Coordinating Coronavirus Research: The Virus Infectious Disease Ontology

Abstract

The COVID-19 pandemic prompted immense work on the investigation of the SARS-CoV-2 virus. Ontologies structured, controlled, vocabularies - are designed to support consistency of interpretation, and thereby to prevent the development of data silos. This paper describes how ontologies are serving this purpose in the virus research domain, following the principles of the Open Biological and Biomedical Ontology (OBO) Foundry and drawing on the resources of the Infectious Disease Ontology (IDO) Core. We report the development of the Virus Infectious Disease Ontology (VIDO), a reference ontology extending IDO Core covering viral infectious diseases. We examine newly minted terms, showcase ontology term reuse, and illustrate the use of VIDO by annotating selections from recent life science research on SAR-CoV-2, in the interest of supporting machine learning projects.

Keywords

• eol>Virus
• SARS-CoV-2
• coronavirus
• COVID-19
• applied ontology
• infectious disease ontology
• CIDO

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1. Introduction entities and relations across disciplines using consensus terminologies – constitute a well-known The volume of data collected by life-science solution to the formation of data silos. The need for researchers, the speed at which it is generated, rapid analysis of evolving datasets representing range of its sources, quality, accuracy, and need for coronavirus research motivated the development of assessment of usefulness, results in complex, the Virus Infectious Disease Ontology (VIDO) multidimensional datasets [ 1,2 ], often annotated comprised of textual definitions for terms and using discipline- or institution-specific relations and logical axioms supporting automated terminologies and coding systems that lead to data consistency checking, querying over datasets, and silos. These undermine interoperability, meta-data interoperability with other ontologies. VIDO is an analysis, pattern identification, and discovery across extension of the widely used Infectious Disease disciplines [ 3 ]. The value of cross-discipline meta- Ontology Core (IDO Core) [ 7 ], comprised of data analysis is evident during the present pandemic terminological content common to all investigations [ 4,5 ]. of infectious disease. VIDO extends IDO with terms specific to the domain of infectious diseases Ontologies – interoperable, logically well-defined, caused by viruses and provides a foundation for controlled vocabularies representing common ontologies representing specific viral infectious diseases such as the Coronavirus Infectious Disease Ontology (CIDO), which is itself an extension of VIDO covering coronavirus infectious diseases such as COVID-19. The most recent version of VIDO can be found at the National Center for Biomedical Ontology Bioportal [ 8 ].

VIDO was developed in collaboration with relevant domain experts and drawing on the expertise of the IDO developers to ensure alignment with OBO Foundry principles [ 9 ], supporting interoperability with Foundry ontologies [ 10 ]. Development of VIDO is transparent, with discussions available on GitHub [ 11 ]. VIDO term additions are driven by the needs of researchers investigating viruses and nearby domains, and so remains sensitive to evolving knowledge.

2. Methods

Biomedical and Biological Ontologies (OBO)

Foundry was created to provide guidance for ontology developers and promote alignment and interoperability. OBO Foundry design principles require ontologies: use a well-specified syntax unambiguous with a common space of identifiers, be openly available in the public domain, be modularly developed with a specified scope in a collaboration with ontologists covering nearby domains and conform to a common top-level architecture. The OBO library consists of over 250 ontologies, including some externally developed ontologies such as the NCI Thesaurus [ 18 ] and the NCBI Taxonomy [ 19 ], and some constructed ab initio to satisfy OBO principles. At its core is Basic Formal Ontology (BFO), a top-level ontology covering general classes such as material entity, quality, process, and role [ 20,21,22 ], which provides the architecture referred to in the last Foundry principle. BFO is, moreover, an ISO/IEC approved standard 21838-2 [ 23 ].

VIDO and is formally represented in OWL 2 Web

Ontology Language. VIDO was developed using the Protégé-OWL editor and tested against automated reasoners such as HermiT and Pellet [ 12,13 ]. Axioms underwriting VIDO were translated into a decidable fragment of first-order logic readable by the Mace4 [ 14 ] model checker, which allowed for manual graphical inspection of classes of models constrained by the asserted axioms. An automated proof-checker Prover9 bundled with Mace4 was used to validate expected theorems while refining axiom models.

