Sample size calculation for the Power Model for dose proportionality studies

There are several approaches to assess or demonstrate pharmacokinetic dose proportionality. One statistical method is the traditional ANOVA model, where dose proportionality is evaluated using the bioequivalence limits. A more informative method is the mixed effects Power Model, where dose proportionality is assessed using a decision rule for the estimated slope. Here we propose analytical derivations of sample sizes for various designs (including crossover, incomplete block and parallel group designs) to be analysed according to the Power Model.     

Analysis of longitudinal data with drop-out: objectives, assumptions and a proposal

Summary. The problem of analysing longitudinal data that are complicated by possibly informative drop-out has received considerable attention in the statistical literature. Most researchers have concentrated on either methodology or application, but we begin this paper by arguing that more attention could be given to study objectives and to the relevant targets for inference. Next we summarize a variety of approaches that have been suggested for dealing with drop-out. A long-standing concern in this subject area is that all methods require untestable assumptions. We discuss circumstances in which we are willing to make such assumptions and we propose a new and computationally efficient modelling and analysis procedure for these situations. We assume a dynamic linear model for the expected increments of a constructed variable, under which subject-specific random effects follow a martingale process in the absence of drop-out. Informal diagnostic procedures to assess the tenability of the assumption are proposed. The paper is completed by simulations and a comparison of our method and several alternatives in the analysis of data from a trial into the treatment of schizophrenia, in which approximately 50% of recruited subjects dropped out before the final scheduled measurement time.     

Use of a historical control group in a noninferiority trial assessing a new antibacterial treatment: A case study and discussion of practical implementation aspects

When recruitment into a clinical trial is limited due to rarity of the disease of interest, or when recruitment to the control arm is limited due to ethical reasons (eg, pediatric studies or important unmet medical need), exploiting historical controls to augment the prospectively collected database can be an attractive option. Statistical methods for combining historical data with randomized data, while accounting for the incompatibility between the two, have been recently proposed and remain an active field of research. The current literature is lacking a rigorous comparison between methods but also guidelines about their use in practice. In this paper, we compare the existing methods based on a confirmatory phase III study design exercise done for a new antibacterial therapy with a binary endpoint and a single historical dataset. A procedure to assess the relative performance of the different methods for borrowing information from historical control data is proposed, and practical questions related to the selection and implementation of methods are discussed. Based on our examination, we found that the methods have a comparable performance, but we recommend the robust mixture prior for its ease of implementation.     

Comparison of dichotomized and distributional approaches in rare event clinical trial design: a fixed Bayesian design

This research was motivated by our goal to design an efficient clinical trial to compare two doses of docosahexaenoic acid supplementation for reducing the rate of earliest preterm births (ePTB) and/or preterm births (PTB). Dichotomizing continuous gestational age (GA) data using a classic binomial distribution will result in a loss of information and reduced power. A distributional approach is an improved strategy to retain statistical power from the continuous distribution. However, appropriate distributions that fit the data properly, particularly in the tails, must be chosen, especially when the data are skewed. A recent study proposed a skew-normal method. We propose a three-component normal mixture model and introduce separate treatment effects at different components of GA. We evaluate operating characteristics of mixture model, beta-binomial model, and skew-normal model through simulation. We also apply these three methods to data from two completed clinical trials from the USA and Australia. Finite mixture models are shown to have favorable properties in PTB analysis but minimal benefit for ePTB analysis. Normal models on log-transformed data have the largest bias. Therefore we recommend finite mixture model for PTB study. Either finite mixture model or beta-binomial model is acceptable for ePTB study.     

Selecting the Optimal Transformation of a Continuous Covariate in Cox's Regression: Implications for Hypothesis Testing

ABSTRACT

Background: Many exposures in epidemiological studies have nonlinear effects and the problem is to choose an appropriate functional relationship between such exposures and the outcome. One common approach is to investigate several parametric transformations of the covariate of interest, and to select a posteriori the function that fits the data the best. However, such approach may result in an inflated Type I error. Methods: Through a simulation study, we generated data from Cox's models with different transformations of a single continuous covariate. We investigated the Type I error rate and the power of the likelihood ratio test (LRT) corresponding to three different procedures that considered the same set of parametric dose-response functions. The first unconditional approach did not involve any model selection, while the second conditional approach was based on a posteriori selection of the parametric function. The proposed third approach was similar to the second except that it used a corrected critical value for the LRT to ensure a correct Type I error. Results: The Type I error rate of the second approach was two times higher than the nominal size. For simple monotone dose-response, the corrected test had similar power as the unconditional approach, while for non monotone, dose-response, it had a higher power. A real-life application that focused on the effect of body mass index on the risk of coronary heart disease death, illustrated the advantage of the proposed approach. Conclusion: Our results confirm that a posteriori selecting the functional form of the dose-response induces a Type I error inflation. The corrected procedure, which can be applied in a wide range of situations, may provide a good trade-off between Type I error and power.     

