Methodological issues facing the interpretation of high-risk studies: biological heterogeneity.

High-risk studies provide a unique opportunity to examine the interaction of biological vulnerability and psychosocial factors in the development of the major psychiatric illnesses. To parcel out the effects of psychosocial variables, high-risk populations need to be separated into offspring who are and who are not biologically/genetically vulnerable, since psychosocial modifiers will be interactive only in the biologically vulnerable offspring. Criteria are suggested for the use of "biological markers" to detect subjects at genetic/biological risk within high-risk cohorts. Presently, only the d' statistic of the continuous performance test (CPT) appears to satisfy the criteria for identification of such biologically vulnerable offspring.