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HL7 Clinical-Genomics SIG: A Shared Genotype Model HL7 V3 Compliant Amnon Shabo (Shvo) IBM Research Lab in Haifa HL7 Clinical-Genomics SIG Facilitator Atlanta, September 2004 Haifa Research Lab Current Work Clinical-Genomics Storyboard Tissue Typing Family History Genotype Clinical-Genomics Storyboard BRCA Shared Cystic Fibrosis Clinical-Genomics Storyboard Model Clinical Statement Shared Model Pharmacogenomics Clinical-Genomics Storyboard Haifa Research Lab The Genotype CMET Represents genomic data in HL7 RIM Classes Not meant to be a biological model Concise and targeted at healthcare use for personalized medicine Consists of: A Genotype (entry point) 1 .. 3 alleles Polymorphisms Mutations SNPs Haplotypes DNA Sequencing Gene expression Proteomics Phenotypes (clinical data such as diseases, allergies, etc.) Haifa Research Lab The Genotype CMET (cont.) Design Principles: Shared model (a reusable component in different use cases) Basic encapsulation of genomic data that might be used in healthcare regardless of the use case Stemmed from looking for commonalities in specific use cases Presented as the CG SIG DIM (Domain Information Model) in ballot#6&8 Most of the clones are optional, thus allowing the representation of merely a genotype with a minimum of one allele (a typical use by early adopters) At the same time, allows the use of finer-grain / raw genomic data, thus accommodating the more complex use cases such as tissue typing or clinical trials Its use is currently illustrated in four R-MIMs: Tissue Typing Cystic Fibrosis Viral genotyping Pharmacogenomics Haifa Research Lab The Genotype Model Entry Point: Genotype Genotype HL7 Clinical Genomics SIG Document: Subject: Facilitator: 0..* priorClinicalPhenotype Individual Allele (1..3) sequelTo Haplotype ClinicalPhenotype (POCG_RM000004) Individual Genotype DIM (to be registered as a CMET) Genomics Data Rev: 0.5 Date: April 24, 2004 Amnon Shabo (Shvo), IBM Research in Haifa Entry point to the Clinical-Genomics Genotype Model 0..* priorClinicalPhenotype sequelTo typeCode*: <= SEQL Haplotype ClinicalPhenotype ClinicalPhenotype typeCode*: <= SEQL classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CE CWE [0..1] componentOf Allele Sequence Genotype 0..* haplotype Note: A related allele that is on a different haplotype, and still has significant interrelation with the source allele. Haplotype typeCode*: <= COMP classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CE CWE [0..1] (e.g., HETEROZYGOTE) text: ED [0..1] effectiveTime: IVL<TS> [0..1] (the time of genotyping) component Note: The classCode should be OBSGENPOLSNP which stands for SNP-polymorphism genomic observation, a subtype of OBSGENPOL (polymorphism genomic observation) which is a subtype of OBSGEN (genomic observation). componentOf typeCode*: <= COMP typeCode*: <= SEQL There must be at least one IndividualAllele and three at the most. The typical case would be an allele pair, one on the paternal chromosome and one on the maternal chromosome. IndividualAllele pertinentInformation5 sequelTo Note: typeCode*: <= COMP 0..* haplotype 0..* priorClinicalPhenotype The third allele could be present if the patient has three copies of a chromosome as in the Down’s Syndrome. 0..* pertinentIndividualAllele typeCode*: <= PERT DeterminantPeptide classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CE CWE (identifier and classification of the determinant, e.g., Entrez) text: ED pertinentInformation2 SNP Note: Use methodCode if you don’t use the associated method procedure. Sequencing 0..* pertinentDeterminantPeptide typeCode*: <= PERT 1..3 individualAllele AlleleSequence SNP classCode*: <= OBS 0..* pertinentSNP moodCode*: <= EVN pertinentInformation1 id: II [0..1] typeCode*: <= PERT code: CE CWE [0..1] (SNP identifier & classification, e.g. Entrez dbSNP) text: ED [0..1] value: BAG<ED> [0..*] (the SNP itself) methodCode: SET<CE> CWE [0..