A mixture model using likelihood‐based and Bayesian approaches for identifying responders and non‐responders in longitudinal clinical trials

A longitudinal mixture model for classifying patients into responders and non‐responders is established using both likelihood‐based and Bayesian approaches. The model takes into consideration responders in the control group. Therefore, it is especially useful in situations where the placebo response is strong, or in equivalence trials where the drug in development is compared with a standard treatment. Under our model, a treatment shows evidence of being effective if it increases the proportion of responders or increases the response rate among responders in the treated group compared with the control group. Therefore, the model has flexibility to accommodate different situations. The proposed method is illustrated using simulation and a depression clinical trial dataset for the likelihood‐based approach, and the same depression clinical trial dataset for the Bayesian approach. The likelihood‐based and Bayesian approaches generated consistent results for the depression trial data. In both the placebo group and the treated group, patients are classified into two components with distinct response rate. The proportion of responders is shown to be significantly higher in the treated group compared with the control group, suggesting the treatment paroxetine is effective. Copyright © 2014 John Wiley & Sons, Ltd.     

Some New Results on the Multinomial Randomized Response Model

ABSTRACT

The randomized response technique is an effective survey method designed to elicit sensitive information while ensuring the privacy of the respondents. In this article, we present some new results on the randomization response model in situations wherein one or two response variables are assumed to follow a multinomial distribution. For a single sensitive question, we use the well-known Hopkins randomization device to derive estimates, both under the assumption of truthful and untruthful responses, and present a technique for making pairwise comparisons. When there are two sensitive questions of interest, we derive a Pearson product moment correlation estimator based on the multinomial model assumption. This estimator may be used to quantify the linear relationship between two variables when multinomial response data are observed according to a randomized-response protocol.     

Randomization tests in recursive response-adaptive randomization procedures

In a randomized clinical trial, response-adaptive randomization procedures use the information gathered, including the previous patients' responses, to allocate the next patient. In this setting, we consider randomization-based inference. We provide an algorithm to obtain exact p-values for statistical tests that compare two treatments with dichotomous responses. This algorithm can be applied to a family of response adaptive randomization procedures which share the following property: the distribution of the allocation rule depends only on the imbalance between treatments and on the imbalance between successes for treatments 1 and 2 in the previous step. This family includes some outstanding response adaptive randomization procedures. We study a randomization test to contrast the null hypothesis of equivalence of treatments and we show that this test has a similar performance to that of its parametric counterpart. Besides, we study the effect of a covariate in the inferential process. First, we obtain a parametric test, constructed assuming a logit model which relates responses to treatments and covariate levels, and we give conditions that guarantee its asymptotic normality. Finally, we show that the randomization test, which is free of model specification, performs as well as the parametric test that takes the covariate into account.     

Mean and sensitivity estimation of a sensitive variable through additive scrambling

Abstract

This article focuses on reducing the additional variance due to randomization of the responses. The idea of additive scrambling and its inverse has been used along with (i) split sample approach and (ii) double response approach. Specifically, our proposal is based on Gupta et al. (2006) randomized response model. We selected this model for improvement because it provides estimator of mean and sensitivity level of a sensitive variable and is better than all of its competitors proposed earlier to it and even Gupta et al. (2006) sensitivity estimator is better than that of Gupta et al. (2010). Our suggested estimators are unbiased estimators and perform better than Gupta et al. (2006) estimator. The issue of privacy protection is also discussed.     

An improved randomized response model: estimation of mean

In this paper, we suggest a new randomized response model useful for collecting information on quantitative sensitive variables such as drug use and income. The resultant estimator has been found to be better than the usual additive randomized response model. An interesting feature of the proposed model is that it is free from the known parameters of the scrambling variable unlike the additive model due to Himmelfarb and Edgell [S. Himmelfarb and S.E. Edgell, Additive constant model: a randomized response technique for eliminating evasiveness to quantitative response questions, Psychol. Bull. 87(1980), 525–530]. Relative efficiency of the proposed model has also been studied with the corresponding competitors. At the end, an application of the proposed model has been discussed.     

