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.     

A new confidence interval in measurement error model with the reliability ratio known

For the slope parameter of the measurement error model with the reliability ratio known, this article constructs a fiducial generalized confidence interval (FGCI) which is proved to have correct asymptotic coverage. Simulation results demonstrate that the FGCI often outperforms the existing intervals in terms of empirical coverage probability, average interval length, and false parameter coverage rate. Two examples are also provided to illustrate our approach.     

The performance of model averaged tail area confidence intervals

We investigate the exact coverage and expected length properties of the model averaged tail area (MATA) confidence interval proposed by Turek and Fletcher, CSDA, 2012, in the context of two nested, normal linear regression models. The simpler model is obtained by applying a single linear constraint on the regression parameter vector of the full model. For given length of response vector and nominal coverage of the MATA confidence interval, we consider all possible models of this type and all possible true parameter values, together with a wide class of design matrices and parameters of interest. Our results show that, while not ideal, MATA confidence intervals perform surprisingly well in our regression scenario, provided that we use the minimum weight within the class of weights that we consider on the simpler model.     

一种简单有效的二项分布比例参数似然比置信区间的求法

对二项分布比例参数p的似然比置信区间,提出一种简便求解方法。在平均覆盖率、平均区间长度及区间长度的95%置信区间准则下与WScore、Plus4、Jeffreys置信区间进行模拟比较。试验表明,在二项分布b(n,p)的参数n≥20且p∈(0.1,0.9)时,该方法获取的似然比置信区间性能优良。当点估计p值不是接近于0或1且n≥20时,推荐使用本方法获取p的置信区间。     

Can Likert Scales be Treated as Interval Scales?—A Simulation Study

The Likert scale is widely used in social work research, and is commonly constructed with four to seven points. It is usually treated as an interval scale, but strictly speaking it is an ordinal scale, where arithmetic operations cannot be conducted. There are pros and cons in using the Likert scale as an interval scale, but the controversy can be handled by increasing the number of points. Several researchers have suggested bringing the number up to eleven, on the basis of empirical data. In this article the authors explore this rational and share the same view, but simulate artificial data from both symmetrical normal and skewed distributions where the underlying metric is known in advance. Results show that more Likert scale points will result in a closer approach to the underlying distribution, and hence normality and interval scales. To increase generalizability social work practitioners are encouraged to use 11-point Likert scales from 0 to 10, a natural and easily comprehensible range.     

Seeking Clarity and Confidence in the Divorce Decision-Making Process

There is a well-established literature dedicated to why couples divorce, transitions associated with divorce, and the impact of divorce on families. However, little is known about the divorce decision-making process. We conducted in-depth interviews with individuals who have recently considered divorce (n = 30) and asked specifically about the roles of 2 concepts in their decision-making process: clarity and confidence. Three major themes emerged from the data: (a) Clarity about a decision to divorce or stay married is desired, it fluctuates, and takes time to find; (b) pivotal moments can bring clarity; and (c) confidence (in the final decision) is desired. Clinical implications and directions for future research are discussed.     

Approximate Bayesianity of Frequentist Confidence Intervals for a Binomial Proportion

The well-known Wilson and Agresti–Coull confidence intervals for a binomial proportion p are centered around a Bayesian estimator. Using this as a starting point, similarities between frequentist confidence intervals for proportions and Bayesian credible intervals based on low-informative priors are studied using asymptotic expansions. A Bayesian motivation for a large class of frequentist confidence intervals is provided. It is shown that the likelihood ratio interval for p approximates a Bayesian credible interval based on Kerman’s neutral noninformative conjugate prior up to O(n^{? 1}) in the confidence bounds. For the significance level α ? 0.317, the Bayesian interval based on the Jeffreys’ prior is then shown to be a compromise between the likelihood ratio and Wilson intervals. Supplementary materials for this article are available online.     

Likelihood inference for the component lifetime distribution based on progressively censored parallel systems data

Point and interval estimators for the scale parameter of the component lifetime distribution of a k-component parallel system are obtained when the component lifetimes are assumed to be independently and identically exponentially distributed. We prove that the maximum likelihood estimator of the scale parameter based on progressively Type-II censored system lifetimes is unique and can be obtained by a fixed-point iteration procedure. In particular, we illustrate that the Newton–Raphson method does not converge for any initial value. Furthermore, exact confidence intervals are constructed by a transformation using normalized spacings and other component lifetime distributions including Weibull distribution are discussed.     

Generalized simultaneous confidence regions for regression coefficients and their ratios

This study constructs a simultaneous confidence region for two combinations of coefficients of linear models and their ratios based on the concept of generalized pivotal quantities. Many biological studies, such as those on genetics, assessment of drug effectiveness, and health economics, are interested in a comparison of several dose groups with a placebo group and the group ratios. The Bonferroni correction and the plug-in method based on the multivariate-t distribution have been proposed for the simultaneous region estimation. However, the two methods are asymptotic procedures, and their performance in finite sample sizes has not been thoroughly investigated. Based on the concept of generalized pivotal quantity, we propose a Bonferroni correction procedure and a generalized variable (GV) procedure to construct the simultaneous confidence regions. To address a genetic concern of the dominance ratio, we conduct a simulation study to empirically investigate the probability coverage and expected length of the methods for various combinations of sample sizes and values of the dominance ratio. The simulation results demonstrate that the simultaneous confidence region based on the GV procedure provides sufficient coverage probability and reasonable expected length. Thus, it can be recommended in practice. Numerical examples using published data sets illustrate the proposed methods.