A simulation study of methods for selecting subgroup‐specific doses in phase 1 trials

Patient heterogeneity may complicate dose‐finding in phase 1 clinical trials if the dose‐toxicity curves differ between subgroups. Conducting separate trials within subgroups may lead to infeasibly small sample sizes in subgroups having low prevalence. Alternatively,it is not obvious how to conduct a single trial while accounting for heterogeneity. To address this problem,we consider a generalization of the continual reassessment method on the basis of a hierarchical Bayesian dose‐toxicity model that borrows strength between subgroups under the assumption that the subgroups are exchangeable. We evaluate a design using this model that includes subgroup‐specific dose selection and safety rules. A simulation study is presented that includes comparison of this method to 3 alternative approaches,on the basis of nonhierarchical models,that make different types of assumptions about within‐subgroup dose‐toxicity curves. The simulations show that the hierarchical model‐based method is recommended in settings where the dose‐toxicity curves are exchangeable between subgroups. We present practical guidelines for application and provide computer programs for trial simulation and conduct.     

Control‐based imputation for sensitivity analyses in informative censoring for recurrent event data

In clinical trials, missing data commonly arise through nonadherence to the randomized treatment or to study procedure. For trials in which recurrent event endpoints are of interests, conventional analyses using the proportional intensity model or the count model assume that the data are missing at random, which cannot be tested using the observed data alone. Thus, sensitivity analyses are recommended. We implement the control‐based multiple imputation as sensitivity analyses for the recurrent event data. We model the recurrent event using a piecewise exponential proportional intensity model with frailty and sample the parameters from the posterior distribution. We impute the number of events after dropped out and correct the variance estimation using a bootstrap procedure. We apply the method to an application of sitagliptin study.     

Colorful Disclosures: Identifying Identity-Based Differences and Enhancing Critical Consciousness in Supervision

ABSTRACT

Managing microaggressions and marginalizing experiences while negotiating the ongoing oppression that occurs in micro, mezzo, and macro settings can be particularly challenging for clinicians of color. Thus, supervision with clinicians of color must include affirmation, empowerment, and exploration of the intracultural/intercultural dynamics inherent in the treatment-providing process and clinical supervision. Through case studies, autoethnographic studies of our supervision experiences, and interviews with supervisors and supervisees, we reflect on how axes of identity, including race, power, and privilege, inform practitioners’ clinical lenses and affect their vulnerability in treatment and the clinical supervision dyad. Special attention is placed on the clinical supervisor–clinician–client triad (the triple process) and the interpersonal dynamics of cultural sensitivity, cultural humility, and authentic responsiveness that supervisors aim to model and cultivate in the supervisory relationship. In addition to sustaining clinical growth for clinicians of color, adding this level of complexity to supervision supports equity in direct clinical practice, enhancing efficacy outcomes for clients and communities. Recommendations and pedagogical strategies are offered to support supervisors in initiating difficult dialogues and shifting the paradigm to promote this transformational perspective.     

Generalized Augmentation to Control the False Discovery Exceedance in Multiple Testing

Abstract.  A new multiple testing procedure, the generalized augmentation procedure (GAUGE), is introduced. The procedure is shown to control the false discovery exceedance and to be competitive in terms of power. It is also shown how to apply the idea of GAUGE to achieve control of other error measures. Extensions to dependence are discussed, together with a modification valid under arbitrary dependence. We present an application to an original study on prostate cancer and on a benchmark data set on colon cancer.     

刑事和解在审判阶段的制度构建

刑事和解系宽严相济刑事政策在诉讼中的具体体现,基于其特殊的价值,我国检察机关开始进行试点与探索,而对于具有普遍意义的刑事和解在审判阶段的应用并没有推开.自诉案件和刑附民案件程序的启动本身就决定于被害人,这类案件的和解并非普遍意义上的刑事和解.就刑事和解在审判阶段应用的价值、程序设置的主要问题进行评析,并在此基础上对程序设置的完善提出建议,以适用于审判实践.认为审判阶段进行刑事和解不仅提升了被害人的诉讼地位,同时,在一定程度上促使刑事审判的功能发生变化,与过去靠"打"来稳定社会治安的作用完全不一样,能使司法活动取得良好的社会效益,实现从有害正义到无害正义的进步,有利于社会和谐的构建.     

