Issues in applying recent CPMP ‘Points to Consider’ and FDA guidance documents with biostatistical implications

The International Conference on Harmonisation guideline ‘Statistical Principles for Clinical Trials’ was adopted by the Committee for Proprietary Medicinal Products (CPMP) in March 1998, and consequently is operational in Europe. Since then more detailed guidance on selected topics has been issued by the CPMP in the form of ‘Points to Consider’ documents. The intent of these was to give guidance particularly to non‐statistical reviewers within regulatory authorities, although of course they also provide a good source of information for pharmaceutical industry statisticians. In addition, the Food and Drug Administration has recently issued a draft guideline on data monitoring committees. In November 2002 a one‐day discussion forum was held in London by Statisticians in the Pharmaceutical Industry (PSI). The aim of the meeting was to discuss how statisticians were responding to some of the issues covered in these new guidelines, and to document consensus views where they existed. The forum was attended by industry, academic and regulatory statisticians. This paper outlines the questions raised, resulting discussions and consensus views reached. It is clear from the guidelines and discussions at the workshop that the statistical analysis strategy must be planned during the design phase of a clinical trial and carefully documented. Once the study is complete the analysis strategy should be thoughtfully executed and the findings reported. Copyright © 2003 John Wiley & Sons, Ltd.     

A simple estimator for a shared frailty regression model

Summary. We propose a simple estimation procedure for a proportional hazards frailty regression model for clustered survival data in which the dependence is generated by a positive stable distribution. Inferences for the frailty parameter can be obtained by using output from Cox regression analyses. The computational burden is substantially less than that of the other approaches to estimation. The large sample behaviour of the estimator is studied and simulations show that the approximations are appropriate for use with realistic sample sizes. The methods are motivated by studies of familial associations in the natural history of diseases. Their practical utility is illustrated with sib pair data from Beaver Dam, Wisconsin.     

Innovation,accountability, and independence at three private foundations funding higher education civic engagement, 1995 to 2005

This case study looks at changes in private foundation funding for higher education civic engagement from 1995 to 2005. The focus is three large, established foundations that were U.S. national leaders in supporting this activity during these years: Carnegie, Pew, and Kellogg. Data sources include (1) in‐depth conversations with four strategically placed foundation insiders and six nationally recognized campus leaders and (2) scans of Web sites of the three foundations that document the change in funding priorities over time, plus Web sites of the main campus initiatives supported and national campus civic engagement organizations such as Campus Compact. Research findings con‐ firm and specify other studies that suggest that foundations shift their funding priorities according to their perceived role as innovators, pressures to be accountable and show clear results, and their independence as private organizations. The article concludes by raising questions about private foundations generally in relation to issues of innovativeness, accountability, and independence.     

The Effect of Learning Experiences and Context on Infant Imitation and Generalization

Over the first years of life, infants gradually develop the ability to retrieve their memories across cue and contextual changes. Whereas maturational factors drive some of these developments in memory ability, experiences occurring within the learning event may also impact infants' ability to retrieve memories in new situations. In 2 experiments we examined whether it was possible to facilitate 12‐month‐old infants' generalization of learning in the deferred imitation paradigm by varying experiences before or during the demonstration session, or during the retention interval. In Experiment 1, altering the length, timing, or variability of training had no impact on generalization; infants showed a low, but consistent level of memory retrieval. In Experiment 2, infants who experienced a unique context for encoding and retrieval exhibited generalization; infants who experienced the context prior to the demonstration session, or during the retention interval, did not. Specificity is a robust feature of infant memory and is not substantially altered by encoding experiences in an observational learning paradigm. Previous history with a learning environment can, however, impact the flexibility of memory retrieval.     

A spatiotemporal auto-regressive moving average model for solar radiation

Summary.  To investigate the variability in energy output from a network of photovoltaic cells, solar radiation was recorded at 10 sites every 10 min in the Pentland Hills to the south of Edinburgh. We identify spatiotemporal auto-regressive moving average models as the most appropriate to address this problem. Although previously considered computationally prohibitive to work with, we show that by approximating using toroidal space and fitting by matching auto-correlations, calculations can be substantially reduced. We find that a first-order spatiotemporal auto-regressive (STAR(1)) process with a first-order neighbourhood structure and a Matern noise process provide an adequate fit to the data, and we demonstrate its use in simulating realizations of energy output.     

The Development of Affect Specificity in Infants' Use of Emotion Cues

This study examined the emergence of affect specificity in infancy. In this study, infants received verbal and facial signals of 2 different, negatively valenced emotions (fear and sadness) as well as neutral affect via a television monitor to determine if they could make qualitative distinctions among emotions of the same valence. Twenty 12‐ to 14‐month‐olds and 20 16‐ to 18‐month‐olds were examined. Results suggested that younger infants showed no evidence of referential specificity, as they responded similarly to both the target and distracter toys, and showed no evidence of affect specificity, showing no difference in play between affect conditions. Older infants, in contrast, showed evidence both of referential and affect specificity. With respect to affect specificity, 16‐ to 18‐month‐olds touched the target toy less in the fear condition than in the sad condition and showed a larger proportion of negative facial expressions in the sad condition versus the fear condition. These findings suggest a developmental emergence after 15 months of age for affect specificity in relating emotional messages to objects.     

Modeling External Risks in Project Management

To ascertain the viability of a project, undertake resource allocation, take part in bidding processes, and other related decisions, modern project management requires forecasting techniques for cost, duration, and performance of a project, not only under normal circumstances, but also under external events that might abruptly change the status quo. We provide a Bayesian framework that provides a global forecast of a project's performance. We aim at predicting the probabilities and impacts of a set of potential scenarios caused by combinations of disruptive events, and using this information to deal with project management issues. To introduce the methodology, we focus on a project's cost, but the ideas equally apply to project duration or performance forecasting. We illustrate our approach with an example based on a real case study involving estimation of the uncertainty in project cost while bidding for a contract.