A COMPARISON OF THE IMPRECISE BETA CLASS, THE RANDOMIZED PLAY-THE-WINNER RULE AND THE TRIANGULAR TEST FOR CLINICAL TRIALS WITH BINARY RESPONSES

This paper develops clinical trial designs that compare two treatments with a binary outcome. The imprecise beta class (IBC), a class of beta probability distributions, is used in a robust Bayesian framework to calculate posterior upper and lower expectations for treatment success rates using accumulating data. The posterior expectation for the difference in success rates can be used to decide when there is sufficient evidence for randomized treatment allocation to cease. This design is formally related to the randomized play‐the‐winner (RPW) design, an adaptive allocation scheme where randomization probabilities are updated sequentially to favour the treatment with the higher observed success rate. A connection is also made between the IBC and the sequential clinical trial design based on the triangular test. Theoretical and simulation results are presented to show that the expected sample sizes on the truly inferior arm are lower using the IBC compared with either the triangular test or the RPW design, and that the IBC performs well against established criteria involving error rates and the expected number of treatment failures.     

How non-normality affects the quadratic discriminant function

The quadratic discriminant function is commonly used for the two group classification problem when the covariance matrices in the two populations are substantially unequal. This procedure is optimal when both populations are multivariate normal with known means and covariance matrices. This study examined the robustness of the QDF to non-normality. Sampling experiments were conducted to estimate expected actual error rates for the QDF when sampling from a variety of non-normal distributions. Results indicated that the QDF was robust to non-normality except when the distributions were highly skewed, in which case relatively large deviations from optimal were observed. In all cases studied the average probabilities of misclassification were relatively stable while the individual population error rates exhibited considerable variability.     

Bayesian two-stage design for drug screening trials with switching hypothesis tests based on continuous endpoints

Abstract

In this paper, we propose a Bayesian two-stage design with changing hypothesis test by bridging a single-arm study and a double-arm randomized trial in one phase II clinical trial based on continuous endpoints rather than binary endpoints. We have also calibrated with respect to frequentist and Bayesian error rates. The proposed design minimizes the Bayesian expected sample size if the new candidate has low or high efficacy activity subject to the constraint upon error rates in both frequentist and Bayesian perspectives. Tables of designs for various combinations of design parameters are also provided.     

A Hybrid Geometric Phase II/III Clinical Trial Design based on Treatment Failure Time and Toxicity

The problem of comparing several experimental treatments to a standard arises frequently in medical research. Various multi-stage randomized phase II/III designs have been proposed that select one or more promising experimental treatments and compare them to the standard while controlling overall Type I and Type II error rates. This paper addresses phase II/III settings where the joint goals are to increase the average time to treatment failure and control the probability of toxicity while accounting for patient heterogeneity. We are motivated by the desire to construct a feasible design for a trial of four chemotherapy combinations for treating a family of rare pediatric brain tumors. We present a hybrid two-stage design based on two-dimensional treatment effect parameters. A targeted parameter set is constructed from elicited parameter pairs considered to be equally desirable. Bayesian regression models for failure time and the probability of toxicity as functions of treatment and prognostic covariates are used to define two-dimensional covariate-adjusted treatment effect parameter sets. Decisions at each stage of the trial are based on the ratio of posterior probabilities of the alternative and null covariate-adjusted parameter sets. Design parameters are chosen to minimize expected sample size subject to frequentist error constraints. The design is illustrated by application to the brain tumor trial.     

On an application of the diffusion approximation of the generalized birth and death process for stochastic population projection

Assuming that both birth and death rates are density and time dependent, a diffusion approximation of the generalized birth and death process has been considered in this paper to obtain a suitable stochastic population model describing the population size and its moments. A simple method of estimating the parameters of the model Is discussed. The predictions of the expected size of the population, and the variance are made and compared with the corresponding census figures as well as with another deterministic projection series made for the corresponding period.     

