Improved variance estimation of classification performance via reduction of bias caused by small sample size

BACKGROUND: Supervised learning for classification of cancer employs a set of design examples to learn how to discriminate between tumors. In practice it is crucial to confirm that the classifier is robust with good generalization performance to new examples, or at least that it performs better than random guessing. A suggested alternative is to obtain a confidence interval of the error rate using repeated design and test sets selected from available examples. However, it is known that even in the ideal situation of repeated designs and tests with completely novel samples in each cycle, a small test set size leads to a large bias in the estimate of the true variance between design sets. Therefore different methods for small sample performance estimation such as a recently proposed procedure called Repeated Random Sampling (RSS) is also expected to result in heavily biased estimates, which in turn translates into biased confidence intervals. Here we explore such biases and develop a refined algorithm called Repeated Independent Design and Test (RIDT). RESULTS: Our simulations reveal that repeated designs and tests based on resampling in a fixed bag of samples yield a biased variance estimate. We also demonstrate that it is possible to obtain an improved variance estimate by means of a procedure that explicitly models how this bias depends on the number of samples used for testing. For the special case of repeated designs and tests using new samples for each design and test, we present an exact analytical expression for how the expected value of the bias decreases with the size of the test set. CONCLUSION: We show that via modeling and subsequent reduction of the small sample bias, it is possible to obtain an improved estimate of the variance of classifier performance between design sets. However, the uncertainty of the variance estimate is large in the simulations performed indicating that the method in its present form cannot be directly applied to small data sets

Opti-Owecs: Final Report Vol. 0: Executive Summary

It was the particular mission of the project 'Structural and Economic Optimisation of Bottom-Mounted Offshore Wind Energy Converters' (Opti-OWECS) to extend the state-of-the-art, to determine required methods and to demonstrate practical solutions which will significantly reduce the electricity cost. This will facilitate the exploitation of true offshore sites on a commercial base in a medium time scale of 5 to 10 years from now. In several fields, e.g. support structure design, installation of the offshore wind energy converters, operation and maintenance, dynamics of the entire offshore wind energy converter, structural reliability considerations, etc., the study demonstrated new propositions which will contribute significantly to a mature offshore wind energy technology. This was achieved due to a smooth cooperation of leading industrial engineers and researchers from the wind energy field, offshore technology and power management. Moreover, an innovative design methodology devoted particularly to offshore wind energy conversion systems (OWECS) was developed and successfully demonstrated. The so-called 'integrated OWECS design approach' considers the components of an offshore wind farm as parts of an entire system. Therefore interactions between sub-systems are considered in a complete and practical form as possible so that the design solution is governed by overall criteria such as: levelised production costs, adaptation to the actual site conditions, dynamics of the entire system, installation effort as well as OWECS availability. Furthermore, a novel OWECS cost model was developed which led among other work of the project to the identification of the main cost drivers, i.e. annual mean wind speed, distance from shore, operation and maintenance aspects including wind turbine reliability and availability. A link between these results and a database of the offshore wind energy potential in Europe, developed by the previous Joule project JOUR 0072, facilitated the first estimate of energy cost consistent over entire regions of Northern Europe. The European Commission has supported the project in the scope of the framework of the Non Nuclear Energy Programme JOULE Ill (Research and Technical Development) under grant JOR3-CT95-0087

Adipocyte-specific protein tyrosine phosphatase 1B deletion increases lipogenesis, adipocyte cell size and is a minor regulator of glucose homeostasis

Peer reviewedPublisher PD

Natural products in modern life science

With a realistic threat against biodiversity in rain forests and in the sea, a sustainable use of natural products is becoming more and more important. Basic research directed against different organisms in Nature could reveal unexpected insights into fundamental biological mechanisms but also new pharmaceutical or biotechnological possibilities of more immediate use. Many different strategies have been used prospecting the biodiversity of Earth in the search for novel structure–activity relationships, which has resulted in important discoveries in drug development. However, we believe that the development of multidisciplinary incentives will be necessary for a future successful exploration of Nature. With this aim, one way would be a modernization and renewal of a venerable proven interdisciplinary science, Pharmacognosy, which represents an integrated way of studying biological systems. This has been demonstrated based on an explanatory model where the different parts of the model are explained by our ongoing research. Anti-inflammatory natural products have been discovered based on ethnopharmacological observations, marine sponges in cold water have resulted in substances with ecological impact, combinatory strategy of ecology and chemistry has revealed new insights into the biodiversity of fungi, in depth studies of cyclic peptides (cyclotides) has created new possibilities for engineering of bioactive peptides, development of new strategies using phylogeny and chemography has resulted in new possibilities for navigating chemical and biological space, and using bioinformatic tools for understanding of lateral gene transfer could provide potential drug targets. A multidisciplinary subject like Pharmacognosy, one of several scientific disciplines bridging biology and chemistry with medicine, has a strategic position for studies of complex scientific questions based on observations in Nature. Furthermore, natural product research based on intriguing scientific questions in Nature can be of value to increase the attraction for young students in modern life science

Evaluation of emergency department performance:A systematic review on recommended performance and quality-in-care measures

