Australian public perspectives on genomic newborn screening: which conditions should be included?

BACKGROUND: Implementing genomic sequencing into newborn screening programs allows for significant expansion in the number and scope of conditions detected. We sought to explore public preferences and perspectives on which conditions to include in genomic newborn screening (gNBS). METHODS: We recruited English-speaking members of the Australian public over 18 years of age, using social media, and invited them to participate in online focus groups. RESULTS: Seventy-five members of the public aged 23-72 participated in one of fifteen focus groups. Participants agreed that if prioritisation of conditions was necessary, childhood-onset conditions were more important to include than later-onset conditions. Despite the purpose of the focus groups being to elicit public preferences, participants wanted to defer to others, such as health professionals or those with a lived experience of each condition, to make decisions about which conditions to include. Many participants saw benefit in including conditions with no available treatment. Participants agreed that gNBS should be fully publicly funded. CONCLUSION: How many and which conditions are included in a gNBS program will be a complex decision requiring detailed assessment of benefits and costs alongside public and professional engagement. Our study provides support for implementing gNBS for treatable childhood-onset conditions.

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.

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.

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.

Eliciting parental preferences and values for the return of additional findings from genomic sequencing.

Health economic evidence is needed to inform the design of high-value and cost-effective processes for returning genomic results from analyses for additional findings (AF). This study reports the results of a discrete-choice experiment designed to elicit preferences for the process of returning AF results from the perspective of parents of children with rare conditions and to estimate the value placed on AF analysis. Overall, 94 parents recruited within the Australian Genomics and Melbourne Genomics programmes participated in the survey, providing preferences in a total of 1128 choice scenarios. Statistically significant preferences were identified for the opportunity to change the choices made about AF; receiving positive AF in person from a genetic counsellor; timely access to a medical specialist and high-quality online resources; receiving automatic updates through a secure online portal if new information becomes available; and lower costs. For AF uptake rates ranging between 50-95%, the mean per person value from AF analysis was estimated at AU$450-$1700 (US$300-$1140). The findings enable the design of a value-maximising process of analysis for AF in rare-disease genomic sequencing.

Australian Public Perspectives on Genomic Newborn Screening: Risks, Benefits, and Preferences for Implementation.

Recent dramatic reductions in the timeframe in which genomic sequencing can deliver results means its application in time-sensitive screening programs such as newborn screening (NBS) is becoming a reality. As genomic NBS (gNBS) programs are developed around the world, there is an increasing need to address the ethical and social issues that such initiatives raise. This study therefore aimed to explore the Australian public's perspectives and values regarding key gNBS characteristics and preferences for service delivery. We recruited English-speaking members of the Australian public over 18 years of age via social media; 75 people aged 23-72 participated in 1 of 15 focus groups. Participants were generally supportive of introducing genomic sequencing into newborn screening, with several stating that the adoption of such revolutionary and beneficial technology was a moral obligation. Participants consistently highlighted receiving an early diagnosis as the leading benefit, which was frequently linked to the potential for early treatment and intervention, or access to other forms of assistance, such as peer support. Informing parents about the test during pregnancy was considered important. This study provides insights into the Australian public's views and preferences to inform the delivery of a gNBS program in the Australian context.

Aligning intuition and theory: a novel approach to identifying the determinants of behaviours necessary to support implementation of evidence into practice.

