Efficacy and toxicity monitoring via Bayesian predictive probabilities in phase II clinical trials

Bayesian monitoring strategies based on predictive probabilities are widely used in phase II clinical trials that involve a single efficacy binary variable. The essential idea is to control the predictive probability that the trial will show a conclusive result at the scheduled end of the study, given the information at the interim stage and the prior beliefs. In this paper, we present an extension of this approach to incorporate toxicity considerations in single-arm phase II trials. We consider two binary endpoints representing response and toxicity of the experimental treatment and define the result as successful at the conclusion of the study if the posterior probability of an high efficacy and that of a small toxicity are both sufficiently large. At any interim look, the Multinomial-Dirichlet distribution provides the predictive probability of each possible combination of future efficacy and toxicity outcomes. It is exploited to obtain the predictive probability that the trial will yield a positive outcome, if it continues to the planned end. Different possible interim situations are considered to investigate the behaviour of the proposed predictive rules and the differences with the monitoring strategies based on posterior probabilities are highlighted. Simulation studies are also performed to evaluate the frequentist operating characteristics of the proposed design and to calibrate the design parameters.

     

Multivariate Capability Indices: Distributional and Inferential Properties

Process capability indices have been widely used in the manufacturing industry for measuring process reproduction capability according to manufacturing specifications. Properties of the univariate processes have been investigated extensively, but are comparatively neglected for multivariate processes where multiple dependent characteristics are involved in quality measurement. In this paper, we consider two commonly used multivariate capability indices MC_p and MC_pm, to evaluate multivariate process capability. We investigate the statistical properties of the estimated MC_p and obtain the lower confidence bound for MC_p. We also consider testing MC_p, and provide critical values for testing if a multivariate process meets the preset capability requirement. In addition, an approximate confidence interval for MC_pm is derived. A simulation study is conducted to ascertain the accuracy of the approximation. Three examples are presented to illustrate the applicability of the obtained results.     

Process capability analysis for serially dependent processes of Poisson counts

Process capability indices evaluate the actual compliance of a process with given external specifications in a single number. For the case of a process of independent and identically distributed Poisson counts, two types of index have been proposed and investigated in the literature. The assumption of serial independence, however, is quite unrealistic for practice. We consider the case of an underlying Poisson INAR(1) process which has an AR(1)-like autocorrelation structure. We show that the performance of the estimated indices is degraded heavily if serial dependence is ignored. Therefore, we develop approaches for estimating the process capability (both for the observation and innovation process), which explicitly consider the observed degree of autocorrelation. For this purpose, we introduce a new unbiased estimator of the innovations’ mean of a Poisson INAR(1) process and derive its exact as well as asymptotic stochastic properties. In this context, we also present new explicit expressions for the third- and fourth-order moments of a Poisson INAR(1) process. Then the capability indices and the performance of their estimators are analysed and recommendations for practice are given.     

On C pk Assessment in the Presence of Tool Wear

Process capability indices are routinely used in manufacturing industries for process monitoring. A basic assumption while using process capability indices is that there are no assignable causes of variation present. However, when variation due to an assignable cause is present and is tolerated, the conventional methods of capability measurement become inaccurate. In this article, we suggest an estimate of C_pk assuming that the process capability changes dynamically. We obtain an exact form of the sampling distribution in the presence of a systematic assignable cause. We discuss the problem of testing whether a given process is capable. The critical values for different sample sizes are obtained based on the sampling distribution. An example involving tool wear problem is presented.     

A note on the asymptotic distribution of the process capability index C pmk

Process capability indices have been widely used to evaluate the process performance to the continuous improvement of quality and productivity. The distribution of the estimator of the process capability index C _pmk is very complicated and the asymptotic distribution is proposed by Chen and Hsu [The asymptotic distribution of the processes capability index C _pmk , Comm. Statist. Theory Methods 24(5) (1995), pp. 1279–1291]. However, we found a critical error for the asymptotic distribution when the population mean is not equal to the midpoint of the specification limits. In this paper, a correct version of the asymptotic distribution is given. An asymptotic confidence interval of C _pmk by using the correct version of asymptotic distribution is proposed and the lower bound can be used to test if the process is capable. A simulation study of the coverage probability of the proposed confidence interval is shown to be satisfactory. The relation of six sigma technique and the index C _pmk is also discussed in this paper. An asymptotic testing procedure to determine if a process is capable based on the index of C _pmk is also given in this paper.     

Process Capability Analysis in Non Normal Linear Regression Profiles

When the distribution of a process characterized by a profile is non normal, process capability analysis using normal assumption often leads to erroneous interpretations of the process performance. Profile monitoring is a relatively new set of techniques in quality control that is used in situations where the state of product or process is represented by a function of two or more quality characteristics. Such profiles can be modeled using linear or nonlinear regression models. In some applications, it is assumed that the quality characteristics follow a normal distribution; however, in certain applications this assumption may fail to hold and may yield misleading results. In this article, we consider process capability analysis of non normal linear profiles. We investigate and compare five methods to estimate non normal process capability index (PCI) in profiles. In three of the methods, an estimation of the cumulative distribution function (cdf) of the process is required to analyze process capability in profiles. In order to estimate cdf of the process, we use a Burr XII distribution as well as empirical distributions. However, the resulted PCI with estimating cdf of the process is sometimes far from its true value. So, here we apply artificial neural network with supervised learning which allows the estimation of PCIs in profiles without the need to estimate cdf of the process. Box-Cox transformation technique is also developed to deal with non normal situations. Finally, a comparison study is performed through the simulation of Gamma, Weibull, Lognormal, Beta and student-t data.     

