Estimating and comparing adverse event probabilities in the presence of varying follow-up times and competing events

Safety analyses of adverse events (AEs) are important in assessing benefit–risk of therapies but are often rather simplistic compared to efficacy analyses. AE probabilities are typically estimated by incidence proportions, sometimes incidence densities or Kaplan–Meier estimation are proposed. These analyses either do not account for censoring, rely on a too restrictive parametric model, or ignore competing events. With the non-parametric Aalen-Johansen estimator as the “gold standard”, that is, reference estimator, potential sources of bias are investigated in an example from oncology and in simulations, for both one-sample and two-sample scenarios. The Aalen-Johansen estimator serves as a reference, because it is the proper non-parametric generalization of the Kaplan–Meier estimator to multiple outcomes. Because of potential large variances at the end of follow-up, comparisons also consider further quantiles of the observed times. To date, consequences for safety comparisons have hardly been investigated, the impact of using different estimators for group comparisons being unclear. For example, the ratio of two both underestimating or overestimating estimators may not be comparable to the ratio of the reference, and our investigation also considers the ratio of AE probabilities. We find that ignoring competing events is more of a problem than falsely assuming constant hazards by the use of the incidence density and that the choice of the AE probability estimator is crucial for group comparisons.     

Default and Punishment in General Equilibrium1

We extend the standard model of general equilibrium with incomplete markets to allow for default and punishment by thinking of assets as pools. The equilibrating variables include expected delivery rates, along with the usual prices of assets and commodities. By reinterpreting the variables, our model encompasses a broad range of adverse selection and signalling phenomena in a perfectly competitive, general equilibrium framework. Perfect competition eliminates the need for lenders to compute how the size of their loan or the price they quote might affect default rates. It also makes for a simple equilibrium refinement, which we propose in order to rule out irrational pessimism about deliveries of untraded assets. We show that refined equilibrium always exists in our model, and that default, in conjunction with refinement, opens the door to a theory of endogenous assets. The market chooses the promises, default penalties, and quantity constraints of actively traded assets.     

PREDICT-1 (CNA106030): the first powered, prospective trial of pharmacogenetic screening to reduce drug adverse events

Pharmacogenetics (PGx) – the study of DNA variation in the human genome and the way this impacts the efficacy and safety of medicines – is becoming an increasingly important research tool as physicians, patients, regulatory authorities and payers look for innovative ways to improve the risk:benefit ratio of medicines. While scientific knowledge about PGx is rapidly increasing, implementation of PGx findings to patient care has yet to be fully achieved. One area where significant progress has been made is in the identification of PGx markers associated with variable response to antiretroviral medicines. For example, the major histocompatibility complex HLA‐B*5701 allele has been associated with hypersensitivity to abacavir (ABC) by several independent researchers. While PGx associations have been identified largely through retrospective examination, the clinical utility of these PGx markers in patient care has not been prospectively determined in a randomized study. This paper outlines the design of a study to evaluate the utility of prospective screening for HLA‐B*5701 to reduce the incidence of ABC hypersensitivity in an ABC‐naïve population of HIV‐infected subjects. This represents the first fully powered, randomized, blinded, prospective study to determine the clinical utility of PGx screening to reduce drug‐associated adverse events in any patient population. This type of trial design may have utility for other important medicines which have treatment‐limiting side effects. Copyright © 2007 John Wiley & Sons, Ltd.     

信号成本与服务外包供应商信号传递关系的博弈模型

由于服务外包市场的信息不对称性和不完美性,外包商难以清楚了解供应商的能力,使得服务外包供应商选择市场出现逆向选择。为解决非对称信息条件下服务外包供应商选择市场运行的低效问题,本文利用信号博弈建立了信号成本与外包供应商信号传递关系的数学模型,并通过案例分析说明了该模型对管理的指导意义。     

医学生的逆商及培养

大量资料显示,一个人事业成功与否,在很大程度上取决于逆商。本课题以研究对象的个性倾向,心理特征为切入点,对逆商培养的方式方法进行了探讨和研究。     

Reconciliation with the Utility of Chance by Elaborated Outcomes Destroys the Axiomatic Basis of Expected Utility Theory

Expected utility theory does not directly deal with the utility of chance. It has been suggested in the literature (Samuelson, 1952, Markowitz, 1959) that this can be remedied by an approach which explicitly models the emotional consequences which give rise to the utility of chance. We refer to this as the elaborated outcomes approach. It is argued that the elaborated outcomes approach destroys the possibility of deriving a representation theorem based on the usual axioms of expected utility theory. This is shown with the help of an example due to Markowitz. It turns out that the space of conceivable lotteries over elaborated outcomes is too narrow to permit the application of the axioms. Moreover it is shown that a representation theorem does not hold for the example.     

Discrepancies between chronological age and personal age as a reflection of unrelieved worker stress

The general proposition that stress-related variables will be associated with discrepancies between chronological age and perceived personal age of working adults was examined. Responses from a field survey of day, afternoon, and night fixed-shift workers in a large manufacturing organization (n = 1674) were used to explore the relationships between a variety of reported stress-related variables and personal age constructs. Discrepancies between perceived personal age and chronological age were reported by a large proportion of the workers surveyed. Three categories of stress-related variables each accounted for a significant proportion of the variance in discrepancies. As hypothesized, the reported presence of stressors and the frequency/extent of strains (stress-related outcomes) were positively correlated with feeling older than one's chronological age. In addition, the reported presence of support mechanisms for coping with stressors was negatively correlated with feeling older than one's chronological age. The manner in which work and non-work stress may impinge upon personal age perceptions is discussed, and appropriate avenues for future research in this domain are considered.     

TITE‐BOIN‐ET: Time‐to‐event Bayesian optimal interval design to accelerate dose‐finding based on both efficacy and toxicity outcomes

One of the primary purposes of an oncology dose‐finding trial is to identify an optimal dose (OD) that is both tolerable and has an indication of therapeutic benefit for subjects in subsequent clinical trials. In addition, it is quite important to accelerate early stage trials to shorten the entire period of drug development. However, it is often challenging to make adaptive decisions of dose escalation and de‐escalation in a timely manner because of the fast accrual rate, the difference of outcome evaluation periods for efficacy and toxicity and the late‐onset outcomes. To solve these issues, we propose the time‐to‐event Bayesian optimal interval design to accelerate dose‐finding based on cumulative and pending data of both efficacy and toxicity. The new design, named “TITE‐BOIN‐ET” design, is nonparametric and a model‐assisted design. Thus, it is robust, much simpler, and easier to implement in actual oncology dose‐finding trials compared with the model‐based approaches. These characteristics are quite useful from a practical point of view. A simulation study shows that the TITE‐BOIN‐ET design has advantages compared with the model‐based approaches in both the percentage of correct OD selection and the average number of patients allocated to the ODs across a variety of realistic settings. In addition, the TITE‐BOIN‐ET design significantly shortens the trial duration compared with the designs without sequential enrollment and therefore has the potential to accelerate early stage dose‐finding trials.     

Non-parametric MANOVA approaches for non-normal multivariate outcomes with missing values

Between-group comparisons often entail many correlated response variables. The multivariate linear model, with its assumption of multivariate normality, is the accepted standard tool for these tests. When this assumption is violated, the non-parametric multivariate Kruskal–Wallis (MKW) test is frequently used. However, this test requires complete cases with no missing values in response variables. Deletion of cases with missing values likely leads to inefficient statistical inference. Here we extend the MKW test to retain information from partially observed cases. Results of simulated studies and analysis of real data show that the proposed method provides adequate coverage and superior power to complete case analyses.