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Introduction: Genetic testing is used across medical disciplines leading to unprecedented demand for genetic services. This has resulted in excessive waitlists and unsustainable pressure on the standard model of genetic healthcare. Alternative models are needed; e-health tools represent scalable and evidence-based solution. We aim to evaluate the effectiveness of the Genetics Navigator, an interactive patient-centred digital platform that supports the collection of medical and family history, provision of pregenetic and postgenetic counselling and return of genetic testing results across paediatric and adult settings., Methods and Analysis: We will evaluate the effectiveness of the Genetics Navigator combined with usual care by a genetics clinician (physician or counsellor) to usual care alone in a randomised controlled trial. One hundred and thirty participants (adults patients or parents of paediatric patients) eligible for genetic testing through standard of care will be recruited across Ontario genetics clinics. Participants randomised into the intervention arm will use the Genetics Navigator for pretest and post-test genetic counselling and results disclosure in conjunction with their clinician. Participants randomised into the control arm will receive usual care, that is, clinician-delivered pretest and post-test genetic counselling, and results disclosure. The primary outcome is participant distress 2 weeks after test results disclosure. Secondary outcomes include knowledge, decisional conflict, anxiety, empowerment, quality of life, satisfaction, acceptability, digital health literacy and health resource use. Quantitative data will be analysed using statistical hypothesis tests and regression models. A subset of participants will be interviewed to explore user experience; data will be analysed using interpretive description. A cost-effectiveness analysis will examine the incremental cost of the Navigator compared with usual care per unit reduction in distress or unit improvement in quality of life from public payer and societal perspectives., Ethics and Dissemination: This study was approved by Clinical Trials Ontario. Results will be shared through stakeholder workshops, national and international conferences and peer-reviewed journals., Trial Registration Number: NCT06455384., Competing Interests: Competing interests: YB and MC are cofounders of Genetics Adviser., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To evaluate the diagnostic utility of publicly funded clinical exome sequencing (ES) for patients with suspected rare genetic diseases., Methods: We prospectively enrolled 297 probands who met eligibility criteria and received ES across 5 sites in Ontario, Canada, and extracted data from medical records and clinician surveys. Using the Fryback and Thornbury Efficacy Framework, we assessed diagnostic accuracy by examining laboratory interpretation of results and assessed diagnostic thinking by examining the clinical interpretation of results and whether clinical-molecular diagnoses would have been achieved via alternative hypothetical molecular tests., Results: Laboratories reported 105 molecular diagnoses and 165 uncertain results in known and novel genes. Of these, clinicians interpreted 102 of 105 (97%) molecular diagnoses and 6 of 165 (4%) uncertain results as clinical-molecular diagnoses. The 108 clinical-molecular diagnoses were in 104 families (35% diagnostic yield). Each eligibility criteria resulted in diagnostic yields of 30% to 40%, and higher yields were achieved when >2 eligibility criteria were met (up to 45%). Hypothetical tests would have identified 61% of clinical-molecular diagnoses., Conclusion: We demonstrate robustness in eligibility criteria and high clinical validity of laboratory results from ES testing. The importance of ES was highlighted by the potential 40% of patients that would have gone undiagnosed without this test., Competing Interests: Conflict of Interest The authors declare no conflicts of interests., (Copyright © 2023. Published by Elsevier Inc.)

We examined the utility of clinical and research processes in the reanalysis of publicly-funded clinical exome sequencing data in Ontario, Canada. In partnership with eight sites, we recruited 287 families with suspected rare genetic diseases tested between 2014 and 2020. Data from seven laboratories was reanalyzed with the referring clinicians. Reanalysis of clinically relevant genes identified diagnoses in 4% (13/287); four were missed by clinical testing. Translational research methods, including analysis of novel candidate genes, identified candidates in 21% (61/287). Of these, 24 families have additional evidence through data sharing to support likely diagnoses (8% of cohort). This study indicates few diagnoses are missed by clinical laboratories, the incremental gain from reanalysis of clinically-relevant genes is modest, and the highest yield comes from validation of novel disease-gene associations. Future implementation of translational research methods, including continued reporting of compelling genes of uncertain significance by clinical laboratories, should be considered to maximize diagnoses., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Importance: Identifying conditions that could be prioritized for research based on health care system burden is important for developing a research agenda for the care of hospitalized children. However, existing prioritization studies are decades old or do not include data from both pediatric and general hospitals., Objective: To assess the prevalence, cost, and variation in cost of pediatric hospitalizations at all general and pediatric hospitals in Ontario, Canada, with the aim of identifying conditions that could be prioritized for future research., Design, Setting, and Participants: This population-based cross-sectional study used health administrative data from 165 general and pediatric hospitals in Ontario, Canada. Children younger than 18 years with an inpatient hospital encounter between April 1, 