Test Development & Validation

Scientific Precedent for Corus™ CAD
Recent Research Established the Potential for Corus CAD
Rigorous Multi-Center Validation Delivered on the Promise of Corus CAD
The PREDICT Study
Corus CAD: From Discovery to Validation

 

Scientific Precedent for Corus CAD

  • There is an established role for inflammation in the pathophysiology of atherosclerosis1,2
  • Large-scale gene expression studies have identified a set of genes differentially expressed between diseased and normal arterial tissues3,4
  • Changes in peripheral blood mononuclear cells (PMBC) and platelet gene expression are correlated with coronary artery disease (CAD) or acute coronary syndrome (ACS)5

Back To Top

Recent Research Established the Potential for Corus CAD

The results of the research reported by Wingrove, et al.6 using two independent archived single-center cohorts directly demonstrated that a correlation exists between the extent of CAD and changes in peripheral blood gene expression.

First Cohort: Helios Heart Center - Siegburg, Germany

  • Subset 1 (27 cases, 14 controls): Microarray analysis yielded 526 genes with >1.3 fold differential expression between cases and controls
  • Subset 2 (63 cases, 32 controls): qRT-PCR replication on 106 genes yielded 35 genes (p <.05) of which 14 genes were significant in multivariate analysis

Second Cohort: Duke University Medical Center - Durham, North Carolina

  • Subset 1 (86 cases, 21 controls): Replicated 11 of the 14 significant genes from the multivariant analysis of first cohort in Germany
  • An analysis of these 14 genes in a superset of 215 CATHGEN patients demonstrated that gene expression was proportional to maximal CAD


3-0-1_Gene_Correlation

Gene expression levels signal the presence of CAD, and the signal is proportional to the extent of disease. Maximal gene expression levels indicate maximal stenosis.6

Back To Top

Rigorous Multi-Center Validation Delivered on the Promise of Corus CAD

Beginning with the hypothesis that there is a strong correlation between peripheral blood gene expression and CAD, CardioDx designed a rigorous scientific plan and a prospective, multi-center clinical study - PREDICT - to determine if a gene expression test could identify obstructive* CAD.7

Using the evidence from Wingrove et al. as a foundation, CardioDx designed a rigorous scientific plan and a prospective, multi-center clinical study - Personalized Risk Evaluation and Diagnosis in the Coronary Tree (PREDICT) - to determine whether a gene expression signature in peripheral blood cells could significantly classify the likelihood of patients having obstructive* CAD.

PREDICT enabled CardioDx to ensure integrity of sample processing and clinical data across a wide variety of clinical sites, going beyond the use of single center cohorts.

Back To Top

The PREDICT Study

PREDICT was a prospective, multi-center, blinded† clinical study that enrolled 1,795 non-diabetic patients in over 40 clinical sites in the United States to develop and validate a gene expression test for obstructive CAD in stable chest pain patients. The result, Corus CAD, is a clinically validated test that has been developed via proven, reproducible clinical and scientific methods. For more information, see Strong Test Performance.

Study Design


3-0-1_Study_Design

Study Overview 

  • Enrolled patients with chest pain undergoing invasive coronary angiography who met study inclusion criteria
  • Employed consistent and reliable sample collection and processing techniques
  • Collected extensive clinical data that was monitored and source-verified for accurate clinical phenotyping and analysis
  • Performed quantitative coronary angiography (QCA) on invasive angiograms using a blinded core laboratory to determine an unbiased reference standard for the primary endpoint of luminal diameter stenosis due to coronary artery disease
  • Compared gene expression between groups of cases with ≥50% diameter stenosis and controls with <50% diameter stenosis as determined by QCA

For more information about the PREDICT study, see clinicaltrials.gov.

Back To Top

Corus CAD: From  Discovery to Validation

How Corus CAD Was Developed

Corus CAD was developed using a rigorous, phased approach that started with gene discovery and proceeded to algorithm development and validation. Independent patient cohorts were used in each of the three phases to ensure a robust product that delivers reliable results in real-world clinical settings.

Phase 1: Gene Discovery

CardioDx used state-of-the-art technologies and in-depth analysis to sort through tens of thousands of genes in over 900 patients, finding signals from hundreds of genes that reflect the presence of obstructive CAD. A rigorous process involving qRT-PCR (quantitative real time polymerase chain reaction) technology was then used to further test and refine this discovery gene set.

Phase 2: Algorithm Development

Using samples from over 600 patients, scientists at CardioDx developed an algorithm that integrates the expression levels of 23 genes and other patient characteristics that have been demonstrated to indicate obstructive CAD. The final score informs on the likelihood a patient has obstructive CAD.

Phase 3: Algorithm Validation

The Corus CAD algorithm was prospectively validated in an independent set of 526 patients. For more information about the results of the validation study, see Corus CAD Benefits.

 3-0-2_Algorithm_Validation

Back To Top

 

* 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).
† Data was analyzed in a blinded fashion.

  1. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352(16):1685-1695.
  2. Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation. 2005;111(25):3481-3488.
  3. King JY, Ferrara R, Tabibiazar R, et al. Pathway analysis of coronary atherosclerosis. Physiol Genomics. 2005;23(1):103-118. Epub 2005 Jun 7.
  4. Seo D, Wang T, Dressman H, et al. Gene expression phenotypes of atherosclerosis. 1: Arterioscler Thromb Vasc Biol. 2004;24(10):1922-1927. Epub 2004 Aug 5.
  5. Healy AM, Pickard MD, Pradhan AD, et al. Platelet expression profiling and clinical validation of myeloid-related protein-14 as a novel determinant of cardiovascular events. Circ. 2006;113(19):2278-2284.
  6. 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; 1:31-28.
  7. PREDICT trial. Clinical trial summary found at: www.clinicaltrials.gov, NCT00500617.
  8. Diamond GA, Forrester JS. Analysis of probability as an aid in the clinical diagnosis of coronary-artery disease. N Engl J Med. 1979. 300(24):1350-8.
  9. CLIA #05D1083624.