Inference and Decision Making for 21st-Century Drug Development and Approval

ABSTRACT

The cost and time of pharmaceutical drug development continue to grow at rates that many say are unsustainable. These trends have enormous impact on what treatments get to patients, when they get them and how they are used. The statistical framework for supporting decisions in regulated clinical development of new medicines has followed a traditional path of frequentist methodology. Trials using hypothesis tests of “no treatment effect” are done routinely, and the p-value < 0.05 is often the determinant of what constitutes a “successful” trial. Many drugs fail in clinical development, adding to the cost of new medicines, and some evidence points blame at the deficiencies of the frequentist paradigm. An unknown number effective medicines may have been abandoned because trials were declared “unsuccessful” due to a p-value exceeding 0.05. Recently, the Bayesian paradigm has shown utility in the clinical drug development process for its probability-based inference. We argue for a Bayesian approach that employs data from other trials as a “prior” for Phase 3 trials so that synthesized evidence across trials can be utilized to compute probability statements that are valuable for understanding the magnitude of treatment effect. Such a Bayesian paradigm provides a promising framework for improving statistical inference and regulatory decision making.     

Bayesian analysis of mixture modelling using the multivariate t distribution

A finite mixture model using the multivariate t distribution has been shown as a robust extension of normal mixtures. In this paper, we present a Bayesian approach for inference about parameters of t-mixture models. The specifications of prior distributions are weakly informative to avoid causing nonintegrable posterior distributions. We present two efficient EM-type algorithms for computing the joint posterior mode with the observed data and an incomplete future vector as the sample. Markov chain Monte Carlo sampling schemes are also developed to obtain the target posterior distribution of parameters. The advantages of Bayesian approach over the maximum likelihood method are demonstrated via a set of real data.     

Maintaining the connection: Parenting as a noncustodial father

The purpose of this study was to identify relevant factors associated with the noncustodial father's frequency of contact with his child following divorce. The findings of the research revealed that a combination of demographic, personal characteristics, and psychosocial factors are related to the father's frequency of contact with the child.     

Agency costs,property rights,and the evolution of labor unions

Collective bargaining requires that an agent represent workers. This paper examines the implications for the trade union movement of the resulting agency costs. Without transferable rights in the union, union members lack the means and incentive to bring forth the innovative agent controls common to the modern corporation. Considerations of the bargaining strengths of employers and employees, each represented by an agent, provide an explanation of the simultaneous decline of private sector union membership (corporate share holders have been more successful at lowering agency costs) and growth of public sector union representation (where the union official, a “double agent,” serves the interest of both employee and bureaucratic employer). The authors acknowledge the helpful remarks Donald L. Martin whose earlier research on property rights in unions inspired this effort. Don Bellante’s work was supported by a grant from the Research Committee of the College of Business Administration, University of South Florida.     

ATSDR Science Panel on the Bioavailability of Mercury in Soils: Lessons Learned

On the basis of discussion and analysis during and following an ATSDR science panel on the bioavailability of mercury in soils, it is apparent that the default assumption of 100% relative bioavailability for mercury-contaminated soils is excessively conservative. However, current knowledge does not allow the development of default assumptions or guidelines for determining relative bioavailability of mercury in soils. Until such default assumptions or guidelines can be developed, site-specific assays of bioavailability, preferably using either animal bioassays or validated in vitro techniques, may provide the best approach for estimating soil-mercury bioavailability.     

The reification of celebrity: global newspaper coverage of the death of David Bowie*

This paper examines global English-language newspaper coverage of the death of David Bowie. Drawing upon the concept of reification, it is argued that the notion of celebrity is discursively (re)produced and configured through a ‘public face’ that is defined, maintained and shaped via media reports and public responses that aim to know and reflect upon celebrity. The findings highlight how Bowie’s reification was supported by discourses that represented him as an observable, reified form. Here, Bowie’s ‘reality’, that is, his authentic/veridical self, was obscured behind a façade of mediation, interpretation and representation that debated and decided his ‘authenticity’ as a cultural icon. Such debates, however, were engagements with a reified image, enveloped in continual (re)interpretation. As a result, Bowie’s reification was grounded in a polysemous process that allowed numerous versions of ‘himself’ to be aesthetically reimagined, reinvented and repeated.     

An Examination of the Communication Styles Associated with Psychopathy and Their Influence on Observer Impressions

Psychopathic individuals are characterized as “intra-species predators”—callous, impulsive, aggressive, and proficient at interpersonal manipulation. For example, despite their high risk for re-offending, psychopathic offenders often receive early release on parole. While reputed to be social chameleons, research suggests that even naive observers can accurately infer high levels of psychopathic traits in others with very brief exposures to behavior, but accuracy degrades with extended observation. We utilized a lens model approach to examine the communication styles (emotional facial expressions, body language, and verbal content) of offenders varying in levels of psychopathic traits using “thin slice” video clips of psychological assessment interviews and to reveal which cues observers use to inform their evaluations of psychopathy. Psychopathic traits were associated with more (a) Duchenne smiles, (b) negative (angry) emotional language, and (c) hand gestures (illustrators). Further, psychopathy was associated with a marked behavioral incongruence; when individuals scoring high in psychopathic traits engaged in Duchenne smiles they were also more likely to use angry language. Naïve observers relied on each of these valid behavioral signals to quickly and accurately detect psychopathic traits. These findings provide insight into psychopathic communication styles, opportunities for improving the detection of psychopathic personality traits, and may provide an avenue for understanding successful psychopathic manipulation.