EFFICIENT BLOCK DESIGNS FOR CORRELATED OBSERVATIONS

Current methods for the design of efficient incomplete block experiments when the observations within a block are dependent usually involve computer searches of binary designs. These searches give little insight into the features that lead to efficiency, and can miss more efficient designs. This paper aims to develop some approximations which give some insight into the features of a design that lead to high efficiency under a generalized least-squares analysis for a known dependence structure, and to show that non-binary designs can be more efficient for some dependence structures. In particular, we show how neighbour balance and end plot balance are related to the design efficiency for low-order autoregressions, and that under moderate positive dependence, replication at lag two can sometimes increase efficiency.     

Asymptotic distribution of least square estimators for linear models with dependent errors

In this paper, we consider the usual linear regression model in the case where the error process is assumed strictly stationary. We use a result from Hannan (Central limit theorems for time series regression. Probab Theory Relat Fields. 1973;26(2):157–170), who proved a Central Limit Theorem for the usual least squares estimator under general conditions on the design and on the error process. Whatever the design satisfying Hannan's conditions, we define an estimator of the covariance matrix and we prove its consistency under very mild conditions. As an application, we show how to modify the usual tests on the linear model in this dependent context, in such a way that the type-I error rate remains asymptotically correct, and we illustrate the performance of this procedure through different sets of simulations.     

Projection array based designs for computer experiments

In this paper we define a new class of designs for computer experiments. A projection array based design defines sets of simulation runs with properties that extend the conceptual properties of orthogonal array based Latin hypercube sampling, particularly to underlying design structures other than orthogonal arrays. Additionally, we illustrate how these designs can be sequentially augmented to improve the overall projection properties of the initial design or focus on interesting regions of the design space that need further exploration to improve the overall fit of the underlying response surface. We also illustrate how an initial Latin hypercube sample can be expressed as a projection array based design and show how one can augment these designs to improve higher dimensional space filling properties.     

Random-effect models with singular precision

We show that smoothing spline, intrinsic autoregression (IAR) and state-space model can be formulated as partially specified random-effect model with singular precision (SP). Various fitting methods have been suggested for the aforementioned models and this paper investigates the relationships among them, once the models have been placed under a single framework. Some methods have been previously shown to give the best linear unbiased predictors (BLUPs) under some random-effect models and here we show that they are in fact uniformly BLUPs (UBLUPs) under a class of models that are generated by the SP of random effects. We offer some new interpretations of the UBLUPs under models of SP and define BLUE and BLUP in these partially specified models without having to specify the covariance. We also show how the full likelihood inferences for random-effect models can be made for these models, so that the maximum likelihood (ML) and restricted maximum likelihood (REML) estimators can be used for the smoothing parameters in splines, etc.     

The random fatigue-limit model in multi-factor experiments

The Random Fatigue-Limit (RFL) model in Pascual and Meeker (1999a) was motivated by the need to describe fatigue life of certain materials. The RFL model describes the relationship between lifetime (measured in cycles) and a single factor, often the applied stress on the material. It has been found to be particularly useful for modeling high-cycle fatigue (HCF), that is, lifetimes that exceed 10 million cycles. Outputs from this model can be used as input for system models for lifetimes of jet engines for design purposes. Understanding how well parts hold up as a function of stress and other environmental variables would be valuable to engineers designing new and better engines. In this article, we show how the RFL model can be extended from single factor (single stress) to multi-factor situations. We fit the proposed model extensions to available data and describe methods to assess the adequacy of the fits.     

Generalization and efficient computation of the box-meyer analysis for orthogonal designs

Box and Meyer (1986) [1] proposed a Bayesian analysis for saturated orthogonal dedigns, based on the widely-used method of examining normal plots of effects estimates. Stephenson, Hulting, and Moore (1989) [5] give an algorithm for computing this analysis, but it can be quite slow for even 2⁵ designs. In this paper we extend the technique to cover all orthogonal factorial designs, rather than just saturated ones, and we show how the computational algorithm can be greatly improved, both in terms of accuracy and speed. With these extensions and improvements the Box-Meyer method becomes viable as a technique for interactive analysis of any orthogonal factorial design, not just small, saturated ones.     

Efficiency of split questionnaire surveys

We consider a general design that allows information for different patterns, or sets, of data items to be collected from different sample units, which we call a Split Questionnaire Design (SQD). While SQDs have been historically used to accommodate constraints on respondent burden, this paper shows they can also be an efficient design option. The efficiency of a design can be measured by the cost required to meet constraints on the accuracy of estimates. Moreover, this paper shows how an SQD provides considerable flexibility when exploring the balance between the design's efficiency and the burden it places on respondents. The targets of interest to the design are analytic parameters, such as regression coefficients. Empirical results show that SQDs are worthwhile considering.     

