Effect of Whole-Genome Sequencing on the Clinical Management of Acutely Ill Infants With Suspected Genetic Disease: A Randomized Clinical Trial.
Effect of Whole-Genome Sequencing on the Clinical Management of Acutely Ill Infants With Suspected Genetic Disease: A Randomized Clinical Trial.
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DOI：
10.1001/jamapediatrics.2021.3496
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发表时间：
2021-12-01
期刊：
影响因子：
26.1
通讯作者：
Taft RJ
中科院分区：
文献类型：
--
作者：
NICUSeq Study Group;Krantz ID;Medne L;Weatherly JM;Wild KT;Biswas S;Devkota B;Hartman T;Brunelli L;Fishler KP;Abdul-Rahman O;Euteneuer JC;Hoover D;Dimmock D;Cleary J;Farnaes L;Knight J;Schwarz AJ;Vargas-Shiraishi OM;Wigby K;Zadeh N;Shinawi M;Wambach JA;Baldridge D;Cole FS;Wegner DJ;Urraca N;Holtrop S;Mostafavi R;Mroczkowski HJ;Pivnick EK;Ward JC;Talati A;Brown CW;Belmont JW;Ortega JL;Robinson KD;Brocklehurst WT;Perry DL;Ajay SS;Hagelstrom RT;Bennett M;Rajan V;Taft RJ
全基因组测序（WGS）对不同急性病婴儿人群的临床管理有何影响？在5家儿童医院进行的这项随机延时临床试验中，354名不同人群的婴儿在入组后15天或60天随机接受WGS。在这两个研究组中，获得WGS的患者比例增加了一倍，并进行了精确诊断和临床管理的改变。这些数据支持WGS对疑似遗传性疾病的急性病婴儿实施。这项随机临床试验研究了全基因组测序对疑似遗传性疾病的急性病婴儿临床管理的影响。全基因组测序（WGS）显示出作为急性病婴儿的一线基因检测的前景，但广泛采用和实施需要临床管理效果的证据。确定WGS对美国不同种族和地理分布的急性病婴儿人群临床管理的影响。这项随机、延时的临床试验从2017年9月11日至2019年4月30日招募了参与者，观察期延长至2019年7月2日。这项研究在美国5个学术医疗中心和附属儿童医院进行。参与者包括年龄在0到120天之间的婴儿，他们因疑似遗传性疾病而被送进重症监护室。数据分析时间为2020年1月14日至8月20日。患者在入组后15天（提前）或60天（延迟）随机接受临床WGS结果，观察期延长至90天。在整个研究过程中继续护理。主要结果是早期和延迟组中在入组后60天接受管理变更（COM）的婴儿比例的差异。其他结局指标包括WGS诊断效率、90天时组内COM、住院时间和死亡率。共有354名婴儿被随机分配到早期（n = 176）或延迟（n = 178）组。平均受试者年龄为15天（IQR，7-32天）; 201名受试者（56.8%）为男孩; 19名（5.4%）为亚裔; 47名（13.3%）为黑人; 250名（70.6%）为白色; 38名（10.7%）为其他种族。在60天时，早期组中接受COM的婴儿是延迟组的两倍（34/161 [21.1%; 95% CI，15.1%-28.2%] vs 17/165 [10.3%; 95% CI，6.1%-16.0%]; P = 0.009;比值比，2.3; 95%CI，1.22-4.32）和分子诊断（176例中的55例[31.0%; 95%CI，24.5%-38.7%] vs 178例中的27例[15.0%; 95%CI，10.2%-21.3%]; P < .001）。在90天时，延迟组显示COM加倍（至161例中的45例[28.0%; 95% CI，21.2%-35.6%]）和诊断有效性（至178例中的56例[31.0%; 95% CI，24.7%-38.8%]）。观察窗内最常见的COM是专科转诊（39/354; 11%）、手术或其他侵入性操作（17/354; 4%）、特定病症药物（9/354; 2%）或其他支持性药物改变（12/354; 3%）。观察到住院时间或生存期无差异。在这项随机临床试验中，对于重症监护室中的急性病婴儿，与常规护理相比，WGS的引入与重点临床管理的显著增加相关。获得一线WGS可以通过实现诊断公平来减少卫生保健差距。这些数据支持WGS在该人群中的采用和实施。ClinicalTrials.gov标识符：NCT 03290469
What is the effect of whole-genome sequencing (WGS) on clinical management in a diverse population of acutely ill infants? In this randomized time-delayed clinical trial conducted at 5 children’s hospitals, a diverse population of 354 infants was randomized to receive WGS either 15 days or 60 days after enrollment. In both study groups, access to WGS doubled the proportion of patients with a precision diagnosis and a change of clinical management. These data support WGS implementation for acutely ill infants with a suspected genetic condition. This randomized clinical trial investigates the effect of whole-genome sequencing on the clinical management of acutely ill infants with suspected genetic disease. Whole-genome sequencing (WGS) shows promise as a first-line genetic test for acutely ill infants, but widespread adoption and implementation requires evidence of an