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.

A national education program for rapid genomics in pediatric acute care: Building workforce confidence, competence, and capability.

PURPOSE: To develop and evaluate a scalable national program to build confidence, competence and capability in the use of rapid genomic testing (rGT) in the acute pediatric setting. METHODS: We used theory-informed approaches to design a modular, adaptive program of blended learning aimed at diverse professional groups involved in acute pediatric care. The program comprised 4 online learning modules and an online workshop and was centered on case-based learning. We evaluated the program using the Kirkpatrick 4-level model of training evaluation and report our findings using the Reporting Item Standards for Education and its Evaluation (RISE2) guidelines for genomics education and evaluation. RESULTS: Two hundred and two participants engaged with at least 1 component of the program. Participants self-reported increased confidence in using rGT, (P < .001), and quiz responses objectively demonstrated increased competence (eg, correct responses to a question on pretest counseling increased from 30% to 64%; P < .001). Additionally, their capability in applying genomic principles to simulated clinical cases increased (P < .001), as did their desire to take on more responsibility for performing rGT. The clinical interpretation of more complex test results (such as negative results or variants of uncertain significance) appeared to be more challenging, indicating a need for targeted education in this area. CONCLUSION: The program format was effective in delivering multidisciplinary and wide-scale genomics education in the acute care context. The modular approach we have developed now lends itself to application in other medical specialties or areas of health care.

Australian Genomics: A Federated Model for Integrating Genomics into Healthcare.

Australian Genomics is a national collaborative research partnership of more than 80 organizations piloting a whole-of-system approach to integrating genomics into healthcare that is based on federation principles. The aim of Australian Genomics is to assess the application of genomic testing in healthcare at the translational interface between research and clinical delivery, with an emphasis on robust evaluation of outcomes. It encompasses two bodies of work: a research program prospectively providing genomic testing through exemplar clinical projects in rare diseases, cancers, and reproductive carrier screening and interdependent programs for advancing the diagnostic, health informatics, regulatory, ethical, policy, and workforce infrastructure necessary for the integration of genomics into the Australian health system.

Rapid acute care genomics: Challenges and opportunities for genetic counselors.

Genomic medicine in pediatric acute care is showing great promise, with rapid results from exome and genome sequencing returned within days providing critically important information for treatment and management of seriously ill children. Many have suggested that rapid acute care genomics presents novel genetic counseling issues. This is due to the need for rapid response to referrals, the immense emotional distress that parents are likely to experience when their child is in acute care, and the unfamiliar environment of the acute care setting. To explore the practice of genetic counselors in this setting, we conducted qualitative interviews with 16 genetic counselors (GCs), representing a large proportion of GCs at the frontline of providing genetic counseling in acute care settings in Australia. Interviews revealed themes describing genetic counseling in acute care, including practical challenges of counseling within a rapid turnaround time, similarities with other contexts such as prenatal counseling, and the need for education of other health professionals. Interestingly, GCs did not raise concerns in the interviews for parents' ability to provide informed consent for rapid genomic sequencing. GCs also encountered practical and organizational challenges with counseling in this setting where 24-hr care is provided, at odds with traditional '9 to 5' Genetics service delivery. Working closely in a multidisciplinary team was common and participants believed that GCs are well positioned to take a leading role in the education of other health professionals as rapid acute care genomics becomes routine clinical practice. Despite views that genetic counseling practice in rapid acute care genomics is unique, these exploratory data suggest that GCs are flexible, adaptable, and sufficiently skilled to deliver patient-centered counseling in this setting. Our work indicates GCs are ready and willing to contribute at an early stage of adoption of genomic investigations in acute care.

Does genomic sequencing early in the diagnostic trajectory make a difference? A follow-up study of clinical outcomes and cost-effectiveness.

