=Paper=
{{Paper
|id=Vol-3073/paper21
|storemode=property
|title=Expanding the Mammalian Phenotype Ontology to Meet the Needs of COVID-19 Model Curation
|pdfUrl=https://ceur-ws.org/Vol-3073/paper21.pdf
|volume=Vol-3073
|authors=Susan M. Bello,Anna V. Anagnostopoulos,Cynthia L. Smith
|dblpUrl=https://dblp.org/rec/conf/icbo/BelloAS21
}}
==Expanding the Mammalian Phenotype Ontology to Meet the Needs of COVID-19 Model Curation==
https://ceur-ws.org/Vol-3073/paper21.pdf
Expanding the Mammalian Phenotype Ontology to Meet the
Needs of COVID-19 Model Curation
Susan M. Bello 1, Anna V. Anagnostopoulos 1 and Cynthia L. Smith 1
1
The Jackson Laboratory, 600 Main St., Bar Harbor, ME, USA
Abstract
Through the course of the COVID-19 pandemic a wide array of signs and symptoms displayed
by patients have been identified. Mouse models of COVID-19 display phenotypes that
correlate to many of these signs and symptoms. To capture the phenotypes of these mouse
models in the Mouse Genome Informatics database the Mammalian Phenotype (MP) ontology
was reviewed to map these symptoms to existing MP terms and add new terms where needed.
This review identified over 350 COVID-19 signs and symptoms and resulted in the addition
of 127 new MP terms.
Keywords 1
COVID-19, phenotype, mouse models
1. Introduction
To meet the needs of researchers working to fight the COVID-19 pandemic, Mouse Genome
Informatics (MGI, www.informatics.jax.org)[1] incorporated data from mouse models of COVID-19
into the existing knowledgebases. Critical to this integration was ensuring that the Mammalian
Phenotype (MP) ontology[2], used by MGI to annotate phenotypes displayed by mouse models, had
the necessary terms to cover the range of signs and symptoms potentially displayed by COVID-19
patients and models. As COVID-19 is a newly emerged disease, the full spectrum of signs and
symptoms has not been fully defined. To identify appropriate terms, the emerging body of COVID-19
literature and resources were reviewed, and relevant terms extracted.
2. Identification of COVID-19 Signs and Symptoms
The initial list of COVID-19 signs and symptoms was seeded from the list developed in the COVID-
19 Virtual Biohackathon 2020[3]. This list was then augmented and expanded by multiple literature
reviews conducted using both PubMed and the bioRxiv/medRxiv COVID-19 collection
[https://connect.biorxiv.org/relate/content/181] to identify relevant articles. Papers were collected
throughout 2020-2021 with resources being accessed weekly or biweekly to collect newly added
articles. Emphasis was placed on papers that collected signs and symptoms for larger sets of patients as
opposed to reports on individual patients. In addition, COVID-19 symptom and sign lists from the
World Health Organization[4] (WHO) and the US Centers for Disease Control[5] (CDC) were
incorporated into the list. Symptoms and signs were extracted from over 220 references. The full set of
references can be found on the working spreadsheet linked in the Mammalian Phenotype GitHub
(https://github.com/mgijax/mammalian-phenotype-ontology/issues) issue #3406.
PubMed was systematically interrogated for peer-reviewed articles with full text availability, using
the search terms “COVID-19”, “SARS-CoV-2” or “2019-nCoV” in conjunction with “symptoms”,
“signs”, “characteristics”, “features”, “manifestations”’ or “complications”. For organ/system-specific
features additional search terms were combined, as appropriate. For example, to search for articles
International Conference on Biomedical Ontologies 2021, September 16–18, 2021, Bozen-Bolzano, Italy
EMAIL: susan.bello@jax.org (A. 1); anna.anagnostopoulos@jax.org (A. 2); cynthia.smith@jax.org (A. 3)
ORCID: 0000-0003-4606-0597 (A. 1); 0000-0002-6490-7723 (A. 2); 0000-0003-3691-0324 (A. 3)
© 2021 Copyright for this paper by its authors.
Use permitted under Creative Commons License Attribution 4.0 International (CC BY 4.0).
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reporting on the ocular manifestations of COVID-19, search terms included “ophthalmological”,
“ocular”, “eye” or “vision”.
