Effect of acyclovir on herpetic ocular recurrence using a ... · Herpetic Eye Disease Study (HEDS)...
Transcript of Effect of acyclovir on herpetic ocular recurrence using a ... · Herpetic Eye Disease Study (HEDS)...
9 Jan 06 Symposium on Causal Inference 1
Effect of acyclovir on herpetic ocular recurrence using a structural nested model (and some context)
Stephen R. Cole and Haitao ChuDepartment of EpidemiologyJohns Hopkins Bloomberg School of Public Health
http://statepi.jhsph.edu/~scole/index.htm
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Herpetic Eye Disease Study (HEDS)
• HEDS Study Group NEJM 1998; 339: 300
• 703 adults with ocular HSV inactive in prior month
• Randomized between 1992.67 and 1997.0
• 365 days of 400 mg oral acyclovir or placebo
• Study visits at 1, 3, 6, 9, 12 months, and as needed
• Patients and physicians well masked
• Endpoint was first recurrence of ocular HSV
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Characteristics at randomization
Acyclovir PlaceboN = 357 N = 346
Male 55 % 52 %Caucasian 80 % 78 %Years of age 50 ± 18 48 ± 18Severe 39 % 38 %
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Number of days followed and treated
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Methods
• Nested structural AFT modelU(i) = 0∫T(i) exp[α0X(i,t)]dt
- U(i) is event time for subject i under no exposure- T(i) is observed event time- X(i,t) is 1 if exposed to acyclovir on day t, else 0- exp(-α0) is the time expansion factor
• G-estimation- line-search across {α} for α* = α0- α* is the member of {α} yielding ƒ[U(i, α*)|R(i)] =
ƒ[U(i,α*)], where R(i) indicates randomized group
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Alpha {α} versus test statistic
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Results
Hazard 95% CIRatio
Intent-to-treat 0.55 0.41, 0.75Structural model 0.41 0.22, 0.76As-treated 0.62 0.45, 0.84
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Survival curves
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Assumptions, Limitations
• Assume potential outcomes of one participant are
independent of potential outcomes of others
• Assume compliance information is correct
• Assume no heterogeneity in effect
• Weibull distribution assumed to obtain hazard ratio
• Dropout model assumed correct
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Context: We do not account for noncompliance in biomedical RCTs
NEJM volumes 352 and 353 in 2005
203 research articles92 randomized clinical trials
≥74 intention-to-treat analyses0 analyses accounting for noncompliance
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Context: When we do, it will only make a difference roughly half the time
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Context: When we do, it will only make a difference roughly half the time
Cole, Chu CCT 2005
Korhonen, et al SIM 1999
Joffe SIM 2001
Mark, Robins
CCT 1993
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Context: Some of the times it makes no difference are particularly insidious
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Context: Some of the times it makes no difference are particularly insidious
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Effect of acyclovir on herpetic ocular recurrence using a structural nested model (and some context)
Stephen R. Cole and Haitao ChuDepartment of EpidemiologyJohns Hopkins Bloomberg School of Public Health
http://statepi.jhsph.edu/~scole/index.htm
Thank you for your time