Coordinating Coronavirus Research: The Virus Infectious Disease Ontology John Beverley1, Shane Babcock2, Barry Smith3, Yongqun He4, Eric Merrell1,3, Lindsay Cowell5, Regina Hurley6, Sebastian Deusing7 1 Johns Hopkins University Applied Physics Laboratory, Laurel, MD, USA 2 Department of Philosophy, Niagara University, Lewiston, NY, USA 3 Department of Philosophy, University at Buffalo, Buffalo, NY, USA 4 University of Michigan Medical School, Ann Arbor, MI, USA 5 University of Texas Southwestern Medical School, Dallas TX, USA 6 Department of Philosophy, Northwestern University, Evanston, IL, USA 7 Loyola University, Chicago, Il, USA 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 Virus, SARS-CoV-2, coronavirus, COVID-19, applied ontology, infectious disease ontology, CIDO 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 ICBO 2022, September 25-28, 2022, Ann Arbor, MI, USA EMAIL: johnbeverley2021@u.northwestern.edu (A.1); babcock8@buffalo.edu (A.2); ifomis@gmail.com (A.3); yongqunh@med.umich.edu (A.4); Lindsay.Cowell@utsouthwestern.edu (A.5); ReginaHurley2023@u.northwestern.edu (A.6); sduesing@luc.edu (A.7) ORCID: 0000-0002-1118-1738 (A. 1); 0000-0003-0798-114X (A. 2); 0000-0003-1384-116X (A. 3); 0000-0001-9189-9661 (A.4); 0000- 0003-1617-8244 (A.5) 2022 Copyright for this paper by its authors. Use permitted under Creative Commons License Attribution 4.0 International (CC BY 4.0). CEUR Workshop Proceedings (CEUR-WS.org) ©️ CEUR ceur-ws.org Workshop ISSN 1613-0073 Proceedings diseases such as the Coronavirus Infectious Disease Biomedical and Biological Ontologies (OBO) Ontology (CIDO), which is itself an extension of Foundry was created to provide guidance for VIDO covering coronavirus infectious diseases ontology developers and promote alignment and such as COVID-19. The most recent version of interoperability. OBO Foundry design principles VIDO can be found at the National Center for require ontologies: use a well-specified syntax Biomedical Ontology Bioportal [8]. unambiguous with a common space of identifiers, be openly available in the public domain, be VIDO was developed in collaboration with relevant modularly developed with a specified scope in a domain experts and drawing on the expertise of the collaboration with ontologists covering nearby IDO developers to ensure alignment with OBO domains and conform to a common top-level Foundry principles [9], supporting interoperability architecture. The OBO library consists of over 250 with Foundry ontologies [10]. Development of ontologies, including some externally developed VIDO is transparent, with discussions available on ontologies such as the NCI Thesaurus [18] and the GitHub [11]. VIDO term additions are driven by the NCBI Taxonomy [19], and some constructed ab needs of researchers investigating viruses and initio to satisfy OBO principles. At its core is Basic nearby domains, and so remains sensitive to Formal Ontology (BFO), a top-level ontology evolving knowledge. covering general classes such as material entity, 2. Methods quality, process, and role [20,21,22], which provides the architecture referred to in the last VIDO and is formally represented in OWL 2 Web Foundry principle. BFO is, moreover, an ISO/IEC Ontology Language. VIDO was developed using approved standard 21838-2 [23]. the Protégé-OWL editor and tested against Where BFO is domain-neutral, OBO Foundry automated reasoners such as HermiT and Pellet ontologies represent types of entities in more [12,13]. Axioms underwriting VIDO were specific domains, using terms such as disease, cell translated into a decidable fragment of first-order division, surgical procedure, and so forth. Each logic readable by the Mace4 [14] model checker, domain ontology is constructed using a which allowed for manual graphical inspection of methodology for formulating definitions through a classes of models constrained by the asserted process of downward population from BFO. The axioms. An automated proof-checker Prover9 resulting alignment with BFO, and the conformance bundled with Mace4 was used to validate expected to OBO Foundry principles, fosters integration theorems while refining axiom models. 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. 2 2.2 Hub and Spokes Approach disorder =def Material entity that is a clinically abnormal part of an extended organism. VIDO follows the “hub and spokes” methodology [25] for ontology development. VIDO is a spoke A part of a material entity is “clinically abnormal” ontology, extending from the Infectious Disease if it is not expected in the life plan for entities of the Ontology Core (IDO Core) as its hub. IDO Core is relevant type and is causally linked to elevated risk an OBO ontology consisting of terms, relations, – that is, risk exceeding some threshold – of illness, natural language definitions and associated logical death, or disfunction [32]. Organism is imported axioms representing phenomena common across from OBI: infectious diseases research [26]. IDO Core has organism =def Object that is an individual living long provided a base from which more specific system, such as animal, plant, bacteria, or virus, infectious disease ontologies extend and has been that is capable of replicating or reproducing, recently updated to keep pace with scientific and growth and maintenance in the right environment. top-level architecture changes [27]. Extensions of An organism may be unicellular or made up, like IDO Core covering specific infectious diseases are humans, of many billions of cells divided into created, first, by importing needed terms from IDO specialized tissues and organs. 