Where BFO is domain-neutral, OBO Foundry ontologies represent types of entities in more specific domains, using terms such as disease, cell division, surgical procedure, and so forth. Each domain ontology is constructed using a methodology for formulating definitions through a process of downward population from BFO. The resulting alignment with BFO, and the conformance to OBO Foundry principles, fosters integration across ontologies. VIDO was designed with 2.1 OBO Foundry Alignment alignment and conformance in mind. Development followed metadata conventions adopted by many Ontologies are widely used in bioinformatics, OBO Foundry ontologies. These conventions supporting data standardization, integration, require that every term introduced into the ontology sharing, reproducibility, and automated reasoning. has a unique IRI, textual definitions, definition The Gene Ontology (GO), for example, maintains source, designation of term editor(s), and preferred species-neutral annotations of gene products and term label. In the interest of coordinating functions, and – since its inception in 1998 – has development with existing OBO ontologies, VIDO inspired an explosion of biomedical ontologies developers imported terms where possible from covering all domains of the life sciences [ 15,16,17 ]. OBO library ontologies and constructed logical These early developments led to worries, however, definitions using imported terms. Development was that data silos – the very problem ontologies were guided by best practices for definition construction designed to address – might reemerge as [ 24 ]. New terms were introduced when needed, researchers developed ontologies using concepts after consultation with domain experts, relevant local to their discipline. By 2007, the Open literature, and examination of the OBO library. disorder =def Material entity that is a clinically abnormal part of an extended organism.

A part of a material entity is “clinically abnormal” if it is not expected in the life plan for entities of the relevant type and is causally linked to elevated risk – that is, risk exceeding some threshold – of illness, death, or disfunction [32]. Organism is imported from OBI: organism =def Object that is an individual living system, such as animal, plant, bacteria, or virus, that is capable of replicating or reproducing, growth and maintenance in the right environment.

An organism may be unicellular or made up, like humans, of many billions of cells divided into specialized tissues and organs.

VIDO follows the “hub and spokes” methodology

[25] for ontology development. VIDO is a spoke ontology, extending from the Infectious Disease Ontology Core (IDO Core) as its hub. IDO Core is an OBO ontology consisting of terms, relations, natural language definitions and associated logical axioms representing phenomena common across infectious diseases research [26]. IDO Core has long provided a base from which more specific infectious disease ontologies extend and has been recently updated to keep pace with scientific and top-level architecture changes [27]. Extensions of IDO Core covering specific infectious diseases are created, first, by importing needed terms from IDO Core and other OBO Foundry ontologies, and second, by constructing the domain-specific terms Here we run into the first of several ontological where needed to adequately characterize entities in puzzles that emerged while developing VIDO. On the relevant domain. Examples include the the one hand, this definition aligns with common Brucellosis Infectious Disease Ontology (IDOBRU) use of the term “organism” among researchers the Influenza Infectious Disease Ontology insofar as instances are cellular entities [33,34]. On (IDOFLU), and more recently the Coronavirus the other hand, the textual definition includes Infectious Disease Ontology (CIDO), each viruses among instances, which are in every case semantically interoperable with other OBO library acellular. Debates [35] among ontology developers ontologies [28,29,30]. over organism have resulted in deprecation of the OBI term in favor of a term from the Common VIDO was designed to occupy the ontological Anatomy Reference Ontology [36]: organism or space between such virus-specific ontologies and virus or viroid. This avoids the preceding worries IDO Core. As a result, more specific virus-related but reveals two more. First, introducing disjunctive ontologies such as CIDO and IDOFLU are being classes suggests closure over instances. We should, curated to extend directly from VIDO, rather than however, avoid suggesting that classes – especially IDO Core. in biological domains – are settled results of scientific discoveries. Second, this disjunctive class 3. Results leads naturally to debates over whether viruses are VIDO takes IDO Core as its starting point, but also alive, since it classifies viruses alongside imports terms relevant to the domain of viruses paradigmatic living entities. Decades of discussion from other OBO Foundry ontologies, such as GO, have not resolved this question [37,38,39], and it is the Ontology for General Medical Science (OGMS) not obvious we need an answer for the purposes of and the Ontology for Biomedical Investigation ontological modelling. Rather than introduce an ad (OBI) [31]. hoc disjunctive class, IDO Core and VIDO developers collaborated to add the following disjoint sibling class of organism to IDO Core:

3.1 Virus

Like IDO Core, VIDO imports from OGMS:

acellular structure =def Object consisting of an arrangement of interrelated acellular parts forming an acellular biological unit that is able to exhaustive classes based on genetic structure. For initiate replication of the structure in a host. example, a subclass of virus:

Imported to VIDO as the parent class of the term

virus. The term virus is imported from the NCBITaxon [40], alongside other terms representing entities investigated by virologists, such as prion, viroid, and satellite. positive-sense single-stranded RNA virus =def Virus with genetic material encoded in singlestranded RNA that can be translated directly into proteins.

