ECOR European Centre for Ontological Research Ontology and Referent Tracking for Neurodegenerative Disorders Dr. Werner Ceusters European Centre for Ontological Research Saarland University, Saarbrcken, Germany ECOR European Centre for Ontological Research Part I. Neurodegenerative disorders: modern history ECOR European Centre for Ontological Research Examples of neurodegenerative diseases Involving the central nervous system: Alzheimer's Disease Parkinson Disease ALS (Lou Gehrig's Disease) Frontal Temporal Dementia Huntington's Disease Cerebellar Ataxias Hereditary Spastic Paraplegias Involving the peripheral nervous system: Charcot-Marie Tooth Hereditary Neuropathies Muscular Dystrophy. ECOR European Centre for Ontological Research Some disease characteristics Neurodegeneration is a major element. But some disorders with ND are not usually classified as degenerative e.g. multiple sclerosis, epilepsy, some inborn errors of metabolism, schizophrenia, and even tumours. selective, at least initially, for a particular neuronal pool both genetic and environmental risk factors play a part in the etiology a long run-in period until sufficient protein accumulates, followed by a cascade of symptoms over 2-20 years, with increasing disability leading to death A. Williams. Defining neurodegenerative diseases. BMJ 2002;324: ( 22 June ) ECOR European Centre for Ontological Research Wide range of phenotypes in same category, e.g. cerebellar ataxias (SCA) SCA 1: hypermetric saccades and hyperreflexia. SCA 2: reduced velocity of saccadic eye movements, areflexia and changes similar to those seen in olivopontocerebellar atrophy on brain imaging. SCA 3: protruded eyes, muscle fasciculations, spasticity, chorea, gaze-evoked nystagmus, parkinsonism and peripheral neuropathy. SCAs 5, 6, 10 and 11: pure cerebellar signs. SCA 7: macular degeneration. SCA 8: mild sensory neuropathy, late-onset spasticity. SCA 10: seizures with ataxia. SCA 12: head and hand tremors. SCA 17: Intellectual deterioration and dysphagia. T.E. King. Molecular diagnosis of adult neurodegenerative diseases and movement disorders. April ECOR European Centre for Ontological Research Histopathological phenomena in some central NDs L. Bertram and R.E. Tanzi. The genetic epidemiology of neurodegenerative disease. J. Clin. Invest. 115: (2005). ECOR European Centre for Ontological Research Multi-factorial with cross-relations, e.g. genetic epidemiology of Alzheimer L. Bertram and R.E. Tanzi. The genetic epidemiology of neurodegenerative disease. J. Clin. Invest. 115: (2005). ECOR European Centre for Ontological Research Main research epochs Early 1900 Microscopic study of stained tissues Alzheimer, Lewy, Pick,... NDs classified as clinicopathological entities Last decade: Molecular genetics and molecular biology Advanced functional and sequential imaging NDs classified by means of pathological biochemical pathways ECOR European Centre for Ontological Research Research purposes for ND characterize the clinical, laboratory, and pathological phenotypes of the various disorders included in this category; identify and clone genes directly causing or functioning as risk factors for these disorders; understand basic mechanisms underlying the biochemical and molecular pathogenesis of these disorders; Find application to treatment and prevention ECOR European Centre for Ontological Research Research purposes from an omics perspective understand the normal functions of genes and proteins involved in neurodegenerative diseases, characterize their role in pathogenic disease mechanisms, model their functions in animals, explore their roles in the diagnosis, treatment and prevention ECOR European Centre for Ontological Research Technical strategy for analysing ND pathogenesis identify pathogenic genes by positional cloning, by cloning genes that encode proteins involved in the disease, or by combining the two approaches; find pathogenic mutations; model and study the disease in cells by transfection and in mice by transgenesis D. L. Price, S. S. Sisodia, D. R. Borchelt, Science 282, 1078 (1998) ECOR European Centre for Ontological Research E.g.: positional cloning identify large multigenerational families with a long history of carrying the disorder determine linkage with polymorphic genetic markers look for cytogenetic rearrangements associated with the disease isolate overlapping DNA clones from the region identifying the gene that is responsible ECOR European Centre for Ontological Research Another strategy for ND gene detection L. Bertram and R.E. Tanzi. The genetic epidemiology of neurodegenerative disease. J. Clin. Invest. 