INFLATION OF SIBLING RECURRENCE-RISK RATIO, DUE TO ASCERTAINMENT BIASAND OR OVERREPORTING/

One widely used measure of familial aggregation is the sibling recurre nce-risk ratio, which is defined as the ratio of risk of disease manif estation, given that one's sibling is affected, as compared with the d isease prevalence in the general population. Known as lambda(S), it ha s been used extensively in the mapping of complex diseases. In this pa per, I show that, for a fictitious disease that is strictly nongenetic and nonenvironmental, lambda(S), can be dramatically inflated because of misunderstanding of the original definition of lambda(S),, ascerta inment bias, and overreporting. Therefore, for a disease of entirely e nvironmental origin, the lambda(S) inflation due to ascertainment bias and/or overreporting is expected to be more prominent if the risk fac tor also is familially aggregated. This suggests that, like segregatio n analysis, the estimation of lambda(S) also is prone to ascertainment bias and should be performed with great care. This is particularly im portant if one uses lambda(S) for exclusion mapping, for discriminatio n between different genetic models, and for association studies, since these practices hinge tightly on an accurate estimation of lambda(S).