A signature enrichment design with Bayesian adaptive randomization

Clinical trials in the era of precision cancer medicine aim to identify and validate biomarker signatures which can guide the assignment of individually optimal treatments to patients. In this article, we propose a group sequential randomized phase II design, which updates the biomarker signature as the trial goes on, utilizes enrichment strategies for patient selection, and uses Bayesian response-adaptive randomization for treatment assignment. To evaluate the performance of the new design, in addition to the commonly considered criteria of Type I error and power, we propose four new criteria measuring the benefits and losses for individuals both inside and outside of the clinical trial. Compared with designs with equal randomization, the proposed design gives trial participants a better chance to receive their personalized optimal treatments and thus results in a higher response rate on the trial. This design increases the chance to discover a successful new drug by an adaptive enrichment strategy, i.e. identification and selective enrollment of a subset of patients who are sensitive to the experimental therapies. Simulation studies demonstrate these advantages of the proposed design. It is illustrated by an example based on an actual clinical trial in non-small-cell lung cancer.     

Uniform Design for Experiments with Mixtures

The goal of uniform mixture design is to scatter the design points in the experimental region uniformly. The commonly used criteria, such as mean square distance, are based on the Euclidean distance. Based on the Lee distance, a new criterion is proposed in this article. And an algorithm, called NTLBG, is also proposed to refine the randomly generated design for the experimental design with mixtures. Some examples show that the design generated by the NTLBG algorithm has a lower criteria value.     

Lower bounds of various criteria in experimental designs

Criterion is essential for measuring the goodness of an experimental design. In this paper, lower bounds of various criteria in experimental designs will be reviewed according to methodology of their construction. The criteria include most well-known ones which are frequently used as benchmarks for orthogonal array, uniform design, supersaturated design and other types of designs. To derive the lower bounds of these criteria, five different approaches are explored. Some new results are given. Throughout the paper, some relationships among different types of lower bounds are also discussed.     

Comparison of Four New General Classes of Search Designs

A factor screening experiment identifies a few important factors from a large list of factors that potentially influence the response. If a list consists of m factors each at three levels, a design is a subset of all possible 3 ^m runs. This paper considers the problem of finding designs with small numbers of runs, using the search linear model introduced in Srivastava (1975). The paper presents four new general classes of these 'search designs', each with 2 m −1 runs, which permit, at most, two important factors out of m factors to be searched for and identified. The paper compares the designs for 4 ≤ m ≤ 10, using arithmetic and geometric means of the determinants, traces and maximum characteristic roots of particular matrices. Two of the designs are found to be superior in all six criteria studied. The four designs are identical for m = 3 and this design is an optimal design in the class of all search designs under the six criteria. The four designs are also identical for m = 4 under some row and column permutations.     

Response surface design evaluation and comparison

Designing an experiment to fit a response surface model typically involves selecting among several candidate designs. There are often many competing criteria that could be considered in selecting the design, and practitioners are typically forced to make trade-offs between these objectives when choosing the final design. Traditional alphabetic optimality criteria are often used in evaluating and comparing competing designs. These optimality criteria are single-number summaries for quality properties of the design such as the precision with which the model parameters are estimated or the uncertainty associated with prediction. Other important considerations include the robustness of the design to model misspecification and potential problems arising from spurious or missing data. Several qualitative and quantitative properties of good response surface designs are discussed, and some of their important trade-offs are considered. Graphical methods for evaluating design performance for several important response surface problems are discussed and we show how these techniques can be used to compare competing designs. These graphical methods are generally superior to the simplistic summaries of alphabetic optimality criteria. Several special cases are considered, including robust parameter designs, split-plot designs, mixture experiment designs, and designs for generalized linear models.     

Designs for two-colour microarray experiments

Summary.  Designs for two-colour microarray experiments can be viewed as block designs with two treatments per block. Explicit formulae for the A- and D-criteria are given for the case that the number of blocks is equal to the number of treatments. These show that the A- and D-optimality criteria conflict badly if there are 10 or more treatments. A similar analysis shows that designs with one or two extra blocks perform very much better, but again there is a conflict between the two optimality criteria for moderately large numbers of treatments. It is shown that this problem can be avoided by slightly increasing the number of blocks. The two colours that are used in each block effectively turn the block design into a row–column design. There is no need to use a design in which every treatment has each colour equally often: rather, an efficient row–column design should be used. For odd replication, it is recommended that the row–column design should be based on a bipartite graph, and it is proved that the optimal such design corresponds to an optimal block design for half the number of treatments. Efficient row–column designs are given for replications 3–6. It is shown how to adapt them for experiments in which some treatments have replication only 2.     

