Outcomes Assessment Across Multiple Sites in the eMERGE ... · Laura J. Rasmussen-Torvik , PhD,...
Transcript of Outcomes Assessment Across Multiple Sites in the eMERGE ... · Laura J. Rasmussen-Torvik , PhD,...
OutcomesAssessmentAcrossMultipleSitesintheeMERGE-PGx Project
Laura J. Rasmussen-Torvik, PhD, MPH, FAHAAssistant ProfessorDepartment of Preventive MedicineCenter for Genetic MedicineNorthwestern University Feinberg School of [email protected]
Laura J. Rasmussen-Torvik
on behalf of the eMERGE-PGxworkgroup
Outcomes
Agenda
• DescribeeMERGE-PGx
• DetailoutcomespublishedtodateineMERGE PGx• HighlightareaswhereeMERGE-PGx hasencounteredchallenges
• FuturedirectionsforeMERGE-PGx outcomesandotheroutcomesprojectstopromoteimplementation
Recruit/CollectSamples
PGRN-Seq Sequencing
ClinicalVariantValidation
ReturnResults:EHRIntegrationandCDS
Patient&ClinicianEducation
PopulateVariantandPhenotypeDataRepository(SPHINX)
SpecificAim1
SpecificAim2
SpecificAim3
eMERGEPGx - OverviewbyAim
PGRNseq:atargetedcapturesequencingpanelforpharmacogenetic researchandimplementation.Gordon AS,FultonRS,QinX,Mardis ER, Nickerson DA,SchererS.Pharmacogenet Genomics.2016Jan5.[Epub aheadofprint]
Clin Pharmacol Ther. 2014 Oct;96(4):482-9. doi: 10.1038/clpt.2014.137.
GHC/UW
NU
MSSM
VU
M/E/PSU
BCH
CCHMCCHOP
GEISINGER
MAYO
GHC/UW
NU
MSSM
VU
M/E/PSU
BCH
CCHMCCHOP
GEISINGER
MAYO
Drug-Genome pairs studyCYP2C19-ClopidogrelVKORC1/CYP2C9-Warfarin*SLCO1B1-Simvastatin* BCH DGI only VKORC1/CYP2C9-Warfarin* Geisinger and M/E/PSU also have CYP4F2-Warfarin
Pediatric Sites
Comparing site implementation details
010002000300040005000600070008000
Caucasian AfricanAmerican Hispanic Asian NativeAmerican Unknown
eMERGE-PGx samplesizebyrace/ethnicity
020040060080010001200140016001800
BCH CCHMC CHOP Geisinger GHC/UW Marshfield Mayo Mt.Sinai NU VU
eMERGE-PGx samplesizebysite
ProposedOutcomes
• Sequence9000+onpharmacogenes anddocumentvariation
• Inprogress:2nd variationpaper,HLA,CYP2D6
• Createasearchablevariantrepository
GeneticVariationamong82Pharmacogenes:thePGRN-Seq datafromtheeMERGE Network.BushWS,Crosslin DR,Obeng AO,WallaceJ,Almoguera B,etal.Clin Pharmacol Ther.2016Jul;100(1):31-3.PubMedPMID:27037844.
SPHINXisaweb-basedtoolforexploringdrugresponseimplicationsofgeneticvariationacrosstheeMERGEPGx projectcohort.
SPHINXwillcontainsdataonnearly9000subjectsfromparticipatingelectronicmedicalrecord(EMR)systems.PGRN-Seqsequencingidentifiescommonvariants,somewithknownclinicalimplications,andalsovariantsofunknownsignificance.
SPHINXhasapublic-facinggenevariantrepositoryandaprivatesearchtoolthatprovidesexploratorydatafiguresfromqueriesofvariantsummarydataplussomephenotypedata.
SPHINX:Sequence,Phenotype,andpHarmacogenomics Integration
https://www.emergesphinx.org/
ProposedOutcomes—ProcessandClinical• eMERGE-PGx sitesarecollaboratingtoreportdescriptivemetadataanddefinequantitativeandqualitativeoutcomesacrosssevendomains:recruitment,sequencing,
• Genotypevalidation– inpressatJMP
• Providereducation—inpressatPharmacogenomics
• Patienteducation– beingrevisedafterrejection
• EHRintegration-- Practicalconsiderationsingenomicdecisionsupport:TheeMERGE experience.HerrTM,Bielinski SJ,Bottinger E,Brautbar A,BrilliantM.JPathol Inform. 2015Sep28;6:50.doi:10.4103/2153-3539.165999.eCollection 2015.PMID:26605115PMCID:PMC4629307
• Actionablerarevariation:1inpress(6ACMGgenes)andAssociationofArrhythmia-RelatedGeneticVariantsWithPhenotypesDocumentedinElectronicMedicalRecords.VanDriestSL,WellsQS,StallingsS,BushWS,GordonA,etal.JAMA. 2016Jan5;315(1):47-57.doi:10.1001/jama.2015.17701.PMID:26746457PMCID:PMC4758131
Whatismissing?
