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.     

Spatial variation in soil inorganic nitrogen across an arid urban ecosystem

We explored variations in inorganic soil nitrogen (N) concentrations across metropolitan Phoenix, Arizona, and the surrounding desert using a probability-based synoptic survey. Data were examined using spatial statistics on the entire region, as well as for the desert and urban sites separately. Concentrations of both NO₃-N and NH₄-N were markedly higher and more heterogeneous amongst urban compared to desert soils. Regional variation in soil NO₃-N concentration was best explained by latitude, land use history, population density, along with percent cover of impervious surfaces and lawn, whereas soil NH₄-N concentrations were related to only latitude and population density. Within the urban area, patterns in both soil NO₃-N and NH₄-N were best predicted by elevation, population density and type of irrigation in the surrounding neighborhood. Spatial autocorrelation of soil NO₃-N concentrations explained 49% of variation among desert sites but was absent between urban sites. We suggest that inorganic soil N concentrations are controlled by a number of ‘local’ or ‘neighborhood’ human-related drivers in the city, rather than factors related to an urban-rural gradient.     

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.     

Statistics for weighing benefits and harms in a proposed genetic substudy of a randomized cancer prevention trial

Summary.  When evaluating potential interventions for cancer prevention, it is necessary to compare benefits and harms. With new study designs, new statistical approaches may be needed to facilitate this comparison. A case in point arose in a proposed genetic substudy of a randomized trial of tamoxifen versus placebo in asymptomatic women who were at high risk for breast cancer. Although the randomized trial showed that tamoxifen substantially reduced the risk of breast cancer, the harms from tamoxifen were serious and some were life threaten-ing. In hopes of finding a subset of women with inherited risk genes who derive greater bene-fits from tamoxifen, we proposed a nested case–control study to test some trial subjects for various genes and new statistical methods to extrapolate benefits and harms to the general population. An important design question is whether or not the study should target common low penetrance genes. Our calculations show that useful results are only likely with rare high penetrance genes.     

Glass ceilings or sticky floors? A model of high-income law graduates

Minorities and females are underrepresented in the top-income quintile of law school graduates. Employing a binary logistic regression model, I examine whether this is due to a“glass ceiling” (an invisible barrier erected by third parties) or a“sticky floor” (self-imposed limitations regarding employment). My major finding is that being female, a minority, or disabled did not significantly reduce one's probability of making the top-income quintile once hours of work, experience, and other factors are taken into account. My findings directly contradict the large body of glass-ceiling literature and support the sticky-floor model. I thank the Law School Admission Council for funding this research. Helpful comments and suggestions were received from Robert Nelson of Northwestern University and the American Bar Foundation, Steven Conroy of the University of West Florida, and R. Kim Craft and Douglas Bonzo of Southern Utah University. The views expressed here are solely those of the author and do not necessarily reflect those of the institutions or persons listed above.     

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.     

An empirical Bayes' procedure for ranking players in Ryder Cup golf

We describe a model to obtain strengths and rankings of players appearing in golf's Ryder Cup. Obtaining rankings is complicated because of two reasons. First, competitors do not compete on an equal number of occasions, with some competitors appearing too infrequently for their ranking to be estimated with any degree of certainty, and second, different competitors experience different levels of volatility in results. Our approach is to assume the competitor strengths are drawn from some common distribution. For small numbers of competitors, as is the case here, we fit the model using Monte-Carlo integration. Results suggest there is very little difference between the top performing players, though Scotland's Colin Montgomerie is estimated as the strongest Ryder Cup player.     

Beyond the urban stream syndrome: organic matter budget for diagnostics and restoration of an impaired urban river

In response to water quality standard violations linked to excessive organic matter (OM) and a lack of sampling data informing the Total Maximum Daily Load (TMDL), an organic matter budget was created to quantify and identify sources of OM in the lower Jordan River (Salt Lake City, UT). By sampling dissolved, fine and coarse particulate OM, as well as measuring ecosystem metabolism at seven different sites, the researchers aimed to identify the origin of excess OM, and understand pathways by which different size classes of the OM pool are generated. The dissolved fraction (DOM; 94 %) was found to be the dominant form of OM transported within the river with fine particulate organic matter (FPOM; 6 %) the second most abundant, and coarse particulate organic matter (CPOM; 1 %) transport relatively insignificant in the overall OM budget. Primary production exceeded respiratory losses in the upper river, and this, along with OM inputs from two tributaries (where water reclamation facilities discharge into the river) delivered excess OM to the impaired lower reaches. Increasing stream metabolism index (SMI) with distance downstream (>1 in the lower river) further demonstrated that transport of excessive organic matter into the lower river was from upstream sources and not due to lateral inputs. This simple approach to characterizing the organic matter budget as it relates to water quality in the Jordan River was effective and could serve as a model for future studies attempting to quantify and identify sources of OM in urban ecosystems.     

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.