MOTIVATION: Incorporating the temporal dimension into multimorbidity studies has shown to be crucial for achieving a better understanding of the disease associations. Furthermore, due to the multifactorial nature of human disease, exploring disease associations from different perspectives can provide a holistic view to support the study of their aetiology. RESULTS: In this work, a temporal systems-medicine approach is proposed for identifying time-dependent multimorbidity patterns from patient disease trajectories, by integrating data from electronic health records with genetic and phenotypic information. Specifically, the disease trajectories are clustered using an unsupervised algorithm based on dynamic time warping and three disease similarity metrics: clinical, genetic and phenotypic. An evaluation method is also presented for quantitatively assessing, in the different disease spaces, both the cluster homogeneity and the respective similarities between the associated diseases within individual trajectories. The latter can facilitate exploring the origin(s) in the identified disease patterns. The proposed integrative methodology can be applied to any longitudinal cohort and disease of interest. In this article, prostate cancer is selected as a use case of medical interest to demonstrate, for the first time, the identification of temporal disease multimorbidities in different disease spaces. AVAILABILITY AND IMPLEMENTATION: https://gitlab.com/agiannoula/diseasetrajectories. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

SUMMARY: Pushed by the growing availability of Electronic Health Records for data mining, the identification of relevant patterns of co-occurring diseases over a population of individuals-referred to as comorbidity analysis-has become a common practice due to its great impact on life expectancy, quality of life and healthcare costs. In this scenario, the availability of scalable, easy-to-use software frameworks tailored to support the study of comorbidities over large datasets of patients is essential. We introduce Comorbidity4j, an open-source Java tool to perform systematic analyses of comorbidities by generating interactive Web visualizations to explore and refine results. Comorbidity4j processes user-provided clinical data by identifying significant disease co-occurrences and computing a comprehensive set of comorbidity indices. Patients can be stratified by sex, age and user-defined criteria. Comorbidity4j supports the analysis of the temporal directionality and the sex ratio of diseases. The incremental upload and validation of clinical input data and the customization of comorbidity analyses are performed by an interactive Web interface. With a Web browser, the results of such analyses can be filtered with respect to comorbidity indexes and disease names and explored by means of heat maps and network charts of disease associations. Comorbidity4j is optimized to efficiently process large datasets of clinical data. Besides a software tool for local execution, we provide Comorbidity4j as a Web service to enable users to perform online comorbidity analyses. AVAILABILITY AND IMPLEMENTATION: Doc: http://comorbidity4j.readthedocs.io/; Source code: https://github.com/fra82/comorbidity4j, Web tool: http://comorbidity.eu/comorbidity4web/.

Nanopublications are a Linked Data format for scholarly data publishing that has received considerable uptake in the last few years. In contrast to the common Linked Data publishing practice, nanopublications work at the granular level of atomic information snippets and provide a consistent container format to attach provenance and metadata at this atomic level. While the nanopublications format is domain-independent, the datasets that have become available in this format are mostly from Life Science domains, including data about diseases, genes, proteins, drugs, biological pathways, and biotic interactions. More than 10 million such nanopublications have been published, which now form a valuable resource for studies on the domain level of the given Life Science domains as well as on the more technical levels of provenance modeling and heterogeneous Linked Data. We provide here an overview of this combined nanopublication dataset, show the results of some overarching analyses, and describe how it can be accessed and queried.

Motivation: In the era of big data and precision medicine, the number of databases containing clinical, environmental, self-reported and biochemical variables is increasing exponentially. Enabling the experts to focus on their research questions rather than on computational data management, access and analysis is one of the most significant challenges nowadays. Results: We present Rcupcake, an R package that contains a variety of functions for leveraging different databases through the BD2K PIC-SURE RESTful API and facilitating its query, analysis and interpretation. The package offers a variety of analysis and visualization tools, including the study of the phenotype co-occurrence and prevalence, according to multiple layers of data, such as phenome, exposome or genome. Availability and implementation: The package is implemented in R and is available under Mozilla v2 license from GitHub (https://github.com/hms-dbmi/Rcupcake). Two reproducible case studies are also available (https://github.com/hms-dbmi/Rcupcake-case-studies/blob/master/SSCcaseStudy_v01.ipynb, https://github.com/hms-dbmi/Rcupcake-case-studies/blob/master/NHANEScaseStudy_v01.ipynb). Contact: [email protected]. Supplementary information: Supplementary data are available at Bioinformatics online.