Which provides the parent class for:

The NCBITaxon provides an exhaustive list of life

science terms but has its limitations. First, with coronavirus =def Positive-sense single-stranded respect to virus terms NCBITaxon appears to align RNA virus with a helically symmetrical with the International Committee on Taxonomy of nucleocapsid, lipid bilayer viral envelope, and Viruses (ICTV). The ICTV, however, lacks surface spike peplomers. systematic classification criteria and consequently Figure 1 illustrates how the Baltimore leaves several viruses unclassified [41,42]. Second, Classification appears in the Protégé visualization when NCBITaxon is combined with automated of the class positive-sense single-stranded RNA importing tools such as Ontofox [43], ontology virus, supplemented by a textbook image of the developers (for example, the developers of the seven viral replication pathways underwritten by Schistosomiasis Ontology [27]) sometimes import virus genetic differences. entire ICTV hierarchies –from kingdom to species – resulting in large, unwieldy, taxonomies obscuring classes of interest. Third, NCBITaxon provides few textual definitions for terms. To align with OBO Foundry metadata conventions and best practices, definitions are needed for virus and its subclasses.

Standard definitions of “virus” provide a starting point, but caution is needed. Viruses are often described as obligate pathogens [44,45], since virus Figure 1: Baltimore Classification in Protégé Editor replication requires host machinery for production and assembly of viral components. However, defining a class virus solely in terms of what viruses typically do runs the risk of overlooking what viruses are, materially speaking. Compare: Homo sapiens are obligate aerobes, but this is no definition of the class. Insofar as we are defining the material entity virus, better to attend to genetic and structural components common to all viruses, and best to define the material entity in a way that captures obligate pathogenicity. VIDO defines:

By incorporating the Baltimore Classification,

VIDO provides developers of more specific virus classes within a succinct, navigable, ontological structure which refers to viral replication pathways, and so to virus pathogenicity.

VIDO subclasses of virus include those common in virology research, such as bacteriophage – viruses that infect bacteria – virophage – viruses that infect viruses – oncovirus – viruses that cause cancer – and mycovirus – viruses that infect fungi. One subclass of virus imported from NCBITaxon is the VIDO term: virus =def Acellular structure with RNA or DNA genetic material which uses host metabolic resources for RNA or DNA replication.

Subclasses of virus in VIDO are imported from NCBITaxon in alignment with the Baltimore Classification [46], which groups viruses into seven

virion =def Virus that is in its assembled state consisting of genomic material (DNA or RNA) surrounded by coating molecules.

Some researchers use “virion” and “virus” synonymously [47]. Some define “virion” so that instances only exist outside host cells [ 48 ] or distinguish virions outside host cells from those inside host cells, calling the former “mature virions.” Some claim “virion” is best understood as analogous to a sperm cell [ 49,50 ]. Ontologically speaking, one might model the relationship between a virus and its virion in a variety of ways: virion is to a virus as human infant is to human, or as human student is to human, or as human gamete is to human. Treating virions as akin to gametes is uncommon among researchers. Between the remaining options, we adopt the first, treating virion as a type of virus, since adopting the alternative would suggest a virion is just a virus in a specific context, with a specific role.

Some viruses do not replicate faithfully, perhaps resulting in genetically distinct mutants or – in extreme cases – an inactive aggregate of virion components. Virus mutations may undermine host immune system recognition of viral threats, as evidenced by the difficulty in developing vaccines for certain influenza strains. Too many mutations, however, and a virus may lose its ability to replicate, an observation used in development of treatments for polio and hepatitis C which exacerbate respective virus mutations [ 51,52 ]. VIDO provides the term: disordered virus =def Acellular structure having some clinically abnormal arrangement of viral components (e.g. viral capsid, viral DNA/RNA) Viruses falling in this class may be associated with diseases much different from those of the clinically normal variety. Terms for viral components are imported to VIDO. From GO, VIDO imports viral nucleocapsid, viral capsid, capsomere, from the Chemical Entities of Biological Interest (ChEBI) ontology [ 53 ] the terms nucleic acid and ribonucleic acid, and from the Protein Ontology [ 54 ] the terms protein and viral protein are imported.

