A simple two-stage design for quantitative responses with application to a study in diabetic neuropathic pain

Two-stage designs offer substantial advantages for early phase II studies. The interim analysis following the first stage allows the study to be stopped for futility, or more positively, it might lead to early progression to the trials needed for late phase II and phase III. If the study is to continue to its second stage, then there is an opportunity for a revision of the total sample size. Two-stage designs have been implemented widely in oncology studies in which there is a single treatment arm and patient responses are binary. In this paper the case of two-arm comparative studies in which responses are quantitative is considered. This setting is common in therapeutic areas other than oncology. It will be assumed that observations are normally distributed, but that there is some doubt concerning their standard deviation, motivating the need for sample size review. The work reported has been motivated by a study in diabetic neuropathic pain, and the development of the design for that trial is described in detail.     

A variable-neighbourhood search algorithm for finding optimal run orders in the presence of serial correlation

The responses obtained from response surface designs that are run sequentially often exhibit serial correlation or time trends. The order in which the runs of the design are performed then has an impact on the precision of the parameter estimators. This article proposes the use of a variable-neighbourhood search algorithm to compute run orders that guarantee a precise estimation of the effects of the experimental factors. The importance of using good run orders is demonstrated by seeking D-optimal run orders for a central composite design in the presence of an AR(1) autocorrelation pattern.     

Doubly adaptive biased coin designs with heterogeneous responses

Doubly adaptive biased coin design (DBCD) is an important family of response-adaptive randomization procedures for clinical trials. It uses sequentially updated estimation to skew the allocation probability to favor the treatment that has performed better thus far. An important assumption for the DBCD is the homogeneity assumption for the patient responses. However, this assumption may be violated in many sequential experiments. Here we prove the robustness of the DBCD against certain time trends in patient responses. Strong consistency and asymptotic normality of the design are obtained under some widely satisfied conditions. Also, we propose a general weighted likelihood method to reduce the bias caused by the heterogeneity in the inference after a trial. Some numerical studies are also presented to illustrate the finite sample properties of DBCD.     

Analysis of robust design experiments with time-dependent ordinal response characteristics: a quality improvement study from the horticulture industry

An approach to the analysis of time-dependent ordinal quality score data from robust design experiments is developed and applied to an experiment from commercial horticultural research, using concepts of product robustness and longevity that are familiar to analysts in engineering research. A two-stage analysis is used to develop models describing the effects of a number of experimental treatments on the rate of post-sales product quality decline. The first stage uses a polynomial function on a transformed scale to approximate the quality decline for an individual experimental unit using derived coefficients and the second stage uses a joint mean and dispersion model to investigate the effects of the experimental treatments on these derived coefficients. The approach, developed specifically for an application in horticulture, is exemplified with data from a trial testing ornamental plants that are subjected to a range of treatments during production and home-life. The results of the analysis show how a number of control and noise factors affect the rate of post-production quality decline. Although the model is used to analyse quality data from a trial on ornamental plants, the approach developed is expected to be more generally applicable to a wide range of other complex production systems.     

Cumulative correspondence analysis of ordered categorical data from industrial experiments

Most studies of quality improvement deal with ordered categorical data from industrial experiments. Accounting for the ordering of such data plays an important role in effectively determining the optimal factor level of combination. This paper utilizes the correspondence analysis to develop a procedure to improve the ordered categorical response in a multifactor state system based on Taguchi's statistic. Users may find the proposed procedure in this paper to be attractive because we suggest a simple and also popular statistical tool for graphically identifying the really important factors and determining the levels to improve process quality. A case study for optimizing the polysilicon deposition process in a very large-scale integrated circuit is provided to demonstrate the effectiveness of the proposed procedure.     

Designing and integrating composite networks for monitoring multivariate gaussian pollution fields

Networks of ambient monitoring stations are used to monitor environmental pollution fields such as those for acid rain and air pollution. Such stations provide regular measurements of pollutant concentrations. The networks are established for a variety of purposes at various times so often several stations measuring different subsets of pollutant concentrations can be found in compact geographical regions. The problem of statistically combining these disparate information sources into a single 'network' then arises. Capitalizing on the efficiencies so achieved can then lead to the secondary problem of extending this network. The subject of this paper is a set of 31 air pollution monitoring stations in southern Ontario. Each of these regularly measures a particular subset of ionic sulphate, sulphite, nitrite and ozone. However, this subset varies from station to station. For example only two stations measure all four. Some measure just one. We describe a Bayesian framework for integrating the measurements of these stations to yield a spatial predictive distribution for unmonitored sites and unmeasured concentrations at existing stations. Furthermore we show how this network can be extended by using an entropy maximization criterion. The methods assume that the multivariate response field being measured has a joint Gaussian distribution conditional on its mean and covariance function. A conjugate prior is used for these parameters, some of its hyperparameters being fitted empirically.     

Diagnostic checks for discrete data regression models using posterior predictive simulations

Model checking with discrete data regressions can be difficult because the usual methods such as residual plots have complicated reference distributions that depend on the parameters in the model. Posterior predictive checks have been proposed as a Bayesian way to average the results of goodness-of-fit tests in the presence of uncertainty in estimation of the parameters. We try this approach using a variety of discrepancy variables for generalized linear models fitted to a historical data set on behavioural learning. We then discuss the general applicability of our findings in the context of a recent applied example on which we have worked. We find that the following discrepancy variables work well, in the sense of being easy to interpret and sensitive to important model failures: structured displays of the entire data set, general discrepancy variables based on plots of binned or smoothed residuals versus predictors and specific discrepancy variables created on the basis of the particular concerns arising in an application. Plots of binned residuals are especially easy to use because their predictive distributions under the model are sufficiently simple that model checks can often be made implicitly. The following discrepancy variables did not work well: scatterplots of latent residuals defined from an underlying continuous model and quantile–quantile plots of these residuals.     

Adaptive Estimation of the Integral of Squared Regression Derivatives

A problem of estimating the integral of a squared regression function and of its squared derivatives has been addressed in a number of papers. For the case of a heteroscedastic model where smoothness of the underlying regression function, the design density, and the variance of errors are known, the asymptotically sharp minimax lower bound and a sharp estimator were found in Pastuchova & Khasminski (1989). However, there are apparently no results on the either rate optimal or sharp optimal adaptive, or data-driven, estimation when neither the degree of regression function smoothness nor design density, scale function and distribution of errors are known. After a brief review of main developments in non-parametric estimation of non-linear functionals, we suggest a simple adaptive estimator for the integral of a squared regression function and its derivatives and prove that it is sharp-optimal whenever the estimated derivative is sufficiently smooth.     

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.