*] pertinentInformation typeCode*: <= PERT IndividualAllele 0..1 pertinentAlleleSequence classCode*: <= OBS moodCode*: <= EVN code*: CE CWE [1..1] (allele identifier & classification, e.g. GeneBank) text: ED [0..1] methodCode: SET<CE> CWE [0..*] (The method by which the code was determined) pertinentInformation2 typeCode*: <= PERT pertinentInformation3 pertinentInformation6 pertinentInformation4 typeCode*: <= PERT typeCode*: <= PERT typeCode*: <= PERT Method Method classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: [1..1] (the sequence standard code, e.g. BSML, GMS) text: (the annotated sequence) effectiveTime: [1..1] value: ED [1..1] (the actual sequence) methodCode: (the sequencing method) classCode*: <= PROC moodCode*: <= EVN id: II [0..1] 0..* pertinentMethod code: CD CWE [0..1] <= pertinentInformation1 ActCode typeCode*: <= PERT(type of method) text: ED [0..1] (free text description of the method used) methodCode: SET<CE> CWE [0..*] outcome typeCode*: <= OUTC 0..* pertinentMutation Mutation 0..1 pertinentMutation Mutation GeneExpression 0..* pertinentMethod Method Mutation 0..1 pertinentGeneExpression pertinentInformation typeCode*: <= PERT classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CE CWE <= ActCode (the standard's code (e.g., MAGEML identifier) text: effectiveTime: value: ED [1..1] (the actual gene expression levels) methodCode: Polymorphism classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CD CWE [0..1] <= ActCode text: ED [0..1] value: ANY [0..1] classCode*: <= OBS moodCode*: <= EVN id: II [0..1] 0..* pertinentPolymorphism code: CE CWE (mutation identifier and classification, e.g. LOINC MOLECULAR GENETICS NAMING) text: sequelTo typeCode*: <= SEQL Constraint: GeneExpression.value Gene Expression Note: The classCode should be OBSGENPOLMUT which stands for mutationpolymorphism genomic observation, a subtype of OBSGENPOL (polymorphism genomic observation) which is a subtype of OBSGEN (genomic observation). Polypeptide classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code*: CE CWE [1..1] (idnetifier & classification of the protein, e.g., SwissProt, ) (PDB, PIR, HUPO) text: 0..* priorClinicalPhenotype Constrained to a restricted MAGE-ML content model, specified elesewhere. Proteomic s 0..* outcomePolypeptide Constraint: AlleleSequence.value Constrained to a restricted BSML or GMS content model, specified elsewhere. Note: Usually this is a computed outcome, i.e., the lab does not produce the actual protein. ClinicalPhenotype Note: The classCode should be OBSGENPOL which stands for polymorphism genomic observation, a subtype of OBSGENPOL (polymorphism genomic observation) which is a subtype of OBSGEN (genomic observation). Note: Could refine ActRelationship typeCode to elaborate on different types of genomic to phenotype effects. classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CE CWE [0..1] (disease, allergy, sensitivity, ADE, etc.) text: ED [0..1] uncertaintyCode: CE CNE [0..1] value: ANY [0..1] Note: An observation of a clinical condition represented internally in this model. reference typeCode*: <= x_ActRelationshipExternalReference 0..* referredToExternalClinicalPhenotype ExternalClinicalPhenotype Polymorphism classCode*: <= OBS moodCode*: <= EVN id*: II [1..1] (The id of an external observation (e.g., in a problem list) Note: An external observation is a valid Observation instance existing in any other HL7-compliant artifact, e.g., a document or a message. Clinical Phenotype Note: Shadowed observations are copies of other observations and thus have all of the original act attributes. Haifa Research Lab Coexistence of HL7 Objects and Bioinformatics Markup Genomic Data Sources Clinical Practice Knowledge (KBs, Ontologies, registries, Evidence-Based, Papers, etc.) EHR System Bubbling up the clinically-significant raw genomic data into specialized HL7 objects and linked them with clinical data from the patient EHR Decision Support Applications Haifa