Efficiency of the generalized-difference-based weighted mixed almost unbiased two-parameter estimator in partially linear model

In this paper, a generalized difference-based estimator is introduced for the vector parameter β in partially linear model when the errors are correlated. A generalized-difference-based almost unbiased two-parameter estimator is defined for the vector parameter β. Under the linear stochastic constraint r = Rβ + e, we introduce a new generalized-difference-based weighted mixed almost unbiased two-parameter estimator. The performance of this new estimator over the generalized-difference-based estimator and generalized- difference-based almost unbiased two-parameter estimator in terms of the MSEM criterion is investigated. The efficiency properties of the new estimator is illustrated by a simulation study. Finally, the performance of the new estimator is evaluated for a real dataset.     

Enabling robust assessment of QTc prolongation in early phase clinical trials

Since the implementation of the International Conference on Harmonization (ICH) E14 guideline in 2005, regulators have required a “thorough QTc” (TQT) study for evaluating the effects of investigational drugs on delayed cardiac repolarization as manifested by a prolonged QTc interval. However, TQT studies have increasingly been viewed unfavorably because of their low cost effectiveness. Several researchers have noted that a robust drug concentration‐QTc (conc‐QTc) modeling assessment in early phase development should, in most cases, obviate the need for a subsequent TQT study. In December 2015, ICH released an “E14 Q&As (R3)” document supporting the use of conc‐QTc modeling for regulatory decisions. In this article, we propose a simple improvement of two popular conc‐QTc assessment methods for typical first‐in‐human crossover‐like single ascending dose clinical pharmacology trials. The improvement is achieved, in part, by leveraging routinely encountered (and expected) intrasubject correlation patterns encountered in such trials. A real example involving a single ascending dose and corresponding TQT trial, along with results from a simulation study, illustrate the strong performance of the proposed method. The improved conc‐QTc assessment will further enable highly reliable go/no‐go decisions in early phase clinical development and deliver results that support subsequent TQT study waivers by regulators.     

Multiphase experiments in practice: A look back

Multiphase experiments are introduced and an overview of their design and analysis as it is currently practised is given via an account of their development since 1955 and a literature survey. Methods that are available for designing and analysing them are outlined, with an emphasis on making explicit the role of the model in their design. The availability of software and its use is described in detail. Overall, while multiphase designs have been applied in areas such as plant breeding, plant pathology, greenhouse experimentation, product storage, gene expression studies, and sensory evaluation, their deployment has been limited.     

Improving the detection of unusual observations in high‐dimensional settings

Multivariate control charts are used to monitor stochastic processes for changes and unusual observations. Hotelling's T² statistic is calculated for each new observation and an out‐of‐control signal is issued if it goes beyond the control limits. However, this classical approach becomes unreliable as the number of variables p approaches the number of observations n, and impossible when p exceeds n. In this paper, we devise an improvement to the monitoring procedure in high‐dimensional settings. We regularise the covariance matrix to estimate the baseline parameter and incorporate a leave‐one‐out re‐sampling approach to estimate the empirical distribution of future observations. An extensive simulation study demonstrates that the new method outperforms the classical Hotelling T² approach in power, and maintains appropriate false positive rates. We demonstrate the utility of the method using a set of quality control samples collected to monitor a gas chromatography–mass spectrometry apparatus over a period of 67 days.     

Mixture inverse Gaussian for unobserved heterogeneity in the autoregressive conditional duration model

In this paper, we assume that the duration of a process has two different intrinsic components or phases which are independent. The first is the time it takes for a trade to be initiated in the market (for example, the time during which agents obtain knowledge about the market in which they are operating and accumulate information, which is coherent with Brownian motion) and the second is the subsequent time required for the trade to develop into a complete duration. Of course, if the first time is zero then the trade is initiated immediately and no initial knowledge is required. If we assume a specific compound Bernoulli distribution for the first time and an inverse Gaussian distribution for the second, the resulting convolution model has a mixture of an inverse Gaussian distribution with its reciprocal, which allows us to specify and test the unobserved heterogeneity in the autoregressive conditional duration (ACD) model.

Our proposals make it possible not only to capture various density shapes of the durations but also easily to accommodate the behaviour of the tail of the distribution and the non monotonic hazard function. The proposed model is easy to fit and characterizes the behaviour of the conditional durations reasonably well in terms of statistical criteria based on point and density forecasts.     

Some novel results on pairwise quasi-asymptotical independence with applications to risk theory

In this article we obtain some novel results on pairwise quasi-asymptotically independent (pQAI) random variables. Concretely speaking, let X₁, …, X_n be n real-valued pQAI random variables, and W₁, …, W_n be another n non negative and arbitrarily dependent random variables, but independent of X₁, …, X_n. Under some mild conditions, we prove that W₁X₁, …, W_nX_n are still pQAI as well. Our result is in a general setting whether the primary random variables X₁, …, X_n are heavy-tailed or not. Finally, a special case of above result is applied to risk theory for investigating the finite-time ruin probability for a discrete-time risk model with a wide type of dependence structure.     

Bayesian quantile regression for skew-normal linear mixed models

Linear mixed models have been widely used to analyze repeated measures data which arise in many studies. In most applications, it is assumed that both the random effects and the within-subjects errors are normally distributed. This can be extremely restrictive, obscuring important features of within-and among-subject variations. Here, quantile regression in the Bayesian framework for the linear mixed models is described to carry out the robust inferences. We also relax the normality assumption for the random effects by using a multivariate skew-normal distribution, which includes the normal ones as a special case and provides robust estimation in the linear mixed models. For posterior inference, we propose a Gibbs sampling algorithm based on a mixture representation of the asymmetric Laplace distribution and multivariate skew-normal distribution. The procedures are demonstrated by both simulated and real data examples.     

Modification of GEE1 and linear mixed-effects models for heteroscedastic longitudinal Gaussian data

A characterization of GLMs is given. Modification of the Gaussian GEE1, modified GEE1, was applied to heteroscedastic longitudinal data, to which linear mixed-effects models are usually applied. The modified GEE1 models scale multivariate data to homoscedastic data maintaining the correlation structure and apply usual GEE1 to homoscedastic data, which needs no-diagnostics for diagonal variances. Relationships among multivariate linear regression methods, ordinary/generalized LS, naïve/modified GEE1, and linear mixed-effects models were discussed. An application showed modified GEE1 gave most efficient parameter estimation. Correct specification of the main diagonals of heteroscedastic data variance appears to be more important for efficient mean parameter estimation.     

Outliers in incomplete multiresponse experiments

Identification of outlier vectors in block designs for incomplete multiresponse experiments has been considered. Design is composed of two sets of experimental units. Different numbers of response variables are observed from these two sets. Cook-statistic has been developed for identification of outliers. The developed statistic has been illustrated with a real-life data set. It has been shown that presence of outliers can distort the overall conclusion from an experiment.