Importance Widespread adoption of rapid genomic testing in pediatric critical care requires robust clinical and laboratory pathways that provide equitable and consistent service across health care systems. Objective To prospectively evaluate the performance of a multicenter network for ultra-rapid genomic diagnosis in a public health care system. Design, Setting, and Participants Descriptive feasibility study of critically ill pediatric patients with suspected monogenic conditions treated at 12 Australian hospitals between March 2018 and February 2019, with data collected to May 2019. A formal implementation strategy emphasizing communication and feedback, standardized processes, coordination, distributed leadership, and collective learning was used to facilitate adoption. Exposures Ultra-rapid exome sequencing. Main Outcomes and Measures The primary outcome was time from sample receipt to ultra-rapid exome sequencing report. The secondary outcomes were the molecular diagnostic yield, the change in clinical management after the ultra-rapid exome sequencing report, the time from hospital admission to the laboratory report, and the proportion of laboratory reports returned prior to death or hospital discharge. Results The study population included 108 patients with a median age of 28 days (range, 0 days to 17 years); 34% were female; and 57% were from neonatal intensive care units, 33% were from pediatric intensive care units, and 9% were from other hospital wards. The mean time from sample receipt to ultra-rapid exome sequencing report was 3.3 days (95% CI, 3.2-3.5 days) and the median time was 3 days (range, 2-7 days). The mean time from hospital admission to ultra-rapid exome sequencing report was 17.5 days (95% CI, 14.6-21.1 days) and 93 reports (86%) were issued prior to death or hospital discharge. A molecular diagnosis was established in 55 patients (51%). Eleven diagnoses (20%) resulted from using the following approaches to augment standard exome sequencing analysis: mitochondrial genome sequencing analysis, exome sequencing-based copy number analysis, use of international databases to identify novel gene-disease associations, and additional phenotyping and RNA analysis. In 42 of 55 patients (76%) with a molecular diagnosis and 6 of 53 patients (11%) without a molecular diagnosis, the ultra-rapid exome sequencing result was considered as having influenced clinical management. Targeted treatments were initiated in 12 patients (11%), treatment was redirected toward palliative care in 14 patients (13%), and surveillance for specific complications was initiated in 19 patients (18%). Conclusions and Relevance This study suggests feasibility of ultra-rapid genomic testing in critically ill pediatric patients with suspected monogenic conditions in the Australian public health care system. However, further research is needed to understand the clinical value of such testing, and the generalizability of the findings to other health care settings.

中文翻译：

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在澳大利亚公共卫生保健系统中对疑似单基因疾病的危重婴儿和儿童进行超快速外显子组测序的可行性

重要性 在儿科重症监护中广泛采用快速基因组检测需要强大的临床和实验室途径，以在整个医疗保健系统中提供公平和一致的服务。目的前瞻性评估多中心网络在公共卫生保健系统中进行超快速基因组诊断的性能。设计、设置和参与者 2018 年 3 月至 2019 年 2 月期间在 12 家澳大利亚医院接受治疗的疑似单基因疾病的危重儿科患者的描述性可行性研究，数据收集到 2019 年 5 月。强调沟通和反馈、标准化流程、协调的正式实施策略、分布式领导和集体学习被用来促进采用。暴露超快速外显子组测序。主要结果和措施主要结果是从样本接收到超快速外显子组测序报告的时间。次要结果是分子诊断率、超快速外显子组测序报告后临床管理的变化、从入院到实验室报告的时间以及在死亡或出院前返回实验室报告的比例。结果 研究人群包括 108 名中位年龄为 28 天（范围，0 天至 17 岁）的患者；34% 是女性；57%来自新生儿重症监护病房，33%来自儿科重症监护病房，9%来自其他医院病房。从样本接收到超快速外显子组测序报告的平均时间为 3.3 天（95% CI，3.2-3.5 天），中位时间为 3 天（范围，2-7 天）。从入院到获得超快速外显子组测序报告的平均时间为 17.5 天（95% CI，14.6-21.1 天），并且在死亡或出院前发布了 93 份报告（86%）。在 55 名患者 (51%) 中建立了分子诊断。11 次诊断 (20%) 源于使用以下方法来增强标准外显子组测序分析：线粒体基因组测序分析、基于外显子组测序的拷贝数分析、使用国际数据库识别新的基因疾病关联，以及额外的表型和 RNA 分析. 在 55 名有分子诊断的患者中的 42 名 (76%) 和没有分子诊断的 53 名患者中的 6 名 (11%)，超快速外显子组测序结果被认为影响了临床管理。12 名患者 (11%) 开始了靶向治疗，14 名患者 (13%) 的治疗转向姑息治疗，19 名患者 (18%) 开始监测特定并发症。结论和相关性 本研究表明在澳大利亚公共卫生保健系统中对疑似单基因疾病的危重儿科患者进行超快速基因组检测的可行性。然而，需要进一步研究以了解此类测试的临床价值，以及研究结果对其他医疗保健环境的普遍性。