Unifying CRM and EWOC designs for phase I cancer clinical trials

The main goal of phase I cancer clinical trials is to determine the highest dose of a new therapy associated with an acceptable level of toxicity for the use in a subsequent phase II trial. The continual reassessment method (CRM) [O’Quigley, J., Pepe, M., Fisher, L., 1990. Continual reassessment method: a practical design for phase I clinical trials in cancer. Biometrics 46, 33–48] and escalation with overdose control (EWOC) [Babb, J., Rogatko, A., Zacks, S., 1998. Cancer phase I clinical trials: efficient dose escalation with overdose control. Statist. Med. 17 (10), 1103–1120] are two model-based designs used for phase I cancer clinical trials. A few modifications of the (original) CRM and EWOC have been made by many authors. In this paper, we show how CRM and EWOC can be unified and present a hybrid design. We study the characteristics of the approach of the hybrid design. The comparisons of the three designs (CRM, EWOC, and the hybrid design) are presented by convergence rates and overdose proportions. The simulation results show that the hybrid design generally has faster convergence rates than EWOC and smaller overdose proportions than CRM, especially when the true maximum tolerated dose (MTD) is above the mid-level of the dose range considered. The performance of these three designs is also evaluated in terms of sensitivity to outliers.     

宋代与中国古代取保候审制度的形成

取保候审古称责保知在,是刑事司法中普遍采用的限制人身自由的强制方法,是借助于保证人的信誉约束诉讼参加人,以配合司法活动的诉讼保障措施.在中国古代史籍中,取保候审于北齐初见使用,<唐律疏议>亦有条文记栽,两宋时期形成制度.与前代相比,宋代取保候审的规定更加具体,其适用条件的详备程度已达到当今立法水平,甚至有些规定今世未能企及.宋代取保候审制度的完善,可为宋代司法制度发达的又一力证.     

Doubly adaptive biased coin designs with heterogeneous responses

Doubly adaptive biased coin design (DBCD) is an important family of response-adaptive randomization procedures for clinical trials. It uses sequentially updated estimation to skew the allocation probability to favor the treatment that has performed better thus far. An important assumption for the DBCD is the homogeneity assumption for the patient responses. However, this assumption may be violated in many sequential experiments. Here we prove the robustness of the DBCD against certain time trends in patient responses. Strong consistency and asymptotic normality of the design are obtained under some widely satisfied conditions. Also, we propose a general weighted likelihood method to reduce the bias caused by the heterogeneity in the inference after a trial. Some numerical studies are also presented to illustrate the finite sample properties of DBCD.     

A simple two-stage design for quantitative responses with application to a study in diabetic neuropathic pain

Two-stage designs offer substantial advantages for early phase II studies. The interim analysis following the first stage allows the study to be stopped for futility, or more positively, it might lead to early progression to the trials needed for late phase II and phase III. If the study is to continue to its second stage, then there is an opportunity for a revision of the total sample size. Two-stage designs have been implemented widely in oncology studies in which there is a single treatment arm and patient responses are binary. In this paper the case of two-arm comparative studies in which responses are quantitative is considered. This setting is common in therapeutic areas other than oncology. It will be assumed that observations are normally distributed, but that there is some doubt concerning their standard deviation, motivating the need for sample size review. The work reported has been motivated by a study in diabetic neuropathic pain, and the development of the design for that trial is described in detail.     

Fast robust feature screening for ultrahigh-dimensional varying coefficient models

In this paper, we propose a new partial correlation, the so-called composite quantile partial correlation, to measure the relationship of two variables given other variables. We further use this correlation to screen variables in ultrahigh-dimensional varying coefficient models. Our proposed method is fast and robust against outliers and can be efficiently employed in both single index variable and multiple index variable varying coefficient models. Numerical results indicate the preference of our proposed method.