hl7 v3 clinical genomics overview - hl7elc.orghl7elc.org/ihic2010/genomics-as.pdf · the hl7...

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IHIC 2010

© 2002-2007 Health Level Seven ®, Inc. All Rights Reserved.

HL7 and Health Level Seven are registered trademarks of

Health Level Seven, Inc. Reg. U.S. Pat & TM Off

The HL7 Clinical Genomics Work Group

Prepared by Amnon Shabo (Shvo), PhD

HL7 Clinical Genomics WG

Co-chair and Modeling Facilitator

HL7 Structured Documents WG

CDA Co-editor

CCD Implementation Guide Co-editor

HL7 v3 Clinical Genomics –

Overview

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The HL7 Clinical Genomics Work Group

Mission To enable the standard use of patient-related genetic data such as DNA sequence variations and gene expression levels, for healthcare purposes („personalized medicine‟) as well as for clinical trials & research

Work Products and Contributions to HL7 ProcessesThe Work Group will collect, review, develop and document clinical genomics use cases in order to determine what data needs to be exchanged. The WG will review existing genomics standards formats such as BSML (Bioinformatics Sequence Markup Language), MAGE-ML (Microarray and GeneExpression Markup Language), LSID (Life Science Identifier) and other. This group will recommend enhancements to and/or extensions of HL7's normative standards for exchange of information about clinical genomic orders and observations.

In addition, Clinical Genomics will seek to assure that related or supportive standards produced by other HL7 groups are robust enough to accommodate their use in both research and clinical care use. The group will also monitor information interchange standards developed outside HL7, and attempt harmonization of information content and representation of such standards with the HL7 content and representation.

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Overview of Activities

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v3:

Family History (Pedigree) Topic

Genetic Variations Topic

Gene Expression Topic

CMETs defined by theDomain

v2:

v2 Implementation Guides

* The IG “Genetic Test Result Reporting to EHR” is modeled after the HL7 Version 2.5.1 Implementation Guide: Orders And Observations; Interoperable Laboratory Result Reporting To EHR (US Realm), Release 1

CDA:

A CDA Implementation Guide for Genetic Testing Reports

Common:

Domain Analysis Models for the various topics

A Domain Information Model (v3) describing the common semantics

Semantic alignment among the various specs

Three Tracks:

Normative

DSTU

Informative

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HL7 Clinical Genomics: The v3 Track

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Family

History

Domain Information Model:

Genome

Gene Expression

Phenotype(utilizing the HL7

Clinical Statement)

Utiliz

e

Co

ns

train

Genetic VariationC

on

stra

in

utilize

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To achieve semantic interoperability…

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Clinical

Trials

Imaging

EHR

Orders &Observations

Pharmacy

Clinical

Guidelines

Health

RIM

Clinical

Documents

Clinical

Genomics

Central Health RIM (e.g., an extended HL7 V3 Reference Information Model):

Bio & medical-informatics standard specs are derived from the same RIM

…we need standard specs derived from a Central Health RIM:

Bioinformatics

Data Models

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Utilizations / Implementation

Utilization by other HL7 Domains HL7 RCRIM Work Group (clinical trials specs) utilizes the CG

models in their new Pharmacogenomics message, which is an extension of the CTLab message

The Lab Work Group might utilize a constrained version of the Genetic Variation model in their Result message

Selected Implementations The Family History spec is used in Mass General Hospital

Expanding to other family history applications including the US Surgeon General Family History tool

The Genetic Variation model is used in Hypergenes (a European project on essential hypertension, http://www.hypergenes.eu/)

The Pedigree and Genetic Variation models are used in Italy, the Rizzoli institute in Bologna

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http://www.hypergenes.eu/

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Health Level Seven, Inc. Reg. U.S. Pat & TM Off 7

0..* associatedObservation

typeCode*: <= COMP

component

0..* associatedProperty

typeCode*: <= DRIV

derivedFrom2

0..* polypeptide

typeCode*: <= DRIV

derivedFrom5

SEQUENCES & PROTEOMICS

0..* expression

typeCode*: <= COMP

component1

0..* sequenceVariation

typeCode*: <= COMP

component3

IndividualAlleleclassCode*: <= OBS

moodCode*: <= EVN

id: II [0..1]

negationInd: BL [0..1]

text: ED [0..1]

effectiveTime: GTS [0..1]

value: CD [0..1] (allele code, drawn from HUGO-HGVS or OMIM)

methodCode: SET<CE> CWE [0..*]