Analyzing continuous randomized response data with an indifference-zone selection procedure

A review of the randomized response model introduced by Warner (1965) is given, then a randomized response model applicable to continuous data that considers a mixture of two normal distributions is considered. The target here is not to estimate any parameter, but rather to select the population with the best parameter value. This article provides a study on how to choose the best population between k distinct populations using an indifference-zone procedure. Also, this article includes tables for the required sample size needed in order to have a probability of correct selection higher than some specified value in the preference zone for the randomized response model considered.     

The Performance of Randomization Tests that Use Permutations of Independent Variables

ABSTRACT

In this article we evaluate the performance of a randomization test for a subset of regression coefficients in a linear model. This randomization test is based on random permutations of the independent variables. It is shown that the method maintains its level of significance, except for extreme situations, and has power that approximates the power of another randomization test, which is based on the permutation of residuals from the reduced model. We also show, via an example, that the method of permuting independent variables is more valuable than other randomization methods because it can be used in connection with the downweighting of outliers.     

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.     

START: single‐to‐double arm transition design for phase II clinical trials

Phase II clinical trials designed for evaluating a drug's treatment effect can be either single‐arm or double‐arm. A single‐arm design tests the null hypothesis that the response rate of a new drug is lower than a fixed threshold, whereas a double‐arm scheme takes a more objective comparison of the response rate between the new treatment and the standard of care through randomization. Although the randomized design is the gold standard for efficacy assessment, various situations may arise where a single‐arm pilot study prior to a randomized trial is necessary. To combine the single‐ and double‐arm phases and pool the information together for better decision making, we propose a Single‐To‐double ARm Transition design (START) with switching hypotheses tests, where the first stage compares the new drug's response rate with a minimum required level and imposes a continuation criterion, and the second stage utilizes randomization to determine the treatment's superiority. We develop a software package in R to calibrate the frequentist error rates and perform simulation studies to assess the trial characteristics. Finally, a metastatic pancreatic cancer trial is used for illustrating the decision rules under the proposed START design.     

Empirical likelihood ratio tests for the linear regression model with inequality constraints

Abstract

In this article, empirical likelihood is applied to the linear regression model with inequality constraints. We prove that asymptotic distribution of the adjusted empirical likelihood ratio test statistic is a weighted mixture of chi-square distribution.     

A sinuous stratified unrelated question randomized response model

ABSTRACT

This paper considers the use of stratified random sampling with proportional as well as Neyman allocations to unrelated question randomized response strategy. It has been shown that, for the prior information given, our new model is more efficient in terms of variance (in the case of completely truthful reporting) and mean square error (in case of less than completely truthful reporting). Numerical illustrations are also given in support of the present study.     

Bayesian analysis of Cannabis offences using generalized Poisson geometric process model with flexible dispersion

ABSTRACT

This paper derives models to analyse Cannabis offences count series from New South Wales, Australia. The data display substantial overdispersion as well as underdispersion for a subset, trend movement and population heterogeneity. To describe the trend dynamic in the data, the Poisson geometric process model is first adopted and is extended to the generalized Poisson geometric process model to capture both over- and underdispersion. By further incorporating mixture effect, the model accommodates population heterogeneity and enables classification of homogeneous units. The model is implemented using Markov chain Monte Carlo algorithms via the user-friendly WinBUGS software and its performance is evaluated through a simulation study.     

Weighted re‐randomization tests for minimization with unbalanced allocation

Re‐randomization test has been considered as a robust alternative to the traditional population model‐based methods for analyzing randomized clinical trials. This is especially so when the clinical trials are randomized according to minimization, which is a popular covariate‐adaptive randomization method for ensuring balance among prognostic factors. Among various re‐randomization tests, fixed‐entry‐order re‐randomization is advocated as an effective strategy when a temporal trend is suspected. Yet when the minimization is applied to trials with unequal allocation, fixed‐entry‐order re‐randomization test is biased and thus compromised in power. We find that the bias is due to non‐uniform re‐allocation probabilities incurred by the re‐randomization in this case. We therefore propose a weighted fixed‐entry‐order re‐randomization test to overcome the bias. The performance of the new test was investigated in simulation studies that mimic the settings of a real clinical trial. The weighted re‐randomization test was found to work well in the scenarios investigated including the presence of a strong temporal trend. Copyright © 2013 John Wiley & Sons, Ltd.     

