Travel and Venous Thrombosis: An Exercise in Thinking About Bias

In a meta-analysis in this issue, Chandra and colleagues (1) conclude that the best estimate of the effect of travel on venous thrombosis (VT) is a close to 3-fold increase in risk. To arrive at that conclusion, they exclude the case–control studies in which the controls were referred with the suspicion of VT, like the case patients, but tested negative for VT. These studies found no excess risk. Their exclusion from the analysis might surprise readers; controls with the same reasons for referral who came from the same population would seem ideal. Our purpose is to discuss the selection of controls for case–control studies, using Chandra and colleagues' article as an example. Our principal conclusion is that Chandra and colleagues' explanation of their results goes in the right direction but is incomplete.

Chandra and colleagues removed case–control studies that used referred controls from their final analysis because, they argue, investigators make a mistake when they think that controls in a case–control study should resemble case patients as closely as possible (1). Making groups as equal as possible is the usual reasoning in follow-up studies or randomized trials. However, as Chandra and colleagues point out, this reasoning is wrong in case–control studies. Case patients will always have more risk factors for disease than controls, whose sole purpose in the study is to yield an estimate of the frequency of the exposure of interest in the population. Matching controls too closely creates the danger that they will have the same level of exposure as the case patients, which would result in a null finding (the key calculation in a case–control study is the ratio of the odds of exposure in the case patients relative to the odds of exposure in the controls). Indeed, Figure 2 of Chandra and colleagues' article (1) …