Applying rigor and reproducibility standards to assay donor-derived cell-free DNA as a non-invasive method for detection of acute rejection and graft injury after heart transplantation

被引：58

作者：

Agbor-Enoh, Sean ^{[1
,2
,3
]}

Tunc, Ilker ^{[1
]}

De Vlaminck, Iwijn ^{[4
]}

Fideli, Ulgen ^{[1
,3
]}

Davis, Andrew ^{[1
,3
]}

Cuttin, Karen ^{[1
,3
]}

Bhatti, Kenneth ^{[1
,3
]}

Marishta, Argit ^{[1
,3
]}

Solomon, Michael A. ^{[1
,5
]}

Jackson, Annette ^{[2
,3
]}

Graninger, Grace ^{[5
]}

Harper, Bonnie ^{[5
]}

Luikart, Helen ^{[6
]}

Wylie, Jennifer ^{[6
]}

Wang, Xujing ^{[1
]}

Berry, Gerald ^{[6
]}

Marboe, Charles ^{[7
]}

Khush, Kiran ^{[6
]}

Zhu, Jun ^{[1
]}

Valantine, Hannah ^{[1
,3
]}

机构：

[1] NHLBI, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA

[2] Johns Hopkins Sch Med, Pulm & Critical Care Med, Baltimore, MD USA

[3] NHLBI, Lab Transplantat Genom, Bldg 10, Bethesda, MD 20892 USA

[4] Cornell Univ, Meinig Sch Biomed Engn, Dept Bioengn, Ithaca, NY USA

[5] NIH, Ctr Clin, Bethesda, MD 20892 USA

[6] Stanford Univ, Sch Med, Dept Med, Palo Alto, CA 94304 USA

[7] New York Presbyterian Univ Hosp Cornell & Columbi, Dept Med, New York, NY USA

来源：

JOURNAL OF HEART AND LUNG TRANSPLANTATION | 2017年 / 36卷 / 09期

基金：

美国国家卫生研究院;

关键词：

reproducibility; cell-free DNA; allograft rejection; heart transplantation; automated; KIDNEY-TRANSPLANTS; GENERATION; VALIDATION; RECIPIENTS; PHENOTYPE; DIAGNOSIS;

D O I：

10.1016/j.healun.2017.05.026

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND: Use of new genomic techniques in clinical settings requires that such methods are rigorous and reproducible. Previous studies have shown that quantitation of donor-derived cell-free DNA (%ddcfDNA) by unbiased shotgun sequencing is a sensitive, non-invasive marker of acute rejection after heart transplantation. The primary goal of this study was to assess the reproducibility of %ddcfDNA measurements across technical replicates, manual vs automated platforms, and rejection phenotypes in distinct patient cohorts. METHODS: After developing and validating the %ddcfDNA assay, we subjected the method to a rigorous test of its reproducibility. We measured %ddcfDNA in technical replicates performed by 2 independent laboratories and verified the reproducibility of %ddcfDNA patterns of 2 rejection phenotypes: acute cellular rejection and antibody-mediated rejection in distinct patient cohorts. RESULTS: We observed strong concordance of technical-replicate %ddcfDNA measurements across 2 independent laboratories (slope = 1.02, R-2 > 0.99, p < 10(-6)), as well as across manual and automated platforms (slope = 0.80, R-2 = 0.92, p < 0.001). The %ddcfDNA measurements in distinct heart transplant cohorts had similar baselines and error rates. The %ddcfDNA temporal patterns associated with rejection phenotypes were similar in both patient cohorts; however, the quantity of ddcfDNA was significantly higher in samples with severe vs mild histologic rejection grade (2.73% vs 0.14%, respectively; p < 0.001). CONCLUSIONS: The %ddcfDNA assay is precise and reproducible across laboratories and in samples from 2 distinct types of heart transplant rejection. These findings pave the way for larger studies to assess the clinical utility of %ddcfDNA as a marker of acute rejection after heart transplantation. (C) 2017 Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. All rights reserved.

引用

页码：1004 / 1012

页数：9

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