an introduction to chemistry ontology

An introduction to chemistry ontology

Colin Batchelor,Royal Society of Chemistry

batchelorc@rsc.org2009-07-21

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About you

Ontology experience Chemistry experience What are you doing at the moment?

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An ontological toolkit for chemistry

1. Classes vs. instances2. Regular polysemy3. Granularity4. What classes should go into the ontology?

Ontological dependence and dispositions5. Identity6. BFO’s independent continuants and chemistry7. An actually-existing chemical ontology: ChEBI8. The Sequence Ontology9. Drugs (if we have time)

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1. Classes and instances

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Instances and classes

TokensInstancesParticulars

This particular cat, this particular portion of water, this particular skin cell, this particular molecule of nitrogen

TypesClassesUniversalsKinds

Cats in general, portions of water in general, skin cells in general, molecules of nitrogen in general

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Classes and instances

This alpha-D-glucose molecule here is an instance_of…

a D-glucopyranose moleculea D-glucose moleculea glucose moleculean aldohexose moleculean aldose moleculea monosaccharide moleculea sugar moleculea carbohydrate moleculea natural product moleculean organic molecular entity

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Why this is confusing

An arbitrary pyridine molecule (in a bottle) is an instance_of…

a pyridines moleculean azaarene moleculea monocyclic

heteroarene moleculea mancude organic

heteromonocyclic parent molecule

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No superclasses

N-hydroxy-L-aspartic acid is_a hydroxamic acids

hydroxamic acids is_a organic functional classes

therefore N-hydroxy-L-aspartic acid is_a organic functional classes

(source: ChEBI, May 2008) This has now been fixed.

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2. Regular polysemy

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Regular polysemy

Let’s say I have a banana. If I feed it to a child, it will get banana all down its front. One might have one table made of oak, and another made of banana. Last week it was frosty so I took in a plant from the back garden to the kitchen. It is a dwarf banana, so it is a banana but not a banana banana. If it ever grows any fruit, the fruit will be a dwarf banana banana. As opposed to a banana banana banana.

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Regular polysemy: banana

bananaFRUIT(COUNT)

bananaFRUIT(MASS) (grinding)bananaWOOD (grinding)bananaTREE

bananaCONTRASTIVE REDUPLICATION FOCUS

Other regular polysemies are available (e.g. colour, leaf, brand names).

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Regular polysemy: banana

“How do you feel now?”“Banana’d out.”

“The banana milkshake is still waiting for the bill.”

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Regular polysemy: Grinding

“tastes like chicken” 447000 Google hits

“tastes like a chicken” 2060(actually “tastes like a chicken tamale” and the like)

“tastes like beef” 8550

“tastes like cow” 1310

“tastes like a cow” 726

“tastes like a beef” 291(but like “tastes like a chicken”)

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Regular polysemy:EXACT vs. CLASS

pyridine

fully-specified nameclosed-world name (anything

not mentioned is a hydrogen atom)

a pyridine

underspecified nameopen-world name (anything

not mentioned could be anything)

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Regular polysemy:A sixfold classification

(from Corbett, Batchelor and Copestake, LREC 2008)

EXACTbenzene molecule

CLASSthe benzene 13a

PARTattacks the benzene ring

SPECIESatmospheric carbon

POLYMER SURFACERu(0001)

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3. Granularity

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Regular polysemy:GRAIN vs. BULK

“The IR and Raman spectra show that the metal interacts with the oxygen atom of the amide group and allow the vibrations of the complexed CdX2 to be characterized.”

BULK for GRAIN.

“Pure americium has a silver and white luster. At room temperatures it slowly tarnishes in dry air.”

GRAIN for BULK.

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portion of wine

portion of water portion of ethanol

waterCHEBI:15377

water–hydroxide + proton equilibrium

ethanolCHEBI:16236

ethanol–ethoxide ion + proton equilibrium

hydroxideCHEBI:16234

protonCHEBI:24636

ethoxideCHEBI:52092

icbo

icao

has_participant

has_grain

has_part

Bulk granularity

Molecular granularity

hydrogen atom

oxygen atom

has_particbo

icao

proton transferfrom ethanolto ethoxide

proton transferfrom ethoxide

to ethanol

has_participanthas_participant

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Chloroform, ethanol

Bulk chloroform (as sold) is stabilized with small quantities of amylene or methanol or ethanol.

Bulk ethanol (as sold) contains small amounts of benzene.

