HL7 v3 Clinical Genomics –

Overview

The HL7 Clinical Genomics Work Group

Prepared by Amnon Shabo (Shvo), PhD

HL7 Clinical Genomics WGCo-chair and Modeling Facilitator

HL7 Structured Documents WGCDA Co-editorCCD Implementation Guide Co-editorGTR Implementation Guide prime editor

HL7 RIMBAA WGPast Co-chair

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The Mission of HL 7 Clinical Genomics Work Group

� The HL7 Clinical Genomics Work Group (CGWG) supports the HL7 mission to create and promote its standards by enabling the communication between interested parties of clinical and genomic data related to an individual. The focus of the CGWG efforts is the personalization of the genomic data, the so-called ’omics differences in an individual’s genomic – and its association with relevant phenotypic and clinical information. Associations to interpretive/expected phenotypes will be modeled as knowledge that can be utilized to transform an individual's data into meaningful information.

� CGWG will facilitate the development of common standards for clinical research information management across a variety of organizations --including national and international government agencies and regulatory bodies, private research efforts, and sponsored research -- and thus the availability of safe and effective therapies by improving the processes and efficiencies associated with regulated clinical research.

� CGWG will strive to achieve common semantics across the clinical and research environments. Consequently, the group will start each standardization effort in Universal specifications that later on can be refined to specific realms.

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Overview of Activities

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 (e.g. , gene.exp, c.seq)

� A Domain Information Model (v3) describing the comm on semantics

� Semantic a lignment among the various specs

Three Tracks:

Normative

DSTU

Informative

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The Underlying Paradigm: Encapsulate & Bubble-up

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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Current activities

� Family History US Implementation Guide

� GTR (Genetic Testing Report) – CDA Implementation Guide

� v2 genetic testing results message – Laboratory Message Implementation Guide

� Clinical Sequencing Domain Analysis Model

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Family History: PHR-EHR-GEN Convergence

EHR PHR

Genomics

Enable

Decision Support

e.g., risk analysis

algorithms

Population Research

and Public Health

* Detailed description can be found in the Family H istory presentation

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The Family History Model (Payload)

Genomic CMETs

Patient

RelativeHL7 Vocabulary=

“FAMMEMB”

Recursive

Relation

Clinical

Data

Family History

Risk Assessment

Results Estimated age of subject

Estimated age of subject at diagnosis

Relative Mother & Father IDs

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Example: Family History XML Encoding

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 DataR

aw g

eno

mic

dat

a re

pre

sent

ed

in

Bio

info

rmat

ics

mar

kup

HL7

v3

XM

L

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The Pedigree Spec - Updates

� HL7 Normative Standard since 2007 and reaffirmed in May 2012 for 5 more years

� Pilots: � Hughes Risk Applications� Surgeon General’s My Family Health Portrait � Many more…

� HL7 US Realm IG � Under development with expected balloting in Sept 2 012� Transmission supported in CCD� Accommodate MU Stage 2 requirements

� Release 2 in progress� Update representation of genetic data� Accommodating ISO ballot comments

� FHIR Pedigree?!10

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Pedigree Implementation Guide for US Realm

� Specify the exchange format to be compliant with MU� Reusing HITSP CCD exchange; CCD instance references a Pedigree

� Simplify the genetic representation by constraining out the full blown genomic CMETs and use GTR suggested conventions

� Specify clinical data using SNOMED (following HughesRiskApp IG)� Do we need dynamic binding?

� Representing interpretation as in GTR (constrain ou t the interpretation code attribute)

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Pedigree Implementation Guide for US Realm -cont.

� Pedigree R 1 was adopted by MU 2 Final Ruling"The HL7 Pedigree standard was originally released in 2007. Release 1 was recently reaffirmed by the American National Standards Institute (ANSI), which is a process that occurs every five years. We have adopted this reaffirmed version as it is the same version (Release 1) of the standard as the version we proposed. An implementation guide for this standard is scheduled to be published shortly after this final rule. Although EHR technology will not be required to conform to the implementation guide for certification, the implementation guide will provide important guidance for use of the HL7 Pedigree standard with EHR technology."

