Optimal Bayesian two-phase designs

In this paper we present a Bayesian decision theoretic approach to the two-phase design problem. The solution of such sequential decision problems is usually difficult to obtain because of their reliance on preposterior analysis. In overcoming this problem, we adopt the Mont-Carlo-based approach of Müller and Parmigiani (1995) and develop optimal Bayesian designs for two-phase screening tests. A rather attractive feature of the Monte-Carlo approach is that it facilitates the preposterior analysis by replacing it with a sequence of scatter plot smoothing/regression techniques and optimization of the corresponding fitted surfaces. The method is illustrated for depression in adolescents using data from past studies.     

Simulation-based Bayesian optimal design for multi-factor accelerated life tests

We consider simulation-based methods for the design of multi-stress factor accelerated life tests (ALTs) in a Bayesian decision theoretic framework. Multi-stress factor ALTs are challenging due to the increased number of simulation runs required as a result of stress factor-level combinations. We propose the use of Latin hypercube sampling to reduce the simulation cost without loss of statistical efficiency. Exploration and optimization of expected utility function is carried out by a developed algorithm that utilizes Markov chain Monte Carlo methods and nonparametric smoothing techniques. A comparison of proposed approach to a full grid simulation is provided to illustrate computational cost reduction.     

Bayesian single-arm phase II trial designs with time-to-event endpoints

For the cancer clinical trials with immunotherapy and molecularly targeted therapy, time-to-event endpoint is often a desired endpoint. In this paper, we present an event-driven approach for Bayesian one-stage and two-stage single-arm phase II trial designs. Two versions of Bayesian one-stage designs were proposed with executable algorithms and meanwhile, we also develop theoretical relationships between the frequentist and Bayesian designs. These findings help investigators who want to design a trial using Bayesian approach have an explicit understanding of how the frequentist properties can be achieved. Moreover, the proposed Bayesian designs using the exact posterior distributions accommodate the single-arm phase II trials with small sample sizes. We also proposed an optimal two-stage approach, which can be regarded as an extension of Simon's two-stage design with the time-to-event endpoint. Comprehensive simulations were conducted to explore the frequentist properties of the proposed Bayesian designs and an R package BayesDesign can be assessed via R CRAN for convenient use of the proposed methods.     

Applications and Implementations of Continuous Robust Designs

In the literature concerning the construction of robust optimal designs, many resulting designs turn out to have densities. In practice, an exact design should tell the experimenter what the support points are and how many subjects should be allocated to each of these points. In particular, we consider a practical situation in which the number of support points allowed is constrained. We discuss an intuitive approach, which motivates a new implementation scheme that minimizes the loss function based on the Kolmogorov and Smirnov distance between an exact design and the optimal design having a density. We present three examples to illustrate the application and implementation of a robust design constructed: one for a nonlinear dose-response experiment and the other two for general linear regression. Additionally, we perform some simulation studies to compare the efficiencies of the exact designs obtained by our optimal implementation with those by other commonly used implementation methods.     

Convergence properties of sequential Bayesian D-optimal designs

We establish convergence properties of sequential Bayesian optimal designs. In particular, for sequential D-optimality under a general nonlinear location-scale model for binary experiments, we establish posterior consistency, consistency of the design measure, and the asymptotic normality of posterior following the design. We illustrate our results in the context of a particular application in the design of phase I clinical trials, namely a sequential design of Haines et al. [2003. Bayesian optimal designs for phase I clinical trials. Biometrics 59, 591–600] that incorporates an ethical constraint on overdosing.     

Bayesian optimal design for changepoint problems

We investigate Bayesian optimal designs for changepoint problems. We find robust optimal designs which allow for arbitrary distributions before and after the change, arbitrary prior densities on the parameters before and after the change, and any log‐concave prior density on the changepoint. We define a new design measure for Bayesian optimal design problems as a means of finding the optimal design. Our results apply to any design criterion function concave in the design measure. We illustrate our results by finding the optimal design in a problem motivated by a previous clinical trial. The Canadian Journal of Statistics 37: 495–513; 2009 © 2009 Statistical Society of Canada     

Maximin efficient design of experiment for exponential regression models

In this paper robust and efficient designs are derived for several exponential decay models. These models are widely used in chemistry, pharmacokinetics or microbiology. We propose a maximin approach, which determines the optimal design such that a minimum of the D-efficiencies (taken over a certain range) becomes maximal. Analytic solutions are derived if optimization is performed in the class of minimal supported designs. In general the optimal designs with respect to the maximin criterion have to be determined numerically and some properties of these designs are also studied. We also illustrate the benefits of our approach by reanalysing a data example from the literature.     

