Prospective cohort study of genomic newborn screening: BabyScreen+ pilot study protocol.

INTRODUCTION: Newborn bloodspot screening (NBS) is a highly successful public health programme that uses biochemical and other assays to screen for severe but treatable childhood-onset conditions. Introducing genomic sequencing into NBS programmes increases the range of detectable conditions but raises practical and ethical issues. Evidence from prospectively ascertained cohorts is required to guide policy and future implementation. This study aims to develop, implement and evaluate a genomic NBS (gNBS) pilot programme. METHODS AND ANALYSIS: The BabyScreen+ study will pilot gNBS in three phases. In the preimplementation phase, study materials, including education resources, decision support and data collection tools, will be designed. Focus groups and key informant interviews will also be undertaken to inform delivery of the study and future gNBS programmes. During the implementation phase, we will prospectively recruit birth parents in Victoria, Australia, to screen 1000 newborns for over 600 severe, treatable, childhood-onset conditions. Clinically accredited whole genome sequencing will be performed following standard NBS using the same sample. High chance results will be returned by genetic healthcare professionals, with follow-on genetic and other confirmatory testing and referral to specialist services as required. The postimplementation phase will evaluate the feasibility of gNBS as the primary aim, and assess ethical, implementation, psychosocial and health economic factors to inform future service delivery. ETHICS AND DISSEMINATION: This project received ethics approval from the Royal Children's Hospital Melbourne Research Ethics Committee: HREC/91500/RCHM-2023, HREC/90929/RCHM-2022 and HREC/91392/RCHM-2022. Findings will be disseminated to policy-makers, and through peer-reviewed journals and conferences.

Evaluation of a two-step model of opportunistic genomic screening.

Increasing use of diagnostic genomic sequencing is pushing health services to confront the issue of opportunistic genomic screening (OGS). To date, OGS has been offered concomitant with diagnostic testing. In contrast, we piloted a service offering OGS after return of diagnostic testing results. Evaluation was designed to provide insights for future models of service and included patient surveys at three time points, semi-structured interviews with genetic counsellors (GCs) and a focus group with medical scientists. Uptake was relatively low: 83 of 200 patients approached (42%) attended the OGS service, with 81 accepting OGS. Whilst many who declined to attend the service cited practical barriers, others gave reasons that indicated this was a considered decision. Despite specific genetic counselling, one third of patients did not understand the scope of re-analysis. Yet after post-test counselling, all respondents with novel pathogenic additional findings (AF) understood the implications and reported relevant follow-up. Recall was high: five months after last contact, 75% recalled being offered OGS without prompting. GC interviews and patient survey responses provide insights into complexities that influence patient support needs, including diagnostic status and AF result type. There was no consensus among patients or professionals about when to offer OGS. There was a clear preference for multiple, flexible methods of information provision; achieving this whilst balancing patient support needs and resource requirements is a challenge requiring further investigation. Decisions about whether, when and how to offer OGS are complex; our study shows the two-step approach warrants further exploration.

Secondary use of genomic data: patients' decisions at point of testing and perspectives to inform international data sharing.

International sharing of genomic data files arising from clinical testing of patients is essential to further improve genomic medicine. Whilst the general public are reluctant to donate DNA for research, the choices patients actually make about sharing their clinical genomic data for future re-use (research or clinical) are unknown. We ascertained the data-sharing choices of 1515 patients having genomic testing for inherited conditions or cancer treatment from clinical consent forms. To understand the experiences and preferences of these patients, surveys were administered after test consent (RR 73%). Almost all patients (98%) consented to share their data. Survey respondents' decision recall was high (90%), but poorer if English was an additional language (p < 0.001). Parents deciding on behalf of children were over-represented amongst data-sharing decliners (p = 0.047) and decliners were more likely to believe that stored data could be easily reidentified (p < 0.001). A quarter of respondents did not know if reidentification would be easy and 44% of them were concerned about this possibility. Of those willing to share data overseas (60%), 23% indicated the recipient researcher's country would affect their decision. Most respondents (89%) desired some ongoing control over research use of their data. Four preliminary data-sharing profiles emerged; their further development could inform tailored patient resources. Our results highlight considerations for establishment of systems to make clinical genomic data files available for reanalysis locally and across borders. Patients' willingness to share their data - and value of the resulting research - should encourage clinical laboratories to consider sharing data systematically for secondary uses.

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.

A novel approach to offering additional genomic findings-A protocol to test a two-step approach in the healthcare system.

Internationally, the practice of offering additional findings (AFs) when undertaking a clinically indicated genomic test differs. In the USA, the recommendation is to include analysis for AFs alongside diagnostic analysis, unless a patient opts-out, whereas European and Canadian guidelines recommend opt-in models. These guidelines all consider the offer of AFs as an activity concurrent with the offer of diagnostic testing. This paper describes a novel two-step model for managing AFs within the healthcare system in Victoria, Australia and presents the study protocol for its evaluation. Adults who have received results of diagnostic whole exome sequencing undertaken within the healthcare system are invited to attend a genetic counseling appointment to consider reanalysis of their stored genomic data for AFs. The evaluation protocol addresses uptake, decision-making, understanding, counseling challenges, and explores preferences for future models of care. Recruitment commenced in November 2017 and will cease when 200 participants have been approached. When the study is concluded, the evaluation results will contribute to the evidence base guiding approaches to counseling and models of care for AFs.

Discussions about predictive genetic testing for Lynch syndrome: the role of health professionals and families in decisions to decline.

Unaffected relatives of individuals with Lynch syndrome can be offered predictive genetic testing to guide surveillance recommendations. The decision-making process of those who decline testing, particularly those who do not attend a clinical genetics service, is poorly understood. We have addressed this gap by interviewing 33 individuals from Lynch syndrome mutation-carrying families, unaffected by cancer, who declined predictive genetic testing. Here, we analyse the data provided by 20 participants who unequivocally declined testing. Those who indicated they did not have enough information to make a decision or intended to undergo testing in the future were excluded. Analysis revealed that few decliners discussed their decision with general practitioners or genetic counsellors. Family members were commonly involved to varying degrees, with participants either (1) making group decisions with family members, (2) feeling persuaded by family members to either accept or decline testing, (3) discussing the test but making their own decision. A minority did not discuss testing with family members while making their decision. This research reveals the health communication activities of an understudied group, those declining predictive testing, and indicates that for many, health professionals play a minor role in the decision compared to family.