1. Corus™ CAD Overview
Corus CAD Intended Use Statement referenced at the end of this presentation
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2. 38% obstructive coronary
Better Diagnostic Methods are Needed to Stratify Patients for Elective Invasive Angiography8
Patient population:
397,954 stable patients with clinical risk factors and/or symptoms of CAD (but no prior history of CAD) undergoing cardiac catheterization for evaluation
Study found:
62% of patients who underwent elective cardiac catheterization did not have significant CAD
40% of patients had minimal to no CADi
Majority of patients (83.9%) received noninvasive diagnostic testsii prior to referral to catheterization
120
100 80
% of total patients
38% obstructive coronary
artery
disease 60 40 20
Pre-Coronary Angiography
Post-Coronary Angiography
i Minimal to no CAD is defined as < 20% stenosis
ii Resting ECG, exercise or pharmacological stress, echocardiography,
radionucleotide, CT scans, or other heart scans
N=397,954
N=149,739
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3. The Challenge of Assessing CAD1-5
Despite advances in imaging technology, non-invasive assessment of obstructive CAD continues to be subjective and challenging
The complexity of CAD diagnosis lies not only in the variation of presenting symptoms, but also in the patient’s unique characteristics
Implementation of standard of care involving non-invasive imaging assessment of CAD is highly variable regarding the type, number, and sequence of tests
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4. Cardiac Imaging Procedures Deliver Significant Amounts of Ionizing Radiation6
Estimates of Effective Doses for Selected
Cardiac Imaging Procedures (in mSv)
Study reported:
MPI procedures contributed to 74.2% of cumulative effective radiation dose from overall cardiac imaging procedures
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5. MPI is the Largest Contributor of Radiation Overall6
Contribution to Cumulative Effective Radiation Dose
by Type of Cardiac Imaging Procedures (in mSv)
Study design:
This is a subset of the NEJM Fazel 2009 study, focused only on cardiac imaging procedures
Study reported:
MPI procedures contributed to 74.2% of cumulative effective radiation dose from overall cardiac imaging procedures
Radiation dose and risk accumulates over a person’s lifetime
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6. Women Receive Higher Radiation Dosing From Medical Imaging7
In 2009, the NEJM reported:
Cumulative effective doses of radiation from imaging procedures were higher in women than in men
Computed tomography and nuclear imaging accounted for 75.4% of the cumulative effective dose
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7. Genomics: A New Era in Medicine
The Human Genome Project has ushered in the era of genomic medicine and the promise of more individualized patient care
Genomic testing has the power to inform about disease processes at the molecular and cellular level
CardioDx delivers the first and only clinically validated gene expression test to turn the promise of genomic medicine into practice for assessing obstructive* coronary artery disease (CAD)
*Obstructive CAD is defined as at least one atherosclerotic plaque causing ≥50% luminal diameter stenosis in a major coronary artery (≥1.5mm lumen diameter) as determined by invasive quantitative coronary angiography (QCA).
