Type I error rates from likelihood‐based repeated measures analyses of incomplete longitudinal data

The last observation carried forward (LOCF) approach is commonly utilized to handle missing values in the primary analysis of clinical trials. However, recent evidence suggests that likelihood‐based analyses developed under the missing at random (MAR) framework are sensible alternatives. The objective of this study was to assess the Type I error rates from a likelihood‐based MAR approach – mixed‐model repeated measures (MMRM) – compared with LOCF when estimating treatment contrasts for mean change from baseline to endpoint (Δ). Data emulating neuropsychiatric clinical trials were simulated in a 4 × 4 factorial arrangement of scenarios, using four patterns of mean changes over time and four strategies for deleting data to generate subject dropout via an MAR mechanism. In data with no dropout, estimates of Δ and SE_Δ from MMRM and LOCF were identical. In data with dropout, the Type I error rates (averaged across all scenarios) for MMRM and LOCF were 5.49% and 16.76%, respectively. In 11 of the 16 scenarios, the Type I error rate from MMRM was at least 1.00% closer to the expected rate of 5.00% than the corresponding rate from LOCF. In no scenario did LOCF yield a Type I error rate that was at least 1.00% closer to the expected rate than the corresponding rate from MMRM. The average estimate of SE_Δ from MMRM was greater in data with dropout than in complete data, whereas the average estimate of SE_Δ from LOCF was smaller in data with dropout than in complete data, suggesting that standard errors from MMRM better reflected the uncertainty in the data. The results from this investigation support those from previous studies, which found that MMRM provided reasonable control of Type I error even in the presence of MNAR missingness. No universally best approach to analysis of longitudinal data exists. However, likelihood‐based MAR approaches have been shown to perform well in a variety of situations and are a sensible alternative to the LOCF approach. MNAR methods can be used within a sensitivity analysis framework to test the potential presence and impact of MNAR data, thereby assessing robustness of results from an MAR method. Copyright © 2004 John Wiley & Sons, Ltd.     

Interpreting DNA Mixtures with Related Contributors in Subdivided Populations

Abstract.  In this paper, we study the statistical interpretation of forensic DNA mixtures with related contributors in subdivided populations. Compact general formulae for match probabilities are obtained for two situations: a relative of one tested person is an unknown contributor of a DNA mixture; and two related unknowns are contributors. The effect of kinship and population structure is illustrated using a real case example.     

一氧化氮的研究进展及应用

一氧化氮(NO)既是气体,又是自由基,是生物体内一种作用广泛而性质独特的信号分子,它不仅对动物的神经系统、循环系统、消化系统等有着重要的调节作用,而且也参与植物生长发育的许多过程,如种子萌发、下胚轴伸长、根生长、细胞凋亡以及植物抗逆反应等。本文就近年来NO的研究进展及应用作简要综述。     

Choice of the primary analysis in longitudinal clinical trials

Missing data, and the bias they can cause, are an almost ever‐present concern in clinical trials. The last observation carried forward (LOCF) approach has been frequently utilized to handle missing data in clinical trials, and is often specified in conjunction with analysis of variance (LOCF ANOVA) for the primary analysis. Considerable advances in statistical methodology, and in our ability to implement these methods, have been made in recent years. Likelihood‐based, mixed‐effects model approaches implemented under the missing at random (MAR) framework are now easy to implement, and are commonly used to analyse clinical trial data. Furthermore, such approaches are more robust to the biases from missing data, and provide better control of Type I and Type II errors than LOCF ANOVA. Empirical research and analytic proof have demonstrated that the behaviour of LOCF is uncertain, and in many situations it has not been conservative. Using LOCF as a composite measure of safety, tolerability and efficacy can lead to erroneous conclusions regarding the effectiveness of a drug. This approach also violates the fundamental basis of statistics as it involves testing an outcome that is not a physical parameter of the population, but rather a quantity that can be influenced by investigator behaviour, trial design, etc. Practice should shift away from using LOCF ANOVA as the primary analysis and focus on likelihood‐based, mixed‐effects model approaches developed under the MAR framework, with missing not at random methods used to assess robustness of the primary analysis. Copyright © 2004 John Wiley & Sons, Ltd.     

Creating a reference to a complex emergency situation using time series methods: war in Guinea-Bissau 1998-1999

Impacts of complex emergencies or relief interventions have often been evaluated by absolute mortality compared to international standardized mortality rates. A better evaluation would be to compare with local baseline mortality of the affected populations. A projection of population-based survival data into time of emergency or intervention based on information from before the emergency may create a local baseline reference. We find a log-transformed Gaussian time series model where standard errors of the estimated rates are included in the variance to have the best forecasting capacity. However, if time-at-risk during the forecasted period is known then forecasting might be done using a Poisson time series model with overdispersion. Whatever, the standard error of the estimated rates must be included in the variance of the model either in an additive form in a Gaussian model or in a multiplicative form by overdispersion in a Poisson model. Data on which the forecasting is based must be modelled carefully concerning not only calendar-time trends but also periods with excessive frequency of events (epidemics) and seasonal variations to eliminate residual autocorrelation and to make a proper reference for comparison, reflecting changes over time during the emergency. Hence, when modelled properly it is possible to predict a reference to an emergency-affected population based on local conditions. We predicted childhood mortality during the war in Guinea-Bissau 1998-1999. We found an increased mortality in the first half-year of the war and a mortality corresponding to the expected one in the last half-year of the war.     

