Is automatic detection of hidden knowledge an anomaly?

Background: The quantity of documents being published requires researchers to specialize to a narrower field, meaning that inferable connections between publications (particularly from different domains) can be missed. This has given rise to automatic literature based discovery (LBD). However, unless heavily filtered, LBD generates more potential new knowledge than can be manually verified and another form of selection is required before the results can be passed onto a user. Since a large proportion of the automatically generated hidden knowledge is valid but generally known, we investigate the hypothesis that non trivial, interesting, hidden knowledge can be treated as an anomaly and identified using anomaly detection approaches. Results: Two experiments are conducted: (1) to avoid errors arising from incorrect extraction of relations, the hypothesis is validated using manually annotated relations appearing in a thesaurus, and (2) automatically extracted relations are used to investigate the hypothesis on publication abstracts. These allow an investigation of a potential upper bound and the detection of limitations yielded by automatic relation extraction. Conclusion: We apply one-class SVM and isolation forest anomaly detection algorithms to a set of hidden connections to rank connections by identifying outlying (interesting) ones and show that the approach increases the F1 measure by a factor of 10 while greatly reducing the quantity of hidden knowledge to manually verify. We also demonstrate the statistical significance of this result. Keywords: literature based discovery; anomaly detection; unified medical language syste

Surfaces Meeting Porous Sets in Positive Measure

Let n>2 and X be a Banach space of dimension strictly greater than n. We show there exists a directionally porous set P in X for which the set of C^1 surfaces of dimension n meeting P in positive measure is not meager. If X is separable this leads to a decomposition of X into a countable union of directionally porous sets and a set which is null on residually many C^1 surfaces of dimension n. This is of interest in the study of certain classes of null sets used to investigate differentiability of Lipschitz functions on Banach spaces

Applying metabolomics to cardiometabolic intervention studies and trials: past experiences and a roadmap for the future

Metabolomics and lipidomics are emerging methods for detailed phenotyping of small molecules in samples. It is hoped that such data will: (i) enhance baseline prediction of patient response to pharmacotherapies (beneficial or adverse); (ii) reveal changes in metabolites shortly after initiation of therapy that may predict patient response, including adverse effects, before routine biomarkers are altered; and( iii) give new insights into mechanisms of drug action, particularly where the results of a trial of a new agent were unexpected, and thus help future drug development. In these ways, metabolomics could enhance research findings from intervention studies. This narrative review provides an overview of metabolomics and lipidomics in early clinical intervention studies for investigation of mechanisms of drug action and prediction of drug response (both desired and undesired). We highlight early examples from drug intervention studies associated with cardiometabolic disease. Despite the strengths of such studies, particularly the use of state-of-the-art technologies and advanced statistical methods, currently published studies in the metabolomics arena are largely underpowered and should be considered as hypothesis-generating. In order for metabolomics to meaningfully improve stratified medicine approaches to patient treatment, there is a need for higher quality studies, with better exploitation of biobanks from randomized clinical trials i.e. with large sample size, adjudicated outcomes, standardized procedures, validation cohorts, comparison witth routine biochemistry and both active and control/placebo arms. On the basis of this review, and based on our research experience using clinically established biomarkers, we propose steps to more speedily advance this area of research towards potential clinical impact

Satellite Positioning - The Surveyor's Operational Requirement

The object of this paper is to develop surveyors' operational requirements for satellite positioning systems for the measurement of coordinates at positions which are inaccessible by conventional surveying methods. The paper briefly reviews positioning requirements with some comments on necessary accuracies, difficulties and technique options. Further developments to the existing capabilities of the Transit satellite positioning system are then suggested and the paper ends with some comments on the way that the surveying profession itself might develop in order to meet the needs of this relatively new surveying method

HiDE : a tool for unrestricted literature based discovery

As the quantity of publications increases daily, researchers are forced to narrow their attention to their own specialism and are therefore less likely to make new connections with other areas. Literature based discovery (LBD) supports the identification of such connections. A number of LBD tools are available, however, they often suffer from limitations such as constraining possible searches or not producing results in real-time. We introduce HiDE (Hidden Discovery Explorer), an online knowledge browsing tool which allows fast access to hidden knowledge generated from all abstracts in Medline. HiDE is fast enough to allow users to explore the full range of hidden connections generated by an LBD system. The tool employs two novel approaches to LBD: a graph-based approach which allows hidden knowledge to be generated on a large scale and an inference algorithm to identify the most promising information. Available at http://nlp.shef.ac.uk/hide</a

Niacin therapy and the risk of new-onset diabetes: a meta-analysis of randomized controlled trials

