Real-world diagnostic outcomes and cost-effectiveness of genome-wide sequencing for developmental and seizure disorders: Evidence from Canada.

PURPOSE: To determine real-world diagnostic rates, cost trajectories, and cost-effectiveness of exome sequencing (ES) and genome sequencing (GS) for children with developmental and/or seizure disorders in British Columbia, Canada. METHODS: Based on medical records review, we estimated real-world costs and outcomes for 491 patients who underwent standard of care (SOC) diagnostic testing at British Columbia Children's Hospital. Results informed a state-transition Markov model examining cost-effectiveness of 3 competing diagnostic strategies: (1) SOC with last-tier access to ES, (2) streamlined ES access, and (3) first-tier GS. RESULTS: Through SOC, 49.4% (95% CI: 40.6, 58.2) of patients were diagnosed at an average cost of C$11,683 per patient (95% CI: 9200, 14,166). Compared with SOC, earlier ES or GS access yielded similar or improved diagnostic rates and shorter times to genetic diagnosis, with 94% of simulations demonstrating cost savings for streamlined ES and 60% for first-tier GS. Net benefit from the perspective of the health care system was C$2956 (95% CI: -608, 6519) for streamlined ES compared with SOC. CONCLUSION: Using real-world data, we found earlier access to ES may yield more rapid genetic diagnosis of childhood developmental and seizure disorders and cost savings compared with current practice in a Canadian health care system.

Frameworks for Health Technology Assessment at an Early Stage of Product Development: A Review and Roadmap to Guide Applications.

OBJECTIVES: Early health technology assessment (eHTA) can be used to evaluate and optimize a medical product's value proposition and to inform go/no-go decisions by using health economic modeling, literature scanning, and stakeholder preference studies at an early stage of development. eHTA frameworks offer high-level guidance on conducting this complex, iterative, and multidisciplinary process. The objective of this study was to review and summarize existing eHTA frameworks, understood as systematic approaches to guide early evidence generation and decision making. METHODS: Using a rapid review methodology, we identified all relevant studies published in English, French, and Spanish from PubMed/MEDLINE and Embase until February 2022. We only included frameworks relevant to the preclinical and early clinical (phase I) stages of medical product development. RESULTS: From 737 reviewed abstracts, 53 publications describing 46 frameworks were selected for inclusion and classified into categories based on their scope: (1) criteria frameworks, which provide an overview of eHTA; (2) process frameworks, which offer stepwise guidance for conducting eHTA, including preferred methods; and (3) methods frameworks, which provide detailed descriptions of specific eHTA methods. Most of the frameworks did not specify their target users or the specific stage of technology development. CONCLUSIONS: Despite some variability and gaps found across existing frameworks, the structure provided by this review helps inform eHTA applications. Remaining challenges are the frameworks' limited accessibility to users without a background in health economics, poor distinctions being made among early lifecycle stages and technology types, and the inconsistent terminology used to describe eHTA in different contexts.

A Rapid Review on the Value of Biobanks Containing Genetic Information.

OBJECTIVES: Increasing access to health data through biobanks containing genetic information has the potential to expand the knowledge base and thereby improve screening, diagnosis, and treatment options for many diseases. Nevertheless, although privacy concerns and risks surrounding genetic data sharing are well documented, direct evidence in favor of the hypothesized benefits of data integration is scarce, which complicates decision making in this area. Therefore, the objective of this study is to summarize the available evidence on the research and clinical impacts of biobanks containing genetic information, so as to better understand how to quantify the value of expanding genomic data access. METHODS: Using a rapid review methodology, we performed a search of MEDLINE/PubMed and Embase databases; and websites of biobanks and genomic initiatives published from 2010 to 2022. We classified findings into 11 indicators including outputs (a direct product of the biobank activities) and outcomes (changes in scientific and clinical capacity). RESULTS: Of 8479 abstracts and 101 gray literature sources were reviewed, 96 records were included. Although most records did not report key indicators systematically, the available evidence concentrated on research indicators such as publications and gene-disorder association discoveries (63% of studies), followed by research infrastructure (26%), and clinical indicators (11%) such as supporting the diagnosis of individual patients. CONCLUSIONS: Existing evidence on the benefits of biobanks is skewed toward easily quantifiable research outputs. Measuring a comprehensive set of outputs and outcomes inspired by value frameworks is necessary to generate better evidence on the benefits of genomic data sharing.