Generalized additive models for location, scale and shape

Summary.  A general class of statistical models for a univariate response variable is presented which we call the generalized additive model for location, scale and shape (GAMLSS). The model assumes independent observations of the response variable y given the parameters, the explanatory variables and the values of the random effects. The distribution for the response variable in the GAMLSS can be selected from a very general family of distributions including highly skew or kurtotic continuous and discrete distributions. The systematic part of the model is expanded to allow modelling not only of the mean (or location) but also of the other parameters of the distribution of y , as parametric and/or additive nonparametric (smooth) functions of explanatory variables and/or random-effects terms. Maximum (penalized) likelihood estimation is used to fit the (non)parametric models. A Newton–Raphson or Fisher scoring algorithm is used to maximize the (penalized) likelihood. The additive terms in the model are fitted by using a backfitting algorithm. Censored data are easily incorporated into the framework. Five data sets from different fields of application are analysed to emphasize the generality of the GAMLSS class of models.     

Temporal pattern in number of staff on sick leave: the effect of downsizing

Summary.  The pattern of absenteeism in the downsizing process of companies is a topic in focus in economics and social science. A general question is whether employees who are frequently absent are more likely to be selected to be laid off or in contrast whether employees to be dismissed are more likely to be absent for the remaining time of their working contract. We pursue an empirical and microeconomic investigation of these theses. We analyse longitudinal data that were collected in a German company over several years. We fit a semiparametric transition model based on a mixture Poisson distribution for the days of absenteeism per month. Prediction intervals are considered and the primary focus is on the period of downsizing. The data reveal clear evidence for the hypothesis that employees who are to be laid off are more frequently absent before leaving the company. Interestingly, though, no clear evidence is seen that employees being selected to leave the company are those with a bad absenteeism profile.     

析我国刑法第十三条之规定

犯罪概念 ,大致上可以分为形式概念、实质概念及混合概念。我国刑法第十三条规定的是犯罪的混合概念 ,这一混合概念存在着逻辑上的缺陷 ,欠缺明确性和可操作性。文章就如何更为科学地定义犯罪 ,完善我国刑法第十三条作了初步探讨     

Statistik für bivariate gemischte Poisson–Prozesse am Beispiel der Kraftfahrthaftpflichtversicherung

Zusammenfassung: In diesem Artikel wird der Weg von einem univariaten gemischten Poisson–Prozess, der in vielen Bereichen zum Z?hlen von Ereignissen benutzt wird, zu einem bivariaten gemischten Poisson–Prozess aufgezeigt. Dazu werden einige Eigenschaften des bivariaten Prozesses angegeben. Im zweiten Teil der Arbeit wird gezeigt, wie mit Hilfe dieses Prozesses der übergang von einem herk?mmlichen Bonus–Malus–System in der Kraftfahrthaftpflichtversicherung zu einem Bonus–Malus–System mit Berücksichtigung der Schadenart beschritten werden kann. Dazu wird zuerst eine Modellprüfung der gegebenen Daten vorgenommen und sodann werden für verschiedene mischende Verteilungen die Verteilungsparameter gesch?tzt und Nettopr?mien angegeben sowie die Prognosegenauigkeit getestet.

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Summary: In this paper we show that the model of the bivariate mixed Poisson process arises in a natural way from the univariate mixed Poisson process, which is used in several areas for counting certain events. Furthermore we state some properties of the bivariate process. In the second part of the paper we illustrate how by means of the bivariate mixed Poisson process a bonus–malus system handling different types of accidents can be derived from the classical bonus–malus system in third–party liability insurance. To this end we first check the model on the given data and then estimate distribution parameters and compute net premiums for different mixing distributions as well as test the prediction probabilities.

* Vortrag am Dresdner Forum zur Versicherungsmathematik: Tarifierung in Erst- und Rückversicherung am 25. Juni 2004. Für die Unterstützung zu dieser Arbeit m?chte der Autor Lothar Partzsch, Klaus D. Schmidt (beide Dresden) und Friedemann Spies (München) recht herzlich danken.     

低阻ITO玻璃的制造工艺

有机发光显示器件是目前平板显示中的热点,所用ITO玻璃比液晶显示所用的有更高更严的要求。该文探讨了OLED用ITO玻璃生产的相关工艺,得出使用直流溅射ITO陶瓷靶时,较好的气氛是低氩微氧,功率约200W左右,溅射时基板温度约250℃,高温无氧退火。得到方阻20?以下、平均透过率大于80%的ITO玻璃。