On the assessment of variability in bioavailability/bioequivalence studies

A procedure is proposed for the assessment of bioequivalence of variabilities between two formulations in bioavailability/bioequivalence studies. This procedure is essentially a two one-sided Pitman-Morgan’s tests procedure which is based on the correlation between crossover differences and subject totals. The nonparametric version of the proposed test is also discussed. A dataset of AUC from a 2×2 crossover bioequivalence trial is presented to illustrate the proposed procedures.     

Viewpoint: observations on scaled average bioequivalence

The two one-sided test procedure (TOST) has been used for average bioequivalence testing since 1992 and is required when marketing new formulations of an approved drug. TOST is known to require comparatively large numbers of subjects to demonstrate bioequivalence for highly variable drugs, defined as those drugs having intra-subject coefficients of variation greater than 30%. However, TOST has been shown to protect public health when multiple generic formulations enter the marketplace following patent expiration. Recently, scaled average bioequivalence (SABE) has been proposed as an alternative statistical analysis procedure for such products by multiple regulatory agencies. SABE testing requires that a three-period partial replicate cross-over or full replicate cross-over design be used. Following a brief summary of SABE analysis methods applied to existing data, we will consider three statistical ramifications of the proposed additional decision rules and the potential impact of implementation of scaled average bioequivalence in the marketplace using simulation. It is found that a constraint being applied is biased, that bias may also result from the common problem of missing data and that the SABE methods allow for much greater changes in exposure when generic-generic switching occurs in the marketplace.     

A fast distance‐based approach for determining the number of components in mixtures

The authors propose a procedure for determining the unknown number of components in mixtures by generalizing a Bayesian testing method proposed by Mengersen & Robert (1996). The testing criterion they propose involves a Kullback‐Leibler distance, which may be weighted or not. They give explicit formulas for the weighted distance for a number of mixture distributions and propose a stepwise testing procedure to select the minimum number of components adequate for the data. Their procedure, which is implemented using the BUGS software, exploits a fast collapsing approach which accelerates the search for the minimum number of components by avoiding full refitting at each step. The performance of their method is compared, using both distances, to the Bayes factor approach.     

Model comparison of linear and nonlinear Bayesian structural equation models with dichotomous data

In this article, dichotomous variables are used to compare between linear and nonlinear Bayesian structural equation models. Gibbs sampling method is applied for estimation and model comparison. Statistical inferences that involve estimation of parameters and their standard deviations and residuals analysis for testing the selected model are discussed. Hidden continuous normal distribution (censored normal distribution) is used to solve the problem of dichotomous variables. The proposed procedure is illustrated by a simulation data obtained from R program. Analyses are done by using R2WinBUGS package in R-program.     

An investigation of Bayesian inference approach to model validation with non-normal data

Quantitative model validation is playing an increasingly important role in performance and reliability assessment of a complex system whenever computer modelling and simulation are involved. The foci of this paper are to pursue a Bayesian probabilistic approach to quantitative model validation with non-normality data, considering data uncertainty and to investigate the impact of normality assumption on validation accuracy. The Box–Cox transformation method is employed to convert the non-normality data, with the purpose of facilitating the overall validation assessment of computational models with higher accuracy. Explicit expressions for the interval hypothesis testing-based Bayes factor are derived for the transformed data in the context of univariate and multivariate cases. Bayesian confidence measure is presented based on the Bayes factor metric. A generalized procedure is proposed to implement the proposed probabilistic methodology for model validation of complicated systems. Classic hypothesis testing method is employed to conduct a comparison study. The impact of data normality assumption and decision threshold variation on model assessment accuracy is investigated by using both classical and Bayesian approaches. The proposed methodology and procedure are demonstrated with a univariate stochastic damage accumulation model, a multivariate heat conduction problem and a multivariate dynamic system.     