PURPOSE: To systematically investigate the longer-term clinical and health economic impacts of genomic sequencing for rare-disease diagnoses. METHODS: We collected information on continuing diagnostic investigation, changes in management, cascade testing, and parental reproductive outcomes in 80 infants who underwent singleton whole-exome sequencing (WES). RESULTS: The median duration of follow-up following result disclosure was 473 days. Changes in clinical management due to diagnostic WES results led to a cost saving of AU$1,578 per quality-adjusted life year gained, without increased hospital service use. Uninformative WES results contributed to the diagnosis of non-Mendelian conditions in seven infants. Further usual diagnostic investigations in those with ongoing suspicion of a genetic condition yielded no new diagnoses, while WES data reanalysis yielded four. Reanalysis at 18 months was more cost-effective than every 6 months. The parents of diagnosed children had eight more ongoing pregnancies than those without a diagnosis. Taking the costs and benefits of cascade testing and reproductive service use into account, there was an additional cost of AU$8,118 per quality-adjusted life year gained due to genomic sequencing. CONCLUSION: These data strengthen the case for the early use of genomic testing in the diagnostic trajectory, and can guide laboratory policy on periodic WES data reanalysis.

Correction: Does genomic sequencing early in the diagnostic trajectory make a difference? A follow-up study of clinical outcomes and cost-effectiveness.

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.

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.

Meeting the challenges of implementing rapid genomic testing in acute pediatric care.

PURPOSE: The purpose of the study was to implement and prospectively evaluate the outcomes of a rapid genomic diagnosis program at two pediatric tertiary centers. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Improving family communication after a new genetic diagnosis: a randomised controlled trial of a genetic counselling intervention.

BACKGROUND: Genetic information given to an individual newly diagnosed with a genetic condition is likely to have important health implications for other family members. The task of communicating with these relatives commonly falls to the newly diagnosed person. Talking to relatives about genetic information can be challenging and is influenced by many factors including family dynamics. Research shows that many relatives remain unaware of relevant genetic information and the possible impact on their own health. This study aims to evaluate whether a specific genetic counselling intervention for people newly diagnosed with a genetic condition, implemented over the telephone on a number of occasions, could increase the number of at-risk relatives who make contact with genetics services after a new genetic diagnosis within a family. METHODS: This is a prospective, multi-centre randomised controlled trial being conducted at genetics clinics at five public hospitals in Victoria, Australia. A complex genetic counselling intervention has been developed specifically for this trial. Probands (the first person in a family to present with a diagnosis of a genetic condition) are being recruited and randomised into one of two arms - the telephone genetic counselling intervention arm and the control arm receiving usual care. The number of at-risk relatives for each proband will be estimated from a family pedigree collected at the time of diagnosis. The primary outcome will be measured by comparing the proportion of at-risk relatives in each arm of the trial who make subsequent contact with genetics services. DISCUSSION: This study, the first randomised controlled trial of a complex genetic counselling intervention to enhance family communication, will provide evidence about how best to assist probands to communicate important new genetic information to their at-risk relatives. This will inform genetic counselling practice in the context of future genomic testing. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ANZCTRN12608000642381.

Prenatal ß-thalassemia carrier screening in Australia: healthcare professionals' perspectives of clinical practice.

OBJECTIVE: To gain a better understanding of healthcare professionals' practice and attitudes regarding prenatal ß-thalassemia carrier screening in Australia. METHOD: Qualitative study with semi-structured interviews of healthcare professionals (obstetricians, general practitioners, midwives, genetic counselors, and hematologists) involved in prenatal thalassemia carrier screening in public and private practice. RESULTS: Twenty-three healthcare providers were interviewed and several themes emerged. Participants described and acknowledged inconsistencies in the ß-thalassemia screening processes, such as variability in ordering the tests, communicating the diagnosis, and action taken after diagnosis. They indicated a preference for more structure and valued the importance of screening guidelines but many of those involved in ordering the screening test were unaware of their availability. These healthcare professionals recognized they lacked knowledge regarding the screening process, and many had not undertaken education activities in this area in recent times. There were mixed views about the consent process, particularly at which stage this should be obtained, and what information is provided. CONCLUSIONS: ß-thalassemia screening in Victoria occurs with apparent lack of awareness of guidelines and an acknowledged preference for a more systematic process and educational support. Informed consent was not considered an important component of this screening process.

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.

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.

Clinicians' Views and Experiences with Offering and Returning Results from Exome Sequencing to Parents of Infants with Hearing Loss.

