@article{063f995a966545b8a8ba4a5b837d6307,
title = "Relationship between donor fraction cell-free DNA and clinical rejection in heart transplantation",
abstract = "Background: Clinical rejection (CR) defined as decision to treat clinically suspected rejection with change in immunotherapy based on clinical presentation with or without diagnostic biopsy findings is an important part of care in heart transplantation. We sought to assess the utility of donor fraction cell-free DNA (DF cfDNA) in CR and the utility of serial DF cfDNA in CR patients in predicting outcomes of clinical interest. Methods: Patients with heart transplantation were enrolled in two sequential, multi-center, prospective observational studies. Blood samples were collected for surveillance or clinical events. Clinicians were blinded to the results of DF cfDNA. Results: A total of 835 samples from 269 subjects (57% pediatric) were included for this analysis, including 28 samples associated with CR were analyzed. Median DF cfDNA was 0.43 (IQR 0.15, 1.36)% for CR and 0.10 (IQR 0.07, 0.16)% for healthy controls (p <.0001). At cutoff value of 0.13%, the area under curve (AUC) was 0.82, sensitivity of 0.86, specificity of 0.67, and negative predictive value of 0.99. There was serial decline in DF cfDNA post-therapy, however, those with cardiovascular events (cardiac arrest, need for mechanical support or death) showed significantly higher levels of DF cfDNA on Day 0 (2.11 vs 0.31%) and Day 14 (0.51 vs 0.22%) compared to those who did not have such an event (p <.0001). Conclusion: DF cfDNA has excellent agreement with clinical rejection and, importantly, serial measurement of DF cfDNA predict clinically significant outcomes post treatment for rejection in these patients.",
keywords = "biopsy, cell-free DNA, heart transplantation, non-invasive detection, outcomes, pediatric heart transplantation, rejection, surveillance",
author = "Deshpande, {Shriprasad R.} and Zangwill, {Steven D.} and Kindel, {Steven J.} and Schroder, {Jacob N.} and Bichell, {David P.} and Wigger, {Mark A.} and Richmond, {Marc E.} and Knecht, {Kenneth R.} and Elfriede Pahl and Gaglianello, {Nunzio A.} and Mahle, {William T.} and Stamm, {Karl D.} and Simpson, {Pippa M.} and Mahua Dasgupta and Liyun Zhang and North, {Paula E.} and Aoy Tomita-Mitchell and Mitchell, {Michael E.}",
note = "Funding Information: The authors thank the DNA‐Based Transplant Rejection Test (DTRT) study coordinators for collecting and shipping thousands of samples and for their tremendous administrative and regulatory support: Columbia University, Jennie McAllister, Andres Gomez, Arielle Repp; Duke University, Stacey Welsh, Earl Schwarz, Diane Stephenson, Angel Barnes, Sarah Casalinova; Emory University and Children{\textquoteright}s Healthcare of Atlanta, Susie Gentry, Raejanna Ashley; Vanderbilt University, Jill Janssen, Cheri Stewart, Norma Suazo Galeano, Karen Trochez, Ellie Dahms Alexandria Manis, Alesia Pruitt; University of Arkansas, Ginger Gilmore, Denise Graves, Grace Goode, Sheila Stroupe; Children{\textquoteright}s Wisconsin, Gail Stendahl, Julie Schmidt, Alyssa Pollow, Jen Yauck; MCW and Froedtert Hospital, Sue Mauermann, Katie Vannucchi, Mary Wexler, Sue Cotey, Heidi Martin, Janet Gosset; Lurie Children{\textquoteright}s Hospital of Chicago, Kathleen Van{\textquoteright}t Hof, Eniola Oke, Kristina Stevanovic and Paul Haschke. 