=Paper=
{{Paper
|id=Vol-1301/ontocomodise2014_3
|storemode=property
|title=Modeling of Continuity and Change in Biology
|pdfUrl=https://ceur-ws.org/Vol-1301/ontocomodise2014_3.pdf
|volume=Vol-1301
|dblpUrl=https://dblp.org/rec/conf/fois/ChaudhriL14
}}
==Modeling of Continuity and Change in Biology==
https://ceur-ws.org/Vol-1301/ontocomodise2014_3.pdf
Modeling of Continuity and Change in Biology
Vinay K. Chaudhri1 and Frank Loebe2
1
Artificial Intelligence Center, SRI International, Menlo Park, CA, 94025, USA
2
Department of Computer Science, University of Leipzig, 04009 Leipzig, Germany
Abstract. Continuity and change is a core theme in biology that refers to how
genetic information is carried forward. This paper reports on our initial steps to-
ward representing this core theme and describes the methodological background
and open challenges. We define continuity and change from a conceptual mod-
eling perspective, identify its facets that require further ontological work, and
present competency questions designed to check the adequacy of its represen-
tation. Moreover, we explore whether continuity and change must be explicitly
represented as primitives in the representation of biological processes or whether
it can be inferred from the process structure.
Introduction
The ability to model genetic information has received considerable attention in the re-
cent literature. A specific example is Gene Ontology (GO), which has been tremen-
dously successful and has been widely adopted for a variety of annotation projects [1,
31]. GO serves the needs of practicing biologists and biomedical researchers by pro-
viding highly specific vocabulary for gene products and functions. We report here on
our work on representing continuity and change in genetic information, a core theme in
biology, as described in an introductory college textbook.
Our work is complementary to molecular and cellular level representations sup-
ported in GO because the textbook covers knowledge at organismal, species and popu-
lation levels. Further, we model knowledge at a much deeper level than GO, by using an
extensive set of relationships which are valuable for question answering and inference.
In the context of our immediate application, the work presented here contributes to
the enrichment of the content contained in an electronic textbook. Campbell Biology
[27] is a widely used textbook for introductory biology courses in the United States.
Substantial parts of its contents have already been transformed into a knowledge base
that is the basis of the prototype of an intelligent textbook that supports question an-
swering and serves as a learning tool for students [8].
Campbell Biology is organized into eight core themes that were defined for ad-
vanced placement courses by the United States College Board [16]. Continuity and
change is one of these eight core themes. Other core themes include structure and func-
tion, energy transfer, regulation, etc. A core theme captures a coherent sub-domain of
biological knowledge and has a specific thematic focus. This framework enables de-
veloping conceptual models and representations with respect to a theme that are self-
contained and interrelated, thereby offering value beyond their specific use in the elec-
tronic version of the textbook.
Representing a core theme begins with a conceptualization of biological processes,
entities, and their interrelations. The representation must then be shown useful for the
purposes requested of the knowledge base (KB). Both tasks involve a variety of chal-
lenges, from general methodological aspects to specific modeling decisions.
In this paper, we provide an initial analysis for conceptualizing continuity and
change. We focus on presenting our methodology as well as modeling challenges that
arise from this core theme. We begin by giving some background on relevant exist-
ing parts of the knowledge base and the steps of core theme design with constraining
aspects. We then define what is meant by continuity and change in the context of bio-
logical processes. This definition sets the scope for our conceptual analysis, where we
next consider examples of entities and processes already represented in the KB and dis-
cuss whether continuity and change could be derived by automated inference or whether
novel explicit encoding needs to be introduced. We define the concepts of continuity and
change based on how the textbook and biology teachers define these concepts and then
state them from a knowledge-engineering perspective. We also consider a few example
questions that can be answered using the representations developed so far. A discussion
of related work and the modeling challenges follows. We conclude with open problems
and directions for future research.
1 Methods and Knowledge Base
The starting point for our work is an upper ontology and a partial encoding of the
textbook knowledge that overlaps with the continuity and change concepts. This KB,
called KB Bio 101, is a rich biological ontology that acts as the central resource for the
electronic textbook [12]. Therefore, an immediate concern in developing our represen-
tations for continuity and change is reusing existing representations when appropriate
and practical. We describe the most relevant components of the KB first, as this ap-
proach eases the formulation of the methodological steps that follow in the remainder
of the paper.
