Sensitivity Measures in Studies of Cancer Early Detection Biomarkers.

Abstract

Background: The sensitivity of a cancer screening biomarker to detect prevalent preclinical cancer drives screening benefit. Studies estimate sensitivity at different points in the biomarker development process. We examine how closely these estimates reflect the sensitivity to detect preclinical cancer (preclinical sensitivity).

Methods: We posit that preclinical sensitivity is inversely proportional to the preclinical sojourn time. We simulate studies and estimates of sensitivity corresponding to the Early Detection Research Network's Phases of Biomarker Development. Sensitivity estimates based on clinically diagnosed cases (Phase 2, clinical sensitivity), archived-sample studies (Phase 3, archived-sample sensitivity), and prospectively screened cohorts (Phases 4 and 5, prospective empirical sensitivity) are defined and compared against the corresponding expected preclinical sensitivity.

Results: Clinical sensitivity is generally optimistic. Archived-sample sensitivity is optimistic near clinical diagnosis but may be pessimistic at longer look-back intervals, with bias dependent also on test specificity. Prospective empirical sensitivity is optimistic when the sojourn time is long relative to the screening interval. Bias in prospective empirical sensitivity depends also on the frequency and accuracy of confirmation testing following a positive screening test.

Conclusions: Sensitivity estimates from different phases of biomarker development should be distinguished and labeled accordingly to facilitate realistic assessment of diagnostic performance and prediction of potential benefit.

Impact: Our study highlights the need for clearer terminology to describe sensitivity of cancer early detection biomarkers. We introduce new labels, explain biases in sensitivity estimates, and advocate for improved communication to enhance understanding of diagnostic test performance.