1. Discovery Seminar /SS1 – Spring 2009 Translational Pharmacogenomics: Discovering New Genetic Methods to Link Diagnosis and Drug Treatment Ontology: Developing a Systematic Approach to Translational Pharmacogenomic Research Data Collection April 15, 2009
Werner CEUSTERS
Center of Excellence in Bioinformatics and Life Sciences
Ontology Research Group
University at Buffalo, NY, USA

2. What does the word ‘ontology’ mean?
‘Ontology’ is popular
‘Ontology’ in Buffalo is famous

3. Google  ‘define: ontology’:
the study of the broadest range of categories of existence, which also asks questions about the existence of particular kinds of objects;
an explicit representation of the meaning of terms in a vocabulary, and their relationships;
a common vocabulary for describing the concepts that exist in an area of knowledge and the relationships that exist between them;
specification of a conceptualisation of a knowledge domain;
a structured information model of a domain capable of supporting reasoning by human users and software agents;
a data model that represents a set of concepts within a domain and the relationships between those concepts; …

4. One term, many definitions
This raises some questions:
Is it possible for a term to have so many meanings?
Can the authors of these definitions all be right at the same time?
Is it possible for something to which one of these definitions applies to be such that also one or more of the other definitions apply ?

5. Is it possible for a term to have so many meanings?
Merriam-Webster on ‘bank’
Entry term
27 occurrence types
3 different word types
Noun
Verb
Part of compound term }

6. Is it possible for a term to have so many meanings?
Merriam-Webster on ‘bank’

7. Is it possible for a term to have so many meanings?
Merriam-Webster on ‘bank’

8. Is it possible for a term to have so many meanings?
Clearly: yes !
This phenomenon is called:
Homonymy

9. Term Meaning
Meaning-1
Meaning-2
Meaning-3
Term-1
Meaning-4
Term-2
Term-3
Meaning-5
Meaning-6
Meaning-7
This is called:
synonymy

10. Homonymous use of the term ‘ontology’
the study of the broadest range of categories of existence, which also asks questions about the existence of particular kinds of objects;
an explicit representation of the meaning of terms in a vocabulary, and their relationships;
a common vocabulary for describing the concepts that exist in an area of knowledge and the relationships that exist between them;
specification of a conceptualisation of a knowledge domain;
a structured information model of a domain capable of supporting reasoning by human users and software agents;
a data model that represents a set of concepts within a domain and the relationships between those concepts; …

11. Can the authors of these definitions all be right at the same time?
Yes, if we are dealing with a case of homonymy.

12. Is it possible for something to which one of these definitions applies to be such that also one or more of the other definitions apply ? ?
information model
is an
data model
representation
is a
is a
‘that’ thing
is a
vocabulary
is a
is a
specification
study

13. Is it possible for something to which one of these definitions applies to be such that also one or more of the other definitions apply ?
Not for all !
Only for some

14. Homonymous use of the term ‘ontology’: at least one clear cut distinction
the study of the broadest range of categories of existence, which also asks questions about the existence of particular kinds of objects;
an explicit representation of the meaning of terms in a vocabulary, and their relationships;
a common vocabulary for describing the concepts that exist in an area of knowledge and the relationships that exist between them;
specification of a conceptualisation of a knowledge domain;
a structured information model of a domain capable of supporting reasoning by human users and software agents;
a data model that represents a set of concepts within a domain and the relationships between those concepts; …

15. ‘Ontology’ as the study of what exists
Key questions:
What exists ?
How do things that exist relate to each other ?
Some hypotheses:
An external reality, time, space
Ideas, concepts
Particulars, universals, objects, processes
God
Ontologists from distinct ‘schools’ differ in opinion about the existence of some of the above:
Realism, nominalism, conceptualism, monism, …

16. An ontology as a representation
Key question: of what ?
Terms  WordNet, MedDRA, RxNORM
Concepts  the majority of ‘ontologies’
But … overwhelming lack of clarity about what ‘concepts’ are:
meaning shared in common by synonymous terms ?
idea shared in common in the minds of those who use these terms ?
unit of knowledge describing meanings ?
feature or property shared in common by entities in the world ?
Universals  Realism-based ontology

