Construction of neighbor designs of block size 4 for all values of v ≥ 5 by using the method of addition

In this article, a general method of construction of neighbor block designs is given. The designs are constructed using variation of a simple method which we refer to as the method of addition (renamed as the method of cyclic shifts). We give complete solution of neighbor balanced designs for k = 4 for any value of v. We also give many series of generalized neighbor designs (GNDs). In the last section, we have constructed GNDs in a sequential manner (as Did John 1981) for v ≤ 50 and r is multiple of k.     

Experimental designs for open pollination in polycross trials

A polycross is the pollination by natural hybridization of a group of genotypes, generally selected, grown in isolation from other compatible genotypes in such a way to promote random open pollination. A particular practical application of the polycross method occurs in the production of a synthetic variety resulting from cross-pollinated plants. Laying out these experiments in appropriate designs, known as polycross designs, would not only save experimental resources but also gather more information from the experiment. Different situations may arise in polycross nurseries where accordingly different polycross designs may be used. For situations in which some genotypes interfere in the growth or production of other genotypes, but have to be grown together, neighbour-restricted design is a better option. Furthermore, when the topography of the nursery is such that a known wind system in a certain direction may prevail, then designs balanced for neighbour effects of genotypes only in the direction of wind are appropriate which may help in saving experimental resources to a great extent. Also, when genotypes are planted in a small area without leaving much space between rows, designs balanced for neighbour effects from all possible eight directions are useful to have equal chance of pollinating and being pollinated by every other genotype. Here, polycross designs have been obtained to match above-mentioned three situations. SAS Macros have also been developed to generate these proposed designs.     

Optimal Designs for the Carryover Model with Random Interactions Between Subjects and Treatments

The paper considers a model for crossover designs with carryover effects and a random interaction between treatments and subjects. Under this model, two observations of the same treatment on the same subject are positively correlated and therefore provide less information than two observations of the same treatment on different subjects. The introduction of the interaction makes the determination of optimal designs much harder than is the case for the traditional model. Generalising the results of Bludowsky's thesis, the present paper uses Kushner's method to determine optimal approximate designs. We restrict attention to the case where the number of periods is less than or equal to the number of treatments. We determine the optimal designs in the important special cases that the number of periods is 3, 4 or 5. It turns out that the optimal designs depend on the variance of the random interactions and in most cases are not binary. However, we can show that neighbour balanced binary designs are highly efficient, regardless of the number of periods and of the size of the variance of the interaction effects.     

Application of Bayesian analyses to doubly randomized delayed start,matched control designs to demonstrate disease modification

Disease modification is a primary therapeutic aim when developing treatments for most chronic progressive diseases. The best treatments do not simply affect disease symptoms but fundamentally improve disease course by slowing, halting, or reversing disease progression. One of many challenges for establishing disease modification relates to the identification of adequate analytic tools to show differences in a disease course following intervention. Traditional approaches rely on the comparisons of slopes or noninferiority margins. However, it has proven difficult to conclusively demonstrate disease modification using such approaches. To address these challenges, we propose a novel adaptation of the delayed start study design that incorporates posterior probabilities identified by hierarchical Bayesian inference approaches to establish evidence for disease modification. Our models compare the size of treatment differences at the end of the delayed start period with those at the end of the early start period. Simulations that compare several models are provided. These include general linear models, repeated measures models, spline models, and model averaging. Our work supports the superiority of model averaging for accurately characterizing complex data that arise in real world applications. This novel approach has been applied to the design of an ongoing, doubly randomized, matched control study that aims to show disease modification in young persons with schizophrenia (the Disease Recovery Evaluation and Modification (DREaM) study). The application of this Bayesian methodology to the DREaM study highlights the value of this approach and demonstrates many practical challenges that must be addressed when implementing this methodology in a real world trial.     

