title: Circulating cell-free DNA enables noninvasive diagnosis of heart transplant rejection.
abstract: Monitoring allograft health is an important component of posttransplant therapy. Endomyocardial biopsy is the current gold standard for cardiac allograft monitoring but is an expensive and invasive procedure. Proof of principle of a universal, noninvasive diagnostic method based on high-throughput screening of circulating cell-free donor-derived DNA (cfdDNA) was recently demonstrated in a small retrospective cohort. We present the results of a prospective cohort study (65 patients, 565 samples) that tested the utility of cfdDNA in measuring acute rejection after heart transplantation. Circulating cell-free DNA was purified from plasma and sequenced (mean depth, 1.2 giga-base pairs) to quantify the fraction of cfdDNA. Through a comparison with endomyocardial biopsy results, we demonstrate that cfdDNA enables diagnosis of acute rejection after heart transplantation, with an area under the receiver operating characteristic curve of 0.83 and sensitivity and specificity that are comparable to the intrinsic performance of the biopsy itself. This noninvasive genome transplant dynamics approach is a powerful and informative method for routine monitoring of allograft health without incurring the risk, discomfort, and expense of an invasive biopsy.
authors.affiliation: Departments of Bioengineering and Applied Physics, Stanford University, Stanford, CA 94305, USA. Howard Hughes Medical Institute, Stanford, CA 94305, USA.
authors.forename: Iwijn
authors.initials: I
authors.lastname: De Vlaminck
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Hannah A
authors.initials: HA
authors.lastname: Valantine
authors.affiliation: Departments of Bioengineering and Applied Physics, Stanford University, Stanford, CA 94305, USA. Howard Hughes Medical Institute, Stanford, CA 94305, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Snyder
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Calvin
authors.initials: C
authors.lastname: Strehl
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Garrett
authors.initials: G
authors.lastname: Cohen
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Luikart
authors.affiliation: Departments of Bioengineering and Applied Physics, Stanford University, Stanford, CA 94305, USA. Howard Hughes Medical Institute, Stanford, CA 94305, USA.
authors.forename: Norma F
authors.initials: NF
authors.lastname: Neff
authors.affiliation: Departments of Bioengineering and Applied Physics, Stanford University, Stanford, CA 94305, USA. Howard Hughes Medical Institute, Stanford, CA 94305, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Okamoto
authors.affiliation: Department of Pediatrics (Cardiology), Stanford University and the Stanford Cardiovascular Research Institute, Stanford, CA 94305, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bernstein
authors.affiliation: Office of Heart Transplant Services, Kaiser Permanente Northern California, Santa Clara Medical Center, Santa Clara, CA 95051, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Weisshaar
authors.affiliation: Departments of Bioengineering and Applied Physics, Stanford University, Stanford, CA 94305, USA. Howard Hughes Medical Institute, Stanford, CA 94305, USA. kiran@stanford.edu quake@stanford.edu.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Quake
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. kiran@stanford.edu quake@stanford.edu.
authors.forename: Kiran K
authors.initials: KK
authors.lastname: Khush
mesh_terms: D004247:DNA / Q000097:blood*; D042241:Early Diagnosis; D006084:Graft Rejection / Q000175:diagnosis*; D016027:Heart Transplantation; D006801:Humans; D012189:Retrospective Studies
chemical_list: D004247:DNA