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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.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.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.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.

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.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.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.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.

Background: This study investigated whether receiving the results of predictive genetic testing for Lynch syndrome, indicating the presence or absence of an inherited predisposition to various cancers, including colorectal cancer, was associated with change in individual colonoscopy and smoking behaviors, which could prevent colorectal cancer.Methods: The study population included individuals with no previous diagnosis of colorectal cancer, whose families had already identified deleterious mutations in the mismatch repair or EPCAM genes. Hypotheses were generated from a simple health economics model and tested against individual-level panel data from the Australasian Colorectal Cancer Family Registry.Results: The empirical analysis revealed evidence consistent with some of the hypotheses, with a higher likelihood of undergoing colonoscopy in those who discovered their genetic predisposition to colorectal cancer and a lower likelihood of quitting smoking in those who discovered their lack thereof.Conclusions: Predictive genetic information about Lynch syndrome was associated with change in individual colonoscopy and smoking behaviors but not necessarily in ways to improve population health.Impact: The study findings suggest that the impact of personalized medicine on disease prevention is intricate, warranting further analyses to determine the net benefits and costs. Cancer Epidemiol Biomarkers Prev; 25(11); 1524–33. ©2016 AACR.

Table S1. Study participants' smoking status. Table S2. Estimation results of the logit regression models only on the study participants who underwent colonoscopy before baseline. Table S3. Estimation results of the logit regression model only on the study participants who smoked before baseline. Table S4. Estimation results: subgroup analyses only on the study participants with no previous cancer diagnosis at follow-up

Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast cancer-specific survival (BCSS) is scarce. The aim of this study was to assess the association of protein-truncating variants (PTVs) and rare missense variants (MSVs) in nine known (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53) and 25 suspected BC-susceptibility genes with CBC risk and BCSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox regression models. Analyses included 34,401 women of European ancestry diagnosed with BC, including 676 CBCs and 3,449 BC deaths; the median follow-up was 10.9 years. Subtype analyses were based on estrogen receptor (ER) status of the first BC. Combined PTVs and pathogenic/likely pathogenic MSVs in BRCA1, BRCA2, and TP53 and PTVs in CHEK2 and PALB2 were associated with increased CBC risk [HRs (95% CIs): 2.88 (1.70-4.87), 2.31 (1.39-3.85), 8.29 (2.53-27.21), 2.25 (1.55-3.27), and 2.67 (1.33-5.35), respectively]. The strongest evidence of association with BCSS was for PTVs and pathogenic/likely pathogenic MSVs in BRCA2 (ER-positive BC) and TP53 and PTVs in CHEK2 [HRs (95% CIs): 1.53 (1.13-2.07), 2.08 (0.95-4.57), and 1.39 (1.13-1.72), respectively, after adjusting for tumor characteristics and treatment]. HRs were essentially unchanged when censoring for CBC, suggesting that these associations are not completely explained by increased CBC risk, tumor characteristics, or treatment. There was limited evidence of associations of PTVs and/or rare MSVs with CBC risk or BCSS for the 25 suspected BC genes. The CBC findings are relevant to treatment decisions, follow-up, and screening after BC diagnosis.

Aim: To develop and evaluate genomics education programs for health professionals to expedite the translation of genomics into healthcare. Methods: Our co-design team of genetic specialists, expert medical specialist peers, and genomics educators developed two continuing genomics education programs for health professionals: stand-alone, specialty-specific workshops and a generic blended learning course, combining online learning with workshops. Both programs referenced adult learning theories; workshops included case-based learning and expert peer-led discussion. Longitudinal surveys evaluated changes in confidence and understanding of genomic testing processes and clinical practice. Results: We delivered eleven specialty workshops (414 attendees) and a blended learning course comprising four self-directed online modules (61 users) and workshops (71 attendees) for mixed-specialty groups with adult, pediatric, or oncology cases. Surveys (214 workshops; 63 blended) showed that both programs significantly increased confidence and understanding of genomic testing processes. Blended learning participants showed additional gains in confidence after attending a workshop following online learning. Workshop discussions with experts were valued, particularly regarding interpreting and applying results. At follow-up, gains in confidence and understanding were maintained for both programs and 81% of respondents had performed a new genomics activity in clinical practice. Conclusion: Scalable education is needed. Our results suggest that specialty-specific genomics education may not be required to meet the needs of multiple specialties across a health system. Online learning can meet foundational learning needs but may not be sufficient to apply learning to practice. Blended learning offers flexible, continuing education pathways for dispersed national audiences as genomics becomes increasingly used across varied specialties.

