Increase in nuclear cell-free DNA is associated with major adverse events in adult and pediatric heart transplant recipients

Steven D. Zangwill; Shriprasad R. Deshpande; Pippa M. Simpson; Huan Ling Liang; Liyun Zhang; Mahua Dasgupta; Marc E. Richmond; Steven J. Kindel; David P. Bichell; William T. Mahle; Mark A. Wigger; Jacob N. Schroder; Kenneth R. Knecht; Elfriede Pahl; Nunzio A. Gaglianello; Paula E. North; Aoy Tomita-Mitchell; Michael E. Mitchell

doi:10.1111/ctr.14509

Increase in nuclear cell-free DNA is associated with major adverse events in adult and pediatric heart transplant recipients

Steven D. Zangwill, Shriprasad R. Deshpande, Pippa M. Simpson, Huan Ling Liang, Liyun Zhang, Mahua Dasgupta, Marc E. Richmond, Steven J. Kindel, David P. Bichell, William T. Mahle, Mark A. Wigger, Jacob N. Schroder, Kenneth R. Knecht, Elfriede Pahl, Nunzio A. Gaglianello, Paula E. North, Aoy Tomita-Mitchell^*, Michael E. Mitchell

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Background: Cell-free DNA is an emerging biomarker. While donor fraction may detect graft events in heart transplant recipients, the prognostic value of total nuclear cell-free DNA (ncfDNA) itself is largely unexplored. Objective: Explore the relationship between ncfDNA and clinical events in heart transplant recipients. Methods: We conducted a multi-center prospective study to investigate the value of cell-free DNA in non-invasive monitoring following heart transplantation. Over 4000 blood samples were collected from 388 heart transplant patients. Total ncfDNA and donor fraction were quantified. Generalized linear models with maximum likelihood estimation for repeated measures with subjects as clusters were used to explore the relationship of ncfDNA and major adverse events. Receiver operating characteristic curves were used to help choose cutpoints. Results: A ncfDNA threshold (50 ng/ml) was identified that was associated with increased risk of major adverse events. NcfDNA was elevated in patients who suffered cardiac arrest, required mechanical circulatory support or died post heart transplantation as well as in patients undergoing treatment for infection. Conclusions: Elevated ncfDNA correlates with risk for major adverse events in adult and pediatric heart transplant recipients and may indicate a need for enhanced surveillance after transplant.

Original language	English (US)
Article number	e14509
Journal	Clinical Transplantation
Volume	36
Issue number	1
DOIs	https://doi.org/10.1111/ctr.14509
State	Published - Jan 2022

Funding

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 analysis, results, conclusions, presentations and publications related to this study are reviewed and approved by the NIH mandated DTRT steering committee consisting of representative members from all the clinical study sites. We thank Karl Stamm, PhD along with all the DTRT research coordinators as well as Donna Mahnke, Mary Goetsch, Mary Krolikowski, Michelle Otto, and Anne Laulederkind.

ASJC Scopus subject areas

Transplantation

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Zangwill, S. D., Deshpande, S. R., Simpson, P. M., Liang, H. L., Zhang, L., Dasgupta, M., Richmond, M. E., Kindel, S. J., Bichell, D. P., Mahle, W. T., Wigger, M. A., Schroder, J. N., Knecht, K. R., Pahl, E., Gaglianello, N. A., North, P. E., Tomita-Mitchell, A., & Mitchell, M. E. (2022). Increase in nuclear cell-free DNA is associated with major adverse events in adult and pediatric heart transplant recipients. Clinical Transplantation, 36(1), Article e14509. https://doi.org/10.1111/ctr.14509

@article{868576ee3d5c4cfbb1f2003e93a0be8b,

title = "Increase in nuclear cell-free DNA is associated with major adverse events in adult and pediatric heart transplant recipients",

abstract = "Background: Cell-free DNA is an emerging biomarker. While donor fraction may detect graft events in heart transplant recipients, the prognostic value of total nuclear cell-free DNA (ncfDNA) itself is largely unexplored. Objective: Explore the relationship between ncfDNA and clinical events in heart transplant recipients. Methods: We conducted a multi-center prospective study to investigate the value of cell-free DNA in non-invasive monitoring following heart transplantation. Over 4000 blood samples were collected from 388 heart transplant patients. Total ncfDNA and donor fraction were quantified. Generalized linear models with maximum likelihood estimation for repeated measures with subjects as clusters were used to explore the relationship of ncfDNA and major adverse events. Receiver operating characteristic curves were used to help choose cutpoints. Results: A ncfDNA threshold (50 ng/ml) was identified that was associated with increased risk of major adverse events. NcfDNA was elevated in patients who suffered cardiac arrest, required mechanical circulatory support or died post heart transplantation as well as in patients undergoing treatment for infection. Conclusions: Elevated ncfDNA correlates with risk for major adverse events in adult and pediatric heart transplant recipients and may indicate a need for enhanced surveillance after transplant.",