• Cost
• Assessmentspost-implementation• Baselineassumption:outcomeswouldbelargelyindividuallevelandassessedthroughtheEHR
• PlannedPGx phenotypes• MACEafterclopiodogrel• MalignantHyperthermia• Methlphenidate Response• MACEonstatin
wasimplementedinahighlyheterogeneousway.Howdoweaccountforthisandcapitalizeonthisforfutureresearch?
ResearchQuestions
ForthosethatimplementedPGx CDS…
1. Howdidyoudoit?2. Howwelldiditwork?
Credit:TimHerr,NUPhDStudent,AMIApresentation
Howdidyoudoit?w didyoudoit?Assessmentprocess:
• RepresentativesfromeMERGE-PGx workgroup• Identifieddimensionsandfactsofinterest
InformalInterviews
• Multiple-choicequestionnaire• Onerepresentativepersite,viae-mail• DGIDetails,AlertCharacteristics,andOrganizationalCharacteristics
FormalQuestionnaire
• Aggregateandidentifytrends
Analysis
Credit:TimHerr,NUPhDStudent,AMIApresentation
Howwelldiditwork? work?
Results:
AlertResponse ClinicalResponse
DrugTotalAlerts Accept Override Ignore Unknown Followed NotFollowed NoAction
Codeine 114 102 0 10 2 69 18 27Clopidogrel 65 14 46 5 0 10 40 15Simvastatin 24 22 1 1 0 11 13 0Warfarin 91 45 28 18 0 34 55 2Total 294 183
(62%)75
(26%)34
(12%)2
(0.8%)124
(42%)126
(43%)44
(17%)
Credit:TimHerr,NUPhDStudent,AMIApresentation
ConclusionsofCDSanalysis
• Despitetheseareasofagreement,thereissignificantvariationinhowPGx CDSalertsaredesignedthroughouttheeMERGE Network.
• Combined,thesedifferencescreateasignificantbarriertoanalyzingaggregatephysicianresponseviaalertlogdataalone.
• Instead,wefoundthattheeMERGE Network hascreatedaseriesofnaturalexperimentswithavarietyofalertdesignandDGIchoices.
• Single-sitestudiescancomparephysicianresponseacrossDGIsonsimilartechnicalinfrastructure.Multi-sitestudiescouldfocusoncloselytargetedanalysesofspecificDGIswheredesignchoicesallowmeaningfulcomparisons.
Credit:TimHerr,NUPhDStudent
Implementationresearchoutcomes• Adoption
• Adherence
• Fidelity
• Levelofimplementation
• Sustainability
CONCLUSIONS*:• Implementationoutcomesinstrumentationisunderdevelopedwithrespecttoboththesheernumberofavailableinstrumentsandthepsychometricqualityofexistinginstruments.Untilpsychometricstrengthisestablished,thefieldwillstruggletoidentifywhichimplementationstrategiesworkbest,forwhichorganizations,andunderwhatconditions.
*LewisCC, FischerS, WeinerBJ, Stanick C, KimM, MartinezRG.Outcomesforimplementationscience:anenhancedsystematicreviewofinstrumentsusingevidence-basedratingcriteria.ImplementSci. 2015Nov4;10:155.doi:10.1186/s13012-015-0342-x.