The effect of rapid exome sequencing on downstream health care utilization for infants with suspected genetic disorders in an intensive care unit.

PURPOSE: This study aimed to compare downstream utilization of medical services among critically ill infants admitted to intensive care units who received rapid exome sequencing (ES) and those who followed alternative diagnostic testing pathways. METHODS: Using propensity score-weighted regression models including sex, age at admission, and severity indicators, we compared a group of 47 infants who underwent rapid ES with a group of 211 infants who did not receive rapid ES. Utilization and cost indicators were compared between cohorts using negative binomial models for utilization and two-part models for costs. RESULTS: After controlling for patients' sociodemographic and clinical characteristics, we found no statistically significant difference in outpatient visits, hospitalizations, intensive care unit or total length of stay, or length of stay-associated costs between the cohorts at 12- or 26-month follow-up. Similarly, there was no evidence of higher utilization or costs by the ES group when infants who died were removed from the analysis. CONCLUSION: When examining utilization during and beyond the diagnostic trajectory, there is no evidence that ES changes frequency of outpatient visits or use of in-hospital resources in critically ill infants with suspected genetic disorders.

The cost trajectory of the diagnostic care pathway for children with suspected genetic disorders.

PURPOSE: This study describes the cost trajectory of the standard diagnostic care pathway for children with suspected genetic disorders in British Columbia, Canada. METHODS: Average annual per-patient costs were estimated using medical records review and a caregiver survey for a cohort of 498 children referred to BC Children's and Women's Hospitals (C&W) with unexplained intellectual disability (the TIDE-BC study) and families enrolled in the CAUSES study, which offered diagnostic genome-wide sequencing (GWS; exome and genome sequencing) to 500 families of children with suspected genetic disorders. RESULTS: Direct costs peaked in the first year of patients' diagnostic odyssey, with an average of C$2257 per patient (95% confidence interval [CI] C$2074, C$2441) for diagnostic testing and C$631 (95% CI C$543, C$727) for specialist consultations at C&W. In subsequent years, direct costs accrued at a constant rate, with an estimated annual per-patient cost of C$511 (95% CI C$473, C$551) for diagnostic testing and C$334 (95% CI C$295, C$369) for consultations at C&W. Travel costs and caregiver productivity loss associated with attending diagnosis-related physician appointments averaged C$1907/family/year. CONCLUSIONS: The continuing long-term accrual of costs by undiagnosed patients suggests that economic evaluations of diagnostic GWS services should use longer time horizons than have typically been used.

The composition and capacity of the clinical genetics workforce in high-income countries: a scoping review.

As genetics becomes increasingly integrated into all areas of health care and the use of complex genetic tests continues to grow, the clinical genetics workforce will likely face greatly increased demand for its services. To inform strategic planning by health-care systems to prepare to meet this future demand, we performed a scoping review of the genetics workforce in high-income countries, summarizing all available evidence on its composition and capacity published between 2010 and 2019. Five databases (MEDLINE, Embase, PAIS, CINAHL, and Web of Science) and gray literature sources were searched, resulting in 162 unique studies being included in the review. The evidence presented includes the composition and size of the workforce, the scope of practice for genetics and nongenetics specialists, the time required to perform genetics-related tasks, case loads of genetics providers, and opportunities to increase efficiency and capacity. Our results indicate that there is currently a shortage of genetics providers and that there is a lack of consensus about the appropriate boundaries between the scopes of practice for genetics and nongenetics providers. Moreover, the results point to strategies that may be used to increase productivity and efficiency, including alternative service delivery models, streamlining processes, and the automation of tasks.

Correction: The composition and capacity of the clinical genetics workforce in high-income countries: a scoping review.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Evaluating Canadians' Values for Drug Coverage Decision Making.

BACKGROUND: Decision makers are facing growing challenges in prioritizing drugs for reimbursement because of soaring drug costs and increasing pressures on financial resources. In addition to cost and effectiveness, payers are using other values to dictate which drugs are prioritized for funding, yet there are limited data on the Canadian public's priorities. OBJECTIVES: To measure the relative societal importance of values considered most relevant in informing drug reimbursement decisions in a representative sample of Canadians. METHODS: An online survey of 2539 Canadians aged 19 years and older was performed in which 13 values used in drug funding prioritization were ranked and then weighted using an analytic hierarchy process. RESULTS: Canadians value safe and efficacious drugs that have certainty of evidence. The values ranked in the top 5 by most of our subjects were potential effect on quality of life (65.4%), severity of the disease (62.6%), ability of drug to work (61.1%), safety (60.5%), and potential to extend life (49.4%). Values related to patient or disease characteristics such as rarity, socioeconomic status, and health and lifestyle choices held the lowest rankings and weights. CONCLUSIONS: Canadians value, above all, treatment-related factors (eg, efficacy and safety) and disease-related factors (eg, severity and equity). Decision makers are currently using additional justifications to prioritize drugs for reimbursement, such as rarity and unmet need, which were not found to be highly valued by Canadians. Decision makers should integrate the public's values into a Canadian reimbursement framework for prioritization of drugs competing for limited funds.

