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Chen M.H.,University of Toronto | Willan A.R.,SickKids Research Institute
Statistics in Medicine | Year: 2014

Value-of-information methods are applied to assess the evidence in support of a new diagnostic test and, where the evidence is insufficient for decision making, to determine the optimal sample size for future studies. Net benefit formulations are derived under various diagnostic and treatment scenarios. The expressions for the expected opportunity loss of adopting strategies that include the new test are given. Expressions for the expected value of information from future studies are derived. One-sample and two-sample designs, with or without known prevalence, are considered. An example is given. © 2014 John Wiley & Sons, Ltd. Source


Eckermann S.,University of Wollongong | Willan A.R.,SickKids Research Institute | Willan A.R.,University of Toronto
PharmacoEconomics | Year: 2013

Risk sharing arrangements relate to adjusting payments for new health technologies given evidence of their performance over time. Such arrangements rely on prospective information regarding the incremental net benefit of the new technology, and its use in practice. However, once the new technology has been adopted in a particular jurisdiction, randomized clinical trials within that jurisdiction are likely to be infeasible and unethical in the cases where they would be most helpful, i.e. with current evidence of positive while uncertain incremental health and net monetary benefit. Informed patients in these cases would likely be reluctant to participate in a trial, preferring instead to receive the new technology with certainty. Consequently, informing risk sharing arrangements within a jurisdiction is problematic given the infeasibility of collecting prospective trial data. To overcome such problems, we demonstrate that global trials facilitate trialling post adoption, leading to more complete and robust risk sharing arrangements that mitigate the impact of costs of reversal on expected value of information in jurisdictions who adopt while a global trial is undertaken. More generally, optimally designed global trials offer distinct advantages over locally optimal solutions for decision makers and manufacturers alike: avoiding opportunity costs of delay in jurisdictions that adopt; overcoming barriers to evidence collection; and improving levels of expected implementation. Further, the greater strength and translatability of evidence across jurisdictions inherent in optimal global trial design reduces barriers to translation across jurisdictions characteristic of local trials. Consequently, efficiently designed global trials better align the interests of decision makers and manufacturers, increasing the feasibility of risk sharing and the expected strength of evidence over local trials, up until the point that current evidence is globally sufficient. © 2013 Springer International Publishing Switzerland. Source


Li Y.,University of Toronto | Goldenberg A.,University of Toronto | Goldenberg A.,SickKids Research Institute | Wong K.-C.,University of Toronto | Zhang Z.,University of Toronto
Bioinformatics | Year: 2014

Motivation: Systematic identification of microRNA (miRNA) targets remains a challenge. The miRNA overexpression coupled with genome-wide expression profiling is a promising new approach and calls for a new method that integrates expression and sequence information.Results: We developed a probabilistic scoring method called targetScore. TargetScore infers miRNA targets as the transformed fold-changes weighted by the Bayesian posteriors given observed target features. To this end, we compiled 84 datasets from Gene Expression Omnibus corresponding to 77 human tissue or cells and 113 distinct transfected miRNAs. Comparing with other methods, targetScore achieves significantly higher accuracy in identifying known targets in most tests. Moreover, the confidence targets from targetScore exhibit comparable protein downregulation and are more significantly enriched for Gene Ontology terms. Using targetScore, we explored oncomir-oncogenes network and predicted several potential cancer-related miRNA-messenger RNA interactions. © 2013 The Author 2013. Published by Oxford University Press. All rights reserved. Source


Justice M.J.,SickKids Research Institute | Dhillon P.,Company of Biologists
DMM Disease Models and Mechanisms | Year: 2016

Experiments that use the mouse as a model for disease have recently come under scrutiny because of the repeated failure of data, particularly derived from preclinical studies, to be replicated or translated to humans. The usefulness of mouse models has been questioned because of irreproducibility and poor recapitulation of human conditions. Newer studies, however, point to bias in reporting results and improper data analysis as key factors that limit reproducibility and validity of preclinical mouse research. Inaccurate and incomplete descriptions of experimental conditions also contribute. Here, we provide guidance on best practice in mouse experimentation, focusing on appropriate selection and validation of the model, sources of variation and their influence on phenotypic outcomes, minimum requirements for control sets, and the importance of rigorous statistics. Our goal is to raise the standards in mouse disease modeling to enhance reproducibility, reliability and clinical translation of findings. © 2016 Published by The Company of Biologists Ltd. Source


Burrell K.,SickKids Research Institute | Hill R.P.,Ontario Cancer Institute | Hill R.P.,University of Toronto | Zadeh G.,University of Toronto | Zadeh G.,University of Western Ontario
PLoS ONE | Year: 2012

Radiation therapy (RT) is a widely accepted treatment strategy for many central nervous system (CNS) pathologies. However, despite recognized therapeutic success, significant negative consequences are associated with cranial irradiation (CR), which manifests months to years post-RT. The pathophysiology and molecular alterations that culminate in the long-term detrimental effects of CR are poorly understood, though it is thought that endothelial injury plays a pivotal role in triggering cranial injury. We therefore explored the contribution of bone marrow derived cells (BMDCs) in their capacity to repair and contribute to neo-vascularization following CR. Using high-resolution in vivo optical imaging we have studied, at single-cell resolution, the spatio-temporal response of BMDCs in normal brain following CR. We demonstrate that BMDCs are recruited specifically to the site of CR, in a radiation dose and temporal-spatial manner. We establish that BMDCs do not form endothelial cells but rather they differentiate predominantly into inflammatory cells and microglia. Most notably we provide evidence that more than 50% of the microglia in the irradiated region of the brain are not resident microglia but recruited from the bone marrow following CR. These results have invaluable therapeutic implications as BMDCs may be a primary therapeutic target to block acute and long-term inflammatory response following CR. Identifying the critical steps involved in the sustained recruitment and differentiation of BMDCs into microglia at the site of CR can provide new insights into the mechanisms of injury following CR offering potential therapeutic strategies to counteract the long-term adverse effects of CR. © 2012 Burrell et al. Source

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