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ENCePP Guide on Methodological Standards in Pharmacoepidemiology


5.3.2. Case-only designs


Case-only designs reduce confounding by using the exposure history of each case as its own control and thereby eliminate confounding by characteristics that are constant over time, as demographics, socio-economic factors, genetics and chronic diseases.


A simple form of a case-only design is the symmetry analysis (initially described as prescription sequence symmetry analysis), introduced as a screening tool in Evidence of depression provoked by cardiovascular medication: a prescription sequence symmetry analysis (Epidemiology 1996;7(5):478-84). In this study, the risk of depression associated with cardiovascular drugs was estimated by analysing the non-symmetrical distribution of prescription orders for cardiovascular drugs and antidepressants.


The case-crossover design studies transient exposures with acute effects (The Case-Crossover Design: A Method for Studying Transient Effects on the Risk of Acute Events. Am J Epidemiol 1991;133:144-53) and The case-time-control design (Epidemiology 1995;6(3):248-53). It uses exposure history data from a traditional control group to estimate and adjust for the bias from temporal changes in prescribing (Case-crossover and Case-Time-Control Designs as Alternatives in Pharmacoepidemiologic Research. Pharmacoepidemiol Drug Saf 1997; Suppl 3. S51-S59). However, if not well matched, the control group may reintroduce selection bias as discussed in Confounding and exposure trends in case-crossover and case-time-control designs(Epidemiology. 1996;7:231-9). In this situation, a ‘case-time-control’ method may be helpful as explained in Future cases as present controls to adjust for exposure trend bias in case-only studies (Epidemiology 2011;22:568–74).


The self-controlled case series (SCCS) design was primarily developed to investigate the association between a vaccine and an adverse event but is increasingly used to study drug exposure. In this design, the observation period following each exposure for each case is divided into risk period(s) (e.g. number(s) of days immediately following each exposure) and a control period (e.g. the remaining observation period). Incidence rates within the risk period after exposure are compared with incidence rates within the control period.


The Tutorial in biostatistics: the self-controlled case series method (Stat Med 2006; 25(10):1768-97) and the associated website explain how to fit SCCS models using standard statistical packages.


Like cohort or case-control studies, the SCCS method remains, however, susceptible to confounding by indication, at least if the indication varies over time. Relevant time intervals for the risk and control periods need also to be defined and this may become complex, e.g. with primary vaccination with several doses. The bias introduced by inaccurate specification of the risk window is discussed and a data-based approach for identifying the optimal risk windows is proposed in Identifying optimal risk windows for self-controlled case series studies of vaccine safety (Stat Med 2011; 30(7):742-52).


The SCCS also assumes that the event itself does not affect the chance of being exposed. The pseudolikelihood method developed to address this possible issue is described in Cases series analysis for censored, perturbed, or curtailed post-event exposures (Biostatistics 2009;10(1):3-16). Based on a review of 40 vaccine studies, Use of the self-controlled case-series method in vaccine safety studies: review and recommendations for best practice (Epidemiol Infect 2011;139(12):1805-17) assesses how the SCCS method has been used, highlights good practice and gives guidance on how the method should be used and reported. Using several methods of analysis is recommended, as it can reinforce conclusions or shed light on possible sources of bias when these differ for different study designs.


Within-person study designs had lower precision and greater susceptibility to bias because of trends in exposure than cohort and nested case-control designs (J Clin Epidemiol 2012;65(4):384-93) compares cohort, case-control, case-cross-over and SCCS designs to explore the association between thiazolidinediones and the risks of heart failure and fracture and anticonvulsants and the risk of fracture. The self-controlled case-series and case-cross over designs were more susceptible to bias, but this bias was removed when follow-up was sampled both before and after the outcome, or when a case-time-control design was used.


When should case-only designs be used for safety monitoring of medicinal products? (Pharmacoepidemiol Drug Saf 2012;21(Suppl. 1):50-61) compares the SCCS and case-crossover methods as to their use, strength and major difference (directionality). It concludes that case-only analyses of intermittent users complement the cohort analyses of prolonged users because their different biases compensate for one another. It also provides recommendations on when case-only designs should and should not be used for drug safety monitoring. Empirical performance of the self-controlled case series design: lessons for developing a risk identification and analysis system (Drug Saf 2013;36(Suppl. 1):S83-S93) evaluates the performance of the SCCS design using 399 drug-health outcome pairs in 5 observational databases and 6 simulated datasets. Four outcomes and five design choices were assessed.


In Persistent User Bias in Case-Crossover Studies in Pharmacoepidemiology (Am J Epidemiol. 2016 Oct 25., Epub ahead of print) it was demonstrated that case-crossover studies of drugs that may be used indefinitely are biased upward. This bias is alleviated, but not removed completely, by using a control group.



Individual Chapters:


1. Introduction

2. Formulating the research question

3. Development of the study protocol

4. Approaches to data collection

4.1. Primary data collection

4.1.1. Surveys

4.1.2. Randomised clinical trials

4.2. Secondary data collection

4.3. Patient registries

4.3.1. Definition

4.3.2. Conceptual differences between a registry and a study

4.3.3. Methodological guidance

4.3.4. Registries which capture special populations

4.3.5. Disease registries in regulatory practice and health technology assessment

4.4. Spontaneous report database

4.5. Social media and electronic devices

4.6. Research networks

4.6.1. General considerations

4.6.2. Models of studies using multiple data sources

4.6.3. Challenges of different models

5. Study design and methods

5.1. Definition and validation of drug exposure, outcomes and covariates

5.1.1. Assessment of exposure

5.1.2. Assessment of outcomes

5.1.3. Assessment of covariates

5.1.4. Validation

5.2. Bias and confounding

5.2.1. Selection bias

5.2.2. Information bias

5.2.3. Confounding

5.3. Methods to handle bias and confounding

5.3.1. New-user designs

5.3.2. Case-only designs

5.3.3. Disease risk scores

5.3.4. Propensity scores

5.3.5. Instrumental variables

5.3.6. Prior event rate ratios

5.3.7. Handling time-dependent confounding in the analysis

5.4. Effect measure modification and interaction

5.5. Ecological analyses and case-population studies

5.6. Pragmatic trials and large simple trials

5.6.1. Pragmatic trials

5.6.2. Large simple trials

5.6.3. Randomised database studies

5.7. Systematic reviews and meta-analysis

5.8. Signal detection methodology and application

6. The statistical analysis plan

6.1. General considerations

6.2. Statistical analysis plan structure

6.3. Handling of missing data

7. Quality management

8. Dissemination and reporting

8.1. Principles of communication

8.2. Communication of study results

9. Data protection and ethical aspects

9.1. Patient and data protection

9.2. Scientific integrity and ethical conduct

10. Specific topics

10.1. Comparative effectiveness research

10.1.1. Introduction

10.1.2. General aspects

10.1.3. Prominent issues in CER

10.2. Vaccine safety and effectiveness

10.2.1. Vaccine safety

10.2.2. Vaccine effectiveness

10.3. Design and analysis of pharmacogenetic studies

10.3.1. Introduction

10.3.2. Identification of generic variants

10.3.3. Study designs

10.3.4. Data collection

10.3.5. Data analysis

10.3.6. Reporting

10.3.7. Clinical practice guidelines

10.3.8. Resources

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