Bayesian adaptive dose‐escalation procedures for binary and continuous responses utilizing a gain function

One of the main aims of early phase clinical trials is to identify a safe dose with an indication of therapeutic benefit to administer to subjects in further studies. Ideally therefore, dose‐limiting events (DLEs) and responses indicative of efficacy should be considered in the dose‐escalation procedure. Several methods have been suggested for incorporating both DLEs and efficacy responses in early phase dose‐escalation trials. In this paper, we describe and evaluate a Bayesian adaptive approach based on one binary response (occurrence of a DLE) and one continuous response (a measure of potential efficacy) per subject. A logistic regression and a linear log‐log relationship are used respectively to model the binary DLEs and the continuous efficacy responses. A gain function concerning both the DLEs and efficacy responses is used to determine the dose to administer to the next cohort of subjects. Stopping rules are proposed to enable efficient decision making. Simulation results shows that our approach performs better than taking account of DLE responses alone. To assess the robustness of the approach, scenarios where the efficacy responses of subjects are generated from an E _max model, but modelled by the linear log–log model are also considered. This evaluation shows that the simpler log–log model leads to robust recommendations even under this model showing that it is a useful approximation to the difficulty in estimating E _max model. Additionally, we find comparable performance to alternative approaches using efficacy and safety for dose‐finding. Copyright © 2015 John Wiley & Sons, Ltd.     

Bayesian adaptive dose‐escalation designs for simultaneously estimating the optimal and maximum safe dose based on safety and efficacy

The main purpose of dose‐escalation trials is to identify the dose(s) that is/are safe and efficacious for further investigations in later studies. In this paper, we introduce dose‐escalation designs that incorporate both the dose‐limiting events and dose‐limiting toxicities (DLTs) and indicative responses of efficacy into the procedure. A flexible nonparametric model is used for modelling the continuous efficacy responses while a logistic model is used for the binary DLTs. Escalation decisions are based on the combination of the probabilities of DLTs and expected efficacy through a gain function. On the basis of this setup, we then introduce 2 types of Bayesian adaptive dose‐escalation strategies. The first type of procedures, called “single objective,” aims to identify and recommend a single dose, either the maximum tolerated dose, the highest dose that is considered as safe, or the optimal dose, a safe dose that gives optimum benefit risk. The second type, called “dual objective,” aims to jointly estimate both the maximum tolerated dose and the optimal dose accurately. The recommended doses obtained under these dose‐escalation procedures provide information about the safety and efficacy profile of the novel drug to facilitate later studies. We evaluate different strategies via simulations based on an example constructed from a real trial on patients with type 2 diabetes, and the use of stopping rules is assessed. We find that the nonparametric model estimates the efficacy responses well for different underlying true shapes. The dual‐objective designs give better results in terms of identifying the 2 real target doses compared to the single‐objective designs.     

A randomized phase I Bayesian dose escalation design for the combination of anti‐cancer drugs

Nowadays, treatment regimens for cancer often involve a combination of drugs. The determination of the doses of each of the combined drugs in phase I dose escalation studies poses methodological challenges. The most common phase I design, the classic ‘3+3' design, has been criticized for poorly estimating the maximum tolerated dose (MTD) and for treating too many subjects at doses below the MTD. In addition, the classic ‘3+3' is not able to address the challenges posed by combinations of drugs. Here, we assume that a control drug (commonly used and well‐studied) is administered at a fixed dose in combination with a new agent (the experimental drug) of which the appropriate dose has to be determined. We propose a randomized design in which subjects are assigned to the control or to the combination of the control and experimental. The MTD is determined using a model‐based Bayesian technique based on the difference of probability of dose limiting toxicities (DLT) between the control and the combination arm. We show, through a simulation study, that this approach provides better and more accurate estimates of the MTD. We argue that this approach may differentiate between an extreme high probability of DLT observed from the control and a high probability of DLT of the combination. We also report on a fictive (simulation) analysis based on published data of a phase I trial of ifosfamide combined with sunitinib.Copyright © 2014 John Wiley & Sons, Ltd.     