Estimation of the Change Point in Monitoring the Process Mean and Variance

Knowing the time of a process change could lead to quicker identification of the special cause and less process down time, as well as help to reduce the probability of incorrectly identifying the special cause. In this article, we propose the maximum likelihood estimator (MLE) for the process change point when a control chart with the fixed sampling rate (FSR) scheme or the variable sampling rate (VSR) scheme is used in monitoring a process to detect changes in the process mean and/or variance of a normal quality variable. We investigate the performance of this estimator when it is used in various types of control charts.     

Elliptical safety region plots for C pk

The process capability index C _pk is widely used when measuring the capability of a manufacturing process. A process is defined to be capable if the capability index exceeds a stated threshold value, e.g. C _pk >4/3. This inequality can be expressed graphically using a process capability plot, which is a plot in the plane defined by the process mean and the process standard deviation, showing the region for a capable process. In the process capability plot, a safety region can be plotted to obtain a simple graphical decision rule to assess process capability at a given significance level. We consider safety regions to be used for the index C _pk . Under the assumption of normality, we derive elliptical safety regions so that, using a random sample, conclusions about the process capability can be drawn at a given significance level. This simple graphical tool is helpful when trying to understand whether it is the variability, the deviation from target, or both that need to be reduced to improve the capability. Furthermore, using safety regions, several characteristics with different specification limits and different sample sizes can be monitored in the same plot. The proposed graphical decision rule is also investigated with respect to power.     

A flexible multi-stage design for phase II oncology trials

Phase II trials evaluate whether a new drug or a new therapy is worth further pursuing or certain treatments are feasible or not. A typical phase II is a single arm (open label) trial with a binary clinical endpoint (response to therapy). Although many oncology Phase II clinical trials are designed with a two-stage procedure, multi-stage design for phase II cancer clinical trials are now feasible due to increased capability of data capture. Such design adjusts for multiple analyses and variations in analysis time, and provides greater flexibility such as minimizing the number of patients treated on an ineffective therapy and identifying the minimum number of patients needed to evaluate whether the trial would warrant further development. In most of the NIH sponsored studies, the early stopping rule is determined so that the number of patients treated on an ineffective therapy is minimized. In pharmaceutical trials, it is also of importance to know as early as possible if the trial is highly promising and what is the likelihood the early conclusion can sustain. Although various methods are available to address these issues, practitioners often use disparate methods for addressing different issues and do not realize a single unified method exists. This article shows how to utilize a unified approach via a fully sequential procedure, the sequential conditional probability ratio test, to address the multiple needs of a phase II trial. We show the fully sequential program can be used to derive an optimized efficient multi-stage design for either a low activity or a high activity, to identify the minimum number of patients required to assess whether a new drug warrants further study and to adjust for unplanned interim analyses. In addition, we calculate a probability of discordance that the statistical test will conclude otherwise should the trial continue to the planned end that is usually at the sample size of a fixed sample design. This probability can be used to aid in decision making in a drug development program. All computations are based on exact binomial distribution.     

The probability density function of process capability index Cpmk

We derive an explicit and computationally convenient form for the probability density function of the estimator of the process capability index C_pmk ( Pearn, Kotz and Johnson ), when sampling from a normal distribution.     

Empirical likelihood confidence bands for distribution functions with missing responses

Distribution function estimation plays a significant role of foundation in statistics since the population distribution is always involved in statistical inference and is usually unknown. In this paper, we consider the estimation of the distribution function of a response variable Y with missing responses in the regression problems. It is proved that the augmented inverse probability weighted estimator converges weakly to a zero mean Gaussian process. A augmented inverse probability weighted empirical log-likelihood function is also defined. It is shown that the empirical log-likelihood converges weakly to the square of a Gaussian process with mean zero and variance one. We apply these results to the construction of Gaussian process approximation based confidence bands and empirical likelihood based confidence bands of the distribution function of Y. A simulation is conducted to evaluate the confidence bands.     

A Bayesian procedure for assessing process performance based on the third-generation capability index

Capability indices that qualify process potential and process performance are practical tools for successful quality improvement activities and quality program implementation. Most existing methods to assess process capability were derived on the basis of the traditional frequentist point of view. This paper considers the problem of estimating and testing process capability based on the third-generation capability index C _pmk from the Bayesian point of view. We first derive the posterior probability p for the process under investigation is capable. The one-sided credible interval, a Bayesian analog of the classical lower confidence interval, can be obtained to assess process performance. To investigate the effectiveness of the derived results, a series of simulation was undertaken. The results indicate that the performance of the proposed Bayesian approach depends strongly on the value of ξ=(μ?T)/σ. It performs very well with the accurate coverage rate when μ is sufficiently far from T. In those cases, they have the same acceptable performance even though the sample size n is as small as 25.     