The bioRxiv/medRxiv COVID-19 collection was manually reviewed to identify non-peer-reviewed
preprints. Papers mentioning in the title specific symptoms or systemic effects of COVID-19 in patients
were selected for further review. As the pandemic progressed, focus shifted to collecting in depth
characterizations of symptoms and reports of symptoms in anatomical systems without existing
symptom reports. In addition, with the identification of long COVID[6] and multisystem inflammatory
syndrome in children (MIS-C)[7] signs and symptoms for these conditions were incorporated into the
extracted signs and symptoms list.
2.1. Mapping of COVID-19 Signs and Symptoms to the MP
Each COVID-19, long COVID, and/or MIS-C sign or symptom was listed on a Google spreadsheet.
The MP and Human Phenotype ontology (HPO)[8] were then searched for a matching term and any
identified term in the ontology was added to the spreadsheet. If no match was identified in the ontology,
then the symptom was reviewed to determine if it was within the scope of the ontology. For missing
terms determined to be within scope of an ontology GitHub issues were created on the relevant
repository to request that new terms be added to the ontology. In the MP GitHub issue tracker tickets
relevant to COVID-19 have a “COVID-19” tag attached to facilitate tracking of relevant requests.
How closely an ontology term matched a given sign or symptom was indicated using Simple
Knowledge Organization System (SKOS) terms[9]. Ontology terms that have the same meaning as a
sign or symptom are marked as exact matches. Ontology terms that cover a wider range of phenotypes
than the sign or symptom are marked as broad matches. For example, while Fever (HP:0001945),
defined in the HPO as “Elevated body temperature due to failed thermoregulation.”, is covered by
increased body temperature (MP:0005533) there are other causes of increased body temperature
besides loss of thermoregulation that may also be encompassed under the MP term. Of the 204 MP
terms mapped to COVID-19 signs or symptoms where the SKOS mapping relation has been assigned,
there are 162 exact, 16 broad, 8 close, 15 related, and 3 narrow mappings. SKOS mappings were not
recorded from the start of the project so there remain 87 MP terms where an SKOS term is unassigned.
Table 1 lists an excerpt from the full set of symptoms. The full list of terms can be accessed online
upon request. The MP GitHub issue #3406 has an Excel spreadsheet with the mappings of MP terms as
of June 7, 2021. In the online list terms are grouped by affected system and the common and disease
severity classifications provided by the CDC or WHO are marked. Throughout the project the full set
of spreadsheets were shared with the HPO team to facilitate coordination of term mapping and
additions. Terms present in both ontologies are being mapped to each other and the resulting mappings
will be deposited in the Mouse-Human Ontology Mapping Initiative repository
(https://github.com/mapping-commons/mh_mapping_initiative).
2.2. Addition of New Terms to the MP
COVID-19 and related syndrome signs and symptoms that did not match an existing MP term were
evaluated for addition to the MP ontology. The most common type of term addition related to signs
associated with standard blood work for patients. For example, elevated blood C-X-C motif chemokine
ligand 10 level was reported in COVID-19 patients (see Table 1). This term was added to the MP
ontology as increased circulating CXCL10 level (MP:0031220) following the standard pattern for
abnormalities of circulating protein level terms in the MP ontology. In addition, terms for abnormal
and decreased circulating CXCL10 level (MP:0031218 and MP:0031219) were added. While these
terms do not directly match the COVID-19 sign they allow for annotation of mouse models where
genetic or environmental interventions alter the phenotypes exhibited by the mouse model. This new
term was then used to annotate the B6.Cg-Tg(K18-ACE2)2Prlmn/J (MGI:6389236) model of COVID-
19 based on phenotypes described by Yinda CK et al[10].
