Comparing the sensitivities of two screening tests in nonblinded randomized paired screen-positive trials with differential screening uptake

Abstract

Before a new screening test can be used in routine screening, its performance needs to be compared to the standard screening test. This comparison is generally done in population screening trials with a screen-positive design where participants undergo one or both screening tests after which disease verification takes place for those positive on at least one screening test. We consider the randomized paired screen-positive design of Alonzo and Kittelson where participants are randomized to receive one of the two screening tests and only participants with a positive screening test subsequently receive the other screening test followed by disease verification. The tests are usually offered in an unblinded fashion in which case the screening uptake may differ between arms, in particular when one test is more burdensome than the other. When uptake is associated with disease, the estimator for the relative sensitivity derived by Alonzo and Kittelson may be biased and the type I error of the associated statistical test is no longer guaranteed to be controlled. We present methods for comparing sensitivities of screening tests in randomized paired screen-positive trials that are robust to differential screening uptake. In a simulation study, we show that our methods adequately control the type I error when screening uptake is associated with disease. We apply the developed methods to data from the IMPROVE trial, a nonblinded cervical cancer screening trial comparing the accuracy of HPV testing on self-collected versus provider-collected samples. In this trial, screening uptake was higher among participants randomized to self-collection.