Teaching statistics to clinical research staff in a pharmaceutical company

Education of clinical research staff in understanding statistical concepts is an area of importance for pharmaceutical companies. This understanding is needed to help them communicate with statisticians using a common language, in designing clinical trials and interpretation of clinical trial results. Such staff has little time for a one-semester or even a one-week continuing education course in statistics. Faced with this reality, we developed a 3-module course,for a total of 1.5 days, which was taught over a period of one month that addresses the needs of this audience. We describe the format and content of the course and provide references that can serve as a resource for teaching such a course.     

Effects of unstratified and centre‐stratified randomization in multi‐centre clinical trials

This paper deals with the analysis of randomization effects in multi‐centre clinical trials. The two randomization schemes most often used in clinical trials are considered: unstratified and centre‐stratified block‐permuted randomization. The prediction of the number of patients randomized to different treatment arms in different regions during the recruitment period accounting for the stochastic nature of the recruitment and effects of multiple centres is investigated. A new analytic approach using a Poisson‐gamma patient recruitment model (patients arrive at different centres according to Poisson processes with rates sampled from a gamma distributed population) and its further extensions is proposed. Closed‐form expressions for corresponding distributions of the predicted number of the patients randomized in different regions are derived. In the case of two treatments, the properties of the total imbalance in the number of patients on treatment arms caused by using centre‐stratified randomization are investigated and for a large number of centres a normal approximation of imbalance is proved. The impact of imbalance on the power of the study is considered. It is shown that the loss of statistical power is practically negligible and can be compensated by a minor increase in sample size. The influence of patient dropout is also investigated. The impact of randomization on predicted drug supply overage is discussed. Copyright © 2010 John Wiley & Sons, Ltd.     

Dynamic Graphical Tools for Teaching Experimental Design and Analysis Concepts

In 1996, computer-based modules were presented that use interactive graphics and simulation to teach basic statistical concepts for undergraduate courses. This article extends that work to develop new modules that can be used to demonstrate important statistical concepts underlying the design and analysis of experiments. Details of their implementation, content and usage are discussed.     

论国民经济核算与国际收支核算之间的内在联系

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A course in constructing effective displays of data for pharmaceutical research personnel

Interpreting data and communicating effectively through graphs and tables are requisite skills for statisticians and non‐statisticians in the pharmaceutical industry. However, the quality of visual displays of data in the medical and pharmaceutical literature and at scientific conferences is severely lacking. We describe an interactive, workshop‐driven, 2‐day short course that we constructed for pharmaceutical research personnel to learn these skills. The examples in the course and the workshop datasets source from our professional experiences, the scientific literature, and the mass media. During the course, the participants are exposed to and gain hands‐on experience with the principles of visual and graphical perception, design, and construction of both graphic and tabular displays of quantitative and qualitative information. After completing the course, with a critical eye, the participants are able to construct, revise, critique, and interpret graphic and tabular displays according to an extensive set of guidelines. Copyright © 2013 John Wiley & Sons, Ltd.     

Choice of Baselines in Clinical Trials: A Simulation Study from Statistical Power Perspective

Multiple assessments of an efficacy variable are often conducted prior to the initiation of randomized treatments in clinical trials as baseline information. Two goals are investigated in this article, where the first goal is to investigate the choice of these baselines in the analysis of covariance (ANCOVA) to increase the statistical power, and the second to investigate the magnitude of power loss when a continuous efficacy variable is dichotomized to categorical variable as commonly reported the biomedical literature. A statistical power analysis is developed with extensive simulations based on data from clinical trials in study participants with end stage renal disease (ESRD). It is found that the baseline choices primarily depend on the correlations among the baselines and the efficacy variable, with substantial gains for correlations greater than 0.6 and negligible for less than 0.2. Continuous efficacy variables always give higher statistical power in the ANCOVA modeling and dichotomizing the efficacy variable generally decreases the statistical power by 25%, which is an important practicum in designing clinical trials for study sample size and realistically budget. These findings can be easily applied in and extended to other clinical trials with similar design.     

Statistical Issues in Macroeconomic Modelling*

The paper describes the influx of mathematical statistics in economics. It focuses on an approach to macroeconometric modelling which is based on fundamental statistical concepts like the joint distribution function of all observable variables for the whole sample period. The methodology relies on valid conditioning and marginalization of this function in order to arrive at tractable subsystems, which can be analysed with statistical methods. Two case studies—the modelling of the household sector and of wages and prices in the Norges Bank RIMINI model—highlight this.     

Multidimensional Scaling for Selecting Small Groups in College Courses

Many college courses use group work as a part of the learning and evaluation process. Class groups are often selected randomly or by allowing students to organize groups themselves. However, if it is desired to control some aspect of the group structure, such as increasing schedule compatibility within groups, multidimensional scaling can be used to form such groups. This article describes how this has been adopted in an undergraduate statistics course. Resulting groups have been more homogeneous with respect to student schedules than groups selected randomly—an example from winter quarter 2004 increased correlations between student schedules from a mean of .29 before grouping to a within-group mean of .50. Further, the exercise allows opportunities to discuss a wealth of statistical concepts in class, including surveys, association measures, multidimensional scaling, and statistical graphics.     

