The SOFG Anatomy Entry List (SAEL): an annotation tool for

Comparative and Functional GenomicsComp Funct Genom 2004; 5: 521–527.Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/cfg.434

Conference Paper

The SOFG Anatomy Entry List (SAEL): anannotation tool for functional genomics dataReport of a Workshop on Integration of Anatomy Ontologies, held at theMRC Human Genetics Unit, Edinburgh, 7–8 April 2004

Helen Parkinson1, Stuart Aitken2, Richard A. Baldock3, Jonathan B. L. Bard4, Albert Burger3,5,Terry F. Hayamizu6, Alan Rector7, Martin Ringwald6, Jeremy Rogers7, Cornelius Rosse8,Christian J. Stoeckert Jr9 and Duncan Davidson3*1European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK2Artificial Intelligence Applications Institute, School of Informatics, University of Edinburgh, Crichton Street, Edinburgh EH8 9LE, UK3MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK4Wolfson Laboratory, Medical School, University of Edinburgh, Edinburgh EH8 9XD, UK5School of Mathematics and Computer Sciences, Heriot–Watt University, Riccarton, Edinburgh EH14 4AS, UK6The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA7Kilburn Building, University of Manchester, Oxford Road, Manchester M13 9PL, UK8Department of Biological Structure and Department of Medical Education and Biomedical Informatics, School of Medicine, University ofWashington, Seattle, WA, USA9Department of Genetics, Center for Bioinformatics, University of Pennsylvania, 423 Guardian Drive, Philadelphia, PA 19104, USA

*Correspondence to:Duncan Davidson, MRC HumanGenetics Unit, Western GeneralHospital, Crewe Road, EdinburghEH4 2XU, UK.E-mail:[email protected]

Received: 23 October 2004Revised: 1 November 2004Accepted: 2 November 2004

AbstractA great deal of data in functional genomics studies needs to be annotated withlow-resolution anatomical terms. For example, gene expression assays based onmanually dissected samples (microarray, SAGE, etc.) need high-level anatomicalterms to describe sample origin. First-pass annotation in high-throughput assays (e.g.large-scale in situ gene expression screens or phenotype screens) and bibliographicapplications, such as selection of keywords, would also benefit from a minimumset of standard anatomical terms. Although only simple terms are required, theresearcher faces serious practical problems of inconsistency and confusion, giventhe different aims and the range of complexity of existing anatomy ontologies. AStandards and Ontologies for Functional Genomics (SOFG) group therefore initiateddiscussions between several of the major anatomical ontologies for higher vertebrates.As we report here, one result of these discussions is a simple, accessible, controlledvocabulary of gross anatomical terms, the SOFG Anatomy Entry List (SAEL).The SAEL is available from http://www.sofg.org and is intended as a resourcefor biologists, curators, bioinformaticians and developers of software supportingfunctional genomics. It can be used directly for annotation in the contexts describedabove. Importantly, each term is linked to the corresponding term in each of themajor anatomy ontologies. Where the simple list does not provide enough detail orsophistication, therefore, the researcher can use the SAEL to choose the appropriateontology and move directly to the relevant term as an entry point. The SAEL links willalso be used to support computational access to the respective ontologies. Copyright 2004 John Wiley & Sons, Ltd.

Keywords: anatomy; annotation; ontology; microarray; high-throughput; pheno-type description; bibliographic keywords

Copyright 2004 John Wiley & Sons, Ltd.

522 H Parkinson et al.

Introduction

This paper addresses the problem of annotat-ing gene function-related data with anatomicalterms. Our focus here is on simple annotation atlow anatomical resolution, such as is required todescribe the origin of tissue used for microarrayor other sample-based analyses. A similar require-ment exists for simple, first-pass annotation in high-throughput screens of in situ gene expression pat-terns or of parts affected in mutant phenotypes. Asimple, standard annotation scheme would also findapplication in selecting keywords, or terms in tablesof results, providing support for automated biblio-graphic data retrieval.

