Prediagnostic evaluation of multicancer detection tests: design and analysis considerations

There is growing interest in multicancer detection tests, which identify molecular signals in the blood that indicate a potential preclinical cancer. A key stage in evaluating these tests is a prediagnostic performance study, in which investigators store specimens from asymptomatic individuals and later test stored specimens from patients with cancer and a random sample of controls to determine predictive performance. Performance metrics include rates of cancer-specific true-positive and false-positive findings and a cancer-specific positive predictive value, with the latter compared with a decision-analytic threshold. The sample size trade-off 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 the positive predictive value. For a 1-year follow-up, with ovarian cancer as the rarest cancer considered, the sample size trade-off 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 multicancer detection tests.