验证供体分数游离 DNA 在儿童和成人经活检证实的心脏移植物排斥反应中的作用。
Validation of donor fraction cell-free DNA with biopsy-proven cardiac allograft rejection in children and adults.
机构信息
Division of Pediatric Cardiology, Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY.
Division of Pediatric Cardiology, Children's National Heart Institute, Children's National Hospital, Washington, DC.
出版信息
J Thorac Cardiovasc Surg. 2023 Feb;165(2):460-468.e2. doi: 10.1016/j.jtcvs.2022.04.027. Epub 2022 Apr 30.
OBJECTIVES
Donor-specific cell-free DNA shows promise as a noninvasive marker for allograft rejection, but as yet has not been validated in both adult and pediatric recipients. The study objective was to validate donor fraction cell-free DNA as a noninvasive test to assess for risk of acute cellular rejection and antibody-mediated rejection after heart transplantation in pediatric and adult recipients.
METHODS
Pediatric and adult heart transplant recipients were enrolled from 7 participating sites and followed for 12 months or more with plasma samples collected immediately before all endomyocardial biopsies. Donor fraction cell-free DNA was extracted, and quantitative genotyping was performed. Blinded donor fraction cell-free DNA and clinical data were analyzed and compared with a previously determined threshold of 0.14%. Sensitivity, specificity, negative predictive value, positive predictive value, and receiver operating characteristic curves were calculated.
RESULTS
A total of 987 samples from 144 subjects were collected. After applying predefined clinical and technical exclusions, 745 samples from 130 subjects produced 54 rejection samples associated with the composite outcome of acute cellular rejection grade 2R or greater and pathologic antibody-mediated rejection 2 or greater and 323 healthy samples. For all participants, donor fraction cell-free DNA at a threshold of 0.14% had a sensitivity of 67%, a specificity of 79%, a positive predictive value of 34%, and a negative predictive value of 94% with an area under the curve of 0.78 for detecting rejection. When analyzed independently, these results held true for both pediatric and adult cohorts at the same threshold of 0.14% (negative predictive value 92% and 95%, respectively).
CONCLUSIONS
Donor fraction cell-free DNA at a threshold of 0.14% can be used to assess for risk of rejection after heart transplantation in both pediatric and adult patients with excellent negative predictive value.
目的
供体游离 DNA 有望成为移植排斥的非侵入性标志物，但尚未在成人和儿童受者中得到验证。本研究旨在验证供体游离 DNA 作为一种非侵入性检测方法，用于评估儿童和成人心脏移植受者发生急性细胞排斥和抗体介导排斥的风险。
方法
从 7 个参与地点招募了儿童和成人心脏移植受者，并在 12 个月或更长时间内进行随访，在每次心内膜心肌活检前采集血浆样本。提取供体游离 DNA 并进行定量基因分型。对供体游离 DNA 和临床数据进行盲法分析，并与之前确定的 0.14%阈值进行比较。计算了敏感性、特异性、阴性预测值、阳性预测值和受试者工作特征曲线。
结果
共收集了 144 例患者的 987 份样本。在应用预先定义的临床和技术排除标准后，130 例患者的 745 份样本产生了 54 份与急性细胞排斥 2R 或更高、病理抗体介导排斥 2 或更高的复合结果相关的排斥样本和 323 份健康样本。对于所有参与者，在 0.14%的阈值下，供体游离 DNA 的敏感性为 67%，特异性为 79%，阳性预测值为 34%，阴性预测值为 94%，曲线下面积为 0.78，用于检测排斥。在相同的 0.14%阈值下，对儿童和成人队列进行独立分析时，这些结果也成立（阴性预测值分别为 92%和 95%）。
结论
在 0.14%的阈值下，供体游离 DNA 可用于评估儿童和成人心脏移植受者发生排斥的风险，具有极好的阴性预测值。
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