Research Lab Coexistence of HL7 Objects and Bioinformatics Markup (cont.) Genetic Counseling DNA Lab Sequencing Example… EHR System Bubbling up the clinically-significant SNP data into HL7 SNP and Mutation objects and linked them with clinical data from the patient EHR Decision Support Applications Haifa Research Lab Coexistence of HL7 Objects and Bioinformatics Markup (cont.) IndividualAllele classCode*: <= OBS The patient's moodCode*: <= EVN id: II [0..1] allele code*: CE CWE [1..1] (allele classification) text: ED [0..1] value: ANY [0..1] (e.g. accession no. in GeneBank) methodCode: SET<CE> CWE [0..*] (The method by which the code was determined) HL7 genomicspecialized Objects Bubbling-up… Bubbling-up… AlleleSequence SNP SNP classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CD CWE [1..1] (the sequence standard code, e.g. BSML, GMS) text: ED [0..1] (sequence's annotations) effectiveTime: GTS [1..1] value: ED [1..1] (the actual sequence) methodCode: SET<CE> CWE [0..*] (the sequencing method) classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CE CWE [0..1] (SNP classification, e.g. from Entrez dbSNP) text: ED [0..1] value: BAG<ED> [0..*] (the SNP itself) methodCode: SET<CE> CWE [0..*] classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CE CWE [0..1] (SNP classification, e.g. from Entrez dbSNP) text: ED [0..1] value: BAG<ED> [0..*] (the SNP itself) methodCode: SET<CE> CWE [0..*] Bubbling-up… bioinformatics markup classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CE CWE [0..1] (mutation classification) text: ED [0..1] value: ANY [0..1] (mutation code, e.g. drawn from LOINC MOLECULAR GENETICS NAMING) ClinicalPhenotype classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CE CWE [0..1] (e.g., disease, allergy, sensitivity, ADE, etc.) text: ED [0..1] value: ANY [0..1] Bubbling-up… Sequencing data encapsulated as Mutation Haifa Research Lab The Family History Model FamilyHistory (COCT_RM999999) Patient This model is intended to be a CMET and has the capability of representing any part of the patient pedigree. classCode*: <= PAT id*: SET<II> [1..*] Note: First-degree relatives. FAMMEMB could be used for unidentified relatives, but also any of the more specific codes like PRN (parent) or NMTH (natural mother). Note: Person holds details that are not specific the family role. Person is also the scoper of the relative roles (for more details see the V3 RoleCode vocabulary, domain = PersonalRelationshipRoleType). typeCode*: <= SBJ 0..* clinicalGenomicChoice 1..1 patientPerson Person classCode*: <= PSN determinerCode*: <= INSTANCE id: SET<II> [0..*] (e.g., SSN) name: BAG<EN> [0..*] telecom: BAG<TEL> [0..*] administrativeGenderCode: CE CWE [0..1] <= AdministrativeGender birthTime: TS [0..1] deceasedInd: BL [0..1] "false" deceasedTime: TS [0..1] raceCode: SET<CE> CWE [0..*] <= Race ethnicGroupCode: SET<CE> CWE [0..*] <= Ethnicity 0..1 relationshipHolder Note: This should be replaced with the Clinical-Genomics Genotype model (as a CMET) to deal with all types of genomic data. classCode*: <= PRS id: SET<II> [0..*] (use this attribute to hold pedigree ID) code: CE CWE [0..1] <= RoleCode "FAMMEMB" 0..* Note: Clinical Genomics choice similar to the choice associated with the Patient role (the entry point of this model). classCode*: <= ACT moodCode*: <= EVN code: CD CWE [1..1] <= ActCode negationInd: BL [0..1] effectiveTime: GTS [0..1] confidentialityCode: SET<CE> CWE [0..*] <= Confidentiality uncertaintyCode: CE CNE [0..1] <= ActUncertainty classCode*: <= OBS moodCode*: <= EVN subjectOf Note: A shadow of Person allows for recursive representation of any higher level degree of relations, e.g., grandfather, through the same clone - PersonalRelationship, nesting in Person. ClinicalStatement Genotype 0..