VR

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VR
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Formal Principles for Biomedical Ontologies

• Barry Smith
• http//ifomis.de

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Three levels of ontology
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Three levels of ontology

• formal (top-level) ontology dealing with
  categories employed in every domain
• object, event, whole, part, instance, class
• 2) domain ontology, applies top-level system to
  a particular domain
• cell, gene, drug, disease, therapy
• 3) terminology-based ontology
• large, lower-level system
• Dupuytrens disease of palm, nodules with no
  contracture

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Three levels of ontology

• formal (top-level) ontology dealing with
  categories employed in every domain
• object, event, whole, part, instance, class
• 2) domain ontology, applies top-level system to
  a particular domain
• cell, gene, drug, disease, therapy
• 3) terminology-based ontology
• large, lower-level system
• Dupuytrens disease of palm, nodules with no
  contracture

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Three levels of ontology

• formal (top-level) ontology dealing with
  categories employed in every domain
• object, event, whole, part, instance, class
• 2) domain ontology, applies top-level system to
  a particular domain
• cell, gene, drug, disease, therapy
• 3) terminology-based ontology
• large, lower-level system
• Dupuytrens disease of palm, nodules with no
  contracture

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Compare

1. pure mathematics (re-usable theories of
   structures such as order, set, function, mapping)
   
2. applied mathematics, applications of these
   theories re-using the same definitions,
   theorems, proofs in new application domains
3. physical chemistry, biophysics, etc. adding
   detail

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Three levels of biomedical ontology
?????

• formal (top-level) ontology
• medical ontology has nothing like the technology
  of re-usable definitions, theorems and proofs
  provided by pure mathematics
• 2) domain ontology
• UMLS Semantic Network, GALEN CORE
• 3) terminology-based ontology
• UMLS, SNOMED-CT, GALEN, FMA

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Description Logic , Protégé,

• and other tools for supporting automatic
  reasoning do not fill this gap
• they do not provide theories of classes,
  functions, processes, etc.
• rather successful coding in a DL-framework
  presupposes that such theories have already been
  applied in the very construction of the
  terminology-based ontology

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IFOMIS

• Institute for Formal Ontology and Medical
  Information Science,
• mission
• use basic principles of philosophical ontology,
  traditional theories of classification and
  definition for quality assurance and alignment of
  biomedical ontologies

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Strategy

• Part 1 Survey of GO
• Part 2 Provide principles for building
  biomedical ontologies derived from formal
  (top-level) ontology, and illustrate how they can
  help in quality assurance of terminology-based
  ontologies like GO
• Part 3 Show how it can be done right

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Part One Survey of GO
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GO is three ontologies

• cellular components
• molecular functions
• biological processes
• December 16, 2003
• 1372 component terms
• 7271 function terms
• 8069 process terms

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GO an impressive achievement

• used by over 20 genome database and many other
  groups in academia and industry
• successful methodology, much imitated
• now part of OBO (open biological ontologies)
  consortium
• Here I focus on problems / errors
• GO here is just an example

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Primary aim of GO

• not rigorous definition and principled
  classification
• but rather providing a practically useful
  framework for keeping track of the biological
  annotations that are applied to gene products

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Each of GOs ontologies

• is organized in a graph-theoretical structure
  involving two sorts of links or edges
• is-a
• (epithelial cell differentiation is-a cell
  differentiation)
• part-of
• (axonemal microtubule part-of axoneme)

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This graph-theoretic architecture

• to designed to help humans, who can use the
  graphs to locate the features and attributes they
  are addressing in their work and thus to
  determine the designated terms for these features
  and attributes within GOs controlled
  vocabulary.

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GOs three ontologies

• When a gene is identified, three important types
  of questions need to be addressed Where is it
  located in the cell? What functions does it have
  on the molecular level? And to what biological
  processes do these functions contribute?