Non‐inferiority and networks: inferring efficacy from a web of data

In the absence of placebo‐controlled trials, the efficacy of a test treatment can be alternatively examined by showing its non‐inferiority to an active control; that is, the test treatment is not worse than the active control by a pre‐specified margin. The margin is based on the effect of the active control over placebo in historical studies. In other words, the non‐inferiority setup involves a network of direct and indirect comparisons between test treatment, active controls, and placebo. Given this framework, we consider a Bayesian network meta‐analysis that models the uncertainty and heterogeneity of the historical trials into the non‐inferiority trial in a data‐driven manner through the use of the Dirichlet process and power priors. Depending on whether placebo was present in the historical trials, two cases of non‐inferiority testing are discussed that are analogs of the synthesis and fixed‐margin approach. In each of these cases, the model provides a more reliable estimate of the control given its effect in other trials in the network, and, in the case where placebo was only present in the historical trials, the model can predict the effect of the test treatment over placebo as if placebo had been present in the non‐inferiority trial. It can further answer other questions of interest, such as comparative effectiveness of the test treatment among its comparators. More importantly, the model provides an opportunity for disproportionate randomization or the use of small sample sizes by allowing borrowing of information from a network of trials to draw explicit conclusions on non‐inferiority. Copyright © 2015 John Wiley & Sons, Ltd.     

Corrigendum for: The Distribution of Family Sizes Under a Time-Homogeneous Birth and Death Process

Regretably, there are a number of significant errors in Moschopoulos and Shpak, (2010). Communications in Statistics—Theory and Methods 39:1761–1775. Most are typographic errors that have the potential to cause confusion, and in some instances, have carried through to several equations.     

Practical approaches for design and analysis of clinical trials of infertility treatments: crossover designs and the Mantel–Haenszel method are recommended

Crossover designs have some advantages over standard clinical trial designs and they are often used in trials evaluating the efficacy of treatments for infertility. However, clinical trials of infertility treatments violate a fundamental condition of crossover designs, because women who become pregnant in the first treatment period are not treated in the second period. In previous research, to deal with this problem, some new designs, such as re‐randomization designs, and analysis methods including the logistic mixture model and the beta‐binomial mixture model were proposed. Although the performance of these designs and methods has previously been evaluated in large‐scale clinical trials with sample sizes of more than 1000 per group, the actual sample sizes of infertility treatment trials are usually around 100 per group. The most appropriate design and analysis for these moderate‐scale clinical trials are currently unclear. In this study, we conducted simulation studies to determine the appropriate design and analysis method of moderate‐scale clinical trials for irreversible endpoints by evaluating the statistical power and bias in the treatment effect estimates. The Mantel–Haenszel method had similar power and bias to the logistic mixture model. The crossover designs had the highest power and the smallest bias. We recommend using a combination of the crossover design and the Mantel–Haenszel method for two‐period, two‐treatment clinical trials with irreversible endpoints. Copyright © 2015 John Wiley & Sons, Ltd.     

Verification bias on sensitivity and specificity measurements in diagnostic medicine: a comparison of some approaches used for correction

Verification bias may occur when the test results of not all subjects are verified by using a gold standard. The correction for this bias can be made using different approaches depending on whether missing gold standard test results are random or not. Some of these approaches with binary test and gold standard results include the correction method by Begg and Greenes, lower and upper limits for diagnostic measurements by Zhou, logistic regression method, multiple imputation method, and neural networks. In this study, all these approaches are compared by employing a real and simulated data under different conditions.     