BACKGROUND AND OBJECTIVES Genomics is moving rapidly into mainstream medicine through clinical genomic testing and consumer-initiated online DNA testing. The aim of this study was to identify Australian general practitioners' (GPs') views on genomics, impact on practice and educational needs to inform continuing education. METHOD Semi-structured interviews were conducted, with constant comparative inductive analysis and governance from a national taskforce. RESULTS Twenty-eight GPs (43% female) were interviewed; 71% worked in a metropolitan workplace. Most initially reported little experience with genetic/genomic tests but, when prompted, recognised encountering genomics, mainly non-invasive prenatal and single-gene tests. Many GPs referred patients for cancer screening to genetic services or specialists. GPs reported needing continuing education and resources, with preferences underpinned by relevance to practice. DISCUSSION GPs are integrating genomic testing into care, mainly through prenatal screening, and anticipate further impact. They want diverse and context-dependent education but are unaware of some available resources, such as The Royal Australian College of General Practitioners' Genomics in general practice guideline.

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., Graphical abstract

The clinical utility of rapid genomic sequencing (rGS) for critically unwell infants and children has been well demonstrated. Parental capacity for informed consent has been questioned, yet limited empirical data exists to guide clinical service delivery. In an Australian nationwide clinical implementation project offering rGS for critically unwell infants and children, parents made a decision about testing in under a day on average. This study reports parents’ experiences of decision making for rGS within this rapid timeframe to inform pre-test counselling procedures for future practice. A nationwide sample of 30 parents, whose children were amongst the first to receive rGS, were interviewed. We found that framing and delivery of rGS require careful consideration to support autonomous decision making and avoid implicit coercion in a stressful intensive care setting. Many parents described feeling ‘special’ and ‘lucky’ that they were receiving access to expensive and typically time-consuming genomic sequencing. Thematic analysis revealed a spectrum of complexity for decision making about rGS. Some parents consented quickly and were resistant to pre-test counselling. Others had a range of concerns and described deliberating about their decision, which they felt rushed to make. This research identifies tensions between the medical imperative of rGS and parents’ decision making, which need to be addressed as rGS becomes routine clinical care.

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.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.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.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).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.

Purpose: To evaluate the resource implications of different delivery models for the provision of additional findings (AF) in genomics from a health-care purchaser perspective. Methods: Data from the Additional Findings study were used to develop and validate a discrete event simulation model that represented the pathway of delivering AF. Resource implications were estimated by microcosting the consultations, sample verifications, bioinformatics, curation, and multidisciplinary case review meetings. A proof-of-concept model was used to generate costing, and then the simulation model was varied to assess the impact of an automated analysis pipeline, use of telehealth consultation, full automation with electronic decision support, and prioritizing case review for cases with pathogenic variants. Results: For the proof-of-concept delivery model, the average total cost to report AF was US$430 per patient irrespective of result pathogenicity (95% confidence interval [CI] US$375–US$489). However, the cost of per AF diagnosis was US$4349 (95% CI US$3794–US$4953). Alternative approaches to genetic counseling (telehealth, decision support materials) and to multidisciplinary case review (pathogenic AF cases only) lowered the total per patient cost of AF analysis and reporting by 41–51%. Conclusion: Resources required to provide AF can be reduced substantially by implementing alternative approaches to counseling and multidisciplinary case review.

Objective To foster implementation of genomic testing in medical care by providing a cadre of physicians with ‘hands on’ experience in genomics, positioning them as opinion leaders in their medical speciality. This paper presents qualitative evaluation of immediate outcomes, in particular its impact on peer interactions. Methods Program design and delivery was informed by implementation science, behavior change and experiential learning theories. Inductive content analysis of transcribed audio-recordings from semi-structured post-project interviews with all participants (n = 12) was conducted. Results Participants reported the immersion experience improved their genomic capability, established them as credible genomic experts within their speciality and altered their practice in genomic medicine. Participants reported strengthening and widening of peer-to-peer and interdisciplinary communication, with both passive diffusion and active dissemination of information to peers. Some also became a resource for genetic professionals. Conclusions Genomic immersion participants described elements which support sustained integration of an innovation, including immediate changes (e.g. use of genomic tests) and wider impacts (e.g. professional networks). Practice implications This study supports a role for immersion as a successful strategy for enhancing engagement of non-geneticist physicians in genomics. Additional study is needed to understand how immersion experiences change the delivery of genomic services at the provider, practice and health system level.