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GOs three ontologies
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The Cellular Component Ontology (counterpart of
anatomy)

• consists of terms such as flagellum, chromosome,
  ferritin, extracellular matrix and virion
• Cellular components are physical and measurable
  entities. They are, in the terminology of
  philosophical ontology, objects or things
  (independent continuants). They endure
  self-identically through time while undergoing
  changes of various sorts
• Cellular component embraces also the
  extracellular environment of cells and cells
  themselves

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No organisms

• GO does not include terms for specific
  organisms, not even for single-celled organisms

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The Molecular Function Ontology

• molecular function the action characteristic of
  a gene product.
• Actions such as ice nucleation or protein
  stabilization do not endure but rather occur.

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The Molecular Function Ontology

• Originally included terms such as anti-coagulant
  (defined as a substance that retards or
  prevents coagulation) and enzyme (defined as a
  substance that catalyzes)
• These refer neither to functions nor to actions
  but rather to components.

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The Molecular Activity Ontology

• Confusion remedied to a degree by policy change
  of March 2003 All GO molecular function term
  names with the exception of the parent term
  molecular function and of the whole node binding
  are to be appended with the word activity.

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Function Activity

• Thus the term structural molecule, which is
  defined as meaning the action of a molecule
  that contributes to structural integrity, is
  amended to structural molecule activity

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still problems with GO Molecular Function
Definitions

• anti-coagulant activity (defined as a
  substance that retards or prevents coagulation)
• enzyme activity (defined as a substance that
  catalyzes)

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and there are still problems with Molecular
Function terms

• GO0005199
• structural constituent of cell wall

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structural constituent of cell wall

• Definition The action of a molecule that
  contributes to the structural integrity of a cell
  wall.
• confuses actions, which GO includes in its
  function ontology, with constituents, which GO
  includes in its cellular component ontology

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• extracellular matrix structural constituent
• puparial glue (sensu Diptera)
• structural constituent of bone
• structural constituent of chorion (sensu Insecta)
  
• structural constituent of chromatin
• structural constituent of cuticle
• structural constituent of cytoskeleton
• structural constituent of epidermis
• structural constituent of eye lens
• structural constituent of muscle
• structural constituent of myelin sheath
• structural constituent of nuclear pore
• structural constituent of peritrophic membrane
  (sensu Insecta)
• structural constituent of ribosome
• structural constituent of tooth enamel
• structural constituent of vitelline membrane
  (sensu Insecta)

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The Biological Process Ontology

• biological process A phenomenon marked by
  changes that lead to a particular result,
  mediated by one or more gene products.
• Examples
• glycolysis,
• death,
• adult walking behavior
• response to blue light

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Occurrents

• Both molecular activity and biological process
  terms refer to what philosophical ontologists
  call occurrents
• entities which do not endure through time but
  rather unfold themselves in successive temporal
  phases.
• Occurrents can be segmented into parts along the
  temporal dimension.
• Continuants exist in toto in every instant at
  which they exist at all.

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Molecular functions and biological processes are
closely interrelated

• E.g. the process anti-apoptosis involves the
  molecular function apoptosis inhibitor activity.
• How can GO express such relations?

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Are they a matter of granularity?

• A biological process is accomplished via one or
  more ordered assemblies of molecular functions.
• ??? Molecular activities building blocks of
  biologica processes ???
• So Functions are parts of processes
• But no

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GOs three ontologies are separate
biological processes
molecular functions

• No links or edges defined between them

cellular constituents
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Question

• How understand granularity
• if not in terms of parthood?

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Molecular functions

• renamed activities,
• because activity unlike process, connotes
  agency ?
• but molecules are not agents
• hypothesis the term function was used for the
  molecular function ontology because the
  activities in question are functional in relation
  to the pertinent organism.

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Functions

• A function is functional
• beneficial to the organism
• If an organism-part has a function, this is
  because the functioning of this organism-part is
  beneficial to the organism
• The function of the heart is to pump blood
• Not the function of the hip is to financially
  support hip-replacement surgeons

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• Some processes are functionings
• E.g. pumping blood

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? Two sorts of processes

• Functionings (realizations of functions
  beneficial to the organism)
• Other processes (e.g. the result of external
  interventions)
• Cf. difference between physiology and pathology

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GO not clear about this distinction

• transport The directed movement of substances
  (such as ions) into, out of, or within a cell
• cell growth and/or maintenance Any process
  required for the survival and growth of a cell
• Synonym cell physiology
• transport is-a cell growth and/or maintenance
• but (GO0019060) viral intracellular protein
  transport
• is-a transport

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Why do these problems arise?