� Balloted in January 2013:� Passed as follows:HL7 Version 3 Implementation Guide: Family History/Pedigree Interoperability, Release 1 - US RealmLvl. I1; Aff. 36; Neg. 3; Abst. 67; NV 13; TotP. 119; Q. 89.08%; A. 24

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FHIR Pedigree

� Scoping:� Risk assessment results� Genetic models� Branching out to any no. of generation

� Backward compatible ?

� Mapped back to the v3 model !

� Do we have the bandwidth to do it ?

� We’re asked on no. and scope of genomic resources

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CDA IG: Genetic Testing Report (GTR)

� Define an implementation guide for a genetic testin g report that is both human readable and machine-processable� Target at all types of GTR producers, e.g., genetic labs, clin. geneticists� Readable content is larger in scope� E.g., detailed description of the tests performed a long with references� Machine-processable should be limited, e.g., exclud e raw data

� Ballot a Universal IG; then derive ���� specific types of GTR:� Healthcare & Research � Realm-specific guides� Omic-specific guides

� Developed using the MDHT open source tool (OHT)

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GTR - Design Principles

� Follow existing report formats commonly used in healthcare & research

� Emphasize interpretations & recommendations

� Provide general background information on tests performed

� Reference HL7 Clinical Genomics instances (e.g., v3 or v2 GeneticVariation and Pedigree) as the place holders of full-blown raw genomic data and fully-structured family histor y data

� Utilize patterns of ‘ genotype-phenotype ’ associations in the HL7 v3 Clinical Genomics Domain� Implement them as ‘ clinical genomic statement ’ entry-level templates

(see next slide), enabling meaningful use of the data

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The Clinical Genomic Statement

� An abstract Clinical Genomic Statement (CGS) templa te that� Has at its core a genomic observation (e.g., a DNA sequence variation)� If it’s a reportable finding, then it should be ass ociated with indications and interpretations,

specimen and genomic source class� The major finding can be associated with associated observation (e.g., amino acid change)� Optionally, performers may be specified (overriding header performers)

� The CGS abstract template is instantiated by specia lized CGS’s, e.g., for genetic variations or cytogenetics

Indications InterpretationsGenomicObservation

Performers

SpecimenGenomic Source

Clin

ical

Ge

nom

ic S

tate

men

t

Associated Observations

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Detailed description can be found in the GTR presentation

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CDA GTR Ballot Status

� Balloted in several cycles for comments and DSTU

� Passed as DSTU in Oct. 10 & Sep. 12

� Decided to publish in December 2012

� Motion passed to approve the Publication Request Fo rm

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Collaboration with APWG around CDA IGs

� Development:� How do we share templates with AP (Anatomic Patholo gy)?� MDHT SVN could be an option

� Harmonization:� One consolidated document template or two interrela ted and harmonized docs?� Workflows could dictate the way documents shape up…� Could we share specimen templates?� Could we harmonize summary / diagnosis templates?� Could we agree on a clinical statement approach whe re all pieces are tied

together in one coherent structure?

� Comments on the APSR sample:� Is problem == reason for AP procedure?� Why “Left upper outer quadrant breast palpable mass” is considered illness?� APSR sample has CDA Validation issues

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V2 Implementation Guides

� A v2 laboratory message implementation guide for genetic testing result� A message from the genetic lab to the EHR � An approved informative spec

� It is modeled after the HL7 Version 2.5.1 Implementation Guide: Orders And Observations; Interoperable Laboratory Result Reporting To EHR (U S 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^2.16.840.1.113883.3.167.1 ISO|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^2.16.840.1.113883.3.167.1 ISO|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^99999^USA^B

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Clinical Sequencing Analysis Model

� Extends ONC Personalized Healthcare Use Case (2008) for support of clinical sequencing and current understanding of the field

� Serve as� Roadmap for further standards

development/extension� Develop use cases and requirements for related

projects (e.g. Specimen DAM and Specimen CMET Release 2)

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C.Seq. Workflows

Different compatible standards may need to be used at different parts in the workflow (e.g. lab order vs. result reporting). Therefore, starting with workflow definition and key data needs is important (e.g. clinical indication for ordering the test).