Computing A-optimal and E-optimal designs for regression models via semidefinite programming

In semidefinite programming (SDP), we minimize a linear objective function subject to a linear matrix being positive semidefinite. A powerful program, SeDuMi, has been developed in MATLAB to solve SDP problems. In this article, we show in detail how to formulate A-optimal and E-optimal design problems as SDP problems and solve them by SeDuMi. This technique can be used to construct approximate A-optimal and E-optimal designs for all linear and nonlinear regression models with discrete design spaces. In addition, the results on discrete design spaces provide useful guidance for finding optimal designs on any continuous design space, and a convergence result is derived. Moreover, restrictions in the designs can be easily incorporated in the SDP problems and solved by SeDuMi. Several representative examples and one MATLAB program are given.     

Repeated Confidence Intervals Under Fractional Brownian Motion in Long-Term Clinical Trials

Repeated confidence interval (RCI) is an important tool for design and monitoring of group sequential trials according to which we do not need to stop the trial with planned statistical stopping rules. In this article, we derive RCIs when data from each stage of the trial are not independent thus it is no longer a Brownian motion (BM) process. Under this assumption, a larger class of stochastic processes fractional Brownian motion (FBM) is considered. Comparisons of RCI width and sample size requirement are made to those under Brownian motion for different analysis times, Type I error rates and number of interim analysis. Power family spending functions including Pocock, O'Brien-Fleming design types are considered for these simulations. Interim data from BHAT and oncology trials is used to illustrate how to derive RCIs under FBM for efficacy and futility monitoring.     

Split-plot designs for robust product experimentation

Genichi Taguchi has emphasized the use of designed experiments in several novel and important applications. In this paper we focus on the use of statistical experimental designs in designingproducts to be robust to environmental conditions. The engineering concept of robust product design is very important because it is frequently impossible or prohibitively expensive to control or eliminate variation resulting from environmental conditions. Robust product design enablesthe experimenter to discover how to modify the design of the product to minimize the effect dueto variation from environmental sources. In experiments of this kind, Taguchi's total experimental arrangement consists of a cross-product of two experimental designs:an inner array containing the design factors and an outer array containing the environmental factors. Except in situations where both these arrays are small, this arrangement may involve a prohibitively large amount of experimental work. One of the objectives of this paper is to show how this amount of work can be reduced. In this paper we investigate the applicability of split-plot designs for thisparticular experimental situation. Consideration of the efficiency of split-plot designs and anexamination of several variants of split-plot designs indicates that experiments conductedin a split-plot mode can be of tremendous value in robust product design since they not only enable the contrasts of interest to be estimated efficiently but also the experiments can be considerably easier to conduct than the designs proposed by Taguchi.     

A balanced multi-level rotation sampling design and its efficient composite estimators

We present a multi-level rotation sampling design which includes most of the existing rotation designs as special cases. When an estimator is defined under this sampling design, its variance and bias remain the same over survey months, but it is not so under other existing rotation designs. Using the properties of this multi-level rotation design, we derive the mean squared error (MSE) of the generalized composite estimator (GCE), incorporating the two types of correlations arising from rotating sample units. We show that the MSEs of other existing composite estimators currently used can be expressed as special cases of the GCE. Furthermore, since the coefficients of the GCE are unknown and difficult to determine, we present the minimum risk window estimator (MRWE) as an alternative estimator. This MRWE has the smallest MSE under this rotation design and yet, it is easy to calculate. The MRWE is unbiased for monthly and yearly changes and preserves the internal consistency in total. Our numerical study shows that the MRWE is as efficient as GCE and more efficient than the existing composite estimators and does not suffer from the drift problem [Fuller W.A., Rao J.N.K., 2001. A regression composite estimator with application to the Canadian Labour Force Survey. Surv. Methodol. 27 (2001) 45–51] unlike the regression composite estimators.     

A design for testing clinical strategies: biased adaptive within-subject randomization

We propose a method for assigning treatment in clinical trials, called the 'biased coin adaptive within-subject' (BCAWS) design: during the course of follow-up, the subject's response to a treatment is used to influence the future treatment, through a 'biased coin' algorithm. This design results in treatment patterns that are closer to actual clinical practice and may be more acceptable to patients with chronic disease than the usual fixed trial regimens, which often suffer from drop-out and non-adherence. In this work, we show how to use the BCAWS design to compare treatment strategies, and we provide a simple example to illustrate the method.     

