MHI501 – Introduction to Health Informatics Ontology and Data Abstraction SUNY at Buffalo - November 14, 2012 Werner CEUSTERS Center of Excellence in Bioinformatics and Life Sciences Ontology Research Group University at Buffalo, NY, USA http://www.org.buffalo.edu/RTU

Short personal history 1959 - 2012 1977 2006 Short personal history 2004 1989 1992 2002 1995 1998 1993

Ontological Realism

‘Ontology’ In philosophy: Ontology (no plural) is the study of what entities exist and how they relate to each other; by some philosophers taken to be synonymous with ‘metaphysics’ while others draw distinctions in many distinct ways (the distinctions being irrelevant for this talk), but almost agreeing on the following classification: metaphysics general metaphysics ontology special metaphysics distinct from ‘epistemology’ which is the study of how we can come to know about what exists.

Some MDs got it quite early… ‘We have to thank the metaphysicians for, if not explaining many things, at least giving us useful terms under which discussions may be carried on.’ Although: ‘Why should he, why should man, ever have been born, if to be born simply means to begin with his first breath a struggle against death?’ question in the realm of special metaphysics. Bryce PH. Ontology in relation to preventive medicine. Am J Public Health (N Y). 1912 Jan;2(1):32-3.

… and worse ‘If he thinks ontologically at all, he can no longer imagine human life only an accident, flotsam and jetsam on a turbulent and never-resting sea, but rather that "being" is an emanation from the Infinite Consciousness which makes the ego in us the occasion for the realization, by each - even in the smallest degree - that he is a constituent atom in Universal Mind, wherein is the definite idea illustrating not alone a common humanity, but also the manifestation of a universal good’. here is not an ontological issue, but a psychiatric one. Bryce PH. Ontology in relation to preventive medicine. Am J Public Health (N Y). 1912 Jan;2(1):32-3.

A legitimate ontological question Do mental illnesses / disorders / diseases exist? The answer can, arguably, be ‘no’: if one does not subscribe to the mind-brain dichotomy: no mind  nothing mental if one does, but also entertains a strong body-related interpretation of what is an illness, disorder, disease: STEDMAN (27th edition): an interruption, cessation, or disorder of body function, system, or organ. DORLAND: any deviation from or interruption of the normal structure or function of a part, organ, or system of the body as manifested by characteristic symptoms and signs; WHO: an interconnected set of one or more dysfunctions in one or more body parts, linking to underling genetic factors and to interacting environmental factors and possibly: to a pattern or patterns of response to interventions. and under the same conditions: ‘yes’: ‘mental disorder’ would be synonymous with ‘brain disorder’

A legitimate ontological question Do mental illnesses / disorders / diseases exist? The answer can, arguably, be ‘no’: if one does not subscribe to the mind-brain dichotomy: no mind  nothing mental if one does, but also entertains a strong body-related interpretation of what is an illness, disorder, disease: STEDMAN (27th edition): an interruption, cessation, or disorder of body function, system, or organ. DORLAND: any deviation from or interruption of the normal structure or function of a part, organ, or system of the body as manifested by characteristic symptoms and signs; WHO: an interconnected set of one or more dysfunctions in one or more body parts, linking to underling genetic factors and to interacting environmental factors and possibly: to a pattern or patterns of response to interventions. and under the same conditions: ‘yes’: ‘mental disorder’ would be synonymous with ‘brain disorder’

A better phrased ontological question Do mental illnesses / disorders / diseases exist? What, if anything at all, do the terms ‘mental illness’, ‘mental disorder’ , … denote?

A better phrased ontological question Do mental illnesses / disorders / diseases exist? What, if anything at all, do the terms ‘mental illness’, ‘mental disorder’ , … denote? terms first-order reality ‘mental disorder’ ‘person’ ‘UB’

This is distinct from terminological questions What does ‘mental disorder’ mean ?