author = "Zangwill, {Steven D.} and Deshpande, {Shriprasad R.} and Simpson, {Pippa M.} and Liang, {Huan Ling} and Liyun Zhang and Mahua Dasgupta and Richmond, {Marc E.} and Kindel, {Steven J.} and Bichell, {David P.} and Mahle, {William T.} and Wigger, {Mark A.} and Schroder, {Jacob N.} and Knecht, {Kenneth R.} and Elfriede Pahl and Gaglianello, {Nunzio A.} and North, {Paula E.} and Aoy Tomita-Mitchell and Mitchell, {Michael E.}",

note = "Publisher Copyright: {\textcopyright} 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.",

year = "2022",

month = jan,

doi = "10.1111/ctr.14509",

language = "English (US)",

volume = "36",

journal = "Clinical Transplantation",

issn = "0902-0063",

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number = "1",

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Zangwill, SD, Deshpande, SR, Simpson, PM, Liang, HL, Zhang, L, Dasgupta, M, Richmond, ME, Kindel, SJ, Bichell, DP, Mahle, WT, Wigger, MA, Schroder, JN, Knecht, KR, Pahl, E, Gaglianello, NA, North, PE, Tomita-Mitchell, A & Mitchell, ME 2022, 'Increase in nuclear cell-free DNA is associated with major adverse events in adult and pediatric heart transplant recipients', Clinical Transplantation, vol. 36, no. 1, e14509. https://doi.org/10.1111/ctr.14509

TY - JOUR

T1 - Increase in nuclear cell-free DNA is associated with major adverse events in adult and pediatric heart transplant recipients

AU - Zangwill, Steven D.

AU - Deshpande, Shriprasad R.

AU - Simpson, Pippa M.

AU - Liang, Huan Ling

AU - Zhang, Liyun

AU - Dasgupta, Mahua

AU - Richmond, Marc E.

AU - Kindel, Steven J.

AU - Bichell, David P.

AU - Mahle, William T.

AU - Wigger, Mark A.

AU - Schroder, Jacob N.

AU - Knecht, Kenneth R.

AU - Pahl, Elfriede

AU - Gaglianello, Nunzio A.

AU - North, Paula E.

AU - Tomita-Mitchell, Aoy

AU - Mitchell, Michael E.

PY - 2022/1

Y1 - 2022/1

N2 - Background: Cell-free DNA is an emerging biomarker. While donor fraction may detect graft events in heart transplant recipients, the prognostic value of total nuclear cell-free DNA (ncfDNA) itself is largely unexplored. Objective: Explore the relationship between ncfDNA and clinical events in heart transplant recipients. Methods: We conducted a multi-center prospective study to investigate the value of cell-free DNA in non-invasive monitoring following heart transplantation. Over 4000 blood samples were collected from 388 heart transplant patients. Total ncfDNA and donor fraction were quantified. Generalized linear models with maximum likelihood estimation for repeated measures with subjects as clusters were used to explore the relationship of ncfDNA and major adverse events. Receiver operating characteristic curves were used to help choose cutpoints. Results: A ncfDNA threshold (50 ng/ml) was identified that was associated with increased risk of major adverse events. NcfDNA was elevated in patients who suffered cardiac arrest, required mechanical circulatory support or died post heart transplantation as well as in patients undergoing treatment for infection. Conclusions: Elevated ncfDNA correlates with risk for major adverse events in adult and pediatric heart transplant recipients and may indicate a need for enhanced surveillance after transplant.

AB - Background: Cell-free DNA is an emerging biomarker. While donor fraction may detect graft events in heart transplant recipients, the prognostic value of total nuclear cell-free DNA (ncfDNA) itself is largely unexplored. Objective: Explore the relationship between ncfDNA and clinical events in heart transplant recipients. Methods: We conducted a multi-center prospective study to investigate the value of cell-free DNA in non-invasive monitoring following heart transplantation. Over 4000 blood samples were collected from 388 heart transplant patients. Total ncfDNA and donor fraction were quantified. Generalized linear models with maximum likelihood estimation for repeated measures with subjects as clusters were used to explore the relationship of ncfDNA and major adverse events. Receiver operating characteristic curves were used to help choose cutpoints. Results: A ncfDNA threshold (50 ng/ml) was identified that was associated with increased risk of major adverse events. NcfDNA was elevated in patients who suffered cardiac arrest, required mechanical circulatory support or died post heart transplantation as well as in patients undergoing treatment for infection. Conclusions: Elevated ncfDNA correlates with risk for major adverse events in adult and pediatric heart transplant recipients and may indicate a need for enhanced surveillance after transplant.

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DO - 10.1111/ctr.14509

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JO - Clinical Transplantation

JF - Clinical Transplantation

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Increase in nuclear cell-free DNA is associated with major adverse events in adult and pediatric heart transplant recipients

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