ProgresswithRareDiseasesintheGenomicsEngland100,000GenomesProject

DrAnnaCNeedGeCIPTeamLead,GenomicsEngland

GenomicsEnglandannouncedbySecretaryofStateforHealthinspeechduringNHS65th AnniversaryCelebrations,July2013

AnnouncedbytheformerPrimeMinisterinDecember2012AnOlympicLegacy

The100,000GenomesProject

CMO’sGenerationGenomeandtheLifeSciencesreportin2017

OpeningofnewSequencingCentrein2016

The100,000GenomesProject

324 May 2018

424May2018

• Nationwidenetworkof13NHSGenomicMedicineCentres – eachserving~3-5millionpopulation

• Includesover85hospitalsacrossEngland

• Integratedwithgeneticlaboratories,geneticservicesandlocalpathologylaboratories

• Scotland,NIandWalesalsonowpartoftheProject

Theinfrastructurefordelivery

524May2018

Howthe100,000GenomesProjectworks

DiscoveryForumIndustryUsers

Whatinformationcanbefedback?

• Informationaboutapatient’smaincondition

• Informationaboutadditional‘seriousandactionable’conditions(optional)

• Carrierstatusfornonaffectedparentsofchildrenwithraredisease(optional)

624May2018

ImagecourtesyofHealthEducationEngland

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Primaryclinicaldatacollection• Coreclinicaldataset:

• Diseasestatus(bespoke)• Pedigreedata(Panogram)• HumanPhenotypingOntology• ICD10,SNOMEDCT,OMIM

• ClinicaltestdatawhererelevantandnotcapturedbyHPO

• Usingestablishedstandardswhereverpossible

Additionaldataemulatingtestrequestinclinicalpractice

GenepanelsPenetrancesettingsOtherbespokeelements

e.g.>1analysisforfamily

PanelApphttps://panelapp.genomicsengland.co.uk/

924May2018

Patient/family

Phenotypes&PedigreeDNA

Genomesequence

AnnotatedVCFs

Tieredvariants

Gene PanelVariant filtering

AnnotationCompanies

Review

GenePanels

Clinicalreporting GeCIP(s)

ValidationOutcomes

Decisionsupporttool

Semi-automatedInterpretationpipeline

ReportQA

Panels+settings

WORKFLOWMANAGER

DATADISTRIBUTIONFRAMEWORK

PanelAssigner

PanelApp

111124May2018

Interpretationatthehospitals

1. ‘Tiering’– Automated focusedinitialanalysissetuppriortointerpretation– Aimstomirrorstandarddiagnosticanalysis– ‘Tier1or2'– variantsin0-5geneswithinprescribedpanel(s)(median=1.2)– Non-penetrancepipelinecanberun

2. Broaderanalysis– Decisionsupportsoftwareallowshospitalsfurther,bespokeanalysis– ‘Tier3’– standardGeL pipelinebutnotrestrictedtogenepanels;20-100svariants(median=285)– Othertools,dependentonwhichCIPsystem

3. Lab-clinicalteamcuratevariantsandrecordoutcomes– Curations(includingACMGclassifications)savedtocentralknowledgebase– Recordclinicalimpactsofdiagnosticresult

1224 May 2018

Progresstodate Figures as at 09/05/2018

Samples

85,898SamplescollectedfromNHSGMCs

Genomes AnalysisandReports

11,883familiessenttoNHSGMCs

24,596

Reportsfor

Equivalentto

genomes66,447

19,451

5,677genomessincelastmonth

20-25%actionablefindings

Genomessequenced

49,272

60,679

11,407

Recruitment• Average~500participants/week• Rarediseaserecruitmentexpectedtoend30thSeptember2018• Meanfamilysize=2.3

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0500100015002000250030003500400045005000

Numberoffamilies

Recruitmentpatterns

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Recruitment-WestMidlands

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Recruitment-WestMidlands

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DiagnosticyieldindifferentdiseaseareasDisease SINGLETONS

No.familiesSINGLETONSDiagnosticyield(%)

TRIOSNo.families

TRIOSDiagnosticyield(%)

ALLNo.families

ALLDiagnosticyield(%)

Intellectualdisability 8 25 38 39.5 63 36.5Rod-conedystrophy 9 11.1 32 53.1 52 42.3

Renaltractcalcification 33 6.1 1 0 38 5.3

Non-CFbronchiectasis 21 4.8 7 0 32 3.1CAKUT 25 8 2 0 29 6.9

Multipleendocrinetumours

21 0 0 NA 22 0

Severemulti-systematopy

4 0 12 0 21 0

181824May2018

Impactoffamilystructureonnumbersoftieredvariants

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Autosomalrecessive Autosomaldominant1member 2members 3members 4members 1member 2members 3members 4members

Improvingannotationofcandidates

Exomiser:Prioritisation• Recovers65%ofthetier3diagnoses• Recovers57%oftheuntiered diagnoses

Tiering:Classification(filtering)• >90%precisionfortier1variants(someascertainmentbias)• >80%recallfortieredvariants(1+2+3)

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0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

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Tier1+2 Exomisertop5 Tier1+2ANDExomisertop5Recall/Sensitivity Precision

VariantshighlightedbytieringandExomiser have>90sensitivityandvariouslevelsofspecificity

~0.2variants/case

~1.2variants/case

~285variants/case ~7variantspercase

Apipelinefordiagnostics

• Majorfocusisthevalidation,QAandaccreditationtoreadyoutplatformsforuseaspartoftheNHSEnglandGenomicMedicineServicefromOctober2018

