Increasing power and robustness in screening trials by testing stored specimens in the control arm

BACKGROUND: Screening trials require large sample sizes and long time-horizons to demonstrate mortality reductions. We recently proposed increasing statistical power by testing stored control-arm specimens, called the "Intended Effect" (IE) design. The IE design increases power by increasing the effect size via restricting analysis to only those people in both arms who are affected by screening, namely, those who test-positive. Hence the design requires storing control-arm specimens for future testing. To evaluate feasibility of the IE design, the US National Cancer Institute (NCI) is collecting blood specimens in the control-arm of the NCI Vanguard Multicancer Detection pilot feasibility trial. However, key assumptions of the IE design require more investigation and relaxation. METHODS: We relax the IE design to (1) reduce costs by testing only a stratified sample of control-arm specimens by incorporating inverse-probability sampling weights, (2) correct for potential loss-of-signal in stored control-arm specimens, and (3) correct for non-compliance with control-arm specimen collections. We also examine sensitivity to "unintended effects" of screening (i.e. outcome rates in screen-negatives increasing due to false reassurance). RESULTS: In simulations, testing all primary-outcome control-arm specimens and a 50% sample of the rest maintains nearly all the power of the IE while only testing half the control-arm specimens. Power usually remains increased from the IE analysis (versus the standard analysis) even if unintended effects exist. The IE design is robust to some loss-of-signal scenarios, but otherwise requires retest-positive fractions that correct bias at a small loss of power. The IE can be biased and lose power under control-arm non-compliance scenarios, but corrections correct bias and can increase power. CONCLUSIONS: The IE design can be made more cost-efficient and robust to loss-of-signal. Unintended effects will not typically reduce the power gain over the standard trial design. Non-compliance with control-arm specimen collections can cause bias and loss of power that can be mitigated by corrections. Although promising, practical experience with the IE design in screening trials is necessary.