Purpose To determine the diagnostic yield and clinical impact of exome sequencing (ES) in patients with suspected monogenic kidney disease. Methods We performed clinically accredited singleton ES in a prospectively ascertained cohort of 204 patients assessed in multidisciplinary renal genetics clinics at four tertiary hospitals in Melbourne, Australia. Results ES identified a molecular diagnosis in 80 (39%) patients, encompassing 35 distinct genetic disorders. Younger age at presentation was independently associated with an ES diagnosis (p

Purpose Cost-effectiveness evaluations of first-line genomic sequencing (GS) in the diagnosis of children with genetic conditions are limited by the lack of well-defined comparative cohorts. We sought to evaluate the cost-effectiveness of early GS in pediatric patients with complex monogenic conditions compared with a matched historical cohort. Methods Data, including investigation costs, were collected in a prospective cohort of 92 pediatric patients undergoing singleton GS over an 18-month period (2016-2017) with two of the following: a condition with high mortality, multisystem disease involving three or more organs, or severe limitation of daily function. Comparative data were collected in a matched historical cohort who underwent traditional investigations in the years 2012-2013. Results GS yielded a diagnosis in 42% while traditional investigations yielded a diagnosis in 23% (p = 0.003). A change in management was experienced by 74% of patients diagnosed following GS, compared with 32% diagnosed following traditional investigations. Singleton GS at a cost of AU$3100 resulted in a mean saving per person of AU$3602 (95% confidence interval [CI] AU$2520-4685). Cost savings occurred across all investigation subtypes and were only minimally offset by clinical management costs. Conclusion GS in complex pediatric patients saves significant costs and doubles the diagnostic yield of traditional approaches.

usc Refereed/Peer-reviewed Purpose: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using clinically accessible specimens (blood, fibroblasts, urothelia, biopsy). Methods: A total of 74 families with diverse monogenic conditions (31% prenatal-congenital onset, 47% early childhood, and 22% teenage-adult onset) were triaged into PCR-based RNA testing, with comparative RNA sequencing for 19 cases. Results: Informative RNA assay data were obtained for 96% of cases, enabling variant reclassification for 75% variants that can be used for genetic counseling (71%), to inform clinical care (32%) and prenatal counseling (41%). Variant-associated mis-splicing was highly reproducible for 28 cases with samples from ≥2 affected individuals or heterozygotes and 10 cases with ≥2 biospecimens. PCR amplicons encompassing another segregated heterozygous variant was vital for clinical interpretation of 22 of 79 variants to phase RNA splicing events and discern complete from partial mis-splicing. Conclusion: RNA diagnostics enabled provision of a genetic diagnosis for 64% of recruited cases. PCR-based RNA diagnostics has capacity to analyze 81.3% of clinically significant genes, with long amplicons providing an advantage over RNA sequencing to phase RNA splicing events. The Australasian Consortium for RNA Diagnostics (SpliceACORD) provide clinically-endorsed, standardized protocols and recommendations for interpreting RNA assay data.

Purpose To investigate leadership in clinical genomics and identify likely implications of different leadership approaches for future implementation of clinical genomics. Methods We undertook 37 interviews in a cross-sectional qualitative study examining implementation of clinical genomics in Australia. Participants were either nongenetic medical specialists working with genomic initiatives (e.g., immunologists, nephrologists) or working at a service/organizational level (e.g., department heads, chief medical officers). We identified participants as genomic migrants (long-established practitioners) and genomic natives (those medical specialists coming into independent practice with genomic technology in situ). Data were analyzed deductively with reference to leadership approach. Results Leadership approaches were often blended or reported to iteratively support development of another. There was concern at both the absence or the excess of entrepreneurial leadership (i.e., risk-taking). Conclusion Entrepreneurial leadership is needed to promote innovativeness, risk-taking, and proactivity, essential in these early stages of clinical genomics. Shared decision-making is required from a wide range of clinicians, calling for both clinical and distributed leadership. Sharing leadership, and the potential loss of positional status from formal senior positions, may prove challenging to genomics “migrants,” who are essential for nurturing genomic “natives.” Clinicians will need support from their organizations and professional bodies to manage the transition.