1.1 Component Library
Component Library (CLIB) is a foundational component of KB Bio 101 that serves as
an important starting point for the representation work in our context. CLIB is an upper
ontology which is linguistically motivated and designed to support the representation of
knowledge for automated reasoning [5]. CLIB adopts four simple top level distinctions
that are comparable to other widely known upper ontologies [7, 30]: (1) entities (things
that are); (2) events (things that happen); (3) relations (associations between things);
and (4) roles (ways in which entities participate in events).
In addition to these distinctions, CLIB provides a vocabulary of actions and seman-
tic relationships that has proven to be easy to use by domain experts [21]. For instance,
the class Action (a direct subclass of Event) has 42 direct subclasses and 147 subclasses
altogether. Examples of direct subclasses include Create, Impair, and Move. Other sub-
classes include Copy (which is a subclass of Create) and Break (a subclass of Damage
which is a subclass of Impair).
CLIB provides a vocabulary to define the participants of an action that is inspired
by a comprehensive study of case roles in linguistics [4]. These relations include agent,
object, instrument, raw-material, result, source, destination, and site. Syntactic and
semantic definitions for these relations are available elsewhere [11]. As an example,
we consider the definition of raw-material. The semantic definition of raw-material
is any entity that is consumed as an input to a process. The syntactic definition of
raw-material is either to be the grammatical object of verbs such as to use or to con-
sume, or to be preceded by using.
We consider two distinguishing features of CLIB that make it especially suitable for
the work considered here. First, CLIB offers a good coverage of domain-independent
actions that are needed to describe the biological processes [11]. Second, it is accom-
panied by a systematic account of guidelines for knowledge engineers to model the
semantic relationships supported in it [11].
CLIB provides good vocabulary to encode the basic process structure (i.e., steps
in a process and their relationships) and participants (i.e., entities that participate in
different steps). However, it does not provide adequate guidelines and vocabulary to
represent knowledge about continuity and change. After surveying many of the avail-
able ontologies, we found that no other ontology addresses these concepts adequately
for our purposes.
1.2 Knowledge Base Format and Biological Contents
The knowledge base uses a fragment of first order logic which is comparable in ex-
pressiveness to datalog with function symbols [14]. The knowledge-engineering effort
is structured in a way that the knowledge engineers have access to the full power of the
language, but the biologist encoders can only extend the taxonomy, declare classes to
be disjoint, assert qualified number constraints [2, ch. 2], and, most importantly, author
existential rules [3].
The existential rules are authored through a graphical interface of the sort shown
below in Figures 2 and 3. Each graph captures an existential rule: each white node
of the graph (e.g., DNA-Replication in Figure 2) is universally quantified, and every
other node is existentially quantified. Such a graph has the intuitive meaning that for
every instance of the class represented by the universally quantified node, there exist
instances of classes represented by the gray nodes that are related to each other by the
relations in the graph. A more formal description is available elsewhere (cf. e.g., [10,
21]). Moreover, all concepts in the KB are inserted into its taxonomy, (i.e., a subsump-
tion (poly-)hierarchy of all concepts) the upper levels of which are constituted by CLIB.
Relationship between Structure and Function is a core theme that is already cap-
tured in the KB [9] and that offers the greatest potential for reusing the knowledge
already represented in the KB for continuity and change. Besides functional intercon-
nections, we have already available representations of mereological modeling of entities
and events. Consequently, for many notions that are central to continuity and change,
the KB already contains representations from a structural and functional point of view.
1.3 Methods
Our goal in developing approaches to representing a new core theme within the KB is a
set of ontology-based modeling patterns that form the basis for converting the biological
knowledge of the theme into extensions of the KB. The latter work can then proceed
mainly sequentially over chapters of the textbook and is distributed over a larger team
of domain experts trained in encoding knowledge.
