Clinical ÛResearch Enterprises A Virtuous Cycle
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Clinical Û Research Enterprises A Virtuous Cycle eMERGE
Transcript of Clinical ÛResearch Enterprises A Virtuous Cycle
ClinicalÛ ResearchEnterprisesAVirtuousCycle
eMERGE
TheConceptofEvidence
HumGenDiscoveryp-valuesentrenched1(patent)vsalot(e.g.ExAC)
ReplicationPriorexpectation
TranslationClinicalimpressionentrenchedProfessionalstandards(expertsandsocieties)Doesnotlikecontradictorydata
ExperimentalDiscovery“Theperfectexperiment”p-valuesReplicationPriorexpectation
EvaluatingtheClinicalValidityofGene-BasedAssociationsStrande etal.AJHG,2017
ClinicalGenomeResource
Rehm etal.ClinGen.
NEJM2015
www.clinicalgenome.org
ClinGen ScoringSystem(s)
Somecommentsabout“actionability”Hunteretal.(2016)GeneticsinMed:Severity,Effectiveness,NatureofIntervention
Whatistheaction?Usuallyconsideredmodifiedtreatmentorpreventivemeasure
appliedtothepatient.Reportingis,byitself,anaction.Thepatient’sfamily?Family
planning?
Whatistheevidenceaboveandbeyondtraditionalevidence(e.g.riskfactors)?
e.g.CholesterollevelsvsLDLRmutationDowetreatthegenotypeorthephenotype?
Whatistherisk/harmofamisappliedaction?Itisassumedtobehigh,butitmaybequitelowinsomecases
Whatwehaveseensofarisgreat,but…...
….itdoesn’tscale.
NIHSequencingEfforts
TOPMed CCDG
● CVDCohorts
● >130KWGS● Multi-omics
● LSACEvolved● 22KWGSFreeze
● MultipleCohorts
● 15KCustomPanel
● ClinicalSignout● HGSC-cl
● 1KFamilyWGS● 11KCase/ControlWES
Neptune
GenesofInterest
VariantCalling
KnowledgeBase
ManualReview
AutomatedReport
BluePrint
PhenotypesofInterest
Mercury
SampleData
VIPFilter
GeneList
RawVCFs
FinalReport
VIPVariants
KnownPositive
NegativeReport
NegativePre-Report
PositiveReport
NovelPositive
SignoutPortal
ReviewPortal
NovelClinicalSignificance
ClinicalDBs
Neptune:AutomatedClinicalReporting
BAYLOR HGSC STATUS UPDATE: Interpretation & ReportingALL sites, n = 2,417, Variable phenotypes
NonindicationbasedConsensusreturnable
results
NonindicationbasedSite-specificreturnableresults
IndicationbasedReturnableresults
Indications Total Pos. Neg.
Cardiomyopathy 1 1 0
CardiacArrythmia 31 0 31
Hyperlipidemiaa 637 16 621
ColorectalCancer 279 2 277
Breast/OvarianCancerb
72 16 56
OthersincludeMEFV,HNF1A,CACNA1A,OTC,COL3A1,SMAD3,SMAD4(x1),MH(x3)
Positive3.7%
(n=45) aNegative96.5%(n=985)
Positive3.5%(n=35) Negative
97%(n=2,343)
Positive3.0%
(n=74) a
a3patientsnotincludedwithindicationbasedresults
Negative96.3%
(n=1,164)
aHyperlipidemiaincludesFH,hypertriglyceridemia,hyperlipidemiaandcoronaryarterydiseaseindications.b Allreturnedgenesbelongtothe68consensusexceptforCHEK2inabreastcancerpatient
PathandLpathvariantsinNUspecificreturned
Total
CHEK2 24
ATM 7
SERPINA1 2
MC4R 3
KCNE1 6
F11,FLG,KCNE2(x1) 3
n=1,020 n=2,417 n=1,209
a1patienthad2variants
Neptune
KnowledgeBase
ManualReview
AutomatedReport
VIPFilter
FinalReport
VIPVariants
KnownPositive
NegativeReport
NegativePre-Report
PositiveReport
NovelPositive
SignoutPortal
ReviewPortal
NovelClinicalSignificance
ClinicalDBs
Neptune:AutomatedClinicalReporting
Howcanexpertcurationbescaled?
