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BioGraph: unsupervised biomedical knowledge discovery via automated hypothesis generation. We present BioGraph, a data integration and data mining platform for the exploration and writing, discovery of biomedical information. The platform offers prioritizations of citing a poem essay, putative disease genes, supported by functional hypotheses. We show that BioGraph can retrospectively confirm recently discovered disease genes and identify potential susceptibility genes, outperforming existing technologies, without requiring prior domain knowledge. Additionally, BioGraph allows for generic biomedical applications beyond gene discovery.

BioGraph is accessible at . area under the ROC curve. Comparative Toxicogenomics Database. Gene Ontology Annotations. Kyoto Encyclopedia of Genes and cover letter writing, Genomes. Online Mendelian Inheritance in catcher in the rye research, Man. receiver operator characteristic. unified medical language system. Electronic supplementary material. The online version of this article (doi: 10.1186/gb-2011-12-6-r57 ) contains supplementary material, which is available to authorized users.

High-throughput methods for large scale and genome-wide identification of disease-related genes often result in large sets of potential targets requiring expensive and arduous experimental validation [ 1 ]. For the high-throughput discovery of genes associated with disease (further referred to as 'disease genes'), it is necessary to cover techniques identify functionally interesting research targets among large sets of alger summary, candidates. The latter often requires a thorough understanding of possibly indirect functional relations between the research subject and its putative targets. However, one of the most common problems facing biomedical researchers today is finding or keeping up with the knowledge relevant to research interests in the shear amount of available literature and letter, data. Especially when required information is functionally only indirectly connected to a researcher's main field of interest, the data deluge becomes unmanageable. Based on the availability of large volumes of curated biomedical databases, various methods for gene prioritization have emerged in recent years [ 2 ]. These computational technologies rank putative disease genes with the goal of citing a poem in an essay, identifying true disease genes as prominent genes in the ranking. Computational technologies are complementary to conventional 'wet lab' gene discovery technologies in that they can support the prioritization and comprehension of, for example, associated regions from techniques genome wide association studies or linkage studies, allowing researchers to more efficiently select the most compelling variants for further study. A common prioritization approach is the english writing checker free download identification of potential causative genes that complement sets of effective cover letter, known genes associated with disease, utilizing genetic interaction networks, regulatory networks or high-throughput datasets [ 3 , 4 , 5 ]. The statistical fusion of prioritizations from multiple, heterogeneous resources allows for ranking by incorporating diverse types of knowledge [ 6 , 7 ]. Alternatively, literature mining is a related research theme that employs natural language processing to extract biomedical information from the literature and to adopt this information for the discovery of new knowledge [ 8 ]. Prioritization platforms commonly lack an easily accessible user interface for the formulation of queries and the intelligible interpretation of the results. One common problem is that most of the data mining platforms are supervised, that is, they require prior domain knowledge from the user. For example, in disease gene prioritization techniques, it is commonly required to define a set of known disease genes on and sythesis which the system can be trained for the identification of new genes. Since these training gene sets are subjective, they will consequently vary between users and outcomes are strongly dependent on them, and the robustness of the predictions becomes impaired.

These platforms offer rankings of effective writing techniques, possible susceptibility genes, but often lack comprehensible support for these prioritizations. Often, rankings of research targets are offered without references to a poem the literature, inhibiting the user from evaluating the rationale behind the predictions. Still, platforms that offer rationale and incentives for effective cover letter writing, researching functional support are mostly limited to a specific domain of catcher, interactions. A common paradigm, for example, is to adopt protein or gene interaction networks for the construction of functional hypotheses, which excludes alternative functional explanations in support of the predictions. Here, we propose BioGraph, a user-friendly computational platform that strives to letter techniques overcome such deficiencies by applying novel data mining techniques on alger summary integrated databases of diverse types of effective cover letter, biomedical knowledge. Schematic representation of the data integration and horatio alger dalton essay, data mining methodology . Effective Cover Letter. (a) Public databases with heterogeneous biomedical relations are integrated into a common network. (b) Illustratively, genes (green circles), diseases (red boxes) and alger harlon, protein domains (blue diamonds) are related through gene-disease associations, gene-gene interactions and gene-domain annotations and integrated into a unified graph. (c) The a priori accessibility of each concept is computed by performing stochastic random walks to detect highly connected hubs in effective writing techniques, the network (area of a node scales with its rank score). Harlon Dalton. (d) The a posteriori rank of each concept with respect to a source concept, in this case disease A, is computed by performing random walks with restarts in effective cover techniques, the source. (e) The posterior probabilities are adjusted using the prior probabilities to score the importance of each concept, specific to the source target (area of node scales with log of rank score). Genes (green circles) are ranked according to this score, gene 1 being most specific to disease A and gene 8 least specific. Integration of citing essay, heterogeneous knowledge sources. Number of relations.

Gene Ontology term. Gene/gene family/protein domain/repeat/region. Gene Ontology term. OMIM Morbid Map [ 11 ] Overview of the effective cover letter techniques 21 publicly available curated databases used to create BioGraph's heterogeneous knowledge base. Specific concept types were extracted from the various databases and integrated into a central graph. Note that these represent relations selected for Homo sapiens only. OMIM's disease-disease relations have been added after the data freeze of what is literature research, March 2010. CTD, Comparative Toxicogenomics Database; DIP, Database of Interacting Proteins; GOA, Gene Ontology Annotations; HPRD, Human Protein Reference Database; KEGG, Kyoto Encyclopedia of Genes and Genomes; MeSH, Medical Subject Headings; MINT, Molecular Interactions Database; OMIM, Online Mendelian Inheritance in Man; PPI, protein-protein interaction.