We pursue the following steps in designing basic core theme representations for the
KB and assessing their adequacy for question answering: (1) Synthesize a textual defi-
nition of the core theme; (2) Establish a set of informal competency questions; (3) Se-
lect/identify key concepts for the theme; (4) Propose/verify the position of the key con-
cepts in the KB’s taxonomy; (5) Draft/determine/refine prototypical concept graphs for
core theme coverage; and (6) Conceive of possible reasoning patterns and simulate tests
of question answering.
In practice, these steps are not followed in a strict sequence and require multiple
iterations. The later steps depend on earlier decisions, but may also have an impact on
the former steps because they provide a limited form of validation. Of course, conver-
gence of this process is sought while the steps are repeated several times. Our process
corresponds to an evolving approach for core theme representations, in line with the
prevailing life cycle model for ontologies as judged in [19, sect. 3.3.8, p.153f.].
The textual definition of the theme provides scope and focus for its coverage in
the KB. Competency questions [20] also contribute to this, and they are adopted for
two further reasons. First, they are a well-established means for evaluating ontology
representations (cf. e.g., [26]). Second, question-answering is the main application. We
adapt the idea of informal competency questions by considering a small set of diagnos-
tic questions for testing representations and a large set of educationally useful questions
as determined by biology teachers and students.
Key concepts (and possibly relations) receive particular attention in the remaining
steps, as major anchor points of the targeted modeling patterns. Usually, entities and
events are identified initially, with those choices leading to respective relations and
roles. To include concepts that are relevant to this core theme in the KB, these elements
must be placed in the taxonomy. In many cases, key concepts are already present in the
KB. Then the task changes to assessing the current concepts: whether their hierarchical
position and modeling already supports the perspective of the theme, its addition to the
representation, or whether re-engineering is required. In the latter case, retaining control
over the effects of changes is especially important. Finally, step 6 is aimed at question-
answering and evaluates representation patterns against diagnostic and educationally
useful questions.
A side aspect of our work concerns the faithfulness to the original biology text-
book [27]. Such fidelity is desirable for the users of the electronic version to recognize
consistent matches between replies to their questions from the KB and relevant parts
of the text. Further, it serves as a simplifying constraint that limits and stabilizes the
knowledge to be formalized. Future alternative applications of the KB may thus require
extensions, for example, to cover more details for specialized domains.
2 Defining Continuity and Change
The first step of our procedure is concerned with finding or developing a definition
of the core theme. We start from characterizations provided by the College Board, the
authors of the textbook, and the biology teachers we work with.
The College Board syllabus [16] provides the following definition for continuity and
change: all species tend to maintain themselves from generation to generation using the
same genetic code. However, there are genetic mechanisms that lead to change over
time, or evolution.
Campbell Biology [27, ch. 1, p. 8 ff.] starts the description of the theme as follows:
The division of cells to form new cells is the foundation for all reproduction and for
the growth and repair of multicellular organisms. After referring to chromosomes as
the main carriers of genetic material, the theme outline continues on the structure and
function of deoxyribonucleic acid (DNA) together with its ability to store information,
further highlighting the processes of replication and gene expression. It also establishes
the link between the genome of organisms and genomics, as the study of genes and sets
of genes within species, as well as cross-species genome comparison.
The key aspects of continuity and change from the perspective of biology teachers
include the following: (1) it involves genetic information; (2) continuity is about the
maintenance of the fidelity of the information from generation to generation, cell to
cell, organism to organism, or species to species; (3) change is about loss or altering of
fidelity of the information from generation to generation, cell to cell, organism to or-
ganism, or species to species; (4) it often involves a measurable or observable outcome,
and this outcome relates directly to continuity or change of information.
We synthesized the three different perspectives into a definition, which evolved dur-
ing later steps in our procedure to the following result:
Continuity and change concerns genetic information and its phenotypic ex-
pression, where the basic form of genetic information is given by nucleotide
sequences. Continuity and change are considered with respect to inheritance,
more precisely regarding the flow of genetic information: (i) within events
occurring in the transition from generation to generation at different levels,
namely of cells (or viruses), organisms, or populations; and (ii) in the evolu-
tionary development of species. Information flow requires information units
(i.e., entities that carry information), which are complemented by observable
effects of that information. We distinguish: (a) sub-cellular information units
that are physical parts of cells (or viruses) (e.g., nucleic acid molecules (DNA,
RNA), genes/alleles, and chromosomes); (b) aggregated information units that
are derived from the sub-cellular units (e.g., genotype, genome, gene pool);
and (c) traits/phenotypes of organisms, which are determined by genetic infor-
mation. On this basis, continuity refers to maintaining the sameness of genetic
information as well as of information units themselves, the latter supporting
the former, and of phenotypes. Change refers to events generating differences
in genetic information, in information units (if affecting carried information),
or in resulting phenotypic characteristics.
