project: cardiodx

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Corus CAD Discovery and Development

Phase 1: Gene Discovery

CardioDx used state-of-the-art technology and in-depth analysis to sort through tens of thousands of genes in more than 900 patients, finding hundreds of genes, that, when differentially expressed, reflect the presence or absence of obstructive coronary artery disease (CAD)*. A rigorous process involving quantitative real time polymerase chain reaction (RT-qPCR) technology was then used to further test and refine this discovery gene set.

Concept testing and discovery for the Corus CAD test 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 RT-qPCR. From these findings, published in Circulation: Cardiovascular Genetics in 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: Product Algorithm Development

A total of 640 patient blood samples were used, and 113 genes were examined by RT-qPCR. 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 genes was derived, as described in BMC Medical Genomics in 2011.2

Phase 3: Product Algorithm Validation

The Corus CAD test was prospectively validated in an independent set of 526 patients from the PREDICT study, where the test demonstrated a sensitivity (the probability that someone with obstructive CAD has a positive test result) of 85% and a negative predictive value (the probability that someone with a negative test result does not have obstructive CAD) of 83%. The results were published in October 2010 in the Annals of Internal Medicine.3

3 0 2 Algorithm Validation V3 


* 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 or coronary computed tomography angiography (≥2.0 mm lumen diameter).

  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 Med 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.