Genetic counseling considerations with rapid genome-wide sequencing in a neonatal intensive care unit.

As genome-wide sequencing (GWS; exome sequencing [ES] and whole genome sequencing [WGS]) is implemented more frequently in the neonatal intensive care unit (NICU), it is important to understand parents' opinions regarding GWS, and views toward incidental findings (IFs) (also known as secondary findings). RAPIDOMICS was a pilot study of rapid trio-based (biological parents and neonate) ES for 25 neonates with a suspected genetic condition at the BC Women's Hospital NICU. As part of RAPIDOMICS, we explored parents' motivations and concerns regarding ES of their child, uptake of IFs for themselves, and rates of anxiety and depression at the time of pre-test genetic counseling via administration of the Generalized Anxiety Disorder Assessment 7 and Patient Health Questionnaire 8. These findings were compared to those from the Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) study (outpatient trio-based GWS) that includes pediatric patients with suspected genetic disease (with an average age of 10 years). Parents in RAPIDOMICS were more likely to identify "diagnosis" as their primary motivation to pursue GWS (p = 0.011), less likely to identify "no concerns" (p = 0.003), and less likely to opt in to receive IFs (p = 0.003) than parents in CAUSES. Rates of depression and anxiety in both groups were higher relative to the general population. We present novel findings regarding the similarities and differences in parental opinions and decisions of these cohorts.

The cost and diagnostic yield of exome sequencing for children with suspected genetic disorders: a benchmarking study.

PURPOSE: This study aimed to generate benchmark estimates for the cost, diagnostic yield, and cost per positive diagnosis of diagnostic exome sequencing (ES) in heterogeneous pediatric patient populations and to illustrate how the design of an ES service can influence its cost and yield. METHODS: A literature review and Monte Carlo simulations were used to generate benchmark estimates for singleton and trio ES. A cost model for the Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) study, which is testing a proposed delivery model for diagnostic ES in British Columbia, is used to illustrate the potential effects of changing the service design. RESULTS: The benchmark diagnostic yield was 34.3% (95% confidence interval (CI): 23.2-46.5) for trio ES and 26.5% (95% CI: 12.9-42.9) for singleton ES. The benchmark cost of delivery was C$6,437 (95% CI: $5,305-$7,704) in 2016 Canadian dollars (US$4,859; 4,391€) for trio ES and C$2,576 (95% CI: $1,993-$3,270) (US$1,944; 1,757€) for singleton ES. Scenario models for CAUSES suggest that alternative service designs could reduce costs but might lead to a higher cost per diagnosis due to lower yields. CONCLUSION: Broad conclusions about the cost-effectiveness of ES should be drawn with caution when relying on studies that use cost or yield assumptions that lie at the extremes of the benchmark ranges.

Defining Need Amid Exponential Change: Conceptual Challenges in Workforce Planning for Clinical Genetic Services.

Rapid growth in the volume of referrals to clinical genetics services in many countries during the past 15 years makes workforce planning a critical policy tool in ensuring that the capacity of the clinical genetics workforce is large enough to meet current and future needs. This article explores the distinctive challenges of workforce planning in clinical genetics and provides recommendations for addressing these challenges using a needs-based planning approach. Specifically, at least 3 features complicate efforts to estimate the need for clinical genetic services: the difficulty in linking many clinical genetic services to concrete health outcomes; the rapidly changing nature of genetic medicine, which creates intrinsic uncertainty about the appropriate level of service; and the heightened relevance of patient preferences in this context. Our recommendations call for needs-based planning studies to include an explicit definition of necessary care, to be flexible in considering nonhealth benefits, to err on the side of including services currently funded by health systems even when evidence about outcomes is limited, and to use scenario analysis and expert input to explore the impact of uncertainty about patients' preferences and future technologies on estimates of workforce requirements.

