Can energy adjustment separate the effects of energy from those of specific macronutrients?

Energy adjustment is used in nutritional epidemiology in an attempt to separate specific effects of macronutrients (carbohydrate, fat, and protein) from one another and from the generic effect of the total quantity of energy consumed. However, models in which the risk of disease is allowed to depend simultaneously on daily total energy consumption and separate components of energy that sum to the total are not identifiable: the specific effects of individual macronutrients and the generic effect of energy cannot be disentangled by multivariate analysis. The standard, residual, and partition methods exclude one or more macronutrients from consideration, thereby allowing estimation, but the parameters that are estimated no longer represent specific macronutrient or generic energy effects. Therefore, an interpretation of a regression coefficient from these methods as a specific effect of a macronutrient or as the generic effect of energy requires additional, almost always questionable, assump tions. For example, a conclusion based on data alone that there is a specific fat effect upon the development of breast cancer but no specific effects of other macronutrients and no generic energy effect is not possible. Notwithstanding these serious problems, some useful etiologic inference still can be made. Am J Epidemiol 1994;140:848-55.