3 Representation from the Perspective of Continuity and Change
This section concerns steps 3–5 of our procedure (see Section 1.3). We start by describ-
ing the representation of entities that are involved in continuity and change followed
by the representation of the processes. There is no formal separation among those two
kinds. Concept graphs can relate entities to processes and vice versa, cf. Figure 3. Di-
agnostic and educationally useful questions as resulting from step 2 are discussed in
combination with initial tests based on these representations (step 6) in the subsequent
Section 4 on question answering.
3.1 Representing Entities in Continuity and Change
The key entities involved in continuity and change that are covered in [27] are ge-
netic information units, namely nucleotide, codon/anti-codon, DNA, RNA, DNA strand,
RNA strand, allele, gene, chromatid, chromosome, genotype, genome, and gene pool.
These entities span across different levels of biological organization. For example, while
a nucleotide corresponds to the molecular level, gene pool is defined only at the popu-
lation level. From the point of view of inheritance at the level of organisms, the notions
of trait and phenotype should be included, as well. To represent all those concepts in
the KB, we need to find suitable positions for them in the taxonomy as well as provide
their detailed definitions, eventually in the form of concept graphs.
Figure 1 shows the current positioning of (most of) these entities in the taxonomy
of the KB. Inspecting some of the corresponding concept graphs, both Genotype and
Gene-Pool have an Allele as an element. Gene-Pool aggregates the Alleles at the level
of a population, whereas Genotype aggregates them at the level of an individual. A
Chromosome has-part a DNA which has-part a DNA-Strand which in turn has-part
a Gene. To define the relationship between Gene and Allele, a novel domain-specific
relationship called has-variant is introduced.
Though the current modeling is backed up by Campbell Biology [27], this sup-
port does not automatically render the representation adequate from the perspective of
continuity and change. One reason for that is the use of concepts in different, partially
incompatible “flavors” throughout the book, especially such key notions that occur with
high frequency. This is not surprising for a natural language source, but it counteracts
finding a consistent model. For example, for the concept of gene, we found statements
supporting at least four competing views of whether gene is subsumed by DNA, DNA
region, Nucleic Acid Sequence, or, generally, Information. The situation is similar for
most key concepts in continuity and change.
In some cases, we can consult existing ontologies or ontological analyses, such as
[25] for gene or [22] for biological sequences. This can be instructive in terms of possi-
bly useful distinctions or novel aspects. For example, [22] distinguishes sequences com-
posed of molecules (molecular tokens) from sequence representations (e.g., as string
Fig. 1. Key entities associated with continuity and change in the ontology. The coloring reflects
the distinction of (a) sub-cellular and (b) aggregated information units, and (c) traits / phenotypes.
tokens) and abstract sequences (as types that can be shared among tokens, bearing in-
formation). However, often drawing a distinction that leads to two (or more) concepts
instead of one beforehand entails a multiplication of model parts that depend on the
“split” concept and remain largely analogous otherwise. Accordingly, the four views on
gene or the three on sequences cannot be adopted automatically by four or three distinct
concepts. Another brief illustration concerns a major decision for representing continu-
ity and change, namely whether to separate the aspect of information into distinct con-
cepts. This approach may be reasonable for having an explicit entity that could be the
object of continuity in certain processes. Contrariwise, all key concepts are information
units, which may easily lead to their duplication into additional information entities.
In general, we tackle this problem of a good trade-off for adequately fine-grained,
but minimal conceptual distinctions by cycling through steps 4–6 of our procedure,
aiming at a converging model. For example, the current modeling of Gene (still as a
single concept) in the KB supports views as a tangible entity as well as a nucleotide
sequence, based on multiple inheritance in the case of Nucleic Acid Sequence. It dis-
penses with gene information as a distinct concept. Nevertheless, we see the general
trade-off problem as a challenge with further potential for improved methodological
approaches.