STATISTICAL INFERENCE OF TRANSMISSION FIDELITY OF DNA METHYLATION PATTERNS OVER SOMATIC CELL DIVISIONS IN MAMMALS

We develop Bayesian inference methods for a recently-emerging type of epigenetic data to study the transmission fidelity of DNA methylation patterns over cell divisions. The data consist of parent-daughter double-stranded DNA methylation patterns with each pattern coming from a single cell and represented as an unordered pair of binary strings. The data are technically difficult and time-consuming to collect, putting a premium on an efficient inference method. Our aim is to estimate rates for the maintenance and de novo methylation events that gave rise to the observed patterns, while accounting for measurement error. We model data at multiple sites jointly, thus using whole-strand information, and considerably reduce confounding between parameters. We also adopt a hierarchical structure that allows for variation in rates across sites without an explosion in the effective number of parameters. Our context-specific priors capture the expected stationarity, or near-stationarity, of the stochastic process that generated the data analyzed here. This expected stationarity is shown to greatly increase the precision of the estimation. Applying our model to a data set collected at the human FMR1 locus, we find that measurement errors, generally ignored in similar studies, occur at a non-trivial rate (inappropriate bisulfite conversion error: 1.6% with 80% CI: 0.9-2.3%). Accounting for these errors has a substantial impact on estimates of key biological parameters. The estimated average failure of maintenance rate and daughter de novo rate decline from 0.04 to 0.024 and from 0.14 to 0.07, respectively, when errors are accounted for. Our results also provide evidence that de novo events may occur on both parent and daughter strands: the median parent and daughter de novo rates are 0.08 (80% CI: 0.04-0.13) and 0.07 (80% CI: 0.04-0.11), respectively.     

A nominal association matrix with feature selection for categorical data

An intrinsic association matrix is introduced to measure category-to-variable association based on proportional reduction of prediction error by an explanatory variable. The normalization of the diagonal gives rise to the expected rates of error-reduction and the off-diagonal yields expected distributions of the rates of error for all response categories. A general framework of association measures based on the proposed matrix is established using an application-specific weight vector. A hierarchy of equivalence relations defined by the association matrix and vector is shown. Applications to financial and survey data together with simulation results are presented.     

Estimating population characteristics by incorporating prior values in stratified random sampling/ranked set sampling

In this paper, we discuss the estimation of population characteristics using stratified random sampling in an infinite population framework, including ranked set sampling as a special case. The use of prior values is considered and the underlying distribution is assumed to be unknown. The estimator considered in each stratum is the weighted mean of the U-statistic and prior value. The optimum weight is obtained by minimizing the mean squared error of the estimator of the population characteristics, but it contains unknown parameters and those parameters are replaced with their estimates. Simulation results show the gains in efficiency of the proposed estimator, yielding gains of at least 1.2 times larger than the usual unbiased estimator under certain condition specified in the text. Guidelines for the usage of the proposed estimator are shown and an application to a real data set is provided.     

ON THE USE OF THE EMPIRICAL DISTRIBUTION AND CHARACTERISTIC FUNCTION TO ESTIMATE PARAMETERS OF REGULAR VARIATION

In this paper we present two new classes of estimators of parameters of regular variation, one based on the empirical distribution function and the other on the empirical characteristic function. They achieve the same rates of mean square error convergence as the estimators proposed by Hall (1982). The estimator based on the empirical characteristic function, unlike the other estimators, utilises the whole sample and not just a few extreme order statistics.     

PERFORMANCE OF THE LOCATION LINEAR DISCRIMINANT FUNCTION UNDER ACROSS-LOCATION HETEROSCEDASTICITY

ABSTRACT

Classification of data consisting of both categorical and continuous variables between two groups is often handled by the sample location linear discriminant function confined to each of the locations specified by the observed values of the categorical variables. Homoscedasticity of across-location conditional dispersion matrices of the continuous variables is often assumed. Quite often, interactions between continuous and categorical variables cause across-location heteroscedasticity. In this article, we examine the effect of heterogeneous across-location conditional dispersion matrices on the overall expected and actual error rates associated with the sample location linear discriminant function. Performance of the sample location linear discriminant function is evaluated against the results for the restrictive classifier adjusted for across-location heteroscedasticity. Conclusions based on a Monte Carlo study are reported.     

ESTIMATING POPULATION SIZE FROM CAPTURE-RECAPTURE EXPERIMENTS IN CONTINUOUS TIME

Estimates for the size of a closed population are given for multiple recapture studies in continuous time. The estimates are derived by a method of moments for martingales. An estimate and associated standard error of the population size are derived for a homogeneous population when the capture rates are permitted to depend on time in an unspecified manner. Corresponding results are obtained when the capture rates vary among individuals as well. Explicit expressions are given for these estimates and standard errors which involve only simple computation.     