Gaining acceptability for the Bayesian decision‐theoretic approach in dose‐escalation studies

There has recently been increasing demand for better designs to conduct first‐into‐man dose‐escalation studies more efficiently, more accurately and more quickly. The authors look into the Bayesian decision‐theoretic approach and use simulation as a tool to investigate the impact of compromises with conventional practice that might make the procedures more acceptable for implementation. Copyright © 2005 John Wiley & Sons, Ltd.     

Escalation strategies for combination therapy Phase I trials

Phase I clinical trials aim to identify a maximum tolerated dose (MTD), the highest possible dose that does not cause an unacceptable amount of toxicity in the patients. In trials of combination therapies, however, many different dose combinations may have a similar probability of causing a dose‐limiting toxicity, and hence, a number of MTDs may exist. Furthermore, escalation strategies in combination trials are more complex, with possible escalation/de‐escalation of either or both drugs. This paper investigates the properties of two existing proposed Bayesian adaptive models for combination therapy dose‐escalation when a number of different escalation strategies are applied. We assess operating characteristics through a series of simulation studies and show that strategies that only allow ‘non‐diagonal’ moves in the escalation process (that is, both drugs cannot increase simultaneously) are inefficient and identify fewer MTDs for Phase II comparisons. Such strategies tend to escalate a single agent first while keeping the other agent fixed, which can be a severe restriction when exploring dose surfaces using a limited sample size. Meanwhile, escalation designs based on Bayesian D‐optimality allow more varied experimentation around the dose space and, consequently, are better at identifying more MTDs. We argue that for Phase I combination trials it is sensible to take forward a number of identified MTDs for Phase II experimentation so that their efficacy can be directly compared. Researchers, therefore, need to carefully consider the escalation strategy and model that best allows the identification of these MTDs. Copyright © 2012 John Wiley & Sons, Ltd.     

A simulation study of methods for selecting subgroup‐specific doses in phase 1 trials

Patient heterogeneity may complicate dose‐finding in phase 1 clinical trials if the dose‐toxicity curves differ between subgroups. Conducting separate trials within subgroups may lead to infeasibly small sample sizes in subgroups having low prevalence. Alternatively,it is not obvious how to conduct a single trial while accounting for heterogeneity. To address this problem,we consider a generalization of the continual reassessment method on the basis of a hierarchical Bayesian dose‐toxicity model that borrows strength between subgroups under the assumption that the subgroups are exchangeable. We evaluate a design using this model that includes subgroup‐specific dose selection and safety rules. A simulation study is presented that includes comparison of this method to 3 alternative approaches,on the basis of nonhierarchical models,that make different types of assumptions about within‐subgroup dose‐toxicity curves. The simulations show that the hierarchical model‐based method is recommended in settings where the dose‐toxicity curves are exchangeable between subgroups. We present practical guidelines for application and provide computer programs for trial simulation and conduct.     

Nonparametric Benchmark Dose Estimation with Continuous Dose‐Response Data

We propose a new method for risk‐analytic benchmark dose (BMD) estimation in a dose‐response setting when the responses are measured on a continuous scale. For each dose level d, the observation X(d) is assumed to follow a normal distribution: . No specific parametric form is imposed upon the mean μ(d), however. Instead, nonparametric maximum likelihood estimates of μ(d) and σ are obtained under a monotonicity constraint on μ(d). For purposes of quantitative risk assessment, a ‘hybrid’ form of risk function is defined for any dose d as R(d) = P[X(d) < c], where c > 0 is a constant independent of d. The BMD is then determined by inverting the additional risk functionR_A(d) = R(d) ? R(0) at some specified value of benchmark response. Asymptotic theory for the point estimators is derived, and a finite‐sample study is conducted, using both real and simulated data. When a large number of doses are available, we propose an adaptive grouping method for estimating the BMD, which is shown to have optimal mean integrated squared error under appropriate designs.     

