From SNPs to pathways: integration of functional effect of sequence variations on models of cell signalling pathways

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Assessment of NER solutions against the first and second CALBC Silver Standard Corpus

Background Competitions in text mining have been used to measure the performance of automatic text processing solutions against a manually annotated gold standard corpus (GSC). The preparation of the GSC is time-consuming and costly and the final corpus consists at the most of a few thousand documents annotated with a limited set of semantic groups. To overcome these shortcomings, the CALBC project partners (PPs) have produced a large-scale annotated biomedical corpus with four different semantic groups through the harmonisation of annotations from automatic text mining solutions, the first version of the Silver Standard Corpus (SSC-I). The four semantic groups are chemical entities and drugs (CHED), genes and proteins (PRGE), diseases and disorders (DISO) and species (SPE). This corpus has been used for the First CALBC Challenge asking the participants to annotate the corpus with their text processing solutions. Results All four PPs from the CALBC project and in addition, 12 challenge participants (CPs) contributed annotated data sets for an evaluation against the SSC-I. CPs could ignore the training data and deliver the annotations from their genuine annotation system, or could train a machine-learning approach on the provided pre-annotated data. In general, the performances of the annotation solutions were lower for entities from the categories CHED and PRGE in comparison to the identification of entities categorized as DISO and SPE. The best performance over all semantic groups were achieved from two annotation solutions that have been trained on the SSC-I. The data sets from participants were used to generate the harmonised Silver Standard Corpus II (SSC-II), if the participant did not make use of the annotated data set from the SSC-I for training purposes. The performances of the participants’ solutions were again measured against the SSC-II. The performances of the annotation solutions showed again better results for DISO and SPE in comparison to CHED and PRGE. Conclusions The SSC-I delivers a large set of annotations (1,121,705) for a large number of documents (100,000 Medline abstracts). The annotations cover four different semantic groups and are sufficiently homogeneous to be reproduced with a trained classifier leading to an average F-measure of 85%. Benchmarking the annotation solutions against the SSC-II leads to better performance for the CPs’ annotation solutions in comparison to the SSC-I

The Role of Spatially Controlled Cell Proliferation in Limb Bud Morphogenesis

Oriented cell behaviors likely have a more important role in limb bud elongation during development than previously suggested by the “growth-based morphogenesis” hypothesis

Gene-Disease Network Analysis Reveals Functional Modules in Mendelian, Complex and Environmental Diseases

Scientists have been trying to understand the molecular mechanisms of diseases to design preventive and therapeutic strategies for a long time. For some diseases, it has become evident that it is not enough to obtain a catalogue of the disease-related genes but to uncover how disruptions of molecular networks in the cell give rise to disease phenotypes. Moreover, with the unprecedented wealth of information available, even obtaining such catalogue is extremely difficult. We developed a comprehensive gene-disease association database by integrating associations from several sources that cover different biomedical aspects of diseases. In particular, we focus on the current knowledge of human genetic diseases including mendelian, complex and environmental diseases. To assess the concept of modularity of human diseases, we performed a systematic study of the emergent properties of human gene-disease networks by means of network topology and functional annotation analysis. The results indicate a highly shared genetic origin of human diseases and show that for most diseases, including mendelian, complex and environmental diseases, functional modules exist. Moreover, a core set of biological pathways is found to be associated with most human diseases. We obtained similar results when studying clusters of diseases, suggesting that related diseases might arise due to dysfunction of common biological processes in the cell. For the first time, we include mendelian, complex and environmental diseases in an integrated gene-disease association database and show that the concept of modularity applies for all of them. We furthermore provide a functional analysis of disease-related modules providing important new biological insights, which might not be discovered when considering each of the gene-disease association repositories independently. Hence, we present a suitable framework for the study of how genetic and environmental factors, such as drugs, contribute to diseases. The gene-disease networks used in this study and part of the analysis are available at http://ibi.imim.es/DisGeNET/DisGeNETweb.html#Download

A landmark-free morphometric staging system for the mouse limb bud

We have created a 2D morphometric analysis of the developing mouse hindlimb bud. This analysis has provided two useful resources for the study of limb development. First, a temporally accurate numerical description of shape changes during normal mouse limb development. Second, a web-based morphometric staging system, which has the advantage of being easy to use, and with a reproducibility of about ±2 hours. It allows users to upload a dorsal-view photo of a limb bud, draw a spline curve and thereby stage the bud within a couple of minutes. We describe how the system is constructed, its robustness to user variation and illustrate one application: the accurate tracking of spatiotemporal dynamics of gene expression patterns

Assessment of NER solutions against the first and second CALBC Silver Standard Corpus

