Re‐framing the Analysis: A 3‐dimensional Perspective of Prisoners’ Children's Well‐being

This article highlights three dimensions to understanding children's well‐being during and after parental imprisonment which have not been fully explored in current research. A consideration of ‘time’ reveals the importance of children's past experiences and their anticipated futures. A focus on ‘space’ highlights the impact of new or altered environmental dynamics. A study of ‘agency’ illuminates how children cope within structural, material and social confines which intensify vulnerability and dependency. This integrated perspective reveals important differences in individual children's experiences and commonalities in broader systemic and social constraints on prisoners’ children. The paper analyses data from a prospective longitudinal study of 35 prisoners’ children during and after their (step) father's imprisonment to illustrate the arguments.     

Towards Uniformly Efficient Trend Estimation Under Weak/Strong Correlation and Non‐stationary Volatility

In this paper, we consider the deterministic trend model where the error process is allowed to be weakly or strongly correlated and subject to non‐stationary volatility. Extant estimators of the trend coefficient are analysed. We find that under heteroskedasticity, the Cochrane–Orcutt‐type estimator (with some initial condition) could be less efficient than Ordinary Least Squares (OLS) when the process is highly persistent, whereas it is asymptotically equivalent to OLS when the process is less persistent. An efficient non‐parametrically weighted Cochrane–Orcutt‐type estimator is then proposed. The efficiency is uniform over weak or strong serial correlation and non‐stationary volatility of unknown form. The feasible estimator relies on non‐parametric estimation of the volatility function, and the asymptotic theory is provided. We use the data‐dependent smoothing bandwidth that can automatically adjust for the strength of non‐stationarity in volatilities. The implementation does not require pretesting persistence of the process or specification of non‐stationary volatility. Finite‐sample evaluation via simulations and an empirical application demonstrates the good performance of proposed estimators.     

Statistical testing strategies for assessing treatment efficacy and marker accuracy in phase III trials

When a candidate predictive marker is available, but evidence on its predictive ability is not sufficiently reliable, all‐comers trials with marker stratification are frequently conducted. We propose a framework for planning and evaluating prospective testing strategies in confirmatory, phase III marker‐stratified clinical trials based on a natural assumption on heterogeneity of treatment effects across marker‐defined subpopulations, where weak rather than strong control is permitted for multiple population tests. For phase III marker‐stratified trials, it is expected that treatment efficacy is established in a particular patient population, possibly in a marker‐defined subpopulation, and that the marker accuracy is assessed when the marker is used to restrict the indication or labelling of the treatment to a marker‐based subpopulation, ie, assessment of the clinical validity of the marker. In this paper, we develop statistical testing strategies based on criteria that are explicitly designated to the marker assessment, including those examining treatment effects in marker‐negative patients. As existing and developed statistical testing strategies can assert treatment efficacy for either the overall patient population or the marker‐positive subpopulation, we also develop criteria for evaluating the operating characteristics of the statistical testing strategies based on the probabilities of asserting treatment efficacy across marker subpopulations. Numerical evaluations to compare the statistical testing strategies based on the developed criteria are provided.     

Inference and Decision Making for 21st-Century Drug Development and Approval

ABSTRACT

The cost and time of pharmaceutical drug development continue to grow at rates that many say are unsustainable. These trends have enormous impact on what treatments get to patients, when they get them and how they are used. The statistical framework for supporting decisions in regulated clinical development of new medicines has followed a traditional path of frequentist methodology. Trials using hypothesis tests of “no treatment effect” are done routinely, and the p-value < 0.05 is often the determinant of what constitutes a “successful” trial. Many drugs fail in clinical development, adding to the cost of new medicines, and some evidence points blame at the deficiencies of the frequentist paradigm. An unknown number effective medicines may have been abandoned because trials were declared “unsuccessful” due to a p-value exceeding 0.05. Recently, the Bayesian paradigm has shown utility in the clinical drug development process for its probability-based inference. We argue for a Bayesian approach that employs data from other trials as a “prior” for Phase 3 trials so that synthesized evidence across trials can be utilized to compute probability statements that are valuable for understanding the magnitude of treatment effect. Such a Bayesian paradigm provides a promising framework for improving statistical inference and regulatory decision making.     

Design selection for strong orthogonal arrays

Strong orthogonal arrays (SOAs) were recently introduced and studied as a class of space‐filling designs for computer experiments. An important problem that has not been addressed in the literature is that of design selection for such arrays. In this article, we conduct a systematic investigation into this problem, and we focus on the most useful SOA(n,m,4,2 + )s and SOA(n,m,4,2)s. This article first addresses the problem of design selection for SOAs of strength 2+ by examining their three‐dimensional projections. Both theoretical and computational results are presented. When SOAs of strength 2+ do not exist, we formulate a general framework for the selection of SOAs of strength 2 by looking at their two‐dimensional projections. The approach is fruitful, as it is applicable when SOAs of strength 2+ do not exist and it gives rise to them when they do. The Canadian Journal of Statistics 47: 302–314; 2019 © 2019 Statistical Society of Canada     