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4. What classes should go into the ontology? Dispositions and ontological dependence.

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Natural kinds

“To say that a kind is natural is to say that it corresponds to a grouping or ordering that does not depend on humans. We tend to assume that science is successful in revealing these kinds;”

A. Bird and E. Tobin, “Natural Kinds” in Stanford Encyclopedia of Philosophy (Spring 2009 Edition), ed. E. N. Zalta, http://plato.stanford.edu/archives/spr2009/entries/natural-kinds/

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Bad natural kinds

Molecules containing exactly 21 atoms Molecules where every atom is from a

different element Portions of material that boil at 300 K and 3

atm. Molecules that are completely surrounded

by water. The largest molecule in a given beaker.

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Good natural kinds

Dienes Carboxylic acids Diatomic molecules Ring-containing molecules Aromatic molecules

… why?

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What is a disposition?

Says BFO:

“A realizable entity that essentially causes a specific process or transformation in the object in which it inheres, under specific circumstances and in conjunction with the laws of nature. A general formula for dispositions is: X (object has the disposition D to (transform, initiate a process) R under conditions C.”

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Realizable entities

For every realizable entity (dispositions, roles, functions, powers, virtues, tendencies, and so forth) there must be a process.

The process must be alienable (there must be no mutual ontological dependence between the bearer of the entity and the process).

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Alienable and inalienable processes

Alienable processes: Breathing Swimming Sleeping

Inalienable processes: Being somewhere (location) Pointing somewhere (orientation) (of pairs of objects) being a given distance apart (relative

location) (of pairs of objects) pointing in different directions (relative

orientation)

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Ontological dependence

X is ontologically dependent on Y if X cannot exist without Y existing.

Qualities cannot exist without the entities that exhibit them.

Roles cannot exist without their players.Functions cannot exist without their exercisers.Dispositions cannot exist without the entities that

realize them.

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Mutual ontological dependence (1)

George Best cannot exist without George Best’s life existing.

conversely

George Best’s life cannot exist without George Best existing.

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Determination, specialization and dispositions (1)

Dispositions are relational entities.

They depend ontologically on both their bearer and the conditions in which they are realized.

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Determination, specialization and dispositions (2)

Material X has disposition D to undergo process M (melting) under conditions pressure P and temperature T.

Here the conditions are determinable.

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Determination, specialization and dispositions (3)

Material X has disposition D to undergo process M (dissolution at rate k) under conditions pressure P and temperature T.

Here the conditions are determinable and the process is a quantified specialization of the process of dissolution.

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Surefire dispositions vs. tendencies

A more thorough account of dispositions:

X has disposition D to undergo process P at rate k with probability p under conditions C.

For surefire dispositions, p = 1.0.For tendencies, p < 1.0.

The disposition D(C) and its associated rates kD(C) and probability pD(C) can be complicated mathematical functions of C.

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Antidotes, finks and fuses

Antidotes: Poison has the disposition to kill people unless the antidote is applied.

(Careful: does this mean X has disposition D to undergo process P except where it doesn’t?)

Finks: where the conditions C are exactly those that prevent X from undergoing process P. Example: a fuse.

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Mutual ontological dependence (2)

There are many mutually ontologically dependent dispositions in chemistry.

Being an acid is the disposition to donate a proton to (or to receive an electron pair from) a base.

Being a base is the disposition to receive a proton from (or to donate an electron pair to) an acid.

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Grounding dispositions

There are no bare dispositions.

All dispositions ought to have a categorical (= quality or independent continuant) basis.

Metals conduct because of their band structure (= quality).

Dienes take part in Diels–Alder reactions because of their electronic structure (= quality).

Objects fall under gravitation because of their mass (= quality).

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What grounds many of these natural kinds?

Structure

or, better,

Parthood

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Exercise

What dispositions do the qualities inhering in the parts that define these classes ground?

CHEBI:22479 amino cyclitol glycosidesCHEBI:47788 3-oxo steroidCHEBI:33726 canonical amino acid residue anionCHEBI:25384 monocarboxylic acidCHEBI:33791 gold coordination entityCHEBI:30879 alcohol

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5. Identity

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Chemical entities and identity criteria

Synchronic (class)

Synchronic identity conditions are for different objects i and j at time t.

Diachronic (instance)

Diachronic identity conditions are for what may be the same object i at times t1 and t2.

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Synchronic identity for small molecules

What follows is an account of identity criteria as understood by chemists expressed in terms of qualities.

