1. Bonferroni: Friend or Foe? Multiple Testing in Cardiovascular Medicine Dhruv S. Kazi, MD, MSc AHA Cardiovascular Outcomes Research Fellow Stanford University kazi@stanford.edu

2. “Off hand, I’d say you’re suffering from an arrow through your head, but just to play it safe, let’s get an echo.”

3. Death from Cardiovascular Causes, Nonfatal Myocardial Infarction, or Stroke = 9 billion dollars Yusuf, S, et al. N Engl J Med 2001;345:494-502 CURE

4. Liver Clopidogrel Cytochrome P450-dependent oxidation Binds to P2Y12 Receptor on Platelets Ticagrelor Binds to P2Y12 Receptor on Platelets CYP2C19

5. Potential Strategies  Clopidogrel  Ticagrelor Which one would you want?

6. Cannon, CP, et al. Lancet 2010; 375: 283-93. Primary Efficacy Endpoint in the PLATO-Invasive RCT

7. Cannon, CP, et al. Lancet 2010; 375: 283-93.

12. Methods  Cohort: 100,000 patients who present with ACS and undergo PCI, age at entry – 65 years  Analytic Horizon: Lifetime  Perspective: “Ideal Insurer”  Interventions – DAPT 12 months from last ACS or PCI, whichever is later – Aspirin monotherapy for life thereafter

13. Possible Explanations?

14.  True Difference  Chance Finding  Fraud?

15. The Multiple-Look Problem Number of analyses Cumulative prob of a positive association

17. So how do you get around this? Traditionally, “don’t run multiple subgroups” unless: -The analyses are pre-specified -The analyses are biologically plausible And if you must, conduct rigorous statistical adjustment!

18. Bonferroni Adjustment  Conservative  Assumes independence  1-(1- α ) 1/n ~ α/n  But does this make sense? BMJ. 1998 April 18; 316(7139): 1236–1238.

20. How Do We Proceed? (Do you still want the drug?)  Multiple testing is problematic (even if pre-specified)  The challenges of a priori hypotheses

21. Conclusions  Multiple testing is a complicated question: with real clinical consequences  Statistical adjustment is a necessary but imperfect solution Trial and Error. Kaul S, et al. J Am Coll Cardiol 2010;55:415–27

22. Conclusion The p value is no substitute for a brain.

23. Thank You! kazi@stanford.edu