Testing for bioequivalence of highly variable drugs from TR‐RT crossover designs with heterogeneous residual variances

Traditional bioavailability studies assess average bioequivalence (ABE) between the test (T) and reference (R) products under the crossover design with TR and RT sequences. With highly variable (HV) drugs whose intrasubject coefficient of variation in pharmacokinetic measures is 30% or greater, assertion of ABE becomes difficult due to the large sample sizes needed to achieve adequate power. In 2011, the FDA adopted a more relaxed, yet complex, ABE criterion and supplied a procedure to assess this criterion exclusively under TRR‐RTR‐RRT and TRTR‐RTRT designs. However, designs with more than 2 periods are not always feasible. This present work investigates how to evaluate HV drugs under TR‐RT designs. A mixed model with heterogeneous residual variances is used to fit data from TR‐RT designs. Under the assumption of zero subject‐by‐formulation interaction, this basic model is comparable to the FDA‐recommended model for TRR‐RTR‐RRT and TRTR‐RTRT designs, suggesting the conceptual plausibility of our approach. To overcome the distributional dependency among summary statistics of model parameters, we develop statistical tests via the generalized pivotal quantity (GPQ). A real‐world data example is given to illustrate the utility of the resulting procedures. Our simulation study identifies a GPQ‐based testing procedure that evaluates HV drugs under practical TR‐RT designs with desirable type I error rate and reasonable power. In comparison to the FDA's approach, this GPQ‐based procedure gives similar performance when the product's intersubject standard deviation is low (≤0.4) and is most useful when practical considerations restrict the crossover design to 2 periods.     

Approximate Bayesian inference for latent Gaussian models by using integrated nested Laplace approximations

Summary.  Structured additive regression models are perhaps the most commonly used class of models in statistical applications. It includes, among others, (generalized) linear models, (generalized) additive models, smoothing spline models, state space models, semiparametric regression, spatial and spatiotemporal models, log-Gaussian Cox processes and geostatistical and geoadditive models. We consider approximate Bayesian inference in a popular subset of structured additive regression models, latent Gaussian models , where the latent field is Gaussian, controlled by a few hyperparameters and with non-Gaussian response variables. The posterior marginals are not available in closed form owing to the non-Gaussian response variables. For such models, Markov chain Monte Carlo methods can be implemented, but they are not without problems, in terms of both convergence and computational time. In some practical applications, the extent of these problems is such that Markov chain Monte Carlo sampling is simply not an appropriate tool for routine analysis. We show that, by using an integrated nested Laplace approximation and its simplified version, we can directly compute very accurate approximations to the posterior marginals. The main benefit of these approximations is computational: where Markov chain Monte Carlo algorithms need hours or days to run, our approximations provide more precise estimates in seconds or minutes. Another advantage with our approach is its generality, which makes it possible to perform Bayesian analysis in an automatic, streamlined way, and to compute model comparison criteria and various predictive measures so that models can be compared and the model under study can be challenged.     

SEMIPARAMETRIC REGRESSION AND GRAPHICAL MODELS

Semiparametric regression models that use spline basis functions with penalization have graphical model representations. This link is more powerful than previously established mixed model representations of semiparametric regression, as a larger class of models can be accommodated. Complications such as missingness and measurement error are more naturally handled within the graphical model architecture. Directed acyclic graphs, also known as Bayesian networks, play a prominent role. Graphical model-based Bayesian 'inference engines', such as bugs and vibes , facilitate fitting and inference. Underlying these are Markov chain Monte Carlo schemes and recent developments in variational approximation theory and methodology.     

民族共生理论:散杂居民族关系及目标范示研究

本文以生物学中的共生理论为参照,基于生物共生理论的理念范畴和分析方法,结合生物共生理论在其他领域的研究成果,重点考察了我国散杂居民族的共生关系,并提供了民族共生目标范式以及实现途径.     

Two new estimators for the proportion of true null hypotheses in multiple test

In multiple hypothesis test, an important problem is estimating the proportion of true null hypotheses. Existing methods are mainly based on the p-values of the single tests. In this paper, we propose two new estimations for this proportion. One is a natural extension of the commonly used methods based on p-values and the other is based on a mixed distribution. Simulations show that the first method is comparable with existing methods and performs better under some cases. And the method based on a mixed distribution can get accurate estimators even if the variance of data is large or the difference between the null hypothesis and alternative hypothesis is very small.     

Estimation of flood frequencies from data sets with outliers using mixed distribution functions

In this paper the estimation of high return period quantiles of the flood peak and volume in the Kolubara River basin are carried out. Estimation of flood frequencies is carried out on a data set containing high outliers which are identified by the Rosner’s test. Simultaneously, low outliers are determined by the multiple Grubbs–Beck. The next step involved the usage of the mixed distribution functions applied to a data set from three populations: floods with low outliers, normal floods and floods with high outliers. The contribution of the data set with low outliers is neglected, since it should underestimate the flood quantiles with large return periods. Consequently, the best fitted mixed distribution from the applied types (EV1, GEV, P3 and LP3) was determined by using the minimum standard error of fit.     

Empirical Uncertain Bayes Methods in Area‐level Models

Random effects model can account for the lack of fitting a regression model and increase precision of estimating area‐level means. However, in case that the synthetic mean provides accurate estimates, the prior distribution may inflate an estimation error. Thus, it is desirable to consider the uncertain prior distribution, which is expressed as the mixture of a one‐point distribution and a proper prior distribution. In this paper, we develop an empirical Bayes approach for estimating area‐level means, using the uncertain prior distribution in the context of a natural exponential family, which we call the empirical uncertain Bayes (EUB) method. The regression model considered in this paper includes the Poisson‐gamma and the binomial‐beta, and the normal‐normal (Fay–Herriot) model, which are typically used in small area estimation. We obtain the estimators of hyperparameters based on the marginal likelihood by using a well‐known expectation‐maximization algorithm and propose the EUB estimators of area means. For risk evaluation of the EUB estimator, we derive a second‐order unbiased estimator of a conditional mean squared error by using some techniques of numerical calculation. Through simulation studies and real data applications, we evaluate a performance of the EUB estimator and compare it with the usual empirical Bayes estimator.     

Score test for homogeneity of dispersion in generalized Poisson mixed models with excess zeros

In many applications, the clustered count data often contain excess zeros and the zero-inflated generalized Poisson mixed (ZIGPM) regression model may be suitable. However, dispersion in ZIGPM is often treated as fixed unknown parameter, and this assumption may be not appropriate in some situations. In this article, a score test for homogeneity of dispersion parameter in ZIGPM regression model is developed and corresponding test statistic is obtained. Sampling distribution and power of the score test statistic are investigated through Monte Carlo simulation. Finally, results from a biological example illustrate the usefulness of the diagnostic statistic.     

The Frisch–Waugh–Lovell theorem for the lasso and the ridge regression

The Frisch–Waugh–Lovell (FWL) (partitioned regression) theorem is essential in regression analysis. This is partly because it is quite useful to derive theoretical results. The lasso regression and the ridge regression, both of which are penalized least-squares regressions, have become popular statistical techniques. This article describes that the FWL theorem remains valid for these penalized least-squares regressions. More precisely, we demonstrate that the covariates corresponding to unpenalized regression parameters in these penalized least-squares regression can be projected out. Some other results related to the FWL theorem in such penalized least-squares regressions are also presented.