At first sight, it seems trivial to annotate thesource of samples for microarray experiments as‘heart’, ‘kidney’, etc. However, even cursory exam-ination of the literature is sufficient to show thata simple ‘free text’ approach leads to inconsis-tencies. These curtail the usefulness of annota-tions for database purposes and for informationretrieval from the literature. The solution is to usea controlled vocabulary or ontology. The long-running study of anatomy and the need for com-mon annotation in biology and medicine haveresulted in a proliferation of biomedical ontologiesbuilt for different purposes, using different knowl-edge representation tools and often very rich interms, structure and relationship types. Anatomycomponents in biomedical ontologies serve variedpurposes, e.g. descriptions of medical proceduresin GALEN (www.opengalen.org), or descriptionsof traits or phenotypes. The multiple anatomyontologies often contain non-orthogonal concepts,although these are often defined and structured dif-ferently within each ontology. For example, theFoundational Model of Anatomy (FMA; Rosse andMejino, 2003), which takes a structural view ofanatomy, contains the concept ‘liver’ defined infree text as ‘Lobular organ the parenchyma ofwhich consists of lobules which communicate withthe biliary tree’. ‘Liver’ is also defined by itsattributes, including: ‘member-of’, ‘bounded-by’,‘component-of’, ‘adjacency’, etc. If we consider‘liver’ in the Mouse Developmental Anatomy Dic-tionary (Bard et al., 1998), which has a develop-mental view, the ‘liver’ is ‘part-of ‘ the ‘liver andbiliary system’ and developmental stage informa-tion is provided. The level of detail provided bythese ontologies is variable and the purposes of

the ontologies are clearly different, although bothcontain the concept ‘liver’.

Selection of anatomical terms for functionalgenomics annotation therefore requires some know-ledge of where to look, some information on thepurpose and scope of the ontology queried, and anability to critically assess whether the term returnedis accurate. These tasks may be intuitive for theaverage scientist who has some notion of the con-cept of each term. However, in a high-throughputsituation it is time consuming to query large andcomplex ontologies directly and, in our experience,many scientists simply annotate with free text. Thiscauses problems for data exchange and query infunctional genomics.

From the viewpoint of the biologist who wishesto annotate data with anatomical terms, there aretwo primary requirements. The first is a standard,high-level vocabulary that is simple and easyto use but nevertheless carries the authority ofthe established anatomical reference sources. Thesecond requirement is a single point of entry tothe available ontology resources in situations thatrequire a more complex anatomical nomenclature.This entry point should enable the biologist tochoose the appropriate ontology and to quickly findthe appropriate terms.

In this paper, we report the results of initial dis-cussions between several of the major anatomicalontologies for higher vertebrates. These discussionswere initiated following a conference on Standardsand Ontologies for Functional Genomics (SOFG,Hinxton, UK 2002) and continued at the Workshopdescribed below. They are aimed at practical movestowards integration. As a first step, we propose astandard anatomy entry list (the SAEL), which aimsto meet the two requirements described above.

The standard anatomy entry list (SAEL)

Following the SOFG 2002 conference, a web-site was established listing many of the majorontologies and resources for human and mouseanatomy (http://www.sofg.org). The website pro-vides URL links and contact names for the ontolo-gies and outlines their purpose and structure. InApril 2004, a 2-day workshop was organized atthe MRC Human Genetics Unit in Edinburghto examine practical ways to integrate informa-tion in different ontologies. In particular, two

Copyright 2004 John Wiley & Sons, Ltd. Comp Funct Genom 2004; 5: 521–527.

The SOFG Anatomy Entry List (SAEL) 523

questions were considered: (a) can a ‘core anatomylist’ be produced for functional genomics appli-cations, specifically microarray experiments? and(b) if so, what are the use cases, limitations,and build criteria? The small group of workshopparticipants represented the following anatomyontologies: Open Galen (www.opengalen.org), theFMA (http://fma.biostr.washington.edu/; Rosseand Mejino, 2003), the ontology of human devel-opmental anatomy, HUMAT (Hunter et al., 2003),the Edinburgh Mouse Atlas Project (EMAP) MouseDevelopmental Anatomical Dictionary (http://genex.hgu.mrc.ac.uk/Databases/Anatomy/; Bardet al., 1998), the Adult Mouse Anatomical Dictio-nary (http://www.informatics.jax.org/searches/AMA form.shtml) and the CIBL Controlled Vo-cabulary for Anatomy (http://www.cbil.upenn.edu/anatomy.php3). Also represented were usersof anatomy ontologies: ArrayExpress (Brazmaet al., 2003); the RNA Abundance Database, RAD(Manduchi et al., 2004); the Gene ExpressionDatabase, GXD (http://www.informatics.jax.org/mgihome/GXD/aboutGXD.shtml; Hill et al.2004) and the Edinburgh Mouse Atlas of GeneExpression, EMAGE (http://genex.hgu.mrc.ac.uk). The group also included expert logicians andcomputer scientists. A more detailed report fromthe workshop is available at the SOFG website(http://www.sofg.org). The efforts of this work-shop and subsequent intensive e-mail discussionsproduced a draft list of anatomy terms, the SOFGAnatomy Entry List (SAEL), described below,which is being mapped to the different ontologiesrepresented at the workshop. Other ontologies rep-resented on the SOFG website are also contributingand providing mappings to the list. We are nowmoving to wider consultation, testing and use withthe eventual aim of wide contribution and ‘owner-ship’ of this simple resource.

