Estimating individual-level interaction effects in multilevel models: a Monte Carlo simulation study with application*

Moderated multiple regression provides a useful framework for understanding moderator variables. These variables can also be examined within multilevel datasets, although the literature is not clear on the best way to assess data for significant moderating effects, particularly within a multilevel modeling framework. This study explores potential ways to test moderation at the individual level (level one) within a 2-level multilevel modeling framework, with varying effect sizes, cluster sizes, and numbers of clusters. The study examines five potential methods for testing interaction effects: the Wald test, F-test, likelihood ratio test, Bayesian information criterion (BIC), and Akaike information criterion (AIC). For each method, the simulation study examines Type I error rates and power. Following the simulation study, an applied study uses real data to assess interaction effects using the same five methods. Results indicate that the Wald test, F-test, and likelihood ratio test all perform similarly in terms of Type I error rates and power. Type I error rates for the AIC are more liberal, and for the BIC typically more conservative. A four-step procedure for applied researchers interested in examining interaction effects in multi-level models is provided.     

A Hybrid Geometric Phase II/III Clinical Trial Design based on Treatment Failure Time and Toxicity

The problem of comparing several experimental treatments to a standard arises frequently in medical research. Various multi-stage randomized phase II/III designs have been proposed that select one or more promising experimental treatments and compare them to the standard while controlling overall Type I and Type II error rates. This paper addresses phase II/III settings where the joint goals are to increase the average time to treatment failure and control the probability of toxicity while accounting for patient heterogeneity. We are motivated by the desire to construct a feasible design for a trial of four chemotherapy combinations for treating a family of rare pediatric brain tumors. We present a hybrid two-stage design based on two-dimensional treatment effect parameters. A targeted parameter set is constructed from elicited parameter pairs considered to be equally desirable. Bayesian regression models for failure time and the probability of toxicity as functions of treatment and prognostic covariates are used to define two-dimensional covariate-adjusted treatment effect parameter sets. Decisions at each stage of the trial are based on the ratio of posterior probabilities of the alternative and null covariate-adjusted parameter sets. Design parameters are chosen to minimize expected sample size subject to frequentist error constraints. The design is illustrated by application to the brain tumor trial.     

Unified Conditional Frequentist and Bayesian Testing of Composite Hypotheses

Testing of a composite null hypothesis versus a composite alternative is considered when both have a related invariance structure. The goal is to develop conditional frequentist tests that allow the reporting of data-dependent error probabilities, error probabilities that have a strict frequentist interpretation and that reflect the actual amount of evidence in the data. The resulting tests are also seen to be Bayesian tests, in the strong sense that the reported frequentist error probabilities are also the posterior probabilities of the hypotheses under default choices of the prior distribution. The new procedures are illustrated in a variety of applications to model selection and multivariate hypothesis testing.     

Bayesian two-stage design for drug screening trials with switching hypothesis tests based on continuous endpoints

Abstract

In this paper, we propose a Bayesian two-stage design with changing hypothesis test by bridging a single-arm study and a double-arm randomized trial in one phase II clinical trial based on continuous endpoints rather than binary endpoints. We have also calibrated with respect to frequentist and Bayesian error rates. The proposed design minimizes the Bayesian expected sample size if the new candidate has low or high efficacy activity subject to the constraint upon error rates in both frequentist and Bayesian perspectives. Tables of designs for various combinations of design parameters are also provided.     

A Bayesian False Discovery Rate for Multiple Testing

Case-control studies of genetic polymorphisms and gene-environment interactions are reporting large numbers of statistically significant associations, many of which are likely to be spurious. This problem reflects the low prior probability that any one null hypothesis is false, and the large number of test results reported for a given study. In a Bayesian approach to the low prior probabilities, Wacholder et al. (2004) suggest supplementing the p-value for a hypothesis with its posterior probability given the study data. In a frequentist approach to the test multiplicity problem, Benjamini & Hochberg (1995) propose a hypothesis-rejection rule that provides greater statistical power by controlling the false discovery rate rather than the family-wise error rate controlled by the Bonferroni correction. This paper defines a Bayes false discovery rate and proposes a Bayes-based rejection rule for controlling it. The method, which combines the Bayesian approach of Wacholder et al. with the frequentist approach of Benjamini & Hochberg, is used to evaluate the associations reported in a case-control study of breast cancer risk and genetic polymorphisms of genes involved in the repair of double-strand DNA breaks.     

Bayesian Variable Selection Under Collinearity

In this article, we highlight some interesting facts about Bayesian variable selection methods for linear regression models in settings where the design matrix exhibits strong collinearity. We first demonstrate via real data analysis and simulation studies that summaries of the posterior distribution based on marginal and joint distributions may give conflicting results for assessing the importance of strongly correlated covariates. The natural question is which one should be used in practice. The simulation studies suggest that posterior inclusion probabilities and Bayes factors that evaluate the importance of correlated covariates jointly are more appropriate, and some priors may be more adversely affected in such a setting. To obtain a better understanding behind the phenomenon, we study some toy examples with Zellner’s g-prior. The results show that strong collinearity may lead to a multimodal posterior distribution over models, in which joint summaries are more appropriate than marginal summaries. Thus, we recommend a routine examination of the correlation matrix and calculation of the joint inclusion probabilities for correlated covariates, in addition to marginal inclusion probabilities, for assessing the importance of covariates in Bayesian variable selection.     