Pilot–pivotal trials for average bioequivalence

Before carrying out a full scale bioequivalence trial, it is desirable to conduct a pilot trial to decide if a generic drug product shows promise of bioequivalence. The purpose of a pilot trial is to screen test formulations, and hence small sample sizes can be used. Based on the outcome of the pilot trial, one can decide whether or not a full scale pivotal trial should be carried out to assess bioequivalence. This article deals with the design of a pivotal trial, based on the evidence from the pilot trial. A two-stage adaptive procedure is developed in order to determine the sample size and the decision rule for the pivotal trial, for testing average bioequivalence using the two one-sided test (TOST). Numerical implementation of the procedure is discussed in detail, and the required tables are provided. Numerical results indicate that the required sample sizes could be smaller than that recommended by the FDA for a single trial, especially when the pilot study provides strong evidence in favor of bioequivalence.     

A nearly unbiased test for individual bioequivalence problems using probability criteria

Statistical bioequivalence has recently attracted lots of attention. This is perhaps due to the importance of setting a reasonable criterion on the part of a regulatory agency such as the FDA in the US in regulating the manufacturing of drugs (especially generic drugs). Pharmaceutical companies are obviously interested in the criterion since a huge profit is involved. Various criteria and various types of bioequivalence have been proposed. At present, the FDA recommends testing for average bioequivalence. The FDA, however, is considering replacing average bioequivalence by individual bioequivalence. We focus on the criterion of individual bioequivalence proposed earlier by Anderson and Hauck (J. Pharmacokinetics and Biopharmaceutics 18 (1990) 259) and Wellek (Medizinische Informatik und Statistik, vol. 71, Springer, Berlin, 1989, pp. 95–99; Biometrical J. 35 (1993) 47). For their criterion, they proposed TIER (test of individual equivalence ratios). Other tests were also proposed by Phillips (J. Biopharmaceutical Statist. 3 (1993) 185), and Liu and Chow (J. Biopharmaceutical Statist. 7 (1997) 49). In this paper, we propose an alternative test, called nearly unbiased test, which is shown numerically to have power substantially larger than existing tests. We also show that our test works for various models including 2×3 and 2×4 crossover designs.     

Controlling Bayes directional false discovery rate in random effects model

Starting with a decision theoretic formulation of simultaneous testing of null hypotheses against two-sided alternatives, a procedure controlling the Bayesian directional false discovery rate (BDFDR) is developed through controlling the posterior directional false discovery rate (PDFDR). This is an alternative to Lewis and Thayer [2004. A loss function related to the FDR for random effects multiple comparison. J. Statist. Plann. Inference 125, 49–58.] with a better control of the BDFDR. Moreover, it is optimum in the sense of being the non-randomized part of the procedure maximizing the posterior expectation of the directional per-comparison power rate given the data, while controlling the PDFDR. A corresponding empirical Bayes method is proposed in the context of one-way random effects model. Simulation study shows that the proposed Bayes and empirical Bayes methods perform much better from a Bayesian perspective than the procedures available in the literature.     

Exact calculation of power and sample size in bioequivalence studies using two one‐sided tests

The number of subjects in a pharmacokinetic two‐period two‐treatment crossover bioequivalence study is typically small, most often less than 60. The most common approach to testing for bioequivalence is the two one‐sided tests procedure. No explicit mathematical formula for the power function in the context of the two one‐sided tests procedure exists in the statistical literature, although the exact power based on Owen's special case of bivariate noncentral t‐distribution has been tabulated and graphed. Several approximations have previously been published for the probability of rejection in the two one‐sided tests procedure for crossover bioequivalence studies. These approximations and associated sample size formulas are reviewed in this article and compared for various parameter combinations with exact power formulas derived here, which are computed analytically as univariate integrals and which have been validated by Monte Carlo simulations. The exact formulas for power and sample size are shown to improve markedly in realistic parameter settings over the previous approximations. Copyright © 2014 John Wiley & Sons, Ltd.     