3.2 Infectious Structure

The term “pathogen” is indexed to species or to stages in the developmental cycle of a species. A given virus may engage in mutual symbiosis with one species, while exhibiting pathogenic behavior towards others [ 55,56 ]. Mature plants are often susceptible to different pathogens than developing plants [ 57,58 ]. We capture virus pathogenicity in VIDO in steps. From IDO Core, we import dispositions borne by pathogens and infectious agents, as follows: pathogenic disposition =def Disposition borne by a material entity to establish localization in or produce toxins that can be transmitted to an organism or acellular structure, either of which may form disorder in the entity or immunocompetent members of the entity’s species. infectious disposition =def Pathogenic disposition borne by a pathogen to be transmitted to a host and then become part of an infection in that host or immunocompetent members of the same species as the host.

The class infectious agent in IDO Core is a subclass of organism, and so cannot include instances of virus. To address this issue, the term infectious structure was developed to parallel the IDO Core term infectious agent and is a logically defined subclass of acellular structure. The term infectious disposition bridges infectious acellular structures and infectious organisms since instances of each bear an infectious disposition. Moreover, the logical definitions of infectious structure and infectious agent are such that, though the former is a defined subclass of acellular structure and the latter a subclass of organism, they are both inferred subclasses of pathogen.

Establishment of localization used in pathogenic disposition is characterized using the GO term establishment of localization in host representing tethering or adhesion to a host, while “formation of disorder” abbreviates two imported IDO Core terms: appearance of disorder, which is a process that results in formation of a disorder. The definition of pathogenic disposition is meant to reflect a temporal ordering between establishment counts as a human infant pathogen. Nevertheless, of localization and appearance of disorder. This is because C. botulinum is not itself disposed to reflected explicitly in the logical axioms associated invade or be transmitted to human infants, we do with the class. Similarly, in the definition of not say the bacterium is infectious [62]. Being part infectious disposition there is an intended temporal of an infection is not itself sufficient to be counted ordering between transmission to a host – as infectious. Pathogens bearing an infectious represented by pathogen transmission process disposition must be disposed to both transmit and imported from the Pathogen Transmission Ontology become part of an infection. Many opportunistic [ 59 ] – and becoming part of an infection – pathogens are not infectious. represented by the IDO Core process of establishing an infection. A pathogen bearing an infectious disposition that generates disorder in a host will have been transmitted to the host prior to establishing localization in the host and will have established an infection prior to the appearance of disorder.

The complexity of the definitions of pathogenic disposition and infectious disposition reflect the variety of pathogen examples in contemporary literature. Consider S. aureus, an opportunistic pathogen [ 60 ] in humans. We count S. aureus as a pathogen, even when it does not realize disorder in a host, since it is nevertheless disposed to localize in a human host and generate disorder if given the opportunity. This is a disposition of S. aureus in BFO terms because it is an “internally-grounded” property of the entity [61]. That is, it is part of the material basis of S. aureus to generate disorder in human hosts if given the chance. This is analogous to the way salt has a disposition to dissolve, based on its lattice structure, independently of whether it ever realizes this disposition. Opportunistic pathogens are not pathogens because of an opportunity; they are pathogens because they are disposed to localize and cause disorder in a host.

Consider now, C. botulinum, a pathogen which produces toxin spores sometimes ingested by humans. This bacterium is a pathogen for adult humans since the toxins often result in disorder when ingested. Furthermore, C. botulinum may cause infection in human infants if, say honey colonized by C. botulinum is ingested. The sugar content of honey inhibits C. botulinum growth, but in the low-oxygen, low-acid intestines of human infants, spores can localize, grow, and produce toxins resulting in disorder. Thus, C. botulinum The immunocompetence and species membership clauses in the respective definitions of infectious disposition and pathogenic disposition are included in IDO Core to address instances where mutations in hosts may block realization of disorder or infection. In such cases, an infectious pathogen may nevertheless be transmissible and cause disorder or infection in others. For example, HIV-1 is a pathogen that may localize in a host with CCR-5 mutations [63] that block the virus from attaching to host cells, and so block pathogenesis to AIDS.

