Residual Confounding, Confounding by Indication, & Reverse Causality

Residual Confounding

Residual confounding is the distortion that remains after controlling for confounding in the design and/or analysis of a study. There are three causes of residual confounding:

  1. There were additional confounding factors that were not considered, or there was no attempt to adjust for them, because data on these factors was not collected.
  2. Control of confounding was not tight enough. For example, a study of the association between physical activity and age might control for confounding by age by a) restricting the study population to subject between the ages of 30-80 or b) matching subjects by age within 20 year categories. In either event there might be persistent differences in age among the groups being compared. Residual differences in confounding might also occur in a randomized clinical trial if the sample size was small. In a stratified analysis or in a regression analysis there could be residual confounding because data on confounding variable was not precise enough, e.g., age was simply classified as "young" or "old".
  3. There were many errors in the classification of subjects with respect to confounding variables.

Confounding by Indication

Confounding by indication is a special type of confounding that can occur in observational (non-experimental) pharmaco-epidemiologic studies of the effects and side effects of drugs. This type of confounding arises from the fact that individuals who are prescribed a medication or who take a given medication are inherently different from those who do not take the drug, because they are taking the drug for a reason. In medical terminology, such individuals have an "indication" for use of the drug. Even if the study population consists of subjects with the same disease, e.g., osteoarthritis, they may differ in the severity of their disease and may therefore differ in the need for medication. Aschengrau and Seage give the example of studies of the association between antidepressant drug use and infertility. The use of antidepressant medications may appear to be associated with an increased risk of infertility. However, depression itself is a known risk factor for infertility. As a result, there would appear to be an association between antidepressants and infertility. One way of dealing with this is to study the association in subjects who are receiving different treatments for the same underlying disease condition.

A variation on this might be dubbed "confounding by contraindication." For example, in the case-control study by Perneger and Whelton examining the association between analgesic drug use and kidney failure the authors compared prior analgesic use between patients receiving kidney dialysis and population controls without known kidney disease. Suppose that patients on dialysis had been advised to avoid taking aspirin because of its effects on blood clotting; they may have been advised to take acetaminophen (Tylenol) instead). If the group of dialysis cases included a number of people who had been on long-term dialysis, this would result in a decreased frequency of aspirin use and and increased use of Tylenol in the case group. As a result, an association with aspirin would be underestimated, while an association with Tylenol would be overestimated.

Reverse Causality

Reverse causality occurs when the probability of the outcome is causally related to the exposure being studied. For example, Child feeding recommendations of the World Health Organization include breastfeeding for two years or more, because of evidence that breast fed children have a reduced risk of infectious agents and are less likely to die. However, some studies have produced conflicting concerns. One possibility is that in communities with very poor resources the children who are at greatest risk and perhaps have the least access to other food sources are more likely to be breast fed for at least two years. A comparison of growth and development between these children and more advantaged children would likely find less progress in the breast fed group. (See "Association of Breastfeeding and Stunting in Peruvian Toddlers: An Example of Reverse Causality" by Marquis GS, et al.: International Journal of Epidemiology 1997; 26: 349–356.

The case-control study by Perneger and Whelton may also have been affected by reverse causality. Diabetes is a leading cause of renal failure in the US, and chronic diabetes is associated with a number of other health problems such as cardiovascular diseases and infections that could result in a greater use of analgesics. If so, the dialysis cases whose renal failure resulted from diabetes might have taken more analgesics because of their diabetes. Nevertheless, it would appear that analgesic use was associated with an increased risk of renal failure rather than vice versa.

Diabetes can increase the risk of infection, need for surgery, vascular diseases and renal failure. These, in turn, may lead to increased use of analgesics. As a result, it may appear that the use of analgesics is associated with an increased risk of renal failure.