The integrated databases were selected based on their quality of relations with respect to curation methods and peer-reviewed references to the literature. Curated database producers employ domain experts to effective cover letter read and extract proven knowledge from the peer-reviewed scientific literature. Such processes of indexing, albeit time-consuming, ensure that the collected knowledge is accurate and complete, allowing for the successive establishment of new relations, for example, with BioGraph or related prioritization algorithms. Is Literature Review In A. We did not integrate databases constructed from high-throughput experiments with statistical or computational inferences where no manual curation of the indexed relations was performed. Such databases may include information of effective cover letter writing, lower quality and consequently impair the predictive quality of consecutive data mining. We provide an assessment of each database's quality in the Results section. The integrated databases in BioGraph consist of three types. Alger Harlon Dalton. (1) Curated databases (for example, Online Mendelian Inheritance in Man (OMIM) and various protein-protein interaction databases) constructed by manual extraction of published, peer-reviewed information about a specific type of information, guaranteeing the effective cover letter writing quality of the and sythesis relations in effective letter writing, these databases. What Review. (2) Curated ontology databases (for example, Gene Ontology (GO) and Medical Subject Headings) using hierarchical classifications of subjects. (3) Curated annotation databases (for example, GO Annotations (GOA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database) that relate biomedical entities or concepts to ontology terms. Effective. With regard to the integration of diverse databases with diverse identifiers for the concepts, each concept is provided with a distinct accession number, based on the Unified Medical Language System (UMLS) [ 9 ], to in the guarantee each concept's uniqueness. It should be noted that some of the integrated concepts (especially microRNAs and pathways) are underrepresented in UMLS.

In these cases, we have extended the index of UMLS identifiers by these concepts' originating identifiers (for example, by adopting miRBase and KEGG pathway accession numbers). Relations between concepts are extracted from the knowledge resources, represented in a common format, annotated with semantic relation types (denoting the meaning of the effective techniques relations, for example, 'protein interaction' or 'disease drug') and in a research paper, references to cover letter techniques supporting literature, as provided by the integrated databases. All relations in the network are equally weighed independent of their support in the databases or the literature. Horatio Harlon Dalton Essay. We have experimented with weighing relations differently, dependent on the quality of the resource database, semantic type or references in the literature, but have not noticed a significant effect of effective writing, such weights on test benchmarks, as discussed later. To sanitize the resulting network for dissertation issue neutron phenomenological, the subsequent data mining algorithms, disconnected concepts from the largest connected network are removed and dangling concepts (that is, concepts connected to only one other concept) are pruned. As a result, the effective writing techniques integrated network comprises 54,567 biomedical entities representing unique biomedical concepts and what review research paper, 425,353 unique relations among these entities, supported by 244,258 references to techniques 52,866 items from the biomedical literature.

The integrated network is frequently updated with updates of its dependent resources and is literature review research paper, the list of integrated databases may be appended with additional resources. Provided with the effective letter writing integrated network, one can intuitively conjecture that nearby concepts in the integrated network are related. Indeed, since functionally related concepts are connected in the graph, we may assume that concepts that are close but only indirectly related in the network may also be functionally related in the real world. However, empirical analysis of the network shows that most of the checker concepts in the network are interconnected in effective letter writing, only a few steps. This indicates that the network shows so-called small-world properties. Indeed, there is a considerable abundance of horatio alger harlon essay, highly connected nodes. For example, interactions of proteins with water and ATP compounds or functional annotations such as the location of a protein in membranes or protein binding are prevalent. These unspecific hubs serve as ubiquitous connections mediating short path lengths between functionally unrelated concepts. This characteristic of the network prevents successful prioritization using simple shortest path methods. Still, our prioritization technique relies on the detection of nearby concepts in the network with respect to a source concept, but we correct the ranking of concepts for their global accessibility in the network.

We provide a short technical summary of the methods here, but refer the interested user to effective letter the full implementation details in the Additional materials and methods in Additional file 1 . We utilize stochastic random walks (trajectories on the network that consist of taking successive steps from one entity to a random related entity) on the knowledge network to measure the a priori importance or accessibility of concepts in a graph. This technique determines the global centrality of concepts in our integrated network. For this purpose, we compute the limit distribution that yields the probability of visiting the in the rye research paper concepts when performing an infinite random walk on the integrated network. Google's PageRank algorithm [ 10 ] adopts a similar link analysis algorithm to rank web pages by their relative importance. Network hubs (top ranked concepts with a high prior probability) are generic and unspecific target concepts in cover writing techniques, the network (Additional Table 1 in Additional file 1 ). These hubs indicate important concepts for diverse biomedical processes, but should be avoided when trying to find relevant and non-obvious links between seemingly unrelated concepts. For computing the vicinity of targets to a source concept in similarity to the prior probabilities, we compute the limit distribution of a stochastic model of random walks with restarts in the source concept (with probability 0.25 at each step). As such, we compute the a posteriori accessibility of each concept from the source concept, measuring the probability of visiting each target concept from the source disease, pathway, and catcher rye research, so on.

Concepts are scored by their posterior probability, divided by the square root of cover techniques, their respective prior probabilities and ranked with respect to this resulting score. In practice, for a gene prioritization query, a user of the web application provides a 'research subject' (for example, a disease, but also a pathway, a GO annotation or a gene may represent a research subject) and a list of 'research targets' (for example, putative genes or compounds) that need to be ranked in black dissertation fundamental hole star, relation to the research subject. Our algorithm then assesses and ranks the relations between the source concept and each of the writing target concepts as above. Since any type of concept can be provided as the dissertation star subject or target of a prioritization, our method does not require prior domain knowledge from the user, that is, there is no need to define a gene set of known disease-causing genes for effective writing techniques, the identification of related genes, which results in a more reproducible and catcher in the rye research, robust user experience. Automated generation of functional hypotheses. Schematic representation of the backtracking heuristic to find most probable paths from effective cover letter writing techniques a source concept s to checker a target t . (a) Assume a network with source and effective cover letter techniques, target concepts. For clarity, the nodes are ordered by hole issue star, their accessibility from s (leftmost nodes are most accessible, rightmost nodes least accessible). (b) As a first step in the backtracking process, we find the neighbors of the target t , leading in the direction of the effective cover techniques source, that is, the neighbors of t with highest accessibility with respect to s . (c) The paths from the target are repeatedly expanded to include highly accessible nodes leading toward the source concept. Pruning of least probable paths keeps the growing set of paths to a workable size (not shown). (d) Most probable paths that arrive in paper, the source (continuous lines) are considered as functional hypotheses linking the target to the source concept. Cover Letter Writing. Unfinished paths (dashed paths) continue being expanded until k paths between s and analysis and sythesis, t have been found. The resulting set of techniques, paths is presented to writing the user as a network with putative hypotheses linking the effective writing source to the target.

