An efficient sequential design of clinical trials

We propose an efficient group sequential monitoring rule for clinical trials. At each interim analysis both efficacy and futility are evaluated through a specified loss structure together with the predicted power. The proposed design is robust to a wide range of priors, and achieves the specified power with a saving of sample size compared to existing adaptive designs. A method is also proposed to obtain a reduced-bias estimator of treatment difference for the proposed design. The new approaches hold great potential for efficiently selecting a more effective treatment in comparative trials. Operating characteristics are evaluated and compared with other group sequential designs in empirical studies. An example is provided to illustrate the application of the method.     

A lower bound for the centred L 2-discrepancy on combined designs under the asymmetric factorials

The foldover is a useful technique in the construction of two-level factorial designs for follow-up experiments. To search an optimal foldover plans is an important issue. In this paper, for a set of asymmetric fractional factorials such as the original designs, a lower bound for centred L ₂-discrepancy of combined designs under a general foldover plan is obtained, which can be used as a benchmark for searching optimal foldover plans. All of our results are the extended ones of Ou et al. [Lower bounds of various discrepancies on combined designs, Metrika 74 (2011), pp. 109–119] for symmetric designs to asymmetric designs. Moreover, it also provides a theoretical justification for optimal foldover plans in terms of uniformity criterion.     

Selection of cost-optimal 2k−p fractional factorials

Selecting an optimal 2^k?pfractional factorial is structured as a mathematical programming problem. An algorithm is defined for the solution, and the case of additive costs is shown to have a known solution for resolution III designs.     

Analyzing Supersaturated Designs by Means of an Information Based Criterion

The cost and time consumption of many industrial experimentations can be reduced using the class of supersaturated designs since this can be used for screening out the important factors from a large set of potentially active variables. A supersaturated design is a design for which there are fewer runs than effects to be estimated. Although there exists a wide study of construction methods for supersaturated designs, their analysis methods are yet in an early research stage. In this article, we propose a method for analyzing data using a correlation-based measure, named as symmetrical uncertainty. This method combines measures from the information theory field and is used as the main idea of variable selection algorithms developed in data mining. In this work, the symmetrical uncertainty is used from another viewpoint in order to determine more directly the important factors. The specific method enables us to use supersaturated designs for analyzing data of generalized linear models for a Bernoulli response. We evaluate our method by using some of the existing supersaturated designs, obtained according to methods proposed by Tang and Wu (1997 Tang , B. , Wu , C. F. J. (1997). A method for constructing supersaturated designs and its E(s ²)-optimality. Canadian Journal of Statistics 25:191–201.[Crossref], [Web of Science ®] , [Google Scholar]) as well as by Koukouvinos et al. (2008 Koukouvinos , C. , Mylona , K. , Simos , D. E. ( 2008 ). E(s ²)-optimal and minimax-optimal cyclic supersaturated designs via multi-objective simulated annealing . Journal of Statistical Planning and Inference 138 : 1639 – 1646 .[Crossref], [Web of Science ®] , [Google Scholar]). The comparison is performed by some simulating experiments and the Type I and Type II error rates are calculated. Additionally, Receiver Operating Characteristics (ROC) curves methodology is applied as an additional statistical tool for performance evaluation.     

A Frailty Model in Crossover Studies with Time-to-Event Response Variable

In this article, we develop a model to study treatment, period, carryover, and other applicable effects in a crossover design with a time-to-event response variable. Because time-to-event outcomes on different treatment regimens within the crossover design are correlated for an individual, we adopt a proportional hazards frailty model. If the frailty is assumed to have a gamma distribution, and the hazard rates are piecewise constant, then the likelihood function can be determined via closed-form expressions. We illustrate the methodology via an application to a data set from an asthma clinical trial and run simulations that investigate sensitivity of the model to data generated from different distributions.     

