TRIAGE-GS: A Randomized Controlled Trial of a Genomics-first Approach to Rare Disease Diagnosis
试验速览
- 阶段
- 不适用
- 状态
- Enrolling By Invitation
- 入组人数
- 200
- 试验地点
- 2
- 主要终点
- 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.
研究概览
简要总结
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:
- Are there more and faster diagnoses with a "genome sequencing first" approach compared to standard-of-care?
- What do patients, families, and healthcare providers think about a "genome sequencing first" approach compared to standard-of-care?
- 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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Diagnostic
- 盲法
- None
入排标准
- 年龄范围
- — 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Genome sequencing pre-geneticist evaluation (Genetic)
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.
结局指标
主要结局
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.
时间窗: From date of randomization until the date of the disclosure of diagnosis/plan, up to 18 months.
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.
Compare clinical utility of GS-first to standard of care from the perspectives of care teams.
时间窗: 0-2 weeks after the first results disclosure to the participant/family.
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.
Compare personal utility of GS-first to standard-of-care from the perspectives of patients, families, and care teams.
时间窗: 0-2 weeks after the first results disclosure to the participant/family.
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.
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.
时间窗: Overall during the study period (up to 18 months).
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.
次要结局
- Proportion of participants with potential genetic diagnoses(Overall during the study period (up to 18 months).)
- 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 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)(Overall during the study period (up to 18 months).)
- Differences in amount of time/effort required for reporting genome sequencing(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(Overall during the study period (up to 18 months).)
- Incremental cost per unit improvement in C-GUIDE score(Overall during the study period (up to 18 months).)
研究者
Gregory Costain
Staff Physician
The Hospital for Sick Children