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.     

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.     

论西夏的司法制度

西夏的行政、军事机关,一般都兼有案件审判和督察复核职责。司法诉讼主要为刑事诉讼,即使民事案件,也是用刑事判断。对人犯的逮捕只需长官的指令,而不履行法律手续。法律上只有对逮捕人的督察,防其奸伪、贪纵、暴掠以及无故杀伤人犯,人犯拒捕反抗格杀勿论。     

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.     

Improved randomized response in additive scrambling models

Randomized response models deal with stigmatizing variables appearing in health surveys. Additive and subtractive scrambling in split sample and double response yield unbiased mean and sensitivity estimators of high precision. The split sample method is protective of privacy. The double response method is as protective only conditionally. To achieve the maximum efficiency, the scrambling variables must be similar to each other and the probability of obtaining a true response must be as large as possible. The randomized response procedures yield more efficient estimates of the average total number of classes missed by university students.     

Estimates of subgroup treatment effects in overall nonsignificant trials: To what extent should we believe in them?

In drug development, it sometimes occurs that a new drug does not demonstrate effectiveness for the full study population but appears to be beneficial in a relevant subgroup. In case the subgroup of interest was not part of a confirmatory testing strategy, the inflation of the overall type I error is substantial and therefore such a subgroup analysis finding can only be seen as exploratory at best. To support such exploratory findings, an appropriate replication of the subgroup finding should be undertaken in a new trial. We should, however, be reasonably confident in the observed treatment effect size to be able to use this estimate in a replication trial in the subpopulation of interest. We were therefore interested in evaluating the bias of the estimate of the subgroup treatment effect, after selection based on significance for the subgroup in an overall “failed” trial. Different scenarios, involving continuous as well as dichotomous outcomes, were investigated via simulation studies. It is shown that the bias associated with subgroup findings in overall nonsignificant clinical trials is on average large and varies substantially across plausible scenarios. This renders the subgroup treatment estimate from the original trial of limited value to design the replication trial. An empirical Bayesian shrinkage method is suggested to minimize this overestimation. The proposed estimator appears to offer either a good or a conservative correction to the observed subgroup treatment effect hence provides a more reliable subgroup treatment effect estimate for adequate planning of future studies.     

A Bayesian sequential design with binary outcome

Several researchers have proposed solutions to control type I error rate in sequential designs. The use of Bayesian sequential design becomes more common; however, these designs are subject to inflation of the type I error rate. We propose a Bayesian sequential design for binary outcome using an alpha‐spending function to control the overall type I error rate. Algorithms are presented for calculating critical values and power for the proposed designs. We also propose a new stopping rule for futility. Sensitivity analysis is implemented for assessing the effects of varying the parameters of the prior distribution and maximum total sample size on critical values. Alpha‐spending functions are compared using power and actual sample size through simulations. Further simulations show that, when total sample size is fixed, the proposed design has greater power than the traditional Bayesian sequential design, which sets equal stopping bounds at all interim analyses. We also find that the proposed design with the new stopping for futility rule results in greater power and can stop earlier with a smaller actual sample size, compared with the traditional stopping rule for futility when all other conditions are held constant. Finally, we apply the proposed method to a real data set and compare the results with traditional designs.     

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.     

Birth preference in women undergoing treatment for childbirth fear: A randomised controlled trial

Background

Childbirth fear is the most common underlying reason for requesting a caesarean section without medical reason. The aim of this randomised controlled study was to investigate birth preferences in women undergoing treatment for childbirth fear, and to investigate birth experience and satisfaction with the allocated treatment.

Program Evaluation and Causal Inference With High‐Dimensional Data

In this paper, we provide efficient estimators and honest confidence bands for a variety of treatment effects including local average (LATE) and local quantile treatment effects (LQTE) in data‐rich environments. We can handle very many control variables, endogenous receipt of treatment, heterogeneous treatment effects, and function‐valued outcomes. Our framework covers the special case of exogenous receipt of treatment, either conditional on controls or unconditionally as in randomized control trials. In the latter case, our approach produces efficient estimators and honest bands for (functional) average treatment effects (ATE) and quantile treatment effects (QTE). To make informative inference possible, we assume that key reduced‐form predictive relationships are approximately sparse. This assumption allows the use of regularization and selection methods to estimate those relations, and we provide methods for post‐regularization and post‐selection inference that are uniformly valid (honest) across a wide range of models. We show that a key ingredient enabling honest inference is the use of orthogonal or doubly robust moment conditions in estimating certain reduced‐form functional parameters. We illustrate the use of the proposed methods with an application to estimating the effect of 401(k) eligibility and participation on accumulated assets. The results on program evaluation are obtained as a consequence of more general results on honest inference in a general moment‐condition framework, which arises from structural equation models in econometrics. Here, too, the crucial ingredient is the use of orthogonal moment conditions, which can be constructed from the initial moment conditions. We provide results on honest inference for (function‐valued) parameters within this general framework where any high‐quality, machine learning methods (e.g., boosted trees, deep neural networks, random forest, and their aggregated and hybrid versions) can be used to learn the nonparametric/high‐dimensional components of the model. These include a number of supporting auxiliary results that are of major independent interest: namely, we (1) prove uniform validity of a multiplier bootstrap, (2) offer a uniformly valid functional delta method, and (3) provide results for sparsity‐based estimation of regression functions for function‐valued outcomes.