{ "abstract": "Introduction Rare diseases (RD) are collectively common and often genetic. Families value and can benefit from precise molecular diagnoses. Prolonged diagnostic odysseys exacerbate the burden of RD on patients, families and the healthcare system. Genome sequencing (GS) is a near-comprehensive test for genetic RD, but existing care models—where consultation with a medical geneticist is a prerequisite for testing—predate GS and may limit access or delay diagnosis. Evidence is needed to guide the optimal positioning of GS in care pathways. While initiating GS prior to geneticist consultation has been trialled in acute care settings, there are no data to inform the utility of this approach in outpatient care, where most patients with RD seek genetics services. We aim to evaluate the diagnostic yield, time to diagnosis, clinical and personal utility and incremental cost-effectiveness of GS initiated at the time of referral triage (pre-geneticist evaluation) compared with standard of care. Methods and analysis 200 paediatric patients referred to one of two large genetics centres in Ontario, Canada, for suspected genetic RD will be randomised into a 1:1 ratio to the intervention (GS first) or standard of care (geneticist first) arm. An unblinded, permuted block randomisation design will be used, stratified within each recruitment site by phenotype and prior genetic testing. The primary outcome measure is time to genetic diagnosis or to cessation of active follow-up. Survival analysis will be used to analyse time-to-event data. Additional measures will include patient-reported and family-reported measures of satisfaction, understanding and perceived test utility, clinician-reported measures of perceived test utility and management impact, and healthcare system utilisation and costs. Ethics and dissemination This study was approved by Clinical Trials Ontario. Results will be disseminated, at minimum, via peer-reviewed journals, professional conferences and internal reports to funding bodies. Efforts will be made to share aggregated study results with participants and their families. Trial registration number NCT06935019.", "authors": [ { "affiliations": [ "Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada" ], "name": "Kaitlin J Stanley" }, { "affiliations": [ "Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada" ], "name": "Caitlin Chisholm" }, { "affiliations": [ "Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada", "Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada" ], "name": "Meredith K Gillespie" }, { "affiliations": [ "Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada" ], "name": "Oana Caluseriu" }, { "affiliations": [ "TRIAGE-GS Patient/Family Partnership Team, The Hospital for Sick Children, Toronto, Ontario, Canada" ], "name": "Natalie del Signore" }, { "affiliations": [ "Fred A. Litwin Family Centre in Genetic Medicine, University Health Network, Toronto, Ontario, Canada" ], "name": "Sonya Elango" }, { "affiliations": [ "Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada", "University of Ottawa, Ottawa, Ontario, Canada" ], "name": "Taila Hartley" }, { "affiliations": [ "Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada", "Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada" ], "name": "Stacy Hewson" }, { "affiliations": [ "Fred A. Litwin Family Centre in Genetic Medicine, University Health Network, Toronto, Ontario, Canada" ], "name": "Raymond H Kim" }, { "affiliations": [ "Child, Youth, Family Services, Centre for Addiction and Mental Health, Toronto, Ontario, Canada" ], "name": "Gordon McSheffrey" }, { "affiliations": [ "Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada", "Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada", "Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada" ], "name": "Roberto Mendoza-Londono" }, { "affiliations": [ "Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada", "University of Ottawa, Ottawa, Ontario, Canada" ], "name": "Sarah L Sawyer" }, { "affiliations": [ "Division of Genome Diagnostics, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada" ], "name": "Martin Somerville" }, { "affiliations": [ "Child Health Evaluative Sciences, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada" ], "name": "Viji Venkataramanan" }, { "affiliations": [ "Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada", "Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada" ], "name": "Alexandre White-Brown" }, { "affiliations": [ "TRIAGE-GS Patient/Family Partnership Team, The Hospital for Sick Children, Toronto, Ontario, Canada", "Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, Ontario, Canada" ], "name": "Stephanie Telesca" }, { "affiliations": [ "Child Health Evaluative Sciences, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada" ], "name": "Salma Shickh" }, { "affiliations": [ "Division of Genome Diagnostics, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada", "Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada" ], "name": "Christian R Marshall" }, { "affiliations": [ "Child Health Evaluative Sciences, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada", "Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada" ], "name": "Wendy J Ungar" }, { "affiliations": [ "Child Health Evaluative Sciences, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada", "Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada" ], "name": "Robin Z Hayeems" }, { "affiliations": [ "School of Occupational and Public Health, Faculty of Community Services, Toronto Metropolitan University, Toronto, Ontario, Canada" ], "name": "Jasmin Bhawra" }, { "affiliations": [ "Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada", "Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada" ], "name": "Kym M Boycott" }, { "affiliations": [ "Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada", "Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada", "Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada", "Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada" ], "name": "Gregory Costain" } ], "title": "TRIAGE-GS: protocol for a randomised controlled trial of a genomics-first approach to rare disease diagnosis for patients awaiting assessment by a clinical geneticist", "uid": "f096880e-b530-5067-980a-3c8ff44d5ece" }