inaccurate assignment of exposure status. Most textbooks on epidemiology cover this topic in detail (e.g., Rothman and Greenland, 1998).
If exposure to a dietary supplement is widespread, case-control studies could be useful for assessing the association of the supplement with an adverse event—even if the adverse event is rare. However, a case-control study also will be useful when assessing risk from a dietary supplement even when use is not widespread if the adverse event rate among users is high. Both situations—wide exposure and a rare outcome and limited exposure with a common outcome—make case-control studies a useful tool for assessing safety of dietary supplements.
Relative risk is a measure of the association between the exposure to some factor (in this case, a dietary supplement ingredient) and the risk of some outcome (e.g., a serious adverse event). It is calculated as the incidence rate of a serious adverse event among persons taking the dietary supplement ingredient divided by the incidence rate of the serious adverse event among persons not taking the ingredient. An incidence rate is the ratio of the number of events (e.g., of a serious adverse event) over a period of time and the number in the population being studied during the time period. For example, relative risk of 2.5 means that the group exposed to the ingredient is 2.5 times (or 150 percent) more likely to have a particular serious adverse event than those not exposed to the ingredient. A relative risk of 1.0 shows no additional risk in the exposed group while a relative risk < 1.0 indicates less risk in the exposed group. For example, a relative risk of 0.67 means the exposed group has 0.67 times the risk (two-thirds the risk or 33 percent less risk) of the event than does the unexposed group.
An odds ratio is approximately equal to the relative risk when the probability of the adverse event is small in both the exposed and unexposed groups. Therefore, odds ratios often are described and interpreted as if they were relative risk values.
If case-control or cohort studies on a dietary supplement ingredient have been completed, the reviewer should consider the magnitude of the odds ratio or relative risk values, p values, or confidence intervals (see below), and the seriousness and severity of the adverse event in question when determining the relative concern about the safety of a dietary supplement ingredient. In general, the reviewer should be alert to relative risks or odds ratios of greater than 2, as described in Table 4-5. That said, a numerical cutoff is not appropriate and greater sensitivity to low values may be appropriate as the seriousness of the adverse event and the number of individuals exposed increases. As a “rule of thumb,” a relative risk or odds