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Clinical Sequencing Workflow – Germline Testing

LaboratoryHealthcare

Provider

Geneticist /

Medical Geneticis t /

Molecular Pathologist

Patient

Clinician/Clinical

Research submits

test order

with clinical/

family history,

indication,

specimen

preference as

appropriate

Specimen

colle ction

Receiving

Accession order and

specimens

Specimen Process ing

Testing

Bioinformatic

Analysis

Interpretation

ReportingReview Re sults/

Report

Care Plan

Development

Receive Structure d

Results

(may include

variome)

into EHR

Consent to Te st

Patient Access to

D ata and Results

(preparation for

future )

Indication for

Genetic Testing

Review Findings

with Patient

Transcoding

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Alternative Workflows

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Systems by Stakeholder Group

These serve as potential integration points (e.g. dbSNP ID for links to dbSNP variant record).

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Clinical Sequencing – Ballot Results

� Balloted in January 2013 for comments only

� Results:� Didn’t pass, tally follows:

HL7 Version 3 Domain Analysis Model: Clinical Sequencing, Release 1Lvl. O1; Aff. 38; Neg.0; Abst. 75; NV 19; TotP. 132; Q. 85.61%; A 0

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For v3 standards – see backup slides

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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 UML and implemen t it in various

ways, e.g., v3 using the existing v3 ITS and v2 bei ng another format (develop an “v2 ITS” for the UML models)

� See proposal made by Amnon in a separate presentati on

� FHIR can be the single source of semantics

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Selected Implementation

� v2� Exchange of genetic testing results between Intermountain and Harvard

� v3� 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

� CDA� GTR has been used in uHealth – a PHR/EHR system in Korea

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Other Domain Analysis Models

Work in progress…

� Clinical Genomics DAM

� Gene Expression DAM

� Harmonize with NCI LS -DAM and CDISC BRIDG

� Specimen (led by OO and AP Work Groups)� Specimen DAM� Specimen Unique ID� Specimen CMET Release 2

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Omics in the LS DAM - Molecular Biology (outdated)

class Molecular Biology Core

Chromosome

+ name: ST

NucleicAcidPhysicalLocation

+ endCoordi nate: INT+ startCoordi nate: INT

NucleicAcidSequence

NucleicAcidSequenceFeature

+ orientation: ST+ typeCode: CD

Protein

+ name: DSET<SC>+ symbol: DSET<SC>

Gene

+ name: DSET<SC>+ symbol: DSET<SC>

SingleNucleotidePolymorphism

AminoAcidSequenceFeature

+ typeCode: CD

ExonIntron

MolecularSequence

+ value: SC

AminoAcidSequence

Genome

+ assembl ySource: ST+ assembl yVersi on: ST

CytobandRange

+ endBand: ST+ endChromosomeArm: ST+ startBand: ST+ startChromosomeArm: ST

AminoAcidPhysicalLocation

+ endCoordi nate: INT+ startCoordinate: INT

GeneticVariation

MessengerRNA

DNASequence

RNASequence

MolecularSequenceAnnotation

+ date: TS

Name: Mol ecular Biol ogy CoreAuthor: lschickVersi on: 1.0Created: 6/17/2011 2:49:18 PMUpdated: 1/9/2012 1:43:45 PM

BRIDG-ali gned

LS DAM

Legend0..*

i ncludes / isi ncluded in

1

1..*

contains / is partof

1

1

is i ncluded i n /incl udes

0..*

1..*i s for /has 0..1

0..*

i s incl uded in /i ncludes

1..*

1

i s l ocated on /has

1..*

1..*

is transl ated to /is transl ated from

0..1

0..*

is representedby / represents

0..*1..*is incl uded i n

/ incl udes 1

0..*is located i n /has

0..*

0..*

is located i n /has

0..*

0..*

is incl uded i n /incl udes

1..*0..*

encodes / i s encodedby

0..*

0..*

i s transcri bed to /i s transcri bed from

0..*

0..*reports / isreported by 0..*

0..*

reports / isreported by 0..*

0..*is representedby / represents 0..*

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Omics in the LS DAM - Experiment (outdated)class Experiment Core

Experiment

+ acti veDa teRange: I VL<TS>+ descr ip tion: ST+ designType : DSET<SC>+ name: ST+ ty peCode : CD

Experi menta lFac tor

+ name: ST+ t ypeCode : SC+ va lue : DS ET<ANY>

Experimenta lPa rame te r

+ descrip ti on : ST+ name: ST+ st at usCode : CD+ typeCode: CD

Experi menta lStudy

+ acti veD ateRange : I VL<TS>+ descr ip tion: ST+ name: ST+ t ypeCode : DSET<CD>

