POPULATION SCREENING FOR CARRIER STATUS - EFFECTS OF TEST LIMITATIONSON PRECISION OF CARRIER PREVALENCE RATES

Because of genetic heterogeneity and ambiguity of test results, only r arely will carrier screening identify all carriers of a given autosoma l recessive disorder. However, the fraction of carriers identified by the test can be estimated in a case frequency study. The population ca rrier rate then is the rate observed in a population screening study d ivided by the fraction of all defective alleles detected by the screen ing test, estimated in the case frequency study. For example, suppose 3% of a population are found to carry the Delta F508 mutation for cyst ic fibrosis (CF) during population screening. If a case frequency stud y in this same population finds that 75% of the alleles of CF cases re present the Delta F508 mutation, then the estimated population carrier rate is 4% (= .03/.75). The precision of this estimate involves the p recision of both the fraction of carriers detected in the case frequen cy study and the proportion of carriers observed in the population scr eening study. Standard formulae for estimating the confidence interval and sample size consider only the variability in the population scree ning study. Since these formulae underestimate the true variability of the estimate of the population carrier rate, the sample size calculat ed for a population screening study is also underestimated. We present formulae which incorporate the variability in both factors, and illus trate the effect of this additional variability on confidence limits f or estimates and sample size when planning a study. (C) 1994 Wiley-Lis s, Inc.