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.     

Dynamic version of weighted cumulative residual entropy

Some extensions of Shannon entropy to the survival function have been recently proposed. Misagh et al. (2011 Misagh, F., Panahi, Y., Yari, G.H., Shahi, R. (2011, September). Weighted cumulative entropy and its estimation. In: Quality and Reliability (ICQR), 2011, IEEE International conference (pp. 477–480), IEEE.[Crossref] , [Google Scholar]) introduced weighted cumulative residual entropy (WCRE) that was studied more by Mirali et al. (2015 Mirali, M., Baratpour, S., Fakoor, V. (2015). On weighted cumulative residual entropy. Commun. Stat. Theory Methods. doi:10.1080103610926.2015.1053932.[Web of Science ®] , [Google Scholar]). In this article, the dynamic version of WCRE is proposed. Some relationships of this measure with well-known reliability measures and ageing classes are studied and some characterization results for exponential and Rayleigh distributions are provided. Also, a non parametric estimation of dynamic version of WCRE is introduced and its asymptotic behavior is investigated.     

Testing monotonic equilibrium residual entropy of N-State Random Evolution

In this study, we propose an information measure of uncertainty associated with the random equilibrium residual lifetime of a system driven by N-State Random Evolution. A U-statistic test driven by a moment inequality is proposed for testing the hypothesis that the uncertainty of equilibrium remaining life of a system remains unchanged (when system is in the steady state) against the alternative situation when system’s equilibrium residual life has increasing uncertainty over time (i.e., the life distribution has Increasing Equilibrium Residual Entropy property). Some numerical results such as tabulated critical values and empirical power of the proposed test statistic are presented as well.     

Decomposition of the main effects and interaction term by using orthogonal polynomials in multiple non symmetrical correspondence analysis

The multiple non symmetric correspondence analysis (MNSCA) is a useful technique for analyzing a two-way contingency table. In more complex cases, the predictor variables are more than one. In this paper, the MNSCA, along with the decomposition of the Gray–Williams Tau index, in main effects and interaction term, is used to analyze a contingency table with two predictor categorical variables and an ordinal response variable. The Multiple-Tau index is a measure of association that contains both main effects and interaction term. The main effects represent the change in the response variables due to the change in the level/categories of the predictor variables, considering the effects of their addition, while the interaction effect represents the combined effect of predictor categorical variables on the ordinal response variable. Moreover, for ordinal scale variables, we propose a further decomposition in order to check the existence of power components by using Emerson's orthogonal polynomials.     

Substance‐dependent women becoming mothers: breaking the cycle of adverse childhood experiences

Parenting may be particularly challenging for substance‐dependent mothers who have grown up with parents who themselves had substance use disorders (SUDs). The aim of this study was to explore how substance‐dependent mothers describe their childhood experiences with substance‐abusing parents and the association between these earlier experiences and their own role as caregivers. Using purposeful sampling, mothers admitted for 1 year to a family ward at a substance abuse clinic were approached. Through in‐depth, qualitative interviews, nine substance‐dependent mothers described their lives in the form of present, past and future tense. The findings indicate that substance‐dependent women, who have experienced SUDs in their families of origin, face several major challenges when they become mothers. Some describe having lived their whole lives ‘on the edge of society'. This makes their rehabilitation process more complex. All mothers work to abstain from substances, process traumatic experiences and integrate their family into society. They need help to build supportive social networks and to establish a safe and predictable family environment for themselves and their children. The therapeutic implications of these findings will be discussed.     

Mortality among elder abuse victims in rural Malaysia: A two-year population-based descriptive study

Our study aims at describing mortality among reported elder abuse experiences in rural Malaysia. This is a population-based cohort study with a multistage cluster sampling method. Older adults in Kuala Pilah (n = 1,927) were interviewed from November 2013 to May 2014. Mortality was traced after 2 years using the National Registration Department database. Overall, 139 (7.2%) respondents died. Fifteen (9.6%) abuse victims died compared to 124 (7.0%) not abused. Mortality was highest with financial abuse (13%), followed by psychological abuse (10.8%). There was a dose-response relationship between mortality and clustering of abuse: 7%, 7.7%, and 14.0% for no abuse, one type, and two types or more, respectively. Among abuse victims, 40% of deaths had ill-defined causes, 33% were respiratory-related, and 27% had cardiovascular and metabolic origin. Results suggest a link between abuse and mortality. Death proportions varied according to abuse subtypes and gender.     

A Note on High-Dimensional Linear Regression With Interactions

The problem of interaction selection in high-dimensional data analysis has recently received much attention. This note aims to address and clarify several fundamental issues in interaction selection for linear regression models, especially when the input dimension p is much larger than the sample size n. We first discuss how to give a formal definition of “importance” for main and interaction effects. Then we focus on two-stage methods, which are computationally attractive for high-dimensional data analysis but thus far have been regarded as heuristic. We revisit the counterexample of Turlach and provide new insight to justify two-stage methods from the theoretical perspective. In the end, we suggest new strategies for interaction selection under the marginality principle and provide some simulation results.     

Flexible objective Bayesian linear regression with applications in survival analysis

We study objective Bayesian inference for linear regression models with residual errors distributed according to the class of two-piece scale mixtures of normal distributions. These models allow for capturing departures from the usual assumption of normality of the errors in terms of heavy tails, asymmetry, and certain types of heteroscedasticity. We propose a general non-informative, scale-invariant, prior structure and provide sufficient conditions for the propriety of the posterior distribution of the model parameters, which cover cases when the response variables are censored. These results allow us to apply the proposed models in the context of survival analysis. This paper represents an extension to the Bayesian framework of the models proposed in [16]. We present a simulation study that shows good frequentist properties of the posterior credible intervals as well as point estimators associated to the proposed priors. We illustrate the performance of these models with real data in the context of survival analysis of cancer patients.     

A new log-location regression model: estimation,influence diagnostics and residual analysis

We introduce a log-linear regression model based on the odd log-logistic generalized half-normal distribution [7 G.M. Cordeiro, M. Alizadeh, R.R. Pescim, and E.M.M. Ortega, The odd log-logistic generalized half-normal lifetime distribution: Properties and applications, Comm. Statist. Theory Methods (2015), accepted for publication. [Google Scholar]]. Some of its structural properties including explicit expressions for the density function, quantile and generating functions and ordinary moments are derived. We estimate the model parameters by the maximum likelihood method. For different parameter settings, proportion of censoring and sample size, some simulations are performed to investigate the behavior of the estimators. We derive the appropriate matrices for assessing local influence diagnostics on the parameter estimates under different perturbation schemes. We also define the martingale and modified deviance residuals to detect outliers and evaluate the model assumptions. In addition, we demonstrate that the extended regression model can be very useful in the analysis of real data and provide more realistic fits than other special regression models. The potentiality of the new regression model is illustrated by means of a real data set.