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.     

Bias Correction in the Dynamic Panel Data Model with a Nonscalar Disturbance Covariance Matrix

Approximation formulae are developed for the bias of ordinary and generalized Least Squares Dummy Variable (LSDV) estimators in dynamic panel data models. Results from Kiviet [Kiviet, J. F. (1995), on bias, inconsistency, and efficiency of various estimators in dynamic panel data models, J. Econometrics68:53-78; Kiviet, J. F. (1999), Expectations of expansions for estimators in a dynamic panel data model: some results for weakly exogenous regressors, In: Hsiao, C., Lahiri, K., Lee, L-F., Pesaran, M. H., eds., Analysis of Panels and Limited Dependent Variables, Cambridge: Cambridge University Press, pp. 199-225] are extended to higher-order dynamic panel data models with general covariance structure. The focus is on estimation of both short- and long-run coefficients. The results show that proper modelling of the disturbance covariance structure is indispensable. The bias approximations are used to construct bias corrected estimators which are then applied to quarterly data from 14 European Union countries. Money demand functions for M1, M2 and M3 are estimated for the EU area as a whole for the period 1991: I-1995: IV. Significant spillovers between countries are found reflecting the dependence of domestic money demand on foreign developments. The empirical results show that in general plausible long-run effects are obtained by the bias corrected estimators. Moreover, finite sample bias, although of moderate magnitude, is present underlining the importance of more refined estimation techniques. Also the efficiency gains by exploiting the heteroscedasticity and cross-correlation patterns between countries are sometimes considerable.     

Markov chain Monte Carlo methods for high dimensional inversion in remote sensing

Summary.  We discuss the inversion of the gas profiles (ozone, NO₃, NO₂, aerosols and neutral density) in the upper atmosphere from the spectral occultation measurements. The data are produced by the 'Global ozone monitoring of occultation of stars' instrument on board the Envisat satellite that was launched in March 2002. The instrument measures the attenuation of light spectra at various horizontal paths from about 100 km down to 10–20 km. The new feature is that these data allow the inversion of the gas concentration height profiles. A short introduction is given to the present operational data management procedure with examples of the first real data inversion. Several solution options for a more comprehensive statistical inversion are presented. A direct inversion leads to a non-linear model with hundreds of parameters to be estimated. The problem is solved with an adaptive single-step Markov chain Monte Carlo algorithm. Another approach is to divide the problem into several non-linear smaller dimensional problems, to run parallel adaptive Markov chain Monte Carlo chains for them and to solve the gas profiles in repetitive linear steps. The effect of grid size is discussed, and we present how the prior regularization takes the grid size into account in a way that effectively leads to a grid-independent inversion.     

Goodness of fit for the inverse Gaussian distribution

For testing the fit of the inverse Gaussian distribution with unknown parameters, the empirical distribution-function statistic A² is studied. Two procedures are followed in constructing the test statistic; they yield the same asymptotic distribution. In the first procedure the parameters in the distribution function are directly estimated, and in the second the distribution function is estimated by its Rao-Blackwell distribution estimator. A table is given for the asymptotic critical points of A². These are shown to depend only on the ratio of the unknown parameters. An analysis is provided of the effect of estimating the ratio to enter the table for A². This analysis enables the proposal of the complete operating procedure, which is sustained by a Monte Carlo study.     

Immigrants and alien workers

VII. Conclusion The number of immigrants now coming to the United States is proportionally only a fraction of the number that came in earlier years, and there is nothing in those numbers to suggest a difficult absorption burden. Immigrants, both legal and illegal, more than pay for the services they use with the taxes they pay, leaving a considerable net surplus that benefits American citizens. Immigrants raise productivity and do not cause an observable amount of unemployment of citizens. Admitting far more immigrants into the country than the law now allows would have positive effects on the incomes of citizens, and would enhance the continuing vitality of the United States.     

Campus attitudes toward alcohol and drugs in a deep southern university.

In our zeal to deal with alcohol and drug abuse, we may have a distorted picture of what the majority of college students actually think about alcohol and drug use. Students in this study done at a public university located in the Deep South report being generally intolerant of substance abuse.     

The historical decline of fertility in Eastern Europe

I test the hypothesis that the growth of autonomy was the factor responsible for the decline of marital fertility in eight Eastern European countries. By growth of autonomy I mean increased control over one's political, personal, religious, economic and reproductive life. This increased control was manifested in revolutions, democratic political reforms, nationalist movements and declining marital fertility. The political reforms were the result of the growth of autonomy but they also accelerated the dissemination of these new ideas among the populace contributing to further growth of autonomy. My hypothesis is generally supported by the historical data.     

Screening for patients with alcohol problems: severity of patients identified by the CAGE.

Primary care physicians are well situated to identify patients with substance abuse problems and motivate them to seek appropriate assistance, but active programs are the exception. A study in a community setting was undertaken to assess the CAGE (the first letters of key words in a series of four questions about drinking: cut down; annoyed; guilty; and eye-opener), instrument in the routine screening for alcohol problems in both new and established patients. The screening process identified subjects for a pilot evaluation of a motivational interview designed to encourage problem-solving behavior. This article focuses on the screening results and the use of the CAGE instrument. During June and July of 1990, 687 patients of two primary care physicians belonging to a large group practice were asked to complete a health questionnaire that included the CAGE. Those who responded affirmatively to at least two of the four CAGE questions were requested to participate in follow-up assessment of problems associated with alcohol and health. The type and severity of alcohol problems experienced by patients who scored positive on the CAGE are described. Prevalence of a positive score on the CAGE was 8.6 percent with males, smokers, and blue collar and unemployed persons being more likely to score positive. The positive predictive value was .68. Primarily, persons with moderate alcohol problems were identified. Results show that the CAGE instrument is a useful screening device for identifying those with mild to moderate substance abuse problems, increasing the opportunity for intervention prior to serious medical complications. The instrument is easily administered, and has demonstrated relatively high levels of sensitivity and specificity. When combined with assessment and motivational interviews, the CAGE shows promise in the secondary prevention of substance abuse and related health problems.