Computing Probabilities of Type I Error and Type II Error of Sequential Bayesian Procedures for Testing One-Sided Hypotheses

In this article, it is shown how to compute, in an approximated way, probabilities of Type I error and Type II error of sequential Bayesian procedures for testing one-sided null hypotheses. First, some theoretical results are obtained, and then an algorithm is developed for applying these results. The prior predictive density plays a central role in this study.     

Testing equality of regression coefficients in heteroscedastic normal regression models

This article addresses the problem of testing whether the vectors of regression coefficients are equal for two independent normal regression models when the error variances are unknown. This problem poses severe difficulties both to the frequentist and Bayesian approaches to statistical inference. In the former approach, normal hypothesis testing theory does not apply because of the unrelated variances. In the latter, the prior distributions typically used for the parameters are improper and hence the Bayes factor-based solution cannot be used.We propose a Bayesian solution to this problem in which no subjective input is considered. We first generate “objective” proper prior distributions (intrinsic priors) for which the Bayes factor and model posterior probabilities are well defined. The posterior probability of each model is used as a model selection tool. This consistent procedure of testing hypotheses is compared with some of the frequentist approximate tests proposed in the literature.     

Revisiting the Berger location model: Fallacious confidence interval or a rigged example?

Since the 1960s the Bayesian case against frequentist inference has been partly built on several “classic” examples which are devised to show how frequentist inference procedures can give rise to fallacious results; see Berger and Wolpert (1988) [2]. The primary aim of this note is to revisit one of these examples, the Berger location model, that is supposed to demonstrate the fallaciousness of frequentist Confidence Interval (CI) estimation. A closer look at the example, however, reveals that the fallacious results stem primarily from the problematic nature of the example itself, since it is based on a non-regular probability model that enables one to (indirectly) assign probabilities to the unknown parameter. Moreover, the proposed confidence set is not a proper frequentist CI in the sense that it is not defined in terms of legitimate error probabilities.     

A Bayesian Approach to Model Interdependent Event Histories by Graphical Models

In event history analysis, the problem of modeling two interdependent processes is still not completely solved. In a frequentist framework, there are two most general approaches: the causal approach and the system approach. The recent growing interest in Bayesian statistics suggests some interesting works on survival models and event history analysis in a Bayesian perspective. In this work we present a possible solution for the analysis of dynamic interdependence by a Bayesian perspective in a graphical duration model framework, using marked point processes. Main results from the Bayesian approach and the comparison with the frequentist one are illustrated on a real example: the analysis of the dynamic relationship between fertility and female employment.     

A note on fiducial model averaging as an alternative to checking Bayesian and frequentist models

Just as frequentist hypothesis tests have been developed to check model assumptions, prior predictive p-values and other Bayesian p-values check prior distributions as well as other model assumptions. These model checks not only suffer from the usual threshold dependence of p-values, but also from the suppression of model uncertainty in subsequent inference. One solution is to transform Bayesian and frequentist p-values for model assessment into a fiducial distribution across the models. Averaging the Bayesian or frequentist posterior distributions with respect to the fiducial distribution can reproduce results from Bayesian model averaging or classical fiducial inference.     

Parametric bootstrap inferences for unbalanced panel data models

This article presents parametric bootstrap (PB) approaches for hypothesis testing and interval estimation for the regression coefficients of panel data regression models with incomplete panels. Some simulation results are presented to compare the performance of the PB approaches with the approximate inferences. Our studies show that the PB approaches perform satisfactorily for various sample sizes and parameter configurations, and the performance of PB approaches is mostly better than the approximate methods with respect to the coverage probabilities and the Type I error rates. The PB inferences have almost exact coverage probabilities and Type I error rates. Furthermore, the PB procedure can be simply carried out by a few simulation steps, and the derivation is easier to understand and to be extended to the multi-way error component regression models with unbalanced panels. Finally, the proposed approaches are illustrated by using a real data example.     

Bayesian point null hypothesis testing via the posterior likelihood ratio

This paper gives an exposition of the use of the posterior likelihood ratio for testing point null hypotheses in a fully Bayesian framework. Connections between the frequentist P-value and the posterior distribution of the likelihood ratio are used to interpret and calibrate P-values in a Bayesian context, and examples are given to show the use of simple posterior simulation methods to provide Bayesian tests of common hypotheses.     