BACKGROUND: Evaluation of emergency department (ED) performance remains a difficult task due to the lack of consensus on performance measures that reflects high quality, efficiency, and sustainability. AIM: To describe, map, and critically evaluate which performance measures that the published literature regard as being most relevant in assessing overall ED performance. METHODS: Following the PRISMA guidelines, a systematic literature review of review articles reporting accentuated ED performance measures was conducted in the databases of PubMed, Cochrane Library, and Web of Science. Study eligibility criteria includes: 1) the main purpose was to discuss, analyse, or promote performance measures best reflecting ED performance, 2) the article was a review article, and 3) the article reported macro-level performance measures, thus reflecting an overall departmental performance level. RESULTS: A number of articles addresses this study’s objective (n = 14 of 46 unique hits). Time intervals and patient-related measures were dominant in the identified performance measures in review articles from US, UK, Sweden and Canada. Length of stay (LOS), time between patient arrival to initial clinical assessment, and time between patient arrivals to admission were highlighted by the majority of articles. Concurrently, “patients left without being seen” (LWBS), unplanned re-attendance within a maximum of 72 hours, mortality/morbidity, and number of unintended incidents were the most highlighted performance measures that related directly to the patient. Performance measures related to employees were only stated in two of the 14 included articles. CONCLUSIONS: A total of 55 ED performance measures were identified. ED time intervals were the most recommended performance measures followed by patient centeredness and safety performance measures. ED employee related performance measures were rarely mentioned in the investigated literature. The study’s results allow for advancement towards improved performance measurement and standardised assessment across EDs

A Facile Strategy for In Situ Core-Template-Functionalizing Siliceous Hollow Nanospheres for Guest Species Entrapment

The shell wall-functionalized siliceous hollow nanospheres (SHNs) with functional molecules represent an important class of nanocarriers for a rich range of potential applications. Herein, a self-templated approach has been developed for the synthesis of in situ functionalized SHNs, in which the biocompatible long-chain polycarboxylates (i.e., polyacrylate, polyaspartate, gelatin) provide the framework for silica precursor deposition by simply controlling chain conformation with divalent metal ions (i.e., Ca2+, Sr2+), without the intervention of any external templates. Metal ions play crucial roles in the formation of organic vesicle templates by modulating the long chains of polymers and preventing them from separation by washing process. We also show that, by in situ functionalizing the shell wall of SHNs, it is capable of entrapping nearly an eightfold quantity of vitamin Bc in comparison to the bare bulk silica nanospheres. These results confirm the feasibility of guest species entrapment in the functionalized shell wall, and SHNs are effective carriers of guest (bio-)molecules potentially for a variety of biomedical applications. By rationally choosing the functional (self-templating) molecules, this concept may represent a general strategy for the production of functionalized silica hollow structures

TumorBoost: Normalization of allele-specific tumor copy numbers from a single pair of tumor-normal genotyping microarrays

<p>Abstract</p> <p>Background</p> <p>High-throughput genotyping microarrays assess both total DNA copy number and allelic composition, which makes them a tool of choice for copy number studies in cancer, including total copy number and loss of heterozygosity (LOH) analyses. Even after state of the art preprocessing methods, allelic signal estimates from genotyping arrays still suffer from systematic effects that make them difficult to use effectively for such downstream analyses.</p> <p>Results</p> <p>We propose a method, TumorBoost, for normalizing allelic estimates of one tumor sample based on estimates from a single matched normal. The method applies to any paired tumor-normal estimates from any microarray-based technology, combined with any preprocessing method. We demonstrate that it increases the signal-to-noise ratio of allelic signals, making it significantly easier to detect allelic imbalances.</p> <p>Conclusions</p> <p>TumorBoost increases the power to detect somatic copy-number events (including copy-neutral LOH) in the tumor from allelic signals of Affymetrix or Illumina origin. We also conclude that high-precision allelic estimates can be obtained from a single pair of tumor-normal hybridizations, if TumorBoost is combined with single-array preprocessing methods such as (allele-specific) CRMA v2 for Affymetrix or BeadStudio's (proprietary) XY-normalization method for Illumina. A bounded-memory implementation is available in the open-source and cross-platform R package <it>aroma.cn</it>, which is part of the Aroma Project (<url>http://www.aroma-project.org/</url>).</p

AMP-activated protein kinase - not just an energy sensor

Orthologues of AMP-activated protein kinase (AMPK) occur in essentially all eukaryotes as heterotrimeric complexes comprising catalytic α subunits and regulatory β and γ subunits. The canonical role of AMPK is as an energy sensor, monitoring levels of the nucleotides AMP, ADP, and ATP that bind competitively to the γ subunit. Once activated, AMPK acts to restore energy homeostasis by switching on alternate ATP-generating catabolic pathways while switching off ATP-consuming anabolic pathways. However, its ancestral role in unicellular eukaryotes may have been in sensing of glucose rather than energy. In this article, we discuss a few interesting recent developments in the AMPK field. Firstly, we review recent findings on the canonical pathway by which AMPK is regulated by adenine nucleotides. Secondly, AMPK is now known to be activated in mammalian cells by glucose starvation by a mechanism that occurs in the absence of changes in adenine nucleotides, involving the formation of complexes with Axin and LKB1 on the surface of the lysosome. Thirdly, in addition to containing the nucleotide-binding sites on the γ subunits, AMPK heterotrimers contain a site for binding of allosteric activators termed the allosteric drug and metabolite (ADaM) site. A large number of synthetic activators, some of which show promise as hypoglycaemic agents in pre-clinical studies, have now been shown to bind there. Fourthly, some kinase inhibitors paradoxically activate AMPK, including one (SU6656) that binds in the catalytic site. Finally, although downstream targets originally identified for AMPK were mainly concerned with metabolism, recently identified targets have roles in such diverse areas as mitochondrial fission, integrity of epithelial cell layers, and angiogenesis