A self-updating road map of The Cancer Genome Atlas.

MOTIVATION: Since 2011, The Cancer Genome Atlas' (TCGA) files have been accessible through HTTP from a public site, creating entirely new possibilities for cancer informatics by enhancing data discovery and retrieval. Significantly, these enhancements enable the reporting of analysis results that can be fully traced to and reproduced using their source data. However, to realize this possibility, a continually updated road map of files in the TCGA is required. Creation of such a road map represents a significant data modeling challenge, due to the size and fluidity of this resource: each of the 33 cancer types is instantiated in only partially overlapping sets of analytical platforms, while the number of data files available doubles approximately every 7 months. RESULTS: We developed an engine to index and annotate the TCGA files, relying exclusively on third-generation web technologies (Web 3.0). Specifically, this engine uses JavaScript in conjunction with the World Wide Web Consortium's (W3C) Resource Description Framework (RDF), and SPARQL, the query language for RDF, to capture metadata of files in the TCGA open-access HTTP directory. The resulting index may be queried using SPARQL, and enables file-level provenance annotations as well as discovery of arbitrary subsets of files, based on their metadata, using web standard languages. In turn, these abilities enhance the reproducibility and distribution of novel results delivered as elements of a web-based computational ecosystem. The development of the TCGA Roadmap engine was found to provide specific clues about how biomedical big data initiatives should be exposed as public resources for exploratory analysis, data mining and reproducible research. These specific design elements align with the concept of knowledge reengineering and represent a sharp departure from top-down approaches in grid initiatives such as CaBIG. They also present a much more interoperable and reproducible alternative to the still pervasive use of data portals. AVAILABILITY: A prepared dashboard, including links to source code and a SPARQL endpoint, is available at http://bit.ly/TCGARoadmap. A video tutorial is available at http://bit.ly/TCGARoadmapTutorial. CONTACT: robbinsd@uab.edu.

ReVeaLD: a user-driven domain-specific interactive search platform for biomedical research.

Bioinformatics research relies heavily on the ability to discover and correlate data from various sources. The specialization of life sciences over the past decade, coupled with an increasing number of biomedical datasets available through standardized interfaces, has created opportunities towards new methods in biomedical discovery. Despite the popularity of semantic web technologies in tackling the integrative bioinformatics challenge, there are many obstacles towards its usage by non-technical research audiences. In particular, the ability to fully exploit integrated information needs using improved interactive methods intuitive to the biomedical experts. In this report we present ReVeaLD (a Real-time Visual Explorer and Aggregator of Linked Data), a user-centered visual analytics platform devised to increase intuitive interaction with data from distributed sources. ReVeaLD facilitates query formulation using a domain-specific language (DSL) identified by biomedical experts and mapped to a self-updated catalogue of elements from external sources. ReVeaLD was implemented in a cancer research setting; queries included retrieving data from in silico experiments, protein modeling and gene expression. ReVeaLD was developed using Scalable Vector Graphics and JavaScript and a demo with explanatory video is available at http://www.srvgal78.deri.ie:8080/explorer. A set of user-defined graphic rules controls the display of information through media-rich user interfaces. Evaluation of ReVeaLD was carried out as a game: biomedical researchers were asked to assemble a set of 5 challenge questions and time and interactions with the platform were recorded. Preliminary results indicate that complex queries could be formulated under less than two minutes by unskilled researchers. The results also indicate that supporting the identification of the elements of a DSL significantly increased intuitiveness of the platform and usability of semantic web technologies by domain users.

Phylotastic! Making tree-of-life knowledge accessible, reusable and convenient.

