Performance of gene-expression profiling test score variability to predict future clinical events in heart transplant recipients

Abstract

BackgroundA 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.MethodsWe 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.ResultsThe 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).ConclusionIn 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.Trial registrationClinicaltrials.gov identifier NCT00761787Electronic supplementary materialThe online version of this article (doi:10.1186/s12872-015-0106-1) contains supplementary material, which is available to authorized users.

High-Sensitivity Troponin T and Soluble Form of AXL as Long-Term Prognostic Biomarkers after Heart Transplantation

“…Based on these results, it is likely that HTx recipients with low hs-cTnT values (<21 ng/L) could undergo less frequent CAV evaluation. Recently, the AlloMap gene expression profile test has also shown a high negative predictive value to estimate the likelihood of events in patients beyond 315 days post-HTx [ 27 ]. However, this test is expensive, not widespread used, and only limited data supports its use for prognosis assessment; in contrast, hs-cTnT is an inexpensive test that can be processed in most centers and can be applied to all HTx patients regardless their renal function status.…”

The AlloMap™ genomic biomarker story: 10 years after

“…Conversely, an individual predicted to be at higher risk for future events may receive further evaluation to detect possible underlying causes of the variability such as overlooked infections or non‐compliance to medications . In an independent validation study on AlloMap variability (AMV) in the CARGO II cohort, the AMV concept was confirmed …”

“…30 In an independent validation study on AlloMap variability (AMV) in the CARGO II cohort, the AMV concept was confirmed. 31…”

Personalized treatment in heart transplantation

“…The “AlloMap score variability (AMV)” was defined as the standard deviation of four AlloMap scores collected ≥315 days post-transplant. In a retrospective analysis of the CARGO II trial,(23) the negative predictive value for an adverse event (death, retransplant, or graft failure) with an AMV score of 0.6 was 97% (95 % CI 91.4–100.0), while the positive predictive value for an AMV score of 1.5 was 35.4% (95 % CI 13.5–75.8). (23) Use of the AMV assay for individualized care has not been widely adopted, however, due to the need for at least four AlloMap scores collected ≥315 days post-transplant, at a time when routine acute rejection surveillance is performed infrequently, and the fact that there is a long lag time between the calculation of an AMV score and a potential clinical event.…”