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Synchronic identity for small molecules

Cyclohexane = A molecule consisting of six carbon atoms and twelve hydrogen atoms with the carbons joined up in a ring.

Hexene = A molecule consisting of six carbon atoms and twelve hydrogen atoms with the carbons joined in a chain.

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Boats and chairs

Boat cyclohexane = A cyclohexane with the carbon atoms in the boat conformation.

Chair cyclohexane = A cyclohexane with the carbon atoms in the chair conformation.

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Qualities vs. realizable entities

Qualities are those entities that have no temporal parts, inhere in objects, and are present (though may change) if the objects they inhere in exist at all.

Realizable entities may never be realized. The only way to realize them is as an alienable process.

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Qualities are (indirectly) multiply-realizable

There are many tests, many processes that can be realized (many dispositions) grounded on qualities, such as:

Triangularity Being 2 m tall. Containing six and only six carbon atoms

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Qualities that determine synchronic identity

Constitution (of a molecule) Being cyclic (of a part) Being linear (of a part)

Hence cyclohexane and the hexenes are different synchronically, despite each molecule containing the same number of each kind of atom.

Loss or gain of an atom or atoms changes the class of the molecule.

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Qualities that are incidental to synchronic identity

Conformation

Hence boat and chair cyclohexane are the same molecule.

Orientation (including relative orientation)

Hence exo- and endo-puckered rings (relative to some plane) are the same ring.

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Synchronic identity and granularity

Molecules with different numbers of atoms belong to different natural kinds.

Portions of material with different numbers of atoms may well belong to the same natural kind.

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Criteria for diachronic identity

We could take the same criteria as for synchronic identity.

So an ethanoic acid molecule M in a portion of vinegar becomes an ethanoate ion M′ becomes a different ethanoic acid molecule M″ becomes a different ethanoate ion M′″ and so on in the course of a day.

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Thought experiment

Consider a large molecule M somehow connected to a piece of glass. It is undergoing protonation and deprotonation processes at a given rate.

1. Turn your back.2. Now look again. Is it the same molecule?

If structure determines identity then:it is the same molecule with probability 1 – p ora different molecule with probability p.

That can’t be right.

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Some ways out

Cyclic processes Biological processes Information macromolecules Synthetic reaction schemes

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Cyclic processes and equilibria

If we have a reaction

A + X ⇌ B

for which the energetic barrier in both directions is low, and where X is a proton, or an otherwise stable species, then A and B are the same molecule (diachronically).

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Growth processes, homologation

Other diachronic identity criteria emerge from functional processes:

RNA transcription (the nascent RNA maintains its identity on gaining bases)

Protein translation (the nascent polypeptide maintains its identity on gaining amino acid residues)

Polyketide synthesis (the nascent polyketide maintains its identity on gaining acetyl and propionyl subunits)

But this requires a notion of function.

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Information macromolecules

Transfer RNAs preserve their identity under base modification.

DNAs preserve their identity under base loss, base repair, proofreading and so forth.

Polypeptides preserve their identity under methylation, phosphorylation and so forth.

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Diachronic identity and RXNO

The Name Reaction Ontologyhttp://www.rsc.org/ontologies/RXNOhttp://rxno.googlecode.com/classifies reactions according to what they do

to the ‘skeleton’ of the molecule.

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Protecting groups and identity criteria

Protecting groups replace functional groups in molecules in order to ensure that only the right parts of the molecule react in a particular way.

But a given protecting group can be of similar size to the rest of the molecule.

In some steps of some syntheses, the vast majority of the mass of the relevant molecule may be protecting groups.

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The paradox of the heap

Take a gold nanoparticle with 55 atoms.

Remove atoms one-by-one (assume we can do this).

At what stage does it cease to be a nanoparticle?

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A further problem:Bonding and temperature

What counts as a bond depends on the temperature of the system.

The helium dimer is held together by a bond weaker than the interactions between different ends of the boats and chairs we saw earlier.

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6. BFO’s independent continuants and chemistrywww.ifomis.org/bfo

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A hierarchy of bonding

covalent nc–ne bonding beatsnc–me (n ≠ m) bonding beatsionic bonding beatshydrogen bonding beatsvan der Waals bonding beatsother, rare kinds of bonding

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Aside: mechanical connection

Catenanes are“Hydrocarbons having two or more rings

connected in the manner of links of a chain, without a covalent bond.” (IUPAC Gold Book)

But in order to break apart a catenane, you need to break one of the covalent bonds in one of the rings.