Objective Previous studies have suggested that niacin treatment raises glucose levels in patients with diabetes and may increase the risk of developing diabetes. We undertook a meta-analysis of published and unpublished data from randomised trials to confirm whether an association exists between niacin and new-onset diabetes. Methods We searched Medline, EMBASE and the Cochrane Central Register of Controlled Trials, from 1975 to 2014, for randomised controlled trials of niacin primarily designed to assess its effects on cardiovascular endpoints and cardiovascular surrogate markers. We included trials with ≥50 non-diabetic participants and average follow-up of ≥24 weeks. Published data were tabulated and unpublished data sought from investigators. We calculated risk ratios (RR) for new-onset diabetes with random-effects meta-analysis. Heterogeneity between trials was assessed using the I2 statistic. Results In 11 trials with 26 340 non-diabetic participants, 1371 (725/13 121 assigned niacin; 646/13 219 assigned control) were diagnosed with diabetes during a weighted mean follow-up of 3.6 years. Niacin therapy was associated with a RR of 1.34 (95% CIs 1.21 to 1.49) for new-onset diabetes, with limited heterogeneity between trials (I2=0.0%, p=0.87). This equates to one additional case of diabetes per 43 (95% CI 30 to 70) initially non-diabetic individuals who are treated with niacin for 5 years. Results were consistent regardless of whether participants received background statin therapy (p for interaction=0.88) or combined therapy with laropiprant (p for interaction=0.52). Conclusions Niacin therapy is associated with a moderately increased risk of developing diabetes regardless of background statin or combination laropiprant therapy

The emergence of proton nuclear magnetic resonance metabolomics in the cardiovascular arena as viewed from a clinical perspective

The ability to phenotype metabolic profiles in serum has increased substantially in recent years with the advent of metabolomics. Metabolomics is the study of the metabolome, defined as those molecules with an atomic mass less than 1.5 kDa. There are two main metabolomics methods: mass spectrometry (MS) and proton nuclear magnetic resonance (1H NMR) spectroscopy, each with its respective benefits and limitations. MS has greater sensitivity and so can detect many more metabolites. However, its cost (especially when heavy labelled internal standards are required for absolute quantitation) and quality control is sub-optimal for large cohorts. 1H NMR is less sensitive but sample preparation is generally faster and analysis times shorter, resulting in markedly lower analysis costs. 1H NMR is robust, reproducible and can provide absolute quantitation of many metabolites. Of particular relevance to cardio-metabolic disease is the ability of 1H NMR to provide detailed quantitative data on amino acids, fatty acids and other metabolites as well as lipoprotein subparticle concentrations and size. Early epidemiological studies suggest promise, however, this is an emerging field and more data is required before we can determine the clinical utility of these measures to improve disease prediction and treatment. This review describes the theoretical basis of 1H NMR; compares MS and 1H NMR and provides a tabular overview of recent 1H NMR-based research findings in the atherosclerosis field, describing the design and scope of studies conducted to date. 1H NMR metabolomics-CVD related research is emerging, however further large, robustly conducted prospective, genetic and intervention studies are needed to advance research on CVD risk prediction and to identify causal pathways amenable to intervention

Requirement for the eIF4E Binding Proteins for the Synergistic Down-Regulation of Protein Synthesis by Hypertonic Conditions and mTOR Inhibition.

The protein kinase mammalian target of rapamycin (mTOR) regulates the phosphorylation and activity of several proteins that have the potential to control translation, including p70S6 kinase and the eIF4E binding proteins 4E-BP1 and 4E-BP2. In spite of this, in exponentially growing cells overall protein synthesis is often resistant to mTOR inhibitors. We report here that sensitivity of wild-type mouse embryonic fibroblasts (MEFs) to mTOR inhibitors can be greatly increased when the cells are subjected to the physiological stress imposed by hypertonic conditions. In contrast, protein synthesis in MEFs with a double knockout of 4E-BP1 and 4E-BP2 remains resistant to mTOR inhibitors under these conditions. Phosphorylation of p70S6 kinase and protein kinase B (Akt) is blocked by the mTOR inhibitor Ku0063794 equally well in both wild-type and 4E-BP knockout cells, under both normal and hypertonic conditions. The response of protein synthesis to hypertonic stress itself does not require the 4E-BPs. These data suggest that under certain stress conditions: (i) translation has a greater requirement for mTOR activity and (ii) there is an absolute requirement for the 4E-BPs for regulation by mTOR. Importantly, dephosphorylation of p70S6 kinase and Akt is not sufficient to affect protein synthesis acutely

A Sustained Dietary Change Increases Epigenetic Variation in Isogenic Mice

Epigenetic changes can be induced by adverse environmental exposures, such as nutritional imbalance, but little is known about the nature or extent of these changes. Here we have explored the epigenomic effects of a sustained nutritional change, excess dietary methyl donors, by assessing genomic CpG methylation patterns in isogenic mice exposed for one or six generations. We find stochastic variation in methylation levels at many loci; exposure to methyl donors increases the magnitude of this variation and the number of variable loci. Several gene ontology categories are significantly overrepresented in genes proximal to these methylation-variable loci, suggesting that certain pathways are susceptible to environmental influence on their epigenetic states. Long-term exposure to the diet (six generations) results in a larger number of loci exhibiting epigenetic variability, suggesting that some of the induced changes are heritable. This finding presents the possibility that epigenetic variation within populations can be induced by environmental change, providing a vehicle for disease predisposition and possibly a substrate for natural selection.This work was supported by the Australian Research Council (DP0771859) and the National Health and Medical Research Council (#459412, #635510)