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.     

应当强调办案的社会效果

法律的概括性、抽象性、发展性等特点决定了有必要强调办案的社会效果。强调办案的社会效果有利于制约司法自由裁量权,是新时期司法工作的必然要求。     

Posterior Analysis for Normalized Random Measures with Independent Increments

Abstract.  One of the main research areas in Bayesian Nonparametrics is the proposal and study of priors which generalize the Dirichlet process. In this paper, we provide a comprehensive Bayesian non-parametric analysis of random probabilities which are obtained by normalizing random measures with independent increments (NRMI). Special cases of these priors have already shown to be useful for statistical applications such as mixture models and species sampling problems. However, in order to fully exploit these priors, the derivation of the posterior distribution of NRMIs is crucial: here we achieve this goal and, indeed, provide explicit and tractable expressions suitable for practical implementation. The posterior distribution of an NRMI turns out to be a mixture with respect to the distribution of a specific latent variable. The analysis is completed by the derivation of the corresponding predictive distributions and by a thorough investigation of the marginal structure. These results allow to derive a generalized Blackwell–MacQueen sampling scheme, which is then adapted to cover also mixture models driven by general NRMIs.     

Racial diversity, minority concentration, and trust in Canadian urban neighborhoods

Using a sample of 42,329 respondents nested within 4254 Canadian urban neighborhoods, this study demonstrates the conceptual and empirical importance of making a distinction between neighborhood racial diversity and minority concentration, and examines how each is uniquely associated with trust. Our analysis shows that at a given level of racial minority concentration, Whites are more trusting when their minority neighbors are more evenly distributed across racial minority groups. Meanwhile, Whites are less trusting as the neighborhood share of racial minorities increases. Overall, the effect of racial minority concentration tends to prevail over that of racial diversity.     

Two-dimensional generalisations of dynamic programming for image analysis

Dynamic programming (DP) is a fast, elegant method for solving many one-dimensional optimisation problems but, unfortunately, most problems in image analysis, such as restoration and warping, are two-dimensional. We consider three generalisations of DP. The first is iterated dynamic programming (IDP), where DP is used to recursively solve each of a sequence of one-dimensional problems in turn, to find a local optimum. A second algorithm is an empirical, stochastic optimiser, which is implemented by adding progressively less noise to IDP. The final approach replaces DP by a more computationally intensive Forward-Backward Gibbs Sampler, and uses a simulated annealing cooling schedule. Results are compared with existing pixel-by-pixel methods of iterated conditional modes (ICM) and simulated annealing in two applications: to restore a synthetic aperture radar (SAR) image, and to warp a pulsed-field electrophoresis gel into alignment with a reference image. We find that IDP and its stochastic variant outperform the remaining algorithms.     

Modified inference about the mean of the exponential distribution using moving extreme ranked set sampling

The maximum likelihood estimator (MLE) and the likelihood ratio test (LRT) will be considered for making inference about the scale parameter of the exponential distribution in case of moving extreme ranked set sampling (MERSS). The MLE and LRT can not be written in closed form. Therefore, a modification of the MLE using the technique suggested by Maharota and Nanda (Biometrika 61:601–606, 1974) will be considered and this modified estimator will be used to modify the LRT to get a test in closed form for testing a simple hypothesis against one sided alternatives. The same idea will be used to modify the most powerful test (MPT) for testing a simple hypothesis versus a simple hypothesis to get a test in closed form for testing a simple hypothesis against one sided alternatives. Then it appears that the modified estimator is a good competitor of the MLE and the modified tests are good competitors of the LRT using MERSS and simple random sampling (SRS).     

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.     

Deconvolution methods for non-parametric inference in two-level mixed models

Summary.  We develop a general non-parametric approach to the analysis of clustered data via random effects. Assuming only that the link function is known, the regression functions and the distributions of both cluster means and observation errors are treated non-parametrically. Our argument proceeds by viewing the observation error at the cluster mean level as though it were a measurement error in an errors-in-variables problem, and using a deconvolution argument to access the distribution of the cluster mean. A Fourier deconvolution approach could be used if the distribution of the error-in-variables were known. In practice it is unknown, of course, but it can be estimated from repeated measurements, and in this way deconvolution can be achieved in an approximate sense. This argument might be interpreted as implying that large numbers of replicates are necessary for each cluster mean distribution, but that is not so; we avoid this requirement by incorporating statistical smoothing over values of nearby explanatory variables. Empirical rules are developed for the choice of smoothing parameter. Numerical simulations, and an application to real data, demonstrate small sample performance for this package of methodology. We also develop theory establishing statistical consistency.     

Clarifying the Association Between Mother–Father Relationship Aggression and Parenting

Although much research examines the association between fathers' relationship aggression and mothers' parenting, little attention is given to mothers' aggression, mutual aggression, or fathers' parenting. Using a sample of coresiding couples from the Fragile Families and Child Wellbeing Study (N = 973), the authors examine the association between mothers' and fathers' relationship aggression, measured as frequency and perpetration–victimization types (mutual, mother only, father only), and mothers' and fathers' parenting. Fixed effects regression models show that fathers' aggression is positively related to mothers' parenting stress, whereas father‐only or mother‐only aggression is related to fathers' stress. For both parents, aggression perpetration is negatively related to their own engagement with children. Mother‐only aggression is negatively related to mothers' spanking and positively related to fathers' spanking. These findings suggest the importance of examining both parents' aggression and perpetrators' as well as victims' parenting to better understand the link between relationship aggression and parenting.     

Relatives in Residence: Relatedness of Household Members Drives Schooling Differentials in Mozambique

Children typically receive investments from their fathers, but absent fathers often invest at low levels. In a father's absence, what types of nonfathers invest heavily in children? This article investigates educational participation as a reflection of childhood investments on Ibo Island, Mozambique, where only one third of school‐aged children live with their biological fathers. Father‐present children generally attended school at the highest rates. Stepchildren and father‐absent relatives (e.g., grandchildren, nieces) attended school at comparably high rates if any coresiding children were father‐present. This may signal high altruism among present fathers toward some nonoffspring. Consistent with this result, a fixed effects model indicates that, within the same household, adult males invested equally in their own children, relatives, and stepchildren. Prejudicially lower investments were made in children who were unrelated to the household's adult males, however; this result has strong negative implications for the well‐being of African children fostered by nonrelatives.