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BFO’s material entities in review

ObjectAn independent continuant that is spatially extended, maximally self-connected and self-contained (the parts of a substance are not separated from each other by spatial gaps) and possesses an internal unity.

ObjectAggregateAn independent continuant that is a mereological sum of separate object entities and possesses non-connected boundaries.

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BFO’s material entities in review

FiatObjectPartAn independent continuant that is part of an object but is not demarcated by any physical discontinuities.

BoundaryAn independent continuant that is a lower dimensional part of a spatial entity, normally a closed two-dimensional surface. Boundaries are those privileged parts of object entities that exist at exactly the point where the object is separated off from the rest of the existing entities in the world.

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How do these map on to the chemical situation?

Positions are replaced by spatially-dispersed wavefunctions.

Spatial gaps and (absolute) physical discontinuities are replaced by regions where the wavefunctions have values very close to zero.

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Folding

When molecules (RNA molecules, polypeptide chains) fold, the new conformation is held together by hydrogen bonding.

This means that there are no spatial discontinuities (except at the outer edges of the folded molecule), only regions where the electron density is lower than in the rest of the molecule (but certainly nowhere near zero).

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Folding and boundaries

This makes it hard to talk of bona fide boundaries, though there are certainly fiat boundaries, say between nucleotides.

Best to talk in terms of tangential proper parts of the unfolded molecule.

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Looking ahead: RNAO

The RNA Ontology is (amongst other things) an ontology of conformations of RNA molecules, their fiat parts and their tangential proper parts.

http://roc.bgsu.edu/

N. Leontis and co-workers, “The RNA Ontology (RNAO)”, this meeting.

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Non-covalently, non-mechanically bound systems

These lie in between objects and object aggregates.

They are held together by forces weaker than those that hold objects together.

Examples: double-stranded DNA, clathrates, pseudorotaxanes.

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Perhaps…

Molecular entity Physically-associated molecular aggregate (e.g.

double-stranded DNA) Non-associated molecular aggregate (e.g. the

products of a reaction) Molecular part

Tangential proper part of unfolded molecular entity Non-tangential proper part of unfolded molecule entity

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Parts and orbitals

The wavefunctions of electrons in atoms are called orbitals.

Molecules are built out of a combination of atoms sharing electrons.

Molecular orbitals can be built (mathematically) by taking a linear combination of atomic orbitals (LCAO).

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Parts and orbitals and atoms

In a free carbon atom, all of the orbitals have spherical symmetry about the nucleus.

In a bound carbon atom, some of the orbitals have polyatomic symmetry.

But is the bound–free distinction more like the boat–chair distinction or the banana–banana–banana–… distinction?

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Methyl, the radical (exact)

In a methyl radical, the mereological sum of the orbitals is coextensive with the species.

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Methyl, the group (part)

In a methyl group, the mereological sum of the orbitals extends into the rest of the molecule.

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7. An actually-existing chemical ontology: ChEBIwww.ebi.ac.uk/chebi

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BackgroundChEBI (an OBO Foundry candidate, and possibly the ontology that most

other ontologies depend on most) contains about 23000 classes, which include

subatomic particles atoms exotic atoms molecules (EXACT), with InChIs and SMILES molecules (CLASS) molecular parts roles

The full name (Chemical Entities of Biological Interest) is both a pun and no longer accurately describes the scope.

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Quantification, modality

Parthood in ChEBI meant at least three things:

1. is necessarily chemically part of

carbonyl group part_of carbonyl compounds

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Quantification, modality

2a. Is sometimes chemically part of:

Lead(2+) ion part_of lead diacetate

(most lead(2+) ions aren’t)

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Basics for a chemical ontology:2. Parthood relations

2b. Is extremely rarely chemically part of

Electron part_of muonium

3. Is part of a mixture

Kanamycin A part_of kanamycin

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How it got fixed

By defining relationships according to pattern: all instances of X have a relationship with some Y. (Smith et al., “Relations in biomedical ontologies”, 2005)

carbonyl compound has_part carbonyl group Lead diacetate has_part lead(2+) (?!) Muonium has_part electron Kanamycin has_part kanamycin A (?!)

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is_a had many meanings!

1. An amount of a compound has a biological role: tris is_a buffer.*

2. An amount of a compound has an application: sodium dodecyl sulfate is_a detergent.*

3. A less-abstract type is an example of a more abstract type: propane is_a alkanes. This is OK.

4. ?!: metals is_a atoms.*

* Not a property of a lone atom or molecule!