Properties of the weighted log‐rank test in the design of confirmatory studies with delayed effects

Proportional hazards are a common assumption when designing confirmatory clinical trials in oncology. This assumption not only affects the analysis part but also the sample size calculation. The presence of delayed effects causes a change in the hazard ratio while the trial is ongoing since at the beginning we do not observe any difference between treatment arms, and after some unknown time point, the differences between treatment arms will start to appear. Hence, the proportional hazards assumption no longer holds, and both sample size calculation and analysis methods to be used should be reconsidered. The weighted log‐rank test allows a weighting for early, middle, and late differences through the Fleming and Harrington class of weights and is proven to be more efficient when the proportional hazards assumption does not hold. The Fleming and Harrington class of weights, along with the estimated delay, can be incorporated into the sample size calculation in order to maintain the desired power once the treatment arm differences start to appear. In this article, we explore the impact of delayed effects in group sequential and adaptive group sequential designs and make an empirical evaluation in terms of power and type‐I error rate of the of the weighted log‐rank test in a simulated scenario with fixed values of the Fleming and Harrington class of weights. We also give some practical recommendations regarding which methodology should be used in the presence of delayed effects depending on certain characteristics of the trial.     

A Bayesian Analysis of Abundance,Trend, and Population Viability for Harbor Seals in Iliamna Lake,Alaska

Harbor seals in Iliamna Lake, Alaska, are a small, isolated population, and one of only two freshwater populations of harbor seals in the world, yet little is known about their abundance or risk for extinction. Bayesian hierarchical models were used to estimate abundance and trend of this population. Observational models were developed from aerial survey and harvest data, and they included effects for time of year and time of day on survey counts. Underlying models of abundance and trend were based on a Leslie matrix model that used prior information on vital rates from the literature. We developed three scenarios for variability in the priors and used them as part of a sensitivity analysis. The models were fitted using Markov chain Monte Carlo methods. The population production rate implied by the vital rate estimates was about 5% per year, very similar to the average annual harvest rate. After a period of growth in the 1980s, the population appears to be relatively stable at around 400 individuals. A population viability analysis assessing the risk of quasi‐extinction, defined as any reduction to 50 animals or below in the next 100 years, ranged from 1% to 3%, depending on the prior scenario. Although this is moderately low risk, it does not include genetic or catastrophic environmental events, which may have occurred to the population in the past, so our results should be applied cautiously.     

Heteroscedastic Global Tests that the Regression Parameters for Two or More Independent Groups are Identical

Simulation results are reported on methods that allow both within group and between group heteroscedasticity when testing the hypothesis that independent groups have identical regression parameters. The methods are based on a combination of extant techniques, but their finite-sample properties have not been studied. Included are results on the impact of removing all leverage points or just bad leverage points. The method used to identify leverage points can be important and can improve control over the Type I error probability. Results are illustrated using data from the Well Elderly II study.     

Modifications of sequential designs in bioequivalence trials

Bioequivalence (BE) studies are designed to show that two formulations of one drug are equivalent and they play an important role in drug development. When in a design stage, it is possible that there is a high degree of uncertainty on variability of the formulations and the actual performance of the test versus reference formulation. Therefore, an interim look may be desirable to stop the study if there is no chance of claiming BE at the end (futility), or claim BE if evidence is sufficient (efficacy), or adjust the sample size. Sequential design approaches specially for BE studies have been proposed previously in publications. We applied modification to the existing methods focusing on simplified multiplicity adjustment and futility stopping. We name our method modified sequential design for BE studies (MSDBE). Simulation results demonstrate comparable performance between MSDBE and the original published methods while MSDBE offers more transparency and better applicability. The R package MSDBE is available at https://sites.google.com/site/modsdbe/ . Copyright © 2015 John Wiley & Sons, Ltd.     

Maternal and paternal reactions to child sadness predict children's psychosocial outcomes: A family‐centered approach

Parents' reactions to children's emotions shape their psychosocial outcomes. Extant research on emotion socialization primarily uses variable‐centered approaches. This study explores family patterns of maternal and paternal responses to children's sadness in relation to psychosocial outcomes in middle childhood. Fifty‐one families with 8‐ to 12‐year‐old children participated. Mothers and fathers reported their reactions to children's sadness and children's social competence and psychological adjustment. Cluster analyses revealed three family patterns: Supportive (high supportive and low non‐supportive reactions from both parents), Not Supportive (low supportive reactions from both parents), and Father Dominant (high paternal supportive and non‐supportive reactions, low maternal supportive and non‐supportive reactions). Supportive families had children with higher social competence and more internalizing symptoms whereas Father Dominant families had children with lower social competence and fewer internalizing symptoms. Not Supportive families had children with average social competence and fewer internalizing symptoms. Findings are discussed in relation to the “divergence model” which proposes that a diverse range of parental responses to children's sadness, rather than a uniformly supportive approach, may facilitate children's psychosocial adjustment.