Optimal two-stage group-sequential designs

We derive optimal two-stage adaptive group-sequential designs for normally distributed data which achieve the minimum of a mixture of expected sample sizes at the range of plausible values of a normal mean. Unlike standard group-sequential tests, our method is adaptive in that it allows the group size at the second look to be a function of the observed test statistic at the first look. Using optimality criteria, we construct two-stage designs which we show have advantage over other popular adaptive methods. The employed computational method is a modification of the backward induction algorithm applied to a Bayesian decision problem.     

Bayesian optimal blocking of factorial designs

The presence of block effects makes the optimal selection of fractional factorial designs a difficult task. The existing frequentist methods try to combine treatment and block wordlength patterns and apply minimum aberration criterion to find the optimal design. However, ambiguities exist in combining the two wordlength patterns and therefore, the optimality of such designs can be challenged. Here we propose a Bayesian approach to overcome this problem. The main technique is to postulate a model and a prior distribution to satisfy the common assumptions in blocking and then, to develop an optimal design criterion for the efficient estimation of treatment effects. We apply our method to develop regular, nonregular, and mixed-level blocked designs. Several examples are presented to illustrate the advantages of the proposed method.     

Bayesian sequential analysis for multiple-arm clinical trials

Use of full Bayesian decision-theoretic approaches to obtain optimal stopping rules for clinical trial designs typically requires the use of Backward Induction. However, the implementation of Backward Induction, apart from simple trial designs, is generally impossible due to analytical and computational difficulties. In this paper we present a numerical approximation of Backward Induction in a multiple-arm clinical trial design comparing k experimental treatments with a standard treatment where patient response is binary. We propose a novel stopping rule, denoted by τ ^p , as an approximation of the optimal stopping rule, using the optimal stopping rule of a single-arm clinical trial obtained by Backward Induction. We then present an example of a double-arm (k=2) clinical trial where we use a simulation-based algorithm together with τ ^p to estimate the expected utility of continuing and compare our estimates with exact values obtained by an implementation of Backward Induction. For trials with more than two treatment arms, we evaluate τ ^p by studying its operating characteristics in a three-arm trial example. Results from these examples show that our approximate trial design has attractive properties and hence offers a relevant solution to the problem posed by Backward Induction.     

Bayesian optimal sequential design for nonparametric regression via inhomogeneous evolutionary MCMC

We develop a novel computational methodology for Bayesian optimal sequential design for nonparametric regression. This computational methodology, that we call inhomogeneous evolutionary Markov chain Monte Carlo, combines ideas of simulated annealing, genetic or evolutionary algorithms, and Markov chain Monte Carlo. Our framework allows optimality criteria with general utility functions and general classes of priors for the underlying regression function. We illustrate the usefulness of our novel methodology with applications to experimental design for nonparametric function estimation using Gaussian process priors and free-knot cubic splines priors.     

Efficient designs for Bayesian networks with sub-tree bounds

We present upper and lower bounds for information measures, and use these to find the optimal design of experiments for Bayesian networks. The bounds are inspired by properties of the junction tree algorithm, which is commonly used for calculating conditional probabilities in graphical models like Bayesian networks. We demonstrate methods for iteratively improving the upper and lower bounds until they are sufficiently tight. We illustrate properties of the algorithm by tutorial examples in the case where we want to ensure optimality and for the case where the goal is an approximate solution with a guarantee. We further use the bounds to accelerate established algorithms for constructing useful designs. An example with petroleum fields in the North Sea is studied, where the design problem is related to exploration drilling campaigns. All of our examples consider binary random variables, but the theory can also be applied to other discrete or continuous distributions.     

Bayesian D-Optimal Designs for Poisson Regression Models

By incorporating informative and/or historical knowledge of the unknown parameters, Bayesian experimental design under the decision-theory framework can combine all the information available to the experimenter so that a better design may be achieved. Bayesian optimal designs for generalized linear regression models, especially for the Poisson regression model, is of interest in this article. In addition, lack of an efficient computational method in dealing with the Bayesian design leads to development of a hybrid computational method that consists of the combination of a rough global optima search and a more precise local optima search. This approach can efficiently search for the optimal design for multi-variable generalized linear models. Furthermore, the equivalence theorem is used to verify whether the design is optimal or not.     

