Phenomics First

Phenomics First Resource Overview

About Phenomics First

Understanding genomic variation is key to precision medicine; however, despite the ease of sequencing, clinical interpretation is still thwarted because available variant-phenotype association data is complex, heterogeneous, and disaggregated across sources. Moreover, this evidence is sometimes incomplete, conflicting, and erroneous. Consequently, clinicians face long lists of candidate diseases, genes, and countless variants of unknown significance. Indeed, the efficiency and affordability of sequencing data has shifted the bottleneck to interpretation, based largely on these phenotype resources.

The Monarch Initiative is developing a community Phenomics-First Resource (PFR) to advance the emerging field of phenomics; its initial focus will be improving the phenotype data that supports variant prioritization in genetic disease diagnosis. Our approach is modeled on the Gene Ontology (GO). GO is the standard for describing gene function, and it benefits from active community use and development. The PFR will provide an overarching complementary solution for phenotypes—the higher-level outcomes of gene function/dysfunction. Our approach acknowledges the complexity of phenomics: currently, curated phenotype data is scattered across multiple databases with different standards (exchange formats, database schemas, and ontologies). More than 100 organizations curate human diseases and their attributes (phenotypes, genes, variants, frequency, treatments, etc.); dozens more curate model organism phenotypes.

The PFR will provide a framework to fundamentally advance and simplify computational approaches for interpreting human genome variation. We are the creators of the Human Phenotype Ontology (HPO), which has been the cornerstone of our pioneering work in data integration. We will leverage this to align phenotype ontologies and clinical terminologies, bringing major model species and clinical domains into the PFR, which we will refine through continual community partnership. The following interlinked approaches will provide a dynamic suite of community-developed knowledge resources to revolutionize variant interpretation applications and drive precision medicine.

Phenomics First Goals

The Phenomics First Resource comprises 3 major sub-components which are integrated into a common platform to transform variant interpretation and drive precision medicine.

  • Create a community-driven framework of interoperable phenotype definitions:
    The Unified Phenotype Ontology (uPheno)
  • Harmonize human disease definitions:
    The Mondo Disease Ontology
  • Create a community-wide phenotype exchange standard:
    Phenopackets

The Unified Phenotype Ontology (uPheno)

The Unified Phenotype Ontology (uPheno) is an effort led by the Monarch Initiative to integrate phenotype terminologies across species. uPheno has to major components: an OWL ontology that imports and deeply integrates phenotype ontologies from a variety of species, including Human and several major model organisms (such as Drosophila, Zebrafish, Xenopus, C. elegans, and Mouse), and a library of phenotype ontology term templates that are developed by the Phenotype Ontologies Reconciliation Effort.

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The Mondo Disease Ontology (Mondo)

The Mondo Disease Ontology (Mondo) aims to harmonize disease definitions across the world. It is a semi-automatically constructed ontology that merges in multiple disease resources to yield a coherent merged ontology. Original versions of Mondo were constructed entirely automatically and used the IDs of source databases and ontologies. Later, additional manually curated cross-ontology axioms were added, and a native Mondo ID system was used to avoid confusion with source databases.

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Phenopackets

Phenopackets are an open standard for sharing disease and phenotype information, with the aim of improving our ability to understand, diagnose, and treat both rare and common diseases. A Phenopacket links detailed phenotype descriptions with disease, patient, and genetic information, enabling clinicians, biologists, and disease and drug researchers to build more complete models of disease. The standard is designed to encourage wide adoption and synergy between the people, organizations and systems that comprise the joint effort to address human disease and biological understanding.

Phenopackets Ecosystem
The Phenopacket schema is a standard exchange format for phenotypes and environmental factors. This packet of phenotype data can be used anywhere, and can be written by anyone. This work is being done in collaboration with the Global Alliance for Genomics and Health (GA4GH).
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