Teaching Elementary Bayesian Statistics with Real Applications in Science

University courses in elementary statistics are usually taught from a frequentist perspective. In this paper I suggest how such courses can be taught using a Bayesian approach, and I indicate why beginning students are well served by a Bayesian course. A principal focus of any good elementary course is the application of statistics to real and important scientific problems. The Bayesian approach fits neatly with a scientific focus. Bayesians take a larger view, and one not limited to data analysis. In particular, the Bayesian approach is subjective, and requires assessing prior probabilities. This requirement forces users to relate current experimental evidence to other available information–-including previous experiments of a related nature, where “related” is judged subjectively. I discuss difficulties faced by instructors and students in elementary Bayesian courses, and provide a sample syllabus for an elementary Bayesian course.     

A dynamic power prior for borrowing historical data in noninferiority trials with binary endpoint

Traditionally, noninferiority hypotheses have been tested using a frequentist method with a fixed margin. Given that information for the control group is often available from previous studies, it is interesting to consider a Bayesian approach in which information is “borrowed” for the control group to improve efficiency. However, construction of an appropriate informative prior can be challenging. In this paper, we consider a hybrid Bayesian approach for testing noninferiority hypotheses in studies with a binary endpoint. To account for heterogeneity between the historical information and the current trial for the control group, a dynamic P value–based power prior parameter is proposed to adjust the amount of information borrowed from the historical data. This approach extends the simple test‐then‐pool method to allow a continuous discounting power parameter. An adjusted α level is also proposed to better control the type I error. Simulations are conducted to investigate the performance of the proposed method and to make comparisons with other methods including test‐then‐pool and hierarchical modeling. The methods are illustrated with data from vaccine clinical trials.     

A matching prior based on the modified profile likelihood in a generalized Weibull stress‐strength model

Bayesian inference of a generalized Weibull stress‐strength model (SSM) with more than one strength component is considered. For this problem, properly assigning priors for the reliabilities is challenging due to the presence of nuisance parameters. Matching priors, which are priors matching the posterior probabilities of certain regions with their frequentist coverage probabilities, are commonly used but difficult to derive in this problem. Instead, we apply an alternative method and derive a matching prior based on a modification of the profile likelihood. Simulation studies show that this proposed prior performs well in terms of frequentist coverage and estimation even when the sample sizes are minimal. The prior is applied to two real datasets. The Canadian Journal of Statistics 41: 83–97; 2013 © 2012 Statistical Society of Canada     

Bayesian Analysis of Multiple Hypothesis Testing with Applications to Microarray Experiments

Recently, the field of multiple hypothesis testing has experienced a great expansion, basically because of the new methods developed in the field of genomics. These new methods allow scientists to simultaneously process thousands of hypothesis tests. The frequentist approach to this problem is made by using different testing error measures that allow to control the Type I error rate at a certain desired level. Alternatively, in this article, a Bayesian hierarchical model based on mixture distributions and an empirical Bayes approach are proposed in order to produce a list of rejected hypotheses that will be declared significant and interesting for a more detailed posterior analysis. In particular, we develop a straightforward implementation of a Gibbs sampling scheme where all the conditional posterior distributions are explicit. The results are compared with the frequentist False Discovery Rate (FDR) methodology. Simulation examples show that our model improves the FDR procedure in the sense that it diminishes the percentage of false negatives keeping an acceptable percentage of false positives.     

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.     

Incorporating historical two‐arm data in clinical trials with binary outcome: A practical approach

The feasibility of a new clinical trial may be increased by incorporating historical data of previous trials. In the particular case where only data from a single historical trial are available, there exists no clear recommendation in the literature regarding the most favorable approach. A main problem of the incorporation of historical data is the possible inflation of the type I error rate. A way to control this type of error is the so‐called power prior approach. This Bayesian method does not “borrow” the full historical information but uses a parameter 0 ≤ δ ≤ 1 to determine the amount of borrowed data. Based on the methodology of the power prior, we propose a frequentist framework that allows incorporation of historical data from both arms of two‐armed trials with binary outcome, while simultaneously controlling the type I error rate. It is shown that for any specific trial scenario a value δ > 0 can be determined such that the type I error rate falls below the prespecified significance level. The magnitude of this value of δ depends on the characteristics of the data observed in the historical trial. Conditionally on these characteristics, an increase in power as compared to a trial without borrowing may result. Similarly, we propose methods how the required sample size can be reduced. The results are discussed and compared to those obtained in a Bayesian framework. Application is illustrated by a clinical trial example.     

Bayesian inference method for model validation and confidence extrapolation

This paper presents a Bayesian-hypothesis-testing-based methodology for model validation and confidence extrapolation under uncertainty, using limited test data. An explicit expression of the Bayes factor is derived for the interval hypothesis testing. The interval method is compared with the Bayesian point null hypothesis testing approach. The Bayesian network with Markov Chain Monte Carlo simulation and Gibbs sampling is explored for extrapolating the inference from the validated domain at the component level to the untested domain at the system level. The effect of the number of experiments on the confidence in the model validation decision is investigated. The probabilities of Type I and Type II errors in decision-making during the model validation and confidence extrapolation are quantified. The proposed methodologies are applied to a structural mechanics problem. Numerical results demonstrate that the Bayesian methodology provides a quantitative approach to facilitate rational decisions in model validation and confidence extrapolation under uncertainty.