 Internal validity of case series studies is usually very low, due to the lack of a comparator group exposed to the same array of intervening variables.For example, the effects seen may be wholly or partly due to intervening effects such as the placebo effect, Hawthorne effect, Rosenthal effect, time effects, practice effects or the natural history effect.Calculating the difference in effects between two treatment groups assumed to be exposed to a very similar array of such intervening effects allows the effects of these intervening variables to cancel out.