* relationshipHolder PersonalRelationship Person ClinicalGenomicChoice subjectOf1 Genotype CMET Note: Should be replaced with a generic clinical statement CMET so it is capable of holding any pertinent clinical data of the patient or his/her relative. Haifa Research Lab Family History – Harmonization Proposals Age: Age of subject when subject’s diagnosis was made Age at time of death Proposed solution: a new data type to refer to from effectiveTime: <effectiveTime xsi:type="TSR"> <!--TSR=Time Stamp Relative--> <epoch code="B"/> <offset value="20" unit="mo"/> </effectiveTime> Vocabulary proposals Observation Interpretation (Deleterious, Unknown significance, Polymorphism, No mutation) Personal relation codes and qualifiers Personal Relationship association names A naming algorithm problem (HL7 tooling issue) Haifa Research Lab The Genotype Model in Tissue Typing BMT Tissue Typing Donor Banks BMT Ward Tissue Typing Observation Individual1 HLA TissueTyping Lab Genotype Matching Allele SNP Haplotype Individual2 HLA Haifa Research Lab How the Genotype fits to Tissue-Typing Tissue Typing in the context of Bone-Marrow Transplantation: BMT Center BMT unique Order/Entry Tissue Typing Observation Donor Bank Haifa Research Lab How the Genotype fits to Tissue-Typing Note: This module is developed by the Clinical-Genomics SIG. It will registered as a CMET but for now it appears here as an observation. For details, see the Genotype R-MIM. All genomic data are encapsulated in this CMET, including mutations which are the essence of the CF testing for example. Genotype CMET Note: The no. of genotypes is dependent on the no. of loci examined in each HLA class (usually, class I includes A, B and C antigens and class II includes the DR antigen family) classCode*: <= OBS moodCode*: <= EVN Class I Antigens component 1..* hLA_AntigenGenotype typeCode*: <= COMP 1..* hLA_AntigenGenotype component typeCode*: <= COMP ClassTissueTypingResultLetter II Antigens TTObservation (UUDD_RMnnnnnn) Tissue-Typing Observation TissueTypingFacility Single classCode*: <= ENT determinerCode*: <= INSTANCE TT-TestingLab classCode*: <= QUAL 0..1 Class II Antigens classCode*: <= OBS moodCode*: <= EVN code: CD CWE [0..1] <= ActCode classCode*: <= OBS moodCode*: <= EVN code: CD CWE [0..1] <= ActCode component2 0..* tissueTypingResultLetter typeCode*: <= DOC 0..1 class II Antigens typeCode*: <= COMP TissueTypingObservation primaryPerformer TissueTypingObservation typeCode*: <= PPRF classCode*: <= PSN determinerCode*: <= INSTANCE SubjectChoice Donor 0..1 participant subject typeCode*: <= SBJ (COCT_MT050000) component1 documentationOf 0..1 tT-TestingLab Person CMET: (PAT) R_Patient [universal] 0..1 class I Antigens typeCode*: <= COMP 0..1 playingPerson classCode*: <= ROL classCode*: <= DOCCLIN moodCode*: <= EVN code: CE CWE <= TissueTypingDocumentType Class I Antigens Tissue Typing Observation The Genotype model is used for each HLA Antigen classCode*: <= OBS moodCode*: <= EVN id: code: CS CWE <= TissueTypingTestingClass 1..1 priorTissueTypingObservation sequelTo typeCode*: <= SEQL 1..1 priorTissueTypingObservationTissueTypingMatchingObservation classCode*: <= OBS sequelTo1 moodCode*: <= EVN typeCode*: <= SEQL code: CS CWE <= TissueTypingMatchingClass text: Note: component TissueTypingMatchingClass typeCode*: <= COMP should be a new vocabulary in HL7, e.g., 2-haplotype match TT-Matching (UUDD_RMnnnnnn) Description Constraint: LocusMatching The number of LocusMatching Observations is dependent on the no. of loci examined in the tissue-typing testing Note: TissueTypingLocusMatchingClass should be a new vocabulary in HL7 (may use recent NMDP effort) 0..