Multi‐arm trials with multiple primary endpoints and missing values

Abstract

We present an extension of multiple contrast tests for multiple endpoints to the case of missing values. The endpoints are assumed to be normally distributed and correlated and to have equal covariance matrices for the different treatments. Different multivariate t distributions will be applied, differing in endpoint-specific degrees of freedom. In contrast to competing methods, the familywise error type I is maintained in the strong sense in an admissible range, and the problem of different marginal errors type I is avoided. The information of all observations is exploited, thereby enabling a gain in power compared with a complete case analysis.

Bivariate Bayesian hypothesis testing with missing data in components

“…is the covariance matrix as (1). We first assume that the missing data mechanism is missing at random.…”

“…To control the overall type I error rate, a global test such as O'Brien's test has been wildly used. [1][2][3] It is straightforward and convenience to use this test in a frequentist analysis setting. The regular O'Brien's test is essentially a weighted combination test to combine the test statistics of different endpoints or components.…”

Closed testing procedures for treatment-versus-control comparisons and multiple correlated endpoint

“…Here, only the parametric maxT test is considered as an asymptotic test version. The extension to multiple contrast tests with correlated endpoints was introduced as max(maxT) test, where one part of the approximate correlation matrix consists of the calculated correlations between the treatment contrasts and the other part consists of the empirical Pearson correlation between the endpoints [5,6,7,8]. Thus, adjusted p-values or simultaneous confidence intervals for both differences and ratios (for control) can be estimated with the CRAN package SimComp.…”

Pseudo-data generation allows the statistical re-evaluation of toxicological bioassays based on summary statistics

“…Although multiple endpoints occur frequently in long-term bioassays, such as hematology, commonly they are analysed univariately and independently. A simultaneous test over correlated endpoints can be formulated, to avoid a too high false positive decision rate (8). As an example, the changes in the activities of GSH-R levels in the testicular tissues of male rabbits after treatment with a daily dose of four nitrosamines (MEN, DEN, DMN, DPN) (17) are used.…”