effect on clinical management. To determine the effect of WGS on clinical management in a racially and ethnically diverse and geographically distributed population of acutely ill infants in the US. This randomized, time-delayed clinical trial enrolled participants from September 11, 2017, to April 30, 2019, with an observation period extending to July 2, 2019. The study was conducted at 5 US academic medical centers and affiliated children’s hospitals. Participants included infants aged between 0 and 120 days who were admitted to an intensive care unit with a suspected genetic disease. Data were analyzed from January 14 to August 20, 2020. Patients were randomized to receive clinical WGS results 15 days (early) or 60 days (delayed) after enrollment, with the observation period extending to 90 days. Usual care was continued throughout the study. The main outcome was the difference in the proportion of infants in the early and delayed groups who received a change of management (COM) 60 days after enrollment. Additional outcome measures included WGS diagnostic efficacy, within-group COM at 90 days, length of hospital stay, and mortality. A total of 354 infants were randomized to the early (n = 176) or delayed (n = 178) arms. The mean participant age was 15 days (IQR, 7-32 days); 201 participants (56.8%) were boys; 19 (5.4%) were Asian; 47 (13.3%) were Black; 250 (70.6%) were White; and 38 (10.7%) were of other race. At 60 days, twice as many infants in the early group vs the delayed group received a COM (34 of 161 [21.1%; 95% CI, 15.1%-28.2%] vs 17 of 165 [10.3%; 95% CI, 6.1%-16.0%]; P = .009; odds ratio, 2.3; 95% CI, 1.22-4.32) and a molecular diagnosis (55 of 176 [31.0%; 95% CI, 24.5%-38.7%] vs 27 of 178 [15.0%; 95% CI, 10.2%-21.3%]; P < .001). At 90 days, the delayed group showed a doubling of COM (to 45 of 161 [28.0%; 95% CI, 21.2%-35.6%]) and diagnostic efficacy (to 56 of 178 [31.0%; 95% CI, 24.7%-38.8%]). The most frequent COMs across the observation window were subspecialty referrals (39 of 354; 11%), surgery or other invasive procedures (17 of 354; 4%), condition-specific medications (9 of 354; 2%), or other supportive alterations in medication (12 of 354; 3%). No differences in length of stay or survival were observed. In this randomized clinical trial, for acutely ill infants in an intensive care unit, introduction of WGS was associated with a significant increase in focused clinical management compared with usual care. Access to first-line WGS may reduce health care disparities by enabling diagnostic equity. These data support WGS adoption and implementation in this population. ClinicalTrials.gov Identifier: NCT03290469
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影响因子：
5.3
作者：
Petrikin, Josh E.;Cakici, Julie A.;Kingsmore, Stephen F.
通讯作者：
Kingsmore, Stephen F.
DOI：
10.1001/jama.2020.19933
发表时间：
2020-11-24
期刊：
JAMA
影响因子：
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通讯作者：
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作者：
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通讯作者：
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