Two-sample post-stratified or subgroup analysis with restricted randomization rules

In a clinical trial to compare two treatments, subjects may be allocated sequentially to treatment groups by a restricted randomization rule. Suppose that at the end of the trial, the investigator is interested in a post-stratified or subgroup analysis with respect to a particular demographic or clinical factor which was not selected prior to the trial for stratified randomization. Under a randomization model, large sample theory of two-sample post-stratified permutational tests is developed with a broad class of restricted randomization treatment allocation rules. The test procedures proposed here are illustrated with a real-life example. The results of this example indicate that it is not always possible to ignore the treatment rule used in the trial in the design-based analysis.     

Block response-adaptive randomization in clinical trials with binary endpoints

In a clinical trial, response-adaptive randomization (RAR) uses accumulating data to weigh the randomization of remaining patients in favour of the better performing treatment. The aim is to reduce the number of failures within the trial. However, many well-known RAR designs, in particular, the randomized play-the-winner-rule (RPWR), have a highly myopic structure which has sometimes led to unfortunate randomization sequences when used in practice. This paper introduces random permuted blocks into two RAR designs, the RPWR and sequential maximum likelihood estimation, for trials with a binary endpoint. Allocation ratios within each block are restricted to be one of 1:1, 2:1 or 3:1, preventing unfortunate randomization sequences. Exact calculations are performed to determine error rates and expected number of failures across a range of trial scenarios. The results presented show that when compared with equal allocation, block RAR designs give similar reductions in the expected number of failures to their unmodified counterparts. The reductions are typically modest under the alternative hypothesis but become more impressive if the treatment effect exceeds the clinically relevant difference.     

Key Attributes of a Modern Statistical Computing Tool

ABSTRACT

In the 1990s, statisticians began thinking in a principled way about how computation could better support the learning and doing of statistics. Since then, the pace of software development has accelerated, advancements in computing and data science have moved the goalposts, and it is time to reassess. Software continues to be developed to help do and learn statistics, but there is little critical evaluation of the resulting tools, and no accepted framework with which to critique them. This article presents a set of attributes necessary for a modern statistical computing tool. The framework was designed to be broadly applicable to both novice and expert users, with a particular focus on making more supportive statistical computing environments. A modern statistical computing tool should be accessible, provide easy entry, privilege data as a first-order object, support exploratory and confirmatory analysis, allow for flexible plot creation, support randomization, be interactive, include inherent documentation, support narrative, publishing, and reproducibility, and be flexible to extensions. Ideally, all these attributes could be incorporated into one tool, supporting users at all levels, but a more reasonable goal is for tools designed for novices and professionals to “reach across the gap,” taking inspiration from each others’ strengths.     

Randomization tests in recursive response-adaptive randomization procedures

In a randomized clinical trial, response-adaptive randomization procedures use the information gathered, including the previous patients' responses, to allocate the next patient. In this setting, we consider randomization-based inference. We provide an algorithm to obtain exact p-values for statistical tests that compare two treatments with dichotomous responses. This algorithm can be applied to a family of response adaptive randomization procedures which share the following property: the distribution of the allocation rule depends only on the imbalance between treatments and on the imbalance between successes for treatments 1 and 2 in the previous step. This family includes some outstanding response adaptive randomization procedures. We study a randomization test to contrast the null hypothesis of equivalence of treatments and we show that this test has a similar performance to that of its parametric counterpart. Besides, we study the effect of a covariate in the inferential process. First, we obtain a parametric test, constructed assuming a logit model which relates responses to treatments and covariate levels, and we give conditions that guarantee its asymptotic normality. Finally, we show that the randomization test, which is free of model specification, performs as well as the parametric test that takes the covariate into account.     

Treatment Choice With Trial Data: Statistical Decision Theory Should Supplant Hypothesis Testing

Abstract

A central objective of empirical research on treatment response is to inform treatment choice. Unfortunately, researchers commonly use concepts of statistical inference whose foundations are distant from the problem of treatment choice. It has been particularly common to use hypothesis tests to compare treatments. Wald’s development of statistical decision theory provides a coherent frequentist framework for use of sample data on treatment response to make treatment decisions. A body of recent research applies statistical decision theory to characterize uniformly satisfactory treatment choices, in the sense of maximum loss relative to optimal decisions (also known as maximum regret). This article describes the basic ideas and findings, which provide an appealing practical alternative to use of hypothesis tests. For simplicity, the article focuses on medical treatment with evidence from classical randomized clinical trials. The ideas apply generally, encompassing use of observational data and treatment choice in nonmedical contexts.     