Optimal control designs using predicting densities for the multivariate linear model

We provide an application of a variety of predicting densities to quality control involving multivariate normal linear models. We produce optimal control designs for single muleivaiiate future observations using predicting densities employing estimative, profile likelihood, Hinkley-Lauritzen, Butler, Bayesian, and Parametric Bootstrap methodologies. The decision-theoretic optimality criterion is an intuitively appealing quadratic consumer-producer risk function. The optimal control design arising from an optimal Kullback-Leibler frequentist prediction density is shown to coincide with that arising from an optimal Kullback-Leibler Bayesian predictive density. An example involving EVOP is provided to illustrate the methodology and to raise questions concerning the relative merics of the variety of predictive approaches in the quality control context.     

Linear Bayesian Inference for Accelerated Weibull Model

In this paper, we present a Bayesian approach for inference from accelerated life tests when the underlying life model is Weibull. Our approach is based on the General Linear Models framework of West, Harrison and Migon (1985). We discuss inference for the model and show that computable results can be obtained using linear Bayesian methods. We illustrate the usefulness of our approach by applying it to some actual data from accelerated life tests. This revised version was published online in July 2006 with corrections to the Cover Date.     

Maximum entropy sampling and optimal Bayesian experimental design

When Shannon entropy is used as a criterion in the optimal design of experiments, advantage can be taken of the classical identity representing the joint entropy of parameters and observations as the sum of the marginal entropy of the observations and the preposterior conditional entropy of the parameters. Following previous work in which this idea was used in spatial sampling, the method is applied to standard parameterized Bayesian optimal experimental design. Under suitable conditions, which include non-linear as well as linear regression models, it is shown in a few steps that maximizing the marginal entropy of the sample is equivalent to minimizing the preposterior entropy, the usual Bayesian criterion, thus avoiding the use of conditional distributions. It is shown using this marginal formulation that under normality assumptions every standard model which has a two-point prior distribution on the parameters gives an optimal design supported on a single point. Other results include a new asymptotic formula which applies as the error variance is large and bounds on support size.     

Hamiltonian Monte Carlo acceleration using surrogate functions with random bases

For big data analysis, high computational cost for Bayesian methods often limits their applications in practice. In recent years, there have been many attempts to improve computational efficiency of Bayesian inference. Here we propose an efficient and scalable computational technique for a state-of-the-art Markov chain Monte Carlo methods, namely, Hamiltonian Monte Carlo. The key idea is to explore and exploit the structure and regularity in parameter space for the underlying probabilistic model to construct an effective approximation of its geometric properties. To this end, we build a surrogate function to approximate the target distribution using properly chosen random bases and an efficient optimization process. The resulting method provides a flexible, scalable, and efficient sampling algorithm, which converges to the correct target distribution. We show that by choosing the basis functions and optimization process differently, our method can be related to other approaches for the construction of surrogate functions such as generalized additive models or Gaussian process models. Experiments based on simulated and real data show that our approach leads to substantially more efficient sampling algorithms compared to existing state-of-the-art methods.     

Adaptive Bayesian compound designs for dose finding studies

We consider the problem of how to efficiently and safely design dose finding studies. Both current and novel utility functions are explored using Bayesian adaptive design methodology for the estimation of a maximum tolerated dose (MTD). In particular, we explore widely adopted approaches such as the continual reassessment method and minimizing the variance of the estimate of an MTD. New utility functions are constructed in the Bayesian framework and are evaluated against current approaches. To reduce computing time, importance sampling is implemented to re-weight posterior samples thus avoiding the need to draw samples using Markov chain Monte Carlo techniques. Further, as such studies are generally first-in-man, the safety of patients is paramount. We therefore explore methods for the incorporation of safety considerations into utility functions to ensure that only safe and well-predicted doses are administered. The amalgamation of Bayesian methodology, adaptive design and compound utility functions is termed adaptive Bayesian compound design (ABCD). The performance of this amalgamation of methodology is investigated via the simulation of dose finding studies. The paper concludes with a discussion of results and extensions that could be included into our approach.     

On the Choice of a Prior for Bayesian D-Optimal Designs for the Logistic Regression Model with a Single Predictor

The Bayesian design approach accounts for uncertainty of the parameter values on which optimal design depends, but Bayesian designs themselves depend on the choice of a prior distribution for the parameter values. This article investigates Bayesian D-optimal designs for two-parameter logistic models, using numerical search. We show three things: (1) a prior with large variance leads to a design that remains highly efficient under other priors, (2) uniform and normal priors lead to equally efficient designs, and (3) designs with four or five equidistant equally weighted design points are highly efficient relative to the Bayesian D-optimal designs.