The influence of the proportion of carcinogens on the cost-effectiveness of short-term tests.

The cost-effectiveness of using short-term genotoxicity tests to screen unknown chemicals for carcinogenicity depends upon the inherent reliability of the tests (sensitivity, or fraction of carcinogens giving positive results, and specificity, or fraction of non-carcinogens giving negative results) and also upon the proportion of carcinogens in the population of chemicals to be screened. Individual tests may be combined into batteries to improve reliability; however, this requires decision rules to declare the overall result positive or negative. A framework for developing such rules based upon minimizing costs of false-positives and false-negatives was presented in a seminal paper by Lave and Omenn (1986, Nature (London), 324, 29-34). We have extended their work, which is based on logit analysis, to consider, using Bayes' theorem, the influence of the proportion of carcinogens upon the decision rules for declaring a battery result positive or negative. If the proportion of carcinogens is high (20% or greater), then the most effective tests are those with high sensitivity, and if the proportion of carcinogens is low, then the most effective tests are those with high specificity.