Incorporating adverse event relatedness into dose-finding clinical trial designs

Dose-finding designs estimate the dose level of a drug based on observed adverse events. Relatedness of the adverse event to the drug has been generally ignored in all proposed design methodologies. These designs assume that the adverse events observed during a trial are definitely related to the drug, which can lead to flawed dose-level estimation. We incorporate adverse event relatedness into the so-called continual reassessment method. Adverse events that have ‘doubtful’ or ‘possible’ relationships to the drug are modelled using a two-parameter logistic model with an additive probability mass. Adverse events ‘probably’ or ‘definitely’ related to the drug are modelled using a cumulative logistic model. To search for the maximum tolerated dose, we use the maximum estimated toxicity probability of these two adverse event relatedness categories. We conduct a simulation study that illustrates the characteristics of the design under various scenarios. This article demonstrates that adverse event relatedness is important for improved dose estimation. It opens up further research pathways into continual reassessment design methodologies.

Non-linear principal components analysis : an alternative method for finding patterns in environmental data

The main purpose of this article is to gain an insight into the relationships between variables describing the environmental conditions of the Far Northern section of the Great Barrier Reef, Australia. Several of the variables describing these conditions had different measurement levels and often they had non-linear relationships. Using non-linear principal component analysis, it was possible to acquire an insight into these relationships. Furthermore, three geographical areas with unique environmental characteristics could be identified.

Finding good differential patterns for attacks on SHA-1

In this paper we analyse properties of the message expansion algorithm of SHA-1 and describe a method of finding differential patterns that may be used to attack reduced versions of SHA-1. We show that the problem of finding optimal differential patterns for SHA-1 is equivalent to the problem of finding minimal weight codeword in a large linear code. Finally, we present a number of patterns of different lengths suitable for finding collisions and near-collisions and discuss some bounds on minimal weights of them.

Finding country

The Finding Country Exhibition seeks a pluralist contest between the traditions of aboriginal space (Country), and European space (property) in Australia. Aboriginal Country is excluded from the Australian city. The city of Brisbane, located on the aboriginal Country of the Turrbal people, is the common ground of this confrontation. It is the show Australia rejected. Despite the 1992 landmark Mabo case High Court decision, a decision that struck down the doctrine of terra nullius (an empty land belonging to no-one), architecture in Australia continues its 18th century European tradition of drawing on empty paper. The aboriginal position is that this paper is not empty, but is full of what can’t be seen. The aboriginal map of Australia reveals a continent with many Countries and many spaces. The prevailing spectrum of architectural positions, bookended by decorated sheds and metaphysical decks, continues to bring aboriginal Country into decline. If the opposite position is considered it is possible to find something lost. Cities historically enter states of decline, frequently associated with some form of catastrophe. Others end in a whimper. It is not unreasonable to imagine an opportunity for the recovery of Country through decline. The central exhibit is an 8×3m drawing of the city of Brisbane consisting of approximately 50 individual grid submissions emptied by half to find something special. Each grid is an explicit architectural negotiation with decline, whilst carrying an implicit personal challenge to non-aboriginal architects to engage Country. Since 2006, the Finding Country project has endeavoured to assert an aboriginal origin for architecture in Australia. It is led and directed by Kevin O’Brien a descendent of the Kaurareg and Meriam people of north-eastern Australia, and an architect working in Brisbane.

Sanctuary Place : Sep Yama / Finding Country 5 Ways

Intelligent architecture allows a generosity of reading. It does not expect that we follow the architect’s instructions but that one is allowed to breath their own meaning into it and take away their own memory. Here, on the fringe of a postured architectural mass of national thinking, is an architectural gem. Its purpose, as I see it, is simple: to make a “camp”. In so doing it has accidentally revealed a passion for Country. Not necessarily Country in the way I might define it but Country in at least how I might recognise it; something alive, something powerful to be engaged.

Tactics for teaching evidence-based practice : improving self-efficacy in finding and appraising evidence in a master's evidence-based practice unit

Universal application of evidence-based practice (EBP) is far from a reality with many clinicians feeling ill equipped to adopt this approach in their clinical practice (Melnyk Fineout- Overholt, Feinstein, Sadler, & Green-Hernandez, 2008; Sherriff, Wallis, & Chaboyer, 2007) and, thus, to be an intelligent consumer of evidence (Ciliska, 2005). While recognizing the benefit of EBP, many health professionals have low confidence in their skills for using evidence in clinical settings (Nagy, Lumby, McKinley, &Macfarlane, 2001). Educational initiatives are often recommended for promoting adoption of EBP with much of the focus being on providing knowledge of associated processes. Levin, Melnyk, Fineout-Overholt, Barnes, and Vetter (2011) demonstrated that providing knowledge of EBP process alone does not increase clinicians’ confidence in their ability to apply EBP to their practice...

