Simulated maximum likelihood estimation in joint models for multiple longitudinal markers and recurrent events of multiple types,in the presence of a terminal event

In medical studies we are often confronted with complex longitudinal data. During the follow-up period, which can be ended prematurely by a terminal event (e.g. death), a subject can experience recurrent events of multiple types. In addition, we collect repeated measurements from multiple markers. An adverse health status, represented by ‘bad’ marker values and an abnormal number of recurrent events, is often associated with the risk of experiencing the terminal event. In this situation, the missingness of the data is not at random and, to avoid bias, it is necessary to model all data simultaneously using a joint model. The correlations between the repeated observations of a marker or an event type within an individual are captured by normally distributed random effects. Because the joint likelihood contains an analytically intractable integral, Bayesian approaches or quadrature approximation techniques are necessary to evaluate the likelihood. However, when the number of recurrent event types and markers is large, the dimensionality of the integral is high and these methods are too computationally expensive. As an alternative, we propose a simulated maximum-likelihood approach based on quasi-Monte Carlo integration to evaluate the likelihood of joint models with multiple recurrent event types and markers.     

A meta-analytic framework to adjust for bias in external control studies

While randomized controlled trials (RCTs) are the gold standard for estimating treatment effects in medical research, there is increasing use of and interest in using real-world data for drug development. One such use case is the construction of external control arms for evaluation of efficacy in single-arm trials, particularly in cases where randomization is either infeasible or unethical. However, it is well known that treated patients in non-randomized studies may not be comparable to control patients—on either measured or unmeasured variables—and that the underlying population differences between the two groups may result in biased treatment effect estimates as well as increased variability in estimation. To address these challenges for analyses of time-to-event outcomes, we developed a meta-analytic framework that uses historical reference studies to adjust a log hazard ratio estimate in a new external control study for its additional bias and variability. The set of historical studies is formed by constructing external control arms for historical RCTs, and a meta-analysis compares the trial controls to the external control arms. Importantly, a prospective external control study can be performed independently of the meta-analysis using standard causal inference techniques for observational data. We illustrate our approach with a simulation study and an empirical example based on reference studies for advanced non-small cell lung cancer. In our empirical analysis, external control patients had lower survival than trial controls (hazard ratio: 0.907), but our methodology is able to correct for this bias. An implementation of our approach is available in the R package ecmeta .     

弹性流体动力润滑牵曳力的数值分析及流变模型评价

采用Ｎｅｗｔｏｎ－Ｒａｐｈｓｏｎ方法求解弹性流体动力润滑（ｅｌａｓｔｏｈｙｄｒｏｄｙｎａｍｉｃｌｕｂｒｉｃａｔｉｏｎＥＨＬ，以下简称弹流）问题，得到了膜厚和压力分布的完全数值解，取得了具有典型弹流特性的数值计算结果，并给出了Ｎｅｗｔｏｎ模型，Ｍａｘｗｅｌｌ模型，Ｊ－Ｔ模型及Ｂ－Ｖ模型的牵曳力数值计算表达式，在基于膜厚和压力分布的完全数值解的基础上，有针对性地选择了前两种模型进行了数值计算，得到了等     

Vaccine clinical trials with dynamic borrowing of historical controls: Two retrospective studies

Traditional vaccine efficacy trials usually use fixed designs with fairly large sample sizes. Recruiting a large number of subjects requires longer time and higher costs. Furthermore, vaccine developers are more than ever facing the need to accelerate vaccine development to fulfill the public's medical needs. A possible approach to accelerate development is to use the method of dynamic borrowing of historical controls in clinical trials. In this paper, we evaluate the feasibility and the performance of this approach in vaccine development by retrospectively analyzing two real vaccine studies: a relatively small immunological trial (typical early phase study) and a large vaccine efficacy trial (typical Phase 3 study) assessing prophylactic human papillomavirus vaccine. Results are promising, particularly for early development immunological studies, where the adaptive design is feasible, and control of type I error is less relevant.     

Accuracy of Numerical Solutions Using the Euler Equation Residuals

This paper is concerned with asymptotic properties on the accuracy of numerical solutions. It is shown that the approximation error of the policy function is of the same order of magnitude as the size of the Euler equation residuals. Moreover, for bounding this approximation error the most relevant parameters are the discount factor and the curvature of the return function. These findings provide theoretical foundations for the construction of tests to assess the performance of alternative computational methods.