Guiding principles for technical infrastructure to support computable biomedical knowledge.

Over the past 4 years, the authors have participated as members of the Mobilizing Computable Biomedical Knowledge Technical Infrastructure working group and focused on conceptualizing the infrastructure required to use computable biomedical knowledge. Here, we summarize our thoughts and lay the foundation for future work in the development of CBK infrastructure, including: explaining the difference between computable knowledge and data, and contextualizing the conversation with the Learning Health Systems and the FAIR principles. Specifically, we provide three guiding principles to advance the development of CBK infrastructure: (a) Promote interoperable systems for data and knowledge to be findable, accessible, interoperable, and reusable. (b) Enable stable, trustworthy knowledge representations that are human and machine readable. (c) Computable knowledge resources should, when possible, be open. Standards supporting computable knowledge infrastructures must be open.

Semantically enabling clinical decision support recommendations.

BACKGROUND: Clinical decision support systems have been widely deployed to guide healthcare decisions on patient diagnosis, treatment choices, and patient management through evidence-based recommendations. These recommendations are typically derived from clinical practice guidelines created by clinical specialties or healthcare organizations. Although there have been many different technical approaches to encoding guideline recommendations into decision support systems, much of the previous work has not focused on enabling system generated recommendations through the formalization of changes in a guideline, the provenance of a recommendation, and applicability of the evidence. Prior work indicates that healthcare providers may not find that guideline-derived recommendations always meet their needs for reasons such as lack of relevance, transparency, time pressure, and applicability to their clinical practice. RESULTS: We introduce several semantic techniques that model diseases based on clinical practice guidelines, provenance of the guidelines, and the study cohorts they are based on to enhance the capabilities of clinical decision support systems. We have explored ways to enable clinical decision support systems with semantic technologies that can represent and link to details in related items from the scientific literature and quickly adapt to changing information from the guidelines, identifying gaps, and supporting personalized explanations. Previous semantics-driven clinical decision systems have limited support in all these aspects, and we present the ontologies and semantic web based software tools in three distinct areas that are unified using a standard set of ontologies and a custom-built knowledge graph framework: (i) guideline modeling to characterize diseases, (ii) guideline provenance to attach evidence to treatment decisions from authoritative sources, and (iii) study cohort modeling to identify relevant research publications for complicated patients. CONCLUSIONS: We have enhanced existing, evidence-based knowledge by developing ontologies and software that enables clinicians to conveniently access updates to and provenance of guidelines, as well as gather additional information from research studies applicable to their patients' unique circumstances. Our software solutions leverage many well-used existing biomedical ontologies and build upon decades of knowledge representation and reasoning work, leading to explainable results.

A semantic web framework to integrate cancer omics data with biological knowledge.

BACKGROUND: The RDF triple provides a simple linguistic means of describing limitless types of information. Triples can be flexibly combined into a unified data source we call a semantic model. Semantic models open new possibilities for the integration of variegated biological data. We use Semantic Web technology to explicate high throughput clinical data in the context of fundamental biological knowledge. We have extended Corvus, a data warehouse which provides a uniform interface to various forms of Omics data, by providing a SPARQL endpoint. With the querying and reasoning tools made possible by the Semantic Web, we were able to explore quantitative semantic models retrieved from Corvus in the light of systematic biological knowledge. RESULTS: For this paper, we merged semantic models containing genomic, transcriptomic and epigenomic data from melanoma samples with two semantic models of functional data - one containing Gene Ontology (GO) data, the other, regulatory networks constructed from transcription factor binding information. These two semantic models were created in an ad hoc manner but support a common interface for integration with the quantitative semantic models. Such combined semantic models allow us to pose significant translational medicine questions. Here, we study the interplay between a cell's molecular state and its response to anti-cancer therapy by exploring the resistance of cancer cells to Decitabine, a demethylating agent. CONCLUSIONS: We were able to generate a testable hypothesis to explain how Decitabine fights cancer - namely, that it targets apoptosis-related gene promoters predominantly in Decitabine-sensitive cell lines, thus conveying its cytotoxic effect by activating the apoptosis pathway. Our research provides a framework whereby similar hypotheses can be developed easily.

FAIR and Interactive Data Graphics from a Scientific Knowledge Graph.

Graph databases capture richly linked domain knowledge by integrating heterogeneous data and metadata into a unified representation. Here, we present the use of bespoke, interactive data graphics (bar charts, scatter plots, etc.) for visual exploration of a knowledge graph. By modeling a chart as a set of metadata that describes semantic context (SPARQL query) separately from visual context (Vega-Lite specification), we leverage the high-level, declarative nature of the SPARQL and Vega-Lite grammars to concisely specify web-based, interactive data graphics synchronized to a knowledge graph. Resources with dereferenceable URIs (uniform resource identifiers) can employ the hyperlink encoding channel or image marks in Vega-Lite to amplify the information content of a given data graphic, and published charts populate a browsable gallery of the database. We discuss design considerations that arise in relation to portability, persistence, and performance. Altogether, this pairing of SPARQL and Vega-Lite-demonstrated here in the domain of polymer nanocomposite materials science-offers an extensible approach to FAIR (findable, accessible, interoperable, reusable) scientific data visualization within a knowledge graph framework.

Summary of fourth annual MCBK public meeting: Mobilizing computable biomedical knowledge-metadata and trust.