Genomic newborn screening raises practical and ethical issues. Evidence is required to build a framework to introduce this technology safely and effectively. We investigated the choices made by a diverse group of parents with newborns when offered tiered genomic information from exome sequencing. This population-derived cohort comprised infants with congenital deafness. Parents were offered exome sequencing and choice regarding the scope of analysis. Options were choice A, diagnostic analysis only; choice B, diagnostic analysis plus childhood-onset diseases with medical actionability; or choice C, diagnostic analysis plus childhood-onset diseases with or without medical actionability. Of the 106 participants, 72 (68%) consented to receive additional findings with 29 (27.4%) selecting choice B and 43 (40.6%) opting for choice C. Family size, ethnicity, and age of infant at time of recruitment were the significant predictors of choice. Parents who opted to have additional findings analysis demonstrated less anxiety and decisional conflict. These data provide evidence from a culturally diverse population that choice around additional findings is important and the age of the infant when this choice is offered impacts on their decision. We found no evidence that offering different levels of genomic information to parents of newborns has a negative psychological impact.

Background: Personal genomic testing (PGT) offers individuals genetic information about relationships, wellness, sporting ability, and health. PGT is increasingly accessible online, including in emerging markets such as Australia. Little is known about what consumers expect from these tests and whether their reflections on testing resonate with bioethics concepts such as autonomy. Methods: We report findings from focus groups and semi-structured interviews that explored attitudes to and experiences of PGT. Focus group participants had little experience with PGT, while interview participants had undergone testing. Recordings were transcribed and analyzed using thematic analysis. Findings were critically interpreted with reference to bioethics scholarship on autonomy. Results: Fifty-six members of the public participated in seven focus groups, and 40 individuals were interviewed separately. Both groups valued the choice of PGT, and believed that it could motivate relevant actions. Focus group themes centered on the perceived value of choices, knowledge enabling action and knowledge about the self. Interview themes suggest that participants reflexively engage with their PGT information to make meaning, and that some appreciate its shortcomings. Critical interpretation of findings shows that while consumers of PGT are able to exercise a degree of autonomy in choosing, they may not be able to achieve a substantive conceptualization of autonomy, one that promotes alignment with higher-order desires. Conclusions: PGT consumers can critically reason about testing. However, they may uncritically accept test results, may not appreciate drawbacks of increased choice, or may overestimate the potential for information to motivate behavioral change. While consumers appear to be capable of substantive autonomy, they do so without ongoing support from companies. PGT companies promote a problematic (“default”) account of autonomy, reliant on empowerment rhetoric. This leaves consumers vulnerable to making decisions inconsistent with their higher-order desires. As PGT expands, claims about its power and value need to be carefully drawn.

Background The Melbourne Genomics Health Alliance (the Alliance) is a collaboration of leading hospitals, research and academic organisations, supported by its member organisations and the Victorian Government. The Alliance was set up by its members in 2013 to steer the translation of genomics, making it an integral part of health care in Victoria, Australia. The Community Advisory Group (CAG) was formed soon after, to give input and advice across the program. This was to ensure consideration of community values, perspectives and priorities, and knowledge translation for patient care. The CAG was charged with providing a strong community voice for the duration of the program. Appointed members were experienced consumer advocates with developed connections to the community. Main body The Alliance progressed from an initial Demonstration Project (2013–2015) to a multifaceted program (2016–2020). The CAG worked strategically to help address complex issues, for example, communication, privacy, informed consent, ethics, patient experience, measurement and evaluation standards and policies, data storage and re-use of genomic data. Many aspects of translating genomics into routine care have been tackled, such as communicating with patients invited to have genomic testing, or their caregivers, and obtaining informed consent, clinical questions across 16 areas of health care, training and education of health and laboratory professionals, genomic data management and data-sharing. Evidence generated around clinical utility and cost-effectiveness led to government funding of testing for complex genetic conditions in children. Conclusion The CAG activities, recorded in a CAG-inspired Activity register, span the full spectrum of information sharing and consultation to co-design and partnership. The CAG were involved at multiple levels of participation and in all tiers of activity including governance, development of policies and procedures, program planning and evaluation. Working relationships were built up and a level of trust instilled to advance the Alliance work program in ensuring an effective patient-care model of delivery of genomics. CAG input into project deliverables has been tangible. Less tangible contributions included presentations at external meetings and conferences, direct interactions at meetings with Alliance members, interactions with visitors and external experts, taking part in consultations with experts, state and federal government., Plain English summary Melbourne Genomics Health Alliance was established in 2013 to steer genomics into health care in Victoria, Australia. The Community Advisory Group (CAG) was formed soon after to provide advice and insights from the patient perspective. The CAG has added value to the Alliance’s complex research-to-clinical service program of work over eight years to date. Following an explanation of the program, the CAG members identified priority areas and mechanisms for their involvement. Areas that members were involved in included: communication, visual identity and website, patient portal and its evaluation, information management, consent processes, laboratory requirements, tools for patient experience and quality of life measures, predictive health issues study, storage and sharing of data, databases, CAG Communication Plan, the Patient Guide, role with Victorian Government Department of Health and Human Services, implementation plan, workshop to upskill patient advocates, financial and strategic planning. Members also presented on the role of the CAG at conferences and symposia. The balanced, trusting relationship that developed between the CAG, the Program Team and its governance structure was of great value to and an achievement for the Alliance. CAG input into project deliverables and impact was recorded in a CAG inspired Activity Register and has been very tangible. Their less tangible contribution to the project is also important. Contributions included presentations at external meetings, direct interactions at annual meetings with Alliance members, interactions with visitors and external experts, taking part in consultations with experts, state and federal government. These provided opportunities to influence mindsets.