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: Donna Mahnke, Angeles Baker, Amanda Schmidt, Kimberly Birmingham, Chris Rosenau, Emily Ziegler, Adam Vepraskas, Michael Wheeler, Brook Fricke, Dianah Kornov, Erin Pederson, Kaitlyn Nielsen, Alfonso Baker, Mary Goestch, Huan ling Liang, Mary Krolikowski, Michelle Otto, Alexa Yrineo, Ernest Allen, Pam Baker, Sandy Miller and Anne Laulederkind. This work was funded by a grant from the National Institutes of Health (5R01HL119747) and TAI Diagnostics Inc. through an NIH‐approved third party agreement. No funding organization had any role in the interpretation or analysis of data, and none provided any input or had any right to influence or authorize publication or modification of this manuscript. All analyses, results, conclusions, presentations and publications related to the DTRT study, including all the work contained, herein, are reviewed and approved by an independent external oversight committee whose leader reports directly to the MCW Research Conflict of Interest Committee. The members of the oversight committee are professors engaged in their respective specialties at a large academic medical center and include N.C.F.—a physician bioethicist, D.L.D.—a biostatistician, and J.S.O.—a transplant surgeon. The authors thank these experts and the MCW Research Conflict of Interest Committee for their considerable effort. All the analyses, results, conclusions, presentations and publications related to this study are also reviewed and approved by the NIH‐mandated DTRT steering committee consisting of representative members from all the clinical study sites. Funding Information: The authors thank the DNA-Based Transplant Rejection Test (DTRT) study coordinators for collecting and shipping thousands of samples and for their tremendous administrative and regulatory support: Columbia University, Jennie McAllister, Andres Gomez, Arielle Repp; Duke University, Stacey Welsh, Earl Schwarz, Diane Stephenson, Angel Barnes, Sarah Casalinova; Emory University and Children{\textquoteright}s Healthcare of Atlanta, Susie Gentry, Raejanna Ashley; Vanderbilt University, Jill Janssen, Cheri Stewart, Norma Suazo Galeano, Karen Trochez, Ellie Dahms Alexandria Manis, Alesia Pruitt; University of Arkansas, Ginger Gilmore, Denise Graves, Grace Goode, Sheila Stroupe; Children{\textquoteright}s Wisconsin, Gail Stendahl, Julie Schmidt, Alyssa Pollow, Jen Yauck; MCW and Froedtert Hospital, Sue Mauermann, Katie Vannucchi, Mary Wexler, Sue Cotey, Heidi Martin, Janet Gosset; Lurie Children{\textquoteright}s Hospital of Chicago, Kathleen Van{\textquoteright}t Hof, Eniola Oke, Kristina Stevanovic and Paul Haschke. 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: Donna Mahnke, Angeles Baker, Amanda Schmidt, Kimberly Birmingham, Chris Rosenau, Emily Ziegler, Adam Vepraskas, Michael Wheeler, Brook Fricke, Dianah Kornov, Erin Pederson, Kaitlyn Nielsen, Alfonso Baker, Mary Goestch, Huan ling Liang, Mary Krolikowski, Michelle Otto, Alexa Yrineo, Ernest Allen, Pam Baker, Sandy Miller and Anne Laulederkind. This work was funded by a grant from the National Institutes of Health (5R01HL119747) and TAI Diagnostics Inc. through an NIH-approved third party agreement. No funding organization had any role in the interpretation or analysis of data, and none provided any input or had any right to influence or authorize publication or modification of this manuscript. All analyses, results, conclusions, presentations and publications related to the DTRT study, including all the work contained, herein, are reviewed and approved by an independent external oversight committee whose leader reports directly to the MCW Research Conflict of Interest Committee. The members of the oversight committee are professors engaged in their respective specialties at a large academic medical center and include N.C.F.—a physician bioethicist, D.L.D.—a biostatistician, and J.S.O.—a transplant surgeon. The authors thank these experts and the MCW Research Conflict of Interest Committee for their considerable effort. All the analyses, results, conclusions, presentations and publications related to this study are also reviewed and approved by the NIH-mandated DTRT steering committee consisting of representative members from all the clinical study sites. Publisher Copyright: {\textcopyright} 2022 Wiley Periodicals LLC.",
year = "2022",
month = jun,
doi = "10.1111/petr.14264",
language = "English (US)",
volume = "26",
journal = "Pediatric Transplantation",
issn = "1397-3142",
publisher = "Wiley-Blackwell",
number = "4",
}