17. Ontology & Data

18. Current mainstream thinking
data
information
knowledge
wisdom
Reality
What is there on the side of the patient

19. Example of data generation at the bench
Proteolysis: treat with trypsin
Separation technique I: chromatography like lectin affinity chromatography
From PNGase F: we get fractions that contain peptides and glycans – we focus only on peptides.
Separation technique II: chromatography like reverse phase chromatography
Amit Sheth. Semantic Web Technology in Support of Bioinformatics for Glycan Expression. W3C workshop on Semantic Web for Life Sciences, October 28, 2004, Cambridge MA

20. Semantic annotation of Scientific Data
Salient point: one ms/ms data element is annotated (mapped to) with multiple concepts in the ontology. Using ontological concepts enables the following:
Comparison of data generated from heterogeneous sources.
Interoperability of heterogeneously generated data
Discovery of a relationship through a chain of mappings/connections.
Hypothesis formulation.
Amit Sheth. Semantic Web Technology in Support of Bioinformatics for Glycan Expression. W3C workshop on Semantic Web for Life Sciences, October 28, 2004, Cambridge MA

21. Ontologies for annotating data
Snomed-CT view on
Serum hepatitis

22. Zoom on Hepatitis B with hepatitis D superinfection
Relationships to other concepts:
Causative agent Hepatitis D virus (organism)
Finding site Liver structure (body structure)
Causative agent Hepatitis B virus (organism)
Associated morphology Inflammation (morphologic abnormality)
Information about this concept:
PREFERRED_TERM Hepatitis B with hepatitis D superinfection
TERM Hepatitis B with delta agent coinfection
TERM Hepatitis B with delta agent superinfection
TERM Hepatitis B with hepatitis D superinfection
TERM Hepatitis D infection
TERM Viral hepatitis B with delta agent superinfection
TERM Viral hepatitis B with hepatitis D superinfection
Comments ?

23. SNOMED-CT generated taxonomy (partial)
General finding of abdomen (finding)
Viscus structure finding (finding)
Abdominal organ finding (finding)
Disorder of abdomen (disorder)
Liver finding (finding)
Disorder of liver (disorder)
Infectious disease of abdomen (disorder)
Inflammatory disease of liver (disorder)
Viral hepatitis (disorder)
Is a
Comments ?
Type B viral hepatitis (disorder)
Hepatitis B with hepatitis D superinfection (disorder)

24. Problem with mainstream thinking:
data
information
knowledge
wisdom
Reality
What is there on the side of the patient
Questions not often enough asked:
What part of our data corresponds with something out there in reality ?
What part of reality is not captured by our data, but should because it is relevant ?

25. Terminological versus Ontological approach
The terminologist defines:
‘a clinical drug is a pharmaceutical product given to (or taken by) a patient with a therapeutic or diagnostic intent’. (RxNorm)
The ontologist thinks:
Does ‘given’ includes ‘prescribed’?
Is manufactured with the intent to … not sufficient?
Are newly marketed products – available in the pharmacy, but not yet prescribed – not clinical drugs?
Are products stolen from a pharmacy not clinical drugs?
What about such products taken by persons that are not patients?
e.g. children mistaking tablets for candies.

26. The solution: the RIGHT sort of ontology Realism-based ontology

27. A multi-disciplinary approach to ontology
In philosophy:
Ontology (no plural) is the study of what entities exist and how they relate to each other;
In computer science and (biomedical informatics) applications:
An ontology (plural: ontologies) is a shared and agreed upon conceptualization of a domain;
Our ‘realist’ view within the Ontology Research Group combines the two:
We use realism, a specific theory of ontology, as the basis for building high quality ontologies, using reality as benchmark.

28. Realist ontology: assumes three levels of reality
The world exists ‘as it is’ prior to a cognitive agent’s perception thereof;
Cognitive agents build up ‘in their minds’ cognitive representations of the world;
To make these representations publicly accessible in some enduring fashion, they create representational artifacts that are fixed in some medium.
Smith B, Kusnierczyk W, Schober D, Ceusters W. Towards a Reference Terminology for Ontology Research and Development in the Biomedical Domain. Proceedings of KR-MED 2006, November 8, 2006, Baltimore MD, USA

29. Three levels of reality
The world exists ‘as it is’ prior to a cognitive agent’s perception thereof;
Smith B, Kusnierczyk W, Schober D, Ceusters W. Towards a Reference Terminology for Ontology Research and Development in the Biomedical Domain. Proceedings of KR-MED 2006, November 8, 2006, Baltimore MD, USA

30. Reality exists before any observation

31. Reality exists before any observation
Humans had a brain well before they knew they had one.
Trees were green before humans started to use the word “green”. R
And also most structures in reality are there in advance.

