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AbstractThe Additive Voronoi Tessellations (AddiVortes) model is a multivariate regression model that uses Voronoi tessellations to partition the covariate space in an additive ensemble model. Unlike other partition methods, such as decision trees, this has the benefit of allowing the boundaries of the partitions to be non-orthogonal and non-parallel to the covariate axes. The AddiVortes model uses a similar sum-of-tessellations approach and a Bayesian backfitting MCMC algorithm to the BART model. We utilize regularization priors to limit the strength of individual tessellations and accepts new models based on a likelihood. The performance of the AddiVortes model is illustrated through testing on several data sets and comparing the performance to other models along with a simulation study to verify some of the properties of the model. In many cases, the AddiVortes model outperforms random forests, BART and other leading black-box regression models when compared using a range of metrics. Supplementary materials for this article are available online. [ABSTRACT FROM AUTHOR]

We harness the power of Bayesian emulation techniques, designed to aid the analysis of complex computer models, to examine the structure of complex Bayesian analyses themselves. These techniques facilitate robust Bayesian analyses and/or sensitivity analyses of complex problems, and hence allow global exploration of the impacts of choices made in both the likelihood and prior specification. We show how previously intractable problems in robustness studies can be overcome using emulation techniques, and how these methods allow other scientists to quickly extract approximations to posterior results corresponding to their own particular subjective specification. The utility and flexibility of our method is demonstrated on a reanalysis of a real application where Bayesian methods were employed to capture beliefs about river flow. We discuss the obvious extensions and directions of future research that such an approach opens up. [ABSTRACT FROM AUTHOR]

BackgroundGeneralized Anxiety Disorder (GAD) is a high prevalence, chronic disorder. Web-based interventions are acceptable, engaging, and can be delivered at scale. Few randomized controlled trials evaluate the effectiveness of prevention programs for anxiety, or the factors that improve effectiveness and engagement. ObjectiveThe intent of the study was to evaluate the effectiveness of a Web-based program in preventing GAD symptoms in young adults, and to determine the role of telephone and email reminders. MethodsA 5-arm randomized controlled trial with 558 Internet users in the community, recruited via the Australian Electoral Roll, was conducted with 6- and 12-month follow-up. Five interventions were offered over a 10-week period. Group 1 (Active website) received a combined intervention of psycho-education, Internet-delivered Cognitive Behavioral Therapy (ICBT) for anxiety, physical activity promotion, and relaxation. Group 2 (Active website with telephone) received the identical Web program plus weekly telephone reminder calls. Group 3 (Active website with email) received the identical Web program plus weekly email reminders. Group 4 (Control) received a placebo website. Group 5 (Control with telephone) received the placebo website plus telephone calls. Main outcome measures were severity of anxiety symptoms as measured by the GAD 7-item scale (GAD-7) (at post-test, 6, and 12 months). Secondary measures were GAD caseness, measured by the Mini International Neuropsychiatric Interview (MINI) at 6 months, Centre for Epidemiologic Studies-Depression scale (CES-D), Anxiety Sensitivity Index (ASI), Penn State Worry Questionnaire (PSWQ), and Days out of Role. ResultsGAD-7 symptoms reduced over post-test, 6-month, and 12-month follow-up. There were no significant differences between Group 4 (Control) and Groups 1 (Active website), 2 (Active website with telephone), 3 (Active website with email), or 5 (Control with telephone) at any follow-up. A total of 16 cases of GAD were identified at 6 months, comprising 6.7% (11/165) from the Active groups (1, 2, 3) and 4.5% (5/110) from the Control groups (4, 5), a difference that was not significant. CES-D, ASI, and PSWQ scores were significantly lower for the active website with email reminders at post-test, relative to the control website condition. ConclusionsIndicated prevention of GAD was not effective in reducing anxiety levels, measured by GAD-7. There were significant secondary effects for anxiety sensitivity, worry, and depression. Challenges for indicated prevention trials are discussed. Trial RegistrationInternational Standard Randomized Controlled Trial Number (ISRCTN): 76298775; http://www.controlled-trials.com/ISRCTN76298775 (Archived by WebCite at http://www.webcitation.org/6S9aB5MAq).