Exome sequencing (ES) is an effective method for identifying the genetic cause of hearing loss in infants diagnosed through newborn hearing screening programs. ES has the potential to be integrated into routine clinical care, yet little is known about the experiences of clinicians offering this test to families. To address this gap, clinicians involved in a clinical study using ES to identify the cause of infants' hearing loss were interviewed to explore their experiences with offering and returning results to parents. Interview transcripts were analysed using inductive content analysis. Twelve clinicians participated: seven genetic counsellors, four clinical geneticists, and one paediatrician. Most clinicians were supportive of offering ES to infants with hearing loss, primarily because results may inform the child's clinical management. However, some expressed concerns, questioning the utility of this information, particularly for isolated hearing loss. Clinicians had differing views regarding the optimal time to offer ES to families; while some felt that families can manage everything at once, others recommended delaying testing until parents have come to terms with their child's diagnosis. These findings show the complexity involved in determining how ES should be offered to families following the diagnosis of a child with hearing loss, particularly with regards to when testing is suggested.

Parents' experiences of decision making for rapid genomic sequencing in intensive care.

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.

Making community voices heard in a research-health service alliance, the evolving role of the Community Advisory Group: a case study from the members' perspective.

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.

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.

Engaged genomic science produces better and fairer outcomes: an engagement framework for engaging and involving participants, patients and publics in genomics research and healthcare implementation.

Genomic science is increasingly central to the provision of health care. Producing and applying robust genomics knowledge is a complex endeavour in which no single individual, profession, discipline or community holds all the answers.  Engagement and involvement of diverse stakeholders can support alignment of societal and scientific interests, understandings and perspectives and promises better science and fairer outcomes. In this context we argue for F.A.I.R.E.R. data and data use that is Findable, Accessible, Interoperable, Reproducible, Equitable and Responsible. Yet there is a paucity of international guidance on how to engage publics, patients and participants in genomics. To support meaningful and effective engagement and involvement we developed an Engagement Framework for involving and engaging participants, patients and publics in genomics research and health implementation. The Engagement Framework is intended to support all those working in genomics research, medicine, and healthcare to deliberatively consider approaches to participant, patient and public engagement and involvement in their work. Through a series of questions, the Engagement Framework prompts new ways of thinking about the aims and purposes of engagement, and support reflection on the strengths, limitations, likely outcomes and impacts of choosing different approaches to engagement. To guide genomics activities, we describe four themes and associated questions for deliberative reflection: (i) fairness; (ii) context; (iii) heterogeneity, and (iv) recognising tensions and conflict. The four key components in the Engagement provide a framework to assist those involved in genomics to reflect on decisions they make for their initiatives, including the strategies selected, the participant, patient and public stakeholders engaged, and the anticipated goals. The Engagement Framework is one step in an actively evolving process of building genomics research and implementation cultures which foster responsible leadership and are attentive to objectives which increase equality, diversity and inclusion in participation and outcomes.

Preparing Medical Specialists for Genomic Medicine: Continuing Education Should Include Opportunities for Experiential Learning.

With the demand for genomic investigations increasing, medical specialists will need to, and are beginning to, practice genomic medicine. The need for medical specialists from diverse specialties to be ready to appropriately practice genomic medicine is widely recognised, but existing studies focus on single specialties or clinical settings. We explored continuing education needs in genomic medicine of a wide range of medical specialists (excluding genetic specialists) from across Australia. Interviews were conducted with 86 medical specialists in Australia from diverse medical specialties. Inductive content analysis categorized participants by career stage and genomics experience. Themes related to education needs were identified through constant comparison and discussion between authors of emerging concepts. Our findings show that participants believe that experiential learning in genomic medicine is necessary to develop the confidence and skills needed for clinical care. The main themes reported are: tailoring of education to the specialty and the individual; peer interactions contextualizes knowledge; experience will aid in developing confidence and skills. In fact, avenues of gaining experience may result in increased engagement with continuing education in genomic medicine as specialists are exposed to relevant applications in their clinical practice. Participants affirmed the need for continuing education in genomic medicine but identified that it would need to be tailored to the specialty and the individual: one size does not fit all, so a multifaceted approached is needed. Participants infrequently attended formal continuing education in genomic medicine. More commonly, they reported experiential learning by observation, case-review or interacting with a "genomics champion" in their specialty, which contextualized their knowledge. Medical specialists anticipate that genomic medicine will become part of their practice which could lessen demand on the specialist genetic workforce. They expect to look to experts within their own medical specialty who have gained genomics expertise for specific and contextualized support as they develop the skills and confidence to practice genomic medicine. These findings highlight the need to include opportunities for experiential learning in continuing education. Concepts identified in these interviews can be tested with a larger sample of medical specialists to ascertain representativeness.

