No abstract

No abstract

Simon's two-stage design is one of the most commonly used methods in phase II clinical trials with binary endpoints. The design tests the null hypothesis that the response rate is less than an uninteresting level, versus the alternative hypothesis that the response rate is greater than a desirable target level. From a Bayesian perspective, we compute the posterior probabilities of the null and alternative hypotheses given that a promising result is declared in Simon's design. Our study reveals that because the frequentist hypothesis testing framework places its focus on the null hypothesis, a potentially efficacious treatment identified by rejecting the null under Simon's design could have only less than 10% posterior probability of attaining the desirable target level. Due to the indifference region between the null and alternative, rejecting the null does not necessarily mean that the drug achieves the desirable response level. To clarify such ambiguity, we propose a Bayesian enhancement two-stage (BET) design, which guarantees a high posterior probability of the response rate reaching the target level, while allowing for early termination and sample size saving in case that the drug's response rate is smaller than the clinically uninteresting level. Moreover, the BET design can be naturally adapted to accommodate survival endpoints. We conduct extensive simulation studies to examine the empirical performance of our design and present two trial examples as applications.

In longitudinal studies, the values of biomarkers are often informatively missing due to dropout. The conventional functional principal component analysis typically disregards the missing information and simply treats the unobserved data points as missing completely at random. As a result, the estimation of the mean function and the covariance surface might be biased, resulting in a biased estimation of the functional principal components. We propose the informatively missing functional principal component analysis (imFunPCA), which is well suited for cases where the longitudinal trajectories are subject to informative missingness. Computation of the functional principal components in our approach is based on the likelihood of the data, where information of both the observed and missing data points are incorporated. We adopt a regression‐based orthogonal approximation method to decompose the latent stochastic process based on a set of orthonormal empirical basis functions. Under the case of informative missingness, we show via simulation studies that the performance of our approach is superior to that of the conventional ones. We apply our method on a longitudinal dataset of kidney glomerular filtration rates for patients post renal transplantation.

No abstract