Site Gene/DrugPairs
PGxServiceType
(#years) CDSSupportAdopters/Regular
UsersChildren'sHospitalofPhiladelphia(CHOP)
GenotypingonlyCYP2C9CYP2c19VKORC1-1639G>A
GCmodel
(1year)
ResultssummarylettersenttoPCP;PGxspecificlettergiventopatientstosharewithprovidersoutsideEHR
Genetics,Neurology-offeredaspartofWES
CincinnatiChildren'sHospitalMedicalCenter
CYP2D6/codeineCYP2D6/SSRIs,tricyclicantidepressantsCYP2C19/SSRIs,tricyclicantidepressantsCYP2C9/warfarinVKORC1/warfarinTPMT/thiopurines
Prescriberpointofcare
(8years)
Passivealertsinelectronicorderingsystem;Resultreportswiththerapeuticrecommendationsincludingdoseadjustmentordrugselectionalternatives
Psychiatryintegratedintostandinginpatientordersby2005;infrequentusebyotherprescribers
GroupHealth GenotypeonlyHLA-B*15:02
Prescriberpointofcare
(8years)
PopupalertwhenevercarbamazepineprescribedregardlessofHLAstatus
Neurology,psychiatryandsometimesprimarycare
MayoClinic CYP2D6/selectSSRIs Prescriberpointofcare
(8years)
None Psychiatryphysiciansandnurses
VanderbiltUniversity CYP2C19/clopidogrelSLCO1B1/simvastatinCYP2C9/warfarinVKORC1/warfarinTPMT/thiopurinesCYP3A5/tacrolimus
Preemptiveandreactivegenotypingorderedbyprovider
Activeandpassivealertsinelectronicordering;pharmacysupportforspecificusecases
Physiciansandotherproviderswhoprescribe
Table1.SiteswithPGxImplementationandEducationPriorto2012eMERGEPGxInitiative
Lessonslearned
• Plantocaptureoutcomes(includinginstitutional-leveloutcomes)inadvance
• Decide:Arewefocusedonclinicaleffectiveness?Implementation?Both?
• Validatedimplementationoutcomesareneeded
• PGx researchersneedtolearnhowtoshareimplementationchallenges
Acknowledgements
• MembersofthePGx workinggroup(andothereMERGE workinggroups)
• Currentco-chair:CindyProws
• Formerco-chairs:DanRoden,JoshDenny
Questions?
•eMERGE-PGx continues………
PGxGene
NumberofvariantsthathaveCPICguideline(knownfunctionanddosingrecommendation)
HowmanyvariantsincolumnBareontheeMERGE"SNPlist"
TotalNumberofSNPsAssociatedwithGeneonSNP_List
NumberofadditionalvariantsonCPICwithpartialknowledge
CYP3A5 3 1 1 0
CYP2C9 2 2 215
(someknownfunction,nodosing)
CYP2C19 8 8 8
6('decreased'function&weaker
dosing+2withnofunctionbutveryrareaddedin2015)
TPMT 4 4 4 0
SLCO1B1 3 1 19
("possible"function&weakerdosing)IFNL3/IFNL4 1 1 1 0VKORC1 1 1 1 0
DPYD 3 3 6
7(withsomeknownfunctionbutno
dosingchange)WillnotreportforeMERGE
CYP2D6 18 16 45HLA-B ?? IMPUTE? 275
RYR1-isingenelistCPICguidelineinprogress ? ?
CFTR-isingenelist 13 ? ?G6PD-notinpanel >100 0 0
UGT1A1-notinpanel 4 0 0 0
ConsiderNOTreportingas2majorvariantsarenotonpanel(limitationforAfricanAmericansandLatinos)-AAcouldcomeacrossas*1/*1(*3isWT)butbe*6or*7ReportonlyforWarfarin(asforphenytoinwouldneedHLAB)
Willnotbereportedclinicallyaswecan'tgetCNVcalls
reportwithCYP2C9forwarfarin
Willnotbereported-wouldneeddiffguidelineinprogress-couldadd?;notinPharmCATyet
PharmCATdoesnotreportG6PD
PharmCATreportsCFTR;limitedutilityineMERGEpatients,willnotreport
2015guidelineforatazanavir;PharmCATdoesreportit
Comments
ThevariantpresentoneMERGEpnl(rs4149056)tagsall*alleles(*5,15,17).Allareassociatedwithdecreasedfunction,so
samerecommendation
SuggesttonotreportCYP3A5
Laboratory for Molecular MedicinePartners Healthcare Personalized Medicine65 Landsdowne Street, Cambridge, MA 02139Phone: 617.768.8500 Fax: 617.768.8513Director:CLIA#: 22D1005307
Referring Physician:
Test performed eMERGE III Sequencing panel
Important disclaimers:
Additionalnotesareincluded(columnB).ForakeypleaseseeAppendixB
Results:
Dip
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Dip
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Phe
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Dip
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Dip
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Phe
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Dip
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Phe
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Dip
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Phe
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1 1, 6, 8, 9 PM09-00655-A 38432489 16-90081 12/31/16 03/01/17 *1,*1 nl metCYP2C9*1/*1; VKORC1 Hap A/Hap A int met *1,*1 int met *1,*1 nl met *1,*1 nl met *1,*1 nl met
This test does not report all pharmacogenomic variants that might alter protein function. Therefore, a normal result does not exclude the possibility that a patient has an increased, intermediate or poor metabolizer phenotype. This risk may vary among ethnic groups. This assay cannot determine if multiple variants are present on the same copy or different copies of the gene, leading to an inability to definitively assign a diplotype and phenotype. This test does not detect copy number variants (CNV). Extrinsic factors (e.g. diet, smoking status, co-administered medications) and intrinsic factors (e.g. gender, age, weight, renal or hepatic function) may affect drug response. In addition, certain ethnic populations may have an increased prevalence of rare genetic variants not reported by this assay that could affect drug response. These factors need to be taken into consideration when interpreting genetic test results. The CPIC Guidelines and PharmGKB website should be consulted for interpretation of all results presented here. These guidelines and frequent updates are found at https://cpicpgx.org/ and https://www.pharmgkb.org/. Please consult a clinical pharmacologist for additional information.