BACKGROUND: Scientists rarely reuse expert knowledge of phylogeny, in spite of years of effort to assemble a great "Tree of Life" (ToL). A notable exception involves the use of Phylomatic, which provides tools to generate custom phylogenies from a large, pre-computed, expert phylogeny of plant taxa. This suggests great potential for a more generalized system that, starting with a query consisting of a list of any known species, would rectify non-standard names, identify expert phylogenies containing the implicated taxa, prune away unneeded parts, and supply branch lengths and annotations, resulting in a custom phylogeny suited to the user's needs. Such a system could become a sustainable community resource if implemented as a distributed system of loosely coupled parts that interact through clearly defined interfaces. RESULTS: With the aim of building such a "phylotastic" system, the NESCent Hackathons, Interoperability, Phylogenies (HIP) working group recruited 2 dozen scientist-programmers to a weeklong programming hackathon in June 2012. During the hackathon (and a three-month follow-up period), 5 teams produced designs, implementations, documentation, presentations, and tests including: (1) a generalized scheme for integrating components; (2) proof-of-concept pruners and controllers; (3) a meta-API for taxonomic name resolution services; (4) a system for storing, finding, and retrieving phylogenies using semantic web technologies for data exchange, storage, and querying; (5) an innovative new service, DateLife.org, which synthesizes pre-computed, time-calibrated phylogenies to assign ages to nodes; and (6) demonstration projects. These outcomes are accessible via a public code repository (GitHub.com), a website (http://www.phylotastic.org), and a server image. CONCLUSIONS: Approximately 9 person-months of effort (centered on a software development hackathon) resulted in the design and implementation of proof-of-concept software for 4 core phylotastic components, 3 controllers, and 3 end-user demonstration tools. While these products have substantial limitations, they suggest considerable potential for a distributed system that makes phylogenetic knowledge readily accessible in computable form. Widespread use of phylotastic systems will create an electronic marketplace for sharing phylogenetic knowledge that will spur innovation in other areas of the ToL enterprise, such as annotation of sources and methods and third-party methods of quality assessment.

Translating standards into practice - one Semantic Web API for Gene Expression.

Sharing and describing experimental results unambiguously with sufficient detail to enable replication of results is a fundamental tenet of scientific research. In today's cluttered world of "-omics" sciences, data standards and standardized use of terminologies and ontologies for biomedical informatics play an important role in reporting high-throughput experiment results in formats that can be interpreted by both researchers and analytical tools. Increasing adoption of Semantic Web and Linked Data technologies for the integration of heterogeneous and distributed health care and life sciences (HCLSs) datasets has made the reuse of standards even more pressing; dynamic semantic query federation can be used for integrative bioinformatics when ontologies and identifiers are reused across data instances. We present here a methodology to integrate the results and experimental context of three different representations of microarray-based transcriptomic experiments: the Gene Expression Atlas, the W3C BioRDF task force approach to reporting Provenance of Microarray Experiments, and the HSCI blood genomics project. Our approach does not attempt to improve the expressivity of existing standards for genomics but, instead, to enable integration of existing datasets published from microarray-based transcriptomic experiments. SPARQL Construct is used to create a posteriori mappings of concepts and properties and linking rules that match entities based on query constraints. We discuss how our integrative approach can encourage reuse of the Experimental Factor Ontology (EFO) and the Ontology for Biomedical Investigations (OBIs) for the reporting of experimental context and results of gene expression studies.

S3QL: a distributed domain specific language for controlled semantic integration of life sciences data.

BACKGROUND: The value and usefulness of data increases when it is explicitly interlinked with related data. This is the core principle of Linked Data. For life sciences researchers, harnessing the power of Linked Data to improve biological discovery is still challenged by a need to keep pace with rapidly evolving domains and requirements for collaboration and control as well as with the reference semantic web ontologies and standards. Knowledge organization systems (KOSs) can provide an abstraction for publishing biological discoveries as Linked Data without complicating transactions with contextual minutia such as provenance and access control.We have previously described the Simple Sloppy Semantic Database (S3DB) as an efficient model for creating knowledge organization systems using Linked Data best practices with explicit distinction between domain and instantiation and support for a permission control mechanism that automatically migrates between the two. In this report we present a domain specific language, the S3DB query language (S3QL), to operate on its underlying core model and facilitate management of Linked Data. RESULTS: Reflecting the data driven nature of our approach, S3QL has been implemented as an application programming interface for S3DB systems hosting biomedical data, and its syntax was subsequently generalized beyond the S3DB core model. This achievement is illustrated with the assembly of an S3QL query to manage entities from the Simple Knowledge Organization System. The illustrative use cases include gastrointestinal clinical trials, genomic characterization of cancer by The Cancer Genome Atlas (TCGA) and molecular epidemiology of infectious diseases. CONCLUSIONS: S3QL was found to provide a convenient mechanism to represent context for interoperation between public and private datasets hosted at biomedical research institutions and linked data formalisms.