Estimation of a finite population total in two-stage and stratified sampling under superpopulation models

Optimal sampling strategies which minimise the expected mean square error for a linear design as well as model-design unbiased estimators for a finite population total for two-stage and stratified sampling are obtained under different superpopu1ation models     

ASSESSING ERROR RATE ESTIMATORS: THE LEAVE-ONE-OUT METHOD RECONSIDERED

Many comparative studies of the estimators of error rates of supervised classification rules are based on inappropriate criteria. In particular, although they fix the Bayes error rate, their summary statistics aggregate a range of true error rates. This means that their conclusions about the performance of classification rules cannot be trusted. This paper discusses the general issues involved, and then focuses attention specifically on the leave-one-out estimator. The estimator is investigated in a simulation study, both in absolute terms and in comparison with a popular bootstrap estimator. An improvement to the leave-one-out estimator is suggested, but the bootstrap estimator appears to maintain superiority even when the criteria are adjusted.     

Systematic and nonrandom sampling in the presence of linear trends

In the case of a finite population with a linear trend, improvements in estimation procedures are suggested for several well-known systematic samplingschemes. The use of the least squares regression estimator is examined and a sampling scheme which reduces its expected mean squared error is proposed.     

THE EFFICIENCY OF TIME SERIES ESTIMATORS FOR REPEATED SURVEYS

The classical approach to the analysis of data from repeated surveys, based on Patterson (1950), has recently been extended by the work of Blight and Scott (1973) and Scott and Smith (1974), by assuming that a time series relationship exists between the population parameters at different times. The purpose of this paper is to compare the efficiencies of these three approaches by computing the mean square error (MSE) of the estimators of the current mean and of the change in mean on the last two occasions.     

Mem squared error estimation in finite populations under nonlinear models

Four estimators of the prediction mean squared error (MSB) of an estimated finite population total for a zero-one characteristic are examined. The characteristic associated with each population unit is modeled as the realization of a Bernoulli random variable whose expected value is a nonlinear function of a parameter vector and a set of known auxiliary variables. To compare the estimators, a simulation study is conducted using a population of hospitals. The MSB estimator Implied by the form of the assumed model underestimates the mean squared error in each of the cases studied and produces confidence lntervals with less than the nominal coverage probabilities. Of the three alternative MSE estimators presented, a linear approximation to the jackknife produces the best results and improves upon the model-specific estimator.     

A new behavioural model for fertility schedules

Modelling age-specific fertility rates is of great importance in demography because of their influence on population growth. Although we have a variety of fertility models in the demographic literature, most of them do not have any demographic interpretation for their parameters. It is generally expected that models with behavioural interpretation are more universal than those without any interpretation. Even though the famous Gompertz model has some behavioural interpretation it suffers from other drawbacks. In the present work, we propose a new fertility model, which has its genesis in the generalization of logistic law. The proposed model has good behavioural interpretation, alongside having nice parameter interpretations.     

Comparison of procedures for estimation of error rates in discriminant analysis under nonnormal population

The parametric and nonparametric methods for estimating the error rates in linear discriminant analysis are examined both in normal and in nonnormal situations. A Monte Carlo experiment was carried out under the assumption that two population distributions were characterized by a mixture of two multivariate normal distributions. The bootstrap bias-corrected apparent error rate compares favourably to other available estimators for nonnormal populations with small Mahalanobis distance. The methods for error estimation are also applied to a practical problem in medical diagnosis     

Parametric bootstrap inferences for the growth curve models with intraclass correlation structure

This paper presents parametric bootstrap (PB) approaches for hypothesis testing and interval estimation of the fixed effects and the variance component in the growth curve models with intraclass correlation structure. The PB pivot variables are proposed based on the sufficient statistics of the parameters. Some simulation results are presented to compare the performance of the proposed approaches with the generalized inferences. Our studies show that the PB approaches perform satisfactorily for various cell sizes and parameter configurations, and tends to outperform the generalized inferences with respect to the coverage probabilities and powers. The PB approaches not only have almost exact coverage probabilities and Type I error rates, but also have the shorter expected lengths and the higher powers. Furthermore, the PB procedure can be simply carried out by a few simulation steps. Finally, the proposed approaches are illustrated by using a real data example.     

Derivation of a biological quality index for river sites: Comparison of the observed with the expected fauna

A method for the national assessment of the biological quality of river sites is developed. Multivariate discrimination, based on site environmental characteristics, is used on a biological classification of reference sites to derive a procedure to predict the fauna to be expected in the absence of environmental stress. Various quality indices, based on a comparison of the observed with the expected fauna, are proposed. The sizes of the various sources of error and variation, and their effects on the rates of misclassification to quality bands, are examined.