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Epidemiology. 1990 Jan;1(1):51-7.

Illustration of the effects of genotype misclassification on the measurement of familial aggregation in epidemiologic studies.

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  • 1Birth Defects and Genetic Diseases Branch, Centers for Disease Control, Atlanta, GA 30333.


Exposure misclassification is a well-known problem in epidemiologic studies and can considerably dilute relative risk (RR) measures toward unity. A vivid illustration of such misclassification occurs in familial aggregation studies, where "exposure" is defined as a specified genetic relationship to an affected individual (case) or to an unaffected individual (control). Even in the simplest single-gene model, only a fraction of relatives of cases have the disease genotype. Also, if the trait is not fully penetrant, a proportion of relatives of controls can have the genotype. Thus the familial RR measures are subject to misclassification bias if they are interpreted as the relative effect of a susceptible genotype. The effects of this form of "exposure" (or more properly genotype) misclassification on familial RR measures were quantified and applied empirically to known disease-genetic trait associations. Expected RRs in first-, second-, and third-degree relatives were generated and plotted for different genotype RRs, disease, and allele frequencies. In general, familial RRs are substantially lower than genotypic RRs. Even in the case of strong associations such as HLA-B27 and ankylosing spondylitis (RR = 100), RR measures in first-, second-, and third-degree relatives are only 6.0, 3.5, and 2.2, respectively. Such strong misclassification effects may result in considerable reduction of statistical power in family studies. It is suggested that etiologic studies of disease explore directly the role of measurable genetic traits in epidemiologic studies in populations as well as in families.

[PubMed - indexed for MEDLINE]
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