore healthcare practitioners' perceptions of the barriers and enablers to implementation. MATERIALS & METHODS: We undertook a systematic review of the literature searching seven databases using health practitioner, screening and implementation terms returning 490 articles. RESULTS: Screening led to the inclusion of 26 articles for full-text review. We found three interconnected themes relating to reproductive genetic carrier screening: (i) use and impact, (ii) practitioners' beliefs and expectations and (iii) resources. DISCUSSION: Barriers and enablers to implementation were present within each theme and grouping these determinants by (a) community for example lack of public interest, (b) practitioner for example lack of practitioner time and (c) organisation for example lack of effective metrics, reveals a preponderance of practitioner barriers and organisational enablers. Linking barriers with potential enablers leaves several barriers unresolved (e.g., costs for couples) implying additional interventions may be required. CONCLUSION: Future research should draw on the findings from this study to develop and test strategies to facilitate appropriate offering of reproductive genetic carrier screening by healthcare practitioners.

Development and Evaluation of a Telephone Communication Protocol for the Delivery of Personalized Melanoma Genomic Risk to the General Population.

Communicating personalized genomic risk results for common diseases to the general population as a form of tailored prevention is novel and may require alternative genetic counseling service delivery models. We describe the development and evaluation of a communication protocol for disclosing melanoma genomic risk information to the asymptomatic general population and assess participants' satisfaction and acceptability. Participants (n = 117) were aged 22-69 years, living in New South Wales, Australia and unselected for family history. They provided a saliva sample and had genomic testing for melanoma for low to moderate penetrant melanoma susceptibility variants in 21 genes. Participants could choose to receive their results from a genetic counselor via telephone, followed by a mailed booklet or to receive their risk result via mailed booklet only with a follow-up call for those at high risk. A follow-up questionnaire was completed by 85% of participants 3-months later. Most participants (80%) elected to receive their result via telephone. Participants were highly satisfied with the delivery of results (mean 3.4 out of 4, standard deviation 0.5), and this did not differ by delivery mode, risk category, age or sex. On follow-up, 75% accurately recalled their risk category, 6% indicated a preference for a different delivery mode, either electronic or face-to-face. The process of disclosing genomic risk results to the general population over the telephone with accompanying written material was feasible and acceptable, and may be useful for communicating polygenic risk for common diseases in the context of increasing demands for genomic testing.

Beyond severity: utility as a criterion for setting the scope of RGCS.

Reproductive genetic carrier screening (RGCS) allows prospective parents to identify and act upon their chances of having a child with a genetic condition. In deciding which genetic conditions to include in RGCS, severity is often used as a criterion. However, the concept is inherently complex, subjective and multidimensional, and determinations of severity will remain intractably contested. We propose the concept of utility as a criterion for setting the scope of RGCS, and put forward two central arguments for doing so. First, utility is a more appropriate and effective concept as it responds to context and makes an explicit connection between the purpose of RGCS and the value of information obtained for that purpose: namely, to facilitate reproductive decision-making. Utility comprises both clinical and personal utility, and varies according to the availability and accessibility of reproductive options, including pre-implantation genetic testing, prenatal genetic diagnosis, and termination of pregnancy. Second, there are ethical reasons for preferring utility over severity. Utility is a property of the information gleaned from RGCS, while severity is a property of a genetic condition or of an instance of this condition in a person. While consideration of the severity of genetic conditions is not lost when focusing on utility, the need to rely on value judgements regarding the quality of life of people who live with genetic conditions is circumvented. Therefore, utility should replace severity as justification for the inclusion of genetic conditions in RGCS programmes.

Views of healthcare professionals on the inclusion of genes associated with non-syndromic hearing loss in reproductive genetic carrier screening.

Genes associated with non-syndromic hearing loss (NSHL) are frequently included in panels for reproductive genetic carrier screening (RGCS), despite a lack of consensus on whether NSHL is a condition appropriate for inclusion in RGCS. We conducted a national online survey using a questionnaire to explore the views of clinicians who facilitate RGCS or provide care to deaf individuals in Australia and New Zealand regarding the inclusion of such genes in RGCS. Results were analysed descriptively, and free-text responses were analysed thematically. The questionnaire was completed by 386 respondents including genetic healthcare providers, obstetricians, ear nose and throat specialists, and general practitioners. The majority of respondents agreed that genes associated with NSHL should be included in RGCS, but there were differences between the groups. 74% of clinicians working in a hearing clinic agreed these genes should be included compared to 67% of genetic healthcare providers, 54% of reproductive care healthcare providers, and 44% of general practitioners. A majority of respondents agreed that moderate to profound deafness is a serious disability, although genetic healthcare providers were less likely to agree than other groups. Overall, respondents agreed that including NSHL in RGCS upholds prospective parents' right to information. However, they also identified major challenges, including concern that screening may express a discriminatory attitude towards those living with deafness. They also identified the complexity of defining the severity of deafness.

