供体来源的无细胞DNA和组织基因表达在心脏移植患者接受因故心肌活检的相关性。

Andrea Fernandez Valledor,Cathrine M Moeller,Daniel Oren,Julia Baranowska,Salwa Rahman,Adi Hertz,Afsana Rahman,Carolyn Hennecken,Gal Rubinstein,Boaz Elad,Ilan Richter,Dor Lotan,Matthew Regan,Brian LaBarre,Adil Yunis,Justin Fried,Ersilia M DeFilippis,Paolo C Colombo,Melana Yuzefpolskaya,Jayant Raihkelkar,Farhana Latif,Kevin D Clerkin,David T Majure,Gabriel T Sayer,Nir Uriel
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This study aims to assess the accuracy of dd-cfDNA in detecting rejection as identified by MMDx and histology, with a focus on determining an optimal dd-cfDNA threshold to improve diagnostic performance.\r\n\r\nMETHODS\r\nSingle-center prospective study of HT recipients undergoing for-cause biopsies with paired MMDx results and dd-cfDNA levels. We employed a Receiver Operator Curve (ROC) to evaluate the performance of dd-cfDNA levels to detect rejection assessed by both histology and MMDx. We also assessed the correlation between dd-cfDNA levels and MMDx rejection scores. A mixed-effects model was applied to account for repeated dependent samples when appropriate.\r\n\r\nRESULTS\r\n247 for-cause biopsies were identified with a median of 21 months from HT and a median of 11 days between dd-cfDNA and biopsy. 56.7% of the samples had dd-cfDNA levels ≥0.20%. MMDx identified rejection in 27.1% of biopsies, compared to 7.7% identified by histology. 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引用次数: 0

摘要

供体来源的无细胞DNA (dd-cfDNA)和分子显微镜(MMDx)的引入正在改变我们诊断心脏移植(HT)后排斥反应的方式。本研究旨在评估dd-cfDNA通过MMDx和组织学检测排斥反应的准确性,重点是确定最佳dd-cfDNA阈值以提高诊断性能。方法:单中心前瞻性研究,接受有配对MMDx结果和dd-cfDNA水平的HT受体活检。我们采用受试者操作曲线(ROC)来评估dd-cfDNA水平的性能,以检测组织学和MMDx评估的排斥反应。我们还评估了dd-cfDNA水平与MMDx排斥评分之间的相关性。适当时,采用混合效应模型来解释重复依赖样本。结果247例因病活检被确定,从HT到dd-cfDNA的中位时间为21个月,从活检到dd-cfDNA的中位时间为11天。56.7%的样本dd-cfDNA水平≥0.20%。MMDx在27.1%的活组织检查中发现排斥反应,而组织学检查发现排斥反应的比例为7.7%。与组织学相比,dd-cfDNA水平升高与MMDx排异率增加4倍相关,主要是由于ABMR检测增加5倍。Dd-cfDNA在预测MMDx排斥反应方面表现优异(AUC为0.77;最佳截断dd-cfDNA值0.30%)。当纳入混合效应模型时,预测性能进一步提高,(AUC为0.89;最佳临界值0.26%)。相比之下,基于组织学的预测结果的AUC较低,为0.64。dd-cfDNA水平与MMDx排斥评分的相关性为中等(r=0.51;p < 0.001)。结论:在有原因的活检人群中,dd-cfDNA水平升高比组织学更能预测MMDx的排斥反应,这表明分子技术可以比传统的组织学方法更早地检测到排斥反应。当在重复测量的混合效应模型中应用时,dd-cfDNA截断率为0.26%,提供了MMDx拒绝的最高预测精度。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Correlation between Donor-Derived Cell-free DNA and Tissue Gene Expression in Heart Transplant Patients Undergoing for-cause Endomyocardial Biopsies.
INTRODUCTION The introduction of donor-derived cell-free DNA (dd-cfDNA) and the Molecular Microscope (MMDx) is changing how we diagnose rejection following heart transplantation (HT). This study aims to assess the accuracy of dd-cfDNA in detecting rejection as identified by MMDx and histology, with a focus on determining an optimal dd-cfDNA threshold to improve diagnostic performance. METHODS Single-center prospective study of HT recipients undergoing for-cause biopsies with paired MMDx results and dd-cfDNA levels. We employed a Receiver Operator Curve (ROC) to evaluate the performance of dd-cfDNA levels to detect rejection assessed by both histology and MMDx. We also assessed the correlation between dd-cfDNA levels and MMDx rejection scores. A mixed-effects model was applied to account for repeated dependent samples when appropriate. RESULTS 247 for-cause biopsies were identified with a median of 21 months from HT and a median of 11 days between dd-cfDNA and biopsy. 56.7% of the samples had dd-cfDNA levels ≥0.20%. MMDx identified rejection in 27.1% of biopsies, compared to 7.7% identified by histology. Elevated dd-cfDNA levels were associated with a fourfold increase in rejection rates by MMDx, mainly driven by a fivefold increase in ABMR detection when compared to histology. Dd-cfDNA demonstrated superior performance in predicting rejection by MMDx (AUC of 0.77; optimal cut-off dd-cfDNA value 0.30%). When incorporating a mixed-effects model, the predictive performance improved further, (AUC of 0.89; optimal cut-off value 0.26%). In contrast, prediction based on histology resulted in a lower AUC of 0.64. The correlation between dd-cfDNA levels and MMDx rejection scores was moderate (r=0.51; p<0.001). CONCLUSIONS In a for-cause biopsy population, elevated dd-cfDNA levels were more predictive of rejection on MMDx than on histology, suggesting that molecular techniques may detect rejection at earlier stages than traditional histological methods. A dd-cfDNA cutoff of 0.26% provided the highest predictive accuracy for rejection by MMDx when applied within a mixed-effects model for repeated measures.
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