Motivation: The study of comorbidities is a major priority due to their impact on life expectancy, quality of life and healthcare cost. The availability of electronic health records (EHRs) for data mining offers the opportunity to discover disease associations and comorbidity patterns from the clinical history of patients gathered during routine medical care. This opens the need for analytical tools for detection of disease comorbidities, including the investigation of their underlying genetic basis. Results: We present comoRbidity, an R package aimed at providing a systematic and comprehensive analysis of disease comorbidities from both the clinical and molecular perspectives. comoRbidity leverages from (i) user provided clinical data from EHR databases (the clinical comorbidity analysis) and (ii) genotype-phenotype information of the diseases under study (the molecular comorbidity analysis) for a comprehensive analysis of disease comorbidities. The clinical comorbidity analysis enables identifying significant disease comorbidities from clinical data, including sex and age stratification and temporal directionality analyses, while the molecular comorbidity analysis supports the generation of hypothesis on the underlying mechanisms of the disease comorbidities by exploring shared genes among disorders. The open-source comoRbidity package is a software tool aimed at expediting the integrative analysis of disease comorbidities by incorporating several analytical and visualization functions. Availability and implementation: https://bitbucket.org/ibi_group/comorbidity. Supplementary information: Supplementary data are available at Bioinformatics online.

MOTIVATION: Psychiatric disorders have a great impact on morbidity and mortality. Genotype-phenotype resources for psychiatric diseases are key to enable the translation of research findings to a better care of patients. PsyGeNET is a knowledge resource on psychiatric diseases and their genes, developed by text mining and curated by domain experts. RESULTS: We present psygenet2r, an R package that contains a variety of functions for leveraging PsyGeNET database and facilitating its analysis and interpretation. The package offers different types of queries to the database along with variety of analysis and visualization tools, including the study of the anatomical structures in which the genes are expressed and gaining insight of gene's molecular function. Psygenet2r is especially suited for network medicine analysis of psychiatric disorders. AVAILABILITY AND IMPLEMENTATION: The package is implemented in R and is available under MIT license from Bioconductor (http://bioconductor.org/packages/release/bioc/html/psygenet2r.html). CONTACT: [email protected] or [email protected]. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: DisGeNET-RDF makes available knowledge on the genetic basis of human diseases in the Semantic Web. Gene-disease associations (GDAs) and their provenance metadata are published as human-readable and machine-processable web resources. The information on GDAs included in DisGeNET-RDF is interlinked to other biomedical databases to support the development of bioinformatics approaches for translational research through evidence-based exploitation of a rich and fully interconnected linked open data. AVAILABILITY AND IMPLEMENTATION: http://rdf.disgenet.org/ CONTACT: [email protected].

UNLABELLED: PsyGeNET (Psychiatric disorders and Genes association NETwork) is a knowledge platform for the exploratory analysis of psychiatric diseases and their associated genes. PsyGeNET is composed of a database and a web interface supporting data search, visualization, filtering and sharing. PsyGeNET integrates information from DisGeNET and data extracted from the literature by text mining, which has been curated by domain experts. It currently contains 2642 associations between 1271 genes and 37 psychiatric disease concepts. In its first release, PsyGeNET is focused on three psychiatric disorders: major depression, alcohol and cocaine use disorders. PsyGeNET represents a comprehensive, open access resource for the analysis of the molecular mechanisms underpinning psychiatric disorders and their comorbidities. AVAILABILITY AND IMPLEMENTATION: The PysGeNET platform is freely available at http://www.psygenet.org/. The PsyGeNET database is made available under the Open Database License (http://opendatacommons.org/licenses/odbl/1.0/). CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

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.

Drug safety issues pose serious health threats to the population and constitute a major cause of mortality worldwide. Due to the prominent implications to both public health and the pharmaceutical industry, it is of great importance to unravel the molecular mechanisms by which an adverse drug reaction can be potentially elicited. These mechanisms can be investigated by placing the pharmaco-epidemiologically detected adverse drug reaction in an information-rich context and by exploiting all currently available biomedical knowledge to substantiate it. We present a computational framework for the biological annotation of potential adverse drug reactions. First, the proposed framework investigates previous evidences on the drug-event association in the context of biomedical literature (signal filtering). Then, it seeks to provide a biological explanation (signal substantiation) by exploring mechanistic connections that might explain why a drug produces a specific adverse reaction. The mechanistic connections include the activity of the drug, related compounds and drug metabolites on protein targets, the association of protein targets to clinical events, and the annotation of proteins (both protein targets and proteins associated with clinical events) to biological pathways. Hence, the workflows for signal filtering and substantiation integrate modules for literature and database mining, in silico drug-target profiling, and analyses based on gene-disease networks and biological pathways. Application examples of these workflows carried out on selected cases of drug safety signals are discussed. The methodology and workflows presented offer a novel approach to explore the molecular mechanisms underlying adverse drug reactions.