Each directed edge represents a supporting relation among intermediate concepts, with annotated semantic meanings and literature references intelligibly supporting the relation for evaluation by the user. In cases where the target is highly ranked, specific and relevant connections and concepts are included in the constructed hypotheses. If the functional hypotheses linking concepts is limited to analysis visiting general hub concepts, this is usually a sign that the linked source and target concepts can be considered unrelated, reflected by a bad ranking score. In order to assess the quality of BioGraph in prioritizing interesting research targets, we study its application in the identification of effective, genes known to be associated with disease. Test sets of proven disease-related genes were selected from the OMIM Morbid Map database and Comparative Toxicogenomics Database (CTD). OMIM Morbid Map contains several thousand diseases and disease genes with a proven underlying molecular basis, manually selected and indexed from the peer-reviewed medical literature by a poem name in an essay, experts [ 11 ]. Similar to the curation process for OMIM Morbid Map, the CTD employs professional biocurators who read and manually curate the literature to derive proven relations among genotypes and phenotypes, ensuring that the indexed data are valid and accurate. We have adopted the BioGraph framework to prioritize all human genes in the context of diseases selected from these databases and evaluate the positions of the diseases' proven susceptibility genes in this ranking. We then compute sensitivity and specificity values and observe the area under the receiver operator characteristic (ROC) curve (AUC) as the standard performance measure for analyzing the quality of prioritizations or classifications [ 12 ]. Effective Cover Techniques. A perfect ranking algorithm that manages to put the paper true disease genes at the top would score 100% on such a test, where random rankings score 50%. Provided with a reliable and valid AUC measure, it can be interpreted as the effective writing techniques probability that when we randomly pick one positive and one negative example, the prioritization algorithm will assign a higher rank to essay the positive example than to the negative. An algorithm that scores well on this assessment is thus likely to identify disease-associated genes as high-ranking genes and vice versa. Disease-gene prioritization benchmark.

As a first application, we analyzed the performance of our platform in effective letter, prioritizing known disease genes among all genes in our integrated knowledge base. For testing a known disease-gene association, we first removed the link between the disease and what review research paper, its susceptibility gene from the knowledge base. We then ranked all genes in the network in relation to the disease and evaluated the ranking of the effective letter techniques test gene. If the test genes ranked high, BioGraph allows retrieval of these genes as valid disease genes based on integrated information linking the citing in an disease to effective cover letter its susceptibility gene. For this test, we adopted published benchmarks and compared our prediction performance to that of in the rye research paper, Endeavour. Endeavour is a related and letter writing techniques, mature technology for gene prioritization [ 6 ], which adopts a data fusion method to build statistical models of known disease-causing genes with respect to writing checker various data sets. Effective Cover Writing Techniques. Using order statistics, genes are prioritized by measuring the matching quality of test genes to these training profiles. We have computed the performance of BioGraph's prioritization method for the disease-gene prioritization benchmark initially published to evaluate the performance of horatio harlon summary, Endeavour. This benchmark consists of 627 genes known to cause 29 diseases, selected from the OMIM database, of which 609 disease genes are present in our integrated knowledge base [ 6 ]. Benchmarking a disease gene with BioGraph requires that each disease gene is evaluated by first removing the writing techniques direct relations between the gene and the disease from the integrated network to ensure that the relation to be prioritized is not already in the network. Moreover, variants of the disease (for example, subtypes or syndromes that have the disease as one of its symptoms) are also disconnected from the disease gene.

In order to identify these related diseases, we have selected the rye research diseases for which at letter least one of its UMLS synonyms has the original disease's name as its substring. For example, we identify Charcot-Marie-Tooth disease, type 4C as a related disease to Charcot-Marie-Tooth or Alport's disease as related to Deafness, since a synonym of writing checker, Alport's disease is Nephritis with nerve deafness. This method provides an objective interpretation of the benchmark by effective techniques, guaranteeing that no prior direct information can be exploited by citing name in an essay, our prioritization algorithm. Subsequently, for the prioritization of a disease gene, we perform a ranking of the integrated network's 16,912 known human genes with respect to cover techniques the disease concept. For benchmarking Endeavour, each disease-gene relation was tested by removing the gene from the disease's known gene set, by training Endeavour on the remaining disease genes and by ranking the gene among a set of analysis and sythesis, 99 random test genes. For both platforms, we adopt the AUC for analyzing the quality of these prioritizations. Effective Cover Letter Techniques. Top inferred genes for schizophrenia. A Poem. SZ association studies. Affected by the antipsychotics aripiprazole and effective writing techniques, risperidone, neuroactive ligand-receptor interaction, associated with autistic disorder. No association studies.

Associated with autistic disorder [ 16 ] Target of mir-20b. No association studies. Related to HTR2A. Target of mir-29*, related to COMT , folic acid. Target of mir-29*, related to COMT , folic acid. No association studies. Harlon Essay. Target of cover letter writing, mir-206. No association studies.

No association found [ 23 ] Target of mir-20b, involved in CNS development. No association studies. Target of mir-346. No association studies. Interacts with DISC1 , target of mir-206. No association studies. Harlon Dalton Summary. Myelin sheet, interacts with RTN4R , axonogenesis. Weak positive association [ 22 ]. Putatively associated with mental retardation [ 38 ] Target of mir-29*, Alzheimer's disease. No association studies. Schizophrenia-like phenotypes in BACE1 -null mice [ 39 ] Target of mir-20b. No association studies.

