Evidence Generation for Genomic Medicine...•Intermediate: Prescribing beta-blocker (process) and...

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Questions: 1. What methods can the eMERGE network develop and/or adopt to assess utility, validity, cost-effectiveness, quality of life, etc. of genetic/genomic testing? 2. How can eMERGE integrate other information (e.g., family history, physical and/or psycho-social environmental factors, etc.) with genetic/genomic testing results to improve our understanding of genomic medicine? Evidence Generation for Genomic Medicine

Transcript of Evidence Generation for Genomic Medicine...•Intermediate: Prescribing beta-blocker (process) and...

Page 1: Evidence Generation for Genomic Medicine...•Intermediate: Prescribing beta-blocker (process) and sudden cardiac death (if adherence measured this is intermediate outcome) •Weak:

Questions:

1. WhatmethodscantheeMERGEnetworkdevelopand/oradopttoassessutility,validity,cost-effectiveness,qualityoflife,etc.ofgenetic/genomictesting?

2. HowcaneMERGEintegrateotherinformation(e.g.,familyhistory,physicaland/orpsycho-socialenvironmentalfactors,etc.)withgenetic/genomictestingresultstoimproveourunderstandingofgenomicmedicine?

EvidenceGenerationforGenomicMedicine

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Deliverable:DevelopmentofaneMERGEseqPlatformGE

NES SITE'S TOP 6

SNVS

CONSENSU

SAC

TIONAB

LELIS

T Genes&

SNVs

Returnedbyallsites

1,551

136

19

- Fingerprint+Ancestry- HLAImpute- PGx- Automatedclassifier

pipeline(LMM)removedLB/B

- 117variantsdeemednon-actionablebyNetworkconsensus

14

- CSGHarmonizationofvariantclassification

- Consultationwithexperts

53

56

+

68

68

14109

Clinicallyactionable

Totalproposed

Clinicallyactionable

• Clinical reports are generated on the “Consensus Actionable List” and any specific genes or SNVs requested by individual sites

• To date: 14,077 samples sequenced and 3,716 reports issued

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0

1

2

3

4

5

ConsensusList AdditionstoConsensusList ExclusionstoConsensusList AdditionsandExclusionstoConsensusList

KPW/UW

Harvard

Columbia

CHOP

CCHMC-adolesc.

NW

Vanderbilt

Mayo

GeisingerCCHMC-biobank

Networkactionability andsitereportingpreferences

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SEQUENCINGandREPORTING:Timelines

BatchOneBatchTwo

GHC/UW-1

Geisinger-1

CCHMC-1

Broadsequencing Baylorsequencing

ClinicalreportingcompletedDec2018

GHC/UW-1

Geisinger-1

CCHMC-1

Harvard-1/2 Harvard-1/2

CCHMC-2 CCHMC-2

Geisinger-2

GHC/UW-2

Partnersreporting Baylorreporting

Geisinger-2

GHC/UW-2

August201

6

Octob

er2016

Decembe

r201

6

February201

7

April201

7

June

2017

August201

7

Octob

er2017

Decembe

r201

7

February201

8

April201

8

June

2018

August201

8

Octob

er2018

Decembe

r201

8

Mayo Mayo

Columbia

Vanderbilt

Northwestern

CHOP CHOP

Northwestern

Columbia

Vanderbilt

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ResulttoSite

Reviewbycommittee

Contactparticipant

ReturnbyGeneticCounselor

UploadtoEMR

InformPCP

ProcessofReturnNotwositesarethesame

MOST(7/9)followthisprotocol

Minority(2/9)followthisprotocol

ResulttoSite

Reviewbycommittee

Contactparticipant

ReturnbyGCorspecialist

UploadtoEMR

InformPCP

ALL(9/9)returnthe68commonsetofgenesplusinstitutionalgenes/SNVs

2/9siteshavereturnedresults

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Rephenotyping byphysicalexam/lab/testsinformPathogenicityandPenetrance:SeattleIFs(CRCprimary)

Gene Disorder Nparticipants

MYBPC3 hypertrophiccardiomyopathy 8(4LP)

HFE* hemochromatosis 7

BRCA2 breast/ovariancancer 4

SCN5A Brugada,Romano-Ward,dilatedcardiomyopathy

3(3LP)

MYH7 cardiomyopathy 2(2LP)

RYR1 malignant hyperthermia 2(2LP)

PALB2* breastcancer 2

DSC2 Arrhythmogenic rightventricularcardiomyopathy

1(1LP)

LDLR Familialhyperlipidemia 1(1LP)

BRCA1 breast/ovariancancer 1->0

MYL3 hypertrophiccardiomyopathy 1

*Not ACMG recommended

15 cardiomyopathy(10 LP) /1163

Either wrong or low penetrance

Clinically treated as P

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Environmentalmeasures:eMERGEGeocodingsupplement

Factors Source Resolution National/ Local

Demographics Coordinating Center/Site EDW Patient Level National

SES Census/ACS Block Group Level NationalBuilt

EnvironmentRUCA (rural-urban-commuting-

area-codes Tract Level National

Traffic Volume Google?

Road Density ArcGIS shapefiles Block Group Level National

Food Accessibility Food Environment Atlas (USDA Economic Research Service) County Level National

Water Quality NURE-HSSR database; Enviromapper? Various

Density of Parks ArcGIS shapefiles Block Group Level National

Walkability Walk Score Professional Zip Code National

Entropy Index Census/ACS Block Group Level National

Crime Local

Hospital Utilization AHRF, HHS, HRSA County Level National

SlidecourtesyofeMERGECC

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Familyhistorydata

§Very useful for stratifying analyses, identifying pathogenic variants, etc.