Designing optimal double-sampling plan based on process capability index

Process capability analysis is applied to monitor the process quality. Process capability can be quantified by process capability index. These indices have wide application in quality control methods and acceptance sampling plans. In this paper, we introduce a double-sampling plan based on process capability index. In this type of scheme, under a decision rule and with the specified rejection and acceptance numbers, the second sample is selected and the decision of rejection or acceptance is made based on the information obtained from two samples. The purpose of this scheme is to reduce the average sample number in order to reduce the time and cost of sampling. A comparison study has been conducted in order to evaluate the performance of proposed method in comparison with classical single sampling plans.     

Generalized confidence intervals for the process capability indices in general random effect model with balanced data

In this paper, we consider the interval estimation problem on the process capability indices in general random effect model with balanced data. The confidence intervals for three commonly used process capability indices are developed by using the concept of generalized confidence interval. Furthermore, some simulation results on the coverage probability and expected value of the generalized lower confidence limits are reported. The simulation results indicate that the proposed confidence intervals do provide quite satisfactory coverage probabilities.     

Integration of support vector machines and control charts for multivariate process monitoring

Statistical process control tools have been used routinely to improve process capabilities through reliable on-line monitoring and diagnostic processes. In the present paper, we propose a novel multivariate control chart that integrates a support vector machine (SVM) algorithm, a bootstrap method, and a control chart technique to improve multivariate process monitoring. The proposed chart uses as the monitoring statistic the predicted probability of class (PoC) values from an SVM algorithm. The control limits of SVM-PoC charts are obtained by a bootstrap approach. A simulation study was conducted to evaluate the performance of the proposed SVM–PoC chart and to compare it with other data mining-based control charts and Hotelling's T ² control charts under various scenarios. The results showed that the proposed SVM–PoC charts outperformed other multivariate control charts in nonnormal situations. Further, we developed an exponential weighed moving average version of the SVM–PoC charts for increasing sensitivity to small shifts.     

Three New Multivariate Process Capability Indices

Different multivariate process capability indices are developed by researchers to evaluate process capability when vectors of quality characteristics are considered in a study. This article presents three indices referred to as NCpM, MCpM, and NMC _PM in order to evaluate process capability in multivariate environment. The performance of the proposed indices is investigated numerically. Simulation results indicate that the proposed indices have descended estimation error and improved performance compared to the existing ones. These results can be important to researchers and practitioners who are interested in evaluating process capability in multivariate domain.     

Process capability index for bivariate exponentially distributed quality characteristics and its sampling properties

In this paper, a process capability index for two correlated quality characteristics jointly following bivariate exponential distribution has been proposed. The expectation and sampling variance of the estimated index have been derived. Choice of the natural process interval corresponding to a specified coverage probability has been discussed.     

The power of monitoring: how to make the most of a contaminated multivariate sample

Diagnostic tools must rely on robust high-breakdown methodologies to avoid distortion in the presence of contamination by outliers. However, a disadvantage of having a single, even if robust, summary of the data is that important choices concerning parameters of the robust method, such as breakdown point, have to be made prior to the analysis. The effect of such choices may be difficult to evaluate. We argue that an effective solution is to look at several pictures, and possibly to a whole movie, of the available data. This can be achieved by monitoring, over a range of parameter values, the results computed through the robust methodology of choice. We show the information gain that monitoring provides in the study of complex data structures through the analysis of multivariate datasets using different high-breakdown techniques. Our findings support the claim that the principle of monitoring is very flexible and that it can lead to robust estimators that are as efficient as possible. We also address through simulation some of the tricky inferential issues that arise from monitoring.     

Confidence sets for the maximizers of intensity functions

Identifying times or time intervals when the intensity function of a Poisson process is maximal is important in a variety of practical problems, for instance in traffic control or with planning issues involving customer arrivals or accident occurrences. For this purpose, we propose confidence sets that are intuitive and easy to obtain, which makes them practicable for a quick exploratory data analysis. They may also be used in the context of mode estimation for probability densities. In the current literature, confidence sets for the mode are based on the assumption of an—at least locally—unique mode. In contrast, our approach retains the coverage probability even if the underlying intensity or density has a flat top. We even allow the intensity to be constant in the extreme.     

A CUSUM control chart for monitoring the variance when parameters are estimated

CUSUM control chart has been widely used for monitoring the process variance. It is usually used assuming that the nominal process variance is known. However, several researchers have shown that the ability of control charts to signal when a process is out of control is seriously affected unless process parameters are estimated from a large in-control Phase I data set. In this paper we derive the run length properties of a CUSUM chart for monitoring dispersion with estimated process variance and we evaluate the performance of this chart by comparing it with the same chart but with assumed known process parameters.