PROBABILITY-BASED OPTIMAL DESIGN

Optimal design of experiments has generally concentrated on parameter estimation and, to a much lesser degree, on model discrimination. Often an experimenter is interested in a particular outcome and wishes to maximize in some way the probability of this outcome. We propose a new class of compound criteria and designs that address this issue for generalized linear models. The criteria offer a method of achieving designs that possess the properties of efficient parameter estimation and a high probability of a desired outcome.     

E-optimal designs for regression models with quantitative factors— a reasonable choice?

For regression models with quantitative factors it is illustrated that the E-optimal design can be extremely inefficient in the sense that it degenerates to a design which takes all observations at only one point. This phenomenon is caused by the different size of the elements in the covariance matrix of the least-squares estimator for the unknown parameters. For these reasons we propose to replace the E-criterion by a corresponding standardized version. The advantage of this approach is demonstrated for the polynomial regression on a nonnegative interval, where the classical and standardized E-optimal designs can be found explicitly. The described phenomena are not restricted to the E-criterion but appear for nearly all optimality criteria proposed in the literature. Therefore standardization is recommended for optimal experimental design in regression models with quantitative factors. The optimal designs with respect to the new standardized criteria satisfy a similar invariance property as the famous D-optimal designs, which allows an easy calculation of standardized optimal designs on many linearly transformed design spaces.     

Construction of optimal designs in random coefficient regression models

We consider the problem of optimal experimental design in random coefficient regression models with respect to a quadratic loss function. By application of WHITTLE'S general equivalence theorem we obtain the structure of optimal designs. An alogrithm is given which allows, under certain assumptions, the construction of the information matrix of an optimal design. Moreover, we give conditions on the equivalence of optimal designs with respect to optimality criteria which are analogous to usual A-D- and _E/-optimality.     

On minimax designs when there are two candidate models

This work is motivated by the need to find experimental designs which are robust under different model assumptions. We measure robustness by calculating a measure of design efficiency with respect to a design optimality criterion and say that a design is robust if it is reasonably efficient under different model scenarios. We discuss two design criteria and an algorithm which can be used to obtain robust designs. The first criterion employs a Bayesian-type approach by putting a prior or weight on each candidate model and possibly priors on the corresponding model parameters. We define the first criterion as the expected value of the design efficiency over the priors. The second design criterion we study is the minimax design which minimizes the worst value of a design criterion over all candidate models. We establish conditions when these two criteria are equivalent when there are two candidate models. We apply our findings to the area of accelerated life testing and perform sensitivity analysis of designs with respect to priors and misspecification of planning values.     

The Use of Treatment Concurrences to Assess Robustness of Binary Block Designs Against the Loss of Whole Blocks

Criteria are proposed for assessing the robustness of a binary block design against the loss of whole blocks, based on summing entries of selected upper non‐principal sections of the concurrence matrix. These criteria improve on the minimal concurrence concept that has been used previously and provide new conditions for measuring the robustness status of a design. The robustness properties of two‐associate partially balanced designs are considered and it is shown that two categories of group divisible designs are maximally robust. These results expand a classic result in the literature, obtained by Ghosh, which established maximal robustness for the class of balanced block designs.     

Use of bayesian analysis to design of clinical trials with one treatment

Assuming a Weibull distribution, the posterior distribution for the median survival time is derived in the presence of arbitrary right censorship. In the design of clinical triaLs, suppose k follow-up periods have been completed and it is desired to plan the follow-up period k+1. In this context, criteria are presented that can be employed in determining the number of new patients to be enrolled in the follow-up period k+1.     

Model Discrimination Criteria on Model-Robust Designs

Recently, interest about model discrimination has been focused on methods based on model estimation. Due to the problem of model aliasing, several criteria have been proposed aimed at assessing the capacity of a design for model discrimination. Three of these measures, along with a new criterion that combines them and assesses the overall discrimination capacity of a design, are implemented to evaluate a class of 27-run orthogonal arrays in three levels.     

Multinomial Probability Estimation by Wavelet Thresholding

In this article, we introduce a wavelet threshold estimator to estimate multinomial probabilities. The advantages of the estimator are its adaptability to the roughness and sparseness of the data. The asymptotic behavior of the estimator is investigated through an often-used criteria: the mean sum of squared error (MSSE). We show that the MSSE of the estimator achieves the optimal rate of convergence. Its performance on finite samples is examined through simulation studies which show favorable results for the new estimator over the commonly used kernel estimator.     