Despite the plethora of empirical studies conducted to date, debate continues about whether and to what extent results should be returned to participants of genomic research. We aimed to systematically review the empirical literature exploring stakeholders' perspectives on return of individual research results (IRR) from genomic research. We examined preferences for receiving or willingness to return IRR, and experiences with either receiving or returning them. The systematic searches were conducted across five major databases in August 2018 and repeated in April 2020, and included studies reporting findings from primary research regardless of method (quantitative, qualitative, mixed). Articles that related to the clinical setting were excluded. Our search identified 221 articles that met our search criteria. This included 118 quantitative, 69 qualitative and 34 mixed methods studies. These articles included a total number of 118,874 stakeholders with research participants (85,270/72%) and members of the general public (40,967/35%) being the largest groups represented. The articles spanned at least 22 different countries with most (144/65%) being from the USA. Most (76%) discussed clinical research projects, rather than biobanks. More than half (58%) gauged views that were hypothetical. We found overwhelming evidence of high interest in return of IRR from potential and actual genomic research participants. There is also a general willingness to provide such results by researchers and health professionals, although they tend to adopt a more cautious stance. While all results are desired to some degree, those that have the potential to change clinical management are generally prioritized by all stakeholders. Professional stakeholders appear more willing to return results that are reliable and clinically relevant than those that are less reliable and lack clinical relevance. The lack of evidence for significant enduring psychological harm and the clear benefits to some research participants suggest that researchers should be returning actionable IRRs to participants. ispartof: PLOS ONE vol:16 issue:11 ispartof: location:United States status: published

This study aimed to assess the extent to which structured approaches to implementation of clinical genomics, proposed or adapted, are informed by evidence.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?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.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.

BACKGROUNDThe complexity of clinical genomics – testing your entire genetic information for health benefit – is a rapidly evolving field demanding swift clinical practice change at multiple levels as widespread testing in healthcare becomes a reality. We aimed to a) describe a combined stakeholder- and evidence-driven approach to developing a toolkit for implementing genomics into the Australian health system, and b) hypothesise key steps in the change to Theoretical Domains Framework (TDF) domains via coded implementation strategies and associated mechanistic links. METHODSThe TDF was used to analyse interview data from 16 nongenetic medical specialists using genomics in practice. Barriers and enablers were identified for three key target behaviour areas across the genomic testing process: 1) identifying patients, 2) test ordering/reporting, and 3) providing results. Barriers were grouped by distinct TDF domains, and, where barriers overlapped, ‘overarching’ domains were identified. Intuitive enabling strategies generated by clinicians were aligned with identified barriers, and retrospectively coded against evidence-based behaviour change techniques (BCTs). Additional theory-driven strategies were developed to address remaining identified barriers. Using structured expert consensus processes, members of the research team participated in a series of workshops to discuss and agree theory-informed links and propose mechanisms through which specific implementation strategies would address TDF-based barriers.RESULTSA total of 32 barriers were coded against TDF domains and constructs, and eight overarching TDF domains were identified on 13 occasions. Across all target behaviour areas, 21 BCTs were represented within the 30 intuitive enabling strategies generated by clinicians, found to be used on 49 occasions. Of these, nine (18%) aligned with a corresponding distinct TDF domain coded barrier that has previously demonstrated statistically significant mechanistic links. 20 new implementation strategies were developed to address nine remaining barriers using a theory-driven approach.CONCLUSIONThis study provides rich detail of crucial stages in intervention development, aiming to ensure implementation strategies are both evidence-informed and contextually appropriate. All barriers were mapped to the TDF, implementation strategies coded against BCTs, and standardised hypothesised behavioural pathways have been proposed, making potential underlying theory explicit. Next steps will be to test toolkit effectiveness for facilitating scale-up of genomics across Australia.