This is distinct from terminological questions What does ‘mental disorder’ mean ? meaning of ‘mental disorder’ ‘mental disorder’

Terminological approaches raise further questions Terminological question: What does ‘mental disorder’ mean ? What are meanings? meaning of ‘mental disorder’ Do meanings denote? How are these related? ‘mental disorder’

The half-baked semantic/semiotic triangle does not provide any good answers despite its overwhelming popularity meaning of ‘mental disorder’ Concept ‘mental disorder’ Symbol / Sign / Term Thing / Referent

The semantic triangle works sometimes fine Ludwig van Beethoven that great German composer that became deaf … term concept referent ‘Beethoven’

The semantic triangle works sometimes fine Beethoven’s symphony dedicated to Bonaparte the symphony played after the Munich Olympics massacre … term concept referent ‘Eroica’ ‘Beethoven's Symphony No. 3’ ‘Beethoven's Opus 55’

Sometimes the semantic triangle fails the symphony Beethoven wrote after the tenth … term concept referent ‘Beethoven's Symphony No. 11’

Sometimes the semantic triangle fails the symphony Beethoven wrote after the tenth … term concept referent some hold this term has meaning ‘Beethoven's Symphony No. 11’

Sometimes the semantic triangle fails the one assembled by Barry Cooper from fragmentary sketches Beethoven’s hypothetical symphony … term concept referent ‘Beethoven's Symphony No. 10’

Prehistoric ‘psychiatry’: drapetomania disease which causes slaves to suffer from an unexplainable propensity to run away … term concept referent painting by Eastman Johnson. A Ride for Liberty: The Fugitive Slaves. 1860. ‘drapetomania’

Some etiologic and diagnostic reflections

The North’s ‘Effugium Discipulorum’

The questions the triangle raises become trickier Beethoven’s 10th symphony a symphony ? Beethoven’s 10th symphony a hypothetical symphony ? a hypothetical symphony a symphony ? In medicine, is … a prevented abortion an abortion ? an absent nipple a nipple ?

Ontology should give the answer In philosophy: Ontology (no plural) is the study of what entities exist and how they relate to each other;

Unfortunately, ‘ontology’ denotes ambiguously In philosophy: Ontology (no plural) is the study of what entities exist and how they relate to each other; In computer science and many biomedical informatics applications: An ontology (plural: ontologies) is a shared and agreed upon conceptualization of a domain;

Ontologies and Software Ontology Authoring Tools Reasoners create Computer Science approach to ‘ontology’ Semantic Applications use Domain ‘Philosophical’ approach to ontology

Ontology in CS: relates concepts drapetomania How concepts are / can be related slave running away mental disorder propensity

Three, thus far unrelated, ways of relating drapetomania How concepts are / can be related slave running away How terms are related How referents are related mental disorder propensity

Ontology as it should be done In philosophy: Ontology (no plural) is the study of what entities exist and how they relate to each other; In computer science and many biomedical informatics applications: An ontology (plural: ontologies) is a shared and agreed upon conceptualization of a domain; The realist view within the Ontology Research Group combines the two: We use Ontological Realism, a specific methodology that uses ontology as the basis for building high quality ontologies, using reality as benchmark.

No serious scholar should work with ‘concepts’

Observations and similarities

Observations and similarities Are these pictures of concepts or of horses ? Is this a sensible question: ‘What concepts have tails and do …?’

Observations and similarities Are these pictures of concepts? If concepts are in brains, that must be awfully big brains! Are these pictures of anything at all?

Slow penetration of the idea …

More serious scholars become convinced … what is a concept description a description of?

but Kantians will never …

The basis of Ontological Realism There is an external reality which is ‘objectively’ the way it is; That reality is accessible to us; We build in our brains cognitive representations of reality; We communicate with others about what is there, and what we believe there is there. 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, Biomedical Ontology in Action, November 8, 2006, Baltimore MD, USA

Ontological Realism makes three crucial distinctions Between data and what data are about; Between continuants and occurrents; Between what is generic and what is specific. Smith B, Ceusters W. Ontological Realism as a Methodology for Coordinated Evolution of Scientific Ontologies. Applied Ontology, 2010.

Linguistic representations about (1), (2) or (3) Clinicians’ beliefs about (1) Representations First Order Reality Entities (particular or generic) with objective existence which are not about anything L1-

A crucial distinction: data and what they are about organization First- Order Reality Representation is about model development observation & measurement further R&D (instrument and study optimization) Δ = outcome use add Generic beliefs verify application

Ontological Realism makes crucial distinctions Between data and what data are about: Level 1 entities (L1): everything what exists or existed some are referents (‘are’ used informally) some are L2, some are L3, none are L2 and L3 Level 2 entities (L2): beliefs all are L1 some are about other L1-entities but none about themselves Level 3 entities (L3): expressions all are L1, none are L2 some are about other L1-entities and some about themselves