Scaling-up and future sustainability of a national reproductive genetic carrier screening program.

An understanding of factors influencing implementation is essential to realise the benefits of population-based reproductive genetic carrier screening programs. The aim of this study was to synthesise data collected during the Australian Reproductive Genetic Carrier Screening Project (Mackenzie's Mission) to track how priorities shifted over time and identify important factors during scaling-up and for sustainment. We used a multi-method qualitative approach to integrate longitudinal project data collected from 10 project committees with 16 semi-structured interviews conducted with study team members. Both datasets were analysed using the Consolidated Framework for Implementation Research (CFIR) to identify constructs of interest within early, mid-point, and future implementation phases. Several CFIR constructs were present across implementation. The complexity of implementation presented challenges that were overcome through a quality-designed and packaged product, formal and informal networks and communication, and access to knowledge and information. Addressing the diverse consumer needs through resources and increasing community and non-genetic speciality engagement remained a priority throughout and for future sustainment. Going forward, further addressing program complexities and securing funding were emphasised. By applying an implementation framework, findings from this study may be useful for future effort towards building and/or sustaining reproductive genetic carrier screening programs.

Do online decision aids reflect new prenatal screening and testing options? An environmental scan and content analysis.

Objective: Decision aids have been developed to help prospective parents make informed, shared decisions about medical tests, but these options are rapidly changing. This study aimed to identify and evaluate publicly available decision aids written in English for prospective parents seeking prenatal test information. Methods: A systematic review process was followed using 3 sources: known decision aid repositories, fetal medicine organisations and Google. The search, screening process, quality assessment, and data extraction was performed by two independent researchers. The quality assessment of the decision aids was based on the International Patient Decision Aids Standards (IPDAS v.4.0). Results: We identified 13 decision aids, which varied in the screening and diagnostic tests that they discussed. No decision aid met all the IPDAS v.4.0. criteria and no decision aid reported updated risk of miscarriage for amniocentesis and chorionic villus sampling (CVS). There was a lack of decision aids for some common decisions in the prenatal context. Conclusion: We identified outdated content in current prenatal decision aids. The findings will inform healthcare professionals of the quality of current prenatal decision aids, which may facilitate their patients' informed decision-making about prenatal tests. Innovation: Considerations for improving future decision aids are outlined.

The Australian Reproductive Genetic Carrier Screening Project (Mackenzie's Mission): Design and Implementation.

Reproductive genetic carrier screening (RGCS) provides people with information about their chance of having children with autosomal recessive or X-linked genetic conditions, enabling informed reproductive decision-making. RGCS is recommended to be offered to all couples during preconception or in early pregnancy. However, cost and a lack of awareness may prevent access. To address this, the Australian Government funded Mackenzie's Mission­the Australian Reproductive Genetic Carrier Screening Project. Mackenzie's Mission aims to assess the acceptability and feasibility of an easily accessible RGCS program, provided free of charge to the participant. In study Phase 1, implementation needs were mapped, and key study elements were developed. In Phase 2, RGCS is being offered by healthcare providers educated by the study team. Reproductive couples who provide consent are screened for over 1200 genes associated with >750 serious, childhood-onset genetic conditions. Those with an increased chance result are provided comprehensive genetic counseling support. Reproductive couples, recruiting healthcare providers, and study team members are also invited to complete surveys and/or interviews. In Phase 3, a mixed-methods analysis will be undertaken to assess the program outcomes, psychosocial implications and implementation considerations alongside an ongoing bioethical analysis and a health economic evaluation. Findings will inform the implementation of an ethically robust RGCS program.

The Development of Clinical Genomics and Genetics Within Healthcare: How Should the Allied Health Professions Respond?

