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.     

Secondary analysis of dangerousness among death sentenced capital murderers

The theory of incapacitation involves reducing an offender's ability or capacity to commit further crimes. Capital punishment accomplishes this goal. An executed murderer never murders again. However, we do not execute all murderers, only capital murderers. This policy produces several research questions. Do capital murderers present a special risk to society? Are capital murderers more likely to murder or commit other violent crimes again than other murderers or the average citizen? To answer these questions, many states require a prediction of future dangerousness of a newly convicted murderer. To what extent has the judgment of future dangerousness matched actuarial data of subsequent murders and serious crimes? Using a secondary analysis, this investigation attempted to assemble available data of postconviction dangerousness of death sentenced capital murderers to create a more comprehensive actuarial account of subsequent dangerousness and to present the data in a common format used by the Federal Bureau of Investigation and the Bureau of Justice Statistics. Across 14 studies identified with relevant data, there were 13 instances of subsequent murder and 462 serious crime or prison rule violations.     

Quantifying uncertainty in the biospheric carbon flux for England and Wales

Summary.  A crucial issue in the current global warming debate is the effect of vegetation and soils on carbon dioxide (CO₂) concentrations in the atmosphere. Vegetation can extract CO₂ through photosynthesis, but respiration, decay of soil organic matter and disturbance effects such as fire return it to the atmosphere. The balance of these processes is the net carbon flux. To estimate the biospheric carbon flux for England and Wales, we address the statistical problem of inference for the sum of multiple outputs from a complex deterministic computer code whose input parameters are uncertain. The code is a process model which simulates the carbon dynamics of vegetation and soils, including the amount of carbon that is stored as a result of photosynthesis and the amount that is returned to the atmosphere through respiration. The aggregation of outputs corresponding to multiple sites and types of vegetation in a region gives an estimate of the total carbon flux for that region over a period of time. Expert prior opinions are elicited for marginal uncertainty about the relevant input parameters and for correlations of inputs between sites. A Gaussian process model is used to build emulators of the multiple code outputs and Bayesian uncertainty analysis is then used to propagate uncertainty in the input parameters through to uncertainty on the aggregated output. Numerical results are presented for England and Wales in the year 2000. It is estimated that vegetation and soils in England and Wales constituted a net sink of 7.55 Mt C (1 Mt C = 10¹² g of carbon) in 2000, with standard deviation 0.56 Mt C resulting from the sources of uncertainty that are considered.     

The use of a model in long term planning—A case history

Long term planning in companies can range from the partial simplistic approach to a structured time-consuming ritual. Either extreme can bring planning into disrepute, and both reflect the lack of the proper tools of the trade. Models, by themselves, are no panacea, but properly conceived, constructed, and developed they can transform the planning process. The key to effective and practical models is use, and this can be achieved through direct management involvement on the model's development, and by making sure the model is basically simple and flexible. This article describes how such a model was constructed using a modular approach, and how it was used effectively in long term planning.     

The risks and incentives of disciplinary neoliberal feminism: the case of microfinance

This article develops an analysis of the concept of disciplinary neo-liberal feminism through a focus on gendered poverty alleviation strategies and illustrates the value of this through a discussion of microfinance. By locating this study within an analysis of the expansion of global capital accumulation, the article argues that the liberal frameworks of female empowerment and entrepreneurialism that are central to these programs and to feminism in this form, mask their underlying political, social and economic objectives. In contrast, a Marxist Feminist approach more adequately explains the interplay of class and gender that underpins poverty alleviation strategies. This article argues that in the context of financial crisis and reduced social provision, women living in poverty in the Global South were identified as targets for the expansion of global finance. Their integration into global financial networks via microfinance and other pro-poor strategies has facilitated the expansion of markets for credit while at the same time disciplining market participation through the twin forces of risk and incentive. Disciplinary neo-liberal feminism has underpinned this incorporation of women into global capital accumulation creating profound effects for households and families, with microfinance programs representing important sites of contestation for the politics of class and gender.     