Purpose of the SAEL

The purpose of the SAEL is to provide a man-ageable list of anatomical terms that can be usedto annotate gene function data at low anatomicalresolution. Importantly, this list also provides anentry point for access to the major, freely avail-able anatomy ontologies for human and rodents.This access aims to be both visual, via graphi-cal user interfaces, and computational, to facilitateautomatic data retrieval. The SAEL therefore aims

to be a community resource for biologists, curators,informaticians and developers of software support-ing functional genomics.

Design and methodsThe SAEL is a controlled vocabulary of termsreferring to gross anatomical structures

The list is envisaged as comprising 100–150 terms,each with a unique identity number. It has sufficientresolution to distinguish samples obtained by grossdissection, e.g. for microarray experiments, and tobroadly classify expression or mutant phenotypes,e.g. in high-throughput screens. Even a list ofsuch low-resolution anatomical terms has wideapplication and can serve to annotate a very largeamount of data.

The SAEL is not an ontology

The SAEL is simply an unstructured list of terms.It is, of course, possible to subdivide the list withheadings such as ‘Developmental structures’ or‘Organ systems’ for purposes of presentation, butsuch headings are not part of the list and haveno identity numbers. SAEL terms are intentionallynot defined, as definitions tie terms to species and‘views’ of anatomy that the authors wish to avoidand the list contains no information about relation-ships between anatomical structures. The advantageof this approach is that it removes from immedi-ate concern differences in the way the specializedontologies view definitions and relationships (e.g.‘part-of’ and ‘is-a’ relationships), while providinglinks to this information for situations where it isneeded.

Each term in the SAEL is mapped to thecorresponding terms in the different participatingontologies

On their own, the SAEL terms are clearly not suf-ficient for all annotation applications, e.g. they donot have sufficient resolution to describe the originsof samples dissected by laser capture microscopyor to describe in situ gene expression patternswhere interest is focused on one particular organ.Access to finer-grain, more sophisticated resourcesis required. By mapping SAEL terms to the partic-ipating ontologies, the simple list provides a meansto find out what ontologies are available, go directlyto the relevant part in any one of these, compare



them and choose the resource that best suits a par-ticular need.

To map the SAEL to a target ontology, eachSAEL term (and its unique identifier) is matchedto the appropriate single term (and its unique iden-tifier) in the ontology. These mappings are beingmade manually by experts from the groups respon-sible for building and maintaining the target ontolo-gies. This is done using the COBrA graphical inter-face, an ontology-linking tool developed by theCross-Species Anatomy Network Project, XSPAN(www.xspan.org). COBrA reads DAGEdit flat fileformat, GO XML/RDF, GO RDFS and OWL for-mats and creates an OWL format mapping file. Nullmappings will be recorded as such (e.g. from theSAEL term ‘tail’ to human anatomy ontologies).

Attributes of objects in the target ontologies willbe returned by queries using the correspondingSAEL term

A biologist or database curator will be able to movedirectly from any SAEL term to the correspondinglocation in a SAEL-mapped ontology resource. Inaddition, it will be possible to use SAEL terms to

make simple queries across SAEL-mapped ontolo-gies in order to support automatic data retrieval inbioinformatics applications. An example would bethe use of a SAEL term (e.g. ‘pancreas; SAEL:78’)to interrogate datasets annotated using differentontologies.

