Powerful exact unconditional tests for agreement between two raters with binary endpoints

Asymptotic and exact conditional approaches have often been used for testing agreement between two raters with binary outcomes. The exact conditional approach is guaranteed to respect the test size as compared to the traditionally used asymptotic approach based on the standardized Cohen's kappa coefficient. An alternative to the conditional approach is an unconditional strategy which relaxes the restriction of fixed marginal totals as in the conditional approach. Three exact unconditional hypothesis testing procedures are considered in this article: an approach based on maximization, an approach based on the conditional p-value and maximization, and an approach based on estimation and maximization. We compared these testing procedures based on the commonly used Cohen's kappa with regards to test size and power. We recommend the following two exact approaches for use in practice due to power advantages: the approach based on conditional p-value and maximization and the approach based on estimation and maximization.