Background: Competitions in text mining have been used to measure the performance of automatic text processing solutions against a manually annotated gold standard corpus (GSC). The preparation of the GSC is time-consuming and costly and the final corpus consists at the most of a few thousand documents annotated with a limited set of semantic groups. To overcome these shortcomings, the CALBC project partners (PPs) have produced a large-scale annotated biomedical corpus with four different semantic groups through the harmonisation of annotations from automatic text mining solutions, the first version of the Silver Standard Corpus (SSC-I). The four semantic groups are chemical entities and drugs (CHED), genes and proteins (PRGE), diseases and disorders (DISO) and species (SPE). This corpus has been used for the First CALBC Challenge asking the participants to annotate the corpus with their text processing solutions. Results: All four PPs from the CALBC project and in addition, 12 challenge participants (CPs) contributed annotated data sets for an evaluation against the SSC-I. CPs could ignore the training data and deliver the annotations from their genuine annotation system, or could train a machine-learning approach on the provided pre-annotated data. In general, the performances of the annotation solutions were lower for entities from the categories CHED and PRGE in comparison to the identification of entities categorized as DISO and SPE. The best performance over all semantic groups were achieved from two annotation solutions that have been trained on the SSC-I. The data sets from participants were used to generate the harmonised Silver Standard Corpus II (SSC-II), if the participant did not make use of the annotated data set from the SSC-I for training purposes. The performances of the participants’ solutions were again measured against the SSC-II. The performances of the annotation solutions showed again better results for DISO and SPE in comparison to CHED and PRGE. Conclusions: The SSC-I delivers a large set of annotations (1,121,705) for a large number of documents (100,000 Medline abstracts). The annotations cover four different semantic groups and are sufficiently homogeneous to be reproduced with a trained classifier leading to an average F-measure of 85%. Benchmarking the annotation solutions against the SSC-II leads to better performance for the CPs’ annotation solutions in comparison to the SSC-I.This work was funded by the EU Support Action grant 231727 under the 7th EU Framework Programme within Theme “Intelligent Content and Semantics” (ICT 2007.4.2). The work performed at IMIM (Laura Furlong) was funded by the EU Support Action grant 231727 under the 7th EU Framework Programme within Theme “Intelligent Content and Semantics” (ICT 2007.4.2) and the Instituto de Salud Carlos III FEDER (CP10/00524) grant. Fabio Rinaldi and Simon Clematide are supported by the Swiss National Science Foundation (grant 105315_130558/1

From SNPs to pathways: integration of functional effect of sequence variations on models of cell signalling pathways

Background: Single nucleotide polymorphisms (SNPs) are the most frequent type of sequence variation between individuals, and represent a promising tool for finding genetic determinants of complex diseases and understanding the differences in drug response. In this regard, it is of particular interest to study the effect of non-synonymous SNPs in the context of biological networks such as cell signalling pathways. UniProt provides curated information about the functional and phenotypic effects of sequence variation, including SNPs, as well as on mutations of protein sequences. However, no strategy has been developed to integrate this information with biological networks, with the ultimate goal of studying the impact of the functional effect of SNPs in the structure and dynamics of biological networks. Results: First, we identified the different challenges posed by the integration of the phenotypic effect of sequence variants and mutations with biological networks. Second, we developed a strategy for the combination of data extracted from public resources, such as UniProt, NCBI dbSNP, Reactome and BioModels. We generated attribute files containing phenotypic and genotypic annotations to the nodes of biological networks, which can be imported into network visualization tools such as Cytoscape. These resources allow the mapping and visualization of mutations and natural variations of human proteins and their phenotypic effect on biological networks (e.g. signalling pathways, protein-protein interaction networks, dynamic models). Finally, an example on the use of the sequence variation data in the dynamics of a network model is presented. Conclusion: In this paper we present a general strategy for the integration of pathway and sequence variation data for visualization, analysis and modelling purposes, including the study of the functional impact of protein sequence variations on the dynamics of signalling pathways. This is of particular interest when the SNP or mutation is known to be associated to disease. We expect that this approach will help in the study of the functional impact of disease-associated SNPs on the behaviour of cell signalling pathways, which ultimately will lead to a better understanding of the mechanisms underlying complex diseases.This work was generated in the framework of the @neurIST and the EUADR projects co-financed by the European Commission through the contracts no. IST-027703 and ICT-215847, respectively

Extraction of relations between genes and diseases from text and large-scale data analysis: implications for translational research.

BACKGROUND: Current biomedical research needs to leverage and exploit the large amount of information reported in scientific publications. Automated text mining approaches, in particular those aimed at finding relationships between entities, are key for identification of actionable knowledge from free text repositories. We present the BeFree system aimed at identifying relationships between biomedical entities with a special focus on genes and their associated diseases. RESULTS: By exploiting morpho-syntactic information of the text, BeFree is able to identify gene-disease, drug-disease and drug-target associations with state-of-the-art performance. The application of BeFree to real-case scenarios shows its effectiveness in extracting information relevant for translational research. We show the value of the gene-disease associations extracted by BeFree through a number of analyses and integration with other data sources. BeFree succeeds in identifying genes associated to a major cause of morbidity worldwide, depression, which are not present in other public resources. Moreover, large-scale extraction and analysis of gene-disease associations, and integration with current biomedical knowledge, provided interesting insights on the kind of information that can be found in the literature, and raised challenges regarding data prioritization and curation. We found that only a small proportion of the gene-disease associations discovered by using BeFree is collected in expert-curated databases. Thus, there is a pressing need to find alternative strategies to manual curation, in order to review, prioritize and curate text-mining data and incorporate it into domain-specific databases. We present our strategy for data prioritization and discuss its implications for supporting biomedical research and applications. CONCLUSIONS: BeFree is a novel text mining system that performs competitively for the identification of gene-disease, drug-disease and drug-target associations. Our analyses show that mining only a small fraction of MEDLINE results in a large dataset of gene-disease associations, and only a small proportion of this dataset is actually recorded in curated resources (2%), raising several issues on data prioritization and curation. We propose that joint analysis of text mined data with data curated by experts appears as a suitable approach to both assess data quality and highlight novel and interesting information