Two-phase designs for cost-effective evaluation of cancer screening tests

Thomas M. Menino Convention & Exhibition Center 

Screening tests are crucial for detecting diseases at preclinical stages when timely intervention can prevent progression to more severe conditions. Advances in technology have facilitated the development of screening tests based on novel markers, but evaluation of their performance using biospecimens from large cohorts can be a logistical and financial challenge. Two-phase designs offer a cost-effective solution by allowing inference when expensive marker measurements are performed on only a carefully selected subsample. While traditional two-phase designs are often focused on estimating associations between a marker and outcome, they can effectively be extended to evaluate the clinical performance of a test, such as the estimation of positive predictive value (PPV, the risk in test positives) and complementary negative predictive value (cNPV, the risk in test negatives). We propose a novel two-phase design for efficiently evaluating the risk stratification utility of screening tests in distinguishing between high- and low-risk individuals for both current asymptomatic disease and future disease development. Using biospecimens from screening studies, our methodology is developed to accommodate cohorts that include both pre-existing cases at an initial screening visit and new cases identified during follow-up. We demonstrate the efficiency gains of our proposed design compared to other subsampling schemes through simulation and illustrate its application in the motivating study evaluating the p16/ki-67 dual-stain test for managing HPV-positive women in cervical cancer screening. Data from Kaiser Permanente Northern California on a screening cohort are used along with stored biospecimen samples in this analysis.

screening test evaluation

risk stratification

human papillomavirus (HPV) and cervical cancer

two-phase design

mixture model