Similarly, P. falciparum may be transmitted to a host with a sickle-cell trait that blocks manifestation of the disease malaria [64,65]. However, P. falciparum and HIV-1 count as pathogens even if they do not result in the formation of disorders for hosts with a sickle-cell trait or CCR-5 mutation, respectively. Each pathogen may be transmitted to immunocompetent members of the same species as the host, and so counts as bearing instances of infectious disposition and pathogenic disposition.

Note, that P. falciparum and HIV-1 do not result in the formation of disorders in hosts with sickle-cell traits or CCR-5 mutations should not suggest there are no clinical abnormalities associated with these traits or mutations. Individuals with, say, CCR-5 mutations may exhibit clinical abnormalities [66], and so do exhibit disorders. But these disorders are due to the CCR-5 mutation rather than the HIV-1 infection. 3.3 Host

IDO Core and VIDO prioritize neither host nor

pathogen in representation of pathogens and associated diseases, adopting the Damage Response Framework (DRF) for guidance in development of relevant terms [67,68]. According to the DRF, pathogenesis results from interactions between both circle to the term disorder introduced above, since host and pathogen interacting primarily through clinical abnormality is associated with disorder. host damage, which is a function of the intensity When that disorder stems from infection it counts as and degree of host response and pathogen factors. an: Host and pathogen interactions thus influence manifestations of signs, symptoms, and disease.

IDO Core defines terms reflecting the DRF: host role=def Role borne by an acellular structure containing a distinct material entity, or organism whose extended organism contains a distinct material entity, realized in use of that structure or organism as a site of reproduction or replication. pathogen host role =def Host role borne by an organism having a pathogen as part of its extended organism.

Symptomatic cases of virus infection can be

represented by importing terms from the Symptom Ontology, such as dry cough, fever, taste alteration, smell alteration, among others [69]. Given the importance of asymptomatic carriers in viral infection spread, moreover, attention is also given to: symptomatic carrier role =def Pathogen host role borne by an organism whose extended organism contains a pathogen bearing an infectious disposition towards the host, and the host has manifested symptoms of the infectious disease caused by the pathogen. asymptomatic carrier role =def Pathogen host role borne by an organism whose extended organism contains a pathogen bearing an infectious disposition towards the host, and the host has no symptoms of the infectious disease caused by the pathogen. subclinical infection =def Infection that is part of an asymptomatic carrier.

The term subclinical infection reflects standard – if somewhat obscure – use of the terms “subclinical” and “asymptomatic” while allowing for cases of clinically abnormal infections without symptoms. VIDO defines subclinical virus infection as an infection caused by some virus part of an asymptomatic carrier. These remarks bring us full infectious disorder =def Disorder that is part of an extended organism which has an infectious pathogen part, that exists as a result of a process of formation of disorder initiated by the infectious pathogen.

And when the adverted pathogen is a virus, it falls in the VIDO class:

virus disorder =def Infectious disorder that exists as a result of a process of formation of disorder initiated by a virus.

Medical researchers draw a distinction between symptoms and signs, which OBO Foundry ontologies respect (from OGMS): symptom =def Process experienced by the patient which can only be experienced by the patient, that is hypothesized to be clinically relevant. qualitative sign =def Abnormal observable quality of a part of a patient that is hypothesized to be clinically relevant. processual sign =def Abnormal processual entity occurring in a patient that is hypothesized to be clinically relevant.

An asymptomatic carrier infected with SARS-CoV2 likely exhibits signs indicating that the infection is clinically abnormal, such as ground-glass opacities or positive PCR test results. Such asymptomatic carriers exhibit an instance of the VIDO class virus disorder which is the material basis of a viral disease: infectious disease =def Disease whose physical basis is an infectious disorder. viral disease =def Infectious disease inhering in a virus disorder that is a disorder due to the presence of the virus.

This result aligns with the CDC’s case criteria

adopted on April 5, 2020 which indicate that the presence of the SARS-CoV-2 genome or relevant antigens in an individual is sufficient to count as a case of COVID-19, asymptomatic or not [70,71].

