TRIAGE-GS: Towards Reducing Inefficiencies Affecting Genetics Encounters Through Genome Sequencing (TRIAGE-GS)

TRIAGE-GS: A Randomized Controlled Trial of a Genomics-first Approach to Rare Disease Diagnosis

Individually rare genetic diseases are collectively common, and affect many Canadian families. Making the right diagnosis is both important and challenging. Healthcare providers and families often remain in the dark for too long, limited by the scope and speed of current genetic testing.

The goal of this clinical trial is to learn if performing genome sequencing (a comprehensive genetic test) as soon as a rare genetic disease is suspected is more effective than usual care, where a person waits to see a genetics specialist and then typically gets offered more targeted testing. Researchers will compare a "genome-sequencing first" approach to the standard-of-care in individuals who were referred to the Genetics Clinic at either SickKids or CHEO and recently had their referral accepted by the clinic.

The main questions this clinical trial aims to answer are:

1. Are there more and faster diagnoses with a "genome sequencing first" approach compared to standard-of-care?
2. What do patients, families, and healthcare providers think about a "genome sequencing first" approach compared to standard-of-care?
3. What is the financial impact of a "genome sequencing first" approach compared to standard-of-care on the healthcare system?

Participants will be asked to:

• Let us review their medical records.
• Complete up to 5 questionnaires over the course of the study.
• Give a blood sample for clinical genome sequencing (if in the genome sequencing first group).

This study aims to provide the robust evidence needed to improve care pathways for rare disease diagnosis in Canada. The findings also promise to help translate new genetic technologies into the clinic. Earlier diagnosis is a key first step towards personalized care, targeted treatments, and better outcomes.

Study Overview

• Status: Enrolling by invitation
• Conditions: Genetic Conditions
• Intervention / Treatment: Genetic: Genome sequencing pre-geneticist evaluation

Detailed Description

This is a multi-centre, prospective, interventional, open randomized controlled trial that compares patient outcomes generated by clinical whole genome sequencing (GS) initiated at time of referral triage (i.e., prior to evaluation with a medical geneticist) to standard-of-care, where genetic testing is ordered post-evaluation. 200 individuals referred to SickKids or CHEO for suspected undiagnosed rare disease (RD) will be enrolled, along with their biological parents when possible. The purpose of this study is to examine the safety, utility, and feasibility of a "genomics first" diagnostic pathway for RD. The investigators hypothesize that a GS-first pathway will have non-inferior diagnostic yield and lead to a shorter duration of time to RD diagnosis, fewer diagnostics-focused clinic visits, and improved stakeholder satisfaction.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 5B2
      • Children's Hospital of Eastern Ontario
    • Toronto, Ontario, Canada, M5G 0A4
      • The Hospital for Sick Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Referral accepted to the Genetics Clinic at SickKids or CHEO within 7 days of screening for study eligibility.
• Referral is for a patient that is ≤18 years old.
• Reason for referral is a suspected but as-yet-undiagnosed RD
• A genetic aetiology is a possible explanation for the phenotype such that genetic testing is likely to be offered in Genetics Clinic, as determined by the research team.

Exclusion Criteria:

