Donor fraction cell-free DNA and rejection in adult and pediatric heart transplantation

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

doi:10.1016/j.healun.2019.11.015

Donor fraction cell-free DNA and rejection in adult and pediatric heart transplantation

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

^*Corresponding author for this work

Pediatrics

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

71 Scopus citations

Abstract

BACKGROUND: Endomyocardial biopsy (EMB) is the current standard for rejection surveillance in heart transplant recipients. The quantification of donor-specific cell-free DNA (cfDNA) may be an appropriate biomarker for non-invasive rejection surveillance. A multicenter prospective blinded study (DNA-Based Transplant Rejection Test, DTRT) investigated the value of donor fraction (DF), defined as the ratio of cfDNA specific to the transplanted organ to the total amount of cfDNA present in a blood sample. METHODS: A total of 241 heart transplant patients were recruited from 7 centers. Age at transplant ranged from 8 days to 73 years, with 146 subjects <18 years and 95 ≥18 years. All the patients were followed for at least 1 year, with blood samples drawn at routine and for-cause biopsies. A total of 624 biopsy-paired samples were included for analysis through a commercially available cfDNA assay (myTAI_HEART, TAI Diagnostics Inc.). A blinded analysis of repeated measures compared the outcomes using receiver operating characteristic (ROC) curves. All primary clinical end-points were monitored at 100%. All analysis and conclusions were reviewed by both an independent external oversight committee and the National Institutes of Health-mandated DTRT steering committee. RESULTS: DF in acute cellular rejection (ACR) 1R/2R (n = 15) was higher than ACR 0R (n = 42) (p = 0.02); DF in antibody-mediated rejection pAMR1 (n = 8) and pAMR2 (n = 12) (p = 0.05) were higher than pAMR0 (n = 466) (p = 0.04 and p = 0.05 respectively). An optimal DF threshold was determined by the use of an ROC analysis, which ruled out the presence of either ACR or antibody-mediated rejection. CONCLUSIONS: The cell-free DNA DF holds promise as a non-invasive diagnostic test to rule out acute rejection in both adult and pediatric heart transplant populations.

Original language	English (US)
Pages (from-to)	454-463
Number of pages	10
Journal	Journal of Heart and Lung Transplantation
Volume	39
Issue number	5
DOIs	https://doi.org/10.1016/j.healun.2019.11.015
State	Published - May 2020

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 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 specialities 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.

Keywords

cell-free DNA
heart transplantation
non-invasive detection
pediatric heart transplantation
rejection

ASJC Scopus subject areas

Surgery
Pulmonary and Respiratory Medicine
Cardiology and Cardiovascular Medicine
Transplantation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.healun.2019.11.015

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Richmond, M. E., Zangwill, S. D., Kindel, S. J., Deshpande, S. R., Schroder, J. N., Bichell, D. P., Knecht, K. R., Mahle, W. T., Wigger, M. A., Gaglianello, N. A., Pahl, E., Simpson, P. M., Dasgupta, M., North, P. E., Hidestrand, M., Tomita-Mitchell, A., & Mitchell, M. E. (2020). Donor fraction cell-free DNA and rejection in adult and pediatric heart transplantation. Journal of Heart and Lung Transplantation, 39(5), 454-463. https://doi.org/10.1016/j.healun.2019.11.015

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title = "Donor fraction cell-free DNA and rejection in adult and pediatric heart transplantation",

abstract = "BACKGROUND: Endomyocardial biopsy (EMB) is the current standard for rejection surveillance in heart transplant recipients. The quantification of donor-specific cell-free DNA (cfDNA) may be an appropriate biomarker for non-invasive rejection surveillance. A multicenter prospective blinded study (DNA-Based Transplant Rejection Test, DTRT) investigated the value of donor fraction (DF), defined as the ratio of cfDNA specific to the transplanted organ to the total amount of cfDNA present in a blood sample. METHODS: A total of 241 heart transplant patients were recruited from 7 centers. Age at transplant ranged from 8 days to 73 years, with 146 subjects <18 years and 95 ≥18 years. All the patients were followed for at least 1 year, with blood samples drawn at routine and for-cause biopsies. A total of 624 biopsy-paired samples were included for analysis through a commercially available cfDNA assay (myTAIHEART, TAI Diagnostics Inc.). A blinded analysis of repeated measures compared the outcomes using receiver operating characteristic (ROC) curves. All primary clinical end-points were monitored at 100%. All analysis and conclusions were reviewed by both an independent external oversight committee and the National Institutes of Health-mandated DTRT steering committee. RESULTS: DF in acute cellular rejection (ACR) 1R/2R (n = 15) was higher than ACR 0R (n = 42) (p = 0.02); DF in antibody-mediated rejection pAMR1 (n = 8) and pAMR2 (n = 12) (p = 0.05) were higher than pAMR0 (n = 466) (p = 0.04 and p = 0.05 respectively). An optimal DF threshold was determined by the use of an ROC analysis, which ruled out the presence of either ACR or antibody-mediated rejection. CONCLUSIONS: The cell-free DNA DF holds promise as a non-invasive diagnostic test to rule out acute rejection in both adult and pediatric heart transplant populations.",

keywords = "cell-free DNA, heart transplantation, non-invasive detection, pediatric heart transplantation, rejection",

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

note = "Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2020",

month = may,

doi = "10.1016/j.healun.2019.11.015",

language = "English (US)",

volume = "39",

pages = "454--463",

journal = "Journal of Heart and Lung Transplantation",

issn = "1053-2498",

publisher = "Elsevier Inc.",

number = "5",

}

Richmond, ME, Zangwill, SD, Kindel, SJ, Deshpande, SR, Schroder, JN, Bichell, DP, Knecht, KR, Mahle, WT, Wigger, MA, Gaglianello, NA, Pahl, E, Simpson, PM, Dasgupta, M, North, PE, Hidestrand, M, Tomita-Mitchell, A & Mitchell, ME 2020, 'Donor fraction cell-free DNA and rejection in adult and pediatric heart transplantation', Journal of Heart and Lung Transplantation, vol. 39, no. 5, pp. 454-463. https://doi.org/10.1016/j.healun.2019.11.015

TY - JOUR

T1 - Donor fraction cell-free DNA and rejection in adult and pediatric heart transplantation

AU - Richmond, Marc E.