• GO has no clear understanding of the role of
  temporal relations in organizing an ontology
• (thus also no clear understanding of the
  difference between a function and the activity
  which is the realization of a function)

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GO excludes organisms from its scope (they are of
the wrong granularity)

• Yet each process or function requires some bearer
  or bearers which it is the process or function
  of.
• Processes are dependent on their bearers
• (Theory of dependence vs. independence part of
  formal ontology)
• (Theory of continuants vs. occurrents part of
  formal ontology)

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Some formal ontology

• Components are independent continuants
• Functions are dependent continuants
• (the function of an object exists continuously in
  time, just like the object which has the
  function
• and it exists even when it is not being
  exercised)
• Processes are (dependent) occurrents

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More generally

• Continuants can be divided into independent
  (objects, things, components) and dependent
  (features, attributes, conditions, functions,
  roles, qualities )
• All occurrents are dependent entities.
• Every occurrent is dependent for its existence on
  one or more continuants.
• A change is always a change in some continuant
  object.

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Part Two

• Principles of Biomedical Ontologies and their
  use in quality assurance of terminology-based
  ontologies

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Principle of Temporal Coherence

• An ontology should rigorously distinguish
  continuants from occurrents.
• (Anatomy is a science of continuants)

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Principle of Dependence

• If an ontology recognizes a dependent entity
  then it (or a linked ontology) should recognize
  also the relevant class of bearers
• Part of our aim here is to lay down principles
  which can support such linkability

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Linking to external ontologies

• can also help to link together GOs own three
  separate parts

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GOs three ontologies
biological processes
molecular functions
? dependent ?
cellular constituents
? independent
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GOs three ontologies
organism-level biological processes
cellular processes
molecular functions
cellular constituents
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molecular functions
cellular processes
organism-level biological processes
molecule complexes
cellular constituents
organisms
part-of is dependent
on
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molecular functions
cellular processes
organism-level biological processes
molecule complexes
cellular constituents
organisms
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molecule complexes
cellular constituents
organisms
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molecule complexes
cellular constituents
organisms
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GO must be linked with other, neighboring
ontologies

• GO has adult walking behavior but not adult
• GO has eye pigmentation but not eye
• GO has response to blue light but not light (or
  blue)
• 94 of words used in GO terms are not GO terms
• Part of the solution Medical FactNet (NLM, 10am
  tomorrow)

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GO taking steps in this direction

• Linking to a good external ontology of organism
  types (to solve some of the problems with sensu)
• It needs to link further to a good external
  ontology of anatomy, to solve the location
  problem
• and to a good external ontology of coarse-grained
  reality, to solve the adult walking behavior
  problem
• Human beings know what walking means

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• Human beings know what adults are older than
  embryos
• GO needs to be linked to ontology of development
• and in general to resources for reasoning about
  time and change

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but such linkages are possible

• only if GO itself has a coherent formal
  architecture

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Principle of Univocity

• univocity terms should have the same meanings
  (and thus point to the same referents) on every
  occasion of use
• UMLS-Semantic Network
• organization body plan (anatomy)
• organization social organization

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Polysemy of GOs part-of

• membrane part-of cell, intended to mean a
  membrane is a part-of any cell
• flagellum part-of cell, intended to mean a
  flagellum is part-of some cells
• replication fork part-of cell cycle, intended
  to mean a replication fork is part-of the
  nucleoplasm only during certain times of the cell
  cycle

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Three meanings of part-of

• part-of can be part of (flagellum part-of
  cell)
• part-of is sometimes part of (replication
  fork part-of the nucleoplasm)
• part-of is included as a sublist in

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THE GOAL IS

• not to impose basic principles of classification
  and definition on biologists
• All the principles presented here should be
  conceived not as iron requirements but rather as
  rules of thumb
• deviation from which is often marked by
  characteristic families of coding errors

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example

• GO 0030430 host cell cytoplasm, defined as
  The cytoplasm of a host cell
• GO0018995 host, defined as Any organism in
  which another organism, especially a parasite or
  symbiont, spends part or all of its life cycle
  and from which it obtains nourishment and/or
  protection

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Why is this an error?