BACKGROUND: Disentangling the interplay between experience-based intuition and theory-informed implementation is crucial for identifying the direct contribution theory can make for generating behaviour changes needed for successful evidence translation. In the context of 'clinicogenomics', a complex and rapidly evolving field demanding swift practice change, we aimed to (a) describe a combined clinician intuition- and theory-driven method for identifying determinants of and strategies for implementing clinicogenomics, and (b) articulate a structured approach to standardise hypothesised behavioural pathways and make potential underlying theory explicit. METHODS: Interview data from 16 non-genetic medical specialists using genomics in practice identified three target behaviour areas across the testing process: (1) identifying patients, (2) test ordering and reporting, (3) communicating results. The Theoretical Domains Framework (TDF) was used to group barriers and facilitators to performing these actions. Barriers were grouped by distinct TDF domains, with 'overarching' TDF themes identified for overlapping barriers. Clinician intuitively-derived implementation strategies were matched with corresponding barriers, and retrospectively coded against behaviour change techniques (BCTs). Where no intuitive strategies were provided, theory-driven strategies were generated. An algorithm was developed and applied to articulate how implementation strategies address barriers to influence behaviour change. RESULTS: Across all target behaviour areas, 32 identified barriers were coded across seven distinct TDF domains and eight overarching TDF themes. Within the 29 intuitive strategies, 21 BCTs were represented and used on 49 occasions to address 23 barriers. On 10 (20%) of these occasions, existing empirical links were found between BCTs and corresponding distinct TDF-coded barriers. Twenty additional theory-driven implementation strategies (using 19 BCTs on 31 occasions) were developed to address nine remaining barriers. CONCLUSION: Clinicians naturally generate their own solutions when implementing clinical interventions, and in this clinicogenomics example these intuitive strategies aligned with theoretical recommendations 20% of the time. We have matched intuitive strategies with theory-driven BCTs to make potential underlying theory explicit through proposed structured hypothesised causal pathways. Transparency and efficiency are enhanced, providing a novel method to identify determinants of implementation. Operationalising this approach to support the design of implementation strategies may optimise practice change in response to rapidly evolving scientific advances requiring swift translation into healthcare.

What's in a name? Justifying terminology for genomic findings beyond the initial test indication: A scoping review.

Genome sequencing can generate findings beyond the initial test indication that may be relevant to a patient or research participant's health. In the decade since the American College of Medical Genetics and Genomics published its recommendations for reporting these findings, consensus regarding terminology has remained elusive and a variety of terms are in use globally. We conducted a scoping review to explore terminology choice and the justifications underlying those choices. Documents were included if they contained a justification for their choice of term(s) related to findings beyond the initial genomic test indication. From 3571 unique documents, 52 were included, just over half of which pertained to the clinical context (n = 29, 56%). We identified four inter-related concepts used to defend or oppose terms: expectedness of the finding, effective communication, relatedness to the original test indication, and how genomic information was generated. A variety of justifications were used to oppose the term "incidental," whereas "secondary" had broader support as a term to describe findings deliberately sought. Terminology choice would benefit from further work to include the views of patients. We contend that clear definitions will improve ethical debate and support communication about genomic findings beyond the initial test indication.

Two-step offer and return of multiple types of additional genomic findings to families after ultrarapid trio genomic testing in the acute care setting: a study protocol.

INTRODUCTION: As routine genomic testing expands, so too does the opportunity to look for additional health information unrelated to the original reason for testing, termed additional findings (AF). Analysis for many different types of AF may be available, particularly to families undergoing trio genomic testing. The optimal model for service delivery remains to be determined, especially when the original test occurs in the acute care setting. METHODS AND ANALYSIS: Families enrolled in a national study providing ultrarapid genomic testing to critically ill children will be offered analysis for three types of AF on their stored genomic data: paediatric-onset conditions in the child, adult-onset conditions in each parent and reproductive carrier screening for the parents as a couple. The offer will be made 3-6 months after diagnostic testing. Parents will have access to a modified version of the Genetics Adviser web-based decision support tool before attending a genetic counselling appointment to discuss consent for AF. Parental experiences will be evaluated using qualitative and quantitative methods on data collected through surveys, appointment recordings and interviews at multiple time points. Evaluation will focus on parental preferences, uptake, decision support use and understanding of AF. Genetic health professionals' perspectives on acceptability and feasibility of AF will also be captured through surveys and interviews. ETHICS AND DISSEMINATION: This project received ethics approval from the Melbourne Health Human Research Ethics Committee as part of the Australian Genomics Health Alliance protocol: HREC/16/MH/251. Findings will be disseminated through peer-review journal articles and at conferences nationally and internationally.

