Chaigneau Megan, Bowman Mackenzie, Grabell Julie, Conboy Megan, Johnson Ana, Thorpe Kevin, Guerin Andrea, Dinchong Rachelle, Paterson Andrew, Good David, Mahar Alyson, Callum Jeannie, Wheaton Laura, Leung Jennifer, Khalife Roy, Sholzberg Michelle, Lillicrap David, James Paula D
Department of Medicine, Queen's University, Kingston, Ontario, Canada
Department of Medicine, Queen's University, Kingston, Ontario, Canada.
BMJ Open. 2025 Apr 17;15(4):e102041. doi: 10.1136/bmjopen-2025-102041.
The current diagnostic pathway for patients with a suspected inherited bleeding disorder is long, costly, resource intensive, emotionally draining for patients and often futile, as half of patients will remain without a diagnosis and be labelled 'bleeding disorder of unknown cause'. Advances in understanding the genetic basis of the inherited bleeding disorders, coupled with both increasing infrastructure for genetic/genomic testing and decreasing costs, have increased the feasibility of introducing genomic testing into the clinical diagnostic pathway as a potential solution to improve the care of these patients. Yet, there remain evidence gaps on the optimal integration of genomic analysis into the diagnostic pathway.
Using a multicentre randomised-controlled trial design, we will evaluate an early genomic testing strategy for the diagnosis of newly referred patients with a suspected inherited bleeding disorder. Eligible participants will be randomised to early genomic testing diagnostic pathway (intervention) or standard diagnostic pathway (control) and will be followed for a 12-month period. Patients in the control group who remain undiagnosed at study end will be offered identical early genomic testing to ensure equitable access to the intervention. The study will follow a parallel fixed design with waitlist control group and a 1:1 allocation ratio. The study will be conducted at three tertiary care centres in Ontario, Canada, with a target sample size of 212 participants. Clinical utility will be evaluated via the primary outcome of diagnostic yield, as well as the secondary outcome of time to diagnosis. Additional secondary outcomes will allow for assessment of patient impact via health-related quality of life and patient burden measures, as well as evaluation of economic impact through a cost-effectiveness analysis and budget impact analysis.
This investigator-initiated study was approved by the Queen's University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board through Clinical Trials Ontario (CTO-4909). Participant informed consent/assent is required. Findings will be disseminated through academic publications.
ClinicalTrials.gov, NCT06736158.
目前，疑似遗传性出血性疾病患者的诊断流程漫长、成本高昂、资源消耗大，让患者心力交瘁，且往往徒劳无功，因为半数患者最终仍无法确诊，只能被贴上“病因不明的出血性疾病”标签。随着对遗传性出血性疾病遗传基础认识的进步，以及基因/基因组检测基础设施的不断完善和成本的降低，将基因组检测引入临床诊断流程作为改善这些患者治疗的潜在解决方案，其可行性日益增加。然而，在将基因组分析最佳整合到诊断流程方面，仍存在证据空白。
我们将采用多中心随机对照试验设计，评估一种早期基因组检测策略，用于诊断新转诊的疑似遗传性出血性疾病患者。符合条件的参与者将被随机分配到早期基因组检测诊断流程（干预组）或标准诊断流程（对照组），并随访12个月。对照组中在研究结束时仍未确诊的患者将接受相同的早期基因组检测，以确保公平获得干预措施。该研究将采用平行固定设计，设有等待名单对照组，分配比例为1:1。研究将在加拿大安大略省的三个三级医疗中心进行，目标样本量为212名参与者。临床效用将通过诊断率这一主要结果以及诊断时间这一次要结果进行评估。其他次要结果将通过健康相关生活质量和患者负担指标评估对患者的影响，并通过成本效益分析和预算影响分析评估经济影响。
这项由研究者发起的研究已获得女王大学健康科学与附属教学医院研究伦理委员会通过安大略临床试验（CTO - 4909）的批准。需要参与者知情同意/同意。研究结果将通过学术出版物进行传播。
ClinicalTrials.gov，NCT06736158。
