AlloMap molecular expression testing
AlloMap molecular expression testing, developed and commercialized by CareDx, formerly known as XDx, is a gene expression profiling test to identify heart transplant recipients with a low probability of one type of transplant rejection. The test is performed on a blood sample, providing a non-invasive test to help manage the care of patients post transplant. Prior to the availability of this test, the primary method for managing heart transplant rejection was the invasive technique of endomyocardial biopsy.[1]
Test results are reported as a single score indicating the probability of moderate/severe acute cellular rejection (ACR). The performance characteristics of the test make it best suited to help indicate that acute cellar rejection is not present. The score is based on the amount of RNA from each gene in a 20-gene panel comprising 11 rejection-related genes and 9 genes used for normalization and quality control. Many of the rejection-related genes are associated with biological pathways involved in the immune response and rejection processes.[2]
The test score is used, along with other standard clinical assessments, to evaluate the patient’s probability of acute cellular rejection and the need for additional evaluations. This test is not designed to be informative about other forms of heart rejections such as antibody-mediated rejection (AMR) or cardiac allograft vasculopathy (CAV).
AlloMap has been commercially available since 2005 as a CLIA approved Laboratory Developed Test (LDT) and was cleared by the U.S. Food and Drug Administration (FDA) in 2008 as a Class II Medical Device.[3] It is available only from the CareDx Reference Laboratory in Brisbane, CA.
The use of the test is described in the recommendations for the non-invasive monitoring of acute heart transplant rejection in the first evidence-based clinical practice guidelines for the care of heart transplant recipients issued by the International Society of Heart and Lung Transplantation.[4]
CareDx, Inc., announced on June 3, 2014 that it has filed a registration statement on Form S-1 with the U.S. Securities and Exchange Commission relating to the proposed initial public offering of shares of its common stock.[5]
Contents
Development
The test was developed using genomics and bioinformatics technologies. DNA microarrays were used to discover 252 candidate genes for which the amount of RNA in blood samples was related to rejection. Quantitative real-time polymerase chain reaction technology (qRT-PCR) confirmed 68 of the candidate genes from which the 20-gene gene expression panel was selected. The diagnostic performance was verified using independent patient samples from a multicenter clinical study.[6] Initial clinical experience at three medical centers was published in 2006, confirming the efficacy and performance of the AlloMap test.[7]
Clinical studies
CARGO Study
The development and clinical validation of the test used patient samples and clinical data obtained during the Cardiac Allograft Rejection Gene Expression Observational (CARGO) Study. From 2001 to 2005, 737 patients from nine U.S. transplant centers enrolled in the Study and contributed 5,834 blood samples and associated clinical data.[6] Initial clinical experience at three medical centers was published in 2006, confirming the efficacy and performance of the test.[7]
IMAGE Study
A comparative effectiveness study, the Invasive Monitoring Attenuation through Gene Expression (IMAGE) Study, compared clinical outcomes of patients managed with AlloMap to outcomes of patients managed with endomyocardial biopsy. The study, which ran from 2005–09, included 602 patients from thirteen U.S. centers who were at least six months post-transplant. The results showed that AlloMap was not inferior to endomyocardial biopsy with respect to clinical outcomes when used to monitor stable, asymptomatic heart transplant patients.[8]
Indications for use
The test is currently indicated for use in heart transplant recipients 15 years of age or older, and at least 2 months (≥55 days) post-transplant.
Method of use
The test is based on standard quantitative real-time polymerase chain reaction technology (qRT-PCR) using RNA isolated from peripheral blood mononuclear cells (PBMC). A blood sample is collected, PBMC are isolated, lysed and the released RNA stabilized and frozen (PBMC lysate). RNA is then purified from the PBMC lysate, converted into complementary DNA (cDNA), and mixed with gene-specific primers and probes. The expression of each gene is measured by amplification and fluorescence detection using a qRT-PCR instrument. A mathematical classifier combines the measured expression values for each gene into a single value reported as a score between 0 and 40.
Each score is associated with a negative predictive value (NPV) and a positive predictive value (PPV). The test is characterized by high negative predictive values and is therefore a test used to help identify patients at low probability of rejection. The test has a relatively low positive predictive value, meaning that even when the score is relatively high, the risk of rejection may still be low.
References
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- ↑ http://www.accessdata.fda.gov/cdrh_docs/reviews/K073482.pdf
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- ↑ http://xdx.com/wp-content/uploads/2014/06/20140603-CareDx-Release_vFINAL.pdf
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