BACKGROUND: Most information on genomic variations and their associations with phenotypes are covered exclusively in scientific publications rather than in structured databases. These texts commonly describe variations using natural language; database identifiers are seldom mentioned. This complicates the retrieval of variations, associated articles, as well as information extraction, e. g. the search for biological implications. To overcome these challenges, procedures to map textual mentions of variations to database identifiers need to be developed. RESULTS: This article describes a workflow for normalization of variation mentions, i.e. the association of them to unique database identifiers. Common pitfalls in the interpretation of single nucleotide polymorphism (SNP) mentions are highlighted and discussed. The developed normalization procedure achieves a precision of 98.1 % and a recall of 67.5% for unambiguous association of variation mentions with dbSNP identifiers on a text corpus based on 296 MEDLINE abstracts containing 527 mentions of SNPs. The annotated corpus is freely available at http://www.scai.fraunhofer.de/snp-normalization-corpus.html. CONCLUSIONS: Comparable approaches usually focus on variations mentioned on the protein sequence and neglect problems for other SNP mentions. The results presented here indicate that normalizing SNPs described on DNA level is more difficult than the normalization of SNPs described on protein level. The challenges associated with normalization are exemplified with ambiguities and errors, which occur in this corpus.

We present the information extraction system Text2SemRel. The system (semi-) automatically constructs knowledge bases from textual data consisting of facts about entities using semantic relations. An integral part of the system is a graph-based interactive visualization and search layer. The second contribution in this paper is the presentation of a case study on the (semi-) automatic construction of a knowledge base consisting of gene-disease associations. The resulting knowledge base, the Literature-derived Human Gene-Disease Network (LHGDN), is now an integral part of the Linked Life Data initiative and represents currently the largest publicly available gene-disease repository. The LHGDN is compared against several curated state of the art databases. A unique feature of the LHGDN is that the semantics of the associations constitute a wide variety of biomolecular conditions.

UNLABELLED: DisGeNET is a plugin for Cytoscape to query and analyze human gene-disease networks. DisGeNET allows user-friendly access to a new gene-disease database that we have developed by integrating data from several public sources. DisGeNET permits queries restricted to (i) the original data source, (ii) the association type, (iii) the disease class or (iv) specific gene(s)/disease(s). It represents gene-disease associations in terms of bipartite graphs and provides gene centric and disease centric views of the data. It assists the user in the interpretation and exploration of the genetic basis of human diseases by a variety of built-in functions. Moreover, DisGeNET permits multicolouring of nodes (genes/diseases) according to standard disease classification for expedient visualization. AVAILABILITY: DisGeNET is compatible with Cytoscape 2.6.3 and 2.7.0, please visit http://ibi.imim.es/DisGeNET/DisGeNETweb.html for installation guide, user tutorial and download.

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.

BACKGROUND: Single Nucleotide Polymorphisms, among other type of sequence variants, constitute key elements in genetic epidemiology and pharmacogenomics. While sequence data about genetic variation is found at databases such as dbSNP, clues about the functional and phenotypic consequences of the variations are generally found in biomedical literature. The identification of the relevant documents and the extraction of the information from them are hampered by the large size of literature databases and the lack of widely accepted standard notation for biomedical entities. Thus, automatic systems for the identification of citations of allelic variants of genes in biomedical texts are required. RESULTS: Our group has previously reported the development of OSIRIS, a system aimed at the retrieval of literature about allelic variants of genes http://ibi.imim.es/osirisform.html. Here we describe the development of a new version of OSIRIS (OSIRISv1.2, http://ibi.imim.es/OSIRISv1.2.html) which incorporates a new entity recognition module and is built on top of a local mirror of the MEDLINE collection and HgenetInfoDB: a database that collects data on human gene sequence variations. The new entity recognition module is based on a pattern-based search algorithm for the identification of variation terms in the texts and their mapping to dbSNP identifiers. The performance of OSIRISv1.2 was evaluated on a manually annotated corpus, resulting in 99% precision, 82% recall, and an F-score of 0.89. As an example, the application of the system for collecting literature citations for the allelic variants of genes related to the diseases intracranial aneurysm and breast cancer is presented. CONCLUSION: OSIRISv1.2 can be used to link literature references to dbSNP database entries with high accuracy, and therefore is suitable for collecting current knowledge on gene sequence variations and supporting the functional annotation of variation databases. The application of OSIRISv1.2 in combination with controlled vocabularies like MeSH provides a way to identify associations of biomedical interest, such as those that relate SNPs with diseases.

UNLABELLED: Sequence variants, in particular single nucleotide polymorphisms (SNPs), are key elements for the identification of genes associated with complex diseases and with particular drug responses. The search for literature about sequence variation is hampered by the large number of allelic variants reported for many genes and by the variability in both gene and sequence variants nomenclatures. We describe OSIRIS, a search tool that integrates different sources of information with the aim to retrieve literature about sequence variation of a gene. In addition, it provides a method to link a dbSNP entry with the articles referring to it. AVAILABILITY: OSIRIS is available for public use at http://ibi.imim.es/