3.2 Representing Continuity and Change in Processes
Key processes that involve continuity and change of genetic information are DNA repli-
cation, mutation, meiosis, sexual reproduction, and natural selection. Each of these is
a complex process that can be modeled using a combination of primitive actions from
CLIB. A straightforward approach to capture continuity and change in these processes
is to identify various CLIB actions as pertaining to continuity and change. For example,
the CLIB actions of Copy and Duplicate involve continuity and Add, Delete, etc. in-
volve making a change. An automated reasoning procedure can then identify which of
those actions involve genetic information and use that information for reasoning about
continuity and change. An alternative approach would be to use continuity and change
themselves as primitive actions and include them as part of the process representation.
This approach has a greater likelihood of producing correct inferences but also requires
additional representation work. We will illustrate these design choices in our approach
by taking DNA replication as an example.
Fig. 2. Structure of major steps in DNA replication.
In Figure 2, we show the major steps of DNA-Replication. The copying process of
DNA, accounting for the continuity of genetic information, is spread across its three
major steps: (1) initiation, (2) elongation, and (3) termination. The bulk of the copy-
ing happens during Synthesis-Of-Leading-Strand and Synthesis-Of-Lagging-Strand.
However, DNA replication does not lead to perfect copies of DNA. A “regular” change
is due to the incapability of reaching the very end of the chromosomes, such that the
telomeres (regions of repetitive DNA at the ends of chromosomes) are shortened by
each replication. Sometimes, errors occur in the replication process. A process called
DNA-Proofreading verifies the newly constructed DNA and, in case of errors, corrects
them by invoking a process called Mismatch-Repair. These steps, however, are not able
to correct all the errors. The effectiveness of the repair process can be explicitly mod-
eled by assigning it a specific property. Any errors that are left uncorrected represent
mutations of the DNA. Not all mutations are due to replication errors, though.
If we were to infer the continuity during DNA-Replication, we will have to gather
specific copying operations in each of its steps. To infer the changes, we will have to
observe that the process can have some errors that are not corrected by the built-in
mechanisms. Creating axioms that allow for such automated inferences is complex.
Fig. 3. Continuity and change in DNA replication.
In Figure 3, we introduce a continuity and change perspective on the process of
DNA-Replication. In this representation, we first state that CC-In-DNA-Replication is
a composite process that happens during DNA-Replication. We next state that a major
mechanism in DNA-Replication is Copy (this is indicated by using the by-means-of
relationship). The Copy action in this perspective can be viewed as an abstraction of
multiple steps in the perspective of Figure 2. The Copy causes the Continuity of DNA.
We further indicate that DNA-Replication has a sub-event of Mutation that causes
a Change in the DNA. Thus, by introducing this additional perspective, we can more
directly state the continuity and change associated with DNA-Replication.
In principle, we could have combined the representation of Figures 2 and 3 into a
single model, but that approach would have led to a considerable conceptual clutter.
Separating this information into a distinct concept graph provides different modeling
views on the KB for human editors. The reasoning is performed over the overall first-
order representation of the KB which covers all the concept graphs including entities
and events. For example, the node DNA-Replication in Figures 2 and 3 refers to the
very same unary predicate in the KB.
Contrary to differentiating biological concepts as in Section 3.1, introducing graphs
for perspectives does not lead to “independent” concepts. DNA-Replication is a biolog-
ical concept (interrelated with others), whereas CC-In-DNA-Replication has a different
status in that it depends on DNA-Replication and is not a naturally occurring concept in
Campbell Biology. We have found similar perspectives to be useful for modeling energy
transfer and regulation [10]. We have performed analogous analysis for the processes of
Meiosis, Recombination, Sexual-Reproduction, and Natural-Selection, where a similar
strategy seems to be effective. This need to separate the representation of a concept into
multiple perspectives is different from the work on connecting independently developed
ontologies [17] in the following way: multiple perspectives are defined by the same user
and need to be present in the same KB as opposed to being defined by different users
and existing in different KBs.
