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Draft Observables Concept Model for Deployment of Anatomic/Molecular Pathology.

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Presentation on theme: "Draft Observables Concept Model for Deployment of Anatomic/Molecular Pathology."— Presentation transcript:

1 Draft Observables Concept Model for Deployment of Anatomic/Molecular Pathology

2 Use cases for molecular pathology/genetics 1) Resected melanoma tests positive for BRAF V600E mutation 2) Patient is heterozygote for BRCA1 mutation 3) Resected colon cancer tests positive for MSH2 gene mutation 4) Finding of Human non-polyposis colon cancer type 1 genetic carrier 5) KRAS codon 12 sequence variant detected in excised malignant neoplasm 6) D2S123 mononucleotide microsatellite stability in excised malignant neoplasm

3 Query use cases for domain ontology in Molecular Pathology 1) Find all patient observations of a specific SNP for resected tumors regardless of lab technique employed (sequencing, IHC, PCR, probes) 2) Retrieve all patients with finding of specified oncogenetic risk factor 3) (Identify all findings for patients with sequence variants of a specific chromosome region) 4) (Identify all protein producing genes on the long arm of chromosome 3)

4 118598001 |Measurement property(qualifier) Expanded SNOMED CT draft Lab/Pathology semantics Measurement property (Entitic properties)  Entitic integrity: degree of wholeness; absence of fragmentation or distortion  Entitic number  Anatomic Location: location of an entity within an organism  Radial location : clockface direction within usually tubular or round structure  Histologic feature : (phenotypic observations, gross or micro) clear demarcation, shape or configuration(propose value sets for exemplar specification) Histologic invasiveness: extension or infiltration of source into adjacent structures Nucleotide sequence property: disease specific assessment of aggressiveness as established by reference clinical classifications; value sets specified <<277457005|Histologic grading systems(staging scale)

5 Concept model extensions we are testing for Molecular Pathology  Agree upon HGNC, NCBI and UNIPROT as build reference resources which will support scalable modeling of SNOMED CT extensions and automated build of content  Expand concept model for Body structures to support fully defined concept of Gene (locus)  Define templates for observables for gene sequencing, DNA probes, immunohistochemistry…  Expand Measurement property to include molecular features  Expand Technique to include nucleotide sequencing, epigenetic and immunohistochemical procedures in clinical use  Agree upon proper application of concept model to definition of findings based upon genomic observables (nucleotide polymorphisms) some of which require molecular lab data

6 Agreed flattened quality observable model template for trial use <<Measurement property *1 <<Scales types(qualifier) *0-1 246514001 |Units | <<Body structure, <<Substance, <<Clinical finding <<Organism *0-1 704319004|Inheres in| <<Body structure, <<Substance, <<Organism, <<Specimen *1 9216841000004100 |Inherent location | <<Body structure, <<Substance, <<Organism, <<Specimen *0-1 ≡ 704318007|Property type| 704320005 |Towards| 370132008 |Scale type| 246501002 |Technique| 704327008 |Direct site| <<Units(qualifier) *0-1 <<Technique (technique) *0-many <<Body structure,<<Specimen *0-1 Fully specified name (observable entity) Observable entity 704326004 |Precondition| 370134009 |Time aspect| <<Time patterns (qualifier) *1 <<Clinical findings, <<Procedures *0-many Specimen preparation technique <<Preparation Technique (technique) *0-many

7 Include molecular

8 Template for gene or nucleotide sequence Chromosome structure(cell structure) Base pair NN Part of Chromosome pair NN(cell structure) GrCh38 Nucleotide Sequence start Base pair NN ≡ GrCh38 Nucleotide Sequence end |Nucleotide sequence/gene locus (cell structure)| Nucleotide sequence(cell structure) Chromosomal region Chromosome(p|q)region May be modeled entirely from HGNC reference data Issues: Addressing for microsatellites Addressing for exon references; eg KRAS (exon 2) codon 12 We are further deploying GrCh37 definitions and expect there will be more in the future

9 Chromosome structure(cell structure) 140,924,764 Part of Chromosome pair 7(cell structure) GrCh38 Nucleotide Sequence start 140,719,327 ≡ GrCh38 Nucleotide Sequence end 100670521000004106 |BRAF gene locus (cell structure)| B-RAF proto-oncogene serine threonine kinase Nucleotide sequence(cell structure) 7q34 Chromosome region

10 Concept model extension: Gene locus

11 Techniques

12 Agreed flattened quality observable model template for trial use Nucleotide sequence property Variant call format Single point in time 704319004|Inheres in| <<Cell structure, <<Morphology 9216841000004100 |Inherent location | <<Gene locus ≡ 704318007|Property type| 370134009 |Time aspect| 370132008 |Scale type| | Gene nucleotide sequence detected (observable entity)| Observable entity 246501002 |Technique 704327008 |Direct site|| <<Specimen Nucleotide sequencing technique (technique) Most sequencing data today is reported in variant call Format with file sizes for multi-sequence tests running Several thousand bytes

