SELECTING A CONTROL-GROUP IN STUDIES OF THE FAMILIAL COAGGREGATION OF2 DISORDERS - A QUANTITATIVE GENETICS PERSPECTIVE

We sought to compare four different definitions of control groups in s tudies of the coaggregation between two disorders (A and B) on: 1) the ir ability to detect valid familial coaggregation; 2) their liability to artifactual evidence for familial coaggregation; and 3) their robus tness to the overselection of comorbid cases, Using a quantitative gen etic model of transmission, we simulated sibling pairs with familial a nd nonfamilial sources of comorbidity. Four different definitions of c ontrols were tested to predict disorder B in siblings of cases vs, con trols: 1) unscreened controls included subjects with A or B as well as subjects with either A or B; 2) in the symmetrical selection method, controls included only subjects without A; 3) supernormal controls inc luded only subjects without A or B; and 4) in the pure proband method, cases included subjects with A only, and controls included only subje cts without A or B, In the absence of selection bias, 1) the unscreene d control and the symmetrical selection methods did not yield spurious evidence for familial coaggregation and could detect familial coaggre gation; 2) the supernormal controls yielded spurious evidence of famil ial coaggregation; and 3) the pure proband method sometimes yielded sp urious evidence for negative familial coaggregation, and had limited p ower to detect familial coaggregation, However, the pure proband metho d was the only one unaffected by overselection of comorbid cases, In t he absence of selection bias, both the unscreened control and the symm etrical selection methods are appropriate, and the robustness of the p ure proband method to overselection of comorbid cases may be an intere sting feature in studies using clinical samples, Moreover, quantitativ e genetics methods may offer important advantages in the study of fami lial coaggregation, Am, J, Med, Genet. 74:296-303, 1997. (C) 1997 Wile y-Liss, Inc.