Sample Size Calculation and Blinded Sample Size Recalculation in Clinical Trials Where the Treatment Effect is Measured by the Relative Risk

In clinical trials with binary endpoints, the required sample size does not depend only on the specified type I error rate, the desired power and the treatment effect but also on the overall event rate which, however, is usually uncertain. The internal pilot study design has been proposed to overcome this difficulty. Here, nuisance parameters required for sample size calculation are re-estimated during the ongoing trial and the sample size is recalculated accordingly. We performed extensive simulation studies to investigate the characteristics of the internal pilot study design for two-group superiority trials where the treatment effect is captured by the relative risk. As the performance of the sample size recalculation procedure crucially depends on the accuracy of the applied sample size formula, we firstly explored the precision of three approximate sample size formulae proposed in the literature for this situation. It turned out that the unequal variance asymptotic normal formula outperforms the other two, especially in case of unbalanced sample size allocation. Using this formula for sample size recalculation in the internal pilot study design assures that the desired power is achieved even if the overall rate is mis-specified in the planning phase. The maximum inflation of the type I error rate observed for the internal pilot study design is small and lies below the maximum excess that occurred for the fixed sample size design.     

Bad Probability,Good Statistics,and Group Testing for Binomial Estimation

This article examines some improperly stated but often used textbook probability problems. Moving from a probabilistic to a statistical setting provides insight into group testing (i.e., observing only whether one or more of a group responds and not the response of each individual). Exact methods are used to construct tables showing (i) that group testing n times to estimate p can be more efficient than n individual tests even for small n and large p, (ii) optimal grouping strategies for various (n, p) combinations, and (iii) the efficiencies and biases achieved.     

In Search of the Optimum Harvey Wallbanger Recipe via Mixture Experiment Techniques

A Harvey Wallbanger is an alcoholic drink composed of three ingredients: orange juice, vodka, and Galliano. One of the authors (Sahrmann), a connoisseur of the libation, was perplexed upon discovering that different bartender handbooks listed different recipes for the drink. Determined to shed some light on this irksome problem, he issued invitations for an evening workshop session (party) to former and current attendees of an experimental-design training course taught within his company. A mixture experiment was designed and data collected using the class participants. This article describes the experimental design and the analysis of the data. The results of the experiment indicate that reducing the proportion of vodka produces better-flavored drinks. The results of the experiment were not entirely conclusive, however, so recommendations are made for future experimentation.     

LogXact 4.1 for Windows

Box's paper helicopter has been used to teach experimental design for more than a decade. It is simple, inexpensive, and provides real data for an involved, multifactor experiment. Unfortunately it can also further an all-too-common practice that Professor Box himself has repeatedly cautioned against, namely ignoring the fundamental science while rushing to solve problems that may not be sufficiently understood. Often this slighting of the science so as to get on with the statistics is justified by referring to Box's oft-quoted maxim that “All models are wrong, however some are useful.” Nevertheless, what is equally true, to paraphrase both Professor Box and George Orwell, is that “All models are wrong, but some are more wrong than others.” To experiment effectively it is necessary to understand the relevant science so as to distinguish between what is usefully wrong, and what is dangerously wrong.

This article presents an improved analysis of Box's helicopter problem relying on statistical and engineering knowledge and shows that this leads to an enhanced paper helicopter, requiring fewer experimental trails and achieving superior performance. In fact, of the 20 experimental trials run for validation—10 each of the proposed aerodynamic design and the conventional full factorial optimum—the longest 10 flight times all belong to the aerodynamic optimum, while the shortest 10 all belong to the conventional full factorial optimum. I further discuss how ancillary engineering knowledge can be incorporated into thinking about—and teaching—experimental design.     

Quantile plots for mean effects in the presence of variance effects for 2k-p designs

In robust parameter design, variance effects and mean effects in a factorial experiment are modelled simultaneously. If variance effects are present in a model, correlations are induced among the naive estimators of the mean effects. A simple normal quantile plot of the mean effects may be misleading because the mean effects are no longer iid under the null hypothesis that they are zero. Adjusted quantiles are computed for the case when one variance effect is significant and examples of 8-run and 16-run fractional factorial designs are examined in detail. We find that the usual normal quantiles are similar to adjusted quantiles for all but the largest and smallest ordered effects for which they are conservative. Graphically, the qualitative difference between the two sets of quantiles is negligible (even in the presence of large variance effects) and we conclude that normal probability plots are robust in the presence of variance effects.