sessing synergy is applicable to genetic interactions only to the extent that the underlying counterfactual causal model is applicable.
The counterfactual approach requires a thought experiment in which we hold everything constant and manipulate the exposure to see what the outcome would be under this new condition. The causal contrast—the index of the true effect of the exposure—is the difference between what was, given the exposure, and what would have been had the exposure been altered but everything else remained constant. Because this thought experiment requires the consideration of an alteration in the exposure and nothing else, the applicability of a counterfactual approach to nonmanipulable exposures has been questioned (e.g., Kaufman and Cooper, 1999). Since, currently, genes are not easily manipulable, this might open the question of the applicability of this approach to the consideration of genetic effects. In a similar vein, some have argued that personal characteristics, such as age, gender, ethnicity, and social class, should not be considered as causes because they are not manipulable.
However, others (Shadish et al., 2002; Susser and Schwartz, 2005) argue that the counterfactual can apply to nonmanipulable causes, although their detection is more difficult. Nonmanipulable causes cannot be randomly assigned to rule out the many potential sources of nonexchangeability between the exposed and unexposed group that cause confounding. Nonetheless, at the least, one can conduct the thought experiment and search for, or design, studies that approximate the thought experiment as closely as possible.
In addition, what is nonmanipulable today may, in the future, become manipulable. The use of animal “knock-out models” clearly indicates the possibility of genetic manipulation and, with increasing knowledge, even when the gene itself is not manipulable the active ingredients of the gene vis-à-vis the disease, the gene product, may be manipulable.
In the final analysis, it seems that in genetic studies in which people are compared who do and do not have a particular gene variant, or who do or do not have a proxy for a genetic predisposition (e.g., family history), the comparison only makes sense if there is some underlying notion of a causal contrast underlying it. The association may not reflect causation due to the nonexchangeability of the exposed and unexposed, but the logic of the methods assumes that barring such methodological problems, the contrast would imply a causal contrast. Otherwise, why do we use such methods to try to detect causes? The counterfactual approach is merely the clear articu-