Ontological Realism makes crucial distinctions Between data and what data are about; Between continuants and occurrents: obvious differences: a person versus his life a disease versus its course space versus time more subtle differences: observation (data-element) versus observing diagnosis versus making a diagnosis message versus transmitting a message

Is depression considered a continuant or occurrent? What do we mean by ‘depression’ ? The name of some disease ?  continuant A bout of feelings of being worth nothing, sobbing, appearance of suicidal thoughts, …  occurrent

Between ‘generic’ and ‘specific’ Basic Formal Ontology Generic Specific Referent Tracking Specific L3. Representation ‘person’ ‘drug’ ‘insulin’ ‘W. Ceusters’ ‘my sugar’ L2. Beliefs (knowledge) DIAGNOSIS INDICATION my doctor’s work plan diagnosis L1. First-order reality MOLECULE PERSON DISEASE PATHOLOGICAL STRUCTURE PORTION OF INSULIN DRUG me my blood glucose level my NIDDM my doctor my doctor’s computer

Basic Formal Ontology: an upper ontology based on Ontological Realism

A useful parallel: Alberti’s grid reality Ontological theory representation

Basic components of the BFO view on the world 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, lacks <particular , particular> e.g. is-member-of, is-part-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

The example to work (partially) out: ‘walking’ process living creature function Is_a Is_a leg Is_a Instance-of at t human being leg moving walking Instance-of at t Instance-of Instance-of at t to make me walk this leg moving Has-function at t Has- Participant at t Instance-of part-of at t part-of my left leg Is-realized- In at t me this walking Has-participant at t2

Particulars 1 Individual entities that carry identity and preserve their identity over time me this walking my left leg this leg moving to make me walk

Universals 1 human being living creature walking leg moving leg function process Entities which exist “in” the particulars amongst which there is a relation of similarity not found with other particulars

Particulars versus Universals for every universal there is or has been at least one instance some universal instanceOf … entities on either site cannot ‘cross’ this boundary every particular is an instance of at least one universal some particular

Particulars and Universals 1 human being living creature walking leg moving leg function process Instance-of at t me this walking my left leg this leg moving to make me walk

The importance of temporal indexing benign tumor malignant tumor stomach instanceOf at t2 instanceOf at t1 instanceOf at t2 instanceOf at t1 partOf at t1 this-4 this-1’s stomach partOf at t2

Continuants and Occurrents 2 human being living creature walking leg moving leg function process Instance-of at t me this walking my left leg this leg moving to make me walk

Continuants 2 Continuants are entities which endure (=continue to exist) while undergoing different sorts of changes, including changes of place. While they exist, they exist “in total”. function leg Instance-of at t human being Instance-of at t Instance-of at t to make me walk my left leg me

Continuants preserve identity while changing 2 t human being living creature me child Instance-of in 1960 adult me Instance-of since 1980 caterpillar butterfly animal

Occurrents are changes. 2 Occurrents are changes. Occurrents unfold themselves during temporal phases. At any point in time, they exist only in part. leg moving walking Instance-of this leg moving Instance-of this walking

Independent versus dependent 3 me this walking human being Instance-of at t living creature Is_a walking my left leg this leg moving leg moving leg to make me walk function process

Independent versus dependent 3 Independent entities Do not require any other entity to exist to enable their own existence Dependent entities Require the existence of another entity for their existence to make me walk this leg moving my left leg me this walking

Independent versus dependent 3 Independent entities Do not require any other entity to exist to enable their own existence Dependent entities Require the existence of another entity for their existence to make me walk this leg moving Independent continuants Dependent continuants Occurrents (are all dependent) my left leg me this walking

Dependent continuants 3 Realized Quality: redness (of blood) Realizable Function: to flex (of knee joint) Role: student Power: boss Disposition: brittleness (of a bone)

Dependent continuants 3 continuants occurrents Realized Quality: redness (of blood) Realizable Function: to flex (of knee joint) Role: student Power: boss Disposition: brittleness (of a bone) Realizations flexing studying ordering breaking

A disposition is a realizable entity which is such that (1) if it ceases to exist, then its bearer is physically changed, (2) whose realization occurs, in virtue of the bearer’s physical make-up, when this bearer is in some special physical circumstances delete ‘and’ after ‘changed,’