The Workshop considered the set of attributesthat might be returned by a web services querywhen using a SAEL term to query a SAEL-mappedontology resource. A provisional list of attributesis shown in Table 1. It is intended that sourceontologies will provide a web service supportingthe attribute list. These attributes, taken together,may constitute a Web Services Description Lan-guage (WSDL) description for anatomy ontologies.

The current list is specifically focused on rodentand human anatomy

In mouse, rat and human anatomy, the equivalenceof terms and the homology of the structures towhich they refer are generally not contentious.Extension to other vertebrates will have to dealwith more contentious issues of homology (seee.g. Hall, 1995). We view such extension of the

Table 1. Definition of example attributes returned from target ontologies by queries using terms on the SOFG AnatomyEntry List (SAEL)

Attribute Allowed values Definition

dev stage n/a The developmental stage(s) that is annotated to the anatomical entity. Note that generalassociations, such as those implied from the anatomical resource being developed for the ‘adult’of the species, are not sufficient

is tissue yes, no, nil The anatomical entity is explicitly categorized as a tissue, e.g. the anatomical entity is within astrict ‘is-a’ hierarchy for tissue

is cell type yes, no, nil The anatomical entity is explicitly categorized as a type of cell, e.g. the anatomical entity is withina strict ‘is-a’ hierarchy for cell type

is organ yes, no, nil The anatomical entity is explicitly categorized as an organ, e.g. the anatomical entity is within astrict ‘is-a’ hierarchy for organ

is system yes, no, nil The anatomical entity is explicitly categorized as a system, e.g. the anatomical entity is within astrict ‘is-a’ hierarchy for system

superclass n/a The immediate class(es) above the anatomical entity in an ‘is-a’ relationshipsubclass n/a The immediate class(es) below the anatomical entity in an ‘is-a’ relationshipPart n/a The immediate class(es) below the anatomical entity in a ‘part-of’ relationshippart of n/a The immediate class(es) above the anatomical entity in a ‘part-of’ relationshipuri n/a The uniform resource identifier for the anatomical entity in the anatomical resource. A URL is a

common type of URI. The URI should provide a pointer directly to information on theanatomical entity in the anatomical resource. This may be in the form of a cgi command

definition n/a The definition provided by the targeted resource for the anatomical entityauthority n/a The source of the information provided at the target resource for the anatomical entity. The

source may be a person, an organization, or a literature citationhistory n/a The data provenance of the anatomical entity. Usually, this is the last modification time and date

at the anatomical resource for information directly associated with the anatomical entityname: n/a The name given to the anatomical entity by the anatomical resourcesynonym n/a The alternative name(s) given to the anatomical entity by the anatomical resource



Figure 1. SAEL web service architecture

SAEL as proceeding later in collaboration withcomparative anatomists and specialist ontologyprojects that are currently dealing with these issues(e.g. XSPAN; www.xspan.org).

Implementation: SAEL Software Architecture

The SAEL and mappings to individual anatomyontologies will be made publicly accessible in sim-ple downloadable form as well as through a pro-grammatic interface and a graphical user interface.Figure 1 shows the preliminary software architec-ture in support of SAEL. The SAEL Anatomy andMapping database will hold representations of theSAEL list of anatomical entities, parts of the targetontologies and mappings between SAEL entitiesand the ontologies. The COBrA tool is used to cap-ture the mappings and make them available to theSAEL database.

Each participating anatomy resource will pro-vide a web service interface to its ontology, sup-porting a simple query mechanism based on theattribute list described in Table 1. Queries basedon those attributes that involve more than oneontology will be supported by the Central SAELWeb Service. The corresponding central and localWSDL descriptions (C-WSDL and L-WSDL) willdefine the exact access details to these services. TheSAEL Portal will provide a graphical user interfacefor researchers to look up the mappings between

the SAEL list of anatomical entities and the targetontologies.

We expect that the SAEL service will becomepart of a wider network of bioinformatics resourcesthat links anatomy ontologies with other ontologies,databases and computational services.

Most of the computational infrastructure — theCentral Web Service, the Anatomy and MappingDB, the Portal and COBrA — required to deliverSAEL services has already been developed as partof the XSPAN project and will be used for SAEL.Implementation will be carried out in two phases:the SAEL portal will be implemented first, thenlocal web services.

