Selection of a Comparison Group

The major challenge for the Air Force Health Study (AFHS) and other special cohort studies is selection of an appropriate comparison group. The goal of analytic studies is to compare health outcomes in exposed and unexposed groups that are otherwise as similar as possible, i.e., having the same distributions of all other factors that could have any association with health outcomes. We will see that intervention studies with large numbers of subjects randomly assigned to two or more treatment groups (exposures) can usually achieve this so that the groups being compared have similar distributions of age, sex, smoking, physical activity, etc., but random assignment does not occur in cohort studies. Suppose that a cohort study had smokers who were older than the non-smokers. It is well established that the risk of heart disease increases with age, i.e., it is an independent risk factor for heart disease, and if the smokers are older, they have an additional risk factor that will cause an overestimate of the association between smoking and heart disease. This phenomenon, called confounding, occurs when the exposure groups that are being compared differ in the distribution of other determinants of the outcome of interest. Another concern is that the exposure groups being compared may differ in the quality or accuracy of the data that is being collected, and this can also bias the results (so-called information bias). Confounding and bias will be discussed later in the course, but for now, it is important to recognize the importance of selecting a comparison group that differs in exposure status but is as similar as possible to the exposed group in all other ways including:

  1. Other factors that can influence the health outcome
  2. The quality and accuracy of their data

The figure below depicts three studies of cardiovascular disease illustrating the general approaches to selecting a comparison group for a cohort study.

As noted earlier, general cohorts employ an internal comparison group, e.g., dividing the cohort into quintiles of BMI or quintiles of activity and using the quintile with the lowest BMI or the lowest activity as the reference group. This is the best comparison group for a general cohort study, because the subjects are likely to be similar in some ways, but they may still differ with respect to potentially confounding factors. For example, nurses who exercise regularly may be generally more health conscious (e.g., less likely to smoke; more likely to eat a healthier diet; more likely to take vitamins, etc.).

The second method is to use an external comparison group. A special exposure cohort consisting of workers in a rayon factory, was selected to study the association between disulfide exposure and risk of cardiovascular disease, and the comparison group consisted of workers in a paper mill. These two groups may be similar in age distribution, socioeconomic status, and other factors, but they may also differ with respect to other confounding factors. In addition, paper mills have their own mix of occupational exposures, which might also affect the likelihood of cardiovascular disease and bias the results.

The third approach is to use the general population as a comparison group, for example, if trying to determine whether workers in a rayon factory had higher mortality rates. This approach is less costly, and it is sometimes used for studies of occupational exposures when it is difficult to find an appropriate internal or external comparison group. However, using rates of death or disease in the general population has a number of limitations:

Test Yourself

In 1981 investigators recruited over 121,000 registered nurses in the US who initially did not have CVD or cancer. Information on a wide variety of exposures was collected by questionnaire after recruitment, and the nurses were followed for CVD and cancer outcomes for many years. After a number of years had passed, the investigators divided the nurses into 5 categories of BMI at baseline and compared these groups with respect to the incidence of fatal or non-fatal myocardial infarction.

Which of the following comparison groups was used?


A study of the association between pesticide exposure and risk of non-Hodgkin lymphoma began in 2011. The incidence of non-Hodgkin's lymphoma was compared in men who worked as pesticide applicators in the 1970s-1980s and men who worked as fertilizer applicators in the 1970s-1980s. Outcome data was collected through 2010.

Which of the following comparison groups was used?