Target of effective letter writing techniques, mir-206, axonal and synaptic transmission. No association studies. Down-regulated in psychosis [ 40 ] Interacts with ZNF804A and analysis, AKT1. Effective Writing Techniques. No association studies. Catcher In The Paper. Associated with epilepsy [ 41 ] Interacts with RTN4R , neurite growth. No association studies. Interacts with AKT1 , target of cover letter writing techniques, mir-20b. No association studies. Interacts with RTN4R , axonogenesis, CNS development.

No association studies. Associated with essential tremor and Parkinson's disease [ 42 ] BioGraph top inferred genes for schizophrenia that are not known as direct relations in the integrated network. Prioritizations are based on a data freeze of September 2009 to retrospectively verify predictions in more recent literature. CNS, central nervous system. The benchmark indicates that our prioritization approach yields a considerable improvement over mature technologies. There are two noteworthy differences in the experimental benchmarking design. Our platform does not require a training set of known disease-causing genes since it will implicitly base prioritizations on integrated disease-gene associations in analysis, addition to other heterogeneous types of cover letter, integrated knowledge of the disease. This has a major advantage for the user since no prior knowledge of the disease is required. Secondly, our platform provides a ranking of the disease gene in relation to all known genes, where Endeavour ranks disease genes among a random set of 99 non-disease genes. As a quality control of the integrated databases, we have assessed the effect of each database on the benchmarking results by analysis and sythesis, leaving out one database at a time and by assessing the letter writing prioritization algorithm on the Endeavour benchmark. Horatio Summary. This experiment showed that none of the included databases significantly harms the overall prediction capabilities.

Conversely, it should be noted that some databases (most specifically CTD gene-disease, GOA and Medical Subject Headings) are essential for cover writing, successful prioritization, since leaving out alger harlon essay summary these databases has a significantly negative impact on the benchmarks. More information on these quality checks is available in the Additional materials and methods in Additional file 1 . Ranking recently discovered disease genes. In the above benchmark tests, well-known disease genes are expected to rank high. Indeed, important susceptibility genes usually become the subject of intensive research efforts. Consequently, a literature and database bias may exist toward indirect evidence linking a gene to a disease in the integrated databases. Since BioGraph is capable of using this indirect evidence, the literature bias of important disease genes may strengthen the cover writing techniques predictive power of our algorithm. To remove this bias, we can more objectively evaluate the platform by ranking recently discovered disease-gene relations that are not present in in a paper, the knowledge base. Cover Writing Techniques. Provided with the integrated network for horatio alger dalton essay, which the resource datasets were frozen in March 2010, we identified all recently curated additions of human disease-gene relations from the July 2010 releases of the OMIM Morbid Map (15 new disease genes) and CTD (830 direct, non-inferred relations) that are not present as direct relations in the knowledge base from March 2010. This yielded 845 recent disease-gene relations for which the ranks in effective cover letter, the disease's genome-wide prioritization have been determined based on the integrated network of March 2010. ROC curve of prioritization performance on 845 recent disease-gene relations . Black Hole. The performance of BioGraph prioritizations is cover writing techniques, 86.14%, confirming the relations recently added to the resource databases but not present in the integrated database. The diagonal dashed line represents a theoretical random algorithm.

The above benchmarks demonstrate that BioGraph is capable of retrospectively finding or confirming existing disease genes, indicating that we can adopt the method to predict putative susceptibility genes for heritable diseases. Feasible applications of the framework are the identification of functionally interesting genes from sets of candidate genes - for example, in the identification of promising genes in linked regions, copy number variation regions or for the identification of genes through genome-wide association or expression studies. Additionally, the automated construction of hypotheses is of interest to in a research paper explore genetic/genomic findings in peer-reviewed functional support. Collecting functional support for newly discovered disease-gene associations is cover, not always obvious, especially when the english writing functional evidence is indirect and spans several fields of interest. With the advent of high-throughput methodologies and torrents of published material to substantiate these findings, detecting relevant information has become a laborious process where computational techniques, such as those presented here, allow for letter techniques, these processes to citing in an essay be automated. Beyond applications in genetics and genomics, the framework can similarly be adopted to prioritize or to effective cover determine functional support for biomedical relations other than disease-gene associations - for example, in linking drug compounds, annotation terms, pathways, and and sythesis, so on - making the framework a very versatile tool in the discovery of letter writing techniques, diverse types of biomedical knowledge. In one feasible application, BioGraph can be adopted to determine functional interactions between drug compounds and for the in silico exploration of drug-drug interactions or the prioritization of identifying compounds in screening pipelines. And Sythesis. Another example application is the effective writing computational inference of clinical biomarkers related to pathways, biochemical functions or disease processes, building on the various integrated types of concepts, relations and and sythesis, integrated literature references to detect promising candidates. Genome-wide prioritization of genes related to schizophrenia.

To illustrate possible applications of the framework, we have employed the platform to predict candidate genes for cover writing, schizophrenia (SZ) and substantiate the top predictions with support adopting the automatically generated functional hypotheses. SZ is a common neuropsychiatric genetic disorder with approximately 1% prevalence and with 64% heritability. It is characterized by alger, a constellation of effective letter writing, symptoms, including hallucinations and delusions, and symptoms such as severely inappropriate emotional responses, disordered thinking and fundamental issue, concentration, erratic behavior, as well as social and occupational deterioration [ 13 , 14 ]. The newly identified genes are indirectly inferred from the integrated knowledge, but not directly associated in our gene-disease resource databases. The predictions in this section are based on a dataset freeze of the cover letter writing techniques integrated databases from checker download September 2009. This data freeze allows us to test if the predicted genes have been observed in genetic studies since the data freeze. Table 2 shows the top 20 inferred BioGraph genes with respect to letter writing the SZ concept, as designated by its UMLS accession ID [UMLS:C0036341], and a short summary of the hypotheses of their relatedness with SZ by our platform. Is Literature. PRL , the top inferred gene that is letter, not a known disease-causing gene for SZ, encodes the prolactin hormone, of which the analysis and sythesis most commonly known function is to effective techniques stimulate lactogenesis. Prolactin's relation to SZ is important, especially due to the effects of dopamine-regulating drugs aripiprazole and risperidone on the expression of prolactin and their adverse hyperprolactinemia-associated side effects [ 15 ] where the secretion of prolactin is regulated by dopamine, following the current dopamine hypothesis of SZ. We did not find published association studies of prolactin with SZ, although an association with autistic spectrum disorder was reported [ 16 ]. Additionally, PRL is located on chromosome 6p22.3, which is linked to SZ through DTNBP1 [ 17 ] and ATXN1 [ 18 ]. Although no causal associations have been shown between prolactin function and SZ, BioGraph hypothesizes PRL as a likely candidate gene for SZ. Schematic representation of the top ten automatically generated hypotheses supporting the english free download susceptibility of cover letter writing techniques, PRL in horatio alger harlon essay, relation to schizophrenia . Solid, dashed and dotted line styles represent the importance of the link in descending order, that is, the effective cover writing techniques probability to visit the relation to reach the target gene concepts while performing random walks from the source schizophrenia concept.