P ointO fContac t

+ ef fectiv eDa teRange : IVL<TS.DATET IME>+ post alA dd ress: AD+ p ri mary Ind ic ato r: BL+ t el ecomAddress: BAG <TEL>+ t ypeCode : CD

cons trai nts{Exc lusi veO r}

Protocol

+ name: ST

Data

+ crea tionDat e: TS. DATETIME

Experi menta lPa rameterVa lue

StringParame te rVa lue

+ v alue : ST

Quanti tat iveParameterVa lue

+ range: IVL<PQ>+ si ng le : PQ

Act ivit y

+ comment : ST+ iden tif ie r: II+ reasonCode : DSET<CD>

Sof tw a re

+ bu ildDat e: TS. DATE+ bu ildNumber: ST+ c on tent : ED+ e ff ect iveDat eRange : IVL<TS>+ i den tifi er : DSET<I I>+ l icenseEffect iveDat eRange : IVL<TS. DATE>+ l icenseKey : ST+ l icenseTypeCode : CD+ name: ST+ t ypeCode : CD+ v ersi on : ST

Product

Equipment

+ manu factu reDa te: TS. DATETIME+ rep rocessedDeviceCode : CD+ va li dat ionDat e: DSE T<TS.DATETIME>

Mate rial

+ descri pt ion: ST+ e ffecti veDa teRange: I VL<TS.DATET IME>+ fo rmCode : CD+ func tionT ypeCode : DSET<CD>+ nameCode : CD+ subTypeCode: CD+ typeCode : C DExperimenta lI tem

+ typeCode : C D

const ra ints{Excl usiveOr }

Def inedAc tiv i ty

+ c at egoryCode : CD+ desc rip tion : ST+ nameCode : CD+ st atusCode : CD+ st atusDat e: TS. DATETIME

PlannedAc tiv it y

+ desc rip tion : ST+ name: ST+ plannedD ura ti on : PQ. TIME+ pu rpose : ST+ targe tAcc rualN umberRange :

URG<INT.NO NNEG >

PerformedActi v ity

+ act ua lDa teRange: I VL<TS.DATETI ME>+ /actual Durati on : PQ. TIME+ /delayDura tion : PQ.TI ME+ missed Ind ic ato r: BL+ missedReason : DSET<SC>+ /repe ti tionNumber : INT.PO S+ st at usCode : CD+ st at usDa te : T S.DATETIME

N ame: Exper imen t CoreA utho r: lsch ickV ersion : 1. 0C rea ted : 11 /16 /2011 9:30 :18 AMU pdat ed : 12 /22 /2011 8:02 :53 AM

Spec imen no att ri butes

BRIDG-al igned

LS D AM

Legend

O rgani zat ion

+ actua lIndi ca tor : BL+ descr ip tion : S T+ name: DSET<ON>+ post al Add ress: AD+ t el ecomAddress:

BAG <TEL>+ t ypeCode : CD

Bio log icEn tity

Person

+ dea th Indi ca tor : BL+ educa tionLeve lCode : CD+ e thni cGroupCode: DSET<CD>+ in it ia ls: ST+ marit al Stat usCode : CD+ name: DSET<PN>+ occupa ti onDat eRange :

IV L<TS.DATE>+ posta lAdd ress: AD+ p rimaryO ccupa ti onCode : CD+ raceCode : DSET<CD >+ te lecomAddress: BAG <T EL>

