Prediagnostic evaluation of multicancer detection tests: Design and analysis considerations.

Abstract

There is growing interest in multicancer detection (MCD) tests, which identify molecular signals in the blood indicating a potential preclinical cancer. A key stage in evaluating MCD tests is a prediagnostic performance study, in which investigators store specimens from asymptomatic persons and later test stored specimens from cancer cases and a random sample of controls to determine predictive performance. Performance metrics include cancer-specific true and false positive rates and a cancer-specific positive predictive value, with the latter compared to a decision-analytic threshold. The sample size tradeoff method, which trades imprecise targeting of the true positive rate for precise targeting of a zero false positive rate can substantially reduce sample size while increasing the lower bound of positive predictive value. For a 1-year follow-up, with ovarian cancer as the rarest cancer considered, the sample size tradeoff method yields a sample size of 163,000 compared with a sample size of 720,000 based on standard calculations. These design and analysis recommendations should be considered in planning a specimen repository and in the prediagnostic evaluation of MCD tests.