The exponential growth of biomedical knowledge in computable formats challenges organizations to consider mobilizing artifacts in findable, accessible, interoperable, reusable, and trustable (FAIR+T) ways1. There is a growing need to apply biomedical knowledge artifacts to improve health in Learning Health Systems, health delivery organizations, and other settings. However, most organizations lack the infrastructure required to consume and apply computable knowledge, and national policies and standards adoption are insufficient to ensure that it is discoverable and used safely and fairly, nor is there widespread experience in the process of knowledge implementation as clinical decision support. The Mobilizing Computable Biomedical Knowledge (MCBK) community formed in 2016 to address these needs. This report summarizes the main outputs of the Fourth Annual MCBK public meeting, which was held virtually July 20 to July 21, 2021 and convened over 100 participants spanning diverse domains to frame and address important dimensions for mobilizing CBK.

Semantic web data warehousing for caGrid.

The National Cancer Institute (NCI) is developing caGrid as a means for sharing cancer-related data and services. As more data sets become available on caGrid, we need effective ways of accessing and integrating this information. Although the data models exposed on caGrid are semantically well annotated, it is currently up to the caGrid client to infer relationships between the different models and their classes. In this paper, we present a Semantic Web-based data warehouse (Corvus) for creating relationships among caGrid models. This is accomplished through the transformation of semantically-annotated caBIG Unified Modeling Language (UML) information models into Web Ontology Language (OWL) ontologies that preserve those semantics. We demonstrate the validity of the approach by Semantic Extraction, Transformation and Loading (SETL) of data from two caGrid data sources, caTissue and caArray, as well as alignment and query of those sources in Corvus. We argue that semantic integration is necessary for integration of data from distributed web services and that Corvus is a useful way of accomplishing this. Our approach is generalizable and of broad utility to researchers facing similar integration challenges.

Finding melanoma drugs through a probabilistic knowledge graph.

Metastatic cutaneous melanoma is an aggressive skin cancer with some progression-slowing treatments but no known cure. The omics data explosion has created many possible drug candidates; however, filtering criteria remain challenging, and systems biology approaches have become fragmented with many disconnected databases. Using drug, protein and disease interactions, we built an evidence-weighted knowledge graph of integrated interactions. Our knowledge graph-based system, ReDrugS, can be used via an application programming interface or web interface, and has generated 25 high-quality melanoma drug candidates. We show that probabilistic analysis of systems biology graphs increases drug candidate quality compared to non-probabilistic methods. Four of the 25 candidates are novel therapies, three of which have been tested with other cancers. All other candidates have current or completed clinical trials, or have been studied in in vivo or in vitro. This approach can be used to identify candidate therapies for use in research or personalized medicine.

Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas.

We report on whole-exome sequencing (WES) of 213 melanomas. Our analysis established NF1, encoding a negative regulator of RAS, as the third most frequently mutated gene in melanoma, after BRAF and NRAS. Inactivating NF1 mutations were present in 46% of melanomas expressing wild-type BRAF and RAS, occurred in older patients and showed a distinct pattern of co-mutation with other RASopathy genes, particularly RASA2. Functional studies showed that NF1 suppression led to increased RAS activation in most, but not all, melanoma cases. In addition, loss of NF1 did not predict sensitivity to MEK or ERK inhibitors. The rebound pathway, as seen by the induction of phosphorylated MEK, occurred in cells both sensitive and resistant to the studied drugs. We conclude that NF1 is a key tumor suppressor lost in melanomas, and that concurrent RASopathy gene mutations may enhance its role in melanomagenesis.

The Semanticscience Integrated Ontology (SIO) for biomedical research and knowledge discovery.

The Semanticscience Integrated Ontology (SIO) is an ontology to facilitate biomedical knowledge discovery. SIO features a simple upper level comprised of essential types and relations for the rich description of arbitrary (real, hypothesized, virtual, fictional) objects, processes and their attributes. SIO specifies simple design patterns to describe and associate qualities, capabilities, functions, quantities, and informational entities including textual, geometrical, and mathematical entities, and provides specific extensions in the domains of chemistry, biology, biochemistry, and bioinformatics. SIO provides an ontological foundation for the Bio2RDF linked data for the life sciences project and is used for semantic integration and discovery for SADI-based semantic web services. SIO is freely available to all users under a creative commons by attribution license. See website for further information: http://sio.semanticscience.org.

The Translational Medicine Ontology and Knowledge Base: driving personalized medicine by bridging the gap between bench and bedside.

BACKGROUND: Translational medicine requires the integration of knowledge using heterogeneous data from health care to the life sciences. Here, we describe a collaborative effort to produce a prototype Translational Medicine Knowledge Base (TMKB) capable of answering questions relating to clinical practice and pharmaceutical drug discovery. RESULTS: We developed the Translational Medicine Ontology (TMO) as a unifying ontology to integrate chemical, genomic and proteomic data with disease, treatment, and electronic health records. We demonstrate the use of Semantic Web technologies in the integration of patient and biomedical data, and reveal how such a knowledge base can aid physicians in providing tailored patient care and facilitate the recruitment of patients into active clinical trials. Thus, patients, physicians and researchers may explore the knowledge base to better understand therapeutic options, efficacy, and mechanisms of action. CONCLUSIONS: This work takes an important step in using Semantic Web technologies to facilitate integration of relevant, distributed, external sources and progress towards a computational platform to support personalized medicine. AVAILABILITY: TMO can be downloaded from http://code.google.com/p/translationalmedicineontology and TMKB can be accessed at http://tm.semanticscience.org/sparql.