Table 1
Example of mapping of reported COVID-19 symptoms to MP and HPO terms
Reported MP term (ID) SKOS Match HPO term (ID) SKOS match Reference
symptom
Dyspnea respiratory exact Respiratory exact PMID:32586739
distress distress
(MP:0001954) (HP:0002098)
Anosmia anosmia exact Anosmia exact PMID:32464367,
(MP:0004512) (HP:0000458) PMID:32383370
Fever increased broad Fever exact PMID:32574165
body (HP:0001945)
temperature
(MP:0005533)
Interstitial interstitial exact Interstitial exact PMID:32526193
pneumonia pneumonia pneumonitis
(MP:0001862) (HP:0006515)
Hemiparesis Hemiparesis exact Hemiparesis exact PMID:32354768,
(MP:0031201) (HP:0001269) PMID:32436105
Cephalgia No term Headache exact PMID:32464367,
(HP:0002315) PMID:32574165
(headache)
Elevated blood increased exact No term PMID:32360286,
C-X-C motif circulating PMID:31986264
chemokine CXCL10 level
ligand 10 level (MP:0031220)
3. Conclusion
A total of 127 new COVID-19 sign and symptom related MP terms have been added as of May 19,
2021. These terms have been used in over 400 genotypes involving 360 mouse markers (data pulled
from MouseMine.org[11] on June 8, 2021 using the list of new COVID-19 related MP identifiers).
These terms were used to identify COVID-19 models and were also used in annotation of discrete
mouse models allowing for integration of COVID-19 data with the full corpus of MGI phenotype data.
The ability to find mutations that alter the expression of COVID-19 phenotypes independent of
infection can then be used to identify potential targets for new treatment strategies.
MGI biocurators continue to expand and refine the MP to reflect the evolving understanding of the
COVID-19 clinical spectrum and ensure robust annotation and retrieval of COVID-19 relevant model
phenotypes and genes.
4. Acknowledgements
This work was funded by program project grant HG000330 from the National Human Genome
Research Institute (NHGRI) of the National Institutes of Health (NIH). We would like to thank the
Human Phenotype Ontology team, in particular Nicole Vasilevsky, for help and feedback during this
project.
5. References
[1] J. A. Blake et al., Mouse Genome Database (MGD): Knowledgebase for mouse–human
comparative biology, Nucleic Acids Res., vol. 49, no. D1, pp. D981–D987, Jan. 2021.
[2] C. L. Smith and J. T. Eppig, The Mammalian Phenotype Ontology as a unifying standard for
experimental and high-throughput phenotyping data, Mamm. Genome, vol. 23, no. 9–10, pp. 653–
668, Sep. 2012.
[3] COVID19 Virtual BioHackathon 2020, 2020. [Online]. Available: https://github.com/virtual-
biohackathons/covid-19-bh20/wiki. [Accessed: 16-Apr-2020].
[4] WHO Headquarters, Clinical management Clinical management Living guidance COVID-19,”
World Health Organization, 2021. [Online]. Available:
https://www.who.int/publications/i/item/WHO-2019-nCoV-clinical-2021-1. [Accessed: 25-Jan-
2021].
[5] CDC, “Symptoms of COVID-19.” [Online]. Available: https://www.cdc.gov/coronavirus/2019-
ncov/symptoms-testing/symptoms.html. [Accessed: 22-Feb-2021].
[6] Long COVID: let patients help define long-lasting COVID symptoms, Nature, vol. 586, no. 7828,
pp. 170–170, Oct. 2020.
[7] N. Nakra, D. Blumberg, A. Herrera-Guerra, and S. Lakshminrusimha, Multi-System Inflammatory
Syndrome in Children (MIS-C) Following SARS-CoV-2 Infection: Review of Clinical
Presentation, Hypothetical Pathogenesis, and Proposed Management, Children, vol. 7, no. 7, p. 69,
Jul. 2020.
[8] S. Köhler et al., Expansion of the Human Phenotype Ontology (HPO) knowledge base and
resources, Nucleic Acids Res., vol. 47, no. D1, 2019.
[9] Mapping Properties. [Online]. Available: https://www.w3.org/TR/skos-reference/#mapping.
[Accessed: 09-Jun-2021].
[10] C. K. Yinda et al., K18-hACE2 mice develop respiratory disease resembling severe COVID-19,
PLOS Pathog., vol. 17, no. 1, p. e1009195, Jan. 2021.
[11] H. Motenko, S. B. Neuhauser, M. O’Keefe, and J. E. Richardson, MouseMine: a new data
warehouse for MGI, Mamm. Genome, vol. 26, no. 7–8, pp. 325–330, Aug. 2015.