TITE‐BOIN‐ET: Time‐to‐event Bayesian optimal interval design to accelerate dose‐finding based on both efficacy and toxicity outcomes

One of the primary purposes of an oncology dose‐finding trial is to identify an optimal dose (OD) that is both tolerable and has an indication of therapeutic benefit for subjects in subsequent clinical trials. In addition, it is quite important to accelerate early stage trials to shorten the entire period of drug development. However, it is often challenging to make adaptive decisions of dose escalation and de‐escalation in a timely manner because of the fast accrual rate, the difference of outcome evaluation periods for efficacy and toxicity and the late‐onset outcomes. To solve these issues, we propose the time‐to‐event Bayesian optimal interval design to accelerate dose‐finding based on cumulative and pending data of both efficacy and toxicity. The new design, named “TITE‐BOIN‐ET” design, is nonparametric and a model‐assisted design. Thus, it is robust, much simpler, and easier to implement in actual oncology dose‐finding trials compared with the model‐based approaches. These characteristics are quite useful from a practical point of view. A simulation study shows that the TITE‐BOIN‐ET design has advantages compared with the model‐based approaches in both the percentage of correct OD selection and the average number of patients allocated to the ODs across a variety of realistic settings. In addition, the TITE‐BOIN‐ET design significantly shortens the trial duration compared with the designs without sequential enrollment and therefore has the potential to accelerate early stage dose‐finding trials.     

Estimation of Non‐Crossing Quantile Regression Curves

Quantile regression methods have been widely used in many research areas in recent years. However conventional estimation methods for quantile regression models do not guarantee that the estimated quantile curves will be non‐crossing. While there are various methods in the literature to deal with this problem, many of these methods force the model parameters to lie within a subset of the parameter space in order for the required monotonicity to be satisfied. Note that different methods may use different subspaces of the space of model parameters. This paper establishes a relationship between the monotonicity of the estimated conditional quantiles and the comonotonicity of the model parameters. We develope a novel quasi‐Bayesian method for parameter estimation which can be used to deal with both time series and independent statistical data. Simulation studies and an application to real financial returns show that the proposed method has the potential to be very useful in practice.     

Characterization of dose‐response for count data using a generalized MCP‐Mod approach in an adaptive dose‐ranging trial

Understanding the dose–response relationship is a key objective in Phase II clinical development. Yet, designing a dose‐ranging trial is a challenging task, as it requires identifying the therapeutic window and the shape of the dose–response curve for a new drug on the basis of a limited number of doses. Adaptive designs have been proposed as a solution to improve both quality and efficiency of Phase II trials as they give the possibility to select the dose to be tested as the trial goes. In this article, we present a ‘shapebased’ two‐stage adaptive trial design where the doses to be tested in the second stage are determined based on the correlation observed between efficacy of the doses tested in the first stage and a set of pre‐specified candidate dose–response profiles. At the end of the trial, the data are analyzed using the generalized MCP‐Mod approach in order to account for model uncertainty. A simulation study shows that this approach gives more precise estimates of a desired target dose (e.g. ED70) than a single‐stage (fixed‐dose) design and performs as well as a two‐stage D‐optimal design. We present the results of an adaptive model‐based dose‐ranging trial in multiple sclerosis that motivated this research and was conducted using the presented methodology. Copyright © 2015 John Wiley & Sons, Ltd.     

MODEL‐BASED DIRECT ESTIMATION OF SMALL‐AREA DISTRIBUTIONS

Much of the small‐area estimation literature focuses on population totals and means. However, users of survey data are often interested in the finite‐population distribution of a survey variable and in the measures (e.g. medians, quartiles, percentiles) that characterize the shape of this distribution at the small‐area level. In this paper we propose a model‐based direct estimator (MBDE, Chandra and Chambers) of the small‐area distribution function. The MBDE is defined as a weighted sum of sample data from the area of interest, with weights derived from the calibrated spline‐based estimate of the finite‐population distribution function introduced by Harms and Duchesne, under an appropriately specified regression model with random area effects. We also discuss the mean squared error estimation of the MBDE. Monte Carlo simulations based on both simulated and real data sets show that the proposed MBDE and its associated mean squared error estimator perform well when compared with alternative estimators of the area‐specific finite‐population distribution function.     