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How is_a got/is being fixed

In cases 1 and 2, the has_role relation was introduced to connect molecules with realizable entities (and maybe some relational qualities). More work needed to distinguish single-molecule from collective from bulk relational entities.

Case 3 is OK.

In case 4, “metal” will be replaced by “metal atom”.

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is_a completeness

(June 2009 release, taken from http://www.berkeleybop.org/ontologies/obo-all/chebi/chebi.stats)

Number of subclass orphans: 1325 (out of 22452) = 5.9%

Average number of is_a parents per class: 1.288Maximum number of is_a parents per class: 9

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Terms without definitions, and only children

(June 2009 release)

Without definitions: 20813 (92.7%)Only children: 1608 (7%)

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Two kinds of relation in CHEBI

Between molecules (and ‘roles’) and between connection tables:

is_a has_part has_role icbo icao is_tautomer_of

Only between connection tables:

is_enantiomer_of is_substituent_group_f

rom has_fundamental_par

ent has_parent_hydride

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Connection tables

The cyano group:

Marvin 10260616462D 3 2 0 0 0 0 999 V2000 0.0000 0.0000 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 0.8250 0.0000 0.0000 N 0 0 0 0 0 0 0 0 0 0 0 0 -0.8250 0.0000 0.0000 * 0 0 0 0 0 0 0 0 0 0 0 0 1 2 3 0 0 0 0 1 3 1 0 0 0 0M END

Connection tables describe how the atoms in a molecule are connected (as long as they’re connected by covalent, ionic or some kinds of multicentre bonding).

They are a kind of specification.

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Generically-dependent continuants

Generically-dependent continuants, unlike specifically-dependent continuants (qualities, dispositions and so forth) can be transferred between bearers.

Molecular connection tables depend ontologically on hard discs, computer memory, punchcards, datagrams, printouts.

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Molecules and connection tables (1)

Pyridine

This pyridinemolecule here

instance_of pyridine.mol

connectiontable

instance_of

this laptop

depends_on

is_about

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Molecules and connection tables (2)

centaur.mol

connectiontable

instance_of

this laptop

depends_on

is_about

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Names, identifiers and molecules

Cambridge changes are changes in the description of an object.

Example: Becoming the tallest spy in Finland.

All changes are Cambridge changes but not vice versa.

Names, identifiers (InChIs, InChIKeys, SMILES, SMARTS, CAS RNs, Chemspider IDs) and connection tables are not properties but only Cambridge properties.

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Formal derivation

IUPAC nomenclature is based on formal derivation.

These are actions like: removing all hydrogen atoms, removing all substituents, replacing non-carbon atoms in a ring with carbon atoms, replacing multiple bonds with single bonds.

They cannot in general be carried out on real molecules.

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Actual derivation

Contrast the processes which take place in biological systems on natural product molecules:

methylation cyclization condensation and many more…

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ChEBI as will be: automatic classification

Systematic (IUPAC) names for molecules reflect their constitution and therefore their parts.

Therefore it is possible to classify much of a large ontology like ChEBI automatically given specifications for the classes.

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ChEBI as will be: automatic classification

Further reading:

Villanueva-Rosales and Dumontier, OWLED 2007.

Low et al., “OWL-DL Ontology for Classification of Lipids”, this meeting (full paper)

Hastings et al., “Towards Automatic Classification of Entities within the ChEBI Ontology”, this meeting (poster session)

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ChEBI as will be: the problem of natural products

However, whereas systematic names such as benzene, thiophene, pyridine and pentacene unambiguously reflect skeleta…

the same is not true of natural product names. Not all chromomycins, aureolic acids or anthracyclines necessary share the same skeleton.

Some kind of actual derivation relations will be needed here.

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8. The Sequence Ontologywww.sequenceontology.org(thanks to Karen Eilbeck, University of Utah for graphics)

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Background

Contains around 2000 terms describing sequence features such as genes, variations such as chromosomal aberrations, effects of sequence variation and sequence feature attributes.

Used by a large number of model organism databases (Flybase, Wormbase, SGD, TAIR…) for genomic annotation work.

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Sequences not molecules

The Sequence Ontology treats sequences such as genes, exons and introns rather than the molecules (DNA, messenger RNAs) that they depend on.

Working assumption: sequences are a kind of generically-dependent continuant.