* locusMatching LocusMatching classCode*: <= OBS moodCode*: <= EVN code: CS CWE <= TissueTypingLocusMatchingClass text: Tissue Typing Matching Observation Haifa Research Lab Tissue Typing Scenario Simulation Real Case with… A Hutch Patient and sibling and unrelated donor candidates are in Hadassah Information exchange… is simulated through a series of XML files following the TT storyboard activity diagram and using the HL R-MIMs + Genotype CMET Documented in the following doc: HL7-Clinical-Genomics-TissueTypingInfoExchangeSimulation.doc Contact Amnon Shabo to get the document ([email protected]) Haifa Research Lab The Genotype Model in Cystic Fibrosis Provider EMR System Entry Point: Blood Sample MGS Report MLG Counselor Patien t ML Consultant DNA Genotype CMET Molecular Genetic lab Haifa Research Lab The Genotype Model in Viral Genotyping Repor t Patient Sponso r Pathoge n Viral DNA Sequencing Entry Point: Specimen Test Panel Resistance Profile Genotype CMET Viral DNA Regions DNA Lab Haifa Research Lab The Genotype Model in PharmacogenomicsBased Clinical Trial & Submission Data Analysis Patient Repor t Pharmacogenomics testing CRO Gene Selection Analysi s device CR O SNP/Hap Discovery Genotype CMET Data Validation Trial design Regulator Sponso r Genomic data Submission Haifa Research Lab Constrained-BSML Schema BSML – Bioinformatics Sequence Markup Language Aimed at any biological sequence, for example: DNA RNA Protein Constraining the BSML DTD to fit the healthcare needs Leave out research and display markup Ensure the patient identification Creating an XML Schema, set up as the content model of an HL7 attribute of type ED Haifa Research Lab Constrained-MAGE-ML Schema Cope with data outside of the XML (referenced) Shared issues: Eliminate research & display elements and requires the presence of certain elements, for example - patient identifiers Require that one and only one patient will be the subject of the data, to avoid bringing data of another patient into the HL7 message Require that data will refer to only one allele with which the encapsulating HL7 object is associated Haifa Research Lab OBS Specialization Examples PublicHealthCase detectionMethodCode :: CE transmissionModeCode :: CE diseaseImportedCode :: CE Diagnostic Image subjectOrientationCode:: CE The above examples are relatively ‘simple’ considering the uniqueness of the genomic observation attributes Propose to add a genomic specialization to the RIM Observation Class Rationale: has additional attributes that are unique to genomics (LSID, Bioinformatics Markup, etc.) Haifa Research Lab Genomic Specializations of Observation GenomicObservation LSID Polymorphism Gene Expression Bio Sequence type position length reference region MAGE BSML SNP tagSNP Mutation knownAssciatedDiseases (not the actual phenotype) Haifa Research Lab New Class Codes Proposal classCode Class name OBSGEN GenomicObservation OBSGENPOL Polymorphism OBSGENPOLMUT Mutation OBSGENPOLSNP SNP Haifa Research Lab New Attributes Proposal GenomicObservation: LSIDIdentifier AlleleSequence: moleculeSequence A constrained XML Markup based on the BSML markup. Polymorphism: o o o o o type (SNP, Mutation, Other) position (the position of the polymorphism) length (the length of the polymorphism) reference (the base reference for the above attributes) region (when the polymorphism scope is a specific gene region) SNP: Tag SNP A Boolean field indicating whether this SNP is part of small SNPSet that determines a SNP-haplotype. GeneExpression: expressionLevels A constrained XML Markup based on the MAGE markup. Proteomic clones: TBD. Haifa Research Lab Proposed HL7 Vocabularies Genomics Vocabularies: Polymorphism: General types (SNP, Mutation, Sequence Variation) Nucleotide-based types (substitution, insertion, deletion, etc.) Alleles Relation (recessive / dominant, homozygote / heterozygote) Genotype-to-phenotype types of effects Genomic observation interpretation (Deleterious, Unknown significance, polymorphism, No mutation) SequencingMethodCode (example in next slide) Haifa Research Lab HL7 Vocabulary Example SequencingMethodCode: SSOPH -Sequence specific oligonucleotide probe hybridization SSP -Sequence specific primers SBT -Sequence-based typing RSCA -Reference strand conformation analysis Haifa Research Lab Proposed HL7 Vocabularies (cont.) Tissue Typing related Vocabularies: TissueTypingLocusMatchingClass TissueTypingMatchingClass TissueTypingTestingClass