Proportional hazards model for discrete data: Some new developments

ABSTRACT

Many times, a product lifetime can be described through a non negative integer valued random variable. In this article, we propose a proportional hazards model for discrete data analogous to the version for continuous data. Some ageing properties of the model are discussed. Stochastic comparison of pair of random variables that follow the model are also made. A new test based on U-statistics is developed for testing that the proportionality parameter in the proposed model is 1. The asymptotic properties of the proposed test are studied. We present some numerical results to asses the performance of the test procedure.     

Estimating finite mixture of continuous trees using penalized mutual information

Abstract

In this paper we introduce continuous tree mixture model that is the mixture of undirected graphical models with tree structured graphs and is considered as multivariate analysis with a non parametric approach. We estimate its parameters, the component edge sets and mixture proportions through regularized maximum likalihood procedure. Our new algorithm, which uses expectation maximization algorithm and the modified version of Kruskal algorithm, simultaneosly estimates and prunes the mixture component trees. Simulation studies indicate this method performs better than the alternative Gaussian graphical mixture model. The proposed method is also applied to water-level data set and is compared with the results of Gaussian mixture model.     

An application of negative binomial distribution of order k in sensitive surveys

This article is an attempt to generalize some of the recent papers on randomized response techniques by using the negative binomial distribution of order k to randomize the responses in the randomization design where respondents can report outcome of one of two binary devices depending upon their actual status. The relative efficiency results are observed to be better than those of many recent and relevant randomized response techniques. The results are also better than those of the base line model used in this study, providing the sensitive attribute is rare. An extra advantage of the proposed technique is that it does not require any additional sampling and administrative cost.     

A mixed effects model for analyzing area under the curve of longitudinally measured biomarkers with missing data

A simple approach for analyzing longitudinally measured biomarkers is to calculate summary measures such as the area under the curve (AUC) for each individual and then compare the mean AUC between treatment groups using methods such as t test. This two-step approach is difficult to implement when there are missing data since the AUC cannot be directly calculated for individuals with missing measurements. Simple methods for dealing with missing data include the complete case analysis and imputation. A recent study showed that the estimated mean AUC difference between treatment groups based on the linear mixed model (LMM), rather than on individually calculated AUCs by simple imputation, has negligible bias under random missing assumptions and only small bias when missing is not at random. However, this model assumes the outcome to be normally distributed, which is often violated in biomarker data. In this paper, we propose to use a LMM on log-transformed biomarkers, based on which statistical inference for the ratio, rather than difference, of AUC between treatment groups is provided. The proposed method can not only handle the potential baseline imbalance in a randomized trail but also circumvent the estimation of the nuisance variance parameters in the log-normal model. The proposed model is applied to a recently completed large randomized trial studying the effect of nicotine reduction on biomarker exposure of smokers.     

Bootstrap likelihood ratio test for Weibull mixture models fitted to grouped data

Abstract

Weibull mixture models are widely used in a variety of fields for modeling phenomena caused by heterogeneous sources. We focus on circumstances in which original observations are not available, and instead the data comes in the form of a grouping of the original observations. We illustrate EM algorithm for fitting Weibull mixture models for grouped data and propose a bootstrap likelihood ratio test (LRT) for determining the number of subpopulations in a mixture model. The effectiveness of the LRT methods are investigated via simulation. We illustrate the utility of these methods by applying them to two grouped data applications.     

A mixture model for the detection of Neosporosis without a gold standard

Neosporosis is a bovine disease caused by the parasite Neospora caninum. It is not yet sufficiently studied, and it is supposed to cause an important number of abortions. Its clinical symptoms do not yet allow the reliable identification of infected animals. Its study and treatment would improve if a test based on antibody counts were available. Knowing the distribution functions of observed counts of uninfected and infected cows would allow the determination of a cutoff value. These distributions cannot be estimated directly. This paper deals with the indirect estimation of these distributions based on a data set consisting of the antibody counts for some 200 pairs of cows and their calves. The desired distributions are estimated through a mixture model based on simple assumptions that describe the relationship between each cow and its calf. The model then allows the estimation of the cutoff value and of the error probabilities.