S3DB core: a framework for RDF generation and management in bioinformatics infrastructures.

BACKGROUND: Biomedical research is set to greatly benefit from the use of semantic web technologies in the design of computational infrastructure. However, beyond well defined research initiatives, substantial issues of data heterogeneity, source distribution, and privacy currently stand in the way towards the personalization of Medicine. RESULTS: A computational framework for bioinformatic infrastructure was designed to deal with the heterogeneous data sources and the sensitive mixture of public and private data that characterizes the biomedical domain. This framework consists of a logical model build with semantic web tools, coupled with a Markov process that propagates user operator states. An accompanying open source prototype was developed to meet a series of applications that range from collaborative multi-institution data acquisition efforts to data analysis applications that need to quickly traverse complex data structures. This report describes the two abstractions underlying the S3DB-based infrastructure, logical and numerical, and discusses its generality beyond the immediate confines of existing implementations. CONCLUSIONS: The emergence of the "web as a computer" requires a formal model for the different functionalities involved in reading and writing to it. The S3DB core model proposed was found to address the design criteria of biomedical computational infrastructure, such as those supporting large scale multi-investigator research, clinical trials, and molecular epidemiology.

Exposing the cancer genome atlas as a SPARQL endpoint.

The Cancer Genome Atlas (TCGA) is a multidisciplinary, multi-institutional effort to characterize several types of cancer. Datasets from biomedical domains such as TCGA present a particularly challenging task for those interested in dynamically aggregating its results because the data sources are typically both heterogeneous and distributed. The Linked Data best practices offer a solution to integrate and discover data with those characteristics, namely through exposure of data as Web services supporting SPARQL, the Resource Description Framework query language. Most SPARQL endpoints, however, cannot easily be queried by data experts. Furthermore, exposing experimental data as SPARQL endpoints remains a challenging task because, in most cases, data must first be converted to Resource Description Framework triples. In line with those requirements, we have developed an infrastructure to expose clinical, demographic and molecular data elements generated by TCGA as a SPARQL endpoint by assigning elements to entities of the Simple Sloppy Semantic Database (S3DB) management model. All components of the infrastructure are available as independent Representational State Transfer (REST) Web services to encourage reusability, and a simple interface was developed to automatically assemble SPARQL queries by navigating a representation of the TCGA domain. A key feature of the proposed solution that greatly facilitates assembly of SPARQL queries is the distinction between the TCGA domain descriptors and data elements. Furthermore, the use of the S3DB management model as a mediator enables queries to both public and protected data without the need for prior submission to a single data source.

AGUIA: autonomous graphical user interface assembly for clinical trials semantic data services.