PtoU: instanceOf, lacks, Sorts of relations Unconstrained reasoning UtoU: isa, partOf, … U1 U2 PtoU: instanceOf, lacks, denotes… OWL-DL reasoning PtoP: partOf, denotes, subclassOf,… P1 P2

.... ..... ....... Relation Ontology universals particulars Continuant has_participant Continuant Occurrent process, event isa isa Independent Continuant ~ thing Dependent Continuant inheres_in instance_of (at t) .... ..... ....... particulars

Transformation Derivation continuation fusion fission

Part-of different for continuants and occurrents process living creature Is_a Is_a leg Is_a human being leg moving walking Instance-of at t Instance-of Instance-of at t this leg moving part-of Instance-of part-of at t my left leg me this walking

Part-of can be generalized, … with care ! Horse legs are not parts of human beings Amputated legs are not parts of human beings ‘Canonical leg is part of canonical human being’, but…, there are (very likely) no such particulars … living creature Part-of ? leg Is_a human being Instance-of at t Instance-of at t part-of at t my left leg me

The essential pieces some temporal region some quality my life dependent continuant material object spacetime region spatial region temporal region history instanceOf t t t participantOf at t occupies some temporal region some quality my life my 4D STR projectsOn me … at t projectsOn at t some spatial region located-in at t

Biomedical Applications of Ontological Realism

a modular annotation catalogue of English phrases The OBO Foundry a family of interoperable biomedical reference ontologies built around the Gene Ontology (GO) at its core and using the same principles as the GO a modular annotation catalogue of English phrases each module created by experts from the corresponding scientific community http://obofoundry.org 73

OBO Website

OBO Foundry ontologies in BFO-dress RELATION TO TIME GRANULARITY CONTINUANT OCCURRENT INDEPENDENT DEPENDENT ORGAN AND ORGANISM Organism (NCBI Taxonomy) Anatomical Entity (FMA, CARO) Organ Function (FMP, CPRO) Phenotypic Quality (PaTO) Biological Process (GO) CELL AND CELLULAR COMPONENT Cell (CL) Cellular Component (FMA, GO) Cellular Function MOLECULE Molecule (ChEBI, SO, RnaO, PrO) Molecular Function Molecular Process 76 76

Ontology of General Medical Science First ontology in which the L1/L2/L3 distinction is used Scheuermann R, Ceusters W, Smith B. Toward an Ontological Treatment of Disease and Diagnosis. 2009 AMIA Summit on Translational Bioinformatics, San Francisco, California, March 15-17, 2009;: 116-120. Omnipress ISBN:0-9647743-7-2

Goal of OGMS To be a consistent, logical and extensible framework (ontology) for the representation of features of disease clinical processes results

Clarity about: disease etiology and progression Motivation Clarity about: disease etiology and progression disease and the diagnostic process phenotype and signs/symptoms

Big Picture

abnormal bodily features Approach a disease is a disposition rooted in a physical disorder in the organism and realized in pathological processes. produces bears realized_in etiological process disorder disposition pathological process font was too small, color inside green boxes was hardly readable produces diagnosis interpretive process signs & symptoms abnormal bodily features produces participates_in recognized_as

No conflation of diagnosis, disease, and disorder The diagnosis is here The disorder is there The disease is there

Cirrhosis - environmental exposure Etiological process - phenobarbitol-induced hepatic cell death produces Disorder - necrotic liver bears Disposition (disease) - cirrhosis realized_in Pathological process - abnormal tissue repair with cell proliferation and fibrosis that exceed a certain threshold; hypoxia-induced cell death Abnormal bodily features recognized_as Symptoms - fatigue, anorexia Signs - jaundice, splenomegaly Symptoms & Signs used_in Interpretive process produces Hypothesis - rule out cirrhosis suggests Laboratory tests Test results – documentation of elevated liver enzymes in serum Result - diagnosis that patient X has a disorder that bears the disease cirrhosis

Foundational Terms (1) Disorder =def. – A causally linked combination of physical components that is (a) clinically abnormal and (b) maximal, in the sense that it is not a part of some larger such combination. Pathological Process =def. – A bodily process that is a manifestation of a disorder and is clinically abnormal.

Clinically abnormal - something is clinically abnormal if: (1) is not part of the life plan for an organism of the relevant type (unlike aging or pregnancy), (2) is causally linked to an elevated risk either of pain or other feelings of illness, or of death or dysfunction, and (3) is such that the elevated risk exceeds a certain threshold level.

