TY - JOUR
T1 - Validation of donor fraction cell-free DNA with biopsy-proven cardiac allograft rejection in children and adults
AU - Richmond, Marc E.
AU - Deshpande, Shriprasad R.
AU - Zangwill, Steven D.
AU - Bichell, David P.
AU - Kindel, Steven J.
AU - Mahle, William T.
AU - Schroder, Jacob N.
AU - Wigger, Mark A.
AU - Knecht, Kenneth R.
AU - Pahl, Elfriede
AU - Gaglianello, Nunzio A.
AU - Goetsch, Mary A.
AU - Simpson, Pippa
AU - Dasgupta, Mahua
AU - Zhang, Liyun
AU - North, Paula E.
AU - Tomita-Mitchell, Aoy
AU - Mitchell, Michael E.
N1 - Funding Information:
The authors thank the DTRT study coordinator team for collection and shipment of thousands of samples and for their tremendous administrative and regulatory support. The teams are from the following institutions: Columbia University, Duke University, Emory University and Children's Healthcare of Atlanta, Vanderbilt University, Children's Wisconsin, MCW and Froedtert Hospital, and Lurie Children's Hospital of Chicago. The authors also thank the TAI Diagnostics, CAN AM, MCW/CW study team for running samples, quality assurance, regulatory support, core support, and data monitoring. All information related to the DTRT study, including work contained herein, was reviewed and approved by the DTRT Steering Committee. Funding: National Institutes of Health/National Heart, Lung, and Blood Institute 5R01HL119747, TAI Diagnostics.
Publisher Copyright:
© 2022 The American Association for Thoracic Surgery
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - cell-free DNA
KW - endomyocardial biopsy
KW - heart transplantation
KW - pediatric heart transplantation
KW - rejection
UR - http://www.scopus.com/inward/record.url?scp=85130912386&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85130912386&partnerID=8YFLogxK
U2 - 10.1016/j.jtcvs.2022.04.027
DO - 10.1016/j.jtcvs.2022.04.027
M3 - Article
C2 - 35643770
AN - SCOPUS:85130912386
JO - Journal of Thoracic and Cardiovascular Surgery
JF - Journal of Thoracic and Cardiovascular Surgery
SN - 0022-5223
ER -