• because organisms do not fall within the scope of
  GO
• An organism is not a cellular component, and it
  is not a molecular function, and not a biological
  process, either

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host cell cytoplasm part-of host

• breaks GOs own granularity constraints

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Why univocity?

• humans are good at disambiguating ambiguous
  expressions, machines not
• 2. quality assurance and ontology maintenance
• 3. GO, SNOMED, etc., are designed to constitute
  controlled vocabularies

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Quality assurance and ontology maintenance must
be automated

• As GO increases in size and scope it will be
  increasingly difficult to maintain the semantic
  consistency we desire without software tools that
  perform consistency checks and controlled
  updates.
• The addition of each new term will require the
  curator to understand the entire structure of GO
  in order to avoid redundancy and to ensure that
  all appropriate linkages are made with other
  terms.

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The purpose of a controlled vocabulary

• to ensure that the same terms are used by
  different research groups with the same meanings
• this has implications also for the syntax of GO
  terms ( the way terms are compounded together
  out of other terms)

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Univocity and syntax

• The story of /

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/

• GO0008608 microtubule/kinetochore interaction
• df Physical interaction between microtubules and
  chromatin via proteins making up the kinetochore
  complex

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/

• GO0001539 ciliary/flagellar motility
• df Locomotion due to movement of cilia or
  flagella.

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/

• GO0045798 negative regulation of chromatin
  assembly/disassembly
• df Any process that stops, prevents or reduces
  the rate of chromatin assembly and/or disassembly

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/

• GO0000082 G1/S transition of mitotic cell cycle
• defined as Progression from G1 phase to S phase
  of the standard mitotic cell cycle.

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/

• GO0001559 interpretation of nuclear/cytoplasmic
  to regulate cell growth
• df The process where the size of the nucleus
  with respect to its cytoplasm signals the cell to
  grow or stop growing.

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/

• GO0015539 hexuronate (glucuronate/galacturonate)
  porter activity
• df Catalysis of the reaction hexuronate(out)
  cation(out) hexuronate(in) cation(in)

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Problems with GOs compositionality
/ (slash) 286
(semi-colon) 177
, (comma) 1206
and 180
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comma

• cytokinesis, site selection

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plurals

• biological process
• physiological processes cellular
  process
• cell growth and/or maintenance

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specification 39 complex 563
formation forming 142 regulator regulatory regulated regulation 1326
determination determinacy 56 acting on 146
with 54 constituting 35
from 141 constituent constitutive 29
in 51 dependent 182
via 164 sensu 469
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Questions regarding operators

• How does constituent relate to component
• If A within B then is A part-of B or
  included-in-the-interior-of B ?
• Does via mean by means of or along the path of ?
• How is un- related to not (how is
  unlocalized related to not localized)

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involved in

• term-forming operator (reflection of GOs limited
  resources for expressing relations)
• hydrolase activity, acting on acid anhydrides,
  involved in cellular and subcellular movement
• asymmetric protein localization involved in cell
  fate commitment
• cell-cell signaling involved in cell fate
  commitment
• protein secretion involved in cell fate
  commitment

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involved in

• hydrolase activity, acting on acid anhydrides,
  involved in cellular and subcellular movement
• This is a term because GO does not have the
  resources to express is-involved-in as a
  relation between terms
• note problems with commas

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involved in

• hydrolase activity,
• acting on acid anhydrides,
• involved in cellular and subcellular
  movement
• is-a hydrolase activity, acting on acid anhydrides

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involved in

• hydrolase activity, acting on acid anhydrides,
  involved in cellular and subcellular movement
  is-a hydrolase activity, acting on acid
  anhydrides
• is ok hydrolase activity, acting on anhydrides
  can but need not be involved in cellular and
  subcellular movement

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involved in

• asymmetric protein localization involved in cell
  fate commitment is-a cell fate commitment
• should be a part-of relation
• (compare breathing involved in running is a
  running)