2014, and March 31, 2019, were included., Main Outcomes and Measures: Condition-specific prevalence, cost of pediatric hospitalizations, and condition-specific variation in cost per inpatient encounter across hospitals. Variation in cost was evaluated using (1) intraclass correlation coefficient (ICC) and (2) number of outlier hospitals. Costs were adjusted for inflation to 2018 US dollars., Results: Overall, 627 314 inpatient hospital encounters (44.8% among children younger than 30 days and 53.0% among boys) at 165 hospitals (157 general and 8 pediatric) costing $3.3 billion were identified. A total of 408 003 hospitalizations (65.0%) and $1.4 billion (43.8%) in total costs occurred at general hospitals. Among the 50 most prevalent and 50 most costly conditions (of 68 total conditions), the top 10 highest-cost conditions accounted for 55.5% of all costs and 48.6% of all encounters. The conditions with highest prevalence and cost included low birth weight (86.2 per 1000 encounters; $676.3 million), preterm newborn (38.0 per 1000 encounters; $137.4 million), major depressive disorder (20.7 per 1000 encounters; $78.3 million), pneumonia (27.3 per 1000 encounters; $71.6 million), other perinatal conditions (68.0 per 1000 encounters; $65.8 million), bronchiolitis (25.4 per 1000 encounters; $54.6 million), and neonatal hyperbilirubinemia (47.9 per 1000 encounters; $46.7 million). The highest variation in cost per encounter among the most costly medical conditions was observed for 2 mental health conditions (other mental health disorders [ICC, 0.28] and anxiety disorders [ICC, 0.19]) and 3 newborn conditions (intrauterine hypoxia and birth asphyxia [ICC, 0.27], other perinatal conditions [ICC, 0.17], and surfactant deficiency disorder [ICC, 0.17])., Conclusions and Relevance: This population-based cross-sectional study of hospitalized children identified several newborn and mental health conditions as having the highest prevalence, cost, and variation in cost across hospitals. Findings of this study can be used to develop a research agenda for the care of hospitalized children that includes general hospitals and to ultimately build a more substantial evidence base and improve patient outcomes.

Background: Health care workers have a critical role in the pandemic response to COVID-19 and may be at increased risk of infection. The objective of this study was to assess the seroprevalence of SARS-CoV-2 immunoglobulin G (IgG) antibodies among health care workers during and after the first wave of the pandemic., Methods: We conducted a prospective multicentre cohort study involving health care workers in Ontario, Canada, to detect IgG antibodies against SARS-CoV-2. Blood samples and self-reported questionnaires were obtained at enrolment, at 6 weeks and at 12 weeks. A community hospital, tertiary care pediatric hospital and a combined adult-pediatric academic health centre enrolled participants from Apr. 1 to Nov. 13, 2020. Predictors of seropositivity were evaluated using a multivariable logistic regression, adjusted for clustering by hospital site., Results: Among the 1062 health care workers participating, the median age was 40 years, and 834 (78.5%) were female. Overall, 57 (5.4%) were seropositive at any time point (2.5% when participants with prior infection confirmed by polymerase chain reaction testing were excluded). Seroprevalence was higher among those who had a known unprotected exposure to a patient with COVID-19 ( p < 0.001) and those who had been contacted by public health because of a nonhospital exposure ( p = 0.003). Providing direct care to patients with COVID-19 or working on a unit with a COVID-19 outbreak was not associated with higher seroprevalence. In multivariable logistic regression, presence of symptomatic contacts in the household was the strongest predictor of seropositivity (adjusted odds ratio 7.15, 95% confidence interval 5.42-9.41)., Interpretation: Health care workers exposed to household risk factors were more likely to be seropositive than those not exposed, highlighting the need to emphasize the importance of public health measures both inside and outside of the hospital., Competing Interests: Competing interests: Shelly Bolotin has received grants for COVID-19 work, unrelated to this manuscript, from the Canadian Institutes of Health Research (CIHR), the Public Health Agency of Canada (PHAC), the COVID-19 Immunity Task Force (CITF) and the Canadian Immunity Research Network; has participated on the executive management committee for the MOSAIC COVID-19 vaccine clinical trial (CITF funded); and is a member of the PHAC Vaccine Surveillance Reference Group and the Canadian Immunization Research Network Management Committee. Michael Silverman reports an unrestricted grant paid to Western University from the Academic Medical Organization of Southwestern Ontario. Allison McGeer reports research grants to her institution from Sanofi Pasteur, Pfizer, Merck, CIHR, CITF, University of Toronto and Appili Therapeutics; funding from AstraZeneca for the preparation and delivery of webinars about vaccination; and participation on a data safety monitoring board or advisory board regarding COVID-19 therapy and vaccines for AstraZeneca, Janssen, Moderna, Pfizer, GlaxoSmithKline, Sanofi Pasteur, Merck, Medicago and Novavax. Upton Allen reports an honorarium provided to SickKids from the St. Jude Pediatric Infectious Diseases course. Jerome Leis reports a grant payment from the University of Toronto COVID-19 Action Initiative to his organization, Sunnybrook Health Sciences Centre, as a participant site; and payment for expert testimony regarding COVID-19 infection prevention and control management for the Ontario Hospital Association and the Ontario Ministry of the Attorney General. Jeffrey Pernica reports grant funding from bioMérieux to his institution for a clinical trial and from MedImmune to his institution for a prospective cohort study; and payment for an educational event from the Canadian Paediatric Review. No other competing interests were declared., (© 2021 CMA Joule Inc. or its licensors.)