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 3.1 Virus disjoint sibling class of organism to IDO Core: Like IDO Core, VIDO imports from OGMS: acellular structure =def Object consisting of an arrangement of interrelated acellular parts 3 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 positive-sense single-stranded RNA virus =def virus. The term virus is imported from the Virus with genetic material encoded in single- NCBITaxon [40], alongside other terms stranded RNA that can be translated directly into representing entities investigated by virologists, proteins. such as prion, viroid, and satellite. Which provides the parent class for: The NCBITaxon provides an exhaustive list of life coronavirus =def Positive-sense single-stranded science terms but has its limitations. First, with RNA virus with a helically symmetrical respect to virus terms NCBITaxon appears to align nucleocapsid, lipid bilayer viral envelope, and with the International Committee on Taxonomy of surface spike peplomers. Viruses (ICTV). The ICTV, however, lacks 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 By incorporating the Baltimore Classification, and assembly of viral components. However, VIDO provides developers of more specific virus defining a class virus solely in terms of what classes within a succinct, navigable, ontological viruses typically do runs the risk of overlooking structure which refers to viral replication pathways, what viruses are, materially speaking. Compare: and so to virus pathogenicity. Homo sapiens are obligate aerobes, but this is no definition of the class. Insofar as we are defining VIDO subclasses of virus include those common in the material entity virus, better to attend to genetic virology research, such as bacteriophage – viruses and structural components common to all viruses, that infect bacteria – virophage – viruses that infect and best to define the material entity in a way that viruses – oncovirus – viruses that cause cancer – captures obligate pathogenicity. VIDO defines: and mycovirus – viruses that infect fungi. One subclass of virus imported from NCBITaxon is the virus =def Acellular structure with RNA or DNA VIDO term: genetic material which uses host metabolic resources for RNA or DNA replication. virion =def Virus that is in its assembled state consisting of genomic material (DNA or RNA) Subclasses of virus in VIDO are imported from surrounded by coating molecules. NCBITaxon in alignment with the Baltimore Classification [46], which groups viruses into seven 4 Some researchers use “virion” and “virus” The term “pathogen” is indexed to species or to synonymously [47]. Some define “virion” so that stages in the developmental cycle of a species. A instances only exist outside host cells [48] or given virus may engage in mutual symbiosis with distinguish virions outside host cells from those one species, while exhibiting pathogenic behavior inside host cells, calling the former “mature towards others [55,56]. Mature plants are often virions.” Some claim “virion” is best understood as susceptible to different pathogens than developing analogous to a sperm cell [49,50]. Ontologically plants [57,58]. We capture virus pathogenicity in speaking, one might model the relationship between VIDO in steps. From IDO Core, we import a virus and its virion in a variety of ways: virion is dispositions borne by pathogens and infectious to a virus as human infant is to human, or as human agents, as follows: student is to human, or as human gamete is to pathogenic disposition =def Disposition borne by a human. Treating virions as akin to gametes is material entity to establish localization in or uncommon among researchers. Between the produce toxins that can be transmitted to an remaining options, we adopt the first, treating virion organism or acellular structure, either of which as a type of virus, since adopting the alternative may form disorder in the entity or would suggest a virion is just a virus in a specific immunocompetent members of the entity’s context, with a specific role. species. Some viruses do not replicate faithfully, perhaps infectious disposition =def Pathogenic disposition resulting in genetically distinct mutants or – in borne by a pathogen to be transmitted to a host extreme cases – an inactive aggregate of virion and then become part of an infection in that host components. Virus mutations may undermine host or immunocompetent members of the same immune system recognition of viral threats, as species as the host. evidenced by the difficulty in developing vaccines for certain influenza strains. Too many mutations, The class infectious agent in IDO Core is a subclass however, and a virus may lose