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involved in

• cell-cell signaling involved in cell fate
  commitment is-a cell fate commitment
• ditto should be a part-of relation

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these, though, are good

• asymmetric protein localization involved in cell
  fate commitment is-a asymmetric protein
  localization
• cell-cell signaling involved in cell fate
  commitment is-a cell-cell signaling

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involved in

• protein secretion involved in cell fate
  commitment synonym of protein secretion
• are there instances of protein secretion not
  involved in cell fate commitment?
• Problems with GOs peculiar use of synonym

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Consequences of inconsistent and/or indeterminate
use of operators

• there are 29.42 distinct terms within GO which
  contain one or more polysemous operators
• but these terms receive only 13.96 of the
  annotations present within GO
• Hypothesis This lower percentage of annotations
  reflects the fact that poorly defined operators
  are not well understood by annotators, who thus
  avoid the corresponding terms

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Principle of Compositionality

• The meanings of compound terms should be
  determined
• 1. by the meanings of constituent terms
• together with
• 2. the rules governing the syntactic operators

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Principle of Objectivity

• which classes exist is not a function of our
  biological knowledge.
• (Terms such as unclassified or unknown
  ligand or not otherwise classified as peptides
  do not designate biological natural kinds.)

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GO0008372 cellular component unknown cellular
component unknown is-a cellular
componentunlocalized is-a cellular
componentHolliday junction helicase complex
is-a unlocalized
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GOs excuse

• unlocalized is used as a placeholder only
• but automatic information retrieval systems
  cannot distinguish it from other, genuine class
  names
• formal tools exist which can deal with the
  addition of knowledge into a classification
  system without the need to create fake classes
• (Theory of Granular Partitions)

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Principle of Positivity

• Class names should be positive. Logical
  complements of classes are not themselves
  classes.
• (Terms such as non-mammal or non-membrane or
  invertebrate or do not designate natural
  kinds.)

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• Terms such as
• Veterinary proprietary drug AND/OR biological
• do not designate natural kinds. (Which biological
  classes exist is not a matter of logic.)
• has 2532 children in SNOMED-CT

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Principle of Explicitness

• if a link between two classes holds only under
  certain specific restrictions, then this
  restriction should be made explicit in the
  statement of the corresponding link-axiom
• cf. GOs sensu

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GO

• can in practice be used only by trained
  biologists (with know how)
• whether a GO-term truly stands in the is_a
  relation depends e.g. on the type of organism
  involved
• glycosome is part-of cytoplasm
• only for Kinetoplastidae
• Computers have no counterpart of such
  context-dependent know-how

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Principle of Single Inheritance

• no class in a classificatory hierarchy should
  have more than one parent on the immediate higher
  level

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Principle of Taxonomic Levels

• the terms in a classificatory hierarchy should
  be divided into predetermined levels (analogous
  to the levels of kingdom, phylum, class, order,
  etc., in traditional biology).
• depth in GOs hierarchies not determinate
  because of multiple inheritance

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Principle of Partonomic Levels

• Terms in a partonomic hierarchy should be divided
  into predetermined granularity levels, for
  example organism, organ, cell, molecule, etc.)
• (GO is about to break physiological process into
  'cell physiological process' and 'organism
  physiological process'.)
• take granularity seriously

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Principle of Exhaustiveness

• the classes on any given level should exhaust
  the domain of the classificatory hierarchy.

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Single Inheritance Exhaustiveness JEPD

• for Jointly Exhaustive and Pairwise Disjoint
• Exhaustiveness often difficult to satisfy in the
  realm of biological phenomena but its acceptance
  as an ideal is presupposed as a goal by every
  scientist.
• Single inheritance accepted in all traditional
  (species-genus) classifications, now under threat
  because multiple inheritances is a
  computationally useful device (allows one to
  avoid certain kinds of combinatory explosion).