Workforce Implications of Increased Referrals to Hereditary Cancer Services in Canada: A Scenario-Based Analysis.

Over the last decade, utilization of clinical genetics services has grown rapidly, putting increasing pressure on the workforce available to deliver genetic healthcare. To highlight the policy challenges facing Canadian health systems, a needs-based workforce requirements model was developed to determine the number of Canadian patients in 2030 for whom an assessment of hereditary cancer risk would be indicated according to current standards and the numbers of genetic counsellors, clinical geneticists and other physicians with expertise in genetics needed to provide care under a diverse set of scenarios. Our model projects that by 2030, a total of 90 specialist physicians and 326 genetic counsellors (1.7-fold and 1.6-fold increases from 2020, respectively) will be required to provide Canadians with indicated hereditary cancer services if current growth trends and care models remain unchanged. However, if the expansion in eligibility for hereditary cancer assessment accelerates, the need for healthcare providers with expertise in genetics would increase dramatically unless alternative care models are widely adopted. Increasing capacity through service delivery innovation, as well as mainstreaming of cancer genetics care, will be critical to Canadian health systems' ability to meet this challenge.

Utilization of telehealth in paediatric genome-wide sequencing: Health services implementation issues in the CAUSES Study.

INTRODUCTION: Genome-wide sequencing (exome or whole genome) is transforming the care and management of paediatric patients with a rare disease because of its diagnostic capabilities. Genome-wide sequencing is most effective when both parents and the child are sequenced as a trio. Genetic counselling is recommended for all families considering genome-wide sequencing. Although telehealth is well established in genetic counselling for hereditary cancer and prenatal genetics, its use with genome-wide sequencing has not been well studied. The CAUSES Clinic at BC Children's and Women's Hospitals was a translational paediatric trio-based genome-wide sequencing initiative. Pre-test genetic counselling via telehealth (at a clinical site near the family's residence) was offered to families who had been previously evaluated by a clinical geneticist. We report on the first 300 families seen in the CAUSES clinic and compare health services implementation issues of families seen via telehealth versus on-site. METHODS: Demographics, cost to families (travel and time), time to first appointment, complete trio sample accrual and diagnostic rates were studied. RESULTS: Of the 300 patients, 58 (19%) were seen via telehealth and 242 (81%) were seen on-site for pre-test counselling. The mean time to completion of accrual of trio samples in the telehealth group was 56.3 (standard deviation ±87.3) days versus 18.9 (standard deviation ±62.4) days in the onsite group (p < 2.2 × 10-16). The mean per-family estimated actual or potential travel/time cost savings were greater in the telehealth group (Can$987; standard deviation = Can$1151) than for those seen on-site (Can$305; standard deviation = Can$589) (p = 0.0004). CONCLUSIONS: Telehealth allowed for access to genome-wide sequencing for families in remote communities and for them to avoid significant travel and time costs; however, there was a significant delay to accrual of the complete trio samples in the telehealth group, impacting on time of result reporting and delaying diagnoses for families for whom genome-wide sequencing was diagnostic.

Allocating healthcare resources to genomic testing in Canada: latest evidence and current challenges.

Precision medicine (PM) informed by next-generation sequencing (NGS) poses challenges for health technology assessment (HTA). To date, there has been limited reimbursement of genomic testing with NGS in Canada, particularly for whole-genome and whole-exome sequencing (WGS/WES). Through a structured literature review, we examine Canadian economic evidence and evidentiary challenges for the adoption of genomic testing. We searched Medline (PubMed) for published Canadian studies generating economic evidence for PM informed by NGS. Our search focused on studies examining the costs and/or value of NGS. We reviewed included studies and summarized results according to evaluation type, clinical context, NGS technology, and test strategy. We then grouped HTA challenges encountered by authors when evaluating NGS. Our review included twenty-five studies. To determine the economic impacts of NGS-informed PM in Canada, studies applied cost-effectiveness analysis (52%, n = 13), stated preference analysis (20%, n = 5), cost-consequence analysis (16%, n = 4), and healthcare resource utilization or costing analysis (12%, n = 3). NGS panels were the most common technology evaluated (n = 13), followed by WGS and/or WES (n = 8). The included studies highlighted multiple challenges when generating economic evidence, many of which remain unaddressed. Challenges were broadly related to (1) accounting for all NGS outcomes; (2) addressing uncertainty; and (3) improving consistency of economic approaches. Canadian studies are beginning to produce estimates of the economic impacts of NGS-informed PM, yet challenges for HTA remain. While solutions and real-world evidence are generated, lifecycle health technology management methods can be designed to better support resource allocation decisions for genomic testing in Canada.