Pharmaceutical companies regularly need to make decisions about drug development programs based on the limited knowledge from early stage clinical trials. In this situation, eliciting the judgements of experts is an attractive approach for synthesising evidence on the unknown quantities of interest. When calculating the probability of success for a drug development program, multiple quantities of interest—such as the effect of a drug on different endpoints—should not be treated as unrelated. We discuss two approaches for establishing a multivariate distribution for several related quantities within the SHeffield ELicitation Framework (SHELF). The first approach elicits experts' judgements about a quantity of interest conditional on knowledge about another one. For the second approach, we first elicit marginal distributions for each quantity of interest. Then, for each pair of quantities, we elicit the concordance probability that both lie on the same side of their respective elicited medians. This allows us to specify a copula to obtain the joint distribution of the quantities of interest. We show how these approaches were used in an elicitation workshop that was performed to assess the probability of success of the registrational program of an asthma drug. The judgements of the experts, which were obtained prior to completion of the pivotal studies, were well aligned with the final trial results. [ABSTRACT FROM AUTHOR]

Many methods for modeling functions over high-dimensional spaces assume global smoothness properties; such assumptions are often violated in practice. We introduce a method for modeling functions that display heterogeneity or contain discontinuities. The heterogeneity is dealt with by using a combination of Voronoi tessellation, to partition the input space, and separate Gaussian processes to model the function over different regions of the partitioned space. The proposed method is highly flexible since it allows the Voronoi cells to combine to form regions, which enables nonconvex and disconnected regions to be considered. In such problems, identifying the borders between regions is often of great importance and we propose an adaptive sampling method to gain extra information along such borders. The method is illustrated by simulated examples and an application to real data, in which we see improvements in prediction error over the commonly used stationary Gaussian process and other nonstationary variations. In our application, a computationally expensive computer model that simulates the formation of clouds is investigated, the proposed method more accurately predicts the underlying process at unobserved locations than existing emulation methods. for this article are available online. [ABSTRACT FROM AUTHOR]

This final report summarises the objectives, activities and delivery, evaluation, and any future recommendations for each of the four trainings delivered under this contract. Sections are organised in chronological order consistent with the order in which trainings were delivered: Section 3 details the Sheffield course, Section 4 Semi‐formal, Section 5 Delphi, and Section 6 Cooke. Section 7 provides overarching conclusions from across all trainings. [ABSTRACT FROM AUTHOR]

Tox21 and ToxCast are high-throughput in vitro screening programs coordinated by the U.S. National Toxicology Program and the U.S. Environmental Protection Agency, respectively, with the goal of forecasting biological effects in vivo based on bioactivity profiling. The present study investigated whether mechanistic insights in the biological targets of food-relevant chemicals can be obtained from ToxCast results when the chemicals are grouped according to structural similarity. Starting from the 556 direct additives that have been identified in the ToxCast database by Karmaus et al. [Karmaus, A. L., Trautman, T. D., Krishan, M., Filer, D. L., and Fix, L. A. (2017). Curation of food-relevant chemicals in ToxCast. Food Chem. Toxicol.   103 , 174–182.], the results showed that, despite the limited number of assays in which the chemical groups have been tested, sufficient results are available within so-called "DNA binding" and "nuclear receptor" target families to profile the biological activities of the defined chemical groups for these targets. The most obvious activity identified was the estrogen receptor-mediated actions of the chemical group containing parabens and structurally related gallates, as well the chemical group containing genistein and daidzein (the latter 2 being particularly active toward estrogen receptor β as a potential health benefit). These group effects, as well as the biological activities of other chemical groups, were evaluated in a series of case studies. Overall, the results of the present study suggest that high-throughput screening data could add to the evidence considered for regulatory risk assessment of food chemicals and to the evaluation of desirable effects of nutrients and phytonutrients. The data will be particularly useful for providing mechanistic information and to fill data gaps with read-across. [ABSTRACT FROM AUTHOR]