Stochastic Bounds with a Low Rank Decomposition

We investigate how we can bound a discrete time Markov chain (DTMC) by a stochastic matrix with a low rank decomposition. In the first part of the article, we show the links with previous results for matrices with a decomposition of size 1 or 2. Then we show how the complexity of the analysis for steady-state and transient distributions can be simplified when we take into account the decomposition. Finally, we show how we can obtain a monotone stochastic upper bound with a low rank decomposition.     

Enhancement of the adaptive signature design for learning and confirming in a single pivotal trial

Because of the complexity of cancer biology, often the target pathway is not well understood at the time that phase III trials are initiated. A 2‐stage trial design was previously proposed for identifying a subgroup of interest in a learn stage, on the basis of 1 or more baseline biomarkers, and then subsequently confirming it in a confirmation stage. In this article, we discuss some practical aspects of this type of design and describe an enhancement to this approach that can be built into the study randomization to increase the robustness of the evaluation. Furthermore, we show via simulation studies how the proportion of patients allocated to the learn stage versus the confirm stage impacts the power and provide recommendations.     

Modifying and using Yates' algorithm

It is well known that Yates' algorithm can be used to estimate the effects in a factorial design. We develop a modification of this algorithm and call it modified Yates' algorithm and its inverse. We show that the intermediate steps in our algorithm have a direct interpretation as estimated level-specific mean values and effects. Also we show how Yates' or our modified algorithm can be used to construct the blocks in a 2 ^k factorial design and to generate the layout sheet of a 2 ^k−p fractional factorial design and the confounding pattern in such a design. In a final example we put together all these methods by generating and analysing a 2^6-2 design with 2 blocks.     

Semiparametric Estimation of a Two-component Mixture Model where One Component is known

Abstract.  We consider a two-component mixture model where one component distribution is known while the mixing proportion and the other component distribution are unknown. These kinds of models were first introduced in biology to study the differences in expression between genes. The various estimation methods proposed till now have all assumed that the unknown distribution belongs to a parametric family. In this paper, we show how this assumption can be relaxed. First, we note that generally the above model is not identifiable, but we show that under moment and symmetry conditions some 'almost everywhere' identifiability results can be obtained. Where such identifiability conditions are fulfilled we propose an estimation method for the unknown parameters which is shown to be strongly consistent under mild conditions. We discuss applications of our method to microarray data analysis and to the training data problem. We compare our method to the parametric approach using simulated data and, finally, we apply our method to real data from microarray experiments.     

Bayesian Experimental Design for Long-Term Longitudinal HIV Dynamic Studies

The study of HIV dynamics is one of the most important developments in recent AIDS research for understanding the pathogenesis of HIV-1 infection and antiviral treatment strategies. Currently a large number of AIDS clinical trials on HIV dynamics are in development worldwide. However, many design issues that arise from AIDS clinical trials have not been addressed. In this paper, we use a simulation-based approach to deal with design problems in Bayesian hierarchical nonlinear (mixed-effects) models. The underlying model characterizes the long-term viral dynamics with antiretroviral treatment where we directly incorporate drug susceptibility and exposure into a function of treatment efficacy. The Bayesian design method is investigated under the framework of hierarchical Bayesian (mixed-effects) models. We compare a finite number of feasible candidate designs numerically, which are currently used in AIDS clinical trials from different perspectives, and provide guidance on how a design might be chosen in practice.     

Regression analysis for a summed missing data problem under an outcome‐dependent sampling scheme

In this paper, we consider a regression analysis for a missing data problem in which the variables of primary interest are unobserved under a general biased sampling scheme, an outcome‐dependent sampling (ODS) design. We propose a semiparametric empirical likelihood method for accessing the association between a continuous outcome response and unobservable interesting factors. Simulation study results show that ODS design can produce more efficient estimators than the simple random design of the same sample size. We demonstrate the proposed approach with a data set from an environmental study for the genetic effects on human lung function in COPD smokers. The Canadian Journal of Statistics 40: 282–303; 2012 © 2012 Statistical Society of Canada     

Adjustment with three continuous variables

Correlation is not causation. Spurious association between X and Y may be due to a confounding variable W. Statisticians may adjust for W using a variety of techniques. This article presents the results of simulations conducted to assess the performance of these techniques under various, elementary, data-generating processes. The results indicate that no technique is best overall and that specific techniques should be selected based on the particulars of the data-generating process. Here, we show how causal graphs can guide the selection or design of techniques for statistical adjustment. R programs are provided for researchers interested in generalization.