Estimation of ascertainment bias and its effect on power in clinical trials with time-to-event outcomes

Abstract

While the gold standard for clinical trials is to blind all parties -- participants, researchers, and evaluators -- to treatment assignment, this is not always a possibility. When some or all of the above individuals know the treatment assignment, this leaves the study open to the introduction of post-randomization biases. In the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial, we were presented with the potential for the unblinded clinicians administering the treatment, as well as the individuals enrolled in the study, to introduce ascertainment bias into some but not all events comprising the primary outcome. In this manuscript, we present ways to estimate the ascertainment bias for a time-to-event outcome, and discuss its impact on the overall power of a trial versus changing of the outcome definition to a more stringent unbiased definition that restricts attention to measurements less subject to potentially differential assessment. We found that for the majority of situations, it is better to revise the definition to a more stringent definition, as was done in STRIDE, even though fewer events may be observed.Comment: 31 pages, 11 figures; submitted to Statistics in Medicin