Evaluations of Bayesian and maximum likelihood methods in PK models with below‐quantification‐limit data

Pharmacokinetic (PK) data often contain concentration measurements below the quantification limit (BQL). While specific values cannot be assigned to these observations, nevertheless these observed BQL data are informative and generally known to be lower than the lower limit of quantification (LLQ). Setting BQLs as missing data violates the usual missing at random (MAR) assumption applied to the statistical methods, and therefore leads to biased or less precise parameter estimation. By definition, these data lie within the interval [0, LLQ], and can be considered as censored observations. Statistical methods that handle censored data, such as maximum likelihood and Bayesian methods, are thus useful in the modelling of such data sets. The main aim of this work was to investigate the impact of the amount of BQL observations on the bias and precision of parameter estimates in population PK models (non‐linear mixed effects models in general) under maximum likelihood method as implemented in SAS and NONMEM, and a Bayesian approach using Markov chain Monte Carlo (MCMC) as applied in WinBUGS. A second aim was to compare these different methods in dealing with BQL or censored data in a practical situation. The evaluation was illustrated by simulation based on a simple PK model, where a number of data sets were simulated from a one‐compartment first‐order elimination PK model. Several quantification limits were applied to each of the simulated data to generate data sets with certain amounts of BQL data. The average percentage of BQL ranged from 25% to 75%. Their influence on the bias and precision of all population PK model parameters such as clearance and volume distribution under each estimation approach was explored and compared. Copyright © 2009 John Wiley & Sons, Ltd.     

Model‐based Prediction In Ecological Surveys Including Those with Incomplete Detection

This paper explores and develops model‐based predictors for surveys of plants and wildlife including those with incomplete detection. The methodology allows for estimating a detection function to account for objects which were not detected at the time of the survey. The model‐based theory utilises generalized linear models (GLMs) and is either new or adapted from other areas of sampling. A simulation study is used to validate the estimators and comparisons are made with an integrated likelihood approach. An aerial survey of kangaroos in western New South Wales is used to illustrate the theory. The area within 50m of the aircraft is treated as a strip transect and mark‐recapture methods are used to estimate the detection function.     

An adaptive model switching approach for phase I dose‐finding trials

Model‐based phase I dose‐finding designs rely on a single model throughout the study for estimating the maximum tolerated dose (MTD). Thus, one major concern is about the choice of the most suitable model to be used. This is important because the dose allocation process and the MTD estimation depend on whether or not the model is reliable, or whether or not it gives a better fit to toxicity data. The aim of our work was to propose a method that would remove the need for a model choice prior to the trial onset and then allow it sequentially at each patient's inclusion. In this paper, we described model checking approach based on the posterior predictive check and model comparison approach based on the deviance information criterion, in order to identify a more reliable or better model during the course of a trial and to support clinical decision making. Further, we presented two model switching designs for a phase I cancer trial that were based on the aforementioned approaches, and performed a comparison between designs with or without model switching, through a simulation study. The results showed that the proposed designs had the advantage of decreasing certain risks, such as those of poor dose allocation and failure to find the MTD, which could occur if the model is misspecified. Copyright © 2013 John Wiley & Sons, Ltd.     

Bayesian spatio‐temporal models based on discrete convolutions

Abstract: The authors consider a class of models for spatio‐temporal processes based on convolving independent processes with a discrete kernel that is represented by a lower triangular matrix. They study two families of models. In the first one, spatial Gaussian processes with isotropic correlations are convoluted with a kernel that provides temporal dependencies. In the second family, AR(p) processes are convoluted with a kernel providing spatial interactions. The covariance structures associated with these two families are quite rich. Their covariance functions that are stationary and separable in space and time as well as time dependent nonseparable and nonisotropic ones.     

ESTIMATING BAYESIAN NETWORKS FOR HIGH‐DIMENSIONAL DATA WITH COMPLEX MEAN STRUCTURE AND RANDOM EFFECTS

The estimation of Bayesian networks given high‐dimensional data, in particular gene expression data, has been the focus of much recent research. Whilst there are several methods available for the estimation of such networks, these typically assume that the data consist of independent and identically distributed samples. It is often the case, however, that the available data have a more complex mean structure, plus additional components of variance, which must then be accounted for in the estimation of a Bayesian network. In this paper, score metrics that take account of such complexities are proposed for use in conjunction with score‐based methods for the estimation of Bayesian networks. We propose first, a fully Bayesian score metric, and second, a metric inspired by the notion of restricted maximum likelihood. We demonstrate the performance of these new metrics for the estimation of Bayesian networks using simulated data with known complex mean structures. We then present the analysis of expression levels of grape‐berry genes adjusting for exogenous variables believed to affect the expression levels of the genes. Demonstrable biological effects can be inferred from the estimated conditional independence relationships and correlations amongst the grape‐berry genes.     