3.4 Viral Pathogenesis

Accurately representing viral pathogenesis is of great importance, in particular, as researchers are still working to understand how SARS-CoV-2 infections cause such a wide range of signs and symptoms across demographics. Representing disease pathogenesis is aided by importing terms from relevant OBO Foundry ontologies, to define: viral pathogenesis =def Pathogenesis process realization of an infectious disposition inhering in a virus or virus population, having at least the proper process parts: (1) pathogen transmission, (2) establishment of localization in host, (3) process of establishing an infection, and (4) appearance of a virus disorder.

Where pathogenesis is imported from GO: pathogenesis =def Process that generates the ability of a pathogen to induce disorder in an organism. needed to characterize transporters are imported from IDO Core: pathogen transporter role =def Role borne by a material entity in or on which a pathogen is located, from which the pathogen may be transmitted to a new host.

A subclass – fomite role, roughly, a pathogen transporter role borne by non-living entities – plays an important function in virus transmission.

Viral pathogenesis involves replication in a host. The term virus replication is defined in VIDO as a subclass of the IDO Core term replication, specifically:

virus replication =def Replication process in which a virus containing some portion of genetic material inherited from a parent virus is replicated.

Instances of virus pathogenesis have virus replication parts. Viral replication typically occurs within an: incubation process =def Process beginning with the establishing of an infection in a host and ending with the onset of symptoms by the host during which pathogens are multiplying in the host.

As defined, pathogenesis is a success term, in that it encompasses formation of disorder in an entity.

This is reflected in (1)-(4) of the viral pathogenesis Which occupies an incubation interval and may definition and motivated by the GO Consortium precede a communicability interval. The focus on canonical biological processes [72]. This is corresponding process during which viral hosts bear not to say all virus infections result in successful a contagiousness disposition has proper part some pathogenesis. An individual may be infected by a latency process which itself has an eclipse process virus without a relevant disorder. Absent the part: disorder, there is no material basis for the associated disease. Consequently, this would not count as an instance of viral pathogenesis. communicability interval =def One-dimensional temporal region during which a pathogen host bears a contagiousness disposition.

Viral pathogenesis involves transmission of virions.

From PTRANS [ 59 ] is imported: pathogen transmission process =def Process during which a pathogen is transmitted directly or indirectly to a new host.

Role terms – reflecting “externally-grounded” realizable entities acquired based on circumstance, such as the role a student takes on in university – latency process =def Process beginning with the establishing of an infection in a host and ending when the host becomes contagious, during which pathogens are multiplying in the host. eclipse process =def Process beginning with the establishment of a virus in a host and ending with the first appearance of a virion following viral release, during which an infecting virus is vaccines. Several members of both the IDO Core uncoating to begin genome replication. and the VIDO development teams are members of the CIDO development team working to ensure The last being specific to viruses, so specific to alignment among these ontologies. Terms reflecting VIDO. The remaining terms are found in IDO Core. common features of coronaviruses can be imported Viral dormancy is a virus-specific term from VIDO occurring over a: from OBO ontologies to characterize features of coronaviruses, such as the viral genome including a five-prime nucleotide cap, or the common glycoprotein spikes found in the viral envelope [76,77]. Some terms are specializations of terms from the Protein Ontology [ 54 ], including membrane protein (SARS-CoV-2) and spike glycoprotein (SARS-CoV-2). Worth noting is that while CIDO is not the only ontology developed to support curation of COVID-19 data [78,79,80,81], most alternatives are stand-alone initiatives, and so subject to the silo problems typically found in ontologies developed outside the scope of the OBO Foundry and with no attention to its principles.

3.6 Annotations

The extent of coverage in VIDO and related ontologies can be illustrated by annotation of coronavirus research articles. viral dormancy interval =def One-dimensional temporal region on which a virus is no longer replicating but remains within a host cell and which may be reactivated to begin replication again.

With participants found from familiar viruses such as varicella zoster and herpes simplex.

Generative stage is imported from IDO Core,

defined as a temporal subdivision of a developmental process, as well as: virus generative stage =def Infectious structure generative stage that is a temporal subdivision of a virus developmental process.

Subclasses of which include the stages through which viruses may proceed during replication: virus attachment stage =def Virus generative stage during which a virion protein binds to molecules on the host surface or host cell surface projection. virus penetration stage =def Virus generative stage during which a virion or viral nucleic acid breaches the barriers of a host.

