Left truncation in linked data: A practical guide to understanding left truncation and applying it using SAS and R

Time-to-event data such as time to death are broadly used in medical research and drug development to understand the efficacy of a therapeutic. For time-to-event data, right censoring (data only observed up to a certain point of time) is common and easy to recognize. Methods that use right censored data, such as the Kaplan–Meier estimator and the Cox proportional hazard model, are well established. Time-to-event data can also be left truncated, which arises when patients are excluded from the sample because their events occur before a specific milestone, potentially resulting in an immortal time bias. For example, in a study evaluating the association between biomarker status and overall survival, patients who did not live long enough to receive a genomic test were not observed in the study. Left truncation causes selection bias and often leads to an overestimate of survival time. In this tutorial, we used a nationwide electronic health record-derived de-identified database to demonstrate how to analyze left truncated and right censored data without bias using example code from SAS and R.     

Pharmacovigilance in Clinical Trials: Current Practice and Challenges

In view of the MENA increasing participation in multinational trials and the increasing number of national/regional trials, this article explores potential areas of pharmacovigilance, requiring reform and provides recommendations for building a robust safety reporting system. Regulatory silence on expedited reporting requirements creates confusion for local sites that are part of multinational trials. Not allowing waiver for serious adverse events that are protocol specified or are study endpoints, along with lack of emphasis on causality as reporting criteria, adds substantial burden of uninformative cases for regulatory review. Despite global focus on Development Safety Update Report, local regulators are not yet insistent on real-time update of a drug’s cumulative safety profile. Issues like reporting requirements for generic trials, pregnancy reporting and lenient timeline for death/life-threatening events need attention. Finally, the need to formulate an all-encompassing local pharmacovigilance guideline, in sync with global practice cannot be overemphasized.     

Max‐infinitely divisible models and inference for spatial extremes

For many environmental processes, recent studies have shown that the dependence strength is decreasing when quantile levels increase. This implies that the popular max‐stable models are inadequate to capture the rate of joint tail decay, and to estimate joint extremal probabilities beyond observed levels. We here develop a more flexible modeling framework based on the class of max‐infinitely divisible processes, which extend max‐stable processes while retaining dependence properties that are natural for maxima. We propose two parametric constructions for max‐infinitely divisible models, which relax the max‐stability property but remain close to some popular max‐stable models obtained as special cases. The first model considers maxima over a finite, random number of independent observations, while the second model generalizes the spectral representation of max‐stable processes. Inference is performed using a pairwise likelihood. We illustrate the benefits of our new modeling framework on Dutch wind gust maxima calculated over different time units. Results strongly suggest that our proposed models outperform other natural models, such as the Student‐t copula process and its max‐stable limit, even for large block sizes.     

Principal stratum strategy: Potential role in drug development

A randomized trial allows estimation of the causal effect of an intervention compared to a control in the overall population and in subpopulations defined by baseline characteristics. Often, however, clinical questions also arise regarding the treatment effect in subpopulations of patients, which would experience clinical or disease related events post-randomization. Events that occur after treatment initiation and potentially affect the interpretation or the existence of the measurements are called intercurrent events in the ICH E9(R1) guideline. If the intercurrent event is a consequence of treatment, randomization alone is no longer sufficient to meaningfully estimate the treatment effect. Analyses comparing the subgroups of patients without the intercurrent events for intervention and control will not estimate a causal effect. This is well known, but post-hoc analyses of this kind are commonly performed in drug development. An alternative approach is the principal stratum strategy, which classifies subjects according to their potential occurrence of an intercurrent event on both study arms. We illustrate with examples that questions formulated through principal strata occur naturally in drug development and argue that approaching these questions with the ICH E9(R1) estimand framework has the potential to lead to more transparent assumptions as well as more adequate analyses and conclusions. In addition, we provide an overview of assumptions required for estimation of effects in principal strata. Most of these assumptions are unverifiable and should hence be based on solid scientific understanding. Sensitivity analyses are needed to assess robustness of conclusions.     