What matters to parents? A scoping review of parents' service experiences and needs regarding genetic testing for rare diseases.

Patient care experiences are key to promoting better outcomes and are an essential consideration for successful implementation of genomics in paediatric care. To understand parents' service experiences and needs regarding testing of their child for rare diseases, we conducted a scoping review. Five databases were searched (2000-2022), with 29 studies meeting the inclusion criteria. Experiences of care wholly delivered by genetic services were most commonly reported (n = 11). Results were synthesised by mapping extracted data to adapted Picker principles of person-centred care. Parents especially valued and emphasised the importance of feeling 'cared for', continuous relationships with clinicians, empathic communication, being kept informed while awaiting genetic test results, linkage with informational and psychosocial resources following results disclosure, and follow-up. Strategies were often proposed by authors to address long-standing unmet needs but evidence from the literature regarding their potential effectiveness was rarely provided. We conclude that 'what matters' to parents regarding genetic testing is not dissimilar to other aspects of care. Paediatric medical specialists have existing skill sets, trusted relationships and can apply familiar principles of 'good' care to enhance experiences of genetic testing. The lack of evidence for service improvement strategies highlights the pressing need to undertake rigorous design and testing of interventions alongside mainstreaming of genomics into paediatric care.

Investigating genomic medicine practice and perceptions amongst Australian non-genetics physicians to inform education and implementation.

Genomic medicine is being implemented on a global scale, requiring a genomic-competent health workforce. To inform education as part of implementation strategies to optimize adoption of genomics by non-genetics physicians, we investigated current practices, perceptions and preferences relating to genomic testing and education. Australian non-genetics physicians completed an online survey; we conducted univariate and multivariate analyses of determinants of confidence and engagement with genomic medicine. Confident or engaged respondents were more likely to be pediatricians, have completed continuing genomics education (CGE) and/or have genomics research experience. Confident or engaged respondents were also more likely to prefer to request genomic testing with support from genetics services than other models. Respondents who had completed CGE and were engaged reported higher confidence than those who were not engaged. We propose a progression of genomic competence aligned with service delivery models, where education is one enabler of mastery or independence to facilitate genomic tests (from referral to requesting with or without clinical genetics support). Workplace learning could provide additional impetus for adoption.

Australian Genomics: Outcomes of a 5-year national program to accelerate the integration of genomics in healthcare.

Australian Genomics is a national collaborative partnership of more than 100 organizations piloting a whole-of-system approach to integrating genomics into healthcare, based on federation principles. In the first five years of operation, Australian Genomics has evaluated the outcomes of genomic testing in more than 5,200 individuals across 19 rare disease and cancer flagship studies. Comprehensive analyses of the health economic, policy, ethical, legal, implementation and workforce implications of incorporating genomics in the Australian context have informed evidence-based change in policy and practice, resulting in national government funding and equity of access for a range of genomic tests. Simultaneously, Australian Genomics has built national skills, infrastructure, policy, and data resources to enable effective data sharing to drive discovery research and support improvements in clinical genomic delivery.

Offering and Returning Secondary Findings in the Context of Exome Sequencing for Hearing Loss: Clinicians' Views and Experiences.