A Bayesian sequential design with adaptive randomization for 2‐sided hypothesis test

Bayesian sequential and adaptive randomization designs are gaining popularity in clinical trials thanks to their potentials to reduce the number of required participants and save resources. We propose a Bayesian sequential design with adaptive randomization rates so as to more efficiently attribute newly recruited patients to different treatment arms. In this paper, we consider 2‐arm clinical trials. Patients are allocated to the 2 arms with a randomization rate to achieve minimum variance for the test statistic. Algorithms are presented to calculate the optimal randomization rate, critical values, and power for the proposed design. Sensitivity analysis is implemented to check the influence on design by changing the prior distributions. Simulation studies are applied to compare the proposed method and traditional methods in terms of power and actual sample sizes. Simulations show that, when total sample size is fixed, the proposed design can obtain greater power and/or cost smaller actual sample size than the traditional Bayesian sequential design. Finally, we apply the proposed method to a real data set and compare the results with the Bayesian sequential design without adaptive randomization in terms of sample sizes. The proposed method can further reduce required sample size.     

A More Powerful Average Bioequivalence Analysis for the 2 × 2 Crossover

The 2 × 2 crossover is commonly used to establish average bioequivalence of two treatments. In practice, the sample size for this design is often calculated under a supposition that the true average bioavailabilities of the two treatments are almost identical. However, the average bioequivalence analysis that is subsequently carried out does not reflect this prior belief and this leads to a loss in efficiency. We propose an alternate average bioequivalence analysis that avoids this inefficiency. The validity and substantial power advantages of our proposed method are illustrated by simulations, and two numerical examples with real data are provided.     

Bayes estimation of Moran–Downton bivariate exponential distribution based on censored samples

In this paper, we discuss a Bayesian estimation procedure for the parameters in a Moran–Downton bivariate exponential distribution based on complete and censored samples. A Markov-chain Monte Carlo method is used to obtain the Bayes estimates of the parameters. An intensive simulation experiment is conducted to study the performance of the proposed Bayesian estimation procedure. Discussions and suggestions are provided based on the simulation results. A numerical example is presented to illustrate the Bayesian estimation procedure developed here and some concluding remarks are provided.     

Objective Bayesian hypothesis testing in regression models with first-order autoregressive residuals

This article considers the objective Bayesian testing in the normal regression models with first-order autoregressive residuals. We propose some solutions based on a Bayesian model selection procedure to this problem where no subjective input is considered. We construct the proper priors for testing the autocorrelation coefficient based on measures of divergence between competing models, which is called the divergence-based (DB) priors and then propose the objective Bayesian decision-theoretic rule, which is called the Bayesian reference criterion (BRC). Finally, we derive the intrinsic test statistic for testing the autocorrelation coefficient. The behavior of the Bayes factor-based DB priors is examined by comparing with the BRC in a simulation study and an example.     

Testing equality of regression coefficients in heteroscedastic normal regression models

This article addresses the problem of testing whether the vectors of regression coefficients are equal for two independent normal regression models when the error variances are unknown. This problem poses severe difficulties both to the frequentist and Bayesian approaches to statistical inference. In the former approach, normal hypothesis testing theory does not apply because of the unrelated variances. In the latter, the prior distributions typically used for the parameters are improper and hence the Bayes factor-based solution cannot be used.We propose a Bayesian solution to this problem in which no subjective input is considered. We first generate “objective” proper prior distributions (intrinsic priors) for which the Bayes factor and model posterior probabilities are well defined. The posterior probability of each model is used as a model selection tool. This consistent procedure of testing hypotheses is compared with some of the frequentist approximate tests proposed in the literature.     

How to build nomogram for type 2 diabetes using a naïve Bayesian classifier technique

In this study, we introduced a method for building a Bayesian nomogram and proposed an appropriate nomogram for type 2 diabetes (T2D) using data from 13,474 subjects collected from the 2013–2015 Korean National Health and Nutrition Examination Survey (KNHANES) data. We identified risk factors related to T2D, proposed a visual nomogram for T2D from a naïve Bayesian classifier model, and predicted incidence rates. Additionally, we computed confidence intervals for the influence of risk factors (attributes) and verified the proposed Bayesian nomogram using a receiver operating characteristic curve. Finally, we compared logistic regression and the Bayesian nomogram for T2D. The results of the analysis of the T2D data showed that the most influential factor among all attributes in the Bayesian nomogram was age group, and the highest risk factor for T2D incidence was cardiovascular disease. Dyslipidemia and hypertension also had significant impacts on T2D incidence while the effects of sex, smoking status, and employment status were relatively small compared to those of other variables. Using the proposed Bayesian nomogram, we can easily predict the incidence rate of T2D in an individual, and treatment plans can be established based on this information.     

