Adaptive phase I/II clinical trials for drug combination assessment in oncology using the outcomes of each cycle

Many new anticancer agents can be combined with existing drugs, as combining a number of drugs may be expected to have a better therapeutic effect than monotherapy owing to synergistic effects. Furthermore, to drive drug development and to reduce the associated cost, there has been a growing tendency to combine these as phase I/II trials. With respect to phase I/II oncology trials for the assessment of dose combinations, in the existing methodologies in which efficacy based on tumor response and safety based on toxicity are modeled as binary outcomes, it is not possible to enroll and treat the next cohort of patients unless the best overall response has been determined in the current cohort. Thus, the trial duration might be potentially extended to an unacceptable degree. In this study, we proposed a method that randomizes the next cohort of patients in the phase II part to the dose combination based on the estimated response rate using all the available observed data upon determination of the overall response in the current cohort. We compared the proposed method to the existing method using simulation studies. These demonstrated that the percentage of optimal dose combinations selected in the proposed method is not less than that in the existing method and that the trial duration in the proposed method is shortened compared to that in the existing method. The proposed method meets both ethical and financial requirements, and we believe it has the potential to contribute to expedite drug development.     

‘There’s a lot of places I’d like to go and things I’d like to do’: the daily living experiences of adults with mild to moderate intellectual disabilities during a time of personalised social care reform in the United Kingdom

Adult social care services in the United Kingdom have undergone a period of transformation over recent years, characterised by a drive towards personalised care. Concurrently, social care budgets have been significantly reduced. This study aimed to explore the daily living experiences of adults with mild/moderate intellectual disabilities, who are at risk of no longer meeting eligibility criteria for statutory support. Focus group discussions, which included both people with intellectual disabilities and support workers, were analysed thematically. Two broad themes are presented: independence and agency; and social capital and well-being. While some participants echoed ideas central to the personalisation narrative, a number of contextual barriers to achieving greater independence and agency were discussed. Moreover, greater independence was not a desired goal for all participants. The findings highlight the potential mismatch between personalised social care, as delivered within significant budget constraints, and the needs of adults with intellectual disabilities.     

Personality profiles of factitious disorder imposed by mothers: A comparative analysis

Factitious Disorder Imposed by Another (FDIA) can be difficult to expeditiously identify. Understanding personality characteristics of FDIA perpetrators via psychological assessment may decrease the time between initial abuse and identification of FDIA. Personality characteristics of FDIA mother-perpetrators were examined through a comparative analysis of MMPI-2 profiles. It was predicted that mother-perpetrators would have significantly higher overall profile elevations on the MMPI-2 and elevations on specific clinical scales than a comparative control group. Results indicated that mother-perpetrators displayed significantly higher, elevations on the Psychasthenia (Pt) and Schizophrenia (Sc) scales and a trend toward significantly higher elevation on the Psychopathic Deviate (Pd) scale than the control group. These findings, along with the demographic information obtained, establish a preliminary foundation for understanding an overall profile of mother-perpetrators.     

Notes on testing carry-over effects in continuous data under an incomplete block crossover design

We consider hypothesis testing and estimation of carry-over effects in continuous data under an incomplete block crossover design when comparing two experimental treatments with a placebo. We develop procedures for testing differential carry-over effects based on the weighted-least-squares (WLS) method. We apply Monte Carlo simulations to evaluate the performance of these test procedures in a variety of situations. We use the data regarding the forced expiratory volume in one second (FEV₁) readings taken from a double-blind crossover trial comparing two different doses of formoterol with a placebo to illustrate the use of test procedures proposed here.     

Bootstrap methods for multivariate hypothesis testing

The nonparametric and parametric bootstrap methods for multivariate hypothesis testing are developed. They are used to approximate the null distribution of the test statistics proposed by Duchesne and Francq (2015 Duchesne, P., Francq, C. (2015). Multivariate hypothesis testing using generalized and {2}-inverses—with applications. Statistics 49:475–496.[Taylor &; Francis Online], [Web of Science ®] , [Google Scholar]), resulting in bootstrap testing procedures. In the problem of testing for the mean vector of a multivariate distribution, the asymptotic validity of the bootstrap methods is proved. The finite sample performance of the new solutions is demonstrated by means of Monte Carlo simulation studies. They indicate that for small-sample size, the bootstrap tests provide a better finite sample properties than the asymptotic tests considered by Duchesne and Francq (2015 Duchesne, P., Francq, C. (2015). Multivariate hypothesis testing using generalized and {2}-inverses—with applications. Statistics 49:475–496.[Taylor &; Francis Online], [Web of Science ®] , [Google Scholar]).     