AU - Zangwill, Steven D.

AU - Kindel, Steven J.

AU - Deshpande, Shriprasad R.

AU - Schroder, Jacob N.

AU - Bichell, David P.

AU - Knecht, Kenneth R.

AU - Mahle, William T.

AU - Wigger, Mark A.

AU - Gaglianello, Nunzio A.

AU - Pahl, Elfriede

AU - Simpson, Pippa M.

AU - Dasgupta, Mahua

AU - North, Paula E.

AU - Hidestrand, Mats

AU - Tomita-Mitchell, Aoy

AU - Mitchell, Michael E.

PY - 2020/5

Y1 - 2020/5

N2 - BACKGROUND: Endomyocardial biopsy (EMB) is the current standard for rejection surveillance in heart transplant recipients. The quantification of donor-specific cell-free DNA (cfDNA) may be an appropriate biomarker for non-invasive rejection surveillance. A multicenter prospective blinded study (DNA-Based Transplant Rejection Test, DTRT) investigated the value of donor fraction (DF), defined as the ratio of cfDNA specific to the transplanted organ to the total amount of cfDNA present in a blood sample. METHODS: A total of 241 heart transplant patients were recruited from 7 centers. Age at transplant ranged from 8 days to 73 years, with 146 subjects <18 years and 95 ≥18 years. All the patients were followed for at least 1 year, with blood samples drawn at routine and for-cause biopsies. A total of 624 biopsy-paired samples were included for analysis through a commercially available cfDNA assay (myTAIHEART, TAI Diagnostics Inc.). A blinded analysis of repeated measures compared the outcomes using receiver operating characteristic (ROC) curves. All primary clinical end-points were monitored at 100%. All analysis and conclusions were reviewed by both an independent external oversight committee and the National Institutes of Health-mandated DTRT steering committee. RESULTS: DF in acute cellular rejection (ACR) 1R/2R (n = 15) was higher than ACR 0R (n = 42) (p = 0.02); DF in antibody-mediated rejection pAMR1 (n = 8) and pAMR2 (n = 12) (p = 0.05) were higher than pAMR0 (n = 466) (p = 0.04 and p = 0.05 respectively). An optimal DF threshold was determined by the use of an ROC analysis, which ruled out the presence of either ACR or antibody-mediated rejection. CONCLUSIONS: The cell-free DNA DF holds promise as a non-invasive diagnostic test to rule out acute rejection in both adult and pediatric heart transplant populations.

AB - BACKGROUND: Endomyocardial biopsy (EMB) is the current standard for rejection surveillance in heart transplant recipients. The quantification of donor-specific cell-free DNA (cfDNA) may be an appropriate biomarker for non-invasive rejection surveillance. A multicenter prospective blinded study (DNA-Based Transplant Rejection Test, DTRT) investigated the value of donor fraction (DF), defined as the ratio of cfDNA specific to the transplanted organ to the total amount of cfDNA present in a blood sample. METHODS: A total of 241 heart transplant patients were recruited from 7 centers. Age at transplant ranged from 8 days to 73 years, with 146 subjects <18 years and 95 ≥18 years. All the patients were followed for at least 1 year, with blood samples drawn at routine and for-cause biopsies. A total of 624 biopsy-paired samples were included for analysis through a commercially available cfDNA assay (myTAIHEART, TAI Diagnostics Inc.). A blinded analysis of repeated measures compared the outcomes using receiver operating characteristic (ROC) curves. All primary clinical end-points were monitored at 100%. All analysis and conclusions were reviewed by both an independent external oversight committee and the National Institutes of Health-mandated DTRT steering committee. RESULTS: DF in acute cellular rejection (ACR) 1R/2R (n = 15) was higher than ACR 0R (n = 42) (p = 0.02); DF in antibody-mediated rejection pAMR1 (n = 8) and pAMR2 (n = 12) (p = 0.05) were higher than pAMR0 (n = 466) (p = 0.04 and p = 0.05 respectively). An optimal DF threshold was determined by the use of an ROC analysis, which ruled out the presence of either ACR or antibody-mediated rejection. CONCLUSIONS: The cell-free DNA DF holds promise as a non-invasive diagnostic test to rule out acute rejection in both adult and pediatric heart transplant populations.

KW - cell-free DNA

KW - heart transplantation

KW - non-invasive detection

KW - pediatric heart transplantation

KW - rejection

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DO - 10.1016/j.healun.2019.11.015

M3 - Article

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AN - SCOPUS:85078178592

SN - 1053-2498

VL - 39

SP - 454

EP - 463

JO - Journal of Heart and Lung Transplantation

JF - Journal of Heart and Lung Transplantation

IS - 5

ER -

Donor fraction cell-free DNA and rejection in adult and pediatric heart transplantation

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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