bonferroni: friend or foe? multiple testing in cardiovascular medicine dhruv s. kazi, md, msc aha...
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Bonferroni: Friend or Foe?Multiple Testing in Cardiovascular Medicine
Dhruv S. Kazi, MD, MScAHA Cardiovascular Outcomes Research FellowStanford Universitykazi@stanford.edu
“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.”
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ardi
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No
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yoca
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arct
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= 9 billion dollars
Yusuf, S, et al. N Engl J Med 2001;345:494-502
CURE
Liver
Clopidogrel
Cytochrome P450-dependent oxidation
Binds to P2Y12 Receptor on Platelets
Ticagrelor Binds to P2Y12 Receptor on Platelets
CYP2C19
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
The Multiple-Look Problem
Number of analyses
Cum
ulati
ve p
rob
of
a po
sitiv
e as
soci
ation
0 10 20 30 40 50 60 70 80 90 1000
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
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!
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.
How Do We Proceed? (Do you still want the drug?) Multiple testing is problematic (even if pre-specified) The challenges of a priori hypotheses
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
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