BACKGROUND: AGUIA is a front-end web application originally developed to manage clinical, demographic and biomolecular patient data collected during clinical trials at MD Anderson Cancer Center. The diversity of methods involved in patient screening and sample processing generates a variety of data types that require a resource-oriented architecture to capture the associations between the heterogeneous data elements. AGUIA uses a semantic web formalism, resource description framework (RDF), and a bottom-up design of knowledge bases that employ the S3DB tool as the starting point for the client's interface assembly. METHODS: The data web service, S3DB, meets the necessary requirements of generating the RDF and of explicitly distinguishing the description of the domain from its instantiation, while allowing for continuous editing of both. Furthermore, it uses an HTTP-REST protocol, has a SPARQL endpoint, and has open source availability in the public domain, which facilitates the development and dissemination of this application. However, S3DB alone does not address the issue of representing content in a form that makes sense for domain experts. RESULTS: We identified an autonomous set of descriptors, the GBox, that provides user and domain specifications for the graphical user interface. This was achieved by identifying a formalism that makes use of an RDF schema to enable the automatic assembly of graphical user interfaces in a meaningful manner while using only resources native to the client web browser (JavaScript interpreter, document object model). We defined a generalized RDF model such that changes in the graphic descriptors are automatically and immediately (locally) reflected into the configuration of the client's interface application. CONCLUSIONS: The design patterns identified for the GBox benefit from and reflect the specific requirements of interacting with data generated by clinical trials, and they contain clues for a general purpose solution to the challenge of having interfaces automatically assembled for multiple and volatile views of a domain. By coding AGUIA in JavaScript, for which all browsers include a native interpreter, a solution was found that assembles interfaces that are meaningful to the particular user, and which are also ubiquitous and lightweight, allowing the computational load to be carried by the client's machine.

Data-driven classification of the certainty of scholarly assertions.

The grammatical structures scholars use to express their assertions are intended to convey various degrees of certainty or speculation. Prior studies have suggested a variety of categorization systems for scholarly certainty; however, these have not been objectively tested for their validity, particularly with respect to representing the interpretation by the reader, rather than the intention of the author. In this study, we use a series of questionnaires to determine how researchers classify various scholarly assertions, using three distinct certainty classification systems. We find that there are three distinct categories of certainty along a spectrum from high to low. We show that these categories can be detected in an automated manner, using a machine learning model, with a cross-validation accuracy of 89.2% relative to an author-annotated corpus, and 82.2% accuracy against a publicly-annotated corpus. This finding provides an opportunity for contextual metadata related to certainty to be captured as a part of text-mining pipelines, which currently miss these subtle linguistic cues. We provide an exemplar machine-accessible representation-a Nanopublication-where certainty category is embedded as metadata in a formal, ontology-based manner within text-mined scholarly assertions.

Text Snippets to Corroborate Medical Relations: An Unsupervised Approach using a Knowledge Graph and Embeddings.

Knowledge graphs have been shown to significantly improve search results. Usually populated by subject matter experts, relations therein need to keep up to date with medical literature in order for search to remain relevant. Dynamically identifying text snippets in literature that confirm or deny knowledge graph triples is increasingly becoming the differentiator between trusted and untrusted medical decision support systems. This work describes our approach to mapping triples to medical text. A medical knowledge graph is used as a source of triples that are used to find matching sentences in reference text. Our unsupervised approach uses phrase embeddings and cosine similarity measures, and boosts candidate text snippets when certain key concepts exist. Using this approach, we can accurately map semantic relations within the medical knowledge graph to text snippets with a precision of 61.4% and recall of 86.3%. This method will be used to develop a novel application in the future to retrieve medical relations and corroborating snippets from medical text given a user query.

RPPAML/RIMS: a metadata format and an information management system for reverse phase protein arrays.

BACKGROUND: Reverse Phase Protein Arrays (RPPA) are convenient assay platforms to investigate the presence of biomarkers in tissue lysates. As with other high-throughput technologies, substantial amounts of analytical data are generated. Over 1,000 samples may be printed on a single nitrocellulose slide. Up to 100 different proteins may be assessed using immunoperoxidase or immunoflorescence techniques in order to determine relative amounts of protein expression in the samples of interest. RESULTS: In this report an RPPA Information Management System (RIMS) is described and made available with open source software. In order to implement the proposed system, we propose a metadata format known as reverse phase protein array markup language (RPPAML). RPPAML would enable researchers to describe, document and disseminate RPPA data. The complexity of the data structure needed to describe the results and the graphic tools necessary to visualize them require a software deployment distributed between a client and a server application. This was achieved without sacrificing interoperability between individual deployments through the use of an open source semantic database, S3DB. This data service backbone is available to multiple client side applications that can also access other server side deployments. The RIMS platform was designed to interoperate with other data analysis and data visualization tools such as Cytoscape. CONCLUSION: The proposed RPPAML data format hopes to standardize RPPA data. Standardization of data would result in diverse client applications being able to operate on the same set of data. Additionally, having data in a standard format would enable data dissemination and data analysis.