0. .*

is used by / uses

0 .. *

0. .*

is pe rfo rmed as pe r /descr ibes the stepsto conduct

0.. *

0. .*

inst an tia tes

0 ..1

speci al izesspecia lizes speci al izes

0 ..*suppo rts / issuppo rted by

0 .. *

0. .*

instant iat es

0. .1

0 .. *

suppo rt s / i ssuppo rt ed by

0 ..*

0. .*

i s processed in to /i s processed from1

0 ..*

is p layed by / p lays

0. .1

spec ia lizes

0. .1i s a col lection of /i sconducted as pa rt of

0 .. *

0 .. *suppor ts / issuppor ted by

0 ..*

0 ..*

suppo rts / issuppo rted by

0 .. *

0. .1resu lts i n / is the resu lt of

0. .*

0. .1

resul ts in / is t he resul t o f

0 ..*

0. .*

pa rt icipa tes in /is per fo rmedon

1

1

has va lue /is v alue fo r

0. .*

0 ..*

i s a pa rt of / i s a col lection o f

0 ..*

0 ..*

uses / de fi nes use o f

0. .*

1

has va lue / is va lue f or

0 .. *

0. .*

suppo rts / issuppo rted by

0.. *

0. .*is p layed by / p lays

0. .1

0 ..*

is pl ay ed by / pl ay s

0 ..1

0.. *

suppor ts / issuppor ted by

0 ..*

0. .*

i s pa rt o f / is a co llect ion o f0 ..*

0 .. *uses / de fines use of

0 ..*

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Omics in the LS DAM - Specimen (outdated)class Specimen Core

SpecimenCollectionPr otocolSubject

B iologicEntity

+ actual Indic ator: BL+ adm inistrativeGenderCode: CD+ birthCountryCode: CD+ birthDate: TS.DATET IME+ birthO rder: INT.PO S+ deathDate: T S.DATETIM E+ sexG enoty peC ode: CD+ subSpec iesRank: SC

Animal

+ breedC ode: CD+ desc ription: ED+ reproduc tiveOrgansPresentIndic ator: BL+ strain: ST

Person

+ deathIndic ator: BL+ educ ationLevelCode: C D+ ethnicG roupC ode: DSET<CD >+ ini tia ls: ST+ mari talStatus Code: CD+ nam e: DSET<PN>+ oc cupationDateRange: IV L<TS .D ATE>+ postalAddress: AD+ prim aryO cc upationCode: CD+ rac eCode: DSE T<CD>+ telec om Address: BAG <TEL>

Subj ect A ctiv ity

+ com m ent: ST+ identi fier: II+ reasonCode: DSET<CD>

P er for medActiv ity

+ actualDateRange: IVL<TS .DATETIM E>+ /ac tualDuration: PQ.TIM E+ /delay Duration: PQ.TIM E+ mis sedIndic ator: BL+ mis sedReas on: DSET <S C>+ /repeti tionN um ber: IN T.POS+ status Code: CD+ status Date: TS.D ATETIM E

PerformedProcedur e

+ approachAnatomic Si teCode: CD+ approachAnatomic Si teLateral i tyCode: CD+ methodCode: CD+ targetAnatom ic Si teC ode: CD+ targetAnatom ic Si teC ondi tionCode: CD+ targetAnatom ic Si teLateral i ty Code: C D

PerformedSpecimenCollection

+ fastingStatusIndic ator: BL

PerformedObservation

+ bodyP os i tionCode: C D+ /foc alDateRange: IVL<TS.DA TETIM E>+ /foc alDuration: PQ .TIM E+ m ethodC ode: DSET<CD >+ targetAnatom icS iteCode: CD+ targetAnatom icS iteLateral i ty Code: CD

PerformedO bserv ationResult

+ bas elineIndicator: B L+ body Sy stem Code: CD+ com m ent: ST+ confidential i tyCode: CD+ identi fier: II+ reportedDate: TS .D ATETIM E+ resul t: ANY+ resul tC odeM odifiedText: ST+ targetAnatomic Si teCode: CD+ targetAnatomic Si teLateral i tyCode: CD+ typeCode: CD+ unc ertainty Code: CD

PerformedM edicalHistoryResult

+ ageAtDiagnosis : PQ+ endRelativ eToReferenceCode: CD+ oc currenc eDateRange: IVL<TS.DATETIM E>

Per for medClinicalResult

+ asCol lectedIndic ator: BL+ biomarkerIndicator: BL+ /infec tious Agent: ST+ /norm alRangeC om parisonCode: CD+ reportedResul tStatus Code: CD

P er for medDiagnosis

+ diseaseStatusCode: CD+ rec urrenc eIndic ator: BL

PerformedHistopathology

+ c el lTypeCode: D SET<CD>+ di fferentiationGradeCode: DSET <C D>+ inv olvedSurgic alMarginIndic ator: BL

PerformedLesionDescription

+ appearanc eTypeCode: C D+ c ontac tAnatom ic Si teCode: CD+ /dim ensionP roduc t: PQ+ lesionNum ber: INT.NO NNEG+ ly m phatic Inv asion: CD+ m easurableIndicator: BL+ perineural Invas ion: CD+ v enous Inv asion: CD+ x Dim ension: PQ+ y Dim ension: PQ+ z Dim ension: PQ