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8. Genetic Testing VS Gene Expression Tests
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9. About Corus™ CAD
The first clinically validated gene expression test for assessing obstructive coronary artery disease (CAD) in non-diabetics
Enables more informed decision-making and risk stratification
Test has high sensitivity and negative predictive value
Test score reflects the presence and extent of obstructive CAD
Test improves classification of patient disease status
A safe and convenient genomic test
Blood sample collection takes minutes, and test results are delivered promptly to the clinician’s office
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10. Clinically Validated Gene Expression Test for the Assessment of Obstructive CAD10,11
Delivers a biological view into a patient’s disease state
Algorithm comprised of expression levels of 23 genes demonstrated to indicate obstructive CAD
Molecular basis includes genes and pathways with known involvement in atherosclerosis and its progression
Based on the detection of a reliable molecular signature for obstructive CAD
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11. Rigorous Multi-Center Product Development and Validation
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12. Corus™ CAD Gene Term Examples3-8
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13. Corus™ CAD Algorithm Terms and Genes4
Males
Females
1) Neutrophil Activation - Apoptosis
Innate Immunity
(IL18RAP, TNFAIP6 CASP5) –
(IL8RB TNFRSF10C, TLR4, KCNE3)
2) Neutrophil Activation/Lymphocytes
Innate Immunity/Cell Necrosis
(S100A8, S100A12, CLEC4E) - RPL28
3) NK Activation/T cells
SLAMF7, KLRC4 - TMC8, CD3D
4) B/T Ratio - Adaptive Immune Response
SPIB, CD79B - TMC8, CD3D
5) AF2- TFCP2, HNRPF
6) TSPAN - TFCP2,HNRPF
1) Neutrophil Activation - Apoptosis
Innate Immunity
(IL18RAP, TNFAIP6 CASP5) –
(IL8RB TNFRSF10C, TLR4, KCNE3)
2) Normalized Neutrophil Activation
Innate Immunity/Cell Necrosis
(S100A8, S100A12, CLEC4E) - (NCF4, AQP9)
3) NK Activation/T cells
SLAMF7, KLRC4 - TMC8, CD3D
4) B/T Ratio - Adaptive Immune Response
SPIB, CD79B - TMC8, CD3D
5) AF2 - TFCP2,HNRPF
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14. Corus™ CAD is Multifactorial
Gene Expression Derived Cell Type Ratios
MOLECULAR & CELLULAR FACTORS
Gene Expression Changes Within a Certain Cell Type
CELL TYPE-SPECIFIC GENE EXPRESSION
Gender-Specific, Age Dependent Coronary Disease Risk Functions
GENDER & AGE RISK FUNCTIONS
U.S. Prevalence of Coronary
Heart Disease by Age & Sex,
NHANES
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15. Clinical Validation Trials PREDICT TRIAL

16. Corus™ CAD Validation Data Published in Annals of Internal Medicine – October 201010
“Rosenberg and colleagues’ study lies at the vanguard of clinical genetics in cardiovascular care. ”
-Excerpt from AIM editorial, Donna Arnett Ph.D., M.S.P.H.

17. PREDICT Summary9,10 Prospective, multi-center, blinded* study
1,343 nondiabetic patients enrolled to develop and validate Corus™ CAD
39 U.S. sites participated
Study PI: Eric Topol, MD, Scripps Research Institute
QCA Core Lab: Alexandra Lansky, MD, Columbia University/CRF
Enrolling sites and investigators included:
Vanderbilt Heart and Vascular Institute (TN)
John McPherson, MD
Washington Hospital Center (DC)
Ron Waksman, MD
Cleveland Clinic Foundation (OH)
Steven Ellis, MD
Minneapolis Heart Institute (MN)
Robert Schwartz, MD
Duke University Medical Center (NC)
Bill Kraus, MD & Kristin Newby MD
Intermountain Medical Center (UT)
Brent Muhlestein, MD
Piedmont Hospital Research Institute (GA)
Szilard Voros, MD
Oklahoma Cardiovascular Research Group (OK)
Naeem Tahirkheli, MD
Allegheny General Hospital (PA)
Tony Farah, MD
*Data was analyzed in a blinded fashion
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18. Personalized Risk Evaluation and Diagnosis In the Coronary Tree
PREDICT Trial Design9,10
Personalized Risk Evaluation and Diagnosis In the Coronary Tree
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19. Probability of CAD in Females and Males as Observed in PREDICT1,2
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20. Corus™ CAD Score is Proportional to Disease Severity4
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21. Clinical Validation Trials COMPASS TRIAL

22. COMPASS Study Overview
Second validation study for Corus™ CAD in the intended use population
Will also evaluate MPI performance in the real-world clinical setting
Prospective, multi-center, blinded* study
450 patients to be enrolled at 21 U.S. sites
QCA Core Lab: Cardiovascular Research Foundation
Study completion: Q4 2010
Steering committee: John McPherson, MD, Alexandra Lansky, MD, Greg Thomas, MD, Szilard Voros, MD
Enrollees include patients referred for a clinically indicated MPI who meet the following criteria**:
Symptomatic (chest pain or anginal equivalent) who have been referred for MPI for the workup of suspected obstructive CAD
Non-diabetic
No known obstructive CAD, prior myocardial infarction, or prior revascularization procedure
*Data to be analyzed in a blinded fashion **Complete inclusion and exclusion criteria may be found in protocol NCT at ClinicalTrials.gov.