A reflected feature space for CART

We present an algorithm for learning oblique decision trees, called HHCART(G). Our decision tree combines learning concepts from two classification trees, HHCART and Geometric Decision Tree (GDT). HHCART(G) is a simplified HHCART algorithm that uses linear structure in the training examples, captured by a modified GDT angle bisector, to define splitting directions. At each node, we reflect the training examples with respect to the modified angle bisector to align this linear structure with the coordinate axes. Searching axis parallel splits in this reflected feature space provides an efficient and effective way of finding oblique splits in the original feature space. Our method is much simpler than HHCART because it only considers one reflected feature space for node splitting. HHCART considers multiple reflected feature spaces for node splitting making it more computationally intensive to build. Experimental results show that HHCART(G) is an effective classifier, producing compact trees with similar or better results than several other decision trees, including GDT and HHCART trees.     

Documenting Pornography Use in America: A Comparative Analysis of Methodological Approaches

Estimates of pornography use in the United States range widely. We explore the reasons for the variation in such estimates among U.S. adults using data from four different recent nationally representative samples—each of which asked a different type of question about pornography use. We attribute the notable variation in estimates to differences in question wording and answer options, and assert that a survey question asking respondents about their most recent use of pornography minimizes recall bias and is better poised to assess the overall prevalence of pornography in a population than is the more common approach of asking respondents about their historical general-use pattern. When we privileged the most-recent-use approach, survey data from 2014 reveal that 46% of men and 16% of women between the ages of 18 and 39 intentionally viewed pornography in a given week. These numbers are notably higher than most previous population estimates employing different types of questions. The results have ramifications for methods of surveying sensitive self-reported behaviors and for contextualizing scholars’ claims as well as popular conversations about the reach and implications of pornography use in the United States.     

Farmer participation in voluntary land diversion schemes: Some predictions from a survey

National and European agricultural policy schemes are now coming forward which rely on land diversion to achieve a variety of supply control, social and environmental policy goals. Operating on a voluntary basis, these will depend for their success on sufficient numbers of farmers agreeing to enrol land in sufficient quantities and in the right localities. Participation is thus a crucial variable in any assessment of land diversion policies. This paper draws on the results of a farm survey to make some predictions about the level and pattern of uptake of a range of such schemes, identifying the characteristics of resistors and adopters and exploring the motives of participants. It is concluded that land diversion will have most appeal to well-placed farmers who are able to justify the diversion of land out of an agricultural use in terms of forestry and conservation plans which have already been laid. The implication is that voluntary schemes may not be especially powerful instruments for bringing about land use changes on the large number of holdings in the U.K. which presently lack any history of conservation or forestry management, at least not without accompanying reductions in the level of market support for agriculture.     

Land-use and environmental pressures resulting from current and future bioenergy crop expansion: A review

Recent energy and climate policies, particularly in the developed world, have increased demand for bioenergy² as an alternative, which has led to both direct and indirect land-use changes and an array of environmental and socio-economic concerns. A comprehensive understanding of the land-use dynamics of bioenergy crop production is essential for the development of sustainable bioenergy and land-use policies. In this paper, we review the patterns and dynamics of land-use change associated with bioenergy crops (hereafter referred to as ’bioenergy-driven land-use change’). The review focuses on four regions as the most prominent locations in which these patterns and changes occur: Brazil; Indonesia and Malaysia; the United States of America (U.S.A.); and the European Union (EU). The review confirms that bioenergy-driven land-use change has affected and will impact most severely on the ’land- and resource-abundant’ developing regions, such as Brazil, where economic development takes priority over sustainable land-use policies, and the enforcement capability is limited. Opportunities for more effective policy are available through the development of international climate change policy (e.g. REDD under the UNFCCC), and certification criteria for sustainable bioenergy products (e.g. EU RED). However, bioenergy produced from no and/or less land-using feedstocks (e.g. wastes and residues), and their associated technologies must be given higher priority to minimise bioenergy-driven land-use change and its negative impacts.