Comparison of response adaptive randomization features in multiarm clinical trials with control

We investigate multiple features of response adaptive randomization (RAR) in the context of a multiple arm randomized trial with control, where the primary goal is the identification of the best arm for use in a broader patient population. We maintain constant control allocation and vary the length of time until RAR is started, interim frequency, the underlying quantity used to calculate the randomization probabilities, and a threshold resulting in temporary arm dropping. We evaluate the designs on five metrics measuring benefit to the internal trial population, the future external population, and statistical estimation. Our results indicate these features have minimal interaction within the space explored, with preference for earlier activation of RAR, more frequent interim analyses, randomizing in proportion to the probability each arm is the best, and aggressive thresholding for temporarily dropping arms. The results illustrate useful principles for maximizing the benefit of RAR in practice.     

Elementary statistics laboratory

Students in elementary statistics traditionally see experiments and data as words and numbers in a text. They receive little exposure to the important statistical activities of sample selection, data collection, experimental design, development of statistical models, the need for randomization, selection of factors, etc. They often leave the first course without a firm understanding of the role of applied statistics or of the statistician in scientific investigations. In an attempt to improve elementary statistics education, we have developed a statistics laboratory similar to those of other elementary science courses. We will discuss our experiences in teaching a laboratory component with the traditional elementary statistics course. In each lab session, students, working in teams, discuss the design of an experiment, carry out the experiment, and analyze their data using Minitab on a Macintosh or MS-DOS based computer. The students then individually either answer a series of short answer questions or write a formal scientific report. The labs are designed to be relatively inexpensive and portable. They do not require a prior background in science, statistics or computing.     

Bayesian randomized clinical trials: A decision‐theoretic sequential design

The authors propose a Bayesian decision‐theoretic framework justifying randomization in clinical trials. Noting that the decision maker is often unable or unwilling to specify a unique utility function, they develop a sequential myopic design that includes randomization justified by the consideration of a set of utility functions. Randomization is introduced over all nondominated treatments, allowing for interim removal of treatments and early stopping. The authors illustrate their approach in the context of a study to find the optimal dose of pegylated interferon for platinum resistant ovarian cancer. They also develop an algorithm to implement their methodology in a phase II clinical trial comparing several competing experimental treatments.     

Response Adaptive Designs with Misclassified Responses

We consider response adaptive designs when the binary response may be misclassified and extend relevant results in the literature. We derive the optimal allocations under various objectives and examine the relationship between the power of statistical test and the variability of treatment allocation. Asymptotically best response adaptive randomization procedures and effects of misclassification on the optimal allocations are investigated. A real-life clinical trial is also discussed to illustrate our proposed approach.     

Randomization tests for small samples: an application for genetic expression data

Summary. An advantage of randomization tests for small samples is that an exact P -value can be computed under an additive model. A disadvantage with very small sample sizes is that the resulting discrete distribution for P -values can make it mathematically impossible for a P -value to attain a particular degree of significance. We investigate a distribution of P -values that arises when several thousand randomization tests are conducted simultaneously using small samples, a situation that arises with microarray gene expression data. We show that the distribution yields valuable information regarding groups of genes that are differentially expressed between two groups: a treatment group and a control group. This distribution helps to categorize genes with varying degrees of overlap of genetic expression values between the two groups, and it helps to quantify the degree of overlap by using the P -value from a randomization test. Moreover, a statistical test is available that compares the actual distribution of P -values with an expected distribution if there are no genes that are differentially expressed. We demonstrate the method and illustrate the results by using a microarray data set involving a cell line for rheumatoid arthritis. A small simulation study evaluates the effect that correlated gene expression levels could have on results from the analysis.     

Methodological issues with adaptation of clinical trial design

Adaptation of clinical trial design generates many issues that have not been resolved for practical applications, though statistical methodology has advanced greatly. This paper focuses on some methodological issues. In one type of adaptation such as sample size re-estimation, only the postulated value of a parameter for planning the trial size may be altered. In another type, the originally intended hypothesis for testing may be modified using the internal data accumulated at an interim time of the trial, such as changing the primary endpoint and dropping a treatment arm. For sample size re-estimation, we make a contrast between an adaptive test weighting the two-stage test statistics with the statistical information given by the original design and the original sample mean test with a properly corrected critical value. We point out the difficulty in planning a confirmatory trial based on the crude information generated by exploratory trials. In regards to selecting a primary endpoint, we argue that the selection process that allows switching from one endpoint to the other with the internal data of the trial is not very likely to gain a power advantage over the simple process of selecting one from the two endpoints by testing them with an equal split of alpha (Bonferroni adjustment). For dropping a treatment arm, distributing the remaining sample size of the discontinued arm to other treatment arms can substantially improve the statistical power of identifying a superior treatment arm in the design. A common difficult methodological issue is that of how to select an adaptation rule in the trial planning stage. Pre-specification of the adaptation rule is important for the practicality consideration. Changing the originally intended hypothesis for testing with the internal data generates great concerns to clinical trial researchers.