Some Classes of Binary Block Neighbor Designs

Neighbor designs are useful to neutralize the neighbor effects. In this paper two classes of these designs are constructed in circular binary blocks of size 4, 8, …, 24. First class consists of six infinite series of nearest neighbor designs in which each pair of distinct treatments appears once as neighbors. Second class also deals with six infinite series of these designs in which each pair of distinct treatments appears twice as neighbors. A catalog of nearest neighbor designs is also compiled in circular binary blocks for odd number of treatments from 23 to 99.     

A Bayesian adaptive blinded sample size adjustment method for risk differences

Adaptive sample size adjustment (SSA) for clinical trials consists of examining early subsets of on trial data to adjust estimates of sample size requirements. Blinded SSA is often preferred over unblinded SSA because it obviates many logistical complications of the latter and generally introduces less bias. On the other hand, current blinded SSA methods for binary data offer little to no new information about the treatment effect, ignore uncertainties associated with the population treatment proportions, and/or depend on enhanced randomization schemes that risk partial unblinding. I propose an innovative blinded SSA method for use when the primary analysis is a non‐inferiority or superiority test regarding a risk difference. The method incorporates evidence about the treatment effect via the likelihood function of a mixture distribution. I compare the new method with an established one and with the fixed sample size study design, in terms of maximization of an expected utility function. The new method maximizes the expected utility better than do the comparators, under a range of assumptions. I illustrate the use of the proposed method with an example that incorporates a Bayesian hierarchical model. Lastly, I suggest topics for future study regarding the proposed methods. Copyright © 2015 John Wiley & Sons, Ltd.     

A cusum control chart approach for screening active effects in orthogonal-saturated experiments

The analysis of designs based on saturated orthogonal arrays poses a very difficult challenge since there are no degrees of freedom left to estimate the error variance. In this paper we propose a heuristic approach for the use of cumulative sum control chart for screening active effects in orthogonal-saturated experiments. A comparative simulation study establishes the powerfulness of the proposed method.     

Universally Optimal Designs Balanced for Neighbor Effects

The performance of a treatment is affected by the treatments applied to its adjacent plots, especially in the experiments of agriculture, horticulture, forestry, serology and industry. Neighbor designs ensure that treatment comparisons are least affected by neighbor effects, therefore, this is a rich field of investigation. In this paper, criterion for construction of universally optimal neighbor balanced designs is discussed.     

A comparative study of adaptive trial designs for dose optimization

Recently, the US Food and Drug Administration Oncology Center of Excellence initiated Project Optimus to reform the dose optimization and dose selection paradigm in oncology drug development. The agency pointed out that the current paradigm for dose selection—based on the maximum tolerated dose (MTD)—is not sufficient for molecularly targeted therapies and immunotherapies, for which efficacy may not increase after the dose reaches a certain level. In these cases, it is more appropriate to identify the optimal biological dose (OBD) that optimizes the risk–benefit tradeoff of the drug. Project Optimus has spurred tremendous interest and urgent need for guidance on designing dose optimization trials. In this article, we review several representative dose optimization designs, including model-based and model-assisted designs, and compare their operating characteristics based on 10,000 randomly generated scenarios with various dose-toxicity and dose-efficacy curves and some fixed representative scenarios. The results show that, compared with model-based designs, model-assisted methods have advantages of easy-to-implement, robustness, and high accuracy to identify OBD. Some guidance is provided to help biostatisticians and clinicians to choose appropriate dose optimization methods in practice.     

Cumulative cohort design for dose-finding

We introduce a new design for dose-finding in the context of toxicity studies for which it is assumed that toxicity increases with dose. The goal is to identify the maximum tolerated dose, which is taken to be the dose associated with a prespecified “target” toxicity rate. The decision to decrease, increase or repeat a dose for the next subject depends on how far an estimated toxicity rate at the current dose is from the target. The size of the window within which the current dose will be repeated is obtained based on the theory of Markov chains as applied to group up-and-down designs. But whereas the treatment allocation rule in Markovian group up-and-down designs is only based on information from the current cohort of subjects, the treatment allocation rule for the proposed design is based on the cumulative information at the current dose. We then consider an extension of this new design for clinical trials in which the subject's outcome is not known immediately. The new design is compared to the continual reassessment method.