Bootstrap approach to test the homogeneity of order restricted mean vectors when the covariance matrices are unknown

Testing homogeneity of multivariate normal mean vectors under an order restriction when the covariance matrices are unknown, arbitrary positive definite and unequal are considered. This problem of testing has been studied to some extent, for example, by Kulatunga and Sasabuchi (1984 Kulatunga, D. D. S., Sasabuchi, S. (1984). A test of homogeneity of mean vectors against multivariate isotonic alternatives. Mem Fac Sci, Kyushu Univ Ser A Mathemat 38:151–161. [Google Scholar]) when the covariance matrices are known and also Sasabuchi et al. (2003 Sasabuchi, S., Tanaka, K., Tsukamodo, T. (2003). Testing homogeneity of multivariate normal mean vectors under an order restriction when the covariance matrices are common but unknown. Annals of Statistics. 31(5):1517–1536.[Web of Science ®] , [Google Scholar]) and Sasabuchi (2007 Sasabuchi, S. (2007). More powerful tests for homogeneity of multivariate normal mean vectors under an order restriction. Sankhya 69(4):700–716. [Google Scholar]) when the covariance matrices are unknown but common. In this paper, a test statistic is proposed and because of the main advantage of the bootstrap test is that it avoids the derivation of the complex null distribution analytically, a bootstrap test statistic is derived and since the proposed test statistic is location invariance the bootstrap p-value defined logical and some steps are presented to estimate it. Our numerical studies via Monte Carlo simulation show that the proposed bootstrap test can correctly control the type I error rates. The power of the test for some of the p-dimensional normal distributions is computed by Monte Carlo simulation. Also, the null distribution of test statistic is estimated using kernel density. Finally, the bootstrap test is illustrated using a real data.     

Convergence rate of wavelet density estimator with data missing randomly when covariables are present

In this article, we study global L₂ error of non linear wavelet estimator of density in the Besov space B^s_pq for missing data model when covariables are present and prove that the estimator can achieve the optimal rate of convergence, which is similar to the result studied by Donoho et al. (1996) Donoho, D.L., Johnstone, I.M., Kerkyacharian, G., Picard, D. (1996). Density estimation by wavelet thresholding. Ann. Stat. 24:508–539.[Crossref], [Web of Science ®] , [Google Scholar] in complete independent data case with term-by-term thresholding of the empirical wavelet coefficients. Finite-sample behavior of the proposed estimator is explored via simulations.     

P2P 网络借贷研究进展及中国问题研究展望

P2P ( 个人对个人) 网络借贷是指通过网络借贷平台,在全球范围内实现个人与个人或小微企业间的小额信用借贷交易． P2P 网络借贷作为全新的互联网金融服务受到商业界的高度关注,而且发展成为学术研究的国际前沿领域． 对 P2P 网络借贷相关研究文献进行了综述,具体从影响借贷交易的信息因素、羊群效应以及社交网络等 3 个方面分析了该领域研究的现状和发展脉络． 因为中国已超越美国成为全球最大的 P2P 网络借贷交易市场,所以结合中国的具体情境和问题,提出了未来研究工作的展望．     

《儿女英雄传》中的副词“都”及其语法化

《儿女英雄传》是《红楼梦》通向现代北京话的中途站,通过它可以了解汉语在19世纪中期的基本面貌。当时,副词“都”已具备表示范围和表示语气等用法,其语气副词用法中有一类兼表已然义。根据《儿女英雄传》中反映的语言事实和语法化的一般规律,副词“都”的语法化路径应该为“范围副词→语气副词→兼表已然义的语气副词”。