BACKGROUND: There is ongoing debate regarding whether and under which circumstances secondary findings (SF) should be offered in the pediatric context. Although studies have examined patient perspectives on receiving SF, little research has been conducted examining the experiences of clinicians offering SF to parents of newborns receiving genomic sequencing for a recently diagnosed medical condition. METHODS: To address this, we conducted qualitative interviews exploring the views and experiences of 12 clinicians who offered SF to parents of infants who had diagnostic exome sequencing (ES) to identify the cause of their hearing loss. Interviews explored clinicians' accounts of parents' choices and decision-making about receiving SF, their views on whether and when to offer SF, their experiences returning SF, and any ethical challenges they encountered. Interviews were audio-recorded, transcribed and analyzed using inductive content analysis. RESULTS: Clinicians reported parents who declined all SF often felt finding out about future conditions unrelated to their child's hearing loss may be unhelpful, or even harmful, or were overwhelmed by their child's diagnosis. Clinicians also reported that some parents chose SF because they felt obliged to, even if they did not want to receive them. They explained that while some parents experienced decision-making regarding SF as positive, for others, this process was challenging or distressing. While clinicians generally agreed SF should be offered, mainly to promote parental choice, most felt SF should be offered after disclosing diagnostic results, primarily to avoid overwhelming parents. Clinicians encountered several ethical challenges, including balancing parental autonomy with non-maleficence, wanting to report or not report certain SF, and questioning whether parents can make an autonomous choice regarding SF. CONCLUSIONS: Our findings, which are novel as they relate to parents of young infants with a recent diagnosis of hearing loss, add new insights into clinicians' and parents' decision-making regarding SF in pediatrics.

Comparing Survival Outcomes for Advanced Cancer Patients Who Received Complex Genomic Profiling Using a Synthetic Control Arm.

BACKGROUND: Complex genomic profiling (CGP) has transformed cancer treatment decision making, yet there is a lack of robust and quantifiable evidence for how utilisation of CGP improves patient outcomes. OBJECTIVE: This study evaluated cohort level clinical effectiveness of CGP to improve overall survival (OS) in real-world advanced cancer patients using a registry-based matched control population. PATIENTS AND METHODS: Two cohorts of advanced and refractory cancer patients were seen in consecutive series for early phase trial enrolment consideration. The first cohort (CGP group) accessed tumour profiling via a research study; while the second cohort that followed was not profiled. Overall survival between cohorts was compared using Kaplan-Meier curves and Cox proportional hazard models. Potential confounding was analysed and adjusted for using stabilised weights based on propensity scores. RESULTS: Within the CGP group, 25 (17.6%) patients received treatment informed by CGP results and this subgroup had significantly improved survival compared with CGP patients in whom results did not impact their treatment (unadjusted HR = 0.44, (0.22-0.88), p = 0.02). However, when comparing the entire CGP cohort with the No CGP cohort, no significant survival benefit was evident with adjusted median OS for CGP of 13.5 months (9.2-17.0) compared with 11.0 (9.2-17.4) for No CGP (adjusted HR = 0.92, (0.65-1.30), p = 0.63). CONCLUSIONS: This study utilised real-world data to simulate a control arm and quantify the clinical effectiveness of genomic testing. The magnitude of survival benefit for patients who had CGP result-led treatments was insufficient to drive an overall survival gain for the entire tested population. Translation of CGP into clinics requires strategies to ensure higher rates of tested patients obtain clinical benefit to deliver on the value proposition of CGP in an advanced cancer population.

Genetics follow up after rapid genomic sequencing in intensive care: current practices and recommendations for service delivery.

The delivery of rapid genomic sequencing (rGS) to critically unwell children in intensive care occurs at a time of immense pressure and stress for parents. Contact with families after result disclosure, particularly after hospital discharge, presents an opportunity to meet their psychological, medical and information needs as they evolve. This study explores the preferences and perspectives of health professionals and parents of genetics follow up after rGS. Semi-structured interviews were conducted with 30 parents, seven genetic counsellors (GCs) and four intensive care physicians with experience in rGS. Transcripts were analysed using reflexive thematic analysis. Current practices surrounding genetics follow up after rGS were highly variable, resulting in some families not receiving the ongoing care they needed. Reasons identified by families for wanting follow-up care represented only a subset of those identified by health professionals. While GCs routinely provided their details to allow parents to initiate further contact, this was not always sufficient for follow-up care. Health professionals identified both organisational and psychosocial barriers to conducting follow up. As rGS transforms the diagnostic pathway in rare disease, there is a need for a co-designed, standardised but flexible model for follow-up care with genetics professionals so that families' evolving needs are met.

