Clinical usefulness of gene-expression profile to rule out acute rejection after heart transplantation: CARGO II

Abstract

AimsA non-invasive gene-expression profiling (GEP) test for rejection surveillance of heart transplant recipients originated in the USA. A European-based study, Cardiac Allograft Rejection Gene Expression Observational II Study (CARGO II), was conducted to further clinically validate the GEP test performance.Methods and resultsBlood samples for GEP testing (AlloMap®, CareDx, Brisbane, CA, USA) were collected during post-transplant surveillance. The reference standard for rejection status was based on histopathology grading of tissue from endomyocardial biopsy. The area under the receiver operating characteristic curve (AUC-ROC), negative (NPVs), and positive predictive values (PPVs) for the GEP scores (range 0–39) were computed. Considering the GEP score of 34 as a cut-off (>6 months post-transplantation), 95.5% (381/399) of GEP tests were true negatives, 4.5% (18/399) were false negatives, 10.2% (6/59) were true positives, and 89.8% (53/59) were false positives. Based on 938 paired biopsies, the GEP test score AUC-ROC for distinguishing ≥3A rejection was 0.70 and 0.69 for ≥2–6 and >6 months post-transplantation, respectively. Depending on the chosen threshold score, the NPV and PPV range from 98.1 to 100% and 2.0 to 4.7%, respectively.ConclusionFor ≥2–6 and >6 months post-transplantation, CARGO II GEP score performance (AUC-ROC = 0.70 and 0.69) is similar to the CARGO study results (AUC-ROC = 0.71 and 0.67). The low prevalence of ACR contributes to the high NPV and limited PPV of GEP testing. The choice of threshold score for practical use of GEP testing should consider overall clinical assessment of the patient's baseline risk for rejection.

Genetic and Functional Profiling of CD16-Dependent Natural Killer Activation Identifies Patients at Higher Risk of Cardiac Allograft Vasculopathy

“…The current challenge is to identify non-invasive biomarkers that enable the early stratification of patients at risk 2,[5][6][7][8] to tailor individualized therapeutic approaches that prevent HT failure 6,9 .…”

Myocardial biopsy: techniques and indications

“…AlloMap molecular expression testing has a very high negative predictive value for ACR, with a negative predictive value range at 6 months found to be 98.1%–100% 35. EMB remains the gold standard investigation to test for presence of rejection but CMR has been shown to have a high negative predictive value and may have a role in non-transplant centres as a screening tool prior to biopsy.…”

The AlloMap™ genomic biomarker story: 10 years after

“…The broad CARGO heart transplantation inclusion criteria had two important consequences: (i) It allowed seamless translation after CLIA‐certification 2005 and FDA‐clearance 2008 into practice in the United States. (ii) It led to reproducibility in the European heart transplant population in the CARGO II study …”

“…The CARGO investigators felt that after completion of internal validation, the external validation in a completely independent clinical cohort needed to be accomplished before CLIA-approval and clinical implementation. In addition, the CARGO investigators felt that the demographics validation in a European cohort (CARGO II Study) 19 and the clinical strategy comparison in the IMAGE study 15 were necessary for full acceptance in the field.…”