The Monarch Initiative Phenotype Grid
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The Monarch Initiative aims to enhance biomedical research by providing tools for semantically aggregating and querying model systems related to human diseases. It focuses on improving phenotype comparisons across species and facilitating data visualization, ultimately aiding in the understanding of complex genetic disorders. The initiative is supported by NIH funding and utilizes various data services and methodologies for effective phenotype analysis.
The Monarch Initiative Phenotype Grid
- 1. monarch I N I T I A T I V E Design Requirements About the Monarch Initiative Model systems are the cornerstone of biomedical research to investigate biological processes, test gene-based disease hypotheses, and develop and test disease treatments. The vast knowledge that we have about model systems can be better utilized if semantically aggregated and made queryable based on any number of facets, such as phenotypic similarity, network analysis, gene expression and function, and genomics. The Monarch Initiative aims to provide easy-to-use tools to navigate this data landscape, services for other resources, and educational outreach regarding the production of structured data for biomedical discovery. l www.monarchinitiative.org Washington, et al. How good is your phenotyping: Methods for quality assessment The Translational Research Challenge l Model systems (cell lines, organisms) are vital tools for the study of human diseases. Implementation Details The Monarch Initiative Phenotype Grid Comparing Phenotypic Similarity across Species Charles Borromeo1 , Nicole L Washington2 , Christopher J. Mungall2 , Rebecca Boes1 , Melissa Haendel3 , Maryann Martone4 , Harry Hochheiser1 1 University of Pittsburgh, Pittsburgh, PA, 2 Lawrence Berkeley National Labs, Berkeley, CA, 3 Oregon Health & Science University, Portland, OR, 4 University of California San Diego, San Diego, CA The Monarch Initiative is supported by NIH Grant 1 R24 OD011883 and NIH contract HHSN268201300036C. Front-end: Middleware: Data Services: Future Work l Roll-up and drill-down of phenotype hierarchies l Comparison across multiple organisms l Inference paths linking human and model phenotypes. l Additional data types l Visual analytics process support Schwartz-Jampel Syndrome Schwartz-Jampel Syndrome (OMIM:255800), a genetic disorder associated with the HSPG2 gene, is used as an example to illustrate the use of the Monarch phenotype grid. This disease has a complex set of phenotypes (112 entries from the Human Phenotype Ontology), spanning eye, ear, genitourinary, skeletal, muscle, growth, and voice characteristics. Human-Mouse Comparison Human-Human Comparison Human Phenotype Ontology (HPO) terms associated with Schwartz-Jampel Syndrome Color-coded cells indicate strength of association between models and phenotypes Similar mouse models/genes shown in columns, ordered by similarity to input phenotype profile. Mouse-over of column or header highlights model and facilitates comparison to other models The ortholog Hspg2 is not the most similar model, recapitulating only a subset of the phenotypes Mouse-over of individual cells provides details on alignment between the input phenotype and the model, including the linking phenotype, and the similarity. Here, we see that the microcephaly input phenotype corresponds to the abnormal hypothalamus physiology phenotype in the Col1a1 mouse via the forebrain phenotype subsumer. Information content (IC) values measure distinctiveness of phenotypes. Menus support selection of target species and comparison metrics. Overview display supports navigation over the remainder of the phenotype/model space Schwartz-Jampel is most similar to itself, with some phenotypes (e.g. Blepharophimosis) occurring in multiple comparable diseases, while others (e.g. Abnormality of the pharynx) are less common. RingoJS server implementation, JSON exchange formats via API callsl Documentation http://www.monarchinitiative.org/page/widgetPhenotype Grid: http://www.monarchinitiative.org/page/phenogridMonarch API: See Monarch at Phenotype Day Borromeo, et al. Toward Interactive visual tools for comparing phenotype profiles Washington, et al. Investigating the relationship between standard laboratory mouse strains and their mutant phenotypes Reusable Javascript/D3/jQuery widgets support customization, adaptation to other data sources adhering to JSON format for similarity data. l l Neuroscience Informatics Framework/DISCO data repository l Scigraph ontology services l OWLSim semantic similarity services: http://www.owlsim.org l Which models are best, and why? l OWLSim: Calculate similarities - input disease phenotypes vs. model phenotypes - disease profile vs. model profile (aggregate over all relevant phenoptypes The Visualization Challenge Given n input characteristics P11, ... P1n, and l m comparison models M1... Mm, each with characteristics Mi,1...Mi,k l How do we interpret the relationships between the models? - Which inputs are informative/distinctive? - How do models differ from input, and from each other? l Sparse space - many inputs/models will not have any relationship. l Display information about the relationships underlying similarity measurements. l Use cross-species models of phenotypes to facilitte comparison - find subsuming phenotypes l Generalization - multidimensional similarity visualization + comparisons of dimensions. R1: Compare individual phenotypes between sets R2: Examine the coverage of a given input phenotype set across several models. R3: Compare models R4: Provide access to details R5: Interpret correspondences between input phenotypes and matching target phenotypes* R6: Examine relative contributions of individual phenotypes to model similarities and consider hypothetical alternatives* R7: Integrate other relevant data sources* R8: Construct arguments in support of candidate models* *Planned future work Here we see that the input phenotype blepharophimosis (narrowing of the eye opening) matches upslanted palpebral fissures observed in geleophysic dysplasia 1, via the common subsumer abnormality of the palpebral fissures. l Phenotypes describe manifestation of disease. l Ontological models of phenotypes provide hierarchical relationships grouping similar phenotypes l Use ontological structures to understand similarity relationships between items.