• Patient has a known or suspected clinical diagnosis using established criteria of a genetic condition with low locus heterogeneity (e.g., HHT, fCCM, NF1, TSC, others)
• Referral considered "Urgent" using established site criteria.
• Genome-wide sequencing (exome sequencing or GS) or a comprehensive panel that encompasses all genes relevant for the reported phenotype previously completed on a clinical or research basis.
• Patient or family member previously assessed by a medical geneticist within the last 2 years for the same phenotype(s).
• Patient lacks Ontario Health Insurance Plan (OHIP) or comparable coverage (as this will limit options for standard genetic testing).
• Referral is solely to facilitate familial variant testing or for genetic counselling.
• A family member is already enrolled in the study and was referred for the same indication.
• Patient/family does not provide informed consent to participate within 2 weeks of being approached.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GS-first arm; The intervention is receiving immediate clinical routine GS, prior to evaluation by a medical geneticist. Pre-test counselling will be done by a research genetic counsellor. Results of GS will be returned during the participant's first visit to Genetics Clinic by their clinical team. Subsequent clinical care (including any other clinically indicated genetic testing or workup) will be arranged by the medical geneticist in clinic.	Genetic: Genome sequencing pre-geneticist evaluation; The intervention is receiving immediate clinical routine GS, prior to evaluation by a medical geneticist. Pre-test counselling will be done by a research genetic counsellor. Results of GS will be returned during the participant's first visit to Genetics Clinic by their clinical team. Subsequent clinical care (including any other clinically indicated genetic testing or workup) will be arranged by the medical geneticist in clinic.
No Intervention: Standard-of-care arm; The intervention group will be compared to the standard-of-care group, where evaluation by a medical geneticist in Genetics Clinic is a prerequisite to ordering of genetic testing. Clinical workups and genetic testing are ordered at the discretion of the medical geneticist involved in their clinical care, following evaluation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the time-to-event (diagnosis or no active follow-up) of a GS-first (pre-geneticist evaluation) outpatient care model for rare disease compared to standard of care.	The primary outcome measure for Aim 1 is a time-to-event variable. The event of interest is "diagnosis or no active follow-up," as measured for each participant from the date of randomization to the date of disclosure of the diagnosis/plan. Selection of a composite event variable was based on input from patients, families, and clinicians regarding the utility of negative GS results in certain scenarios. For example, a negative GS result might lower the index of suspicion for Mendelian disorders of known genetic basis, such that no further testing or short-term follow-up is recommended, or a clinical diagnosis of exclusion is made with confidence.	From date of randomization until the date of the disclosure of diagnosis/plan, up to 18 months.
Compare clinical utility of GS-first to standard of care from the perspectives of care teams.	The main outcome for Aim 2 will be differences in C-GUIDE total score, comparing the perceived utility of GS (in the GS-first group) with the first genetic test initiated by the geneticist for participants in the standard-of-care group.	0-2 weeks after the first results disclosure to the participant/family.
Compare personal utility of GS-first to standard-of-care from the perspectives of patients, families, and care teams.	The other main outcome for Aim 2 will be differences in GENE-U total score, comparing the perceived utility of GS (in the GS-first group) with the first genetic test initiated by the geneticist for participants in the standard-of-care group.	0-2 weeks after the first results disclosure to the participant/family.
Assess cost-effectiveness as the incremental cost per additional case detected for GS-first compared to standard-of-care from a healthcare system payer perspective.	An incremental cost-effectiveness analysis (CEA) that compares GS-first to standard-of-care per additional positive finding will be undertaken from the perspectives of the healthcare system and society. The economic evaluation will use recommended methods.	Overall during the study period (up to 18 months).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary diagnostic yield		Overall during the study period (up to 18 months), and within a 6-month time interval from the date of randomization.
Proportion of participants with dual diagnoses		Overall during the study period (up to 18 months).
Proportion of participants with partial genetic diagnoses		Overall during the study period (up to 18 months).
Proportion of participants with potential genetic diagnoses		Overall during the study period (up to 18 months).
Proportion of participants with variants of uncertain significance deemed non-contributory by the clinician		Overall during the study period (up to 18 months).
Proportion of participants with secondary/incidental findings		Overall during the study period (up to 18 months).
Number of new informative HPO terms coded after evaluation by a geneticist (compared with data extracted from collateral records at the time of the referral)	This can be stratified by the original referral source (i.e., internal referrals from providers at SickKids/CHEO vs. referrals from external providers).	Overall during the study period (up to 18 months).
Differences in amount of time/effort required for reporting genome sequencing	Including time recorded by the analyst, number/type of variants unnecessarily reported due to incomplete phenotypic information, etc.	Overall during the study period (up to 18 months).
Number of diagnoses missed by GS in the intervention arm that were later made after geneticist evaluation	Including variants seen by GS that were not reported based on phenotypic information known prior to geneticist assessment, variants identified on reanalysis using new HPO terms entered post-geneticist assessment, or variant types (e.g., repeat expansions) that were missed by GS due to technical limitations, etc.	Overall during the study period (up to 18 months).
Incremental cost per unit improvement in C-GUIDE score	A secondary analysis under the CEA will examine the incremental cost per unit improvement in C-GUIDE score	Overall during the study period (up to 18 months).