Some adjusted orthogonal,variance balanced,multidimensional block designs

A multidimensional block design (MBD) is an experimental design with d > 1 blocking criteria geometrically represented as a d-dimensional lattice with treatment varieties assigned to some or all nodes of the lattice. Intrablock analysis of variance tables for some special classes of two- and three-dimensional block designs with some empty nodes are given. Design plans and efficiencies for 31 two-dimensional designs, each universally optimal in defined classes of designs, and 7 three-dimensional designs, each nearly optimal in defined classes of designs, are listed in the appendices. A need for such designs is apparent when the blocking criteria are implemented successively and empty nodes do not represent wasted experimental units.     

Classification of three-level strength-3 arrays

Generalized aberration (GA) is one of the most frequently used criteria to quantify the suitability of an orthogonal array (OA) to be used as an experimental design. The two main motivations for GA are that it quantifies bias in a main-effects only model and that it is a good surrogate for estimation efficiencies of models with all the main effects and some two-factor interaction components. We demonstrate that these motivations are not appropriate for three-level OAs of strength 3 and we propose a direct classification with other criteria instead. To illustrate, we classified complete series of three-level strength-3 OAs with 27, 54 and 81 runs using the GA criterion, the rank of the matrix with two-factor interaction contrasts, the estimation efficiency of two-factor interactions, the projection estimation capacity, and a new model robustness criterion. For all of the series, we provide a list of admissible designs according to these criteria.     

Equally spaced design points in polynomial regression: A comparison of systematic sampling methods with the optimal design of experiments

In some situations an experimenter may desire to have equally spaced design points. Three methods of obtaining such points on the interval [—1,1]—namely systematic random sampling, centrally located systematic sampling, and a purposive systematic sampling method which includes the endpoints - 1 and 1 as two of the design points-are evaluated under the D-optimal and G-optimal criteria. These methods are also compared to the optimal designs in polynomial regression and to the limiting designs of Kiefer and Studden (1976).     

Comparing tests judged asymptotically equally efficient

For comparing two competing testing procedures whose power functions cannot be calculated exactly, the Pitman asymptotic relative efficiency is commonly used. This measure offers the advantages of simplicity in computation and interpretation, but is asymptotic in nature. In particular, it cannot distinguish between certain pairs of tests, namely, those with an asymptotic relative efficiency of 1. In this paper, we offer an alternative basis for making finite sample comparisons between tests judged asymptotically equally efficient. The criteria for comparison is based on the ratio of efficacies. Using this new criterion, we consider a series of examples in which two tests with an ARE of 1 are compared for finite n. In each case, either exact or simulated power curves are used to evaluate the effectiveness of this criterion in properly discriminating between the competing test procedures. Lastly, conditions are specified where the proposed criterion should be most effective.     

Optimal designs for the logit and probit models for binary data

We consider optimal designs for a class of symmetric models for binary data which includes the common probit and logit models. We show that for a large group of optimality criteria which includes the main ones in the literature (e.g. A-, D-, E-, F- and G-optimality) the optimal design for our class of models is a two-point design with support points symmetrically placed about the ED50 but with possibly unequal weighting. We demonstrate how one can further reduce the problem to a one-variable optimization by characterizing various of the common criteria. We also use the results to demonstrate major qualitative differences between the F - and c-optimal designs, two design criteria which have similar motivation.     

ON THE CHOICE OF ESTIMATOR IN SURVERY SAMPLING*

We re-examine the criteria of “hyper-admissibility” and “necessary bestness”, for the choice of estimator, from the point of view of their relevance to the design of actual surveys. Both these criteria give rise to a unique choice of estimator (viz. the Horvitz-Thompson estimator ?_HT) whatever be the character under investigation or sample design. However, we show here that the “principal hyper-surfaces” (or “domains”) of dimension one (which are practically uninteresting)play the key role in arriving at the unique choice. A variance estimator v₁(?_HT) (due to Horvitz-Thompson), which takes negative values “often”, is shown to be uniquely “hyperadmissible” in a wide class of unbiased estimators of the variance of ?_HT. Extensive empirical evidence on the superiority of the Sen-Yates-Grundy variance estimator v₂(?_HT) over v₁(?_HT) is presented.