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23. COMPASS Trial Design
All non-diabetic patients referred for clinically indicated MPI for chest pain or anginal equivalent symptoms without known obstructive CAD, MI or revascularization were enrolled.
MPI positive patients received invasive angiography if clinically indicated.
MPI negative patients received CT angiography. If clinically indicated, patients went onto catheterization for further evaluation.
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24. Rigorous Data Analysis and Approach Undertaken in the COMPASS Trial
Core lab interpretation with QCA
QCA Core Lab: Cardiovascular Research Foundation
Invasive Angiography
CTA Core Lab Readers: Szilard Voros, MD James R Adams, MD
Core lab interpretation
CT Angiography
On site interpretation
MPI
Core lab interpretation
MPI Core Lab Reader: Timothy M Bateman, MD
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25. Corus® CAD vs. MPI Performance
Site-read MPI
P-value
Sensitivity
89%
27%
p<0.001
NPV
96%
88%
In the COMPASS trial, Corus CAD outperformed MPI in sensitivity and (89% vs. 27%, p<0.001) and negative predictive value (96% vs. 88%, p< 0.001) for ruling out obstructive coronary artery disease
There were 199 (46%) of patients with GES <=15. Corus CAD shows very good sensitivity and NPV for obstructive CAD. This suggests the Corus CAD is significantly better at ruling-out disease without missing patients.
*Summary statistics at a pre-specified threshold of 15
Core-read MPI Sensitivity: 36%
Core-read MPI NPV: 88%
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26. Corus™ CAD Decreases the Rate of False Positive Classifications From MPI4
Case/Total (case %)
MPI Positive*
Corus CAD Overall
76/223 (34%)
Corus CAD Low
6/57 (11%)
Corus CAD Intermediate
21/78 (27%)
Corus CAD High
49/88 (56%)
Legend
MPI Positive
76 cases/223 patients
(34% case rate)
When Corus CAD and MPI disagreed, Corus CAD was correct* 89% of the time and MPI was correct 11% of the time
*MPIs were defined as positive if at least one reversible or fixed defect consistent with obstructive CAD was reported. Indeterminate or intermediate defects were considered negative.
60% of PREDICT validation cohort patients had MPI.
Data from the PREDICT validation cohort, as determined by quantitative coronary angiography (QCA).