TissueTypingTestingMethod TissueTypingDocumentType TissueTypingOrderClass DonorType (allogeneic, autologous, etc.) Class I & II antigens classification Haifa Research Lab XML Examples Genotype Examples: o GenotypeSample1.xml A genotype of two HLA alleles in the B locus o GenotypeSample2.xml A genotype of two HLA alleles in the B locus, along with a SNP designation in the first allele Tissue Typing Observation Examples: o TissueTypingObservationSample1.xml Consists of a single tissue typing observation of a patient or a donor o TissueTypingObservationSample2.xml Consists of two tissue typing observations of a patient & donor, leading to a tissue typing matching observation Donor Search Examples: o TissueTypingDonorBankSample1.xml This example is aimed at illustrating an unsolicited message from a BMT Center to a donor bank, sending a patient's tissue typing observation for the purpose of searching an appropriate donor Haifa Research Lab Next Steps HL7 Formally submission of our harmonization proposals Continue with 2 alternatives until harmonization is resolved Register the Genotype Family History models as CMETs Hand craft sample instances (for review and experimental use) Derive a Genetic Testing model from the HL7 Lab SIG Models Vocabularies HL7 External- develop get HL7 to recognize them Constraining Bioinformatics Markup (continue the effort and include markup in the next ballot) MAGE-ML or MIAME BSML (done) caBIO (?) Haifa Research Lab Linking to the NCI Rembrandt Model Use-case driven modeling, designed with the HL7-Genotype model as a starting point and will eventually extend the caBio model. Haifa Research Lab Alternative Genotype Models Genotype HL7 Clinical Genomics SIG A model without genomic specializations of the HL7 RIM Observation class: Document: Subject: Facilitator: ClinicalPhenotype (POCG_RM000004) Individual Genotype DIM (to be registered as a CMET) - Genomic Attributes as HL7 Clones Genomics Data Rev: 0.17 Date: September 14, 2004 Amnon Shabo (Shvo), IBM Research in Haifa, [email protected] Entry Point: Genotype Constraint: translationalData.value Constrained to a restricted caBio content model, specified elsewhere. Entry point to the Clinical-Genomics Genotype Model 0..* causedClinicalPhenotype causeOf typeCode*: <= CAUS 0..* causedClinicalPhenotype causeOf Haplotype classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CE CWE [0..1] value: ANY [0..1] ClinicalPhenotype ClinicalPhenotype typeCode*: <= CAUS Note: The presence of this 0..* haplotype clone indicates that the source SNP clone is a typeCode*: <= COMP tag SNP (note that it has a DEF mood), Note: A related allele that is on a different haplotype, and still has significant interrelation with the source allele. Haplotype componentOf translationalData classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CE CWE [0..1] (e.g., HETEROZYGOTE) text: ED [0..1] effectiveTime: IVL<TS> [0..1] (the time of genotyping) classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CD CWE [0..1] <= ActCode value: ANY [0..1] 0..* pertinenttranslationalData pertinentInformation typeCode*: <= PERT typeCode*: <= COMP typeCode*: <= CAUS DeterminantPeptide typeCode*: <= COMP tagSNP IndividualAllele classCode*: <= OBS moodCode*: <= DEF There must be at least one IndividualAllele and three at the most. The typical case would be an allele pair, one on the paternal chromosome and one on the maternal chromosome. 0..* referredToIndividualAllele reference typeCode*: <= SUBJ classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CE CWE [0..1] (classification of the determinant) text: ED [0..1] value: ANY [0..1] 0..* derivedDeterminantPeptide derivation Note: 0..1 tagSNP subject The third allele could be present if the patient has three copies of a chromosome as in the Down’s Syndrome. typeCode*: <= REFR typeCode*: <= DRIV Note: Use methodCode if you don’t use the associated method procedure. 