GeneticLocusclassCode*: <= OBS

moodCode*: <= EVN

id: II [0..1]

code: CE CWE [0..1] (e.g., ALLELIC, NON_ALLELIC)

text: ED [0..1]

effectiveTime: IVL<TS> [0..1]

confidentialityCode: SET<CE> CWE [0..*] <= Confidentiality

uncertaintyCode: CE CNE [0..1] <= Uncertainty

value: CD [0..1] (identifying a gene through GenBank GeneID with an optional translation to HUGO name.)


0..* individualAllele

typeCode*: <= COMP

component1

SequenceclassCode*: <= OBS

moodCode*: <= EVN

id: II [0..1]

code: CD CWE [1..1] (the sequence standard code, e.g. BSML)

text: ED [0..1] (sequence's annotations)



value: ED [1..1] (the actual sequence)

interpretationCode: SET<CE> CWE [0..*] <= ObservationInterpretation

methodCode: SET<CE> CWE [0..*] (the sequencing method)

ExpressionclassCode*: <= OBS

moodCode*: <= EVN

id: II [0..1]

code: CE CWE [1..1] (the standard's code (e.g., MAGE-ML identifier)


text: ED [0..1]



value: ED [1..1] (the actual gene or protein expression levels)



PolypeptideclassCode*: <= OBS

moodCode*: <= EVN

id: II [0..1]

text: ED [0..1]


value: CD [0..1]

(protein code, drawn from SwissProt, PDB, PIR,

HUPO, etc.)


DeterminantPeptidesclassCode*: <= OBS

moodCode*: <= EVN

id: II [0..1]

text: ED [0..1]


value: CD [0..1]

(peptide code, drawn from reference

databases like

those used in the Polypeptide class)


Constrained to a restricted

MAGE-ML constrained schema,

specified separately.

Constraint: GeneExpression.value

Note:

A related allele that is on

a different locus, and has

interrelation with the

source allele, e.g.,

translocated duplicates

of the gene.

0..* clinicalPhenotype

typeCode*: <= PERT

pertinentInformation

ExternalObservedClinicalPhenotypeclassCode*: <= OBS

moodCode*: <= EVN

id*: II [1..1]

(The unique id of an external observation residing outside of the instance)

code: CD CWE [0..1]

text: ED [0..1]


Note:

An external observation is preferably a valid observation

instance existing in any other HL7-compliant instance,

e.g., a document or a message.

Use the id attribute of this class to point to the unique

instance identifier of that observation.

Note:

A phenotype which has been actually

observed in the patient represented

internally in this model.

Note:

This is a computed outcome, i.e.,

the lab does not test for the actual

protein, but secondary processes

populate this class with the

translational protein.

SequenceVariationclassCode*: <= OBS

moodCode*: <= EVN

id: II [0..1]

code: CD CWE [0..1]


text: ED [0..1]


value: ANY [0..1]

(The variation itself expressed with recognized notation like 269T>C or markup like BSML or drawn from an

external reference like OMIM or dbSNP.)



KnownClinicalPhenotypeclassCode*: <= OBS

moodCode*: <= DEF

code: CD CWE [0..1]

text: ED [0..1]


uncertaintyCode: CE CNE [0..1] <= ActUncertainty

value: ANY [0..1]

Note:

These phenotypes are not the actual (observed)

phenotypes for the patient, rather they are the

scientifically known phenotypes of the source

genomic observation (e.g., known risks of a

mutation or know responsiveness to a medication).

Note:

Code: COPY_NUMBER, ZYGOSITY, DOMINANCY, GENE_FAMILY,

etc. For example, if code = COPY_NUMBER, then the value is of

type INT and is holding the no. of copies of this gene or allele.


typeCode*: <= PERT


EXPRESSION DATA

SEQUENCE VARIATIONS

Polypeptide

Note:

The Expression class refers to both gene and protein

expression levels. It is an encapsulating class that allows

the encapsulation of raw expression data in its value attribute.

