On construction of single-arm two-stage designs with consideration of both response and toxicity.

When establishing a treatment in clinical trials, it is important to evaluate both effectiveness and toxicity. In phase II clinical trials, multinomial data are collected in m-stage designs, especially in two-stage ( m=2 ) design. Exact tests on two proportions, pr for the response rate and pt for the nontoxicity rate, should be employed due to limited sample sizes. However, existing tests use certain parameter configurations at the boundary of null hypothesis space to determine rejection regions without showing that the maximum Type I error rate is achieved at the boundary of null hypothesis. In this paper, we show that the power function for each test in a large family of tests is nondecreasing in both pr and pt ; identify the parameter configurations at which the maximum Type I error rate and the minimum power are achieved and derive level-α tests; provide optimal two-stage designs with the least expected total sample size and the optimization algorithm; and extend the results to the case of m>2 . Some R-codes are given in the Supporting Information.

[Research progress on identification and quality control of Cervi Cornu Pantotrichum].

Cervi Cornu Pantotrichum, as a traditional Chinese medicine, has great potential for development. However, the identification and quality control system is not perfect, leading to the market chaos and chronic slow growth in deep processing of Cervi Cornu Pantotrichum. This paper gives an overview of present situation in identification and quality control system of the Cervi Cornu Pantotrichum, and analyzes present problems. Based on these results, the feasibility study scheme in identification and quality control system for Cervi Cornu Pantotrichum would be then put forward, providing ideas to establish its comprehensive evaluation system.

Expression of Cre recombinase in alveolar epithelial cells of the AQP2-Cre transgenic mini-pigs.

BACKGROUND/AIMS: Optimal use of Cre mediated recombination in conditional animal models depends on well characterized Cre driver lines. Unfortunately, some Cre driver lines exhibit unexpected expression patterns hindering their utility in Cre/loxP systems. Thus, systematic assessment of new Cre lines is essential for generating useful Cre driver lines for future studies. METHODS: Here, we describe a Cre Transgenic (Tg) mini-pig line in which the expression of Cre is directed by a 3-kb 5' fragment of the kidney-specific aquaporin 2 (AQP2); however, the AQP2-Cre Tg mini-pig line exhibits expression of Cre in alveolar epithelial cells (AECs) instead of collecting duct cells. The specificity of the AQP2-Cre plasmid was validated in vitro, and indicating that the AQP2-Cre was specifically expressed in the transfected LLC-PK1 cells. Absolute quantitative real-time PCR (qRT-PCR) and inverse PCR were performed to determine the copy numbers and integration sites of the AQP2-Cre transgene. Relative qRT-PCR was performed to evaluate variation in Cre expression levels over time. RESULTS: Our data indicated that this AQP2-Cre Tg mini-pig line exhibits stable expression of Cre recombinase over time and in subsequent generations, even though the AQP2-Cre transgene was segregated and reduced in subsequent generations. CONCLUSION: Combined with our previous studies of the activity of this Cre, we conclude that this Cre Tg mini-pig line will provide a reliable tool for generating lung-specific gene targeting mini-pig models, thereby allowing the investigation of gene functions in lung development and studying the molecular mechanisms of human lung disease.

Frequency estimator for assessing of follow-on biologics.

For approval of generic drugs, the U.S. Food and Drug Administration (FDA) requires the evidence of bioequivalence in average bioavailability be provided. This is based on the Fundmental Bioequivalence Assumption from FDA that if two drug products are shown to be bioequivalent, it is assumed that they are therapeutically equivalent and can be used interchangeably. Recently, there are a few statistical considerations for assessing biosimilarity. In this article, we propose a new method based on a frequency estimator to evaluate biosimilarity; the large sample properties of the estimator, the power analysis, and calculation of the sample size are considered. Under a three-arm parallel design, the power comparison between the frequency estimator method and the other existing methods is studied through simulation, and the statistical test based on the proposed method is more powerful than for the other two methods. Simultaneously, we compared the relative performance of the three methods, and the empirical consistency and inconsistency probability are obtained in evaluating the biosimilarity.

Optimal single-arm two-stage designs with consideration of dependency on efficacy and safety.

In phase II clinical trials on cancer, it is of great interest to establish the efficacy and safety of a new treatment simultaneously. Existing hypotheses may not achieve this goal effectively. We introduce two new sets of hypotheses that consider the association between the two factors, then construct the optimal two-stage designs for the hypotheses. The proposed designs strictly control the maximum type I error rate at the given nominal level α, maintain the minimum power at least the given 1-ß, and have the smallest expected total sample size under the null hypothesis. Furthermore, an algorithm is provided to compute these designs. R-codes are given in the Supplemental Material.

Exact tests using binary data in adaptive two or multi-stage designs.

When establishing an effective treatment with binary data in a two-stage design, one-sided tests for a proportion p are employed. Researchers use the parameter configuration at the boundary of the null hypothesis space to determine a rejection region and an optimal design. However, it is unclear whether the (maximum) Type I error rate is achieved at the boundary especially when the sample size in stage 2 varies. In this paper, we first prove that this is true for a large family of tests in adaptive two-stage designs by showing that any test in the family has a nondecreasing power in p and then derive optimal designs. Second, similar results are established for m-stage designs with m > 2. Supplementary materials for this article are available online.

On construction of smallest one-sided confidence intervals for the response rate in adaptive two- or multi-stage designs.

To assess the effectiveness of a treatment in phase II clinical trial for cancer study, an adaptive multi-stage design, especially a two-stage one, is commonly used. This type of design allows an on-going study to end early for the participant's safety and design's efficiency. Since a large value of the response rate p for the treatment is wanted, lower one-sided confidence intervals for p are of interest. Due to the limited sample size, exact intervals with a guaranteed confidence level are derived using a rank function that is based on the Clopper-Pearson lower confidence limit. When the sample size in stage 2 is a constant, two kinds of smallest intervals are constructed with or without using the sufficiency principle. The proposed intervals outperform the existing exact intervals, and the intervals not based on minimal sufficient statistic are recommended for practice due to their small expected lengths. When the sample size in stage 2 varies, the smallest interval is also proposed.

Bayesian regression on non-parametric mixed-effect models with shape-restricted Bernstein polynomials.

We develop a Bayesian estimation method to non-parametric mixed-effect models under shape-constrains. The approach uses a hierarchical Bayesian framework and characterizations of shape-constrained Bernstein polynomials (BPs). We employ Markov chain Monte Carlo methods for model fitting, using a truncated normal distribution as the prior for the coefficients of BPs to ensure the desired shape constraints. The small sample properties of the Bayesian shape-constrained estimators across a range of functions are provided via simulation studies. Two real data analysis are given to illustrate the application of the proposed method.