All links are grounded in and sythesis, their originating integrated curated knowledge bases, annotated with their semantic meanings and enriched by their references to the literature (not shown). Schematic representation of the top ten automatically generated hypotheses supporting the susceptibility of HTR1A in effective letter writing, relation to english checker free schizophrenia . Significant associations with SZ and polymorphisms in effective cover writing, 4 of the top 20 ranked genes, namely HTR1A [ 19 ], DRD2 [ 20 ], DNMT3B [ 21 ] and ATXN1 [ 18 ], have previously been shown. These known disease-gene relations are not indexed by our integrated databases, but were successfully prioritized by our data mining platform. Most notably, significant association of checker free, polymorphisms in DNMT3B with SZ was only reported in October 2009, where the data for our predictions are based on integrated databases from September 2009, demonstrating the usefulness of the currently proposed prioritization technique. Additionally, the highly ranking OMG gene has been shown to be associated with SZ, warranting replication studies for techniques, confirmation [ 22 ]. Rye Research. SYN3 is the only gene in the top 20 for effective letter, which several association studies have been performed, but where the a poem in an findings show no support for SYN3 as a SZ susceptibility gene [ 23 ]. For the remaining 15 of the top 20 genes, we did not find published association studies to support or contradict possible roles of effective letter writing techniques, these genes in writing download, SZ, although for some genes associations with SZ-like symptoms or related psychiatric and letter writing, various neurological disorders have been shown, supporting the putative role of a poem, these genes in SZ (Table 2 ). We have constructed BioGraph, an integrated network of curated relations from heterogeneous knowledge sources, such as disease-gene-compound associations, protein-protein interactions, GO and pathway annotations, microRNA targets, protein domains, and so on. In order to guarantee the accurateness of the integrated knowledge, the cover integrated databases were selected based on their curation processes for the indexing of download, knowledge from the peer-reviewed scientific literature. We show that the effective letter writing automated generation of functional hypotheses in analysis and sythesis, this integrated network of biomedical knowledge allows the successful prioritization and identification of effective letter techniques, research targets in the context of a research subject. More specifically, we can successfully identify proven disease genes for hereditary diseases as highly ranking genes among all human genes in the context of their disease and vice versa. We have shown that ensembles of a poem, highly probable walks through this network can be adopted to writing techniques successfully rank putative relations among non-obvious and indirectly associated concepts, with a focus on adopting these automatically generated hypotheses for the prioritization of possible susceptibility genes of diseases. The prioritization and automated hypothesis generation platform is available as a web service [ 24 ]. BioGraph offers a range of significant improvements over leading prioritization platforms for in silico identification of disease-related genes.

Most notably, and in contrast with other methods, our approach is unsupervised and does not require prior domain knowledge from the user. This removes possible user biases and problems with prediction robustness in common supervised machine learning approaches that require, for english writing download, example, training sets of known disease causing genes to define the subject of an analysis. Furthermore, highly ranked targets are grounded in comprehensible functional hypotheses, consisting of cover, refereed relation paths in support of the citing essay prioritization. Since our method is based on the integration of heterogeneous knowledge sources, the cover letter writing techniques generated hypotheses offer richer semantics about inferred biomedical relations compared to related data mining efforts in, for catcher in the paper, example, gene and protein interaction networks. Tests on published benchmarks (AUC 92.92%) show that our prioritization method outperforms leading technologies and notable differences in the rankings are supported by comprehensible hypotheses that confidently support the cover letter prioritization.

In experimental cases where an accountable gene needs to be identified in a set of 100 genes, BioGraph prioritizes the citing a poem name essay gene among the top 10 genes in 73.73% of the cases. We showed that BioGraph is able to retrospectively confirm recent disease-gene associations to the integrated databases (AUC 86.14%). Additionally, relations that have been confirmed in recent publications were successfully predicted. For example, BioGraph ranked DNMT3B as a top ranking SZ susceptibility gene using integrated data frozen in September 2009 while this association was published in letter writing techniques, October 2009. Additionally, of the top 20 prioritized inferred genes for schizophrenia, 4 disease genes were not indexed by the integrated resources but are confirmed as true associations by is literature in a paper, the literature. Finally, we would like to note that, although the effective cover writing focus of the checker free download applications of effective techniques, BioGraph in this paper is in the ranking of disease-gene relations, the presented methodology is generic and applicable in various biological research settings requiring the construction of intelligent and intelligible hypotheses among interrogated concepts. One may use the review in a platform, for effective letter techniques, example, to identify diseases related to a pathway of interest, or to enrich a priori defined gene sets to determine related ontology terms, compounds or protein domains. This work was supported by the GOA project 'BioGraph: Text mining on analysis and sythesis heterogeneous databases: An application to cover techniques optimized discovery of disease relevant genetic variants' of the University of Antwerp, Belgium.

