Validation of donor fraction cell-free DNA with biopsy-proven cardiac allograft rejection in children and adults |
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| Affiliation: | 1. Division of Pediatric Cardiology, Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY;2. Division of Pediatric Cardiology, Children''s National Heart Institute, Children''s National Hospital, Washington, DC;3. Division of Cardiology, Phoenix Children''s Hospital, Phoenix, Ariz;4. Division of Pediatric Cardiac Surgery, Department of Surgery, Vanderbilt University, Nashville, Tenn;5. Division of Pediatric Cardiology, Department of Pediatrics, Medical College of Wisconsin, Herma Heart Institute, Children''s Wisconsin, Milwaukee, Wis;6. Division of Cardiology, Department of Pediatrics, Emory University, Children''s Healthcare of Atlanta, Atlanta, Ga;7. Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Duke University, Durham, NC;8. Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University, Nashville, Tenn;9. Department of Pediatrics, Arkansas Children''s Hospital, Little Rock, Ark;10. Cardiology, Lurie Children''s Hospital, Chicago, Ill;11. Department of Medicine, Medical College of Wisconsin, Milwaukee, Wis;12. Department of Surgery, Medical College of Wisconsin, Milwaukee, Wis;13. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wis;14. Department of Pathology, Medical College of Wisconsin, Children''s Wisconsin, Milwaukee, Wis;15. Division of Pediatric Cardiothoracic Surgery, Department of Surgery, Medical College of Wisconsin, Herma Heart Institute, Milwaukee, Wis;1. Department of Pediatrics, Children''s Hospital & Medical Center, University of Nebraska, Omaha, Nebraska;2. Department of Pediatrics, Children''s Hospital & Regional Medical Center, University of Washington, Seattle, Washington;3. Department of Pediatrics, The Heart Institute, Cincinnati Children''s Hospital & Medical Center, University of Cincinnati, Cincinnati, Ohio;4. Department of Pediatrics, Great Ormond Street Hospital, London, United Kingdom;6. Department of Surgery, University of Alabama Birmingham, Birmingham, Alabama;5. Department of Pediatrics, Duke Children''s Hospital, Durham, North Carolina;7. Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina;11. Department of Pediatrics, Texas Children''s Hospital, Baylor College of Medicine, Houston, Texas;12. Department of Pediatrics, Sibley Heart Center, Children''s Health Care of Atlanta, Emory University School of Medicine, Atlanta, Georgia;1. Division of Thoracic Surgery and Interventional Pulmonology, Beth Israel Deaconess Medical Center, Boston, Mass;2. Department of Radiology, Cardiothoracic Imaging, Beth Israel Deaconess Medical Center, Boston, Mass;1. University of Arizona College of Medicine–Phoenix Campus, Phoenix, Ariz;2. Norton Thoracic Institute Research Laboratory, St Joseph''s Hospital and Medical Center, Phoenix, Ariz;3. Division of Thoracic Surgery, Norton Thoracic Institute, St Joseph''s Hospital and Medical Center, Phoenix, Ariz;1. Division of Cardiac Surgery, University of Virginia, Charlottesville, Va;2. Virginia Cardiac Services Quality Initiative, Falls Church, Va;3. Michigan Society of Thoracic and Cardiovascular Surgeons Quality Collaborative, Ann Arbor, Mich;4. Department of Cardiac Surgery, Queen Elizabeth University Hospital, Birmingham, United Kingdom;5. Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY;6. Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, Md;7. Inova Heart and Vascular Institute, Falls Church, Va;8. Department of Cardiac Surgery, University of Michigan, Ann Arbor, Mich;9. Department of Cardiovascular and Thoracic Surgery, West Virginia University, Morgantown, WVa |
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| Abstract: | ObjectivesDonor-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.MethodsPediatric 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.ResultsA 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).ConclusionsDonor 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. |
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| Keywords: | cell-free DNA endomyocardial biopsy heart transplantation pediatric heart transplantation rejection ACR" },{" #name" :" keyword" ," $" :{" id" :" kwrd0040" }," $$" :[{" #name" :" text" ," _" :" acute cellular rejection AMR" },{" #name" :" keyword" ," $" :{" id" :" kwrd0050" }," $$" :[{" #name" :" text" ," _" :" antibody-mediated rejection AUC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0060" }," $$" :[{" #name" :" text" ," _" :" area under the curve cfDNA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0070" }," $$" :[{" #name" :" text" ," _" :" cell-free DNA DF" },{" #name" :" keyword" ," $" :{" id" :" kwrd0080" }," $$" :[{" #name" :" text" ," _" :" donor fraction DTRT" },{" #name" :" keyword" ," $" :{" id" :" kwrd0090" }," $$" :[{" #name" :" text" ," _" :" DNA-based Transplant Rejection Test ISHLT" },{" #name" :" keyword" ," $" :{" id" :" kwrd0100" }," $$" :[{" #name" :" text" ," _" :" International Society for Heart and Lung Transplantation NPV" },{" #name" :" keyword" ," $" :{" id" :" kwrd0110" }," $$" :[{" #name" :" text" ," _" :" negative predictive value pAMR" },{" #name" :" keyword" ," $" :{" id" :" kwrd0120" }," $$" :[{" #name" :" text" ," _" :" pathologic antibody-mediated rejection PPV" },{" #name" :" keyword" ," $" :{" id" :" kwrd0130" }," $$" :[{" #name" :" text" ," _" :" positive predictive value QC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0140" }," $$" :[{" #name" :" text" ," _" :" quality control ROC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0150" }," $$" :[{" #name" :" text" ," _" :" receiver operating characteristic |
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