MISCLASSIFICATION OF GENETIC SUSCEPTIBILITY BIOMARKERS - IMPLICATIONSFOR CASE-CONTROL STUDIES AND CROSS-POPULATION COMPARISONS

Phenotype and genotype markers of genetic susceptibility are of increa sing interest in case-control studies of cancer. It is well establishe d that bias to the odds ratio is caused by less-than-perfect assay sen sitivity and specificity and varies with risk factor prevalence. As su ch, the observed variation in odds ratio between studies of genetic ma rkers and cancer risk may be real, or may be attributed, in part, to v ariation in assay accuracy or in risk factor prevalence (e.g., prevale nce differences between racial groups). The latter can be a particular concern when the prevalence of the ''at risk'' polymorphism in one or more populations is either very high (e.g., >85%) or very low (e.g., <15%). For example, even very high sensitivity (e.g., 98%) can produce substantial bias to the odds ratio when the risk factor prevalence is high. Under some prevalence conditions, however, assays with only mod erate accuracy are sufficient and result in minimal bias to the odds r atio. Understanding misclassification in the context of marker prevale nce may help to explain disparate findings in the literature and shoul d assist investigators in selecting markers that are appropriate for f uture studies.