As the structure, description and interconnectedness of life science data has become more sophisticated, a shared formalisation of all data for systems biology has become easier to imagine. Tools are available, such as those used by the Semantic Web community, to capture any area of biology in the form of a semantically defined model. While challenges such as achieving tractable reasoning over highly expressive ontologies still remain to be addressed, a future where vast amounts of data and metadata are modelled according to a shared formalisation is not just fantasy as shown by the work described in this thesis. The research presented here demonstrates the transformation of existing systems biology data models into more computationally amenable and more semantically aware structures.
The work presented also enables a more computationally amenable approach to systems biology, ultimately aiding the progression of systems biology metadata into a more formal structure. There is a general trend towards “big data”, both with in-house private repositories and open data across all of the sciences, making maintenance and structuring of that data of primary importance [1, 2]. SyMBA (Chapter 2) aids the formalisation of systems biology knowledge by providing a common structure for experimental metadata and limiting the complexity of metadata input at the user interface. Traditionally, metadata input procedures are time consuming and often complex for large volumes of data. SyMBA was created to make it easy for researchers to add metadata even when large amounts of data are involved. In general the easier metadata entry becomes, the more metadata will be stored by users. By structuring systems biology metadata in a common format, it is made much more accessible to computational techniques and to the systems biology community as a whole.
Saint (Chapter 3) helps researchers find appropriate biological data for systems biology models by reusing existing data from disparate locations. Saint provides a method of integrating multiple Web-accessible resources using syntactic clues in the query model, providing prospective annotation to the modeller. This type of syntactic data integration is fast, providing a large amount of integrated data for relatively low cost and high scalability. However, syntactic integration does not resolve semantic differences in the data, nor does it allow a high level of expressivity between data sources or in the description of those data sources. The schema reconciliation in non-semantic approaches is generally hard-coded for the immediate integrative task, and not easily reused. Often, data is aligned by linking structural units such as XSD components or table and row names rather than the underlying biological components. Further, concepts between the source and target schema are often linked based on syntactic similarity, which does not necessarily account for possible differences in the meanings of those concepts.
Semantic data integration allows greater expressivity at the expense of scalability. Controlled vocabularies and ontologies are of primary importance in the resolution of heterogeneity via semantic means . By using ontologies, entities can be integrated across domains according to their meaning. Ruttenberg and colleagues view the Semantic Web, of which both OWL and RDF are components, as having the potential to aid translational and systems biology research; indeed, any life science field where there are large amounts of data in distributed, disparate formats should benefit from Semantic Web technologies . However, application of such techniques in bioinformatics is difficult, partly due to the bespoke nature of the majority of available tools . MFO (Chapter 4) transforms existing SBML specification documents into a single model in OWL, allowing the storage both of SBML models and the restrictions on those models. While some of the SBML specification documents are already computationally accessible, one document is readable only by humans and each of the others are in different formats. MFO brings concepts from all of the SBML documents into a single computationally accessible format which can be used with a variety of Semantic Web technologies.
Rule-based mediation (Chapter 5) transforms multiple systems biology data models into a single, more computationally accessible model. This work examines the feasibility of semantic data integration within a systems biology context. To gain access to the underlying semantics of the data, a semantically-rich core ontology is utilised together with mappings to and from source ontologies representing the data sources of interest. New data sources can be easily inserted without modification of the biologically-relevant core ontology. Separation of syntactic integration and semantic description of the biology is robust to changes to both the source ontologies and the core ontology. The use of existing tools decreased development time and increased the applicability of this approach for future projects. While some hurdles–such as scalability and the creation of a simple user interface—remain, rule-based mediation has been shown to be an effective approach for model annotation.
The field of semantics and ontologies in the life sciences is continuing to mature. The traditional and highly useful role of the ontology as metadata and link provider is pervasive. In this role, a particular database entry structures the data according to a defined data format, and within that format links are provided to specific ontology terms. The data format is the primary structure, and the ontological terms are keywords and links out to more information and to other database entries sharing that term. Very recently, new research such as rule-based mediation has freed ontologies, reversing the roles of ontology and structured format [6, 7, 8, 9]. With semantic integration methodologies, ontologies—rather than the syntactic format—have become the backbone from which data hangs. Ontologies can therefore be used to describe the entirety of a data model or biological domain rather than just provide links to further information. The use of ontologies as a sophisticated semantic integration tool allows the creation of a methodology which not only follows cross-referenced links from one database entry to the next, but aligns information according to biological knowledge, limiting ambiguity and making that knowledge accessible to both humans and computers.