32. Three levels of reality
The world exists ‘as it is’ prior to a cognitive agent’s perception thereof;
Cognitive agents build up ‘in their minds’ cognitive representations of the world;
Smith B, Kusnierczyk W, Schober D, Ceusters W. Towards a Reference Terminology for Ontology Research and Development in the Biomedical Domain. Proceedings of KR-MED 2006, November 8, 2006, Baltimore MD, USA

33. B
The cognitive agent acknowledges the existence of some Portion of Reality (POR) R

34. Some portions of realityB
Some portions of reality
escape his attention. R

35. Three levels of reality
The world exists ‘as it is’ prior to a cognitive agent’s perception thereof;
Cognitive agents build up ‘in their minds’ cognitive representations of the world;
To make these representations publicly accessible in some enduring fashion, they create representational artifacts that are fixed in some medium.
Smith B, Kusnierczyk W, Schober D, Ceusters W. Towards a Reference Terminology for Ontology Research and Development in the Biomedical Domain. Proceedings of KR-MED 2006, November 8, 2006, Baltimore MD, USA

36. He represents only what he considers relevantB
RU1B1
Both RU1B1 and RU1O1 are representational units referring to #1;
RU1O1 is NOT a representation of RU1B1;
RU1O1 is created through concretization of RU1B1 in some medium.
RU1O1 O #1 R

37. The three levels applied to medication management
Generic
Specific
3. Representation
‘person’
‘drug’
‘penicillin’
‘W. Ceusters’
‘my pneumonia’
2. Beliefs (knowledge)
CONTRA-INDICATION
INDICATION
my doctor’s
work plan
diagnosis 1.
First-order reality me
my toxic reaction
to penicillin
my bronchitis
my doctor
my pharmacist’s computer
MOLECULE
PERSON
DISEASE
PATHOLOGICAL
STRUCTURE
PORTION OF
PENICILLIN
DRUG

38. A realism-based ontology
is a representation of some pre-existing domain of reality which
(1) reflects the properties of the objects within its domain in such a way that there obtains a systematic correlation between reality and the representation itself,
(2) is intelligible to a domain expert
(3) is formalized in a way that allows it to support automatic information processing

39. Our foundations: Basic Formal Ontology
An ontology which is
Realist:
Fallibilist:
Perspectivalist:
Adequatist:
There is only one reality and its constituents exist independently of our (linguistic, conceptual, theoretical, cultural) representations thereof,
theories and classifications can be subject to revision,
there exists a plurality of alternative, equally legitimate perspectives on that one reality
these alternative views are not reducible to any single basic view.

40. Basic Formal Ontology The world consists of entities that are
Either particulars or universals;
Either occurrents or continuants;
Either dependent or independent; and,
relationships between these entities of the form
<particular , universal> e.g. is-instance-of,
<particular , particular> e.g. is-member-of
<universal , universal> e.g. isa (is-subtype-of)
Smith B, Kusnierczyk W, Schober D, Ceusters W. Towards a Reference Terminology for Ontology Research and Development in the Biomedical Domain. Proceedings of KR-MED 2006, November 8, 2006, Baltimore MD, USA

41. Accept that everything may change:
changes in the underlying reality:
Particulars and universals come and go
changes in our (scientific) understanding:
The planet Vulcan does not exist
reassessments of what is considered to be relevant for inclusion (notion of purpose).
encoding mistakes introduced during data entry or ontology development.

42. Example: continuants preserve identity while changing
human
being
living
creature me
child
Instance-of
in 1960
adult me
Instance-of
since 1980
caterpillar
butterfly
animal

43. Are we done ?
Is an accurate coding system, classification system, terminology, ontology, …, a necessary and sufficient condition for obtaining “better” information ?
Necessary: yes !
Sufficient: no !

