Presentations in this series1. Introduction2. Self-matching3. Proxies4. Intermediates5. Instruments6. Equipoise
Avoiding Bias Due toUnmeasured Covariates
Alec Walker
T D
U
T D
URandomization
T D
URandomizationSelf-matching
Celecoxibversus
Naproxen versus
No Treatment
PUBHospital
Admission
Celecoxib, Naproxen and GI Bleeding
in the treatment of pain
MD-perceived risk of peptic ulcer & bleeding (PUB)
True risk of PUB
Confounding by Contraindication
High risk for peptic ulcer and bleeding makes treatment with naproxen inadvisable. Celecoxib would be better. No treatment at all is safest.
Celecoxibversus
Naproxenversus
No Treatment
PUBHospital
Admission
MD-perceived risk of peptic ulcer & bleeding (PUB)
True risk of PUB
The physician’s belief, not the true risk, is what affects the choice of therapy.
Celecoxibversus
Naproxenversus
No Treatment
PUBHospital
Admission
MD-perceived risk of peptic ulcer & bleeding (PUB)
True risk of PUB
Celecoxib Ulcer
PUB
Celecoxib Ulcer
Celecoxib UlcerConfounded
Self-Matching
KeyCelecoxibNaproxen
No TherapyEvent X
X
X
Self-Matching
KeyCelecoxibNaproxen
No TherapyEvent X
X
X
When there is no event, there is no within-person comparison to be made, if we’re looking at relative risk.
Celecoxibversus
Naproxenversus
No Treatment
PUBHospital
Admission
MD-perceived risk of peptic ulcer & bleeding (PUB)
True risk of PUB
Matching on person means that all comparisons are within person and therefore at a common level of physician perception.
Celecoxibversus
Naproxenversus
No Treatment
PUBHospital
Admission
MD-perceived risk of peptic ulcer & bleeding (PUB)
True risk of PUB
Celecoxibversus
Naproxenversus
No Treatment
PUBHospital
Admission
MD-perceived risk of peptic ulcer & bleeding (PUB)
True risk of PUB
The time of observation needs to be sufficiently short that true risk and physician perception do not change.
Compare the Exposure at Case Occurrenceto Sampled Exposure(s) in the Past
Non-Cases Drop Out of Consideration
Uninformative Time Drops Out as Well
Case windo
w
Control windo
w
Case and Control Windows Case window: period preceding the event (GI
bleeding) during which the exposure (celecoxib, naproxen, no treatment) may have altered the risk
Control window(s): periods of the same length as, and not overlapping with, the case window that furthermore provide an estimate of the null-hypothesis probability of exposure for each case.
The core study technique is to identify cases, then ascertain exposure status in the case window and at earlier points in time – the control windows.
Estimating the Relative RiskCase
WindowControl Window
ExposedExposed Yes No
Yes f10
No f01
Place each case in the above table, according to exposure in the case window and the control window
Mantel-Haenszel odds ratio for matched sets Reduces to ratio of counts in discordant exposure windows (
f10 / f01 ) when there is one control Conditional logistic regression
When there are concurrent time-varying confounders Accommodates many-to-one matching of control and case
windows Concordant case-control windows are uninformative
Pharmacoepidemiology and Drug Safety 2011; 20: 763–771
Purpose This study aimed to evaluate risks of upper gastrointestinal (GI) adverse events across a variety of oral and parenteral coxibs and nonselective nonsteroidal anti‐inflammatory drugs (nsNSAIDs) in the general population of Taiwan.Methods In a case‐crossover study, all patients aged ≥20 years who were hospitalized for upper GI adverse events (peptic ulcer and bleeding; gastritis and duodenitis) in 2006 were identified ... For each patient, the case period was defined as 1–30 days and the control period as 31–60 days before the date of hospitalization. Outpatient pharmacy prescription database was searched for individual NSAID use during the case and control periods. A conditional logistic regression model was applied ...Results A total of 40 635 patients hospitalized for upper GI adverse events were included. The adjusted OR was 1.52 (95%CI: 1.27–1.82) for celecoxib and 2.56 (95%CI: 2.44–2.69) for oral nsNSAIDs…Conclusion Use of celecoxib and all nsNSAIDs studied was associated with a greater risk of upper GI toxicity as compared with nonuse…
Case Window
Control Window Exposed
Exposed Yes NoYes f10
No f01
Pharmacoepidemiology and Drug Safety 2011; 20: 763–771
Case Window
Control Window Exposed
Exposed Yes NoYes 413No f01
Pharmacoepidemiology and Drug Safety 2011; 20: 763–771
Case Window
Control Window Exposed
Exposed Yes NoYes 413No 232
Pharmacoepidemiology and Drug Safety 2011; 20: 763–771
Case Window
Control Window Exposed
Exposed Yes NoYes 413No 232
RRcrude = 413/232
= 1.78Pharmacoepidemiology and Drug Safety 2011; 20: 763–771
*Conditional logistic regression adjusted for important potential time‐varying confounding variables including selective serotonin reuptake inhibitors, other antidepressants, calcium channel blockers, nitrates, systemic corticosteroids, low‐dose aspirin, proton pump inhibitors, histamine 2 receptor blockers, and sucralfate.
Self-matched studies compare exposure at the time of an outcome event to the probability of exposure in the same person Calculated from the individuals own history Assuming the null hypothesis of no effect of exposure on
the risk of outcome. Unmeasured covariates that do not vary over time within
person do not confound the estimate of relative risk. Self-matched studies work well for intermittent exposures
whose associated risks rise and fall quickly Self-matched studies give mathematical meaning to the
question you might well hear from your doctor: “Were you doing anything unusual just before you got sick?”
Presentations in this series1. Overview
and Randomization2. Self-matching3. Proxies4. Intermediates5. Instruments
Avoiding Bias Due toUnmeasured Covariates
Alec Walker