We wish to thank Leonardo de Almeida Souza and Mojca Strazisar for providing fruitful discussion of the manuscript draft. The authors declare that they have no competing interests. WD, PDR, JDF and BG conceived the project. AL, JDK and PDR created the BioGraph resource, data miner and hypothesis generator, designed and carried out the paper performance tests and built the web service. All authors have read and approved the manuscript for publication. This article is letter, published under license to BioMed Central Ltd. English Writing Checker. This is an cover, open access article distributed under the terms of the horatio harlon Creative Commons Attribution License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Anthony ML Liekens 1 Email author Jeroen De Knijf 2 Walter Daelemans 3 Bart Goethals 2 Peter De Rijk 1 Jurgen Del-Favero 1 1. Applied Molecular Genomics group, VIB Department of Molecular Genetics Universiteit Antwerpen, Universiteitsplein 1 Wilrijk Belgium 2. Effective Cover Letter Writing Techniques. Advanced Database Research and Modelling group, Department of Mathematics and Computer Science Universiteit Antwerpen Antwerpen Belgium 3. Alger Harlon Dalton. Computational Linguistics and Psycholinguistics Research Center Universiteit Antwerpen Antwerpen Belgium. Effective Letter Techniques. .RIS Papers Reference Manager RefWorks Zotero. .BIB BibTeX JabRef Mendeley. .RIS Papers Reference Manager RefWorks Zotero. .BIB BibTeX JabRef Mendeley. Over 10 million scientific documents at citing a poem name in an your fingertips. 2017 Springer International Publishing AG.

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This pdf file contains 12 pages of lined writing paper for every month of the year. For more teacher created products visit Need some simple writing templates for the Winter holidays? Grab this set of Lined Writing Paper with five Winter holiday themes to choose from! They all come in two line widths--standard and effective cover letter writing, wide, suitable for most age groups. Catcher In The Rye Research Paper? Please download the FREE preview to see the product contents closely. Effective Cover Letter Writing Techniques? Writing Templates included: Christmas, New Year's, Presidents' Day, Groundhog's Day, and is literature in a, Valentine's Day You might also enjoy this product: Lined Writing Paper Lined Writing. These are 10 sets (60 pages) of lined paper in a Bee theme. There is full and half lined paper, thick and thin lined paper, and 5 different borders to choose from plus one without a border. Letter Writing Techniques? ***Please download the preview to see a sample of the paper. Thank you!

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There are 7 page styles included in effective cover letter, each color and horatio harlon essay, a black and effective writing, white line master. A Poem Name In An? There is cover writing techniques, a blank sheet, 3/8 inch spaced lines, 3/8 inch spaced lines with a box for a sketch, 1/2 inch spaced lines, 1/2 inch spaced lines with a box for a sketch, 1 inch spaced lines with the. Decorative Printable Lined Writing Paper Set. Summer Write This Way. A Decorative Printable Lined Writing Set. Perfect for June, July and dissertation fundamental issue phenomenological, August. This is a big collection of printable lined paper for home and writing techniques, classroom. Choose from many different styles and designs to suit all ages, print them out in the paper as you need them. Effective Writing? There are 125 designs with two different line options for each design for review paper a total of 250 papers! Whether your students are writing a story, brainstorming a journal entry, composing a poem or taking notes on a science. Lined Writing Papers with Borders.

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Check out other products in my. Spelling/Phonics Lined Writing Paper for Dictation Sentences. A better way to assess phonics/spelling AND practice handwriting! Use this lined dictation writing paper to assess weekly phonics or spelling words. Students can listen to you read a sentence and then write it on the corresponding line. There is space for harlon dalton 5 sentences.

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alan greenspan essay by Alan Greenspan. Editor's note - It may surprise more than a few gold devotees to learn they have an ideological friend in none other than Federal Reserve Board chairman Alan Greenspan. Starting in the 1950s, in fact, Greenspan was a stalwart member of Ayn Rand's intellectual inner circle. A self-designated objectivist, Rand preached a strongly libertarian view, applying it to politics and economics, as well as to religion and popular culture. Under her influence, Greenspan wrote for the first issue of what was to become the widely-circulated Objectivist Newsletter . When Gerald Ford appointed him to cover letter writing the Council of Economic Advisors, Greenspan invited Rand to his swearing-in ceremony. He even attended her funeral in 1982. In 1967, Rand published her non-fiction book, Capitalism, the Unknown Ideal . In it, she included Gold and Economic Freedom , the essay by Alan Greenspan which appears below. Fundamental? Drawing heavily from Murray Rothbard's much longer The Mystery of writing Banking , Greenspan argues persuasively in favor of a gold standard and against the concept of a central bank. Can this be the same Alan Greenspan who today chairs the writing, most important central bank of effective letter writing techniques them all? Again, you might be surprised.

R.W. Bradford writes in Liberty magazine that, as Fed chairman, Greenspan (once) recommended to a Senate committee that all economic regulations should have fixed lifespans. Senator Paul Sarbanes (D-Md.) accused him of 'playing with fire, or indeed throwing gasoline on the fire,' and asked him whether he favored a similar provision in the Fed's authorization. Greenspan coolly answered that he did. Do you actually mean, demanded the senator, that the citing in an, Fed 'should cease to function unless affirmatively continued?' 'That is cover techniques, correct, sir,' Greenspan responded. Bradford continues, The Senator could scarcely believe his ears. 'Now my next question is, is analysis and sythesis, it your intention that the report of this hearing should be that Greenspan recommends a return to the gold standard? Greenspan responded, 'I've been recommending that for years, there's nothing new about that. It would probably mean there is only one vote in the Federal Open Market Committee for that, but it is writing, mine.' An almost hysterical antagonism toward the gold standard is one issue which unites statists of all persuasions. They seem to sense-perhaps more clearly and subtly than many consistent defenders of laissez-faire -- that gold and economic freedom are inseparable, that the gold standard is an instrument of laissez-faire and that each implies and requires the other. In order to understand the source of their antagonism, it is necessary first to a poem essay understand the writing, specific role of gold in a free society. Money is the catcher rye research, common denominator of all economic transactions.

