Abstract
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.
Graphical abstract
Graphical Abstract
Key Words
Abbreviations and Acronyms:
ACR (acute cellular rejection), AMR (antibody-mediated rejection), AUC (area under the curve), cfDNA (cell-free DNA), DF (donor fraction), DTRT (DNA-based Transplant Rejection Test), ISHLT (International Society for Heart and Lung Transplantation), NPV (negative predictive value), pAMR (pathologic antibody-mediated rejection), PPV (positive predictive value), QC (quality control), ROC (receiver operating characteristic)To read this article in full you will need to make a payment
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References
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Article info
Publication history
Published online: April 30, 2022
Accepted:
April 19,
2022
Received in revised form:
April 4,
2022
Received:
September 14,
2021
Footnotes
ClinicalTrials.gov ID NCT02109575.
Funding: National Institutes of Health/National Heart, Lung, and Blood Institute 5R01HL119747, TAI Diagnostics.
Institutional Review Board approval (CW DTRT-2 846823), first approval on February 3, 2016. All participants had signed written informed consent/assent for participation in the study and publication of their data as appropriate.
Identification
Copyright
© 2022 by The American Association for Thoracic Surgery
ScienceDirect
Access this article on ScienceDirectLinked Article
- Commentary: Set me free—cell-free DNA may soon provide reprieve to pediatric heart transplant recipientsThe Journal of Thoracic and Cardiovascular SurgeryVol. 165Issue 2
- PreviewRecent studies evaluating the potential of cell-free DNA testing in adult cardiac transplant recipients have demonstrated promise in creating a so-called “liquid biopsy” to serve as a screening laboratory test to assess for allograft rejection.1,2 The authors should be commended for expanding on these efforts and including pediatric cardiac transplant recipients in their analysis.3
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