‘It’s about finding a way’ : children, sites of opportunity, and building everyday peace in Colombia

The multiple forms of violence associated with protracted conflict disproportionately affect young people. Literature on conflict-affected children often focuses on the need to provide stability and security through institutions such as schools but rarely considers how young people themselves see these sites as part of their everyday lives. The enduring, pervasive, and complex nature of Colombia’s conflict means many young Colombians face the challenges of poverty, persistent social exclusion, and violence. Such conditions are exacerbated in ‘informal’ barrio communities such as los Altos de Cazucá, just south of the capital Bogotá. Drawing on field research in this community, particularly through interviews conducted with young people aged 10 to 17 this article explores how young people themselves understand the roles of the local school and ngo in their personal conceptualisations of the violence in their everyday lives. The evidence indicates that children use spaces available to them opportunistically and that these actions can and should be read as contributing to local, everyday forms of peacebuilding. The ways in which institutional spaces are understood and used by young people as ‘sites of opportunity’ challenges the assumed illegitimacy of young people’s voices and experiences in these environments.

Diagnose this if you can: On the effectiveness of search engines in finding medical self-diagnosis information

An increasing amount of people seek health advice on the web using search engines; this poses challenging problems for current search technologies. In this paper we report an initial study of the effectiveness of current search engines in retrieving relevant information for diagnostic medical circumlocutory queries, i.e., queries that are issued by people seeking information about their health condition using a description of the symptoms they observes (e.g. hives all over body) rather than the medical term (e.g. urticaria). This type of queries frequently happens when people are unfamiliar with a domain or language and they are common among health information seekers attempting to self-diagnose or self-treat themselves. Our analysis reveals that current search engines are not equipped to effectively satisfy such information needs; this can have potential harmful outcomes on people’s health. Our results advocate for more research in developing information retrieval methods to support such complex information needs.

Neuroimaging and genetics: Exploring, searching, and finding

This issue on the genetics of brain imaging phenotypes is a celebration of the happy marriage between two of science's highly interesting fields: neuroscience and genetics. The articles collected here are ample evidence that a good deal of synergy exists in this marriage. A wide selection of papers is presented that provide many different perspectives on how genes cause variation in brain structure and function, which in turn influence behavioral phenotypes (including psychopathology). They are examples of the many different methodologies in contemporary genetics and neuroscience research. Genetic methodology includes genome-wide association (GWA), candidate-gene association, and twin studies. Sources of data on brain phenotypes include cortical gray matter (GM) structural/volumetric measures from magnetic resonance imaging (MRI); white matter (WM) measures from diffusion tensor imaging (DTI), such as fractional anisotropy; functional- (activity-) based measures from electroencephalography (EEG), and functional MRI (fMRI). Together, they reflect a combination of scientific fields that have seen great technological advances, whether it is the single-nucleotide polymorphism (SNP) array in genetics, the increasingly high-resolution MRI imaging, or high angular resolution diffusion imaging technique for measuring WM connective properties.

Finding the leverage point in the sustainability crisis: Global, national and regional Australian responses

From an economic perspective, the sustainability crisis is ultimately characterized by a worsening relationship between the resources required to support the global population and the ability of the earth to supply them. Despite the ever-increasing threat of a calamity, modern society appears unable to alter its course. The very systems which underpin global human endeavor seem to actively prevent meaningful change and the one irrepressible goal to which all societies seem to strive is the very thing that makes such endeavor ultimately life threatening: that of global growth. Using the Australian experience as an exemplar, this paper explores how the concept of growth infiltrates societal reactions to the crisis at various scales – global, national and regional. Analysis includes historic studies, a critique of current misconceptions around population demographics, comparative evaluation of various interventions in the Australian context and considerations around potential ways to address the crisis.

Finding within-organisation spatial information on the web

Information available on company websites can help people navigate to the offices of groups and individuals within the company. Automatically retrieving this within-organisation spatial information is a challenging AI problem This paper introduces a novel unsupervised pattern-based method to extract within-organisation spatial information by taking advantage of HTML structure patterns, together with a novel Conditional Random Fields (CRF) based method to identify different categories of within-organisation spatial information. The results show that the proposed method can achieve a high performance in terms of F-Score, indicating that this purely syntactic method based on web search and an analysis of HTML structure is well-suited for retrieving within-organisation spatial information.