Choice of Parametric Accelerated Life and Proportional Hazards Models for Survival Data: Asymptotic Results

We discuss the impact of misspecifying fully parametric proportional hazards and accelerated life models. For the uncensored case, misspecified accelerated life models give asymptotically unbiased estimates of covariate effect, but the shape and scale parameters depend on the misspecification. The covariate, shape and scale parameters differ in the censored case. Parametric proportional hazards models do not have a sound justification for general use: estimates from misspecified models can be very biased, and misleading results for the shape of the hazard function can arise. Misspecified survival functions are more biased at the extremes than the centre. Asymptotic and first order results are compared. If a model is misspecified, the size of Wald tests will be underestimated. Use of the sandwich estimator of standard error gives tests of the correct size, but misspecification leads to a loss of power. Accelerated life models are more robust to misspecification because of their log-linear form. In preliminary data analysis, practitioners should investigate proportional hazards and accelerated life models; software is readily available for several such models.     

Inference for a Class of Stochastic Volatility Models Using Option and Spot Prices: Application of a Bivariate Kalman Filter

In this paper Bayesian methods are applied to a stochastic volatility model using both the prices of the asset and the prices of options written on the asset. Posterior densities for all model parameters, latent volatilities and the market price of volatility risk are produced via a Markov Chain Monte Carlo (MCMC) sampling algorithm. Candidate draws for the unobserved volatilities are obtained in blocks by applying the Kalman filter and simulation smoother to a linearization of a nonlinear state space representation of the model. Crucially, information from both the spot and option prices affects the draws via the specification of a bivariate measurement equation, with implied Black-Scholes volatilities used to proxy observed option prices in the candidate model. Alternative models nested within the Heston (1993) framework are ranked via posterior odds ratios, as well as via fit, predictive and hedging performance. The method is illustrated using Australian News Corporation spot and option price data.     

Inference for a Class of Stochastic Volatility Models Using Option and Spot Prices: Application of a Bivariate Kalman Filter

In this paper Bayesian methods are applied to a stochastic volatility model using both the prices of the asset and the prices of options written on the asset. Posterior densities for all model parameters, latent volatilities and the market price of volatility risk are produced via a Markov Chain Monte Carlo (MCMC) sampling algorithm. Candidate draws for the unobserved volatilities are obtained in blocks by applying the Kalman filter and simulation smoother to a linearization of a nonlinear state space representation of the model. Crucially, information from both the spot and option prices affects the draws via the specification of a bivariate measurement equation, with implied Black–Scholes volatilities used to proxy observed option prices in the candidate model. Alternative models nested within the Heston (1993) framework are ranked via posterior odds ratios, as well as via fit, predictive and hedging performance. The method is illustrated using Australian News Corporation spot and option price data.     

Inference for Epidemics with Three Levels of Mixing: Methodology and Application to a Measles Outbreak

Abstract. A stochastic epidemic model is defined in which each individual belongs to a household, a secondary grouping (typically school or workplace) and also the community as a whole. Moreover, infectious contacts take place in these three settings according to potentially different rates. For this model, we consider how different kinds of data can be used to estimate the infection rate parameters with a view to understanding what can and cannot be inferred. Among other things we find that temporal data can be of considerable inferential benefit compared with final size data, that the degree of heterogeneity in the data can have a considerable effect on inference for non‐household transmission, and that inferences can be materially different from those obtained from a model with only two levels of mixing. We illustrate our findings by analysing a highly detailed dataset concerning a measles outbreak in Hagelloch, Germany.     

农村居民消费融资需求及影响因素分析——以陕西省渭南市为例

基于渭南市2 636户农户问卷调查数据,从农户分化与演变视觉分析农村居民消费融资需求状况。采用概率模型分析了影响农户融资消费的主要因素是收支的＂非均衡性＂、户主个性、消费环境、城乡融合程度和存贷款利率水平高低。建议调整国民收入分配结构,完善农村基本社会保障体系,推进农村居民生产生活集聚,构建以农户需求为导向的农村金融体系。     

On square ordinal contingency tables: a comparison of social class and income mobility for the same individuals

Summary.  Square contingency tables with matching ordinal rows and columns arise in particular as empirical transition matrices and the paper considers these in the context of social class and income mobility tables. Such tables relate the socio-economic position of parents to the socio-economic position of their child in adulthood. The level of association between parental and child socio-economic position is taken as a measure of mobility. Several approaches to analysis are described and illustrated by UK data in which interest focuses on comparisons of social class and income mobility tables that are derived from the same individuals. Account is taken of the use of the same individuals in the two tables. Additionally comparisons over time are considered.