Where is genetic medicine headed? Exploring the perspectives of Canadian genetic professionals on future trends using the Delphi method.

Driven by technological and scientific advances, the landscape of genetic medicine is rapidly changing, which complicates strategic planning and decision-making in this area. To address this uncertainty, we sought to understand genetic professionals' opinions about the future of clinical genetic and genomic services in Canada. We used the Delphi method to survey Canadian genetic professionals about their perspectives on whether scenarios about changes in service delivery and the use of genomic testing would be broadly implemented in their jurisdiction by 2030. We conducted two survey rounds; the response rates were 32% (27/84) and 67% (18/27), respectively. The most likely scenario was the universal use of noninvasive prenatal screening. The least likely scenarios involved population-based genome-wide sequencing for unaffected individuals. Overall, the scenarios perceived as most likely were those that have existing evidence about their benefit and potential medical necessity, whereas scenarios were seen as unlikely if they involved emerging technologies. Participants expected that the need for genetic healthcare services would increase by 2030 owing to changes in clinical guidelines and increased use of genome-wide sequencing. This study highlights the uncertainty in the future of genetic and genomic service provision and contributes evidence that could be used to inform strategic planning in clinical genetics.

Far and wide: Exploring provider utilization of remote service provision for genome-wide sequencing in Canada.

BACKGROUND: In Canada, funding for genome-wide sequencing (GWS; exome and whole genome) is provincially regulated. We characterized the uptake of GWS by genetics health professionals (GHPs) across Canada and describe how they use remote technologies for patient access to GWS and genomic counseling. METHODS: We distributed a survey to 574 Canadian GHPs addressing: GWS use, remote technologies (e.g., telephone, videoconferencing) for GWS and provider opinions regarding these technologies. Data were summarized using descriptive statistics. Associations between variables were evaluated using Chi-square and Fisher's Exact tests for categorical data, and t-tests or Mann-Whitney U tests for continuous data. RESULTS: Of 116 GHPs, 50% reported using GWS in the last year and 57% of GWS users reported using remote technologies. Clinical geneticists who did not use GWS reported lack of provincial funding as the principal reason. Remote technologies were most commonly used for informed consent and results, and rarely used for initial consultations. Average wait times for a GWS appointment were shorter for remote appointments (mean 44.2 (SD 40.2) weeks) than for in-person (mean 58.2 (SD 42.9), p = 0.036). CONCLUSION: The use of GWS varied across Canada, professional designation, and discipline. Funding remains a barrier to GWS access. Remote technologies increase patient access with reduced wait times.

Evaluating New Zealanders' Values for Drug Coverage Decision Making: Trade-Offs between Treatments for Rare and Common Conditions.

BACKGROUND: New Zealand's near static healthcare budget limits access to expensive medications including those for rare conditions. As such, it is necessary to know the public's priority for values in the drug funding decision-making process. OBJECTIVES: The objectives of this study were to measure the relative societal importance of values of New Zealanders in informing drug funding decisions and to determine how New Zealanders trade off funding in various scenarios between common and rare diseases. METHODS: An online survey was conducted between 17 April and 17 May, 2019 on a sample of 500 New Zealanders aged ≥ 18 years. Participants ranked 13 values using an analytical hierarchy process. Participants were then presented with different trade-off scenarios to measure their attitudes towards funding drugs for common and rare diseases. RESULTS: The values ranked in the top five by most were potential effect on quality of life (71.8%), ability of the drug to work (57.6%), severity (57.6%), safety (57%), and potential to extend life (56%). Adherence and rarity held the lowest and second lowest ranking. Most believe that resources should be allocated towards drugs that have been proven to work and have the greatest health benefits. In trade-offs between access to an expensive drug therapy for a rare disease with uncertain benefits or receive a fixed cash payment, the overwhelming consensus was to receive the cash payment. CONCLUSIONS: New Zealanders ultimately value drug-related factors (e.g. quality of life and efficacy) and disease-related factors (e.g. severity of disease and equity) the most but did not value disease rarity.

Economic Evidence on Potentially Curative Gene Therapy Products: A Systematic Literature Review.