PurposeClinical genomics is a complex, innovative medical speciality requiring clinical and organizational engagement to fulfil the clinical reward promised to date. Focus thus far has been on gene discovery and clinicians’ perspectives. The purpose of this study was to use implementation science theory to identify organizational barriers and enablers to implementation of clinical genomics along an organizations’ implementation journey from Preadoption through to Adoption and Implementation.Design/methodology/approachWe used a deductive qualitative approach study design drawing on implementation science theory - (1) Translation Science to Population Impact Framework, to inform semi structured interviews with organizational decision-makers collaborating with Australian and Melbourne Genomics, alongside and (2) Theoretical Domains Framework (TDF), to guide data analysis.FindingsWe identified evolving organizational barriers across the implementation journey from Preadoption to Implementation. Initially the organizational focus is on understanding the value of clinical genomics (TDF code: belief about consequences) and setting the scene (TDF code: goals) before organizational (TDF codes: knowledge and belief about consequences) and clinician (TDF codes: belief about capability and intentions) willingness to adopt is apparent. Once at the stage of Implementation, leadership and clarity in organizational priorities (TDF codes: intentions, professional identity and emotion) that include clinical genomics are essential prerequisites to implementing clinical genomics in practice. Intuitive enablers were identified (e.g. ‘providing multiple opportunities for people to come on board) and mapped hypothetically to barriers.Originality/valueAttention to date has centred on the barriers facing clinicians when introducing clinical genomics into practice. This paper uses a combination of implementation science theories to begin to unravel the organizational perspectives of implementing this complex health intervention.

PURPOSE: Widespread, quality genomics education for health professionals is required to create a competent genomic workforce. A lack of standards for reporting genomics education and evaluation limits the evidence base for replication and comparison. We therefore undertook a consensus process to develop a recommended minimum set of information to support consistent reporting of design, development, delivery, and evaluation of genomics education interventions.METHODS: Draft standards were derived from literature (25 items from 21 publications). Thirty-six international experts were purposively recruited for three rounds of a modified Delphi process to reach consensus on relevance, clarity, comprehensiveness, utility, and design.RESULTS: The final standards include 18 items relating to development and delivery of genomics education interventions, 12 relating to evaluation, and 1 on stakeholder engagement.CONCLUSION: These Reporting Item Standards for Education and its Evaluation in Genomics (RISE2 Genomics) are intended to be widely applicable across settings and health professions. Their use by those involved in reporting genomics education interventions and evaluation, as well as adoption by journals and policy makers as the expected standard, will support greater transparency, consistency, and comprehensiveness of reporting. Consequently, the genomics education evidence base will be more robust, enabling high-quality education and evaluation across diverse settings.

Background Consumer genomic testing for nutrition and wellness, (nutritional genomics), is becoming increasingly popular. Concurrently, health‐care practitioners (HPs) working in private practice (including doctors interested in integrative medicine, private genetic counsellors, pharmacists, dieticians, naturopaths and nutritionists) are involved as test facilitators or interpreters. Objective To explore Australian consumers’ and HPs’ experiences with nutrigenomic testing. Method Semi‐structured in‐depth interviews were conducted using predominantly purposive sampling. The two data sets were analysed individually, then combined, using a constant comparative, thematic approach. Results Overall, 45 interviews were conducted with consumers (n = 18) and HPs (n = 27). Many of the consumer interviewees experienced chronic ill‐health. Nutrigenomic testing was perceived as empowering and a source of hope for answers. While most made changes to their diet/supplements post‐test, self‐reported health improvements were small. A positive relationship with their HP appeared to minimize disappointment. HPs’ adoption and views of nutrigenomic testing varied. Those enthusiastic about testing saw the possibilities it could offer. However, many felt nutrigenomic testing was not the only ‘tool’ to utilize when offering health care. Discussion This research highlights the important role HPs play in consumers’ experiences of nutrigenomics. The varied practice suggests relevant HPs require upskilling in this area to at least support their patients/clients, even if nutrigenomic testing is not part of their practice. Patient or public contribution Advisory group included patient/public group representatives who informed study design; focus group participants gave feedback on the survey from which consumer interviewees were sourced. This informed the HP data set design. Interviewees from HP data set assisted with snowball sampling.