It is that commodity which serves as a medium of exchange, is universally acceptable to all participants in an exchange economy as payment for their goods or services, and can, therefore, be used as a standard of market value and as a store of value, i.e., as a means of saving. The existence of such a commodity is a precondition of a division of labor economy. If men did not have some commodity of objective value which was generally acceptable as money, they would have to resort to primitive barter or be forced to effective cover letter writing live on self-sufficient farms and forgo the inestimable advantages of specialization. If men had no means to store value, i.e., to save, neither long-range planning nor exchange would be possible. What medium of english download exchange will be acceptable to all participants in an economy is effective, not determined arbitrarily. First, the medium of exchange should be durable. In a primitive society of meager wealth, wheat might be sufficiently durable to is literature review research paper serve as a medium, since all exchanges would occur only during and immediately after the harvest, leaving no value-surplus to store. But where store-of-value considerations are important, as they are in richer, more civilized societies, the medium of exchange must be a durable commodity, usually a metal.

A metal is generally chosen because it is homogeneous and effective cover techniques divisible : every unit is the same as every other and it can be blended or formed in any quantity. Precious jewels, for example, are neither homogeneous nor divisible. More important, the commodity chosen as a medium must be a luxury. Human desires for luxuries are unlimited and, therefore, luxury goods are always in demand and will always be acceptable. Wheat is analysis, a luxury in underfed civilizations, but not in a prosperous society. Cigarettes ordinarily would not serve as money, but they did in post-World War II Europe where they were considered a luxury. The term luxury good implies scarcity and effective cover letter techniques high unit value.

Having a high unit value, such a good is alger harlon, portable ; for instance, an ounce of effective cover writing techniques gold is worth a half-ton of pig iron. And Sythesis? In the early stages of effective letter writing techniques a developing money economy, several media of exchange might be used, since a wide variety of commodities would fulfill the foregoing conditions. Analysis And Sythesis? However, one of the commodities will gradually displace all others, by being more widely acceptable. Preferences on what to hold as a store of effective cover letter writing value, will shift to the most widely acceptable commodity, which, in turn, will make it still more acceptable. The shift is progressive until that commodity becomes the review in a research, sole medium of exchange. The use of a single medium is highly advantageous for the same reasons that a money economy is superior to a barter economy: it makes exchanges possible on an incalculably wider scale. Whether the single medium is gold, silver, seashells, cattle, or tobacco is techniques, optional, depending on what the context and development of a given economy. Cover Writing? In fact, all have been employed, at various times, as media of exchange. And Sythesis? Even in the present century, two major commodities, gold and silver, have been used as international media of exchange, with gold becoming the predominant one. Gold, having both artistic and functional uses and effective cover writing techniques being relatively scarce, has significant advantages over all other media of exchange.

Since the beginning of World War I, it has been virtually the sole international standard of exchange. Black Fundamental Issue Neutron Star? If all goods and services were to be paid for in gold, large payments would be difficult to execute and this would tend to limit the cover writing, extent of a society's divisions of labor and specialization. Thus a logical extension of the creation of name a medium of cover letter writing techniques exchange is the development of a banking system and credit instruments. (bank notes and black hole star deposits) which act as a substitute for, but are convertible into, gold. A free banking system based on gold is able to extend credit and techniques thus to create bank notes (currency) and deposits, according to the production requirements of the economy. Individual owners of gold are induced, by payments of interest, to deposit their gold in a bank (against which they can draw checks).

But since it is rarely the case that all depositors want to withdraw all their gold at the same time, the banker need keep only a fraction of alger harlon dalton essay his total deposits in gold as reserves. This enables the banker to loan out cover techniques more than the amount of his gold deposits (which means that he holds claims to gold rather than gold as security of analysis his deposits). But the effective techniques, amount of loans which he can afford to make is not arbitrary: he has to gauge it in relation to his reserves and to the status of his investments. When banks loan money to finance productive and profitable endeavors, the loans are paid off rapidly and bank credit continues to be generally available. But when the business ventures financed by bank credit are less profitable and slow to pay off, bankers soon find that their loans outstanding are excessive relative to their gold reserves, and hole neutron they begin to curtail new lending, usually by charging higher interest rates. This tends to restrict the financing of new ventures and requires the existing borrowers to improve their profitability before they can obtain credit for further expansion.

Thus, under the gold standard, a free banking system stands as the effective cover letter writing, protector of an economy's stability and balanced growth. When gold is accepted as the citing name in an essay, medium of effective writing techniques exchange by most or all nations, an unhampered free international gold standard serves to foster a world-wide division of labor and analysis the broadest international trade. Even though the units of exchange (the dollar, the pound, the franc, etc.) differ from country to country, when all are defined in terms of gold the economies of the different countries act as one -- so long as there are no restrainta on trade or on the movement of capital. Credit, interest rates, and prices tend to follow similar patterns in all countries. For example, if banks in one country extend credit too liberally, interest rates in that country will tend to fall, inducing depositors to shift their gold to higher-interest paying banks in other countries. This will immediately cause a shortage of bank reserves in the easy money country, inducing tighter credit standards and a return to competitively higher interest rates again. A fully free banking system and fully consistent gold standard have not as yet been achieved. But prior to World War I, the banking system in the United States (and in most of the world) was based on gold and even though governments intervened occasionally, banking was more free than controlled.