0..* sequence

typeCode*: <= COMP

component2


typeCode*: <= PERT



typeCode*: <= PERT


Note:

The code attribute indicates in

what molecule the variation occurs,

i.e., DNA, RNA or Protein.

0..* expression

typeCode*: <= COMP

component5

Note:

Use the associations to the shadow

classes when the data set type (e.g.,

expression) is not at deeper levels

(e.g., allelic level) and needs to be

associated directly with the locus

(e.g., the expression level is the

translational result of both alleles).

0..* associatedObservationtypeCode*: <= COMP

component2

0..1 associatedObservation

typeCode*: <= COMP

component4 Note:

This recursive association

enables the association of an

RNA sequence derived from

a DNA sequence and a

polypeptide sequence derived

from the RNA sequence.


typeCode*: <= PERT


Note:

This class is a placeholder for a specific locus on the genome - that is - a position of a particulargiven sequence in the subject’s genome or linkage map.Note that the semantics of the locus (e.g., gene, marker, variation, etc.) is defined by data assignedin the code & value attributes of this class, and also by placing additional data relating to thislocus into the classes associated with this class like Sequence, Expression, etc..

Note:

The term 'Individual Allele' doesn't refer necessarily to a

known variant of the gene/locus, rather it refers to the

individual patient data regarding the gene/locus and might

well contain personal variations w/unknown significance.

AssociatedObservationclassCode*: <= OBS

moodCode*: <= EVN

id: SET<II> [0..*]

code: CD CWE [0..1]

text: ED [0..1]


value: ANY [0..1]


Note:

The code attribute could hold codes like

NORMALIZED_INTENSITY, P_VALUE, etc.

The value attribute is populated based on the

selected code and its data type is then setup

accordingly during instance creation.

Note:

The code attribute could hold codes like TYPE,

POSITION.GENOME, LENGTH, REFERENCE, REGION, etc..

The value attribute is populated based on the selected code

and its data type is then setup accordingly during instance

creation. Here are a few examples:

If code = TYPE, then the value is of type CV and holds one of the

following: SNP (tagSNP), INSERTION, DELETION,

TRANSLOCATION, etc.

if code = POSITION, then value is of type INT and holds

the actual numeric value representing the variation position

along the gene.

if code = LENGTH, then value is of type INT and holds

the actual numeric value representing the variation length.

If code = POSITION.GENE, then value is of type CV and is one

of the following codes:

INTRON, EXON, UTR, PROMOTER, etc.

If code = POSITION.GENOME, then value is of type CV and is one

of the following codes:

NORMAL_LOCUS, ECTOPIC, TRANSLOCATION, etc.

If the code = REFERENCE, then value is

type CD and holds the reference gene identifier drawn from a

reference database like GenBank.

The full description of the allowed vocabularies for codes and its

respective values could be found in the specification.

AssociatedObservation

Note:

Code: CLASSIFICATION, etc.

For example, if code =

CLASSIFICATION, then the value

is of type CV and is holding either

KNOWN or NOVEL.

reference

0..* geneticLocus

typeCode*: <= REFR

Note:

A related gene that is on a

different locus, and still

has significant interrelation

with the source gene (similar

to the recursive association

of an IndividualAllele).

ClinicalPhenotypeclassCode*: <= ORGANIZER

moodCode*: <= EVN

0..* observedClinicalPhenotype

typeCode*: <= COMP

component1

0..* knownClinicalPhenotype

typeCode*: <= COMP

component2

0..* externalObservedClinicalPhenotype

typeCode*: <= COMP

component3

At least one of the target acts of

the three component act relationships

should be populated, since this is

just a wrapper class.

Constraint: ClinicalPhenotype

Note:

- code should indicate the type of source, e.g., OMIM

- text could contain pieces from research papers

- value could contain a phenotype code if known

(e.g., if it’s a disease, then the disease code)

ClinicalPhenotype

ClinicalPhenotype

ClinicalPhenotype

ClinicalPhenotype

ClinicalPhenotype

ClinicalPhenotype

0..1 identifiedEntity

typeCode*: <= SBJ

contextControlCode: CS CNE [0..1] <= ContextControl "OP"

subject

reference

0..* individualAllele

typeCode*: <= REFR

ObservedClinicalPhenotype

Note:

This CMET might be replaced

with the Clinical Statement Shared

Model for richer expressivity, when

the that mode is approved

(currently in ballot).