its ability to of organism, and so cannot include instances of replicate, an observation used in development of virus. To address this issue, the term infectious treatments for polio and hepatitis C which structure was developed to parallel the IDO Core exacerbate respective virus mutations [51,52]. term infectious agent and is a logically defined VIDO provides the term: subclass of acellular structure. The term infectious disposition bridges infectious acellular structures disordered virus =def Acellular structure having and infectious organisms since instances of each some clinically abnormal arrangement of viral bear an infectious disposition. Moreover, the logical components (e.g. viral capsid, viral DNA/RNA) definitions of infectious structure and infectious Viruses falling in this class may be associated with agent are such that, though the former is a defined diseases much different from those of the clinically subclass of acellular structure and the latter a normal variety. Terms for viral components are subclass of organism, they are both inferred imported to VIDO. From GO, VIDO imports viral subclasses of pathogen. nucleocapsid, viral capsid, capsomere, from the Establishment of localization used in pathogenic Chemical Entities of Biological Interest (ChEBI) disposition is characterized using the GO term ontology [53] the terms nucleic acid and ribonucleic establishment of localization in host representing acid, and from the Protein Ontology [54] the terms tethering or adhesion to a host, while “formation of protein and viral protein are imported. disorder” abbreviates two imported IDO Core 3.2 Infectious Structure terms: appearance of disorder, which is a process that results in formation of a disorder. The definition of pathogenic disposition is meant to 5 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 The immunocompetence and species membership an infection. A pathogen bearing an infectious clauses in the respective definitions of infectious disposition that generates disorder in a host will disposition and pathogenic disposition are included have been transmitted to the host prior to in IDO Core to address instances where mutations establishing localization in the host and will have in hosts may block realization of disorder or established an infection prior to the appearance of infection. In such cases, an infectious pathogen may disorder. nevertheless be transmissible and cause disorder or The complexity of the definitions of pathogenic infection in others. For example, HIV-1 is a disposition and infectious disposition reflect the pathogen that may localize in a host with CCR-5 variety of pathogen examples in contemporary mutations [63] that block the virus from attaching to literature. Consider S. aureus, an opportunistic host cells, and so block pathogenesis to AIDS. pathogen [60] in humans. We count S. aureus as a Similarly, P. falciparum may be transmitted to a pathogen, even when it does not realize disorder in host with a sickle-cell trait that blocks manifestation a host, since it is nevertheless disposed to localize of the disease malaria [64,65]. However, P. in a human host and generate disorder if given the falciparum and HIV-1 count as pathogens even if opportunity. This is a disposition of S. aureus in they do not result in the formation of disorders for BFO terms because it is an “internally-grounded” hosts with a sickle-cell trait or CCR-5 mutation, property of the entity [61]. That is, it is part of the respectively. Each pathogen may be transmitted to material basis of S. aureus to generate disorder in immunocompetent members of the same species as human hosts if given the chance. This is analogous the host, and so counts as bearing instances of to the way salt has a disposition to dissolve, based infectious disposition and pathogenic disposition. on its lattice structure, independently of whether it Note, that P. falciparum and HIV-1 do not result in ever realizes this disposition. Opportunistic the formation of disorders in hosts with sickle-cell pathogens are not pathogens because of an traits or CCR-5 mutations should not suggest there opportunity; they are pathogens because they are are no clinical abnormalities associated with these disposed to localize and cause disorder in a host. traits or mutations. Individuals with, say, CCR-5 mutations may exhibit clinical abnormalities [66], Consider now, C. botulinum, a pathogen which and so do exhibit disorders. But these disorders are produces toxin spores sometimes ingested by due to the CCR-5 mutation rather than the HIV-1 humans. This bacterium is a pathogen for adult infection. humans since the toxins often result in disorder when ingested. Furthermore, C. botulinum may 3.3 Host cause infection in human infants if, say honey colonized by C. botulinum is ingested. The sugar IDO Core and VIDO prioritize neither host nor content of honey inhibits C. botulinum growth, but pathogen in representation of pathogens and in the low-oxygen, low-acid intestines of human associated diseases, adopting the Damage Response infants, spores can localize, grow, and produce Framework (DRF) for guidance in development