This work described in this thesis is one step towards the formalisation of biological knowledge useful to systems biology. Experimental metadata has been transformed into common structures, data appropriate to the annotation of systems biology models can be retrieved and presented to users and multiple data models have been formalised and made accessible to semantic integration techniques.
1 Simplicity versus complexity
When transforming data and metadata into a common structure or model, there are always compromises to be made between simplicity and complexity. Rather than there being a single correct answer, researchers investigating particular integration techniques choose points along this spectrum amenable to their requirements. The dichotomy of simplicity and complexity is appropriate for a range of topics relevant to systems biology data integration including metadata, simulatable model creation and expressivity. The question of expressivity versus scalability is discussed in more detail below as it has a direct effect on the performance of semantic data integration techniques such as rule-based mediation.
In general, researchers find it easier to create data than to annotate that data with large amounts of metadata; while simplistic metadata requirements allow quicker data deposition, complex metadata requirements can create a barrier to data entry. While standards are often developed once ’just-enough’ data description strategies are no longer enough (as described in Section 1.4), as the amount of metadata asked of researchers grows, the chance of receiving complete metadata shrinks.
Systems biology models themselves are another example of choosing between simplicity and complexity. This is not simply a question of the granularity of such models, as whole organism models and single pathway models of a similar level of complexity can be produced. However, simpler models with fewer species and less complex interactions can be more easily understood by people and simulated by computers. While complex models present a more complete picture, the resources required to simulate and understand will be correspondingly greater.
As a final example, formal models such as ontologies can be either simple and scalable or complex and expressive; there is always a balance to be made between these two choices. Expressivity is a measure of what it is possible to say with a language, and as such has a direct bearing on the inferences possible with that language; too little expressivity results in a lack of “reasoning opportunities” in a language which would otherwise not provide any benefits over existing languages . Simple formal models are usually scalable and can easily be reasoned over but do not, by definition, contain a high amount of expressivity. Complex models have a higher level of expressivity and are capable of modelling more biological context, for example. With such models a more precise description of the domain of interest is created at the cost of reasoning time.
OWL-DL is an ontology formalism which is guaranteed to be decidable. The decidable subsets of OWL, such as OWL-DL, are intended to allow both expressivity and tractability for reasoning purposes; these requirements are typically in opposition to each other, and as such it is a goal of OWL to find a suitable balance . Specifically, there are no guarantees made about the level of scalability of any given ontology written in OWL-DL. The more complex an ontology the less amenable it is to reasoning; a change of even a single axiom can result in a reasoner completing in days rather than seconds. Detailed studies of the complexity of ontological reasoning and how that complexity increases with the expressiveness of an ontology are available [11, Chapter 3], and are beyond the scope of this thesis. However, expressivity versus tractability is of vital importance in semantic data integration in general and in rule-based mediation specifically, where the core ontology is intended to be small but highly expressive.
Decidability and expressiveness are vital considerations when choosing a language for rule-based mediation; languages such as OBO were not originally created with these challenges in mind. Not only is it important to choose a language which supports a balance between expressivity and tractability, but it is important to create ontologies with those considerations in mind. Even if a decidable language such as OWL-DL is used, an ontology can be easily created which cannot be reasoned over in sensible time scales. Currently, in semantic data integration methods such as rule-based mediation, scalability issues occur before more general integration issues such as database churn become important. Therefore for many in the life sciences, ontology engineering involves keeping ontologies as simple as possible for the stated requirements, adding detail and expressivity only where necessary and in a non-disruptive way .
2 The future of data integration
The use of confidence values for particular mappings between ontologies has been described , although research in this area is still limited. However, the ability to modify the set of mappings between source and core ontologies based on the perceived quality of the mappings would be an interesting area of further research. Rule-based mediation makes use of an expressive core ontology, which currently places limitations on its scalability. As brute computational power and technology such as reasoners improve, methodologies such as rule-based mediation could go from precise, small-scale integrative tasks to much larger integrative challenges. Additional automation is also a necessary step if semantic methods such as rule-based mediation are to be implemented on a wider scale. However, existing and future collaborations should provide scope for these and other possibilities for this research. A collaboration of the CellML project with the Saint project started in 2009 and has continued in 2011 and 2012 with additional programmer support to extend the functionality of Saint with respect to CellML, and further aid the integration of the MIRIAM annotation with the CellML format and API. Rule-based mediation has also been identified by Hoehndorf and co-workers as a possible source of collaboration .