4 Answering Questions Using the Representation
Let us now consider the questions that we wish to answer using the representations of
continuity and change. The questions directly address the steps 2 and 6 in our procedure
(see Section 1.3). We consider two families of questions: diagnostic and educational.
Diagnostic questions are aimed at testing whether the system adequately represents con-
tinuity and change, and they are purely driven by the representation. The educationally
useful questions are gathered by convening a focus group of teachers and students who
provide a set of questions that they wish to pose to a computational tool.
Our current set of diagnostic question patterns for the core theme is as follows. This
set results from the first iteration over all steps, with primary feedback from steps 4–6.
D1 What remains the same/changes during X?
D2 What causes the continuity/changes of X during Y?
D3 Describe continuity/changes during a process X.
D4 What is an example of a process that maintains the continuity of/changes X?
D5 What does X contribute to continuity/change of Y?
D6 Which processes contribute to continuity/changes of X during process Y?
We consider example instantiations of these question patterns that involve the con-
cept of DNA-Replication, and discuss resolutions and open aspects of answer genera-
tion from the knowledge base (KB). More detailed descriptions of our query answering
methods are available elsewhere [13, 15]. All the questions that we consider can be an-
swered using the specification of the behavior of processes. None of the questions that
we consider here require executing a process.
D1 will be instantiated as: What changes during DNA-Replication? If we use the
continuity and change perspective of this process (cf. Figure 3), we can derive a straight-
forward answer to this question by detecting DNA as changing due to Mutation. By ex-
amining the detailed representation of DNA-Replication, one can further infer that the
replication and the proofreading processes themselves are faulty and can cause changes.
Another type of change, limited to eukaryotes, is that telomeres are shortened every
time DNA replication occurs, because DNA-Polymerases cannot replicate DNA effi-
ciently at the end of linear chromosomes. We will need to capture this aspect in the
detailed structural model of DNA-Replication as well as in the continuity and change
perspective of the process.
Let us next consider an instantiation of D2: What causes the continuity of Genes dur-
ing DNA-Replication? Relying on the continuity and change perspective of this process
again, together with the linkage between the concept graphs of Gene and DNA, we can
answer this question at an abstract level by saying that the Copying of DNA causes the
continuity of genes. However, for a detailed answer, we will need to examine the more
detailed representation of the process to argue that a newly synthesized DNA molecule
is identical to the original, thereby maintaining the continuity of genes.
Corresponding arguments that are desirable from the perspective of biology teachers
can be found in a sample response to an instance of pattern D3, namely Describe con-
tinuity during DNA-Replication: “Complementary base pairing and semi-conservative
replication ensure that a newly synthesized DNA molecule is identical to the original.
The DNA double helix is opened, and each strand serves as template for making a new
strand. DNA polymerase enzymes add nucleotides to the new strand according to the
base-pairing rules (A-T and C-G), so the continuity of the original DNA molecule is
maintained. Additionally, during DNA replication, DNA polymerases proofread each
nucleotide against its template as soon as it is added to the growing strand. Upon find-
ing an incorrectly paired nucleotide, the polymerase removes the nucleotide and then
resumes synthesis.”
Producing such an answer requires iterating through all the steps that are involved
in DNA-Replication, identifying how they are contributing to the continuity of the DNA
molecule and explaining them. From the modeling and reasoning perspective, this in-
volves the challenge of determining which levels of (mereological) granularity should
be considered when constructing answers. For example, in the above case, including
only concepts that have a direct subevent link from DNA-Replication to themselves is
insufficient.
An example instance of D4 is: What is an example of a process that changes DNA?
Based on the continuity and change perspective, this question is straightforward to an-
swer as Mutation. A more elaborate answer will also point out other processes such as
insertion or removal of transposons or viral DNA, which will appear in both perspec-
tives.
We can instantiate D5 as follows: What processes contribute to changes of DNA
during DNA-Replication? The answer to this question is that during DNA replication,
DNA-Polymerase inserts an incorrect nucleotide approximately once every 1,000 nu-
cleotides. If this error is not corrected by the proofreading process, a Mutation has
resulted, causing change in the DNA sequence. This answer can follow if we repre-
sent in our model a causal link between failure of proofreading to correct an error in
DNA-Replication and Mutation.