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27. Potential New Paradigm of Care based on COMPASS Results
Thomas et al, Circ Cardiovasc Genetics 2 /15/2013; DOI: /CIRCGENETICS
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28. COMPASS Trial Follow-up: Patients with Low Corus® CAD Scores Showed Very Low Event Rates at 6 Months
6-month Follow-up
n=420/431 (97%)
Early Revascularization (within 1 month)
Late Revascularization and MACE (between 1 and 6 months)
Corus CAD ≤15
(n=192)
1 (0.5%)
0 (0%)
Corus CAD >15
(n=228)
24 (11%)
3 (1.3%)
Corus CAD had a sensitivity of 96% and NPV >99% for events and revascularizations at 6-month follow-up
Significant correlation between increasing Corus CAD scores and increased event likelihood*
*p-value =
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29. Relationship Between Corus® CAD Score and Percent Coronary Artery Stenosis
In patients with low Corus CAD scores ( ≤ 15), 96% of patients did not have obstructive CAD
The higher the Corus CAD score, the higher the likelihood of obstructive (≥ 50% stenosis), minimal (1-24%) and moderate (25-49%) CAD, and the lower the likelihood of no disease
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30. CORUS CAD PERFORMANCE at threshold score of 15
Corus® CAD Demonstrates Consistent, Strong Performance in Three Independent Cohorts
CORUS CAD PERFORMANCE at threshold score of 15
COMPASS
(total N=431)
PREDICT-CTA*
(total N=216)
PREDICT
(total N=526)
Sensitivity
89%
83%
85%
Specificity
52%
45%
43%
NPV
96%
93%
Prevalence
15%
16%
37%
Corus CAD outperformed MPI in diagnostic accuracy in the assessment of obstructive CAD in symptomatic patients
Corus CAD AUC** = 0.79*** and MPI AUC = 0.59****
Statistically significant with p < 0.001
*Core-lab CTA **AUC: Area under the curve, a method of measuring diagnostic accuracy
***95% CI **** 95% CI
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31. Corus™ CAD Intended Patients
Corus CAD is intended for use in the following non-diabetic patients that a clinician suspects may have coronary artery disease (CAD):
Asymptomatic High-Risk Patients
Patients with a recent positive or inconclusive test result (ECG, ETT, Echo, MPI, CTA, Calcium Score)
and/or
Patients with 3 or more major risk factors for CAD (e.g., high cholesterol, hypertension, family history, smoker, morbid obesity, known non-cardiac vascular disease, male > 50, female > 60)
Corus CAD is NOT intended for patients:
With known prior myocardial infarction, or who have had a revascularization procedure
Younger than 21 or older than 99 years of age
Who are asymptomatic and not considered at high risk for CAD
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32. Corus™ CAD Patient Sample Kit
All-in-one solution in a convenient patient sample kit
All-in-one solution: sample collection kit, sample shipper, self-contained cooling system
PAXgene®-based sample collection means no processing, no spin-down at the clinic
On-demand cooling system* means no dry-ice, no ice packs for sample shipment back to CardioDx
*Evaporative, adsorption cooling system. Validated to maintain 4°C for 48 hours. For more information visit
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33. Corus™ CAD Test Requisition Form
Account Information
Patient Information
Ordering Clinician's Signature
Billing Information
Blood Draw Information
Comments
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34. Corus™ CAD Patient Report
Patient Score: Ranges between 1 and 40, with higher
values associated with higher
likelihood of obstructive CAD.
Graph: Depicts the relationship between test score and the likelihood of obstructive
CAD in the clinical validation study.
Likelihood of Obstructive CAD: Derives from the patient score and
is reported with a 95% confidence
interval (CI). A 95% CI indicates
there is a 95% chance that the
actual likelihood is within this
range.
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35. Corus™ CAD Intended Use (page 1 of 2)
The Corus CAD test is a quantitative in vitro diagnostic test performed in a single laboratory, using the gene expression profile of cells found in peripheral blood specimens to be used as an aid to identify patients who are likely to have coronary artery stenosis of at least 50%.
The test should be performed on patients with a history of chest pain, with suspected anginal equivalent to chest pain, or with a high risk of coronary artery disease, but with no known prior myocardial infarction or revascularization procedures.
The test is not intended for patients with acute myocardial infarction, high risk unstable angina, systemic infectious or systemic inflammatory conditions, diabetes, and/or who are currently taking steroids, immunosuppressive agents, or chemotherapeutic agents.
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36. Corus™ CAD Intended Use (page 2 of 2)
The test is performed on a blood specimen obtained from the patient.
The test incorporates the expression levels of multiple genes using an algorithm with weighted functions to generate a quantitative score.
The results of the test should be used by clinicians in conjunction with other tests and clinical information in their assessment of a patient’s coronary artery disease.
The Corus CAD test is for prescription use only.
The test is not intended to be used to screen for stenosis among patients who are asymptomatic and not considered at high risk for coronary artery disease, to predict or detect response to therapy, or to help select the optimal therapy for patients.
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