Effects of misclassification on estimates of relative risk in family history studies.

Two types of misclassification that commonly occur in family-genetic studies are distinguished: 1) nondifferential misclassification, in which the probability of error as to phenotype (presence or absence of psychiatric disorder) does not depend on exposure status (being kin to a case or control proband) and 2) differential misclassification, in which it does. Nondifferential misclassification of phenotype reduces the observed relative risk towards the null value, sometimes quite dramatically. Differential misclassification can bias the observed relative risk in either direction, depending on the different values of sensitivity and specificity among relatives of cases and controls. The impact of these biases on genetic-epidemiologic studies is reviewed and discussed. In particular, the ability to detect major gene effects from the pattern of relative risks in first-, second-, and third-degree relatives can be severely compromised. Although there are some methods available to correct the effects of nondifferential misclassification, a major priority for family history studies is to minimize differential misclassification.