Efficient Bayesian sampling plans for exponential distributions with type-I-censored samples

The aim of this paper is to introduce an efficient Bayesian sampling procedure for exponential distribution with type-I censoring. An online inspection method is suggested to reach a Bayes decision prior the termination time of life test. Bayesian sampling plans (BSPs) with quadratic loss function are established to illustrate the use of the proposed method. Some BSPs are tabulated, and the performance of the proposed BSPs is compared with two existing competitive methods. Numerical results indicate that a significant reduction in the experimental time over the conventional BSP can be achieved when the online inspection method is applied.     

An adaptive empirical Bayesian thresholding procedure for analysing microarray experiments with replication

Summary.  A typical microarray experiment attempts to ascertain which genes display differential expression in different samples. We model the data by using a two-component mixture model and develop an empirical Bayesian thresholding procedure, which was originally introduced for thresholding wavelet coefficients, as an alternative to the existing methods for determining differential expression across thousands of genes. The method is built on sound theoretical properties and has easy computer implementation in the R statistical package. Furthermore, we consider improvements to the standard empirical Bayesian procedure when replication is present, to increase the robustness and reliability of the method. We provide an introduction to microarrays for those who are unfamilar with the field and the proposed procedure is demonstrated with applications to two-channel complementary DNA microarray experiments.     

Objective Testing Procedures in Linear Models: Calibration of the p-values

Abstract.  An optimal Bayesian decision procedure for testing hypothesis in normal linear models based on intrinsic model posterior probabilities is considered. It is proven that these posterior probabilities are simple functions of the classical F -statistic, thus the evaluation of the procedure can be carried out analytically through the frequentist analysis of the posterior probability of the null. An asymptotic analysis proves that, under mild conditions on the design matrix, the procedure is consistent. For any testing hypothesis it is also seen that there is a one-to-one mapping – which we call calibration curve – between the posterior probability of the null hypothesis and the classical bi p -value. This curve adds substantial knowledge about the possible discrepancies between the Bayesian and the p -value measures of evidence for testing hypothesis. It permits a better understanding of the serious difficulties that are encountered in linear models for interpreting the p -values. A specific illustration of the variable selection problem is given.     

Bayesian inference method for model validation and confidence extrapolation

This paper presents a Bayesian-hypothesis-testing-based methodology for model validation and confidence extrapolation under uncertainty, using limited test data. An explicit expression of the Bayes factor is derived for the interval hypothesis testing. The interval method is compared with the Bayesian point null hypothesis testing approach. The Bayesian network with Markov Chain Monte Carlo simulation and Gibbs sampling is explored for extrapolating the inference from the validated domain at the component level to the untested domain at the system level. The effect of the number of experiments on the confidence in the model validation decision is investigated. The probabilities of Type I and Type II errors in decision-making during the model validation and confidence extrapolation are quantified. The proposed methodologies are applied to a structural mechanics problem. Numerical results demonstrate that the Bayesian methodology provides a quantitative approach to facilitate rational decisions in model validation and confidence extrapolation under uncertainty.     

A Bayesian analysis for the multivariate point null testing problem

A Bayesian test for the point null testing problem in the multivariate case is developed. A procedure to get the mixed distribution using the prior density is suggested. For comparisons between the Bayesian and classical approaches, lower bounds on posterior probabilities of the null hypothesis, over some reasonable classes of prior distributions, are computed and compared with the p-value of the classical test. With our procedure, a better approximation is obtained because the p-value is in the range of the Bayesian measures of evidence.