of toxins resulting in disorder. Thus, C. botulinum relevant terms [67,68]. According to the DRF, 6 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 infectious disorder =def Disorder that is part of an manifestations of signs, symptoms, and disease. extended organism which has an infectious IDO Core defines terms reflecting the DRF: pathogen part, that exists as a result of a process host role=def Role borne by an acellular structure of formation of disorder initiated by the infectious containing a distinct material entity, or organism pathogen. whose extended organism contains a distinct And when the adverted pathogen is a virus, it falls material entity, realized in use of that structure or in the VIDO class: organism as a site of reproduction or replication. virus disorder =def Infectious disorder that exists pathogen host role =def Host role borne by an as a result of a process of formation of disorder organism having a pathogen as part of its initiated by a virus. extended organism. Medical researchers draw a distinction between Symptomatic cases of virus infection can be symptoms and signs, which OBO Foundry represented by importing terms from the Symptom ontologies respect (from OGMS): Ontology, such as dry cough, fever, taste alteration, smell alteration, among others [69]. Given the symptom =def Process experienced by the patient importance of asymptomatic carriers in viral which can only be experienced by the patient, that infection spread, moreover, attention is also given is hypothesized to be clinically relevant. to: qualitative sign =def Abnormal observable quality symptomatic carrier role =def Pathogen host role of a part of a patient that is hypothesized to be borne by an organism whose extended organism clinically relevant. contains a pathogen bearing an infectious disposition towards the host, and the host has processual sign =def Abnormal processual entity manifested symptoms of the infectious disease occurring in a patient that is hypothesized to be caused by the pathogen. clinically relevant. asymptomatic carrier role =def Pathogen host role An asymptomatic carrier infected with SARS-CoV- borne by an organism whose extended organism 2 likely exhibits signs indicating that the infection is contains a pathogen bearing an infectious clinically abnormal, such as ground-glass opacities disposition towards the host, and the host has no or positive PCR test results. Such asymptomatic symptoms of the infectious disease caused by the carriers exhibit an instance of the VIDO class virus pathogen. disorder which is the material basis of a viral disease: subclinical infection =def Infection that is part of an asymptomatic carrier. infectious disease =def Disease whose physical basis is an infectious disorder. The term subclinical infection reflects standard – if somewhat obscure – use of the terms “subclinical” viral disease =def Infectious disease inhering in a and “asymptomatic” while allowing for cases of virus disorder that is a disorder due to the clinically abnormal infections without symptoms. presence of the virus. VIDO defines subclinical virus infection as an This result aligns with the CDC’s case criteria infection caused by some virus part of an adopted on April 5, 2020 which indicate that the asymptomatic carrier. These remarks bring us full 7 presence of the SARS-CoV-2 genome or relevant needed to characterize transporters are imported antigens in an individual is sufficient to count as a from IDO Core: case of COVID-19, asymptomatic or not [70,71]. pathogen transporter role =def Role borne by a 3.4 Viral Pathogenesis material entity in or on which a pathogen is located, from which the pathogen may be Accurately representing viral pathogenesis is of transmitted to a new host. great importance, in particular, as researchers are still working to understand how SARS-CoV-2 A subclass – fomite role, roughly, a pathogen infections cause such a wide range of signs and transporter role borne by non-living entities – plays symptoms across demographics. Representing an important function in virus transmission. disease pathogenesis is aided by importing terms Viral pathogenesis involves replication in a host. from relevant OBO Foundry ontologies, to define: The term virus replication is defined in VIDO as a viral pathogenesis =def Pathogenesis process subclass of the IDO Core term replication, realization of an infectious disposition inhering in a specifically: virus or virus population, having at least the proper virus replication =def Replication process in which process parts: a virus containing some portion of genetic (1) pathogen transmission, material inherited from a parent virus is (2) establishment of localization in host, replicated. (3) process of establishing an infection, and (4) appearance of a virus disorder. Instances of virus pathogenesis have virus replication parts. Viral replication typically occurs Where pathogenesis is imported from GO: within an: pathogenesis =def Process that generates the ability incubation process =def Process beginning with the of a pathogen to induce disorder in an organism. establishing of an infection in a host and ending As defined, pathogenesis is a success term, in that it with the onset of symptoms by the host during encompasses formation of disorder in an entity. which pathogens are multiplying in the host. 