115: (2005). ECOR European Centre for Ontological Research New NDs are discovered a previously unrecognized adult-onset dominantly inherited ND that affects the basal ganglia associated with iron accumulation. Phenotype: extrapyramidal symptoms and low ferritin serum levels. lesions in the globus pallidus with abundant spherical inclusions containing aggregates of ferritin and iron. axonal swellings throughout the brain organs such as the pancreas, liver, and heart that are typically affected in iron accumulation disease, appear to function normally Curtis ARJ, Fey C, Morris CM, et al. Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nature Genetics 2001; 28: ECOR European Centre for Ontological Research Intermediate conclusions NDs are challenging with respect to reality representation Involve entities of diverse nature true nature of some entities not yet understood Type of relationships unclear ECOR European Centre for Ontological Research Part II. Role of ontology ECOR European Centre for Ontological Research Ontology Ontology: the study of being as a science An ontology : 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 ontological (as adjective): Within an ontology. Derived by applying the methodology of ontology ... ECOR European Centre for Ontological Research Need for widely accepted Top Level Ontology (TLO) TLO: an ontology that describes by means of theories or specifications the most general, domain-independent categories of reality such as time, space, inherence, instantiation, identity, processes, events, attributes, relations,... Ongoing efforts: BFO DOLCE SUMO ECOR European Centre for Ontological Research Need for widely accepted Biomedical Domain Ontology (BMO) domain ontology: an ontology that describes the most general categories within a specific domain, using the framework of the top level ontology. In our case: the domain is biomedicine. Where a top level ontology describes entities such as objects and processes, a biomedical domain ontology: describes entities such as genes and insulin, and transcription and hormon secretion. further classifies these entities within the framework of the top level ontology, thereby adding new descriptive elements that are relevant at that level of reality. ECOR European Centre for Ontological Research Essential (and missing) components for a biomedical domain ontology Ontology for functions and processes levels of granularity for functions: localizing functions and processes to understand their mutual relationships: functional states of molecules Ontology for anatomical levels of granularities levels of granularity based on grains and structure determination of parthood relations across entities in different levels of granularity Pathophysiology ontology Dependence relations between physiological entities and pathology Determination of parthood relations for pathological entities An upper ontology for health information stored in public health information databases ECOR European Centre for Ontological Research Links to ongoing efforts Use BMO: To make more DB semantics explicit and formal to make the various databases semantically interoperable at both structure and content level. ECOR European Centre for Ontological Research Example: KEGG Pathway Database on Neurodegenerative Disorders Alzheimer's disease Parkinson's disease Amyotrophic lateral sclerosis (ALS) Huntington's disease Dentatorubropallidoluysian atrophy (DRPLA) Prion disease ECOR European Centre for Ontological Research KEGG Pathway ND ECOR European Centre for Ontological Research KEGG Pathway Alzheimer ECOR European Centre for Ontological Research KEGG Pathway notation ECOR European Centre for Ontological Research Part III. Referent Tracking ECOR European Centre for Ontological Research The missing link From genotype to phenotype Most DBs contain data without reference to particular patients Some DBs (usually not publicly accessible) just have snapshots of correlations No DBs provide a dynamically growing pool of data about interrelated patient phenomena Note: NOT interrelated data Relationships between data are distinct from relationships amongst the entities the data are about The right approach: Referent Tracking ECOR European Centre for Ontological Research Referent Tracking... Corrects the overemphasis on data and information and too little attention to reality: data modelling information modelling Does right what the Object Oriented model claims to do