Structured approaches to implementation of clinical genomics: A scoping review.

PURPOSE: This study aimed to assess the extent to which structured approaches to implementation of clinical genomics, proposed or adapted, are informed by evidence. METHODS: A systematic approach was used to identify peer-reviewed articles and gray literature to report on 4 research questions: 1. What structured approaches have been proposed to support implementation? 2. To what extent are the structured approaches informed by evidence? 3. How have structured approaches been deployed in the genomic setting? 4. What are the intended outcomes of the structured approaches? RESULTS: A total of 30 unique structured approaches to implementation were reported across 23 peer-reviewed publications and 11 gray literature articles. Most approaches were process models, applied in the preadoption implementation phase, focusing on a "service" outcome. Key findings included a lack of implementation science theory informing the development/implementation of newly designed structured approaches in the genomic setting and a lack of measures to assess implementation effectiveness. CONCLUSION: This scoping review identified a significant number of structured approaches developed to inform the implementation of genomic medicine into clinical practice, with limited use of implementation science to support the process. We recommend the use of existing implementation science theory and the expertise of implementation scientists to inform the design of genomic programs being implemented into clinical care.

Is faster better? An economic evaluation of rapid and ultra-rapid genomic testing in critically ill infants and children.

PURPOSE: To evaluate whether the additional cost of providing increasingly faster genomic results in pediatric critical care is outweighed by reductions in health care costs and increases in personal utility. METHODS: Hospital costs and medical files from a cohort of 40 children were analyzed. The health economic impact of rapid and ultra-rapid genomic testing, with and without early initiation, relative to standard genomic testing was evaluated. RESULTS: Shortening the time to results led to substantial economic and personal benefits. Early initiation of ultra-rapid genomic testing was the most cost-beneficial strategy, leading to a cost saving of AU$26,600 per child tested relative to standard genomic testing and a welfare gain of AU$12,000 per child tested. Implementation of early ultra-rapid testing of critically ill children is expected to lead to an annual cost saving of AU$7.3 million for the Australian health system and an aggregate welfare gain of AU$3.3 million, corresponding to a total net benefit of AU$10.6 million. CONCLUSION: Early initiation of ultra-rapid genomic testing can offer substantial economic and personal benefits. Future implementation of rapid genomic testing programs should focus not only on optimizing the laboratory workflow to achieve a fast turnaround time but also on changing clinical practice to expedite test initiation.

Cost-Effectiveness of Targeted Exome Analysis as a Diagnostic Test in Glomerular Diseases.

BACKGROUND: Despite the emergence of diagnostic and clinical utility evidence in nephrology, publicly funded access to genomic testing is restricted in most health care systems. To establish genomic sequencing as a clinical test, an evaluation of cost-effectiveness is urgently required. METHODS: An economic evaluation, informed by a primary clinical study and available clinical evidence and guidelines in nephrology, was performed to evaluate the cost-effectiveness and optimal timing of exome sequencing (ES) in adults and children with suspected monogenic glomerular diseases compared with nongenomic investigations (NGIs). Six diagnostic strategies reflecting current practice and recommended models of care in Australia were modeled: (i) NGIs, (ii) late gene panel followed by ES, (iii) late ES, (iv) early gene panel, (v) early gene panel followed by ES, and (vi) early ES. RESULTS: ES with targeted analysis achieved a diagnosis in 23 of 63 (36.5%) adults and 10 of 24 (41.6%) children. NGIs were estimated to diagnose 4.0% of children, with an average estimated cost of AU$6120 per child. Integrating ES as a first-line test in children was cost saving, with an incremental cost saving of AU$3230 per additional diagnosis compared with NGIs. In adults, NGIs was estimated to diagnose 8% of patients, with an average estimated cost of AU$1830 per person. In adults, integrating ES early resulted in an incremental cost per additional diagnosis of AU$5460 relative to NGIs. CONCLUSIONS: Early ES with targeted analysis was effective for diagnosing monogenic kidney disease, with substantial cost savings in children.