A simple Bayesian decision-theoretic design for dose-finding trials

A flexible and simple Bayesian decision-theoretic design for dose-finding trials is proposed in this paper. In order to reduce the computational burden, we adopt a working model with conjugate priors, which is flexible to fit all monotonic dose-toxicity curves and produces analytic posterior distributions. We also discuss how to use a proper utility function to reflect the interest of the trial. Patients are allocated based on not only the utility function but also the chosen dose selection rule. The most popular dose selection rule is the one-step-look-ahead (OSLA), which selects the best-so-far dose. A more complicated rule, such as the two-step-look-ahead, is theoretically more efficient than the OSLA only when the required distributional assumptions are met, which is, however, often not the case in practice. We carried out extensive simulation studies to evaluate these two dose selection rules and found that OSLA was often more efficient than two-step-look-ahead under the proposed Bayesian structure. Moreover, our simulation results show that the proposed Bayesian method's performance is superior to several popular Bayesian methods and that the negative impact of prior misspecification can be managed in the design stage.

Decision-theoretic designs for dose-finding clinical trials with multiple outcomes

A decision-theoretic framework is proposed for designing sequential dose-finding trials with multiple outcomes. The optimal strategy is solvable theoretically via backward induction. However, for dose-finding studies involving k doses, the computational complexity is the same as the bandit problem with k-dependent arms, which is computationally prohibitive. We therefore provide two computationally compromised strategies, which is of practical interest as the computational complexity is greatly reduced: one is closely related to the continual reassessment method (CRM), and the other improves CRM and approximates to the optimal strategy better. In particular, we present the framework for phase I/II trials with multiple outcomes. Applications to a pediatric HIV trial and a cancer chemotherapy trial are given to illustrate the proposed approach. Simulation results for the two trials show that the computationally compromised strategy can perform well and appear to be ethical for allocating patients. The proposed framework can provide better approximation to the optimal strategy if more extensive computing is available.

Ultrasound of paediatric appendicitis and its secondary sonographic signs: Providing a more meaningful finding

Sonography is an important clinical tool in diagnosing appendicitis in children as it can obviate both exposure to potentially harmful ionising radiation from computed tomography scans and the need for unnecessary appendicectomies. This review examines the diagnostic accuracy of ultrasound in the identification of acute appendicitis, with a particular focus on the the utility of secondary sonographic signs as an adjunct or corollary to traditionally examined criteria. These secondary signs can be important in cases where the appendix cannot be identified with ultrasound and a more meaningful finding may be made by incorporating the presence or absence of secondary sonographic signs. There is evidence that integrating these secondary signs into the final ultrasound diagnosis can improve the utility of ultrasound in cases where appendicitis is expected, though there remains some conjecture about whether they play a more important role in negative or positive prediction in the absence of an identifiable appendix.

Finding genes for economically important traits: Brahman cattle puberty.

Age at puberty is an important component of reproductive performance in beef cattle production systems. Brahman cattle are typically late-pubertal relative to Bos taurus cattle and so it is of economic relevance to select for early age at puberty. To assist selection and elucidate the genes underlying puberty, we performed a genome-wide association study (GWAS) using the BovineSNP50 chip (similar to 54 000 polymorphisms) in Brahman bulls (n = 1105) and heifers (n = 843) and where the heifers were previously analysed in a different study. In a new attempt to generate unbiased estimates of single-nucleotide polymorphism (SNP) effects and proportion of variance explained by each SNP, the available data were halved on the basis of year and month of birth into a calibration and validation set. The traits that defined age at puberty were, in heifers, the age at which the first corpus luteum was detected (AGECL, h(2) = 0.56 +/- 0.11) and in bulls, the age at a scrotal circumference of 26 cm (AGE26, h(2) = 0.78 +/- 0.10). At puberty, heifers were on average older (751 +/- 142 days) than bulls (555 +/- 101 days), but AGECL and AGE26 were genetically correlated (r = 0.20 +/- 0.10). There were 134 SNPs associated with AGECL and 146 SNPs associated with AGE26 (P < 0.0001). From these SNPs, 32 (similar to 22%) were associated (P < 0.0001) with both traits. These top 32 SNPs were all located on Chromosome BTA 14, between 21.95 Mb and 28.4 Mb. These results suggest that the genes located in that region of BTA 14 play a role in pubertal development in Brahman cattle. There are many annotated genes underlying this region of BTA 14 and these are the subject of current research. Further, we identified a region on Chromosome X where markers were associated (P < 1.00E-8) with AGE26, but not with AGECL. Information about specific genes and markers add value to our understanding of puberty and potentially contribute to genomic selection. Therefore, identifying these genes contributing to genetic variation in AGECL and AGE26 can assist with the selection for early onset of puberty.