We aimed to determine capacity and readiness of Australian clinical genetic healthcare professionals to provide genomic medicine. An online survey was administered to individuals with genetic counseling or clinical genetics qualifications in Australia. Data collected included: education, certification, continuing professional development (CPD), employment, and genetic versus genomic clinical practice. Of the estimated 630 clinical genetic healthcare professionals in Australia, 354 completed the survey (56.2% response rate). Explanatory interviews were conducted with 5.5% of the genetic counselor respondents. Those working clinically reported being involved in aspects of whole exome or genome sequencing (48.6% genetic counselors, 88.6% clinical geneticists). Most genetic counselors (74.2%) and clinical geneticists (87.0%) had attended genomics CPD in the last two years, with 61.0% and 39.1% self-funding, respectively. Genetic counselors desire broad involvement in genomics, including understanding classifying and interpreting results to better counsel patients. The majority of respondents (89.9%) were satisfied with their job and 91.6% planned to work in genetics until retirement. However, 14.1% of the genetic counselors in clinical roles and 24.6% of the clinical geneticists planned to retire within 10 years. This is the first national audit of clinical genetic healthcare professionals, revealing the Australian workforce is motivated and prepared to embrace new models to deliver genomic medicine but consideration of education and training is required to meet demand.

The original PDF version of this Article omitted to list Clara L Gaff as a corresponding author and the affiliations were incorrectly labelled as Present Addresses. Furthermore, Tables 1 and 2 have been updated to clarify that the Australian dollar is used for the values. These errors have now been corrected in the PDF and HTML versions of the Article.

The purpose of the study was to implement and prospectively evaluate the outcomes of a rapid genomic diagnosis program at two pediatric tertiary centers. Rapid singleton whole-exome sequencing (rWES) was performed in acutely unwell pediatric patients with suspected monogenic disorders. Laboratory and clinical barriers to implementation were addressed through continuous multidisciplinary review of process parameters. Diagnostic and clinical utility and cost-effectiveness of rWES were assessed. Of 40 enrolled patients, 21 (52.5%) received a diagnosis, with median time to report of 16 days (range 9–109 days). A result was provided during the first hospital admission in 28 of 36 inpatients (78%). Clinical management changed in 12 of the 21 diagnosed patients (57%), including the provision of lifesaving treatment, avoidance of invasive biopsies, and palliative care guidance. The cost per diagnosis was AU$13,388 (US$10,453). Additional cost savings from avoidance of planned tests and procedures and reduced length of stay are estimated to be around AU$543,178 (US$424,101). The clear relative advantage of rWES, joint clinical and laboratory leadership, and the creation of a multidisciplinary “rapid team” were key to successful implementation. Rapid genomic testing in acute pediatrics is not only feasible but also cost-effective, and has high diagnostic and clinical utility. It requires a whole-of-system approach for successful implementation.

