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Confounding occurs when the estimate of measure of association is distorted by the presence of another risk factor. For a variable to be a confounder, it must be associated with both the exposure and the outcome, without being in the causal pathway.
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. Other names for this type of confounding are ‘channelling’ or ‘confounding by severity’.
This type of confounding has frequently been reported in studies evaluating the efficacy of pharmaceutical interventions and is almost always encountered in various extents in pharmacoepidemiological studies. 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).
Unmeasured confounding
Complete adjustment for confounders would require detailed information on clinical parameters, lifestyle or over-the-counter medications, which are often not measured in electronic healthcare records, causing residual confounding bias. Using directed acyclic graphs to detect limitations of traditional regression in longitudinal studies (Int J Public Health 2010;55:701-3) reviews confounding and intermediate effects in longitudinal data and introduces causal graphs to understand the relationships between the variables in an epidemiological study.
Unmeasured confounding can be adjusted for only through randomisation. When this is not possible, as most often in pharmacoepidemiological studies, the potential impact of residual confounding on the results should be estimated and considered in the discussion.
Sensitivity analysis and external adjustment for unmeasured confounders in epidemiologic database studies of therapeutics (Pharmacoepidemiol Drug Saf 2006;15(5):291-303) provides a systematic approach to sensitivity analyses to investigate the impact of residual confounding in pharmacoepidemiological studies that use healthcare utilisation databases. In the article, four basic approaches to sensitivity analysis were identified: (1) sensitivity analyses based on an array of informed assumptions; (2) analyses to identify the strength of residual confounding that would be necessary to explain an observed drug-outcome association; (3) external adjustment of a drug-outcome association given additional information on single binary confounders from survey data using algebraic solutions; (4) external adjustment considering the joint distribution of multiple confounders of any distribution from external sources of information using propensity score calibration. The paper concludes that sensitivity analyses and external adjustments can improve our understanding of the effects of drugs in epidemiological database studies. With the availability of easy-to-apply spreadsheets (e.g. at http://www.drugepi.org/dope-downloads/), sensitivity analyses should be used more frequently, substituting qualitative discussions of residual confounding.
The amount of bias in exposure-effect estimates that can plausibly occur due to residual or unmeasured confounding has been debated. The impact of residual and unmeasured confounding in epidemiologic studies: a simulation study (Am J Epidemiol 2007;166:646–55) considers the extent and patterns of bias in estimates of exposure-outcome associations that can result from residual or unmeasured confounding, when there is no true association between the exposure and the outcome. With plausible assumptions about residual and unmeasured confounding, effect sizes of the magnitude frequently reported in observational epidemiological studies can be generated. This study also highlights the need to perform sensitivity analyses to assess whether unmeasured and residual confounding are likely problems. Another important finding of this study was that when confounding factors (measured or unmeasured) are interrelated (e.g. in situations of confounding by indication), adjustment for a few factors can almost completely eliminate confounding.