PerformedS pecimenQ ualityReview

PerformedPathologicalStaging

+ dis tantM etastasisStage: CD+ lym phNodeStage: CD+ metastasisS ite: CD+ num berLym phNodesE xam ined: INT+ num berLym phNodesInv olv ed: IN T+ prim aryT um orStage: CD

PerformedSpecimenReview Result

+ nam eCode: CD

PerformedMaterialProcessS tep

P er for medSpecimenEmbedded

+ embeddingM ediumTy pe: C D

PerformedSpecimenFixed

+ fix ationTy pe: CD

PerformedSpecimenFroz en PerformedSpecimenR eturn

PerformedSpecimenSpun

+ grav i tyForce: PQ

PerformedSpecimenThaw

PerformedSpecimenC heckInCheckO ut

+ storageStatus: CD

M aterial

+ desc ription: ST+ effectiv eDateR ange: IVL<T S.DATETIM E>+ form Code: CD+ func tionTy peC ode: DSET<CD >+ nam eCode: CD+ s ubTy peCode: CD+ ty peCode: CD

Specimen no attributesCellCulture

+ biosafety Level : CD

ExperimentalItem

+ typeCode: C D

constraints{Exc lusiveO r}

Product

+ ex pirationDate: T S.DATE.FULL+ lotNum berT ex t: ST.SIM PLE+ ty peCode: CD

Equipment

+ manufactureDate: TS .DATETIM E+ reproc es sedDevic eC ode: CD+ val idationDate: DSET<TS.DATETIM E>

M aterialR elationship

+ subTy peC ode: CD+ ty peCode: CD

Nam e: Specim en CoreAuthor: lsc hic kVersion: 1.0Created: 2/7/2011 9:02:28 AMUpdated: 1/10/2012 12:56:05 P M

C ontainer

+ c ontainerType: CD+ desc ription: ST+ dim ens ionO neCapaci ty : INT+ dim ens ionO neLabel : ST+ dim ens ionPointOfO rigin: ST+ dim ens ionThreeCapac i ty: INT+ dim ens ionThreeLabel : ST+ dim ens ionTwoCapaci ty : INT+ dim ens ionTwoLabel : ST+ nam e: ST

Place

+ identifier: DSET<II>+ loc atorTy peC ode: CD+ loc atorValue: S T+ phys icalAddres s: AD+ ty peCode: CD

StorageEquipment

+ dim ensionO neCapac i ty: INT+ dim ensionO neLabel : ST+ dim ensionP ointO fOrigin: ST+ dim ensionT hreeCapaci ty : INT+ dim ensionT hreeLabel : ST+ dim ensionT woCapac i ty: INT+ dim ensionT woLabel : ST

PerformedS pecimenP lacement

+ from Posi tionDim ensionO ne: INT+ from Posi tionDim ensionThree: INT+ from Posi tionDim ensionTwo: INT+ toP os i tionDim ensionO ne: INT+ toP os i tionDim ensionT hree: INT+ toP os i tionDim ensionT wo: INT

B iologicEntityIdentifier

+ effectiv eD ateRange: IVL<TS.D ATETIM E>+ identifier: II+ ty peCode: CD

Organization

+ ac tual Indic ator: BL+ des cription: ST+ nam e: DSET<O N>+ pos talAddress: AD+ telec omAddress: BAG <TEL>+ typeCode: CD

SubjectIdentifier

+ effec tiv eDateR ange: IV L<TS.D ATETIM E>

+ identi fier: II+ prim aryIndicator: BL+ ty peCode: CD

Manufacturer

Pr ocessor

R eprocessor

MaterialName

+ nam e: E N.TN+ ty peCode: CD

M aterialIdentifier

+ identi fier: II+ typeCode: CD

SpecimenCollectionG roup

+ nam e: ST

SpecimenCollectionProtocol

+ ac tiveDateRange: IVL<TS>+ al iquotInSam eContainer: BL+ c onsentsWaiv ed: BL+ enrol lm ent: INT+ i rbIdentifier: ST+ s hortTi tle: ST

