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ENCePP Guide on Methodological Standards in Pharmacoepidemiology Confounding by indication

Confounding by indication refers to a determinant of the outcome parameter that is present in people at perceived high risk or poor prognosis and is an indication for intervention. This means that differences in care, for example, between cases and controls may partly originate from differences in indication for medical intervention such as the presence of risk factors for particular health problems. The latter has frequently been reported in studies evaluating the efficacy of pharmaceutical interventions. A good example can be found in Confounding and indication for treatment in evaluation of drug treatment for hypertension (BMJ 1997;315:1151-4).


The article Confounding by indication: the case of the calcium channel blockers (Pharmacoepidemiol Drug Saf 2000;9:37-41) demonstrates that studies with potential confounding by indication can benefit from appropriate analytic methods, including separating the effects of a drug taken at different times, sensitivity analysis for unmeasured confounders, instrumental variables and G-estimation.

With the more recent application of pharmacoepidemiological methods to assess effectiveness, confounding by indication is a greater challenge and the article Approaches to combat with confounding by indication in observational studies of intended drug effects (Pharmacoepidemiol Drug Saf 2003;12:551-8) focusses on its possible reduction in studies of intended effects. An extensive review of these and other methodological approaches discussing their strengths and limitations is discussed in Methods to assess intended effects of drug treatment in observational studies are reviewed (J Clin Epidemiol 2004;57:1223-31).


Individual Chapters:


1. General aspects of study protocol

2. Research question

3. Approaches to data collection

3.1. Primary data collection

3.2. Secondary use of data

3.3. Research networks

3.4. Spontaneous report database

3.5. Using data from social media and electronic devices as a data source

3.5.1. General considerations

4. Study design and methods

4.1. General considerations

4.2. Challenges and lessons learned

4.2.1. Definition and validation of drug exposure, outcomes and covariates Assessment of exposure Assessment of outcomes Assessment of covariates Validation

4.2.2. Bias and confounding Choice of exposure risk windows Time-related bias Immortal time bias Other forms of time-related bias Confounding by indication Protopathic bias Surveillance bias Unmeasured confounding

4.2.3. Methods to handle bias and confounding New-user designs Case-only designs Disease risk scores Propensity scores Instrumental variables Prior event rate ratios Handling time-dependent confounding in the analysis

4.2.4. Effect modification

4.3. Ecological analyses and case-population studies

4.4. Hybrid studies

4.4.1. Pragmatic trials

4.4.2. Large simple trials

4.4.3. Randomised database studies

4.5. Systematic review and meta-analysis

4.6. Signal detection methodology and application

5. The statistical analysis plan

5.1. General considerations

5.2. Statistical plan

5.3. Handling of missing data

6. Quality management

7. Communication

7.1. Principles of communication

7.2. Guidelines on communication of studies

8. Legal context

8.1. Ethical conduct, patient and data protection

8.2. Pharmacovigilance legislation

8.3. Reporting of adverse events/reactions

9. Specific topics

9.1. Comparative effectiveness research

9.1.1. Introduction

9.1.2. General aspects

9.1.3. Prominent issues in CER Randomised clinical trials vs. observational studies Use of electronic healthcare databases Bias and confounding in observational CER

9.2. Vaccine safety and effectiveness

9.2.1. Vaccine safety General aspects Signal detection Signal refinement Hypothesis testing studies Meta-analyses Studies on vaccine safety in special populations

9.2.2. Vaccine effectiveness Definitions Traditional cohort and case-control studies Screening method Indirect cohort (Broome) method Density case-control design Test negative design Case coverage design Impact assessment Methods to study waning immunity

9.3. Design and analysis of pharmacogenetic studies

9.3.1. Introduction

9.3.2. Identification of genetic variants

9.3.3. Study designs

9.3.4. Data collection

9.3.5. Data analysis

9.3.6. Reporting

9.3.7. Clinical practice guidelines

9.3.8. Resources

Annex 1. Guidance on conducting systematic revies and meta-analyses of completed comparative pharmacoepidemiological studies of safety outcomes