TopFed: TCGA tailored federated query processing and linking to LOD.

BACKGROUD: The Cancer Genome Atlas (TCGA) is a multidisciplinary, multi-institutional effort to catalogue genetic mutations responsible for cancer using genome analysis techniques. One of the aims of this project is to create a comprehensive and open repository of cancer related molecular analysis, to be exploited by bioinformaticians towards advancing cancer knowledge. However, devising bioinformatics applications to analyse such large dataset is still challenging, as it often requires downloading large archives and parsing the relevant text files. Therefore, it is making it difficult to enable virtual data integration in order to collect the critical co-variates necessary for analysis. METHODS: We address these issues by transforming the TCGA data into the Semantic Web standard Resource Description Format (RDF), link it to relevant datasets in the Linked Open Data (LOD) cloud and further propose an efficient data distribution strategy to host the resulting 20.4 billion triples data via several SPARQL endpoints. Having the TCGA data distributed across multiple SPARQL endpoints, we enable biomedical scientists to query and retrieve information from these SPARQL endpoints by proposing a TCGA tailored federated SPARQL query processing engine named TopFed. RESULTS: We compare TopFed with a well established federation engine FedX in terms of source selection and query execution time by using 10 different federated SPARQL queries with varying requirements. Our evaluation results show that TopFed selects on average less than half of the sources (with 100% recall) with query execution time equal to one third to that of FedX. CONCLUSION: With TopFed, we aim to offer biomedical scientists a single-point-of-access through which distributed TCGA data can be accessed in unison. We believe the proposed system can greatly help researchers in the biomedical domain to carry out their research effectively with TCGA as the amount and diversity of data exceeds the ability of local resources to handle its retrieval and parsing.

DASMiner: discovering and integrating data from DAS sources.

BACKGROUND: DAS is a widely adopted protocol for providing syntactic interoperability among biological databases. The popularity of DAS is due to a simplified and elegant mechanism for data exchange that consists of sources exposing their RESTful interfaces for data access. As a growing number of DAS services are available for molecular biology resources, there is an incentive to explore this protocol in order to advance data discovery and integration among these resources. RESULTS: We developed DASMiner, a Matlab toolkit for querying DAS data sources that enables creation of integrated biological models using the information available in DAS-compliant repositories. DASMiner is composed by a browser application and an API that work together to facilitate gathering of data from different DAS sources, which can be used for creating enriched datasets from multiple sources. The browser is used to formulate queries and navigate data contained in DAS sources. Users can execute queries against these sources in an intuitive fashion, without the need of knowing the specific DAS syntax for the particular source. Using the source's metadata provided by the DAS Registry, the browser's layout adapts to expose only the set of commands and coordinate systems supported by the specific source. For this reason, the browser can interrogate any DAS source, independently of the type of data being served. The API component of DASMiner may be used for programmatic access of DAS sources by programs in Matlab. Once the desired data is found during navigation, the query is exported in the format of an API call to be used within any Matlab application. We illustrate the use of DASMiner by creating integrative models of histone modification maps and protein-protein interaction networks. These enriched datasets were built by retrieving and integrating distributed genomic and proteomic DAS sources using the API. CONCLUSION: The support of the DAS protocol allows that hundreds of molecular biology databases to be treated as a federated, online collection of resources. DASMiner enables full exploration of these resources, and can be used to deploy applications and create integrated views of biological systems using the information deposited in DAS repositories.

