Coronary Artery Disease

Development of the Corus CAD Gene Expression Test


Phase 1: Gene Discovery
CardioDx® used state-of-the-art technology and in-depth analysis to sort through tens of thousands of genes in over 900 patients, finding hundreds of genes whose expression reflects the presence of obstructive* coronary artery disease (CAD). A rigorous process involving quantitative real time polymerase chain reaction (qRT-PCR) technology was then used to further test and refine this discovery gene set.

Corus® CAD concept testing and discovery was accomplished by defining patients as cases and controls based on coronary angiographic data. A series of microarray experiments led to candidate genes whose expression levels were significantly associated with the presence of obstructive CAD. These results were then extended by literature data mining and confirmed for the most significant genes by qRT-PCR. As published in Wingrove et al., Circulation Cardiovascular Genetics 2008, two major conclusions were reached: first, that of the 35 genes found significant in the Siegburg cohort, 27 were confirmed in the Duke CATHGEN registry samples, and second, that the changes in gene expression were proportional to the maximum percent stenosis.1

Phase 2: Algorithm Development
A total of 640 patient blood samples were used and 113 genes were examined by qRT-PCR. Analysis of clinical data with these gene expression results identified sex, age, and diabetic status as the most important variables affecting gene expression. Using a variety of statistical techniques, an algorithm that incorporates sex and age and the expression levels of 23 genes was derived, as described in Elashoff et al (2011).2

Phase 3: Algorithm Validation
The Corus CAD test was prospectively validated in an independent set of 526 patients, where the test demonstrated a sensitivity (the probability that someone with obstructive CAD has a positive test result ) of 85 percent and a negative predictive value (the probability that someone with a negative test result does not have obstructive CAD) of 83 percent.

The results were published in October of 2010 in the Annals of Internal Medicine.3

Click here for more information about PREDICT.4

 

PREDICT Development and Validation Approach for Corus CAD


* Obstructive CAD is defined as at least one atherosclerotic plaque causing ≥50% luminal diameter stenosis in a major coronary artery (≥1.5 mm lumen diameter) as determined by invasive quantitative coronary angiography (QCA).
  1. Wingrove JA, Daniels SE, Sehnert AJ, et al. Correlation of peripheral-blood gene expression with the extent of coronary artery stenosis. Circ Cardiovasc Genet. 2008;1:31–38
  2. Elashoff MR, Wingrove JA, Beineke P, et al. Development of a blood-based gene expression algorithm for assessment of obstructive coronary artery disease in non-diabetic patients. BMC Medical Genomics. 2011;4:26.
  3. Rosenberg S, Elashoff MR, Beineke P, et al. Multicenter validation of the diagnostic accuracy of a blood-based gene expression test for assessing obstructive coronary artery disease in nondiabetic patients. Ann Intern Med. 2010;153:425–434.
  4. PREDICT trial. Clinical trial summary found at: www.clinicaltrials.gov, NCT00500617.