A much broader perspective on the future of data integration is not just which integrative methodology is best suited for a task, but whether data integration will even have a place in biological research. If all life science data were expressed in a homogeneous manner, data integration would be unnecessary. The rest of this section explores some of the ways in which data might become accessible to all, without the need for interfaces and integration layers among formats.
If standards become fully utilised within the life sciences, every researcher would be publishing data in recognised, common formats. However, this does not necessarily mean a single format for the entirety of the life sciences; more likely, a large number of standards would remain, as described in Section 1.4. While it is true that many community standards are already in common use (e.g. SBML and BioPAX), standards efforts have a history of slow development (e.g. OBI) and slow uptake (e.g. FuGE). Additionally, new questions will continue to be asked and experimental types will continue to be invented. By definition, these new experiment types will be created faster than the corresponding standards can be developed. Even as experiment types and, ultimately, community standards mature, new standards or combinations of standards might be required. Through experience gained as a developer of many community standards it has become clear that, irrespective of both the number of experimental types and the quality of standardised data formats, there will likely always be some overlap in the data descriptions among the formats. If there is even a small amount of information in one community standard that is of use to another community, data integration will continue to play a vital role in the life sciences. As such even widespread, endemic use of standards will not remove the need for high-quality data integration. As quickly as standards are made, new data is created and new descriptions of data are written which require standardisation.
Alternatively, existing data integration methods might become useless as newer methodologies are investigated. For instance, semantic methodologies are able to capture more knowledge about the data than syntactic methods. More complete, less ambiguous models of the domain of interest leads to less confusion and fewer mapping errors during the integration process. But as has been described in Section 1.6, many syntactic data integration methods remain popular and are being successfully developed throughout the life sciences. Emerging technologies such as reasoner-accessible semantic methods have been proven to be useful, but are not yet supplanting existing methods. Scalability and tractability are core issues when reasoners are applied, and the very employment of the expressivity which make ontology-based techniques useful quickly exposes such issues.
There is a growing movement within science towards openness of data. Open Data movements such as the Panton Principles (Note: http://pantonprinciples.org/) describe appropriate licensing for open experimental data, while many others have advocated open models of publishing papers as well as data (Note: More information can be found at http://cameronneylon.net/ and https://opencitations.wordpress.com/2011/08/04/the-plate-tectonics-of-research-data-publication/.). For instance arXiv (Note: http://arxiv.org/), an e-print archive for topics including physics, mathematics, computer science, quantitative biology and statistics, provides open access to both data and papers. Conferences are also becoming more open, with the publishing of papers and presentations in open access journals and with the use of social networking to provide live coverage of conferences [14, 15]. It may seem as if this increased availability and openness of data and publications might decrease the importance of data integration. However, open data is a prime example of why data reuse and integration will remain important. Larger amounts of data do not lessen the need of integration methodologies, as open data is not guaranteed to be in the same format.
Finally, if there is a move away from small, tightly-scoped experiments towards large-scale experiments, large amounts of data could be produced in a single format. For example, there would be no need to integrate disparate experimental data files the research could be reproduced cheaply and quickly. While large-scale experimentation would ease the burden of integration within one community or experimental type, it will not solve the integration problems across multiple communities. As such, this would not make data integration redundant.
Although there are a number of ways in which data will become more homogeneous, none will render data integration obsolete. If all of systems biology was formalised and structured according to a common data model, transformations on that data model would still be required. For instance, the model could go through rounds of optimisation or updating during schema evolution. Syntactic methods will most likely play a pivotal role in data integration for the foreseeable future, until the limitations of semantic methods are ameliorated and ontologies and other Semantic Web technologies gain much higher coverage within the life sciences. The ability of Semantic Web formats such as RDF to describe any type of data, and of Semantic Web languages such as ontologies to model any type of biology will ensure that semantic data integration will only increase in importance as scaling issues are addressed and the time taken to perform the integration decreases.
3 Guidance for modellers and other researchers
If data generators and systems biology modellers followed just a few guidelines when describing their information, data integration tasks could become much more straightforward and many existing methods of integration would immediately become more powerful. Small changes could result in substantive improvements in the way data is described and ultimately, the quality of the integration that can be performed. For instance, unambiguous naming would result in better hits against external data sources using a systems biology annotation application such as Saint (Chapter 3). The list below describes these guidelines, and how their use would aid data integration in general as well as help the integration methods presented in this thesis.