Geneticist Approval
PHARMACOGENOMICS REPORT
SLCO1B1NM_006446
.4CYP2C19
NM_000769.1
TPMTNM_000367
.2
CYP2C9NM_000771.3
VKORC1NM_024006.5
IFNL3NM_172139.2
DPYDNM_000110
.3
IND
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SIO
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LAST
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(PA
TIEN
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)
FIR
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AM
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TUD
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DA
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ECEI
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DA
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EPO
RTE
D
SAMPLEPGx REPORT
TPMTc.238 TPMTc.460 TPMTc.719 TPMTc.626-1 DiplotypeWT(G/G) WT(G/G) WT(A/A) WT(G/G) TPMT*1/*1WT(G/G) WT(G/G) WT(A/A) MUT(A/A) TPMT*4/*4WT(G/G) WT(G/G) WT(A/A) HET(G/A) TPMT*1/*4WT(G/G) WT(G/G) MUT(G/G) WT(G/G) TPMT*3C/*3CWT(G/G) WT(G/G) HET(A/G) WT(G/G) TPMT*1/*3CWT(G/G) MUT(A/A) WT(A/A) WT(G/G) TPMT*3B/*3BWT(G/G) MUT(A/A) MUT(G/G) WT(G/G) TPMT*3A/*3AWT(G/G) HET(G/A) WT(A/A) WT(G/G) TPMT*1/*3BWT(G/G) HET(G/A) HET(A/G) WT(G/G) TPMT*1/*3AWT(G/G) HET(G/A) HET(A/G) HET(G/A) TPMT*3A/*4HET(G/C) WT(G/G) WT(A/A) WT(G/G) TPMT*1/*2HET(G/C) WT(G/G) WT(A/A) HET(G/A) TPMT*2/*4HET(G/C) WT(G/G) HET(A/G) WT(G/G) TPMT*2/*3CHET(G/C) HET(G/A) WT(A/A) WT(G/G) TPMT*2/*3BHET(G/C) HET(G/A) HET(A/G) WT(G/G) TPMT*2/*3AMUT(C/C) WT(G/G) WT(A/A) WT(G/G) TPMT*2/*2
DiplotypeTestResultforTPMT
CodedGenotype/Phen
otypeSummaryb
EHRPriorityResult
NotationcDrug LMMInterpretationandBackground CPICConsultation(Interpretation)TextProvidedwithTestResultd
Azathioprine(immunosuppressant)
LowerconcentrationsofTGN(thioguaninenucleotide)metabolites,highermethylTIMP(secondarymetaboliteofmercaptopurine),thisisthe"normal"pattern.Startwithnormalstartingdose(e.g.,2–3mg/kg/d)andadjustdosesofazathioprinebasedondisease-specificguidelines.Allow2weekstoreachsteadystateaftereachdoseadjustment
Mercaptopurine(immunosuppressant)
LowerconcentrationsofTGN(thioguaninenucleotide)metabolites,highermethylTIMP(secondarymetaboliteofmercaptopurine),thisisthe"normal"pattern.Startwithnormalstartingdose(e.g.,75mg/m2/dor1.5mg/kg/d)andadjustdosesofmercaptopurine(andofanyothermyelosuppressivetherapy)withoutanyspecialemphasisonmercaptopurinecomparedtootheragents.Allow2weekstoreachsteadystateaftereachdoseadjustment
Thioguanine(immunosuppressant)
LowerconcentrationsofTGN(thioguaninenucleotide)metabolites,butnotethatTGNafterthioguanineare5-10xhigherthanTGNaftermercaptopurineorazathioprine.Startwithnormalstartingdose.AdjustdosesofthioguanineandofothermyelosuppressivetherapywithoutanyspecialemphasisonTG.Allow2weekstoreachsteadystateaftereachdoseadjustment
TPMT,*1/*1,Extensivemetabolizer.Thiopurines:Standarddosage.Thiopurinemethyltransferase(TPMT)metabolizesthiopurineprodrugs(azathioprine,6-
mercaptopurine,andthioguanine)intotheiractivethioguaninenucleotide(TGN)
metabolites.TPMTalleles*3A,*3B,and*3C,leadtoreducedproteinexpressionand/orfunctionandcarriersmaybeatriskoflife-threateningmyelosuppressionwhentreatedwithstandarddosesofthiopurines.Adapted
fromRelling2011.