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Problems with multiple inheritance

• B C
• is-a1 is-a2
• A
• is-a no longer univocal

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GOs is-a is pressed into service to mean a
variety of different things

• the resulting ambiguities make the rules for
  correct coding difficult to communicate to human
  curators in terms of generally intelligible
  principles
• they also serve as obstacles to integration with
  neighboring ontologies

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Problems with multiple inheritance

• B C
• is-a1
  is-a2
• A
  E
• D
• sibling is no longer determinate
• Principle of levels is violated
  

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A storage vacuole is not a special kind of vacuole

• a box used for storage is not a special kind of
  box

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Another term-forming operator

• lytic vacuole within a protein storage vacuole
• lytic vacuole within a protein storage vacuole
  is-a protein storage vacuole
• time-out within a baseball game is-a baseball
  game
• embryo within a uterus is-a uterus

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Problems with Location

• is-located-at / is-located-in and similar
  relations need to be expressed in GO via some
  combination of is-a and part-of
• is-a unlocalized
• is-a site of
• within
• in

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Problems with location

• extrinsic to membrane part-of membrane
• extrinsic to plasma membrane part-of plasma
  membrane
• extrinsic to vacuolar membrane part-of vacuolar
  membrane

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Differentiation and Development

• development cellular process
• cell differentiation

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Cell differentation is-a development

• But according to GOs own definitions the agent
  or subject of differentiation is the cell, while
  the agent or subject of development is the whole
  organism
• (again GO has problems in keeping track of
  entities on differerent levels of granularity)

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cell differentiation is-a development

• but
• hemocyte differentiation hemocyte
  development

part-of
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• GO0007514 garland cell differentiation
• Definition Development of garland cells, a small
  group of nephrocytes which take up waste
  materials from the hemolymph by endocytosis.
• (Illustrates GOs problems with definitions)

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Part Three

• How to do things right
• so far only scratched the surface
• sensu
• synonyms
• GOs definitions
• GOs logical relationships

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Principles for GO terms

• Temporal coherence
• Dependence
• Univocity
• Compositionality
• Objectivity
• Positivity
• Explicitness
• Taxonomic Levels
• Partonomic Levels
• Single Inheritance
• Exhaustiveness

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Should these principles be satisfied?

• Michael Ashburner
• GOs philosophy from the beginning was just in
  time - that is, we made no great attempt to
  complete the ontologies . If you try and
  complete an ontology, or worse try and get it
  right, then you will fail

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Can these principles be satisfied?

• Compare GO with Foundational Model of Anatomy
  (FMA)

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Principle GO FMA
Temporal coherence No N/A
Dependence No N/A
Univocity No Yes
Compositionality No Yes
Objectivity No Yes
Positivity No Yes
Explicitness No N/A
Taxonomic Levels No Yes
Partonomic Levels No Yes
Single Inheritance No Yes
Exhaustiveness No No
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• The End

Principle GO FMA
Temporal coherence No N/A
Dependence No N/A
Univocity No Yes
Compositionality No Yes
Objectivity No Yes
Positivity No Yes
Explicitness No N/A
Taxonomic Levels No Yes
Partonomic Levels No Yes
Single Inheritance No Yes
Exhaustiveness No No
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Is GO an ontology

• GO a controlled vocabulary
• (ramshackle) syntactic regimentation
• but because is-a and part-of are not given
  uniform readings, this does NOT mean the sort of
  semantic regimentation which would amount to an
  ontology in the proper sense of the word

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rules for definitions

• intelligibility the terms used in a definition
  should be simpler (more intelligible) than the
  term to be defined
• definitions do not confuse definitions with the
  communication of new knowledge

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Principle of Substitutability

• in all so-called extensional contexts a defined
  term should be substitutable by its definition in
  such a way that the result is both grammatically
  correct and has the same truth-value as the
  sentence with which we begin
• GO0015070 toxin activity
• Definition Acts as to cause injury to other
  living organisms.

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substitutability

• There is toxin activity here
• There is acts as to cause injury to other living
  organisms here

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Defining is-a

• A is-a B every instance of A is an instance of
  B
• A is-a B A and B are natural kinds and every
  instance of A is an instance of B
• A is-a B A and B are natural kinds and every
  instance of A is as a matter of necessity an
  instance of B

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Solutions to these problems

• part_of should mean part_of