1..3 individualAllele AlleleSequence SNP Polymorphism classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CE CWE [0..1] (SNP classification, e.g. from Entrez dbSNP) text: ED [0..1] value: BAG<ED> [0..*] (the SNP itself) methodCode: SET<CE> CWE [0..*] IndividualAllele 0..* sNP subject6 typeCode*: <= SUBJ sequelTo subject9 typeCode*: <= SEQL typeCode*: <= SUBJ 0..1 alleleSequence classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code*: CE CWE [1..1] (allele classification) text: ED [0..1] value: ANY [0..1] (e.g. accession no. in GeneBank) methodCode: SET<CE> CWE [0..*] (The method by which the code was determined) subject7 typeCode*: <= SUBJ 0..* causeDeterminantPeptide manifestationOf DeterminantPeptide typeCode*: <= MFST subject5 subject4 subject typeCode*: <= SUBJ typeCode*: <= SUBJ typeCode*: <= SUBJ Note: These diseases are not the actual phenotype for the patient, rather they are the known risks of this mutation. 0..1 polymorphismAttributes PolymorphismAttributes 0..* mutation 0..1 priorMutation Mutation Polymorphism Attributes Container pertinentInformation typeCode*: <= PERT classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CE CWE <= ActCode (the standard's code (e.g., MAGEML identifier) text: effectiveTime: value: ED [1..1] (the actual gene expression levels) methodCode: Constrained to a restricted MAGE-ML content model, specified elesewhere. Note: A container of common polymorphism attributes. 0..* polymorphism Polymorphism classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CD CWE [0..1] <= ActCode text: ED [0..1] value: ANY [0..1] subject typeCode*: <= RISK classCode*: <= OBS moodCode*: <= DEF code: CD CWE [0..1] <= ActCode text: ED [0..1] value: ANY [0..1] Constraint: AlleleSequence.value Constrained to a restricted BSML content model, specified elsewhere. 0..* causePolypeptide classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code*: CE CWE [1..1] (classification of the protein, e.g., SwissProt, PDB, PIR, HUPO) text: ED [0..1] value: ANY [0..1] Note: This might be a computed outcome, i.e., the lab does not provide the actual protein, but secondary processes populate this clone with the translational protein. 0..* causedClinicalPhenotype Note: An observation of a clinical condition represented internally in this model. ClinicalPhenotype classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CE CWE [0..1] (e.g., disease, allergy, sensitivity, ADE, etc.) text: ED [0..1] value: ANY [0..1] reference component4 component5 component6 component7 typeCode*: <= COMP typeCode*: <= COMP typeCode*: <= COMP typeCode*: <= COMP 0..1 polyPosition component8 typeCode*: <= x_ActRelationshipExternalReference typeCode*: <= COMP 0..1 polyReference PolyType PolyLength PolyPosition PolyReference PolyRegion classCode*: <= OBS moodCode*: <= EVN id: II [0..1] value: CE CWE [1..1] classCode*: <= OBS moodCode*: <= EVN id: II [0..1] value: INT [1..1] classCode*: <= OBS moodCode*: <= EVN id: II [0..1] value: INT [1..1] classCode*: <= OBS moodCode*: <= EVN id: SET<II> [0..*] value: ED [0..1] classCode*: <= OBS moodCode*: <= EVN id: SET<II> [0..*] value: ED [0..1] Note: A code attribute was not added to any of the polymorphism attribute clones as this seems to be implicit from the clone name. typeCode*: <= SUBJ classCode*: <= PROC moodCode*: <= EVN id: II [0..1] code: CD CWE [0..1] <= ActCode (type of method) text: ED [0..1] (free text description of the method used) methodCode: SET<CE> CWE [0..*] Polypeptide Note: Should refine ActRelationship typeCode to elaborate on different types of genomic to phenotype interrelations. PolymorphismAttributes classCode*: <= ActContainer moodCode*: <= EVN 0..1 polyLength subject typeCode*: <= MFST Note: The classCode should be OBSGENPOLMUT which stands for mutationpolymorphism genomic observation. typeCode*: <= CAUS 0..1 polymorphismAttributes 0..1 polyType 0..* method manifestationOf 0..1 polymorphismAttributes PolymorphismAttributes Polymorphism Attributes 0..