- Informative naming. In general, systems biology modellers name model entities using non-informative names and identifiers as well as non-intuitive naming schemes. A species might be called “A” or “species1”, providing no clue as to the identity of the species for prospective users of the model. Further, while an individual modeller might conform to their own personal naming scheme, there is no guarantee that others will know that the “_p” added to a species name means it is the phosphorylated form; it could equally mean gene product, probable name, or even possibly unknown. An informative naming methodology is simple and quick to implement while also being a great help to others. Even if no further information is provided about a model entity, educated guesses as to the identity of that entity can be made both by humans and computers if commonly-used names are provided.
- Consider standards from the start of the research. The life science community has many ways to store experimental data in a format recognisable to computers and to humans, and many helper applications to do most of the work for the researcher. SyMBA (Chapter 2) is an archival application capable of storing experimental data and metadata. The ISA Suite  assists with data management and standards-compliant storage while the experiments are being run, and does so in a spreadsheet-style environment comfortable to many researchers. Ensuring that the correct information is stored while the data is being gathered saves time for the researcher and eases submission of that data to public repositories prior to publication.
- Think about the future. As described by one twitter user, “metadata is a love note to the future” (Note: http://twitpic.com/6ry6ar). High quality metadata makes data integration easier, and enables greater reuse, sharing and re-purposing of the underlying information both for the creator of that information and for future interested researchers. The use of systems such as Saint (Chapter 3) and rule-based mediation (Chapter 5), which add annotation in a semi-automated way, can help with the addition of metadata, fostering understanding and allowing the research to reach a wider audience.
The early releases of life science databases such as EMBL/GenBank/DDBJ  and UniProtKB  provided data in a structured, text-based flat file format. As techniques, knowledge and computing power improved, the storage and exchange formats for these and other databases have become more complex. While EMBL/GenBank/DDBJ and UniProtKB can still be retrieved as flat files, internally the data is stored in relational databases, and UniProtKB provides both an XML and an RDF export. Newer life science databases such as BioModels  and Pathway Commons  never even produced a flat file format; instead, XML and OWL began to be used as the primary data format. The progression of the structure of data from text file to XML to OWL is a progression towards a formalisation of the representation of biology.
Semantic technologies are being heavily researched and used in the life sciences and in larger-scale commercial portals such as Google. However, not all semantic projects have been successful. For instance, the semantic database and publishing system Ambra (Note: http://www.topazproject.org/trac/wiki/Ambra), in use by the PLoS group of journals for a number of years (Note: http://blogs.plos.org/everyone/2009/05/13/all-plos-titles-now-on-the-same-publishing-platform/), was dropped in November 2011 for a faster system called New Hope (Note: http://blogs.plos.org/plos/2011/12/new-hope-the-new-platform-for-the-plos-journal-websites/). In contrast, both social networks and other large commercial portals have begun increasing their usage of semantic technologies. As of October 2011, Facebook has begun supporting linked data and RDF (Note: http://www.w3.org/wiki/SweoIG/TaskForces/CommunityProjects/LinkingOpenData). Google makes use of RDFa and microformats for their Rich Snippets (Note: http://support.google.com/webmasters/bin/answer.py?hl=enanswer=99170,
http://www.readwriteweb.com/archives/google_semantic_web_push_rich_snippets_usage_grow.php) technology. The massive amounts of data stored by companies such as Google and Facebook, or to a lesser degree by semantically-aware life science databases such as Bio2RDF  may provide the volume of metadata required to increase awareness and usage of the Semantic Web (Note: http://semanticweb.com/the-evolution-of-search-at-google_b25042). As the amount of life science data grows, improved semantic structure of that data will aid integration and querying tasks.
The research presented in this thesis standardises experimental metadata (Chapter 2) and integrates (Chapter 3, Chapter 5) and formalises (Chapters 4–5) systems biology knowledge. As a result, new biological annotation can be added to systems biology models, and information useful for systems biology has been transformed into more computationally amenable and semantically aware structures.
This research demonstrates the advantages gained with an increase in the formalisation of biological knowledge. The use of richer semantics allows the automation of many aspects of the annotation process for systems biology models as well as computational access to those models to rigorously assess their correctness. While this comes with a cost of a greater formality and standardisation for experimental data, the cost can be partially alleviated with the use of appropriate applications to make the input of the biological descriptions easier. As the life sciences become ever more data rich, this formalisation becomes less of an option and more of a necessity to ensure that the multitude of data resources remain accessible and manageable to researchers and computers.
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