*1/*1TPMTExtensivemetabolizer
Normal/Routine/LowRisk
PLANNEDSUPPLEMENTALINFORMATION
Phenotype EHRPriorityResultNotation
DrugswithCPICGuidelines
DosageSummary* References-seeAppendixD
GeneBackground
CYP2C9Normalmetabolizer&NormalVKORC1expression
CYP2C9Normalmetabolizer&IntermediateVKORC1expression
CYP2C9Normalmetabolizer&LowVKORC1expression
CYP2C9Intermediatemetabolizer&NormalVKORC1expression
CYP2C9Intermediatemetabolizer&IntermediateVKORC1expression
CYP2C9Intermediatemetabolizer&LowVKORC1expression
CYP2C9Poormetabolizer&NormalVKORC1expression
CYP2C9Poormetabolizer&IntermediateVKORC1expression
CYP2C9Poormetabolizer&LowVKORC1expression
CYP2C9Normalmetabolizer Normal/Routine/LowRisk Standarddosage
CYP2C9Intermediatemetabolizer Abnormal/Priority/HighRisk
CYP2C9Poormetabolizer Abnormal/Priority/HighRisk
Allshouldconsultsourceslistedatright
(colD).Warfarin(anticoagulant)
Usethealgorithmsavailableon
http://www.warfarindosing.organdFigures2&3ofJohnson_2017
Johnson_2011,Johnson_2017
CommongeneticvariantsinthecytochromeP450-2C9(CYP2C9)andvitaminK-epoxidereductasecomplex1(VKORC1)enzymeshaveaneffectonwarfarinmetabolism.CarriersoftheCYP2C9*2,CYP2C9*3,andVKORC1-1639Aallelesareatincreasedriskofbleedingandmayrequirelowerdosesofwarfarin.(Johnson_2011)Thealgorithmsavailableonhttp://www.warfarindosing.orgshouldbeusedtodeterminewarfarindosing.The2016guidelineupdate(Johnson_2017)includesadditionalallelesinCYP2C9,CYP4F2,andtheCYP2CclusterthatareNOTincludedinthistestpanel.Theupdatealsohasimportantancestry-specificdosingrecommendations,andmustbecarefullyreviewed.
Phenytoin/fosphenytoin(anticonvulsant) Caudle_2014
TheCPICguidelinesforphenytoinincludethegenesCYP2C9andHLA-B.(ThistestdoesnotincludeHLA-B;theHLA-B*15:02allelehasbeenassociatedwithanincreasedriskofSJS/TEN.)However,SupplementalTable13bofCaudle_2014providessomerecommendationsbasedonCYP2C9diplotypeintheabsenceofHLA-Btesting.Decreasedosage
CYP2C9&VKORC1-theseareinterpretedtogetherforwarfarindosing.
TPMT
TPMTNormalmetabolizer Normal/Routine/LowRisk
Azathioprine,Mercaptopurine,
Thioguanine(thiopurines,immunosuppressant)
Standarddosage
Relling_2011,Relling_2013
Thiopurinemethyltransferase(TPMT)metabolizesthiopurineprodrugs(azathioprine,6-mercaptopurine,andthioguanine)intotheiractivethioguaninenucleotide(TGN)metabolites."IndividualswhoinherittwononfunctionalTPMTallelesareat100%riskforlife-threateningmyelosuppression,duetohighTGNs,iftheyreceivechronictherapywithconventionaldosesofMP(orazathioprine).DespitehavinghigherTGNsthanwild-typehomozygotes,only~30–60%ofpatientswhoareheterozygousforTPMTareunabletotoleratefulldosesofMPorazathioprine"(Relling_2011).
TPMTIntermediatemetabolizer Abnormal/Priority/HighRisk Decreasedosage
TPMTPoormetabolizer Abnormal/Priority/HighRisk
Greatlydecreasedosage
Themesinimplementationscience
• Understandingthe“voltage”gap
• Successfulapproachestoprogramdissemination
• Tensionbetweenlocalcontextandfidelity