Prepared for Agency for Healthcare Research and Quality AHRQ wwwahrqgov T his presentation will Provide a rationale for study design choice and describe key design features Define start of ID: 911198
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Slide1
Study Design Considerations for Observational Comparative Effectiveness Research
Prepared for:
Agency for Healthcare Research and Quality (AHRQ)
www.ahrq.gov
Slide2T
his presentation will
:Provide a rationale for study design choice and describe key design featuresDefine start of followup Define inclusion and exclusion criteria at start of followupDefine exposures of interest at start of followup.Define outcome(s) of interestDefine potential confounders
Outline of Material
Slide3Conventional designs
Cohort
Case-controlCase-cohortSelf-controlled designsCase-crossoverCase-time-controlledSelf-controlled case series
Study Design Overview
Slide4Exposures or treatments are not assigned, a situation which leads to challenges ensuring internal validity, that is, the absence of bias.
To ensure internal validity, treatment groups compared must have the same underlying risk for outcome within subgroups definable by measured covariates (e.g., no unmeasured confounding).
Confounding by indication leads to higher propensity for/more intensive treatment in those with the most severe disease.With confounding by frailty, frail patients (close to death) are less likely to be treated with preventive treatments.Ensuring a study’s internal validity is a prerequisite for its external validity or generalizability.Issues of Bias in Observational
Comparative Effectiveness Research
Slide5Cohorts are defined by their exposure at a certain point in time (i.e., baseline date) and are followed over time for the occurrence of the outcome.
Advantages:
Has a clear timeline separating potential confounders from the exposure and the exposure from the outcome Allows estimation of actual incidence (risk or rate)Can assess multiple outcomes Is easy to conceptualize Limitations:Is inefficient for ad hoc studies when the incidence of the outcome is lowStudy Design: Cohort Study
Slide6Identifies all incident cases that develop an outcome and compares exposure history to controls
Samples controls at random from cohort members at risk for developing an outcome
Advantages:Oversampling cases increases computational efficiency of ad hoc studies when compared with a cohort study Can assess multiple exposuresLimitations:Is difficult to conceptualizeHas potential for recall bias in ad hoc studies
Study Design: Case-Control Study
Slide7Cohorts defined as in a cohort study
Cohort members followed for incidence of outcomes
Additional information required for analysis collected for a random sample of the cohort and all casesIncreased efficiency, when compared with a full-cohort design, if additional information needs to be collectedDecreased efficiency, when compared with a nested case-control design, unless studying multiple outcomes or estimating riskStudy Design: Case-Cohort Study
Slide8Prior exposure history of cases used as the control
Removes confounding effect of measured and
unmeasured characteristics that are stable over time (e.g., genetics)Appropriate for studying acute effects of transient exposures Advantages:Self-controlledAbility to assess short-term reversible effectsAbility to inform about the time window for these effectsLimitations:
Assumes constant prevalence of treatments over time
Does not allow estimation of treatment effect in a population
Study Design: Case-Crossover Study
Slide9Adjusts for calendar time trends in the prevalence of treatments, which can bias the case-crossover design
Divides the case-crossover odds ratio by the equivalent odds ratio estimated in controls
Advantages:Not dependent on assumption of no temporal changes in the prevalence of treatmentLimitations:Need for controls adds complexityControl for time trend can introduce confoundingStudy Design: Case-Time-Controlled Study
Slide10Estimates the immediate effect of treatment in those treated at least once
Dependent on cases that have changes in treatment during a defined observation period
Advantages:Controls for factors that are stable over timeCohort design has the potential to increase efficiency Well suited for rare adverse events in vaccine safety studiesLimitations:Limited applicability in many comparative effectiveness research studiesStudy Design: Self-Controlled Case-Series
Slide11Study setting
Consideration of the study population and data source(s)
Inclusion and exclusion criteriaShould be clearly defined Include details about the study time periodChoice of comparators Reduces potential for confounding by comparing treatment of interest with a different treatment for the same indication or an indication with the same potential for confoundingStudy Design Features
Slide12New-User Design
The conventional
prevalent user design is prone to confounding and selection bias as a result of changes in treatment effects over time.Including only new users reduces bias and confounding associated with inclusion of prevalent users.There must be a clear starting point for followup under similar conditions of medicalization.Immortal Time BiasOccurs as a result of defining the exposure during the followup time rather than before followup New-user design and use of comparator treatments reduce potential for this bias
Other Study Design Considerations
Slide13Knowledge of study design options is essential to increase internal and external validity of observational comparative effectiveness research.
Biases introduced by suboptimal study design cannot usually be removed by statistical analysis.
Cohort design is preferred when data have already been collected; the validity of a nested case-control study is equivalent, given proper control selection and timing of exposures and covariates. It is important to define the start of followup, inclusion and exclusion criteria, outcome of interest, and potential confounders at the outset. Conclusions
Slide14Summary Checklist (1 of 3)
Guidance
Key Considerations
Provide
rationale for study design choice and describe key design features
Cohort study proposals should clearly
define the cohort entry date (baseline date), employ a new-user design (or provide a rationale for including prevalent users), and plans for reporting losses to followup.
Case-control study proposals should clearly describe the control sampling method, employ a new-user design (or provide a rationale for assessing confounders at the index date), and assess potential for recall bias (if applicable).
Case-cohort study proposals should include how the sampling scheme will be accounted for during analysis.
Case-crossover study proposals should discuss the potential for confounding by time-varying factors and clearly state how the resulting effect estimate can be interpreted.
Case-time-controlled study proposals should clearly weigh the pros and cons of accounting for calendar time trends in the prevalence of exposure.
Slide15Summary Checklist (2 of 3)
Guidance
Key Considerations
Define start of followup (baseline)
The time point
for start of followup should be clearly defined, meaningful, and ideally anchored to the time of a medical intervention (e.g., initiation of drug use).
If alternative approaches are proposed, the rationale should be provided and implications discussed.
Define
inclusion and exclusion criteria at start of followup
Exclusion and inclusion criteria should be defined at the start of
followup (baseline) and solely based on information available at this point in time (i.e., ignoring potentially known events after baseline).
The definition should include the time window for assessment (usually the same for all cohort members).
Slide16Summary Checklist (3 of 3)
Guidance
Key Considerations
Define exposure (treatments) of interest at start of followup
Use an active comparator (indicated as alternative treatment at same stage of disease progression) when possible.
Define outcome(s) of interest
Provide information on measures of accuracy if possible.
Define potential confounders
Potential confounders known to be associated with treatment and outcome should be prespecified when possible.
Confounders should be assessed before exposure or treatment initiation to ensure they are not affected by the exposure.
Approaches to empirical identification of confounders should be described if planned.