Our suite of educationally useful questions on continuity and change has approxi-
mately 100 different questions. Here, we consider only a few examples of such ques-
tions that are related to DNA-Replication.
E1 What happens if crossing over occurs in the middle of a gene?
E2 What would happen to the chromosomes in eukaryotes if teleromerase were lack-
ing?
E3 What is the difference between a translocation and an inversion?
E4 Due to their structure, DNA polymerases can add nucleotides only to the 5 prime
end of a primer of a growing DNA strand, never to the 3 prime end. True or False?
Explain in terms of the antiparallel arrangement of the double helix the effect on
replication.
E5 A father with blue eyes and blonde hair, a mother with green eyes and brown hair
have four children, what are the features the kids would have if DNA replication
followed the dispersive model?
E6 The disorder xeroderma pigmentosum is caused by what? Can it be passed from
generation to generation in species and organisms? If so, how can this be prevented
during DNA replication error correction?
We have done only a preliminary analysis of such questions to identify a few candi-
date question formats. For example, E1 and E2 follow the format of: What is the effect
if X were to happen? E3 has the format of: What is the difference between X and Y?
We have an extensive prior work on questions in this form [13]. E4 could be reduced to
two sub-questions: Is it true that DNA polymerase can add nucleotides to the 5 prime
end of a DNA strand? Is it true that DNA polymerase can add nucleotides to the 3 prime
end of a DNA strand? The sub-questions help answer the overall question. E5 requires
an explicit representation of the dispersive model and using it to predict how certain
features get passed on during replication. E6 requires knowing the connection between
xeroderma pigmentosum and the mutations, and reasoning that preventing mutations
would require the error correction during replication to be successful.
5 Related Work and Discussion
We look at related work from two angles: (1) biomedical ontologies and models of
biological knowledge, and (2) conceptual modeling issues that need to be addressed.
A survey of biomedical ontologies revealed that there is no ontology that deals with
the notions of continuity and change we considered. Most entity concepts such as Gene
and DNA can be found in multiple biomedical ontologies (e.g., in SNOMED-CT1 , the
NCI-Thesaurus2 , the Sequence Ontology3 , the Gene Regulation Ontology4 (GRO), and
in the top-domain ontology BioTop5 [6], to name a few6 ). Direct reuse (e.g., of frag-
ments of these ontologies) remains limited and usually involves re-engineering for in-
tegration into our ontology/knowledge base. Taken together, the existing sources do not
provide a consistent, integrated picture. Their coverage is typically limited to classifi-
cation hierarchies with short, natural language definitions of concepts, in some cases
1
http://www.ihtsdo.org/snomed-ct
2
http://ncit.nci.nih.gov/
3
http://sequenceontology.org/
4
http://www.ebi.ac.uk/Rebholz-srv/GRO/GRO.html
5
http://www.imbi.uni-freiburg.de/ontology/biotop/
6
All of these are also available from the National Center for Biomedical Ontology (NCBO)
through its BioPortal, http://bioportal.bioontology.org/ .
extended with a few semantic relations among them, such as part-of. Our work re-
lies on a much larger set of relations, which enables explicitly stating and reasoning
over detailed interconnections among concepts. The same applies to ontological anal-
ysis that focuses on very few specific concepts, where we mention [22, 25] in Section
3.1 on representing entities. The depth of such analysis is adequate for our needs, but
re-engineering and harmonization with the present KB are still necessary. We identify
three major problems that our work addresses:
1. Methodological guidance on explicitly representing ontological distinctions (poten-
tially with multiplicative effects) and/or using “overloaded” concepts, exemplified
by Gene, NucleicAcidSequence, and (genetic) information.
2. Supporting different perspectives on concepts (cf. the case of the perspective-based
concept graph in Figure 3).
3. Representation of and reasoning across levels of granularity.
In the context of biomedical ontologies, we see no method to address the first issue.
As noted, a fundamental question for us concerns how to represent genetic informa-
tion. However, available conceptualizations vary significantly: BioTop explicitly dis-
tinguishes between gene (subsumed by material object) and genetic information (sub-
sumed by information object), whereas gene in GRO is a subconcept of information
biopolymer (with an implicit information aspect), itself subsumed by molecular entity.
