Self-Controlled Studies Case Crossover Case Series Extreme Cohort Stratification with and without Sampling September 2014 Alec Walker With thanks to Sonia

Self-Controlled Studies

Case Crossover Case Series

Extreme Cohort Stratification with and without Sampling

September 2014Alec Walker

With thanks to Sonia Hernandez-Díaz

What “Triggering” Means

Ref. Maclure M. Am J Epidemiol 1991:133:144-53.

What “Triggering” MeansExp

osu

re

Hypothesized Curves of Incidence Rate in Temporal Relation to Exposure

True

Approximated

Baselin

e

Incid

en

ce

Risk Periods

Ref. Maclure M. Am J Epidemiol 1991:133:144-53.

Comparative vs. Crossover Designs

Randomized trial Cohort Study

Randomized trial Cross-over design

Cohort Study with Changing Exposure

“Self-controlled” analyses, in which treatments are compared within individuals, are common in intervention trials, but are also possible in purely observational studies. The design greatly enhances the baseline similarity of comparison groups.

Treatments are compared between individuals. Baseline comparability of groups is sought through random allocation (RCT) or through careful subject selection and covariate control.

Cohorts with Changing Exposure

Black: Unexposed person-time Red: Exposed person-time Dot: Case event

Time

E

vent

E

nd of f

u

no eve

nt

You Can Match Analyses on Person

Persons with no event drop out

Sampling Frames for Controls

Choose past days from the same person

Compare the Exposure at Case Occurrenceto Sampled Exposure(s) in the Past

Case windo

w

Control windo

w

Compare the Exposure at Case Occurrenceto Sampled Exposure(s) in the Past

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Celecoxibversus

Naproxen versus

No Treatment

PUBHospital

Admission

Celecoxib, Naproxen and GI Bleeding

MD-perceived risk of peptic ulcer & bleeding (PUB)

True risk of PUB

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Confounding by Contraindication

The physician’s belief in the patient’s risk for peptic ulcer and bleeding cannot be measured directly.

Celecoxibversus

Naproxenversus

No Treatment

PUBHospital

Admission


True risk of PUB

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Self-Matching by Case-Crossover

KeyCelecoxibNaproxen

No TherapyEvent X

X

X

X

X

Case-crossover studies stratify the analysis on individuals, looking at exposure history leading up to an event.

Individuals with no event drop out of the analysis.

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Celecoxibversus

Naproxen versus

No Treatment

PUBHospital

Admission


True risk of PUB

Matching on person and examining time on and time off therapy has the effect of removing the confounding effect of time-invariant (or time-slowly-variant) covariates.

Case-Crossover Matching

Case-Crossover Mechanics

Use only for discrete events that may be triggered by an exposure whose timing is well characterized

There needs to be an articulated relation between exposure and risk periods

For each case, identify the presence or absence of the exposure during the postulated trigger period

Identify the “expected” exposure in the trigger period from Usual frequency of exposure over a long time Documented occurrence of exposure during one or

more comparable times in the past Summarize Observed-to-Expected ratio across all

cases

Case and Control Windows

Case window: period preceding the event (GI bleeding) during which the exposure (e.g. celecoxib) may have altered the risk

Control window(s): periods of the same length as, and not overlapping with, the case window that provide an estimate of the expected frequency 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 Risk

Case Window

Control Window Exposed

Exposed Yes No

Yes f10

No f01

For dichotomous exposures

Form the matched 2x2 table

Place each case according to exposures in the case and control windows Mantel-Haenszel odds ratio for matched sets

Reduces to ratio of counts in discordant exposure windows ( f10 / f01 ) when there is one control

Concordant case-control windows are uninformative

OtherwiseConditional logistic regression is used when

There are several different exposures or exposure levels There are concurrent time-varying confounders

Pharmacoepidemiology and Drug Safety 2011; 20: 763–771 18

Risk of hospitalization for upper GI adverse events associated with nonsteroidal anti‐inflammatory drugs…Chia‐Hsuin Chang, Hsi‐Chieh Chen, Jou‐Wei Lin, Chuei‐Wen Kuo, Wen‐Yi Shau and Mei‐Shu Lai

Purpose This study aimed to evaluate the 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…

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*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.

Case Window


Exposed Yes No

Yes f10

No f01

Pharmacoepidemiology and Drug Safety 2011; 20: 763–771

Case Window


Exposed Yes No

Yes 413

No f01


Case Window


Exposed Yes No

Yes 413

No 232


Case Window


Exposed Yes No

Yes 413

No 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.

Another Option for Case-Crossover Design: Usual frequency

Ref. Mueller JE. Am J Cardiol 2000;86(2, Suppl 1):14F–18F

Another Option for Case-Crossover Design: Usual frequency

Ref. Mueller JE. Am J Cardiol 2000;86(suppl):14F–18

Less frequently done because of the difficulty of directly ascertaining usual frequency of exposure.

Case-Series Analyses

Originally developed for analysis of vaccination. Same data set-up as case-crossover Rationale: Individually stratified cohort analysis Only persons with both exposure and event contribute

person-time For display, person-time is summed over the

contributing individuals collectively. For analysis, the matching is taken into consideration. The person-time in the people with events may not

have the same distribution as in the general population in non-vaccine studies.

Example: Murphy et al. N Engl J Med 2001;344:564-72 (next slide)

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Exposure-time categories for case-series analysis of individuals in motor vehicle collisons,UK, 1986–2004.

Gibson J E et al. Am. J. Epidemiol. 2009;aje.kwn364

American Journal of Epidemiology © The Author 2009. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: [email protected].

1 = unexposed time; 2 = 4-week preexposure period, up to and including the date of the first prescription; 3 = first 4 weeks following the first prescription; 4 = remainder of the course of treatment; 5 = first 12 weeks after the end of the course of treatment; 6 = second 12 weeks after the end of the course of treatment.

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1 = unexposed time; 2 = 4-week preexposure period, up to and including the date of the first prescription; 3 = first 4 weeks following the first prescription; 4 = remainder of the course of treatment; 5 = first 12 weeks after the end of the course of treatment; 6 = second 12 weeks after the end of the course of treatment.





There are too many theories of cause-and-effect for the pre-exposure periods to be readily interpretable. (Did the effect possibly cause or prevent the exposure?)




Similar concerns may apply to the earlier reference period. Period 6 in this example (second 12 weeks after the end of the course of treatment) may be the best reference. Recall that RRs for Period 6 were all close to 1.0, so there is not much substantive difference.

Key Points

Case-crossover studies compare exposure at the time of an event to times in the past

Case-series studies compare event frequencies at different exposure windows in exposed persons with events

Very efficient, not always feasible Works for easily ascertained, intermittent exposures

whose associated risks rise and fall quickly Requires that the onset time of the outcome event can

be pinned down with a precision that is substantially tighter than the width of the exposure window

Cautions on interpreting pre-exposure time in case-series studies

Thank You!

Case-crossover time categories a study of motor vehicle collisions in the UK, 1986–2004.



Documents

Self-Controlled Studies Case Crossover Case Series Extreme Cohort Stratification with and without Sampling September 2014 Alec Walker With thanks to Sonia