Constrained to a restricted BSML

content model, specified in a

separate schema.

Constraint: Sequence.value

0..* sequence

typeCode*: <= COMP

component4

0..* sequenceVariation

typeCode*: <= COMP

component3

AssociatedPropertyclassCode*: <= OBS

moodCode*: <= EVN

code: CD CWE [0..1]

text: ED [0..1]

value: ANY [0..1]


typeCode*: <= DRIV

derivedFrom1


0..* associatedObservation

typeCode*: <= COMP

component

AssociatedProperty



typeCode*: <= DRIV

derivedFrom

AssociatedProperty0..* associatedProperty

typeCode*: <= DRIV

derivedFrom1

AssociatedObservation0..* associatedObservation

typeCode*: <= COMP

component

0..* sequenceVariationtypeCode*: <= DRIV

derivedFrom3derivedFrom2

0..* sequence

typeCode*: <= DRIV

0..* determinantPeptides

typeCode*: <= DRIV

derivedFrom4

0..* determinantPeptides

typeCode*: <= DRIV

derivedFrom


typeCode*: <= PERT

pertinentInformation 0..* clinicalPhenotype

typeCode*: <= PERT


AssociatedProperty


typeCode*: <= DRIV

derivedFrom

AssociatedProperty

GeneticLociclassCode*: <= OBS

moodCode*: <= EVN

id: SET<II> [0..*]

code: CD CWE [0..1]


value: ANY [0..1]

0..* geneticLocitypeCode*: <= COMP

componentOf


typeCode*: <= PERT


GeneticLoci

0..* geneticLoci

typeCode*: <= COMP

componentOf

GeneticLoci

0..* geneticLoci

typeCode*: <= COMP

componentOf

0..* polypeptide

typeCode*: <= DRIV

derivedFrom1

Polypeptide

0..* polypeptide

typeCode*: <= DRIV

derivedFrom2

Note:

Use this class to indicate a set of genetic loci

to which this locus belongs. The loci set could

be a haplotype, a genetic profile and so forth.

Use the id attribute to point to the GeneticLoci

instance if available. The other attributes

serve as a minimal data set about the loci group.

PHENOTYPES

Note:

Any observation related to the variation and is not

an inherent part of the variation observation (the latter

should be represented in the AssociatedProperty class).

For example, the zygosity of the variation.

Note:

Use this class to point to a variation

group to which this variation belongs.

For example, a SNP haplotype.

Note:

Any observation related to the sequence and is not

an inherent part of the sequence observation (the latter

should be represented in the AssociatedProperty class).

For example, splicing alternatives.

Note:

Key peptides in the protein

that determine its function.

Note:

There could be zero to many

IndividualAllele objects in a

specific instance. A typical

case would be an allele pair,

one on the paternal

chromosome and one on the

maternal chromosome.

Note:

Use this class to

show an allele

haplotype like in HLA.

Note:

Any observation

related to the

expression assay

and is not an

inherent part of

the expression

observation.

Note:

Use this class for

inherent data

about the locus, e.g.

chromosome no.

IdentifiedEntityclassCode*: <= IDENT

id: SET<II> [0..*]

code: CE CWE [0..1] <= RoleCode

Note:

Use this role to identify a different subject

(e.g., healthy tissue, virus, etc.) than the

one propagated from the wrapping

message or payload (e.g., GeneticLoci).

ScopingEntityclassCode*: <= LIV

determinerCode*: <= INSTANCE

id: SET<II> [0..*]

code: CE CWE [0..1] <= EntityCode

0..* assignedEntity

typeCode*: <= PRF

contextControlCode: CS CNE [0..1] <= ContextControl "OP"

performer

0..*

performer

0..*

performer1

0..*

performer2

0..*

performer1

0..*

performer2

Genetic Locus(POCG_RM000010)

The entry point to

the GeneticLocus model

is any locus on the genome.