SEQUENTIAL,BOTTOM‐UP VARIABLE SELECTION FOR HIGH‐DIMENSIONAL CLASSIFICATION

Most methods for variable selection work from the top down and steadily remove features until only a small number remain. They often rely on a predictive model, and there are usually significant disconnections in the sequence of methodologies that leads from the training samples to the choice of the predictor, then to variable selection, then to choice of a classifier, and finally to classification of a new data vector. In this paper we suggest a bottom‐up approach that brings the choices of variable selector and classifier closer together, by basing the variable selector directly on the classifier, removing the need to involve predictive methods in the classification decision, and enabling the direct and transparent comparison of different classifiers in a given problem. Specifically, we suggest ‘wrapper methods’, determined by classifier type, for choosing variables that minimize the classification error rate. This approach is particularly useful for exploring relationships among the variables that are chosen for the classifier. It reveals which variables have a high degree of leverage for correct classification using different classifiers; it shows which variables operate in relative isolation, and which are important mainly in conjunction with others; it permits quantification of the authority with which variables are selected; and it generally leads to a reduced number of variables for classification, in comparison with alternative approaches based on prediction.     

A win ratio approach to comparing continuous non‐normal outcomes in clinical trials

Clinical trials are often designed to compare continuous non‐normal outcomes. The conventional statistical method for such a comparison is a non‐parametric Mann–Whitney test, which provides a P‐value for testing the hypothesis that the distributions of both treatment groups are identical, but does not provide a simple and straightforward estimate of treatment effect. For that, Hodges and Lehmann proposed estimating the shift parameter between two populations and its confidence interval (CI). However, such a shift parameter does not have a straightforward interpretation, and its CI contains zero in some cases when Mann–Whitney test produces a significant result. To overcome the aforementioned problems, we introduce the use of the win ratio for analysing such data. Patients in the new and control treatment are formed into all possible pairs. For each pair, the new treatment patient is labelled a ‘winner’ or a ‘loser’ if it is known who had the more favourable outcome. The win ratio is the total number of winners divided by the total numbers of losers. A 95% CI for the win ratio can be obtained using the bootstrap method. Statistical properties of the win ratio statistic are investigated using two real trial data sets and six simulation studies. Results show that the win ratio method has about the same power as the Mann–Whitney method. We recommend the use of the win ratio method for estimating the treatment effect (and CI) and the Mann–Whitney method for calculating the P‐value for comparing continuous non‐Normal outcomes when the amount of tied pairs is small. Copyright © 2016 John Wiley & Sons, Ltd.     

Block‐threshold‐adapted Estimators via a Maxiset Approach

We study the maxiset performance of a large collection of block thresholding wavelet estimators, namely the horizontal block thresholding family. We provide sufficient conditions on the choices of rates and threshold values to ensure that the involved adaptive estimators obtain large maxisets. Moreover, we prove that any estimator of such a family reconstructs the Besov balls with a near‐minimax optimal rate that can be faster than the one of any separable thresholding estimator. Then, we identify, in particular cases, the best estimator of such a family, that is, the one associated with the largest maxiset. As a particularity of this paper, we propose a refined approach that models method‐dependent threshold values. By a series of simulation studies, we confirm the good performance of the best estimator by comparing it with the other members of its family.     

A Bayesian non‐inferiority test for two independent binomial proportions

In drug development, non‐inferiority tests are often employed to determine the difference between two independent binomial proportions. Many test statistics for non‐inferiority are based on the frequentist framework. However, research on non‐inferiority in the Bayesian framework is limited. In this paper, we suggest a new Bayesian index τ = P(π₁ > π₂ ? Δ₀ | X₁,X₂), where X₁ and X₂ denote binomial random variables for trials n₁ and n₂, and parameters π₁ and π₂, respectively, and the non‐inferiority margin is Δ₀ > 0. We show two calculation methods for τ, an approximate method that uses normal approximation and an exact method that uses an exact posterior PDF. We compare the approximate probability with the exact probability for τ. Finally, we present the results of actual clinical trials to show the utility of index τ. Copyright © 2013 John Wiley & Sons, Ltd.