Development of predictive signatures for treatment selection in precision medicine with survival outcomes

For survival endpoints in subgroup selection, a score conversion model is often used to convert the set of biomarkers for each patient into a univariate score and using the median of the univariate scores to divide the patients into biomarker‐positive and biomarker‐negative subgroups. However, this may lead to bias in patient subgroup identification regarding the 2 issues: (1) treatment is equally effective for all patients and/or there is no subgroup difference; (2) the median value of the univariate scores as a cutoff may be inappropriate if the sizes of the 2 subgroups are differ substantially. We utilize a univariate composite score method to convert the set of patient's candidate biomarkers to a univariate response score. We propose applying the likelihood ratio test (LRT) to assess homogeneity of the sampled patients to address the first issue. In the context of identification of the subgroup of responders in adaptive design to demonstrate improvement of treatment efficacy (adaptive power), we suggest that subgroup selection is carried out if the LRT is significant. For the second issue, we utilize a likelihood‐based change‐point algorithm to find an optimal cutoff. Our simulation study shows that type I error generally is controlled, while the overall adaptive power to detect treatment effects sacrifices approximately 4.5% for the simulation designs considered by performing the LRT; furthermore, the change‐point algorithm outperforms the median cutoff considerably when the subgroup sizes differ substantially.     

Response‐adaptive designs for binary responses: How to offer patient benefit while being robust to time trends?

Response‐adaptive randomisation (RAR) can considerably improve the chances of a successful treatment outcome for patients in a clinical trial by skewing the allocation probability towards better performing treatments as data accumulates. There is considerable interest in using RAR designs in drug development for rare diseases, where traditional designs are not either feasible or ethically questionable. In this paper, we discuss and address a major criticism levelled at RAR: namely, type I error inflation due to an unknown time trend over the course of the trial. The most common cause of this phenomenon is changes in the characteristics of recruited patients—referred to as patient drift. This is a realistic concern for clinical trials in rare diseases due to their lengthly accrual rate. We compute the type I error inflation as a function of the time trend magnitude to determine in which contexts the problem is most exacerbated. We then assess the ability of different correction methods to preserve type I error in these contexts and their performance in terms of other operating characteristics, including patient benefit and power. We make recommendations as to which correction methods are most suitable in the rare disease context for several RAR rules, differentiating between the 2‐armed and the multi‐armed case. We further propose a RAR design for multi‐armed clinical trials, which is computationally efficient and robust to several time trends considered.     

Double shrinkage estimators for large sparse covariance matrices

Covariance matrices play an important role in many multivariate techniques and hence a good covariance estimation is crucial in this kind of analysis. In many applications a sparse covariance matrix is expected due to the nature of the data or for simple interpretation. Hard thresholding, soft thresholding, and generalized thresholding were therefore developed to this end. However, these estimators do not always yield well-conditioned covariance estimates. To have sparse and well-conditioned estimates, we propose doubly shrinkage estimators: shrinking small covariances towards zero and then shrinking covariance matrix towards a diagonal matrix. Additionally, a richness index is defined to evaluate how rich a covariance matrix is. According to our simulations, the richness index serves as a good indicator to choose relevant covariance estimator.     

Adaptive designs for single‐arm phase II trials in oncology

Clinical phase II trials in oncology are conducted to determine whether the activity of a new anticancer treatment is promising enough to merit further investigation. Two‐stage designs are commonly used for this situation to allow for early termination. Designs proposed in the literature so far have the common drawback that the sample sizes for the two stages have to be specified in the protocol and have to be adhered to strictly during the course of the trial. As a consequence, designs that allow a higher extent of flexibility are desirable. In this article, we propose a new adaptive method that allows an arbitrary modification of the sample size of the second stage using the results of the interim analysis or external information while controlling the type I error rate. If the sample size is not changed during the trial, the proposed design shows very similar characteristics to the optimal two‐stage design proposed by Chang et al. (Biometrics 1987; 43:865–874). However, the new design allows the use of mid‐course information for the planning of the second stage, thus meeting practical requirements when performing clinical phase II trials in oncology. Copyright © 2012 John Wiley & Sons, Ltd.     

Spectral Estimation of Covolatility from Noisy Observations Using Local Weights

We propose localized spectral estimators for the quadratic covariation and the spot covolatility of diffusion processes, which are observed discretely with additive observation noise. The appropriate estimation for time‐varying volatilities is based on an asymptotic equivalence of the underlying statistical model to a white‐noise model with correlation and volatility processes being constant over small time intervals. The asymptotic equivalence of the continuous‐time and discrete‐time experiments is proved by a construction with linear interpolation in one direction and local means for the other. The new estimator outperforms earlier non‐parametric methods in the literature for the considered model. We investigate its finite sample size characteristics in simulations and draw a comparison between various proposed methods.     

落实最严格水资源管理的适应性政策选择研究

由于最严格水资源管理存在着水资源供给、用水总量、用水关系和用水管理等诸多不确定,采用可操作的实施就成为落实最严格水资源管理的关键。研究发现:(1)通过最严格水资源管理的压力—状态—响应(PSR)分析可知,最严格水资源管理的实施路径与水资源适应性管理在目标理念、工作途径、核心问题和保障需求方面有着一致性;(2)水资源适应性政策选择能够促进最严格水资源管理的有效落实,为此给出了适应性政策选择程序,为最严格水资源管理落实的政策选择提供参考依据。     

金融创新背景下个体网络借贷犯罪行为的认定

个体网络借贷发展迅速,但监管缺失导致了该行业的畸形发展,刑事风险攀升。《关于促进互联网金融健康发展的指导意见》首次对个体网络借贷做出规定,意义重大。个体网络借贷中债权转让和平台担保两种模式游走于罪与非罪的模糊地带,在相关立法和司法解释出台前,对这两种平台经营模式,刑法应该保持谦抑,谨慎介入。     

Distribution of the two‐sample t‐test statistic following blinded sample size re‐estimation

We consider the blinded sample size re‐estimation based on the simple one‐sample variance estimator at an interim analysis. We characterize the exact distribution of the standard two‐sample t‐test statistic at the final analysis. We describe a simulation algorithm for the evaluation of the probability of rejecting the null hypothesis at given treatment effect. We compare the blinded sample size re‐estimation method with two unblinded methods with respect to the empirical type I error, the empirical power, and the empirical distribution of the standard deviation estimator and final sample size. We characterize the type I error inflation across the range of standardized non‐inferiority margin for non‐inferiority trials, and derive the adjusted significance level to ensure type I error control for given sample size of the internal pilot study. We show that the adjusted significance level increases as the sample size of the internal pilot study increases. Copyright © 2016 John Wiley & Sons, Ltd.     

稳压电源的自适应去火弧技术

针对传统基于继电器控制的稳压电源在带负载工作时,档位切换常常伴随火弧现象的问题,设计了一种可广泛 应用于此类稳压电源上的自适应去火弧技术：使用光耦和多级运放完成对零点和电压电流的采样;基于单片机的10量, 实现对继电器的驱动和控制;基于RCC自激震荡原理为系统提供稳定电源;设计了稳压器的完整软件系统程序,并在软 件中应用自适应去火弧算法。实验结果表明：自适应去火弧技术,能够有效地规避火弧现象的产生,并能够根据条件作 出调整。采用自适应去火弧技术的稳压系统达到了设计目标,延长了系统工作寿命。