Confounding in association studies: month of birth and multiple sclerosis

Association studies form the backbone of biomedical research, with almost every effort in the field ultimately boiling down to a comparison between groups, coupled with some form of statistical test intended to determine whether or not any observed difference is more or less than would be expected by chance. Unfortunately, although the paradigm is powerful and frequently effective, it is often forgotten that false positive association can easily arise if there is any bias or systematic difference in the way in which study subjects are selected into the considered groups. To protect against such confounding, researchers generally try to match cases and controls for extraneous variables thought to correlate with the exposures of interest. However, if seemingly homogenously distributed exposures are actually more heterogeneous than appreciated, then matching may be inadequate and false positive results can still arise. In this review, we will illustrate these fundamental issues by considering the previously proposed relationship between month of birth and multiple sclerosis. This much discussed but false positive association serves as a reminder of just how heterogeneous even easily measured environmental risk factors can be, and how easily case control studies can be confounded by seemingly minor differences in ascertainment.