• Thisinvolvesanalysisofsamplesalreadyheldaspartoftheprogramme

• Plussequencingofadditionalpositivecontrolsamples

• Existingpipelinecomponents• Newcomponents

• STRs• CNVsandSVs• LowlevelmtDNA variants

Validation,QAandaccreditation

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LP2000254−DNA_D06

LP2000261−DNA_B10

LP2000266−DNA_G04

LP2000268−DNA_E01

LP2000269−DNA_A04

LP2000269−DNA_F06

LP2000711−DNA_G11

LP2000860−DNA_F08

LP2000860−DNA_F11

LP2000860−DNA_G03

LP2000860−DNA_G06

LP2000861−DNA_A03

LP2000861−DNA_H06

10 20 30Repeat size (repeat units)

Sam

ples

from

NH

NN

EH estimates

Experimental estimates

ATXN7 − SCA7 comparison

DiagnosticSTRresults

Disease Gene Expansionconsistentwithphenotype

Status

Fragile-Xsyndrome FMR1 2 1validated;1 inprogress

ALS/MND C9orf72 1 Validated

HuntingtonDisease HTT 3 2validated;1 inprogress

SCA6 CACNA1A 1 Validated

SCA12 PPP2R2B 1 Validated

DRPLA ATN1 1 Inprogress

Kennedydisease AR 1 Inprogress

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18diagnosticlociexamined;first~5,000families

24May2018

• Collectionofupto180positivecontrolsinprocessacrossarangeofallelesizes

ComplementaryClinicalDatasets

Lifecoursedata:Secondarysources

NHSDigital• HospitalEpisodes• ONSdeathdetails• DiagnosticImaging• Patientrecordedoutcomes• Mentalhealth&intellectualdisability

PublicHealthEngland• Cancerregistry&datasets(COSD,SACT,RTDS,DID)

• Otherdiseaseregistries• Clinicalaudit• Screeningprogrammes

GPdata• Prescribing/dispensing• Reports/letters• Notes(freetext)

GeLgenomicresults

InterpretationValidationClinicalapplicationGermlineSomaticExitquestionnaire

GMCclinicaldataInterpretationdata:RD:HPOterms,PedigreeCa:Diagnosis&staging

Comprehensiveclinicaldata:DatamodelsforkeydataIncludinglabtestresultsEHRdatadumpTreatments&Investigations

GMCregistration

DemographicsConsentstatusAdditionalfindingsRegistrationSamplemanagement

2224May2018

NHSDsuccess:annualagreement,receivedquarterly,matched98.2%participantsAprilHESdelivery2.3mepisodeson31,781participants,increases400K/quarterDeathdatareceivedon430participants,otherdatasetsarrivingnow

FontcolourkeyReceivingdataDatarequestedPlannedsource

HESdata OutpatientepisodesA&EInpatientCriticalcare

=cancertreatment=non-cancertreatment

3rd MainProgrammedatarelease:April2018

24May2018

42,700genomesGenomes GMCClinicaldata

61,500participants380+datafields

Secondarydata

• HospitalEpisodeStatistics(HES)• DiagnosticImagingDataset(DID)• PatientReportedOutcomeMeasures(PROMs)

• MentalHealthServicesDataSet(MHSDS)• OfficeforNationalStatistics(ONS)–mortalitydataandcancerflagging

Tiering data

• Tier1,2and3variantsfrominterpretationpipeline

• FacilitateGeCIPinterpretationofProjectcases

Headline

tables

• KeyinformationfromdifferentLabKeytables,mergedandfilterable

• MergedwithQCdata• Willfacilitatecohort-buildingandprojectfeasibilityassessment

TheResearchEnvironmentataglance

2524May2018

Toolsandanalysis

GenomesstoredinbydatefoldersonIsilon share

Dataanddocumentation

Collaborationanddataflow

ClinicaldatastoredinLabKey

Confluencecontains:

VirtualdesktopinterfaceprovidesGUIandsecurity

Terminalallowscommandlinequeryingofthedata

RandRstudio allowsstatisticalanalysisofthedata

Firefoxbrowserallowsaccesstowhitelistedsites

Accesstomodulesandthesubmissionnodetorunlargescaleanalysis

• datareleasenotes• userguides• workaround

instructions

Domain-specificandsharedstorageforfiles

Socialmediaplatformforcommunication

Researchregistry–topromote

collaborationandenforcepublication

moratorium

GoingForward

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TheResearchEnvironment

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GoingForward

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TheResearchEnvironment

24May2018

GoingForward

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TheResearchEnvironment

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2924May2018

ParticipantID

Sex EthnicGroup Participanttype

Germlinegenomebuild37

GermlineGenomebuild38

Tumourgenomebuild37

Tumourgenomebuild38

TieredData Disorder

0000001 M BlackorBlackBritish Proband PassedQC NA NA NA 1 Intellectualdisability0000002 M BlackorBlackBritish Mother PassedQC NA NA NA NA NA0000003 F BlackorBlackBritish Father PassedQC NA NA NA NA NA0000004 F WhiteBritish Proband NA PassedQC NA PassedQC NA Ductal0000005 M Other Proband NA PassedQC NA PassedQC NA Endometrioid adenocarcinoma

TheDiscoveryForumA driveroftranslationalresearch

3024May2018

ResearchEnvironment

Genomicdataset

Geno

micsE

ngland

Stakeh

olde

rs Academic

StakeholdersHealthserviceStakeholders

IndustryStakeholders

Businessvalue

Discovery Forum

• Exploring thebusinessvalueofgenomicmedicinedata.

• Connecting industrystakeholderstotheGenomicsEnglandcommunity.

• Providingagateway toourResearchEnvironmentanddataset.

• Leadingtodiscovery anddevelopmentofprecisionmethods,diagnostics,andtherapeutics.

Precisiondevelopm

ent

Thankyou!

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