The NCI-Thesaurus comprises the concept gene (as a top-level concept), and no explicit
concept of genetic information.
The second issue is related to the first, but is oriented at viewing one concept from
different angles. It does not arise before we start the detailed modeling of concepts
(i.e., transcending taxonomies). Clearly, multiple perspectives are widely accepted, for
example, in conceptual or systems modeling. Using different models for distinct per-
spectives or views, even in different (sub-)languages, is also the case in the Unified
Modeling Language [28] (cf., e.g., the discussion of viewpoint [28, p. 678]). But much
freedom appears to be left to the modeler as to when and how a model is dissected into
several models capturing distinct perspectives.
Addressing the third problem, in [23] an elaborate theory of granularity is presented,
based on ontological and logical analysis. However, to apply this approach a domain-
granularity framework needs to be derived from the domain- and implementation-in-
dependent theory of granularity. We need to evaluate this approach further to judge the
benefits in our particular setting, as it seems to be complex. For BioTop, the authors
of [29] aim at a neutral position with respect to granularity issues, in the context of
integrating biomedical ontologies.
For all three issues, we see the need and potential for novel solutions by method-
ological means, although these problems have been met in earlier and ongoing work. No
generic methods were available in the literature that we could readily apply in our con-
text. Addressing these problems satisfactorily requires further research in conceptual
modeling, ontology design patterns, applied ontology, and modeling and using context.
Solutions to the problems of representing information objects, granularity and mul-
tiple perspectives are not limited to the domain of continuity and change in biology.
Our present focus on biology has an advantage that it gives us concrete versions of
these problems to be solved, with a clear set of computational and application require-
ments. Our modeling proposals for continuity and change are domain-specific, but the
underlying techniques lend themselves to adoption in other areas. As an example, in the
context of business process modeling, there is a need for process representations that
allow for querying for the continuity (or maintenance) of certain business objects for
which similar modeling patterns can be adopted.
6 Summary and Conclusions
Continuity and change is an extremely rich topic area in biology, and in this paper, we
have merely scratched its surface, with an eye on modeling methods and open problems.
Even though our work is preliminary, it does make several important contributions.
First, we presented a definition of this core theme that unifies the perspectives from
U.S. College Board, biology teachers, and Campbell Biology [27]. The need to augment
and streamline the theme description from the textbook highlights the complexity of
biological knowledge and the value added by viewing it from conceptual modeling
perspectives. Therefore, we see the comprehensive definition as a contribution in itself.
Second, we outlined a preliminary ontology of the entities involved in continuity
and change. An obvious connection exists between these entities and information ob-
jects, which is a topic of great current interest in upper ontologies. We hope that our
initial analysis will further facilitate the convergence between the theory on informa-
tion objects and the entities involved in continuity and change.
Third, we argued that supporting multiple perspectives on processes is required, so
that certain aspects can be factored out into separate models. Clearly, more work is
needed to develop guidelines on how one should decide which information should go
into each perspective and how different perspectives should be related to each other.
Fourth, we presented several examples of questions that need to be answered using
representations of continuity and change. Many of the diagnostic questions follow in a
straightforward manner from the representation. Answering these questions, however,
requires reasoning across multiple perspectives, for which we do not yet have an ade-
quate theory. These questions also require reasoning with processes, in some cases how
processes behave, and in others, effects if certain processes did or did not happen.
Finally, we outlined our steps in core theme design and related constraints, fram-
ing the analysis of continuity and change. Besides supporting multiple perspectives,
two other major challenges for systematically improving the current representations
were identified, namely more guidance on explicitly representing ontological distinc-
tions (e.g., for the notion of gene) and improved support of granularity.
In summary, we hope that this paper yields a good overview of problems and chal-
lenges in representing and reasoning over continuity and change, and that it provides
promising starting points for further ontological and methodological research.
Acknowledgments
This work work has been funded by Vulcan Inc. and SRI International. We thank Nikhil
Dinesh, Sue Hinojoza and William Webb for numerous discussions that helped develop
the ideas presented in this paper.
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