Data driven semantic integration of translational lung cancer research at MDAnderson Cancer Center.

The Lung Cancer SPORE at University Texas MDAnderson Cancer Center and Southwestern Medical School requires the integration of heterogeneous multi-institutional sources comprising both molecular and clinical data. In this report we describe a novel method for converging domain specific experimental ontologies that relies on propagating permissions in Resource Description Framework triplets rather than the single access point of conventional relational databases. We address this challenge by combining semantic web data reposition with code distribution.

Exploratory analysis of the copy number alterations in glioblastoma multiforme.

BACKGROUND: The Cancer Genome Atlas project (TCGA) has initiated the analysis of multiple samples of a variety of tumor types, starting with glioblastoma multiforme. The analytical methods encompass genomic and transcriptomic information, as well as demographic and clinical data about the sample donors. The data create the opportunity for a systematic screening of the components of the molecular machinery for features that may be associated with tumor formation. The wealth of existing mechanistic information about cancer cell biology provides a natural reference for the exploratory exercise. METHODOLOGY/PRINCIPAL FINDINGS: Glioblastoma multiforme DNA copy number data was generated by The Cancer Genome Atlas project for 167 patients using 227 aCGH experiments, and was analyzed to build a catalog of aberrant regions. Genome screening was performed using an information theory approach in order to quantify aberration as a deviation from a centrality without the bias of untested assumptions about its parametric nature. A novel Cancer Genome Browser software application was developed and is made public to provide a user-friendly graphical interface in which the reported results can be reproduced. The application source code and stand alone executable are available at (http://code.google.com/p/cancergenome) and (http://bioinformaticstation.org), respectively. CONCLUSIONS/SIGNIFICANCE: The most important known copy number alterations for glioblastoma were correctly recovered using entropy as a measure of aberration. Additional alterations were identified in different pathways, such as cell proliferation, cell junctions and neural development. Moreover, novel candidates for oncogenes and tumor suppressors were also detected. A detailed map of aberrant regions is provided.

A Semantic Web management model for integrative biomedical informatics.

BACKGROUND: Data, data everywhere. The diversity and magnitude of the data generated in the Life Sciences defies automated articulation among complementary efforts. The additional need in this field for managing property and access permissions compounds the difficulty very significantly. This is particularly the case when the integration involves multiple domains and disciplines, even more so when it includes clinical and high throughput molecular data. METHODOLOGY/PRINCIPAL FINDINGS: The emergence of Semantic Web technologies brings the promise of meaningful interoperation between data and analysis resources. In this report we identify a core model for biomedical Knowledge Engineering applications and demonstrate how this new technology can be used to weave a management model where multiple intertwined data structures can be hosted and managed by multiple authorities in a distributed management infrastructure. Specifically, the demonstration is performed by linking data sources associated with the Lung Cancer SPORE awarded to The University of Texas MD Anderson Cancer Center at Houston and the Southwestern Medical Center at Dallas. A software prototype, available with open source at www.s3db.org, was developed and its proposed design has been made publicly available as an open source instrument for shared, distributed data management. CONCLUSIONS/SIGNIFICANCE: The Semantic Web technologies have the potential to addresses the need for distributed and evolvable representations that are critical for systems Biology and translational biomedical research. As this technology is incorporated into application development we can expect that both general purpose productivity software and domain specific software installed on our personal computers will become increasingly integrated with the relevant remote resources. In this scenario, the acquisition of a new dataset should automatically trigger the delegation of its analysis.

Adapting experimental ontologies for molecular epidemiology.

We have identified a set of indicators to track usage patterns of ontologies developed using the semantically explicit S3DB model (www.s3db.org, Nature Biotechnology (2006) 24(9):1070-1071). These indicators are quantitative measures that assess the maturity of the data model. As a case study, we have allowed experimental researchers working on molecular epidemiology to incubate a data model for molecular epidemiology by restructuring the underlying ontology and evaluating it with real data.