Introduction: Clinical genomics, reading a person’s entire genetic material for healthcare benefit, is a complex transformative approach to patient care offering the potential for diagnosis and changes in treatment plans for patient groups who have few conventional diagnostic and treatment options available. However, the promise of this new technology can only be delivered with the close interaction of a range of scientists and healthcare practitioners. This cross-discipline collegial expectation is challenged by the speed at which the field of genomics is evolving, with new discoveries and technological advances unbalancing the delicately emerging status quo. To identify the challenges and benefits of team working for clinical genomics, we drew on three qualitative datasets to investigate how these professional groups manage the necessity of integrated working to maximise clinical outcomes. Theory/method: Interviews examining the determinants of implementation and improvement of clinical genomics were undertaken in 2018/19 with laboratory scientists, genetic and other medical specialists’ (n=56). Group 1 interviews provided in depth findings of the experience from identifying patients for whom this test is appropriate to communicating results back to patients; Group 2 interviews explored the relationship between the laboratory and the genetic clinician; Group 3 interviews focused on perceptions from one clinical area (acutely unwell children). Interviews were audio recorded with participants’ permission, fully transcribed and managed in NVivo 12. We used the Framework approach (Ritchie & Lewis, 2003) to analyse all three datasets to identify themes of integrated teamworking in an evolving sociotechnical healthcare context. Results:Three themes were identified; i) Knowledge: e.g. the capacity to cope with the speed of evolving knowledge and the importance of external links for knowledge development, ii) Professional Identity: e.g. the ability to recognise and value the skills of others and ‘stepping up’ as needed, and finally iii) Team Dynamics: e.g. the importance of external representation and managing the ‘emotional load’. Discussion: For integrated teams in a new disruptive healthcare discipline, Knowledge, Professional Identity and Team Dynamics all play a vital role in establishing, maintaining and progressing the functioning of the team. Inter-theme contribution occurs to promote teamworking that serves to improve patient care. Conclusion: As scientific technology progresses, and plays an increasing role in healthcare, it is essential we understand how teams straddling the scientist/clinical divide negotiate the interaction of Knowledge, Professional Identity and Team Dynamics. Learnings from the experience in clinical genomics can be used in other emerging technologies to maximise the experience for team members and clinical benefit for patients. Lessons:Understanding how the themes of Knowledge, Professional Identity and Team Dynamics interact is essential to facilitate teamworking in novel sociotechnical healthcare fields. Using evidence-based approaches to promote theme-related concepts may act to support the functioning of teams. Lmitations: These data were gathered from three different datasets focused on implementation/improvement. Further study is required in this field to explore how the three key themes interact longitudinally as knowledge progresses. Future research also needs to focus on how more recently emerging professions (such as bioinformaticians and genetic counsellors) establish their role in these dynamic teams.

Despite the overwhelming interest in clinical genomics, uptake has been slow. Implementation science offers a systematic approach to reveal pathways to adoption and a theory informed approach to addressing barriers presented. Using case study methodology, we undertook 16 in-depth interviews with nongenetic medical specialists to identify barriers and enablers to the uptake of clinical genomics. Data collection and analysis was guided by two evidence-based behaviour change models: the Theoretical Domains Framework (TDF), and the Capability, Opportunity Motivation Behaviour model (COM-B). Our findings revealed the use of implementation science not only provided a theoretical structure to frame the study but also facilitated uncovering of traditionally difficult to access responses from participants, e.g., “safety in feeling vulnerable” (TDF code emotion/COM-B code motivation). The most challenging phase for participants was ensuring appropriate patients were offered genomic testing. There were several consistent TDF codes: professional identity, social influences, and environmental context and resources and COM-B codes opportunity and motivation, with others varying along the patient journey. We conclude that implementation science methods can maximise the value created by the exploration of factors affecting the uptake of clinical genomics to ensure future interventions are designed to meet the needs of novice nongenetic medical specialists.

Currently there is no secured ongoing funding in Australia for next generation sequencing (NGS) such as exome sequencing (ES) for adult neurological disorders. Studies have focused on paediatric populations in research or highly specialised settings, utilised standard NGS pipelines focusing only on small insertions, deletions and single nucleotide variants, and not explored impacts on management in detail. This prospective multi-site study performed ES and an extended bioinformatics repeat expansion analysis pipeline, on patients with broad phenotypes (ataxia, dementia, dystonia, spastic paraparesis, motor neuron disease, Parkinson's disease and complex/not-otherwise-specified), with symptom onset between 2 and 60 years. Genomic data analysis was phenotype-driven, using virtual gene panels, reported according to American College of Medical Genetics and Genomics guidelines. One-hundred-and-sixty patients (51% female) were included, median age 52 years (range 14-79) and median 9 years of symptoms. 34/160 (21%) patients received a genetic diagnosis. Highest diagnostic rates were in spastic paraparesis (10/25, 40%), complex/not-otherwise-specified (10/38, 26%) and ataxia (7/28, 25%) groups. Findings were considered 'possible/uncertain' in 21/160 patients. Repeat expansion detection identified an unexpected diagnosis of Huntington disease in an ataxic patient with negative ES. Impacts on management, such as more precise and tailored care, were seen in most diagnosed patients (23/34, 68%). ES and a novel bioinformatics analysis pipepline had a substantial diagnostic yield (21%) and management impacts for most diagnosed patients, in heterogeneous, complex, mainly adult-onset neurological disorders in real-world settings in Australia, providing evidence for NGS and complementary multiple, new technologies as valuable diagnostic tools.