§Not captured well or systematically in most medical records

§Some sites may have clinical patient survey data on family history

§A standardized format would be useful

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Familycascadetestingandcommunication

§ Used in pathogenicity assessment; important tool for estimating variant penetrance

§ A major driver of cost effectiveness of genetic testing is follow-up testing of relatives

§ How do we spread the word?

§ Need results early to be successful

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ChallengesandOpportunitiesChallenge Opportunities

Knowvariantpathogenicityandpenetrance(evenforACMGgenes!)

• Standardizewhatisreturned(aspossible)• Rephenotypingby EHRANDnewPE• Familycascadetestingforcosegregation• Pooldataacrosssites• Reanalysisofsequenceforpathchanges• Methodstosharevariantreclassifications

Addfamilyhistorytoanalyses • StandardizetoolacrosssitesAdddemographic datatoanalyses • GeocodingCost-effectwhenfamilygetsinformation/tested

• Family communicationtools(Psycho-socialdata)• Cascadetesting• Moreefficientreturnofresults/counseling• Sharenegativereports

Datatoolateformuchfollow-up • Generate sequenceearlier:frontloadsequencingbudget,useexistingplatform(medicalexome,exome,genome)

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eMERGEOUTCOMESWORKGROUP

Co-Chairs: Hakon Hakonarson(CHOP)JoshPeterson(Vanderbilt)MarcWilliams(Geisinger)

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eMERGEOUTCOMESWORKGROUP:Charter

Missionstatement:TheOutcomesworkgroupwilldevelopcross-siteoutcomestotrackimplementationandimpactofeMERGEIIIsequencing. Theworkgroupwillfocusonansweringtheoverarchingquestionofwhetherreturned eMERGE III-generatedgenomicresultsimpacthealthcareutilizationandoutcomesofimportancetopatientsandfamilies.

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• ProcessOutcomes• potentialchangesinhealthcareutilizationrelatedtoreturninggeneticinformation• Example:Colonoscopyordered

• IntermediateorSurrogateOutcomes• abiomarkerindicatingbenefitorharmismorelikely

• Example:PositiveFOBT• adherencetoarecommendation

• Example:Colonoscopyperformed• ClinicalOutcomes

• thebenefitsorharmstoapatientwhoreceivesanintervention• Example:Adenomatouspolypremoved

OutcomeTypes(examplepathogenicvariantinMLH1 associatedwithLynchsyndrome)

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Chainofevidence

• Evidencethataprocessorintermediateoutcomehasadirectimpactonhealthoutcomesofinterest

• Examples:• Strong:Colonoscopy(intermediate)andcolorectalcancer;LDLc <100mg/dl(intermediate)andCAD

• Intermediate:Prescribingbeta-blocker(process)andsuddencardiacdeath(ifadherencemeasuredthisisintermediateoutcome)

• Weak:CEA125(intermediate)andovariancancer;TotalbodyMR(intermediate)andLi-Fraumeni associatedcancermortality

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eMERGEOUTCOMESWORKGROUP–StandardDataCollectionForms

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Challenges

• RelianceonprocessandintermediateoutcomesduetolengthofeMERGE 3

• Onetimepointforoutcomesassessment(6monthspost-RoR)• Timingofsequencingandreporting• AttributionofoutcometoRoR (relyonassertionbysite)

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Opportunities-Measurehealthoutcomes• PotentialtofollowsomepatientswithRoR ineMERGE 4

• LessstraightforwardthatphenotypeandGWASeffortsacrosseMERGE 1-3

• Identifyconditionsorgenomicresultswherehealthoutcomesaremorelikelytoaccrueinafouryeartimeframe(orstrongchainofevidence)

• Pharmacogenomicsforcommondrugs• Unrecognizedgeneticdisorders(e.g.atypicalCysticFibrosis,metabolicdisorders,renaldiseaseindialysispatients)

• FamilialHypercholesterolemia

• Getsequencingresultsfastertoallowlongerfollow-up• DevelopandtestmethodstoattributeoutcomestotheReturnofResults

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Challenges

• Outcomecollectionapproachessite-specific(incontrasttophenotypes)

• Manualprocessesrequiredforcascadetesting

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Opportunities-ImplementationandDissemination• Studyvariationinimplementationandtheimpactonoutcomes

• R01DisseminationandImplementationLynchsyndromescreening(Rahm-GeisingerandHCSRN)

• IfcompleteineMERGE 3canusetostandardizeimplementationofRoR ineMERGE 4• Studyvariationinimplementationandtheimpactonoutcomes

• R01DisseminationandImplementationLynchsyndromescreening(Rahm-GeisingerandHCSRN)

• CollaborationwithpragmatictrialsinIGNITE2aroundcertainconditions(2approachestoevidencecollection)

• Needtousestandardoutcomemeasure• Givenpublichealthimpactofcascadetestingmakethisapointofemphasistodevelopandtestmethods

• Couldincludelegalandpolicyemphasistoinformnovelapproachestocontactingatriskrelatives

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Opportunities-Economic/CostEffectiveness• Addineconomicoutcomes

• R01(Vanderbilt,UWashington,Geisinger)developingandtestingmodelstounderstandwhichoutcomesdrivecost-effectivenessandotheroutcomesofsequencing

• UsethisworktoprioritizeoutcomestocollectineMERGE 4


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