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working_draft.obo

http://song.cvs.sourceforge.net/*checkout*/song/ontology/working_draft.obo

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Four kinds of sequence

Biological sequences depend on single molecules used by the replication machinery of the cell. Their sequence information may be stored in databases, memory sticks and so forth.

Biomaterial sequences describe molecules such as plasmids and vectors which are used for genetic engineering.

Experimental features are those information artefacts created by sequencing experiments.

Sequence variations depend on more than one molecule: see next slide.

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Mutual ontological dependence (3)

A deletion depends on two molecules.It has two parts.

The deleted sequence depends on its carrier molecule and the deletion junction on the other.

The deletion junction depends on its carrier molecule and the deleted sequence on the other.

Likewise substitutions, inversions, indels.

SNPs and CNVs depend on many molecules.

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Looking ahead

Robert Hoehndorf, Janet Kelso and Heinrich Herre, “A Formal Ontology of Sequences”, this meeting.

Karen Eilbeck and Chris Mungall, “Evolution of the Sequence Ontology Terms and Relationships”, this meeting.

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9. On drugs

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Huge invisible ontology of drugs (1)

I go into a shop in the High Street, hand over a piece of paper signed by a physician to the woman behind the counter, am told to come back in ten minutes, go off and read the paper in a café, return and am given a white card box containing a piece of paper listing terrible things that may happen to me and a blister package containing small lumps of calcium carbonate.

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Huge invisible ontology of drugs (2)

a shop in the High Street: only some organizations are licensed to sell drugs

a physician: only some people are allowed legally to prescribe drugs

the woman behind the counter: only some people are allowed to prepare drugs

a piece of paper listing terrible things that may happen to me: drugs in most jurisdictions must come with a list of side effects

a blister package: drugs must be packaged so as not to degrade

small lumps of calcium carbonate: the active ingredients must be further packaged as pills, linctus and so forth

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Huge invisible ontology of drugs (3)

Hansard, 19th February 1997

“When I visited the prescription pricing agency in Newcastle, it had a number of interesting examples of items that GPs had prescribed. You, Mr. Deputy Speaker, might consider it unusual if, when you next visited your GP, he prescribed you a pint of Guinness, but it has been done—and done within the letter of the rules. Another example involved a prescription for a Christmas pudding.” The Minister for Health (Mr. Gerald Malone)

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Huge invisible ontology of drugs (4)

Brute objects and processes (X) are those that are mind-independent.

Status functions (Y, BFO: roles) are realized by brute objects X in institutional contexts (C).

Constitutive rule: “X counts as Y in context C”—Searle (1995)

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Huge invisible ontology of drugs (5)

X (a lump of calcium carbonate containing various small organic molecules) counts as Y (a drug) in contexts:

C1 registration by the appropriate authorityC2 being listed in a formularyC3 prescription by a physician or self-medication (for

over-the-counter drugs)C4 preparation according to the standards in a

pharmacopoeia

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Huge invisible ontology of drugs (6)

antitussive disposition= suppresses cough when applied to throat

+cause–intentionality

antitussive agent function= suppresses cough when applied to throat and I want to stop coughing

+cause+intentionality

antitussive drug status function= designed, registered and prescribed to suppress cough when applied to throat and I want to stop

coughing?cause+intentionality+collective intentionality

antitussive placebo function= administered to suppress cough when applied to throat

?cause?intentionality?collective intentionality

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Huge invisible ontology of drugs (7)

Regulative rules vs. constitutive rules

Regulative rules regulate an already existing activity (Searle: driving)

Constitutive rules define an activity (Searle: chess)

Regulative rules, intended to regulate existing practices of medication, quack doctors, midwives and so forth depend on constitutive rules.

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Huge invisible ontology of drugs (8)

See also:

C. Denney et al.,“Creating a Translational Medicine Ontology”,this conference (poster session).

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Thanks to…Alan RuttenbergAnn CopestakeBarry SmithCelia GittermanChris MungallChristi DenneyDavid BardenDuncan HullElena BeisswangerHilary BurchJane LomaxJane RichardsonJanna HastingsJesse StombaughKaren EilbeckKirill Degtyarenko

Luc SchneiderMarcus EnnisMarijke KeetMatthew Batchelor (no relation)Michael AshburnerMichel DumontierNeocles LeontisNico AdamsPeter CorbettRobert HoehndorfRob KnightStefan SchulzSusie StephensSuzanna LewisTom Bittner

Aileen DayJeff WhiteRichard Kidd