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 communicability interval =def One-dimensional count as an instance of viral pathogenesis. temporal region during which a pathogen host bears a contagiousness disposition. Viral pathogenesis involves transmission of virions. From PTRANS [59] is imported: latency process =def Process beginning with the establishing of an infection in a host and ending pathogen transmission process =def Process during when the host becomes contagious, during which which a pathogen is transmitted directly or pathogens are multiplying in the host. indirectly to a new host. eclipse process =def Process beginning with the Role terms – reflecting “externally-grounded” establishment of a virus in a host and ending with realizable entities acquired based on circumstance, the first appearance of a virion following viral such as the role a student takes on in university – 8 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 from OBO ontologies to characterize features of occurring over a: coronaviruses, such as the viral genome including a viral dormancy interval =def One-dimensional five-prime nucleotide cap, or the common temporal region on which a virus is no longer glycoprotein spikes found in the viral envelope replicating but remains within a host cell and [76,77]. Some terms are specializations of terms which may be reactivated to begin replication from the Protein Ontology [54], including again. membrane protein (SARS-CoV-2) and spike glycoprotein (SARS-CoV-2). Worth noting is that With participants found from familiar viruses such while CIDO is not the only ontology developed to as varicella zoster and herpes simplex. support curation of COVID-19 data [78,79,80,81], Generative stage is imported from IDO Core, most alternatives are stand-alone initiatives, and so defined as a temporal subdivision of a subject to the silo problems typically found in developmental process, as well as: ontologies developed outside the scope of the OBO Foundry and with no attention to its principles. virus generative stage =def Infectious structure generative stage that is a temporal subdivision of 3.6 Annotations a virus developmental process. The extent of coverage in VIDO and related Subclasses of which include the stages through ontologies can be illustrated by annotation of which viruses may proceed during replication: coronavirus research articles. 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 Figure 2: Relationships in the VIDO ecosystem 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 Following replication, cell lysis of SARS- Infectious Disease Ontology (CIDO). CIDO CoV-2 coronavirus virions causes host cells 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 9 in the lungs, then propagate to and damage challenges, however. Often, terms were developed other organs. In normal immune systems, then presented to domain specialists for vetting, inflammation attracts T cells which after which they were refined through discussion. neutralize the virus at the site of infection. As in the case of all scientific ontologies, Antibodies circulate, preventing SARS-CoV- refinement will continue as research advances, and 2 infection, and alveolar macrophages further collaborators are welcome and necessary. recognize SARS-CoV-2 and eliminate virions via phagocytosis [82]. The existence of IDO Core extensions covering infectious disease-causing entities other than In more a more ontologically oriented language, we viruses suggests a need for the creation of reference speak of the relevant part of a host’s immune ontology extensions of IDO covering bacteria, response as being disposed to manifest a response fungi, and parasites. The methodology illustrated in that eliminates SARS-CoV-2 infection, while the development of VIDO provides a recipe for SARS-CoV-2 has a disposition to block such reference ontology creation. Additionally, the manifestation of this immune system response. methodology illustrated in the development of Consider next a color-coded selection from the coronavirus-specific terms outlined above provides Lancet [83] concerning SARS-CoV-2: a recipe for the creation of novel virus-specific “The viral loads in throat swabs and sputum ontologies, namely, by extending them from samples peaked at around 5-6 days after existing virus ontologies such as CIDO where symptom onset, ranging from around 10^4 to possible. Adoption of these methodologies by 10^7 copies per mL during this time.” developers during ontology construction will significantly reduce the labor involved in ontology SARS-CoV-2 infected hosts contain the highest creation. 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 viral load =def Quality inhering in a portion of data. fluid that is the proportion of virions to volume of that portion of fluid. 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. Many thanks to Asiyah Yu Lin for assistance in 4. 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