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Motivations and barriers to study participation	The investigators will assess factors that motivated families to participate, as well as factors that presented potential barriers at T0. These questions were developed by the study team for the purposes of this study. This component of the outcome measures will also be offered to individuals who decline to participate in an attempt to better understand barriers and improve the study.	0-2 weeks post-study enrolment, or offered immediately after declining to participate.
Sociodemographics	The study team will collect detailed sociodemographic, and equity related variables at T0. Some of this information is already collected in the electronic medical record as part of routine clinic visits. In cases where this information is readily available, the study team will gather it from the chart and not ask families to answer the questions again.	0-2 weeks post-study enrolment.
BRIEF Health Literacy Screening Tool	Health literacy is described as the degree to which one can read, understand, exchange, and use health information and resources. The BRIEF: Health Literacy Screening Tool consists of four questions that participants respond to on a 5-point Likert scale, and will be administered at T0. It measures patients' health literacy, where higher scores indicate higher levels of health literacy.	0-2 weeks post-study enrolment.
Everyday Discrimination Scale (Short Version)	The Everyday Discrimination Scale (Short Version) consists of 6 items intended to capture respondents' experiences with discrimination in their life. It is reliable (α = 0.77). It will be administered at T0 only.	0-2 weeks post-study enrolment.
University of North Carolina Genomic Knowledge Scale (UNC-GKS)	The UNC-GKS consists of 25 items to measure genomic knowledge among people facing decisions about genome-wide sequencing. It was shown to assess genomic knowledge with good internal reliability (Cronbach's α = 0.90), and convergent validity supported by association with health literacy and numeracy (rs = 0.41-0.46). It will be administered at T0, T1, T2 and TN (up to a maximum of T4) to allow comparison throughout families' diagnostic journeys, and assess whether there are differences in knowledge/understanding between the study arms.	0-2 weeks after study enrolment; 0-2 weeks after pre-test counselling; 0-2 weeks after each results disclosure (up to a maximum of 3 disclosures).
Short-Form State-Trait Anxiety Inventory (STAI)	The short form of the Spielberger STAI consists of 6 items that measure fluctuations in state anxiety.60 This short form version was found to be reliable (α = 0.32) and valid as compared to the full (20-item) version.60 It will be administered at all time points, starting at T0.	0-2 weeks after study enrolment; 0-2 weeks after pre-test counselling; 0-2 weeks after each results disclosure (up to a maximum of 3 disclosures).
Genetic Counselling Satisfaction Scale (GCSS)	The GCSS is a 6-item instrument to measure an individual's satisfaction with the genetic counselling they received. It is reliable (Cronbach's α = 0.90) and described as face valid. It will be administered at all time points, starting at T1.	0-2 weeks after pre-test counselling; 0-2 weeks after each results disclosure (up to a maximum of 3 disclosures).
GENEtic Utility (GENE-U) Scale for Pediatric Diagnostic Testing	The GENEtic Utility (GENE-U) scale consists of 21 items that capture the caregiver's test-specific reactions. It is designed for administration after test completion and results disclosure, and it is intended to be complementary to assessments of clinical utility. Convergent validity has been calculated using the Pearson correlation coefficient between scores on the GENE-U and measures of theoretically related constructs, and scores supported construct validity. It will be administered at all time points, starting at T2.	0-2 weeks after each results disclosure (up to a maximum of 3 disclosures).
Clinician-reported Genetic Testing Utility InDEx (C-GUIDE™)	To capture clinicians' assessment of utility, the investigators will use the Clinician-reported Genetic Testing Utility InDEx (C-GUIDE™). C-GUIDE™ was developed to assess the post-test utility of diagnostic and secondary variants generated by germline genetic tests. Evaluation using case vignettes has demonstrated that C-GUIDE v1.2 is reliable (Krippendorff's α=0.675) and valid. Consulting geneticists or genetic counsellors will be asked to complete C-GUIDE™ ratings on each enrolled index case within two weeks of the first result disclosure (T1), and for each subsequent result disclosure during the study period (TN), to allow for an assessment of clinical utility overtime.	0-2 weeks after each results disclosure.
Supplemental aspects of clinical utility	The study team will supplement the C-GUIDE™ ratings by documenting information from the patient's chart about the care plan that was recommended based each result (e.g., follow-up visits, referrals, surveillance plans, investigations, treatments, procedures). The source for this information will be the consult note written by the consulting geneticist following results disclosure.	0-2 weeks after each results disclosure.

Collaborators and Investigators

• Sponsor: The Hospital for Sick Children
• Collaborators: Ottawa Hospital Research Institute; Children's Hospital of Eastern Ontario; Toronto Metropolitan University

Publications and helpful links

General Publications

• Stanley KJ, Chisholm C, Gillespie MK, Caluseriu O, Del Signore N, Elango S, Hartley T, Hewson S, Kim RH, McSheffrey G, Mendoza-Londono R, Sawyer SL, Somerville M, Venkataramanan V, White-Brown A, Telesca S, Shickh S, Marshall CR, Ungar WJ, Hayeems RZ, Bhawra J, Boycott KM, Costain G. 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. BMJ Open. 2025 Aug 10;15(8):e107603. doi: 10.1136/bmjopen-2025-107603.

Study record dates

Study Major Dates

• Study Start (Actual): May 14, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): May 1, 2028

Study Registration Dates

• First Submitted: March 28, 2025
• First Submitted That Met QC Criteria: April 11, 2025
• First Posted (Actual): April 18, 2025

Study Record Updates

• Last Update Posted (Actual): April 24, 2026
• Last Update Submitted That Met QC Criteria: April 21, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: TRIAGE-GS
• Other Study ID Numbers: CTO5061

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Study protocol, including statistical analysis plan, and informed consent form template will be submitted for open-access publication. Individual participant data can be shared upon request and execution of a data transfer agreement when consent was given by the participant or their substitute decision maker. Potentially identifying data (e.g., variable represented less than 5 times in the cohort) will not be shared.
• IPD Sharing Time Frame: The data will be made available within 6 months of the study's conclusion, and will remain available for at least 5 years.
• IPD Sharing Access Criteria: Accessing the data set will require a signed data transfer agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No