Constrained to a restricted MAGE-ML

content model, specified in a

separate schema.

Constraint: Expression.value

Expression

Sequence

SequenceVariation

SequenceVariation

0..* clinicalPhenotypetypeCode*: <= PERT


ClinicalPhenotype

CMET: (ASSIGNED)

R_AssignedEntity

[universal](COCT_MT090000)

0..1 scopedRoleName

CMET: (ACT)

A_SupportingClinicalInformation

[universal](COCT_MT200000)

The Locus

and its Alleles

Sequence

Variations

Expression

Data

Sequence

and

Proteomics

Clinical

Phenotypes

The DSTU GeneticLocus Model Focal Areas (DIM forerunner):

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The Underlying Paradigm:Encapsulate & Bubble-up

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Clinical PracticesGenomic Data

Sources

EHR

System

Bubble up the most clinically-significant raw

genomic data into specialized HL7 objects and

link them with clinical data from the patient EHR

Decision Support Applications

Knowledge(KBs, Ontologies, registries,

reference DBs, Papers, etc.)

Bridging is the challenge…

Encapsulation by

predefined &

constrained

bioinformatics

schemas

Bubbling-up is

done continuously

by specialized DS

applications

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Encapsulate & Bubble-up Example

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Decision Support Applications

Genetic CounselingDNA Lab

Bubble up the most clinically-significant SNP data into

HL7 SNP and Mutation objects and

link them with clinical data from the patient EHR

Sequencing Example…

Encapsulation by

a constrained

BSML schema

Bubbling-up is

done dynamically

by specialized

applications, e.g.,

sequence

analyzing

programs

EHR

System

Knowledge Sources

on genetic variants

(e.g., OMIM)

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Example: Family History XML Encoding

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Point

back…

Bubble

up…To

phenotype

and beyond….

Taken from a patient pedigree, the

portion related to patient’s daughter

(in collaboration with Partners HealthCare

& other HL7 CG SIG members)

Point back to the raw data of

this relative providing

“personal evidence”

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XML Fusion: Encapsulation of Raw Genomic Data

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Ra

w g

en

om

ic d

ata

re

pre

se

nte

d in

Bio

info

rma

tic

s m

ark

up

HL

7 v

3 X

ML

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The Domain Information Model - Genome

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Individual

Allele

Bio

Sequenc

e

Sequence Variation

(SNP, Mutation,

Polymorphism,

etc.)

Polypeptide

Expression Data

Phenotype

Entry Point:

Geneome

Expression

Attributes

Variation

Attributes

Encapsulating Obj.

Bubbled-up Obj.

genotypephenotype

Genetic

LociGenetic

Locus

Non-locus

specific

data

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The Phenotype Model

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Observed

Phenotype

Interpretiv

e

Phenotype

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The Genetic Variation CMET (passed

normative in Jan. 2010)

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Geneti

c Loci

Geneti

c

Locus

Individual

Allele

Sequenc

e

Variation

Sequence

(observed or

reference)

Participants

(including

specimen)

Associated

data (vocab.

Controlled)

Observed or

Interpretive

phenotypes

Genetic

Report (CDA)

Genetic

Testing

Order

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The HL7 RCRIM CT Laboratory Model-The Pharmacogenomics Extension

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Utilizes the Clinical

Genomics CMET

Genetic Lab

Clinical

Trial

Enrolled

Subject

Specimen

Consent to

Genotype

Pharmacogenomics

Test

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Gene Expression Topic

Domain Analysis

Model (DAM)

Passed informative

ballot

Based on several

models for gene

expression data

along with extensions

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New v3 Models for Future Ballot

Gene Expression CMET Model An Implementation Guide constraining the Genotype

models for gene expression data

Domain Information Model (Genome ) Allows non-locus specific data (e.g., large deletions,

cytogenetics, etc.) to be represented

Link to the locus-specific models, i.e., GeneticLoci & GeneticLocus

Query Model Based on the HL7 V3 Query by Parameter Infrastructure

Adds selected attributes from the Clinical Genomics models as parameters of the query message