right. objects are said to be those things that exist in reality But: The object-oriented model is based on a collection of objects An object contains values stored in instance variables within the object. Unlike the record-oriented models, these values are themselves objects. ECOR European Centre for Ontological Research /07/ closed fracture of shaft of femur /07/ Fracture, closed, spiral /07/ closed fracture of shaft of femur /07/ Accident in public building (supermarket) /07/ Essential hypertension /12/ benign polyp of biliary tract /03/ closed fracture of shaft of femur /03/ Accident in public building (supermarket) /04/ Other lesion on other specified region /05/ Essential hypertension 29822/08/ Closed fracture of radial head 29822/08/ Accident in public building (supermarket) /04/ closed fracture of shaft of femur /04/ Essential hypertension PtIDDateObsCodeNarrative /12/ malignant polyp of biliary tract A look at the database: Use of SNOMED codes for unambiguous understanding * * * * cause, not disorder How many disorders have patients 5572, 2309 and 298 each had thus far in their lifetime ? How many numerically different disorders are listed here ? How many different types of disorders are listed here ? ECOR European Centre for Ontological Research Would it be easier if you could see the code labels ? /07/ closed fracture of shaft of femur557204/07/ Fracture, closed, spiral557212/07/ closed fracture of shaft of femur557212/07/ Accident in public building (supermarket) /07/ Essential hypertension /12/ benign polyp of biliary tract /03/ closed fracture of shaft of femur /03/ Accident in public building (supermarket) /04/ Other lesion on other specified region557217/05/ Essential hypertension29822/08/ Closed fracture of radial head29822/08/ Accident in public building (supermarket)557201/04/ closed fracture of shaft of femur557201/04/ Essential hypertension PtIDDateObsCodeNarrative /12/ malignant polyp of biliary tract ECOR European Centre for Ontological Research Proposed solution: Referent Tracking Purpose: explicit reference to the concrete individual entities relevant to the accurate description of each patients condition, therapies, outcomes,... Method: Introduce an Instance Unique Identifier (IUI) for each relevant individual (= particular, = instance). Distinguish between IUI assignment: for instances that do exist IUI reservation: for entities expected to come into existence in the future ECOR European Centre for Ontological Research No confusion with explicit references /07/ closed fracture of shaft of femur /07/ Fracture, closed, spiral /07/ closed fracture of shaft of femur /07/ Accident in public building (supermarket) /07/ Essential hypertension /12/ benign polyp of biliary tract /03/ closed fracture of shaft of femur /03/ Accident in public building (supermarket) /04/ Other lesion on other specified region /05/ Essential hypertension 29822/08/ Closed fracture of radial head 29822/08/ Accident in public building (supermarket) /04/ closed fracture of shaft of femur /04/ Essential hypertension PtIDDateObsCodeNarrative /12/ malignant polyp of biliary tract IUI-001 IUI-003 IUI-004 IUI-005 IUI-007 IUI-002 IUI-012 ECOR European Centre for Ontological Research Essentials of Referent Tracking Generation of universally unique identifiers; deciding what particulars should receive a IUI; finding out whether or not a particular has already been assigned a IUI (each particular should receive maximally one IUI); using IUIs in the EHR, i.e. issues concerning the syntax and semantics of statements containing IUIs; determining the truth values of statements in which IUIs are used; correcting errors in the assignment of IUIs. ECOR European Centre for Ontological Research Architecture of a Referent Tracking System (RTS) RTS: system in which all statements referring to particulars contain the IUIs for those particulars judged to be relevant. Ideally set up as broad as possible: some metrics: % of particulars referred to by means of IUI % of HCs active in a region Geographic region functional region: defined by contacts amongst patients % of patients referred to within a region Services: IUI generator IUI repository: statements about assignments and reservations Referent Tracking Database (RTDB): index (LSID) to statements relating instances to instances and classes ECOR European Centre for Ontological Research Ultimate goal #IUI-1 affects #IUI-2 #IUI-3 affects #IUI-2 #IUI-1 causes #IUI-3... Referent Tracking Database EHR CAG repeat Juvenile HD person disorder continuant Ontology