The SAEL list

The current version (1.1) of the SAEL is freelyavailable at the SOFG website (http://www.sofg.org) and may be downloaded in OBO for-mat or as plain text. The list will be modifiedand extended as necessary, with careful version-ing, and within the limits of the requirementthat it be manageable. New terms may be pro-posed via the Microarray Gene Expression DataSociety (MGED) Ontology Tracker. Please mail:[email protected] with feed-back. The SAEL is currently maintained by theMGED Ontology group, with anatomical curationby Jackson Laboratory GXD database curator Terry



Hayamizu. Mappings between the SAEL and par-ticipating anatomy ontologies are also availablefrom the SOFG website.

Gene–function databases that will use the SAEL

The SAEL will be used by the following gene–function related databases: RAD, ArrayExpress,MIAMExpress. In most cases, annotation in thesedatabases will not, of course, be confined to SAELterms, but the ontologies employed will be mappedto the SAEL. The MIAMExpress–ArrayExpressdata capture tool uses the SAEL. Data in Array-Express will be mapped to SAEL and future sub-missions will use the SAEL. The SAEL will beincluded in MGED Ontology v1.2 (http://mged.sourceforge.net/ontologies/index.php).

Discussion

The current status of the work is that version 1.1of the SAEL is available. Mappings have beenmade to the FMA and the Jackson LaboratoryAdult Mouse ontology and are in progress for otherparticipating ontologies (these will be availableby December 2004). The interfaces and the webservices portal are being developed. Current SAELresources are available at http://www.sofg.org

In a preliminary survey, the content of theSAEL was tested for correspondence to annota-tions of sample-based data in the following geneexpression databases: ArrayExpress/MIAMExpress(http://www.ebi.ac.uk/arrayexpress/, http://www.ebi.ac.uk/miamexpress/) (OrganismPart);microarray data at the MRC Rosalind FranklinCentre for Genomics Research (http://www.hgmp.mrc.ac.uk/Registered/Menu/microarrays.html)(mouse and human only); Stanford MicroarrayDatabase (http://genome-www5.stanford.edu)(free text microarray sample annotations mined forterms); GXD (for blot and cDNA data only); RAD(microarray data). Overall, the SAEL matched 80%of terms in these annotations. We are therefore con-fident that its use will cover the annotation of alarge fraction of sample-based data. We will con-tinue to refine and extend the SAEL in response tothe requirements of the bio-ontologies and researchcommunities. For example, it is clear that there areadvantages to be gained by relating gross anatom-ical terms to terms denoting cell types and by

relating embryological anatomy to developmentalstage.

The principal aim of the SAEL is to fulfil thepractical purposes described in the introduction. Inrelation to wider goals, it is clear that the ‘inte-gration’ achieved by the SAEL is rather super-ficial with respect to the very significant differ-ences in concept and purpose between anatomi-cal ontologies. However, by focusing attention onthe definitions and relationships of the same high-level terms in different ontologies, it may pro-vide a useful step towards deeper integration. Theapproach taken in developing the SAEL bringscomplex and growing anatomy ontologies intothe functional genomics domain. As ontologiesgrow larger, they become more difficult to han-dle in applications and a detailed knowledge isrequired to use them. A similar approach has beentaken by the Gene Ontology consortium, who pro-vide GO slims. GO slims provide a high levelview of the ontologies and are used in applica-tions such as the GO slim tool provided by SGD(http://www.yeastgenome.org/help/goslimhelp.html), which allows mapping of the granular GOannotations of a query set of genes to one ormore high-level, parent GO Slim terms for a givenspecies. One can imagine a use case where a setof gene products are mapped to GO terms usingsuch a tool, and where complex anatomical anno-tation from source anatomy ontologies for the sameset of query genes are mapped to high-level con-cepts, such as ‘heart’. Combinatorial use of suchhigh-level ontologies allows first-pass analysis ofgene function and provides anatomical informationfor high-throughput data. Further analysis can thenbe performed where gene products of interest areidentified.

Acknowledgements

We are grateful to the MRC Human Genetics Unit forhosting and partly funding the SOFG Workshop in April2004. The Workshop was organized by Albert Burger,Jonathan Bard and Duncan Davidson. The text of this paperis based on a presentation given by Helen Parkinson at theISMB Bio-ontologies meeting in Glasgow, 30 July 2004.

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The SOFG Anatomy Entry List (SAEL): an annotation tool for