1. 1 Comparing Zero Coronary Artery Calcium With Other Negative Risk Factors for Coronary Heart Disease A Novel Methodology: Risk-Adjusted Negative Likelihood Ratios Multi-Ethnic Study of Atherosclerosis (MESA) Michael J. Blaha 1, Bill McEvoy 1, Ron Blankstein 2, Matthew J. Budoff 3, Chris Sibley 4, Moyses Szklo 5, Richard Kronmal 6, Roger S. Blumenthal 1, Khurram Nasir 1, 7 ** Author affiliations in acknowledgements

2. 2 Negative Risk Factors Most novel biomarkers marginally improve risk prediction at population level, adding little for individual patient Theme of reporting: risk factor X adds slightly increases predicted risk  more testing, more treatment needed! Less attention is paid to “negative” risk factors despite tremendous potential public health implications “Imaging Hypothesis” – due to high sensitivity, NPV >> PPV, potential value as negative risk factors

3. 3 Tools for Comparing Risk Factors Survival analysis - HR ROC Analysis – c-statistic Net reclassification improvement (NRI) Do not communicate change in “risk” to the clinician decision-maker Do not emulate Bayesian decision making Specific Aim: Adapt a methodology for calculating and comparing risk-adjusted LRs and apply to “negative risk factors” Likelihood Ratios (LRs) – “Bayes Factors” Directly communicate the change in risk before and after knowledge of a new test result

4. 4 Methods: Risk-Adjusted Likelihood Ratios logit P post-test = logit P pre-test + log LR * X = Framingham Risk Factors + race/ethnicity (Gu and Pepe 2009) ** Y = Negative Risk Factor, i.e. CAC=0 ** *** Calculate estimated LR for each MESA participant, for negative risk factor *** METHODS *

5. August 20, 20155 Multi-Ethnic Study of Atherosclerosis Negative Risk Factor Prevalence in MESA hsCRP <2 mg/L52% Homocysteine <10 umol/L 69% BNP <100 pg/mL71% No Metabolic Syndrome 67% No microalbuminuria 90% No family history57% Normal ABI (1.0 – 1.3) 85% No carotid plaque58% Normal cIMT (<25 th percentile) 25% Zero CAC50% Multicenter study of 6,814 individuals free of known cardiovascular disease Follow-up for All CHD events over mean 7.1 years **

6. Post-Test Risk vs. Pre-Test Risk (Baseline logistic model) (Augmented logistic model) * Linear fit Zero CAC

7. August 20, 20157 Patient 1 Intermediate Risk White Man Pre-Test Risk 10% 55 years old Total cholesterol 200 mg/dL HDL 35 mg/dL Moderate treated hypertension Logit p post = logit p pre + log LR CAC=0, post-test risk ~4%** ** 10-year risk extrapolated from 7.1 year risk 0 0.35

8. 8 Important Covariates Influencing Likelihood Ratio for CAC=0 AgePre-Test Risk

9. Limitations – Pre-Test risk estimate What is the correct tool for estimating pre-test risk? Very poor calibration of FRS in MESA  Recalibrated 10-year “MESA FRS” for All CHD  Therefore LRs immediately useful for MESA FRS, not traditional FRS Rescale factor = (MESA FRS/Traditional FRS) = 0.67  All CHD vs. Hard CHD Rescale factor = 0.40

10. 10 Intermediate Risk AA Woman 70 years old Smoker Total cholesterol 240 mg/dL HDL 50 mg/dL Mild treated hypertension  MESA Risk All CHD = 10%  FRS Hard CHD Risk = 14% Logit p post = logit p pre + log LR Post-test All CHD risk ~3% Post-test Hard CHD risk ~1.8% Rescaled Likelihood Ratio  FRS All CHD = 0.20  FRS Hard CHD = 0.12 EXAMPLE USING CAC=0 Likelihood Ratio if CAC=0  MESA All CHD = 0.30

11. 11 iJACC paper, Lancet paper

12. August 20, 201512 Conclusions and Implications The risk-adjusted likelihood ratio is a powerful, clinically-usable tool for comparing incremental value of risk factors Imaging tests, specifically CAC=0, are strongest negative risk factors for CHD CAC=0, which is present in 50% of MESA, appears to have a LR consistently in “clinically helpful” range

13. 13 Acknowledgements We wish to thank all the volunteer research participants who made this study possible. This research was supported by contracts R01 HL071739, N01- HC-95159 through N01-HC-95165, and N01-HC-95169 from the National Heart, Lung, and Blood Institute. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. http://www.mesa-nhlbi.org Author Affiliations: 1 Johns Hopkins Ciccarone Center for Prevention of Heart Disease, Baltimore, MD 2 Brigham and Women's Hosp Non-invasive CV Imaging Program, Boston, MA 3 Division of Cardiology, Harbor-UCLA Medical Center, Torrance, CA 4 National Institutes of Health, Bethesda, MD 5 Johns Hopkins University, School of Public Health, Baltimore, MD 6 University of Washington, Seattle, WA 7 Yale University School of Medicine, New Haven, CT

14.  Prevalence of coronary calcium increases with age.

15. Mortality Rate (per 1000 person-years) With Increasing Coronary Artery Calcium Scores & Traditional Risk Factors Nasir K, Blaha MJ, et al. Circulation Outcomes. 2011