* riskKnownAssociatedDiseases risk causeOf typeCode*: <= SUBJ typeCode*: <= SUBJ Note: The classCode should be OBSGENPOL which stands for polymorphism genomic observation, a subtype of OBSGENPOL (polymorphism genomic observation) which is a subtype of OBSGEN (genomic observation). Method knownAssociatedDiseases classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CE CWE [0..1] (mutation classification) text: ED [0..1] value: ANY [0..1] (mutation code, e.g. drawn from LOINC MOLECULAR GENETICS NAMING) subject Constraint: GeneExpression.value classCode*: <= OBS moodCode*: <= EVN id: II [0..1] code: CD CWE [1..1] (the sequence standard code, e.g. BSML, GMS) text: ED [0..1] (sequence's annotations) effectiveTime: GTS [1..1] value: ED [1..1] (the actual sequence) methodCode: SET<CE> CWE [0..*] (the sequencing method) Mutation 0..1 geneExpression GeneExpression 0..* pertinentMethod Method 0..* causedClinicalPhenotype causeOf component 0..* haplotype componentOf Note: The classCode should be OBSGENPOLSNP which stands for SNP-polymorphism genomic observation. Genotype Polymorphism Attributes Shadow asso. W / Mutation 0..1 polyRegion 0..* referredToExternalClinicalPhenotype ExternalClinicalPhenotype classCode*: <= OBS moodCode*: <= EVN id*: II [1..1] (The id of an external observation (e.g., in a problem list) Note: An external observation is a valid Observation instance existing in any other HL7-compliant artifact, e.g., a document or a message. Note: Shadowed observations are copies of other observations and thus have all of the original act attributes as well as all ‘outbound’ associations. Haifa Research Lab Comments received on the Genotype Model Revalidate/collapse the polymorphism hierarchy Add a RIM class “SequenceVariance” Representing all types of polymorphisms Type could be placed in the code attribute ‘position’ and ‘length’ could be parts of a boundary in a RegionOfInterest type of Observation Could represent any bio-sequence (DNA, RNA, Protein, etc.) Patient data vs. generic knowledge tagSNP, knownAssociatedDiseases and haplotype are a type of knowledge Should they only be referenced (pointing to KBs)? Types of relationships between the various Genotype observations: Pertinent, Component, Subject,…? It’s tricky as it should apply to the observations and not to the observed entities Haifa Research Lab Comments on the Genotype Model (cont.) Distinguishing the encapsulating objects from the bubbled-up ones associate encapsulated objects to a bubbled-up objects, with options: XFRM (transformation), XCRPT (excerpt), SUMM (summary), DRIV (derived from)… what’s best? Method object should be in DEF mood? Could it be that there is a need to describe a method per patient? Is the SNP Mutation association useful? Changed the association type to XFRM to demonstrate a possible “bubbled-up” association, i.e., a SNP was encountered as a mutation Haifa Research Lab SLIST Data Type Use HL7 data types to represent bio-sequences SLIST<CV> (applied to CV=Coded Value) could hold either of the following: ACGTCGGTTCA… Leu-Ala-Met-Gly-Ala-… Table 37: Components of Sampled Sequence Name origin scale digits Type Description T The origin of the list item value scale, i.e., the physical quantity that a zero-digit in the sequence would represent. T.diff A ratio-scale quantity that is factored out of the digit sequence. list<int> A sequence of raw digits for the sample values. This is typically the raw output of an A/D converter. Haifa Research Lab Issues with just SequenceVariation… SNP: Link to Haplotype is valid only for SNP type of Polymorphism tagSNP is valid only for SNP Mutation: code&value are constrained to LOINC or other medical-oriented taxonomy rather than to an LS taxonomy as in polymorphism The attribute knownAssociatedDiseases moves to the phenotype choice so it’s resolved SNP Mutation association needs now a recursive association within Sequence Variation Technical issue: cannot shadow a choice box Haifa Research Lab The End… Thank you…