Attendance of men at the familial cancer clinic: what they value from the consultation.

PURPOSE: This study examined what men from high-risk breast/ovarian cancer families valued from attending a familial cancer clinic. METHODS: One hundred men from families with a BRCA1 or BRCA2 mutation completed a self-administered questionnaire. RESULTS: Seventy- two percent (72%) of men attended the familial cancer clinic at the request of a family member. Multivariate analyses showed that men with a preference for a collaborative decision-making style (B = -4.651, 95% CI = -9.014 to -0.289, P = 0.04), those with lower levels of education (B = -4.850, 95% CI = -9.16 to -0.537, P = 0.03), and those with higher levels of cancer-related anxiety (intrusion) (B = 0.920, 95% CI = 0.441-1.399, P < 0.001) were more likely to value emotional support from the clinic. Men with a collaborative decision-making style (B = -2.68, 95% CI = -4.91 to -0.467, P = 0.02) were less likely, and those with higher total levels of cancer-related anxiety (intrusion and avoidance) (B = 0.393, 95% CI = 0.008-0.779, P = 0.04) were more likely to value receiving information from the clinic. CONCLUSIONS: A preference for collaborative decision making and cancer-related anxiety predicted men valuing information and emotional support from the consultation. The finding that men's attendance is initiated by family members highlights the value men place on family responsibility.

Attitudes of Australian health professionals towards rapid genomic testing in neonatal and paediatric intensive care.

We investigated the attitudes of intensive care physicians and genetics professionals towards rapid genomic testing in neonatal and paediatric intensive care units (NICU/PICU). A mixed-methods study (surveys and interviews) was conducted at 13 Australian hospitals and three laboratories involved in multi-center implementation of rapid genomic testing. We investigated experience and confidence with genomic tests among intensivists; perceived usefulness of genomic diagnostic results; preferences for service delivery models; and implementation readiness among genetic services. The overall survey response rate was 59%, 47% for intensivists (80/170), and 75% (91/121) for genetics professionals. Intensivists reported moderate confidence with microarray tests and lower confidence with genomic tests. The majority of intensivists (77%), clinical geneticists (87%) and genetic counsellors (82%) favoured a clinical genetics-led service delivery model of genomic testing. Perceived clinical utility of genomic results was lower in the intensivist group compared to the genetics professionals group (20 v 50%, p < 0.001). Interviews (n = 6 intensivists; n = 11 genetic counselors) demonstrated support for implementation, with concerns relating to implementation environment and organizational readiness. Overall, our findings support initial implementation of genomic testing in NICU/PICU as part of an interdisciplinary service delivery model that promotes gradual adoption of genomics by the intensive care workforce while ensuring safety, sustainability, and efficiency.

A head-to-head evaluation of the diagnostic efficacy and costs of trio versus singleton exome sequencing analysis.

Diagnostic exome sequencing (ES) can be performed on the proband only (singleton; sES) or with additional samples, often including both biological parents with the proband (trio; tES). In this study we sought to compare the efficiencies of exome sequencing (ES) by trio (tES) versus singleton (sES) approach, determine costs, and identify factors to consider when deciding on optimal implementation strategies for the diagnosis of monogenic disorders. We undertook ES in 30 trios and analysed each proband's sES and tES data in parallel. Two teams were randomly allocated to either sES or tES analysis for each case and blinded to each other's work. Each task was timed and cost analyses were based on time taken and diagnostic yield. We modelled three scenarios to determine the factors to consider in the implementation of tES. sES diagnosed 11/30 (36.7%) cases and tES identified one additional diagnosis (12/30 (40.0%)). tES obviated the need for Sanger segregation, reduced the number of variants for curation, and had lower cost-per-diagnosis when considering analysis alone. When sequencing costs were included, tES nearly doubled the cost of sES. Reflexing to tES in those who remain undiagnosed after sES was cost-saving over tES in all as first-line. This approach requires a large differential in diagnostic yield between sES and tES for maximal benefit given current sequencing costs. tES may be preferable when scaling up laboratory throughput due to efficiency gains and opportunity cost considerations. Our findings are relevant to clinicians, laboratories and health services considering tES over sES.