13 Agreed flattened quality observable model template for trial use Nucleotide sequence property Variant call format Single point in time 704319004|Inheres in| Malignant neoplasm 9216841000004100 |Inherent location | BRAF gene locus ≡ 704318007|Property type| 370134009 |Time aspect| 370132008 |Scale type| 455350031000004100 |BRAF nucleotide sequence detected in excised malignant neoplasm (observable entity)| Observable entity 246501002 |Technique 704327008 |Direct site|| Formalin-fixed paraffin embedded tissue sample Nucleotide sequencing technique (technique)

14 Features of human nucleotide sequence by variant call format (Alexis) PropertyExample ValueValuesets (not comprehensive, by far) Human Genome ReferenceGRCh37GRCh38 HUGO Gene AbbreviationBRAFSTK11 TP53 Nucleic Acid Type ExaminedDNARNA Mitochondrial DNA Nucleic acid variant typeSingle nucleotide variantInsertion Deletion Translocation Copy number variant Methylation Predicted protein variant type Single amino acid substitution Silent (no protein change) Insertion with frameshift and early truncation Insertion with frameshift and late truncation Deletion with frameshift and early truncation Deletion with frameshift and late truncation Fusion protein (translocation with another gene's protein) Complete non-expression of protein Splice region variant Start coordinate140453135140453155 Stop coordinate140453135140453156 HGVS nucleic acid nomenclature c.1799T>Ac.1779_1780delTGinsGA HGVS protein nomenclaturep.Val600Glup.Asp594Asn Human genetic variant from reference

15 Agreed flattened quality observable model template for trial use Nucleotide sequence variant Chr7 140719927 BRAFV600E V G… |GRCh38;CM000669.2 Finding site BRAF gene locus Interprets BRAF nucleotide sequence detected in malignancy ≡ Associated morphology Has value BRAF V600E mutation identified in excised malignant neoplasm (finding) Evaluation finding

16 SNOW OWL exemplars

17 Agreed flattened quality observable model template for trial use Entitic number (qualifier) Scales (qualifier) 704327008 |Direct site| Protein (substance) 704319004|Inheres in| <<Cell structure, <<Morphology 9216841000004100 |Inherent location | Gene locus or nucleotide seq (cell structure) ≡ 704318007|Property type| 704320005 |Towards| 370132008 |Scale type| <<Specimen Immunohistochemical test for protein expression of gene or gene mutation (observable entity) Tumor observable (observable entity) 246501002 |Technique| 370134009 |Time aspect| Single point in time(qualifier)\ Immunohistochemical technique(technique)

18 Agreed flattened quality observable model template for trial use Entitic number (qualifier) Nominal value (qualifier) 704327008 |Direct site| BRAF human cellular protein (substance) 704319004|Inheres in| Malignant neoplasm (morphology) 9216841000004100 |Inherent location | BRAF gene locus (cell structure) ≡ 704318007|Property type| 704320005 |Towards| 370132008 |Scale type| Formalin fixed paraffin embedded tissue specimen BRAF protein expression by immunoperoxidase staining of excised malignant neoplasm (observable entity) Tumor observable (observable entity) 246501002 |Technique| 370134009 |Time aspect| Single point in time(qualifier)\ Immunoperoxidase technique(technique)

19 |Chromosome structure(cell structure)| 43,170,295 Part of |Chromosome pair 17(cell structure)| GrCh38 Nucleotide start 43,044,295 ≡ GrCh38 Nucleotide end 437494961000004105 |BRCA1 gene locus (cell structure)| Breast cancer 1 BRCA1 gene locus |Nucleotide sequence(cell structure)| Chromosome region 17q21.31

20 Agreed flattened quality observable model template for trial use Nucleotide sequence property Variant call format Single point in time 704319004|Inheres in| Body structure 9216841000004100 |Inherent location | BRCA1 gene locus ≡ 704318007|Property type| 370134009 |Time aspect| 370132008 |Scale type| 613814021000004100 |BRCA1 nucleotide sequence detected (observable entity)| Observable entity 246501002 |Technique Nucleotide sequencing technique (technique)

21 Agreed flattened quality observable model template for trial use Nucleotide sequence variant Chr7 140719927 BRAFV600E V G… |GRCh38;CM000669.2 Finding site BRAF gene locus Interprets BRAF nucleotide sequence detected in malignancy ≡ Associated morphology Has value 412734009 |BRCA1 gene mutation positive (finding) Evaluation finding Currently defined with 405823003|BRCA1 mutation carrier test (procedure)

22 Molecular pathology build  Literature review should easily identify the genes reported with clinically significant variants  Automated build of genetic structures is feasible using HGNC reference data sets  Observables build could be templated from those gene concepts and significant clinical findings could be fully modeled

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