Protocol

+ name: ST

Laboratory

+ identifier: II

CollectingLabor atory

BRIDG-al igned LS DA M

LS DAM

Legend

DefinedActiv ity

DefinedCompositionR elationship

CellLine

+ originC el lNam e: ST+ passageNum ber: INT+ sourc eA ge: PQ+ sourc eA natom icSi teCode: C D+ sourc eD ev elopm entalS tage: SC+ sourc eT is sueType: CD

M icrobiologicalCulture

0..1

plays / is played by

0..*

0..*

is the parent of 1

spec ial iz es

s pec ial iz es

0..*

identi fies

1

1..*

names/ isnamedby

1

0..*

is assigned by

0..1

spec ial iz es

0..1

play s / is play ed by

0..*

0..*

is a function perform ed by

{functions as}0..1

special iz es

0..*

iscontainedin

0..1

0..*

ins tantiates

0..1

s pec ial izes

1

is the produc t of / produc es

1

1

is the subjec t of / is performed on

0..*

spec ial izes0..*

is a func tion performed by

{functions as}1

0..1

is a func tionperform ed by

{func tions as}

1

0..*

is ass igned by{assigns}

1

0..*

identi fies / isidenti fied by

{is identi fied by } 1

0..1

is a function perform ed by{func tions as }

1

0..*

produc es

1..*

0..*

ex ec utes/ is executed at 1..*

0..*is the c om ponent of

1

0..*

is located at/is the location of

1

0..*

is enc losed by / enc los es

1

0..*is c onv erted into

0..1

1

is ass igner of/is as signed to

0..*

0..*

is assessed via / is an as sessm ent of

0..*

0..*

is part of / inc ludes

0..1

0..1is tak enfrom / takes

0..*

1

has / is a part of

0..*

0..*

is assignedby / ass igns

1

0..*

produces / is produc ed by

0..*

0..*

is deriv ed from / is source of

1

0..*

is perform ed on / is the subject of

1..*

0..*partic ipates in / is perform ed on

1

1

func tions as / is afunc tion perform ed by

0..*

0..*

is a resul t of

1

special iz es

special izes

special izes special iz es

s pec ial izes

1

isplac edat/plac es 0..*

0..1

res ul ts in / is the resul t of

0..*

1..*is col lected during / res ul ts in

0..1

0..1

produces / is the product of

0..1

0..* is part of / iscom pos ed of

1

0..*

is an assess ment of / is as sessed via

0..*

0..1

perform s / is perform ed at

1..*

0..*

is partic ipated inby / partic ipatesin

0..1

1

is identi fiedby /identi fies

0..*

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Gene Expression Topic (outdated)

� Domain Analysis Model (DAM)� Passed informative

ballot� Based on several

models for geneexpression dataalong with extensions

Haifa Research Lab

Looking forward….

36

Haifa Research Lab

The rise of the 'narciss-ome‘…

� Transformative paper in the Cell Journal

� Reviewed in Nature (http://www.nature.com/news/the-rise-of-the-narciss-ome-1.10240)

� iPOP – Integrative Personal Omics Profile� Our personal omics change over time!� Longitudinal examinations of genome, proteome, meta bolome,

autoantibodies, etc. of an individual (one of the a uthors)� Monitor healthy and disease states� Predict and act accordingly (the data predicted dia betes and diabetes

was diagnosed; life style changes make it manageabl e!)

37

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iPOP –Integrative Personal

Omics Profile

Should be standardized and be part of

the lifetime EHR !!

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HL7 WG Health Check – Need to Improve!

� Active projects� SWOT current� 3 year plan current� Mission and charter current� Co-chair post-WGM survey participation� Ballot presence� Minutes posted since last WGM� Last listserv activity� Wiki presence � WG conference calls schedules� Steering division conference call participation� Steering division co-chair (TSC representation) election participatio n� WG rep at steering division WGM� WG meetings at WGM scheduled� WG has an approved DMP based on review of the updat ed template

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Planning ahead

� May 2013 WGM (Atlanta)� Schedule (from Tuesday Q4 to Thursday Q1)� Joint meetings with:

� Wed. Q1: OO+AP+II� Wed. Q3: AP

� Weekly conf. calls� Continue Tuesday’s 11EST

� Three year plan update

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Summary

� Small group coping with � Various HL7 formats: v3, v2 and CDA� Clinical & Research environments

� Developing a DAM and component models (CMETs) to be used in other HL7 domains� Genetic Variation� Gene Expression