44. Using codes does not prevent ambiguities as to what is described: how many disorders are listed?
The same type of location code used
in relation to three different events might or might not refer to the same
location.
5572
04/07/1990
closed fracture of shaft of femur
Fracture, closed, spiral
12/07/1990
Accident in public building (supermarket)
79001
Essential hypertension
0939
24/12/1991
benign polyp of biliary tract
2309
21/03/1992
47804
03/04/1993
Other lesion on other specified region
17/05/1993
298
22/08/1993
Closed fracture of radial head
01/04/1997
PtID
Date
ObsCode
Narrative
20/12/1998
malignant polyp of biliary tract
Three references of hypertension for the same
patient denote three times the same disease.
If the same fracture code is used for the same patient on different dates, then these codes might or might not refer to the same fracture.
If two different fracture codes are used in relation to observations made on the same day for the same patient, they might refer to the same fracture
If two different tumor codes are used
in relation to observations made on different
dates for the same patient,
they may still refer to the same tumor.
The same fracture code used in relation
to two different patients can not refer to
the same fracure.

45. Consequences Very difficult to:
Count the number of (numerically) different diseases
Bad statistics on incidence, prevalence, ...
Bad basis for health cost containment
Relate (numerically the same or different) causal factors to disorders:
Dangerous public places (specific work floors, swimming pools),
dogs with rabies,
HIV contaminated blood from donors,
food from unhygienic source, ...
Hampers prevention
...

46. Referent Tracking: Being clear what the data are about !

47. Now! That should clear up a few things around here !
Purpose:
explicit reference to the concrete individual entities relevant to the accurate description of each patient’s condition, therapies, outcomes, ...
Ceusters W, Smith B. Strategies for Referent Tracking in Electronic Health Records. J Biomed Inform Jun;39(3):

48. Referent Tracking: Numbers instead of words!
Method:
Introduce an Instance Unique Identifier (IUI) for each relevant particular (individual) entity
235 78
5678
321
322
666
427
Ceusters W, Smith B. Strategies for Referent Tracking in Electronic Health Records. J Biomed Inform Jun;39(3):

49. The principle of Referent Tracking
‘John Doe’s
liver
tumor
was treated
with
RPCI’s
irradiation device’
‘John Doe’s ‘John Smith’s
liver liver
tumor tumor
was treated was treated
with with
RPCI’s RPCI’s
irradiation device’ irradiation device’ #1 #3 #2 #4 #5 #6
instance-of at t1
inst-of
at t2
treating
person
liver
tumor
clinic
device
#10
#30
#20
#40 #5 #6

50. EHR – Ontology “collaboration”

51. Advantage: better reality representation
5572
04/07/1990
closed fracture of shaft of femur
Fracture, closed, spiral
12/07/1990
Accident in public building (supermarket)
79001
Essential hypertension
0939
24/12/1991
benign polyp of biliary tract
2309
21/03/1992
47804
03/04/1993
Other lesion on other specified region
17/05/1993
298
22/08/1993
Closed fracture of radial head
01/04/1997
PtID
Date
ObsCode
Narrative
20/12/1998
malignant polyp of biliary tract
IUI-001
IUI-003
IUI-004
IUI-005
IUI-007
IUI-002
IUI-012
IUI-006
7 distinct disorders

52. Did you pay attention ? A final test
In John Smith’s EHR:
At t1: “male” at t2: “female”
What are the possibilities ?
Change in reality:
transgender surgery
change in legal self-identification
Change in understanding: it was female from the very beginning but interpreted wrongly
Correction of data entry mistake: it was understood as male, but wrongly transcribed
(Change in meaning of the words)

53. Conclusion (1) Building high quality ontologies is hard.
Not everybody has the right skills
Experts in driving cars are not necessarily experts in car mechanics (and the other way round).
Ontologies should represent the state of the art in a domain, i.e. the science.
Science is not a matter of consensus or democracy
Natural language relates more to how humans talk about reality or perceive it, than to how reality is structured.
No high quality ontology without the involvement of ontologists.

54. Conclusion (2)
Realist ontology is a powerful QA tool for building high quality ontologies AND high quality databases;
Referent tracking, based on realist ontology, is a means to remove the ambiguity in data that cannot be solved by realist ontology alone;
It is a form of “adult” annotation
Application of RT requires a globally accessible repository
Adds another level to interoperability.
The use of “meaningless” IUIs allows very strict safety and security measures to be implemented.

55. Goal: new form of Evidence Based Medicine
Now:
Decisions based on (motivated/justified by) the outcomes of (reproducable) results of well-designed studies
Guidelines and protocols
Evidence is hard to get, takes time to accumulate.
Future:
Each discovered fact or expressed belief should instantly become available as contributing to ‘evidence’, wherever its description is generated.
Data ‘eternally’ reusable independent of the purpose for which they have been generated.