Foundational Terms (2) Disorder =def. – A causally linked combination of physical components that is (a) clinically abnormal and (b) maximal, in the sense that it is not a part of some larger such combination. Pathological Process =def. – A bodily process that is a manifestation of a disorder and is clinically abnormal. Disease =def. – A disposition (i) to undergo pathological processes that (ii) exists in an organism because of one or more disorders in that organism.

Diagnosis Clinical Picture =def. – A representation of a clinical phenotype that is inferred from the combination of laboratory, image and clinical findings about a given patient. Diagnosis =def. – A conclusion of an interpretive process that has as input a clinical picture of a given patient and as output an assertion to the effect that the patient has a disease of such and such a type.

A well-formed diagnosis of ‘pneumococal pneumonia’ A configuration of representational units; Believed to mirror the person’s disease; Believed to mirror the disease’s cause; Refers to the universal of which the disease is believed to be an instance. Disease isa Pneumococcal pneumonia Instance-of at t1 #78 John’s relevant portion of pneumococs #56 John’s Pneumonia caused by

Some motivations and consequences (1) No use of debatable or ambiguous notions such as proposition, statement, assertion, fact, ... The same diagnosis can be expressed in various forms. Disease isa caused by Instance-of at t1 #56 #78 Pneumonia caused by Portion of pneumococs #56 #78 Pneumococcal pneumonia caused by Instance-of at t1

Some motivations and consequences (2) A diagnosis can be of level 2 or level 3, i.e. either in the mind of a cognitive agent, or in some physical form. Allows for a clean interpretation of assertions of the sort ‘these patients have the same diagnosis’:  The configuration of representational units is such that the parts which do not refer to the particulars related to the respective patients, refer to the same portion of reality.

Distinct but similar diagnoses Pneumococcal pneumonia Instance-of at t1 Instance-of at t2 #78 John’s portion of pneumococs #56 John’s Pneumonia #956 Bob’s pneumonia #2087 Bob’s portion of pneumococs caused by caused by

Some motivations and consequences (3) Allows evenly clean interpretations for the wealth of ‘modified’ diagnoses: With respect to the author of the representation: ‘nursing diagnosis’, ‘referral diagnosis’ When created: ‘post-operative diagnosis’, ‘admitting diagnosis’, ‘final diagnosis’ Degree of belief: ‘uncertain diagnosis’, ‘preliminary diagnosis’

Adverse events

A bad definition of adverse event an ‘incident [that] occurred during the past and [is] documented in a database of adverse events’ Stefano Arici, Paolo Bertele. ReMINE Deliverable D4.1 – RAPS Taxonomy: approach and definition. V1.0 (Final) August 8, 2008. (p21) … which is a ‘occurrent’ - ibidem (p26) … ‘that occurs to a patient’ - ibidem (p23) an expectation of some future happening that can be prevented - ibidem (p23)

Terminologists agree, ontologists think … Can something which is an incident be at the same time an expectation ? Can something which is an incident a time t, later become an adverse event simply because it [?] has been entered in a database ? Can adverse events really occur in software ? …

Intermediate conclusion The ReMINE taxonomy (and all concept-based terminologies and ‘ontologies’ in general) provides a distorted view of reality. For good reasons: the distortion is such that it reflects a pragmatic view on what is relevant for the purposes it is designed, it does away with complexities that do not help human beings in doing a better job. But with some negative consequences: reusability out of the ReMINE context is hampered, integration with other descriptive systems becomes cumbersome, and advanced reasoning turns out to be impossible.

Using the 3 levels and the particular/universal/class distinctions #1: an incident that happened in the past; Level 2: #2: the interpretation by some cognitive agent that #1 is an adverse event; #3: the expectation by some cognitive agent that similar incidents might happen in the future; Level 3: #4: an entry in the adverse event database concerning #1; #5: an entry in some other system about #3 for mitigation or prevention purposes.

Allows appropriate error management Some possibilities: #1with unjustified absence of #2: #1 was not perceived at all, or not assessed as being an adverse event Unjustified presence of #2: There was no #1 at all, or #1 was not an adverse event Unjustified absence of #4 Same reasons as under (1) above Justified presence of #2 but not reported in the database … Ceusters W, Smith B. A Realism-Based Approach to the Evolution of Biomedical Ontologies. Proceedings of AMIA 2006, Washington DC, 2006;:121-125.

