Transcript The Case of the Women's Health Initiative Randomized Trial

The Case of the Women's Health
Initiative Randomized Trial:
A Statistician Reads a Paper
Dan Freeman, Ph.D.
Professor, Preventive Medicine and Community Health
Director, Office of Biostatistics
2-6355 [email protected]
The Rationale for the Trial
“The preponderance of evidence from the
epidemiologic studies strongly supports
the view that postmenopausal estrogen
therapy can substantially reduce the risk
for coronary heart disease....This effect is
unlikely to be explained by confounding
factors or selection.”
(Stampfer Colditz 1991: p 61)
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And, an unexpected ending
“Results from the WHI [Women’s Health
Initiative] indicate that the combined
postmenopausal hormones ... should not
be initiated or continued for the primary
prevention of CHD ....”
(Writing Group for the Women’s Health Initiative
Investigators 2002: p 332)
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July 10, 2002
Hormone Replacement Study A Shock
to the Medical System
By GINA KOLATA with MELODY PETERSEN
September 3, 2002
The announcement yesterday
that a Through
hormone
Sorting
the Confusion
replacement regimen taken by six million American
Over
women did more harm than
goodEstrogen
was met with
By JANE E. BRODY
puzzlement and disbelief by women and their doctors
Susan McGee of Bethesda, Md., and Jane
across the country.
Quinn of Brooklyn were not planning to take
hormones at menopause. But after many months
of sleep disrupted nightly by drenching sweats and
changes of bedclothes, they gave in.
JAMA, November 6, 2002 – Vol 288, No. 17
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What went wrong?
• Was it study design?
– Observational vs Experimental
• Was it statistical inference?
– Multiple Comparisons
• Conclusions
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Study Designs in
Medical Research
• Observational Studies
– Traditional medicine
• Experimental Studies
– Scientific basis of modern medicine
• Meta-analyses
– Evidenced based medicine
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Controlled Trials
Direction of Inquiry and Time
Intervention
Onset of Study
No
Outcome
Experimental
Outcome
Study Eligible
Subjects
Randomization
No
Outcome
Controls
Outcome
What will happen?
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Controlled Trials: Examples
Lind’s study of scurvy
• Physician’s Health
Study
– Aspirin and
cardiovascular
disease
• Women’s Health
Initiative – HRT
• Virtually, all new
drug applications
require RCT’s
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Comparison of Proportions
Science 297, 19 July 2002: 326
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Multiple
Hypothesis
Tests
Something has to
be ‘significant’
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Confidence Intervals
Uncertainty. The range of likely risk from hormone therapy is
wider when the data are adjusted for multiple sampling.
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Conclusions
1. The statistical issues hinge on multiple
comparisons
2. The earlier observational studies were
correctly executed but have inherent
weaknesses.
3. It is possible that the factors that led to the
long-term use are also protective against
CHD: Exercise – Diet – Not Smoking
4. Further clinical trials are critical
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Further Conclusions
Dr. Susan Hendrix, a gynecologist at Wayne State University in
Detroit who was an investigator in the federal study. "It's pretty
astounding to go from a year ago thinking this is one of the most
benign drugs to a 180-degree turn in the opposite direction."
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