论网络语境下当代青年的爱国主义教育

随着互联网时代的到来,网络语境下当代青年的爱国主义教育缺失日渐凸显,在部分青年群体中存在潜在的网络极端化爱国主义舆论倾向。分析发现:从问题的出现或偶然性事件的刺激到多数个体发表的评价性意见,再到群体极化现象的出现,最终极端化爱国主义舆论在互联网上广泛传播是网络极端化爱国主义舆论的基本形成机制。如此网络极端化爱国主义舆论不可避免地对国家、社会、制度和青年自身产生一系列的危害。网络语境下当代青年的爱国主义引导是新时期爱国主义教育的重要课题:应该正视青年的爱国情感,加强爱国主义教育;立足祖国长远利益,培养青年的理性爱国情感;增强舆论引导,减少青年非理性情绪的蔓延,对青年的网络极端化爱国主义舆论进行积极有效的引导。     

Local press meets transnational activism: news dynamics in an anti‐WTO protest

Transnational protests often involve a cross‐cultural encounter between “foreign” protesters and the local media and public, whose repertoires of contentious practices and discourses may differ. Examining how transnational and local actors interact in these events is one way to understand the significance and impact of transnational activism. At the same time, local media coverage of transnational protests can also be analyzed as such a cross‐cultural encounter. Following these premises, this article examines Hong Kong media coverage of the transnational protests during the World Trade Organization's 6th Ministerial Conference, which was held in the city in December 2005. The analysis focuses particularly on how this non‐routine news event provided the conditions for a more reflective interactive dynamics between the protesters and journalists, which contributed to emergence of media discourses negotiating and redefining the existing cultural understanding of protest actions. However, the case study also shows the limits regarding how far the redefinition and negotiation can go. Theoretical implications of the analysis are discussed.     

Estimation of the parameter of a dynamically selected population for two subclasses of the exponential family

We introduce the problem of estimation of the parameters of a dynamically selected population in an infinite sequence of random variables and provide its application in the statistical inference based on record values from a non stationary scheme. We develop unbiased estimation of the parameters of the dynamically selected population and evaluate the risk of the estimators. We provide comparisons with natural estimators and obtain asymptotic results. Finally, we illustrate the applicability of the results using real data.     

Bayesian adaptive dose‐escalation designs for simultaneously estimating the optimal and maximum safe dose based on safety and efficacy

The main purpose of dose‐escalation trials is to identify the dose(s) that is/are safe and efficacious for further investigations in later studies. In this paper, we introduce dose‐escalation designs that incorporate both the dose‐limiting events and dose‐limiting toxicities (DLTs) and indicative responses of efficacy into the procedure. A flexible nonparametric model is used for modelling the continuous efficacy responses while a logistic model is used for the binary DLTs. Escalation decisions are based on the combination of the probabilities of DLTs and expected efficacy through a gain function. On the basis of this setup, we then introduce 2 types of Bayesian adaptive dose‐escalation strategies. The first type of procedures, called “single objective,” aims to identify and recommend a single dose, either the maximum tolerated dose, the highest dose that is considered as safe, or the optimal dose, a safe dose that gives optimum benefit risk. The second type, called “dual objective,” aims to jointly estimate both the maximum tolerated dose and the optimal dose accurately. The recommended doses obtained under these dose‐escalation procedures provide information about the safety and efficacy profile of the novel drug to facilitate later studies. We evaluate different strategies via simulations based on an example constructed from a real trial on patients with type 2 diabetes, and the use of stopping rules is assessed. We find that the nonparametric model estimates the efficacy responses well for different underlying true shapes. The dual‐objective designs give better results in terms of identifying the 2 real target doses compared to the single‐objective designs.     

当前中国群体性事件的政治学思考——基于亨廷顿政治稳定理论的视角

亨廷顿政治稳定理论认为,现代性孕育着稳定,而现代化却滋生着动乱.为了实现现代化进程中的政治稳定,要建设强大政府,保持政治参与水平与政治制度化的平衡发展.该理论对于理解当前中国群体性事件,解决当前中国发展与稳定问题具有借鉴意义:必须强化执政党的执政力能力建设,树立政治权威,建设有能力推动经济持续较快发展、促进社会公平正义、制衡政治参与需求、化解社会危机的强大政府.同时,要积极推进政治体制改革,使群众政治参与和政治制度化在更高水平上保持相对均衡、和谐.     

1954—1956年间的《长生殿》讨论：爱情主题说及其批判

建国以来开展的思想运动和新文艺观的确立,对开始于1954年的《长生殿》讨论产生了深刻影响。而讨论伊始即对尚处于萌芽状态的“爱情主题说”进行批判,并将其提升到“资产阶级思想”的高度,则多少偏离了学术讨论的常态。从这个角度看,1954—1956间的《长生殿》讨论虽然不能说已具有了“思想事件”的性质,但却透露了向这种性质演变的迹象。