1. An extended SNOMED CT concept model for observations in molecular genetics
James R. Campbell MDac
Geoffrey Talmon MDad
Allison Cushman-Vokoun MD PhDa
Daniel Karlsson PhDbc
W. Scott Campbell PhDad
aDepartments of Internal Medicine and Pathology
University of Nebraska Medical Center
bDepartment of Biomedical Engineering; Linkoping University; Linkoping, Sweden
CObservables Project Group and diPALM SIG; IHTSDO

2. Outline Terminology challenges created by Personalized Medicine
What is an ‘Observable entity? Where do they fit in the SNOMED CT concept model? …the ONC terminology model?
LOINC – SNOMED CT harmonization model for observable entities
Anatomic and molecular pathology project at UNMC …Application of the harmonized model to genomics and molecular pathology?
Where do we go from here?

3. Revolution in healthcare
Sequencing of human genome has led to flood of new observational data appearing in scientific literature and now…clinical records
Majority of this clinical data is unstructured and not useful for decision support in the EHR or clinical research
Understanding of genetic and molecular basis of human disease now having impact on therapy
Challenge for precision medicine - to have sufficiently detailed molecular genetics observations and diagnostic data for clinical care and research

4. Limitations of ONC terminologies for observables in molecular pathology
Research community
NCBI: Gene Ontology; HGNC; OMIM; Orphanet; Protein Ontology; Cell ontology
Clinical community
SNOMED CT:
No concept model for subcellular anatomy (genes) or molecular structure (proteins)
No concept model for Observable entity or molecular basis of disease in Clinical findings
Little content
LOINC 2.54:
1275 PCR; 1406 MOLGEN; 116 FISH; 1502 CELL MARKERS
LOINC defining attributes inadequate to fully specify what is being resulted
Provides only tag-level interoperability of molecular data
No meaningful bridge joining genetic research findings with clinical concept models

5. Observable entity? IHTSDO Regenstrief institute
“Observables are considered to be partial observation results, where there is a defined part of the observation missing.”
“Concepts in this hierarchy can be thought of as representing a question or procedure which can produce an answer or a result”
“Observable + Evaluation (test) result = Finding”
Regenstrief institute
“…a set of universal names and ID codes for identifying laboratory and clinical test results”
“…master file of standard ‘test’ names and codes that will cover most of the entries in these files of operational laboratory systems”
“…organization of LOINC is divided first into four categories, ‘lab’, ‘clinical’ ‘attachments’ and ‘surveys’ ”

6. LOINC – SNOMED CT Harmonization of Observable entities
2008 agreement between Regenstrief (RI) and IHTSDO
Extend and harmonize a shared concept model for |Observable entity|
Map and instantiate LOINC parts in SNOMED CT content
Jointly publish expression data set defining (lab) LOINC concepts within the harmonized concept model
Technology preview alpha January 2016
Assertion: What is needed to support clinical decision making and research in molecular genetics is a unified domain ontology for Observable entities spanning clinical and research content including genomics

7. MP: Domain ontology Terminology Use Cases
Retrieve all colon cancer tissue specimens which had BRAF gene testing (IHC or sequencing)
Retrieve all breast cancer cases that tested ER-, PR- and Her2/Neu-
Identify all colon cancer cases with high degree microsatellite instability by PCR or absence of mismatch repair protein by IHC
Identify all cases with Stage IIIa non-small cell lung cancer that had EGFR mutation testing by any method

8. UNMC: Project for structured encoding of AP/MP cancer reports
Objective: Detailed structured reporting of all anatomic and molecular pathology observations for all CAP synoptic cancer worksheets (82 types of malignancies)
Proposal: Analyze detailed semantics of CAP worksheets; apply harmonized concept model to develop terminology requirements; deploy as real-time structured reporting from COPATH system interfaced to tissue biobank and EPIC
Tooling: Nebraska Lexicon© extension namespace; SNOWOWL authoring platform; SNOMED CT International + US Extension + Technology preview; ELK DL classifier
Penciled into IHTSDO workplan for 2017

9. Fully Encoded Checksheet

10. Observables Project: Concept model draft

11. SNOMED extensions for MP: Genes and proteins
Body structures>>Cell structures>>Nucleotide sequences and Genes
Substances>>Proteins
Qualifiers>>Techniques>> AP and MP methods
Qualifiers>>Measurement Properties>>AP and MP properties
Observable entity>>AP and MP observables
Clinical findings>>Anatomic and molecular genetic observation results and disorders

12. Developments for MP: Genes and proteins
Body structures>>Cell structures>>Nucleotide sequences and Genes
Substances>>Proteins
Qualifiers>>Techniques>> AP and MP methods
Qualifiers>>Measurement Properties>>AP and MP properties
Observable entity>>AP and MP observables
Clinical findings>>Anatomic and molecular genetic observation results and disorders
Define genes and related subcellular structures by
mapped reference to scientific ontologies classified
in conjunction with SNOMED CT & LOINC Observables

13. Developments for MP: Genes and proteins
Body structures>>Cell structures>>Nucleotide sequences and Genes
Substances>>Proteins
Qualifiers>>Techniques>> AP and MP methods
Qualifiers>>Measurement Properties>>AP and MP properties
Observable entity>>AP and MP observables
Clinical findings>>Anatomic and molecular genetic observation results and disorders
Define proteins and related molecular structures by
mapped reference to scientific ontologies classified
in conjunction with SNOMED CT & LOINC Observables

14. MP: Immunohistochemistry

15. Development for MP: Sequence datatypes

16. Molecular Pathology Finding: Fully defining observations of somatic sequence variants

17. Patient Problem List: Somatic mutation patient condition

18. Congenital (germline) mutations “Familial adenomatous polyposis”
Cancer predilection syndrome found to originate with multiple genetic etiologies:
FAP 1: heterozygous germline mutation of the APC gene
Gardner syndrome: clinical variant of FAP 1; includes desmoid tumors and other hamartomas; mutation of APC gene
FAP 2: mutation of MUTYH
FAP 3: mutation of MTHL1
FAP 4: mutation of MSH3

19. MP: Germline mutation use case: steps to define “Familial adenomatous polyposis 1”

20. MP: Germline mutations

21. MP: Germline mutations

22. Terminology development summary: Colorectal and Breast Cancer
SNOMED CT
hierarchy
Anatomic Pathology
Concepts/Primitives
Molecular Genetic
Exemplar molecular extension concepts
Observable entities
61/1
32/3
“BRAF nucleotide sequence detected in excised malignancy”
Body Structures
10/9
29/3
“BRAF gene locus”
Clinical findings
6/2
7/3
“BRAF V600E variant identified in excised malignancy”
Procedures
2/1
Techniques
4/4
7/7
“Pyrosequencing”
Property types
8/8
2/2
“Sequence property”
Scale types
9/9
“Variant call format”
Situations
1/0
Substances
0/0
11/11
“BRAF human cellular protein”
Attributes
3/3
Qualifiers
TOTALS
88/29
100/41

23. Deployment of MP data
HL7 interface to tissue biobank for indexing of tissue for research community
ETL of data to i2b2 data warehouse
Publication of laboratory/pathology observables ontology with NLM and RI
Interface development and extension to structured pathology data for EHR

24. HLA Histocompatibility

27. Gene and associated protein
HLA-A gene locus(cell structure)
ISA Nucleotide sequence
ISA Chromosome structure
Part of Chromosome pair 6
Chromosome region 6p22.1
|HLA-A antigen(substance)|