No abstract

No abstract

No abstract

Quantitative systems pharmacology (QSP) models aim to describe mechanistically the pathophysiology of disease and predict the effects of therapies on that disease. For most drug development applications, it is important to predict not only the mean response to an intervention but also the distribution of responses, due to inter-patient variability. Given the necessary complexity of QSP models, and the sparsity of relevant human data, the parameters of QSP models are often not well determined. One approach to overcome these limitations is to develop alternative virtual patients (VPs) and virtual populations (Vpops), which allow for the exploration of parametric uncertainty and reproduce inter-patient variability in response to perturbation. Here we evaluated approaches to improve the efficiency of generating Vpops. We aimed to generate Vpops without sacrificing diversity of the VPs' pathophysiologies and phenotypes. To do this, we built upon a previously published approach (Allen et al., 2016) by (a) incorporating alternative optimization algorithms (genetic algorithm and Metropolis-Hastings) or alternatively (b) augmenting the optimized objective function. Each method improved the baseline algorithm by requiring significantly fewer plausible patients (precursors to VPs) to create a reasonable Vpop.

Fiducial Inference, introduced by Fisher in the 1930s, has a long history, which at times aroused passionate disagreements. However, its application has been largely confined to relatively simple parametric problems. In this paper, we present what might be the first time fiducial inference, as generalized by Hannig et al. (2016), is systematically applied to estimation of a nonparametric survival function under right censoring. We find that the resulting fiducial distribution gives rise to surprisingly good statistical procedures applicable to both one sample and two sample problems. In particular, we use the fiducial distribution of a survival function to construct pointwise and curvewise confidence intervals for the survival function, and propose tests based on the curvewise confidence interval. We establish a functional Bernstein-von Mises theorem, and perform thorough simulation studies in scenarios with different levels of censoring. The proposed fiducial based confidence intervals maintain coverage in situations where asymptotic methods often have substantial coverage problems. Furthermore, the average length of the proposed confidence intervals is often shorter than the length of competing methods that maintain coverage. Finally, the proposed fiducial test is more powerful than various types of log-rank tests and sup log-rank tests in some scenarios. We illustrate the proposed fiducial test comparing chemotherapy against chemotherapy combined with radiotherapy using data from the treatment of locally unresectable gastric cancer.