Part of the ReMINE Domain Ontology

Higher order logical representation an incident (#1) that happened at time t2 to a patient (#2) after some intervention (#3 at t1) is judged at t3 to be an adverse event, thereby giving rise to a belief (#4) about #1 on the part of some person (#5, a caregiver as of time t6). This requires the introduction (at t4) of an entry (#6) in the adverse event database (#7, installed at t0).

Advantages Synchronisation of two distinct representations of the same reality: taxonomies: user-oriented view data annotation Domain ontology compatible with OBO-Foundry ontologies: no overlap, easier to re-use. Not only tracking of incidents, but also: how well individual clinicians and organizations manage adverse events, how well one learns from past experiences. ontologies: realism-based view unconstrained reasoning

Use in study design and data collection

Typical approach (1) Building a huge matrix with patient cases in one dimension and patient characteristics in the other dimension Cases Characteristics ch1 ch2 ch3 ch4 ch5 ch6 ... case1   case2 case3 case4 case5 case6 say where the word ‘characteristics’ comes from

Typical approach (2) Use statistical correlation techniques to find associations between characteristics and (dis)similarities between cases Cases Characteristics ch1 ch2 ch3 ch4 ch5 ch6 ... case1   case2 case3 case4 case5 case6

Fundamental questions What is a characteristic ? What (sorts of) characteristics (relevant for, e.g., psychiatry) go in here ? How can we make distinct studies comparable? Because such matrices tend to become huge, how can we make analysis feasible ? How can we make results re-usable?

Q1: what is a characteristic ? it is for sure not a category entities can belong to: there is no natural class of entity for which the name ‘characteristic’ would be appropriate; there is also no particular entity that you could point to and state ‘that over there is the only existing characteristic’ thus: there are no characteristics, there is just the term ‘characteristic’ which is used to describe that some entities are (acknowledged to be) in some way of interest in some context and for some purpose.

This requires rephrasing Q2 What (sorts of) characteristics (relevant for psychiatry) go in here? What entities described as being characteristic for psychiatric purposes should be represented here? what does ‘here’ mean?

Examples Universals Particulars Independent Continuant Dependent Occurrent Independent Dependent Universals Particulars portion of C17H19ClN2S.HCl human being gene portion of chlorpromazine in this tablet me the HTR2A gene on chromosome 13 of the most frontal cell in the tip of my nose shape temperature length the shape of my nose the temperature of the chlorpromazine tablet in front of me the length of that HTR21 gene change in shape motion rise in temperature unfolding of a DNA molecule the circulation of a chlorpromazine molecule in my bloodstream the rise of my body temperature while teaching this seminar

Q3: How can we make distinct studies comparable? Map any characteristic used to relevant, standard and high quality ontologies

The positive effects of appropriate mappings

The positive effects of appropriate mappings identification of ontological relations prior to statistical correlation: ch1 and ch4 ch1 and ch5 ch1 and ch2 … Contributes to answering ‘Q4: how can we make analysis feasible’ this method allows for data-reduction without information loss.

We know now that labels from appropriate ontologies go here Filling the grid We know now that labels from appropriate ontologies go here But, what goes here?

Remember we had this … Universals Particulars Independent Continuant portion of C17H19ClN2S.HCl human being gene portion of chlorpromazine in this tablet me the HTR2A gene on chromosome 13 of the most frontal cell in the tip of my nose Dependent Continuant shape temperature length the shape of my nose the temperature of the chlorpromazine tablet in front of me the length of that HTR21 gene Occurrent change in shape motion rise in temperature unfolding of a DNA molecule the circulation of a chlorpromazine molecule in my bloodstream the rise of my body temperature while talking here

Or after transposition … Universals Continuant Occurrent Independent Continuant Dependent Continuant portion of C17H19ClN2S.HCl human being gene shape temperature length change in shape motion rise in temperature Particulars portion of chlorpromazine in the tablet in front of me me the HTR2A gene on chromosome 13 of the most frontal cell in the tip of my nose the shape of my nose the temperature of the chlorpromazine tablet in front of me the length of that HTR21 gene unfolding of a DNA molecule the circulation of a chlorpromazine molecule in my bloodstream the rise of my body temperature while teaching this seminar

. … and for many patients Particulars case1 case2 case3 case4 case5

Referent Tracking unique identification by means of ‘codes’ unique identification by means of ‘instance unique identifiers’