� CDA Genetic Testing Report (GTR)� Bridge from raw data to human readable reports and bubbled-up data� Model-driven development of standards (use of MDHT CDA Editor)

Haifa Research Lab

A new member? Here is how to participate:

� Through our mailing list (open to nonmembers as wel l)

� Provide comments to specs� Formally through the balloting process� Informally through the list or by corresponding wit h spec editors

� Weekly conference calls

� Project specific conf. calls:� Clinical sequencing� CG & GE DAMs� Specimen

42

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43

The End

• Thank you for your attention… ☺☺☺☺

• Questions? Contact Amnon at shabo@il.ibm.com

• Comments of general interest should be posted to the CG mailing list at clingenomics@lists.hl7.org

•See backup slides for more info on v3 standards

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HL7 Clinical Genomics v3 Static Models

Family

History

Utilize

Genetic

Locus(DSTU Expired)

Constrained GeneticVariation

Phenotype(utilizing the HL7

Clinical Statement)

Utilize

Implementation Topic

Normative

DSTU

Constrained Gene Expression

Implementation Topic

Comments

RCRIM LAB

Other domains

Utilize

Utilize

CDA IG

Re

fere

nce

Reference

Domain Information

Model: Genome

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To achieve semantic interoperability…

ClinicalTrials

Imaging

EHR

Orders &Observations

Pharmacy

ClinicalGuidelines

Health RIM

ClinicalDocuments

ClinicalGenomics

Central Health RIM (e.g., an extended HL7 V3 Refere nce Information Model):Bio & medical-informatics standard specs are derive d from the same RIM

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

Bioinformatics

Data Models

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The Locus

and its Alleles

Sequence

Variations

Expression

Data

Sequence

and

Proteomics

(Clinical)

Phenotypes

The DSTU GeneticLocus Model (deprecated) Focal Area s:

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The Underlying Paradigm: Encapsulate & Bubble-up

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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Decision Support Applications

Encapsulate & Bubble-up Example

Genetic CounselingDNA Lab

Bubble up the most clinically-significant SNP data intoHL7 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

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 DataR

aw g

eno

mic

dat

a re

pre

sent

ed

in

Bio

info

rmat

ics

mar

kup

HL7

v3

XM

L

Haifa Research Lab

Other v3 Models / Efforts

� The Genome � An HL7 Domain Information Model (DIM)� Evolved as generalization of the Genotype DSTU model s� Was not balloted� Will be updated based on the DAM efforts� In the future, DAM balloting will require the mappi ng to DIM

� The RCRIM use of our DSTU CMETs

� Query model

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The Domain Information Model - Genome

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.

genotype ��������phenotype

Genetic Loci

Genetic Locus

Non-locus specific

data

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The HL7 RCRIM CT Laboratory Model-The Pharmacogenomics Extension

Utilizes the Clinical Genomics CMET

Genetic Lab

Clinical

Trial

Enrolled Subject

Specimen

Consent to Genotype

Pharmacogenomics Test

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The CG V3 Query Model: Query by Parameter

GeneticLocus parameters

Starting point with query

identifiers and attributes

Miscellaneous parameters

GeneticLoci parameters

participants parameters

Phenotype parameters

Haifa Research Lab

HL7 Clinical Genomics CMETs

� CMET – a shared v3 model used by domain models

� Current CMET efforts:� Phenotype � Genetic Variation � Gene Expression� Pedigree

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The Phenotype CMET Model

Observed Phenotype

Interpretive Phenotype

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The Genetic Variation CMET (passed normative in Jan. 2010)

Genetic Loci

Genetic

Locus

Individual Allele

Sequence

Variation

Sequence

(observed or reference)

Participants

(including specimen)

Associated data (vocab. Controlled)

Observed or Interpretive phenotypes

Genetic Report (CDA)

Genetic Testing Order

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

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The Gene Expression CMET Draft

Genetic Loci

Genetic Locus

Gene Expression

Associated observations

GTR Report

Participants

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Utilizations in HL7

� Clinical Trials:HL7 RCRIM Work Group (clinical trials specs) utilized the CG DSTU model (Genetic Locus) in their Pharmacogenomics message, which was an extension of the CTLab message(an approved but expired DSTU)

� Laboratory:The Lab Work Group might utilize a constrained version of the Genetic Variation model in their next release if the Lab Result message