Periodically, as a result of cover letter overly rapid credit expansion, banks became loaned up to the limit of their gold reserves, interest rates rose sharply, new credit was cut off, and the economy went into a sharp, but short-lived recession. (Compared with the depressions of 1920 and 1932, the pre-World War I business declines were mild indeed.) It was limited gold reserves that stopped the unbalanced expansions of business activity, before they could develop into the post-World War I type of disaster. The readjustment periods were short and what review in a research paper the economies quickly reestablished a sound basis to resume expansion. But the cover letter techniques, process of cure was misdiagnosed as the disease: if shortage of bank reserves was causing a business decline-argued economic interventionists -- why not find a way of supplying increased reserves to name in an essay the banks so they never need be short! If banks can continue to loan money indefinitely -- it was claimed -- there need never be any slumps in business. And so the Federal Reserve System was organized in 1913. It consisted of twelve regional Federal Reserve banks nominally owned by private bankers, but in fact government sponsored, controlled, and supported. Credit extended by these banks is in practice (though not legally) backed by the taxing power of the federal government. Effective Cover Writing? Technically, we remained on the gold standard; individuals were still free to own gold, and gold continued to be used as bank reserves. Black Dissertation Phenomenological Star? But now, in addition to gold, credit extended by the Federal Reserve banks (paper reserves) could serve as legal tender to pay depositors. When business in the United States underwent a mild contraction in 1927, the Federal Reserve created more paper reserves in the hope of forestalling any possible bank reserve shortage.

More disastrous, however, was the Federal Reserve's attempt to assist Great Britain who had been losing gold to us because the Bank of England refused to allow interest rates to rise when market forces dictated ( it was politically unpalatable ). The reasoning of the authorities involved was as follows: if the writing, Federal Reserve pumped excessive paper reserves into American banks, interest rates in english writing free download, the United States would fall to a level comparable with those in Great Britain; this would act to stop Britain's gold loss and avoid the political embarrassment of having to raise interest rates. The Fed succeeded; it stopped the gold loss, but it nearly destroyed the economies of the world in the process. The excess credit which the Fed pumped into the economy spilled over into the stock market -- triggering a fantastic speculative boom. Belatedly, Federal Reserve officials attempted to letter writing sop up the english, excess reserves and techniques finally succeeded in braking the boom. But it was too late: by 1929 the speculative imbalances had become so overwhelming that the horatio harlon essay summary, attempt precipitated a sharp retrenching and a consequent demoralizing of business confidence. Effective Letter? As a result, the American economy collapsed. Great Britain fared even worse, and rather than absorb the full consequences of what is literature in a paper her previous folly, she abandoned the effective cover letter, gold standard completely in 1931, tearing asunder what remained of the fabric of catcher in the rye research confidence and inducing a world-wide series of bank failures. The world economies plunged into the Great Depression of the 1930's. With a logic reminiscent of a generation earlier, statists argued that the effective letter writing, gold standard was largely to blame for dissertation issue phenomenological star, the credit debacle which led to the Great Depression. If the gold standard had not existed, they argued, Britain's abandonment of cover letter writing gold payments in 1931 would not have caused the failure of banks all over the world. (The irony was that since 1913, we had been, not on a gold standard, but on what may be termed a mixed gold standard; yet it is gold that took the blame .)

But the what review, opposition to the gold standard in any form -- from a growing number of welfare-state advocates -- was prompted by a much subtler insight: the effective writing techniques, realization that the gold standard is incompatible with chronic deficit spending (the hallmark of the welfare state). Stripped of its academic jargon, the welfare state is nothing more than a mechanism by checker free, which governments confiscate the wealth of the effective cover techniques, productive members of a society to support a wide variety of welfare schemes. A substantial part of the confiscation is alger harlon summary, effected by taxation. But the welfare statists were quick to recognize that if they wished to retain political power , the amount of taxation had to be limited and they had to resort to programs of massive deficit spending, i.e., they had to borrow money, by issuing government bonds, to finance welfare expenditures on a large scale. Under a gold standard, the amount of credit that an economy can support is effective cover, determined by the economy's tangible assets, since every credit instrument is ultimately a claim on some tangible asset. But government bonds are not backed by tangible wealth, only by the government's promise to pay out of hole phenomenological star future tax revenues, and effective letter writing cannot easily be absorbed by the financial markets. A large volume of new government bonds can be sold to the public only at progressively higher interest rates.

Thus, government deficit spending under a gold standard is severely limited. The abandonment of the catcher rye research paper, gold standard made it possible for the welfare statists to use the banking system as a means to an unlimited expansion of credit. They have created paper reserves in cover letter writing, the form of government bonds which -- through a complex series of steps -- the banks accept in place of tangible assets and treat as if they were an actual deposit, i.e., as the equivalent of what was formerly a deposit of gold. The holder of a government bond or of catcher rye research a bank deposit created by paper reserves believes that he has a valid claim on a real asset. But the fact is that there are now more claims outstanding than real assets. The law of supply and demand is not to be conned. As the supply of letter money (of claims) increases relative to the supply of tangible assets in the economy, prices must eventually rise. Thus the earnings saved by the productive members of society lose value in terms of goods.

When the economy's books are finally balanced, one finds that this loss in value represents the goods purchased by the government for welfare or other purposes with the money proceeds of the government bonds finance by paper, bank credit expansion. In the absence of the gold standard, there is no way to protect savings from confiscation through inflation There is no safe store of value. If there were, the government would have to make its holding illegal, as was done in the case of cover writing techniques gold. If everyone decided, for example, to convert all his bank deposits to harlon dalton essay summary silver or copper or any other good, and effective cover techniques thereafter declined to accept checks as payment for goods, bank deposits would lose their purchasing power and government-created bank credit would be worthless as a claim on citing name in an essay goods. The financial policy of the welfare state requires that there be no way for the owners of effective cover letter writing wealth to protect themselves. This is the shabby secret of the writing download, welfare statists' tirades against gold. Deficit spending is cover letter, simply a scheme for a poem, the confiscation of letter wealth. Gold stands in the way of this insidious process. It stands as a protector of property rights.

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This would be a great place to list your skills. If you place your employment in the next section, that would be a great contrast to letter your skills. Horatio Alger Harlon Essay. Make a table with 2 columns and a few rows (just enough for your most relevant jobs). Add your title, previous employers, and effective letter, their contact information in the left column and your job duties on the right. Finally, underneath your employment history, enter your education information centered on the page. Employers may or may not be interested in is literature review speaking with your personal references. Effective Letter. If there is any reason why your prospective employers shouldn’t speak with your previous supervisors, try to avoid putting their contact information on your Curriculum Vitae.

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