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V2 Implementation Guides

The IG “Genetic Test Result Reporting to EHR” passed informative ballot

It is modeled after the HL7 Version 2.5.1 Implementation Guide: Orders And Observations; Interoperable Laboratory Result Reporting To EHR (US Realm), Release 1

Is used in a pilot of information exchange between Partners Healthcare and Intermountain Health Care

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The v2 Message Structure

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V2 Sample Message OBR|1||PM-08-J00094^HPCGG-

LMM^2.16.840.1.113883.3.167.1ÎSO|lm_DCM-pnlB_L^Dilated Cardiomyopathy Panel B (5 genes)^99LMM-ORDER-TEST-ID||20080702000000|20080702100909|||||||||234567891^Pump^Patrick^^^^^^NPI^L||||||20080703000000|||F||||||00000009^Cardiovascular^99HPCGG-GVIE-INDICATION^^^^^^Clinical Diagnosis and Family History of DCM|&Geneticist&Gene&&&&&NPI^^^^^^^HPCGG-LMM&2.16.840.1.113883.3.167.1&ISO|||||||||||||||55233-1^Genetic analysis master panel ^LN

SPM|1|||119273009&Peripheral blood&SNM3&&&&0707Intl&&Blood,Peripheral|||||||||||||20080702000000

OBR|2||PM-08-J00094-1^HPCGG-LMM^2.16.840.1.113883.3.167.1ÎSO|55232-3^Genetic analysis summary panel^LN|||20080702000000|||||||||||||||20080703000000|||F||||^PM-08-J00094&HPCGG-LMM&2.16.840.1.113883.3.167.1&ISO

OBX|1|CWE|51967-8^Genetic disease assessed^LN||399020009^DCM-Dilated Cardiomyopathy^SNM3^^^0707Intl||||||F|20080702100909|||||||||||Laboratory for Molecular Medicine^L^22D1005307^^^CLIA&2.16.840.1.113883.4.7&ISO|1000 Laboratory Lane^Ste. 123^Cambridge^MA^99999ÛSA^B

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CDA IG for Genetic Testing Reports

Scope The Clinical Genomics and Structured Documents Work Groups

jointly develop a CDA Implementation Guide (IG) for genetic testing report

Design principles Follow existing report formats commonly used in healthcare &

research

Emphasize interpretations & recommendations

Provide general background information on tests performed

Represent interpretation by utilizing patterns of „genotype-phenotype‟ associations in the HL7 v3 Clinical Genomics and implement them as harmonized clinical statement entry-level templates in this IG

Reference HL7 Clinical Genomics instances as the place holders of raw data (personal evidences), similarly to referencing images (technically-wise)

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CDA GTR Section Outline

Section outline

Section: Tests Performed & Respective Results (including tests with no findings or failures)

Sub-section: Specimen Details

Sub-section: Genetic Variations

Sub-section: Gene & Protein Expression

Sub-section: Other tests & results

In each of the above optional sub-sections there should be zero to many testing details sub-sections.

Sub-section: Testing DetailsIn each of the Testing Details sub-sections, there should be the following nesting sub-sections and components: Sub-section: Tests Performed and Indications

Sub-section: Specimen details

Sub-section: Findings

(more)

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Alignment Among the Various Specs

v3 specs and CDA are all based the RIM CDA GTR-IG will be based on CDA R3

Depending on the “right side” of R3, if it allows RIM-based domain models, then alignment is trivial

v3-v2 alignment: Proposal: represent semantics with v3 and

implement it in various ways, one of which is v2; develop an “v2 ITS” for the v3 models

See proposal made by Amnon in a separate presentation(click here to see that presentation)

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HL7 Clinical Genomics - Implementation Roadmap - Jan2008.ppt

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Summary

Small group coping with v3, v2 and CDA

Clinical & Research environments

Genetic Variation - Normative CMET Vocabulary harmonization's (facilitator is back to activity)

Timing confusing: collecting specimen, extracting genetic material, identifying genomic observations, interpretation

Entry point into a choice box

CDA GTR through OHT CDA Editor

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The End

• Thank you for your attention…

• Questions? Contact Amnon at

[email protected]

• Comments of general interest should be

posted to

the CG mailing list at

[email protected]

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mailto:[email protected]


