title: Performance of gene-expression profiling test score variability to predict future clinical events in heart transplant recipients.
abstract: BACKGROUND
  A single non-invasive gene expression profiling (GEP) test (AlloMap®) is often used to discriminate if a heart transplant recipient is at a low risk of acute cellular rejection at time of testing. In a randomized trial, use of the test (a GEP score from 0-40) has been shown to be non-inferior to a routine endomyocardial biopsy for surveillance after heart transplantation in selected low-risk patients with respect to clinical outcomes. Recently, it was suggested that the within-patient variability of consecutive GEP scores may be used to independently predict future clinical events; however, future studies were recommended. Here we performed an analysis of an independent patient population to determine the prognostic utility of within-patient variability of GEP scores in predicting future clinical events.
  
  
  METHODS
  We defined the GEP score variability as the standard deviation of four GEP scores collected ≥315 days post-transplantation. Of the 737 patients from the Cardiac Allograft Rejection Gene Expression Observational (CARGO) II trial, 36 were assigned to the composite event group (death, re-transplantation or graft failure ≥315 days post-transplantation and within 3 years of the final GEP test) and 55 were assigned to the control group (non-event patients). In this case-controlled study, the performance of GEP score variability to predict future events was evaluated by the area under the receiver operator characteristics curve (AUC ROC). The negative predictive values (NPV) and positive predictive values (PPV) including 95 % confidence intervals (CI) of GEP score variability were calculated.
  
  
  RESULTS
  The estimated prevalence of events was 17 %. Events occurred at a median of 391 (inter-quartile range 376) days after the final GEP test. The GEP variability AUC ROC for the prediction of a composite event was 0.72 (95 % CI 0.6-0.8). The NPV for GEP score variability of 0.6 was 97 % (95 % CI 91.4-100.0); the PPV for GEP score variability of 1.5 was 35.4 % (95 % CI 13.5-75.8).
  
  
  CONCLUSIONS
  In heart transplant recipients, a GEP score variability may be used to predict the probability that a composite event will occur within 3 years after the last GEP score.
  
  
  BACKGROUND
  Clinicaltrials.gov identifier NCT00761787.
authors.affiliation: Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), SERGAS. Universidade da Coruña (UDC), Coruña, Spain. marisa.crespo.leiro@sergas.es.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Crespo-Leiro
authors.affiliation: University Hospital Muenster, Muenster, Germany. stypmann@ukmuenster.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.affiliation: Ruhr University of Bochum, Bad Oeynhausen, Germany. uschulz@hdz-nrw.de.
authors.forename: Uwe
authors.initials: U
authors.lastname: Schulz
authors.affiliation: Medical University of Vienna, Vienna, Austria. andreas.zuckermann@meduniwien.ac.at.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zuckermann
authors.affiliation: University Hospital Bern, Bern, Switzerland. Paul.Mohacsi@insel.ch.
authors.forename: Paul
authors.initials: P
authors.lastname: Mohacsi
authors.affiliation: Hannover Medical School, Hannover, Germany. bara.christoph@mh-hannover.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bara
authors.affiliation: Toronto General Hospital, Toronto, Canada. Heather.Ross@uhn.ca.
authors.forename: Heather
authors.initials: H
authors.lastname: Ross
authors.affiliation: Papworth Hospital, Papworth Everard, Cambridge, UK. Jayan.Parameshwar@papworth.nhs.uk.
authors.forename: Jayan
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authors.lastname: Parameshwar
authors.affiliation: Silesian Center for Heart Disease, Zabrze, Poland. zaklimed@onet.pl.
authors.forename: Michal
authors.initials: M
authors.lastname: Zakliczyński
authors.affiliation: Ospedali Riuniti di Bergamo, Bergamo, Italy. roberto.fiocchi@gmail.com.
authors.forename: Roberto
authors.initials: R
authors.lastname: Fiocchi
authors.affiliation: Innsbruck Medical University, Innsbruck, Austria. Daniel.Hoefer@i-med.ac.at.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hoefer
authors.affiliation: David Geffen School of Medicine, University of California, Los Angeles, USA. MDeng@mednet.ucla.edu.
authors.forename: Mario
authors.initials: M
authors.lastname: Deng
authors.affiliation: Groupe Hospitalier Pitié-Salpêtrière, Paris, France. pascal.leprince@psl.aphp.fr.
authors.forename: Pascal
authors.initials: P
authors.lastname: Leprince
authors.affiliation: CareDx, Brisbane, USA. dhiller@caredx.com.
authors.forename: David
authors.initials: D
authors.lastname: Hiller
authors.affiliation: CareDx, Brisbane, USA. leubank@caredx.com.
authors.forename: Lane
authors.initials: L
authors.lastname: Eubank
authors.affiliation: CareDx, Brisbane, USA. edeljkich@caredx.com.
authors.forename: Emir
authors.initials: E
authors.lastname: Deljkich
authors.affiliation: CareDx, Brisbane, USA. Jyee@caredx.com.
authors.forename: James P
authors.initials: JP
authors.lastname: Yee
authors.affiliation: University Hospital of Leuven, Leuven, Belgium. johan.vanhaecke@uzleuven.be.|Department of Cardiology, Herestraat 49, 3000, Leuven, Belgium. johan.vanhaecke@uzleuven.be.
authors.forename: Johan
authors.initials: J
authors.lastname: Vanhaecke
mesh_terms: D005260:Female; D020869:Gene Expression Profiling; D006084:Graft Rejection; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D012086:Reoperation; D012307:Risk Factors