Clinical genomics is becoming mainstream, providing personalized information that is relevant to clinical assessment, management, and decision-making on a patient-by-patient basis. This emphasis on personalized medicine has been featured in medical and nursing/midwifery entry-level curricula for some time. These curricula frameworks enable work-ready professionals to embrace genomics as part of standard care. The uptake of genomics across healthcare should also feature across the allied health professions worldwide. While some allied health professions are active in the research and clinical domains, there is, to our knowledge, scant evidence of a collective effort to bring genomics into mainstream allied health practice. It is suggested that the allied health professions need to recognize and embrace opportunities to collaborate with our colleagues in medicine, nursing/midwifery, and healthcare consumers to integrate genomics into and across allied health clinical practice. This includes: understanding what "genomics" is; recognizing who may benefit from genetic testing; the cultural, ethical, and legal implications of genomics in practice; and the potential to inform treatment decisions and/or justify referral. Discussion surrounding the integration of genomics competencies within the allied health professions is required to both enlighten and determine professional practice roles in response to this increasingly relevant element of healthcare delivery worldwide.

A Pilot Randomized Controlled Trial of the Feasibility, Acceptability, and Impact of Giving Information on Personalized Genomic Risk of Melanoma to the Public.

BACKGROUND: Communication of personalized melanoma genomic risk information may improve melanoma prevention behaviors. METHODS: We evaluated the feasibility and acceptability of communicating personalized genomic risk of melanoma to the public and its preliminary impact on behaviors and psychosocial outcomes. One hundred eighteen people aged 22 to 69 years provided a saliva sample and were randomized to the control (nonpersonalized educational materials) or intervention (personalized booklet presenting melanoma genomic risk as absolute and relative risks and a risk category based on variants in 21 genes, telephone-based genetic counseling, and nonpersonalized educational materials). Intention-to-treat analyses overall and by-risk category were conducted using ANCOVA adjusted for baseline values. RESULTS: Consent to participate was 41%, 99% were successfully genotyped, and 92% completed 3-month follow-up. Intervention participants reported high satisfaction with the personalized booklet (mean = 8.6, SD = 1.6; on a 0-10 scale) and genetic counseling (mean = 8.1, SD = 2.2). No significant behavioral effects at 3-month follow-up were identified between intervention and control groups overall: objectively measured standard erythemal doses per day [-16%; 95% confidence interval (CI), -43% to 24%] and sun protection index (0.05; 95% CI, -0.07 to 0.18). There was increased confidence identifying melanoma at 3 months (0.40; 95% CI, 0.10-0.69). Stratified by risk category, effect sizes for intentional tanning and some individual sun protection items appeared stronger for the average-risk group. There were no appreciable group differences in skin cancer-related worry or psychologic distress. CONCLUSIONS: Our results demonstrate feasibility and acceptability of providing personalized genomic risk of melanoma to the public. IMPACT: Genomic risk information has potential as a melanoma prevention strategy. Cancer Epidemiol Biomarkers Prev; 26(2); 212-21. ©2016 AACR.

Diagnostic validation of a familial hypercholesterolaemia cohort provides a model for using targeted next generation DNA sequencing in the clinical setting.

Our aim was to assess the sensitivity and specificity of a next generation DNA sequencing (NGS) platform using a capture based DNA library preparation method. Data and experience gained from this diagnostic validation can be used to progress the applications of NGS in the wider molecular diagnostic setting. A technical cross-validation comparing the current molecular diagnostic gold standard methods of Sanger DNA sequencing and multiplex ligation-dependant probe amplification (MLPA) versus a customised capture based targeted re-sequencing method on a SOLiD 5500 sequencing platform was carried out using a cohort of 96 familial hypercholesterolaemia (FH) samples. We compared a total of 595 DNA variations (488 common single nucleotide polymorphisms, 73 missense mutations, 9 nonsense mutations, 3 splice site point mutations, 13 small indels, 2 multi-exonic duplications and 7 multi-exonic deletions) found previously in the 96 FH samples. DNA variation detection sensitivity and specificity were both 100% for the SOLiD 5500 NGS platform compared with Sanger sequencing and MLPA only when both LifeScope and Integrative Genomics Viewer softwares were utilised. The methods described here offer a high-quality strategy for the detection of a wide range of DNA mutations in diseases with a moderate number of well described causative genes. However, there are important issues related to the bioinformatic algorithms employed to detect small indels.