Modified Large-Sample Confidence Intervals for Linear Combinations of Variance Components

We consider the problem of setting a confidence interval or bound for a linear combination of variance components related to a multivariate normal distribution, which includes important applications such as comparing variance components and testing the bioequivalence between two drug products. The lack of an exact confidence interval for a general linear combination of variance components spurred the development of a modified large-sample (MLS) method that was shown to be superior to many other approximation methods. But existing MLS method requires the use of independent estimators of variance components. Using a chi-squared representation of a quadratic form of a multivariate normal vector, we extend the MLS method to situations in which estimators of variance components are dependent. Using Edgeworth and Cornish–Fisher expansions, we explicitly derive the second-order asymptotic coverage error of the MLS confidence bound. Our results show that the MLS confidence bound is not second-order accurate in general, but is much better than the confidence bound based on normal approximation and is nearly second-order accurate in some special cases. Our results also show how to construct an MLS confidence bound that is second-order accurate. As an application, we discuss the use of the MLS method in assessing population bioequivalence, with some simulation results and an example.