OBJECTIVE: The aim of this review was to summarize all available evidence on the cost effectiveness of potentially curative gene therapies and identify challenges that economic evaluations face in this area. METHODS: We conducted a systematic review of four databases (PubMed/MEDLINE, Embase, CINAHL, EconLit) and grey literature sources. We conducted the search on August 23, 2019 and updated it on November 26, 2020. We included all English, French and Spanish language studies that addressed a gene therapy that had received regulatory approval or had entered a phase III trial, and also reported on costs related to the therapy. Critical appraisal was conducted to assess quality of reporting in included studies. RESULTS: Fifty-six studies were identified. Of the 42 full economic evaluations, 71% (n = 30) evaluated chimeric antigen receptor T-cell therapies, most used either a Markov model (n = 17, 40%) and/or a partitioned survival model (n = 17, 40%), and 76% (n = 32) adopted a public or private payer perspective. The model characteristics with the greatest impact on cost effectiveness included assumptions about the efficacy of the treatment and the comparators used. CONCLUSION: All gene therapies in this review were shown to be more effective than their comparators, although due to high costs not all were considered cost effective at standard cost-effectiveness thresholds. Despite their high cost, some gene therapies have the potential to dominate the alternatives in conditions with high mortality/disability. The choice of comparator and assumptions regarding long-term effectiveness had substantial impacts on cost-effectiveness estimates and need to be carefully considered. Both the quality of inputs and the quality of reporting were highly variable.

Integration of genetic counsellors in genomic testing triage: Outcomes of a genomic consultation service in British Columbia, Canada.

PURPOSE: Clinical diagnostic genome-wide (exome or genome) sequencing (GWS) in British Columbia requires funding approval by a provincial agency on a case-by-case basis. The CAUSES Clinic was a pediatric translational trio-based GWS study at BC Children's and Women's Hospitals. Referrals to the CAUSES Clinic were made through a Genomic Consultation Service (GCS), a multidisciplinary team led by genetic counsellors that provided advice regarding genomic testing for physicians considering GWS for their patients. Here we review the outcomes of the GCS, focusing on patients not recommended for the CAUSES Study. METHODS: Demographic, clinical, and testing data were abstracted from patient charts. Logistic regression analysis was used to explore associations between demographic and clinical variables and two outcomes: the type of recommendation and referring physicians' decisions to follow the recommendation. RESULTS: Of 972 GCS referrals, 248 patients were not referred to the CAUSES Study. GWS (vs. a targeted test; e.g. multi-gene panel) was more likely to be recommended to physicians of patients with ID than physicians of patients without ID (OR = 2.98; 95% CI = 1.46 to 6.27; n = 149). In total, 40% of physicians who were recommended to pursue clinical genomic testing submitted an application for funding approval; 71% of applications were approved for funding. Among approved tests, 50% resulted in a diagnosis, including 33% of targeted tests and 82% of GWS tests (χ2 (1) = 5.0, p = 0.026). CONCLUSION: The GCS provided an effective model in which physicians can interface with genetic specialists, including genetic counsellors, to facilitate appropriate genomic test selection.

Toward the diagnosis of rare childhood genetic diseases: what do parents value most?

Genomic testing is becoming routine for diagnosing rare childhood genetic disease. Evidence underlying sustainable implementation is limited, focusing on short-term endpoints such as diagnostic yield, unable to fully characterize patient and family valued outcomes. Although genomic testing is becoming widely available, evidentiary and outcomes uncertainty persist as key challenges for implementation. We examine whether the current evidence base reflects public tolerance for uncertainty for genomics to diagnose rare childhood genetic disease. We conducted focus groups with general population parents in Vancouver, Canada, and Oxford, United Kingdom, to discuss expectations and concerns related to genomic testing to diagnose rare childhood genetic disease. Applying a purposive sampling technique, recruitment continued until thematic saturation was reached. Transcripts were analysed using thematic analysis. Thirty-three parents participated across four focus groups. Participants valued causal diagnoses alongside management strategies to improve patient health and wellbeing. Further, participants valued expanding the evidence base to reduce evidentiary uncertainty while ensuring security of information. Willingness to pay out of pocket for testing reflected perceived familial health benefit. Diagnostic yield fails to fully capture valued outcomes, and efforts to resolve uncertainty better reflect public priorities. Evaluations of genomic testing that fully integrate valued endpoints are necessary to ensure consistency with best practices and public willingness to accept the uncertain familial benefit.