3.5 Bridge to CIDO

VIDO serves as a bridge between IDO Core and the IDO extension ontologies representing specific viral Consider the following overview of SARS-CoV-2 diseases. An extension of importance during the pathogenesis (color coded as in Figure 5): pandemic is the recently developed Coronavirus Infectious Disease Ontology (CIDO). CIDO FCoolVlo-w2icnogrroenpalvicirautisovni,rcioelnlslycsaiussoefs ShAosRt Sc-ells provides semantic resources needed for to release molecules which function to warn representing coronavirus genome, surveillance, nearby cells. When recognized by epithelial vaccine, and host data. The ontology has been used cells, endothelial, and alveolar macrophages, to annotate data pertaining to 136 known anti- proteins such as IL-6, IP-10, and MCPI, are coronavirus drugs [73], to identify 110 candidate released which attract T cells, macrophages, drugs for potential COVID-19 drug repurposing and monocytes to the site of infection, [74,75], and to provide input to machine learning promoting inflammation. In disordered efforts [ 4 ] in identifying potential COVID-19 immune systems, immune cells accumulate in the lungs, then propagate to and damage other organs. In normal immune systems, inflammation attracts T cells which neutralize the virus at the site of infection.

Antibodies circulate, preventing SARS-CoV2 infection, and alveolar macrophages recognize SARS-CoV-2 and eliminate virions via phagocytosis [82].

In more a more ontologically oriented language, we speak of the relevant part of a host’s immune response as being disposed to manifest a response that eliminates SARS-CoV-2 infection, while SARS-CoV-2 has a disposition to block manifestation of this immune system response.

Consider next a color-coded selection from the Lancet [83] concerning SARS-CoV-2: “The viral loads in throat swabs and sputum samples peaked at around 5-6 days after symptom onset, ranging from around 10^4 to 10^7 copies per mL during this time.” challenges, however. Often, terms were developed then presented to domain specialists for vetting, after which they were refined through discussion.

As in the case of all scientific ontologies, refinement will continue as research advances, and further collaborators are welcome and necessary.

The existence of IDO Core extensions covering infectious disease-causing entities other than viruses suggests a need for the creation of reference ontology extensions of IDO covering bacteria, fungi, and parasites. The methodology illustrated in the development of VIDO provides a recipe for such reference ontology creation. Additionally, the methodology illustrated in the development of coronavirus-specific terms outlined above provides a recipe for the creation of novel virus-specific ontologies, namely, by extending them from existing virus ontologies such as CIDO where possible. Adoption of these methodologies by developers during ontology construction will significantly reduce the labor involved in ontology creation. viral load =def Quality inhering in a portion of fluid that is the proportion of virions to volume of that portion of fluid.

SARS-CoV-2 infected hosts contain the highest concentration of SARS-CoV-2 virions – the viral load – during the incubation interval [84]. Viral VIDO represents a substantial effort to characterize load is a common measurement of the proportion of viruses in a collaborative, computationally tractable virions to fluid, and for SARS-CoV-2 is frequently manner. Ontologies like these are crucial in the measured from host sputum. VIDO also provides contemporary Big Data era and will provide resources for annotating virus quantification: researchers needed resources for gathering and coordinating increasingly important life science data.

5. Acknowledgments

Our color-coding of this passage models term reuse JB, SB supported by NIH/NLM T15LM012495-01 across existing ontologies. For example, developers Buffalo Research Innovation in Genomic and can use VIDO terms alongside terms from the Healthcare Technology (BRIGHT) Education Common Core Ontology [85] such as is measured Training Programs, 2020-2021. BS’s contributions by, measurement information content entity, has were supported by the NIH under NCATS integer value, uses measurement unit, and milliliter 1UL1TR001412 (Buffalo Clinical and Translational measurement unit. Other virus quantification metric Research Center). VIDO is available under the terms, such as multiplicity of viral infection - the Creative Commons Attribution 4.0 license and an ratio of virions to susceptible cells in a target area – up-to-date version of the ontology. can be found in VIDO as well.

4. Discussion

VIDO enables extensive representation of virusrelated research. The very scope of VIDO provides

Many thanks to Asiyah Yu Lin for assistance in VIDO development; to Darren Natale for helpful critical feedback on an earlier draft. Figures were designed by or in consultation with Rain Yuan.

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