Utility of Gene Expression Profiling Score Variability to Predict Clinical Events in Heart Transplant Recipients

Deng, Mario C.1,15,16; Elashoff, Barbara2; Pham, Michael X.3,4; Teuteberg, Jeffrey J.5; Kfoury, Abdallah G.6; Starling, Randall C.7; Cappola, Thomas P.8; Kao, Andrew9; Anderson, Allen S.10; Cotts, William G.11; Ewald, Gregory A.12; Baran, David A.13; Bogaev, Roberta C.14; Shahzad, Khurram15; Hiller, David2; Yee, James2; Valantine, Hannah A.3; for the IMAGE Study Group

Transplantation:
doi: 10.1097/01.TP.0000443897.29951.cf
Clinical and Translational Research
Abstract

Background: Gene expression profiling test scores have primarily been used to identify heart transplant recipients who have a low probability of rejection at the time of surveillance testing. We hypothesized that the variability of gene expression profiling test scores within a patient may predict risk of future events of allograft dysfunction or death.

Method: Patients from the IMAGE study with rejection surveillance gene expression profiling tests performed at 1- to 6-month intervals were selected for this cohort study. Gene expression profiling score variability was defined as the standard deviation of an individual’s cumulative test scores. Gene expression profiling ordinal score (range, 0–39), threshold score (binary value=1 if ordinal score ≥34), and score variability were studied in multivariate Cox regression models to predict future clinical events.

Results: Race, age at time of transplantation, and time posttransplantation were significantly associated with future events in the univariate analysis. In the multivariate analyses, gene expression profiling score variability, but not ordinal scores or scores over threshold, was independently associated with future clinical events. The regression coefficient P values were <0.001, 0.46, and 0.773, for gene expression profiling variability, ordinal, and threshold scores, respectively. The hazard ratio for a 1 unit increase in variability was 1.76 (95% CI, 1.4–2.3).

Discussion: The variability of a heart recipient’s gene expression profiling test scores over time may provide prognostic utility. This information is independent of the probability of acute cellular rejection at the time of testing that is rendered from a single ordinal gene-expression profiling test score.

In Brief

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Author Information

1 University of California, Los Angeles, CA.

2 XDx Inc., Brisbane, CA.

3 Stanford University Medical Center, Stanford, CA.

4 VA Palo Alto Health Care System, Palo Alto, CA.

5 University of Pittsburgh Medical Center, Pittsburgh, PA.

6 Intermountain Medical Center and Intermountain Healthcare, Salt Lake City, UT.

7 Cleveland Clinic, Cleveland, OH.

8 Hospital of the University of Pennsylvania, Philadelphia, PA.

9 Mid America Heart Institute, Saint Luke’s Hospital, Kansas City, MO.

10 University of Chicago Medical Center, Chicago, IL.

11 Northwestern University, Chicago, IL.

12 Washington University School of Medicine, St. Louis, MO.

13 Newark Beth Israel Medical Center, Newark, NJ.

14 Texas Heart Institute, Houston, TX.

15 Columbia University, New York City, NY.

16 Address correspondence to: Mario Deng, M.D., F.A.C.C., F.E.S.C., Advanced Heart Failure/Mechanical Support/Heart Transplant, David Geffen School of Medicine at UCLA, Ronald Reagan UCLA Medical Center, 100 Medical Plaza Drive, Suite 630 Los Angeles, CA 90095.

This study was supported by XDx.

Dr. Deng has received grant support, consulting fees, and honorarium from XDx. Ms Elashoff has received consulting fees from XDx. Dr. Pham has received grant support from XDx. Dr. Teuteberg has received grant support from XDx and has served on an advisory board to XDx. Dr. Kfoury has received grant support, consulting fees, and honorarium from XDx; Dr. Starling has received grant support from XDx. Dr. Cappola has received grant support from XDx and Celladon. A patent on gene expression assays to diagnose and track cardiac allograft rejection arising from independent research is pending. Dr. Cappola is one of the inventors. Dr. Kao has received grant support, consulting fees, and honorarium from XDx. Dr. Anderson has received grant support from XDx. Dr. Cotts has received grant support from XDx. Dr. Ewald has received grant support from XDx. Dr. Baran has received grant support from XDx. Dr. Bogaev has received grant support, consulting fees, and financial support for a Texas Heart Institute CME conference from XDx. Dr. Shahzad has received grant support from XDx. Dr. Hiller is an employee in XDx, and Dr. Yee is an employee and owns equity in XDx. Dr. Valantine has received grant support from XDx and has served on an advisory board to XDx.

E-mail: mdeng@mednet.ucla.edu

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number, NCT00351559.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Received 8 July 2013. Revision requested 30 July 2013.

Accepted 30 September 2013.

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