Carcinogenic potency is a key factor in the understanding of chemical risk assessment. Measures of carcinogenic potency, for example TD50, are instrumental in the determination of metrics such as the threshold of toxicological concern (TTC), acceptable intake (AI) and permitted daily exposure (PDE), which in turn impact on human exposure. The Carcinogenic Potency Data Base (CPDB) has provided a source of study information, complete with calculated TD50 values. However, this is no longer actively updated. An understanding of carcinogenic potency, which can be derived from dose–response data, can be used as part of human risk assessments to generate safety thresholds under which cancer risk is judged to be minimal. The aim of this paper is to produce a transparent methodology for calculating TD50 values from experimental data in a manner consistent with the CPDB. This was then applied across the same data as used in the CPDB and analysis done on the correlation with the CPDB TD50 values. While the two sets of values showed a high level of correlation overall, there were some significant discrepancies. These were predominantly due to a lack of clarity in the CPDB methodology and inappropriate use of a linear model in TD50 calculation where the data was not suitable for such an approach. [ABSTRACT FROM AUTHOR]

The article aims to provide new and more robust evidence on the hypothetical effect that the sentencing guidelines might have had on sentence severity. It informs that Time-series analyses have been used previously in the literature to assess the effect of different sentencing policy reforms in the U.S. It presents information on trends of offence severity.

Background: There is considerable interest in understanding the immunological variables that have the greatest influence on the effectiveness of sensitization by contact allergens, particularly in the context of developing new paradigms for risk assessment of novel compounds. Objectives: To examine the relationship between patch test score for three different contact allergens and the characteristics of T cell responses. Methods: A total of 192 patients with confirmed nickel, p‐phenylenediamine (PPD) or methylisothiazolinone (MI) allergy were recruited from the Contact Dermatitis Investigation Unit at Salford Royal Hospital. Severity of allergy was scored by the use of patch testing, peripheral blood lymphocytes were characterized for T cell phenotype by flow cytometry, and proliferative activity was characterized by radiolabelled thymidine incorporation. Comparisons were drawn with buffy coat samples from healthy volunteers. Results: Patch test positivity for nickel, PPD and MI was associated with changes in the phenotype of peripheral blood T cells: increases in naïve cells, decreases in regulatory T cell frequency and the CD4+/CD8hi ratio, and increased expression of the skin‐homing marker cutaneous lymphocyte antigen (CLA), particularly for those patients with a +++ patch test score. Conclusions: This increased understanding of the characteristics of the T cell responses to contact allergens may provide parameters with which to better measure health risks associated with skin sensitization. [ABSTRACT FROM AUTHOR]

John Gosling interviews Bill Hayes, author of the memoir Insomniac City: New York, Oliver, and Me. This interview explores Bill's experience of his creative process in writing this moving memoir. His six-year relationship (and subsequent loss to death) with renowned neurologist and author Oliver Sacks served as a source of inspiration for him. Bill reveals how his remarkable creative process, which was different from anything he had previously experienced, unfolded over a six-week period while on a scholarship in Rome. He describes how the many losses and deaths he has experienced have informed his creativity and capacity to be more present in his life. He is also a photographer, and he interspersed several of his New York photographs in the book while describing quite movingly his love affair with New York and the people he encounters on its streets. He ascribes his interest in photography to a template in his unconscious from his childhood experiences of being surrounded by books and magazines of photojournalism. Our creativity—what inspires us, where it originates, and how it manifests in us as humans—remains a mystery. This interview offers a window through which we can glimpse the unique creative process of one person who is an author and a photographer. [ABSTRACT FROM AUTHOR]

Conditional preference networks (CP-nets) are a graphical representation of a person's (conditional) preferences over a set of discrete features. In this paper, we introduce a novel method of quantifying preference for any given outcome based on a CP-net representation of a user's preferences. We demonstrate that these values are useful for reasoning about user preferences. In particular, they allow us to order (any subset of) the possible outcomes in accordance with the user's preferences. Further, these values can be used to improve the efficiency of outcome dominance testing. That is, given a pair of outcomes, we can determine which the user prefers more efficiently. Through experimental results, we show that this method is more effective than existing techniques for improving dominance testing efficiency. We show that the above results also hold for CP-nets that express indifference between variable values. [ABSTRACT FROM AUTHOR]