CLSI EP及GP文件\EP17-A

EP17-AVol.24No.34ReplacesEP17-PVol.24No.10ProtocolsforDeterminationofLimitsofDetectionandLimitsofQuantitation;ApprovedGuidelineThisdocumentprovidesguidancefordeterminingthelowerlimitofdetectionofclinicallaboratorymethods,forverifyingclaimedlimits,andfortheproperuseandinterpretationofthelimits.AguidelineforglobalapplicationdevelopedthroughtheNCCLSconsensusprocess.NCCLS...GlobalConsensusStandardizationforHealthTechnologiesNCCLSisaninternational,interdisciplinary,nonprofit,MostNCCLSdocumentsaresubjecttotwolevelsofstandards-developing,andeducationalorganizationthatconsensus—“proposed”and“approved.”Dependingonpromotesthedevelopmentanduseofvoluntarytheneedforfieldevaluationordatacollection,consensusstandardsandguidelineswithinthehealthcaredocumentsmayalsobemadeavailableforreviewatancommunity.Itisrecognizedworldwidefortheintermediateconsensuslevel.applicationofitsuniqueconsensusprocessintheProposedAnNCCLSconsensusdocumentundergoesthedevelopmentofstandardsandguidelinesforpatientfirststageofreviewbythehealthcarecommunityasatestingandrelatedhealthcareissues.NCCLSisbasedonproposedstandardorguideline.Thedocumentshouldtheprinciplethatconsensusisaneffectiveandcost-receiveawideandthoroughtechnicalreview,includinganeffectivewaytoimprovepatienttestingandhealthcareoverallreviewofitsscope,approach,andutility,andaline-services.by-linereviewofitstechnicalandeditorialcontent.InadditiontodevelopingandpromotingtheuseofApprovedAnapprovedstandardorguidelinehasachievedvoluntaryconsensusstandardsandguidelines,NCCLSconsensuswithinthehealthcarecommunity.Itshouldbeprovidesanopenandunbiasedforumtoaddresscriticalreviewedtoassesstheutilityofthefinaldocument,toissuesaffectingthequalityofpatienttestingandhealthensureattainmentofconsensus(i.e.,thatcommentsoncare.earlierversionshavebeensatisfactorilyaddressed),andtoPUBLICATIONSidentifytheneedforadditionalconsensusdocuments.AnNCCLSdocumentispublishedasastandard,NCCLSstandardsandguidelinesrepresentaconsensusguideline,orcommitteereport.opinionongoodpracticesandreflectthesubstantialagreementbymateriallyaffected,competent,andinterestedStandardAdocumentdevelopedthroughtheconsensuspartiesobtainedbyfollowingNCCLS’sestablishedprocessthatclearlyidentifiesspecific,essentialconsensusprocedures.ProvisionsinNCCLSstandardsandrequirementsformaterials,methods,orpracticesforuseguidelinesmaybemoreorlessstringentthanapplicableinanunmodifiedform.Astandardmay,inaddition,regulations.Consequently,conformancetothisvoluntarycontaindiscretionaryelements,whichareclearlyconsensusdocumentdoesnotrelievetheuserofidentified.responsibilityforcompliancewithapplicableregulations.GuidelineAdocumentdevelopedthroughtheCOMMENTSconsensusprocessdescribingcriteriaforageneraloperatingpractice,procedure,ormaterialforvoluntaryThecommentsofusersareessentialtotheconsensususe.Aguidelinemaybeusedaswrittenormodifiedbyprocess.Anyonemaysubmitacomment,andallcommentstheusertofitspecificneeds.areaddressed,accordingtotheconsensusprocess,bytheNCCLScommitteethatwrotethedocument.Allcomments,ReportAdocumentthathasnotbeensubjectedtoincludingthosethatresultinachangetothedocumentwhenconsensusreviewandisreleasedbytheBoardofpublishedatthenextconsensuslevelandthosethatdonotDirectors.resultinachange,arerespondedtobythecommitteeinanCONSENSUSPROCESSappendixtothedocument.ReadersarestronglyencouragedtocommentinanyformandatanytimeonanyNCCLSTheNCCLSvoluntaryconsensusprocessisaprotocoldocument.AddresscommentstotheNCCLSExecutiveestablishingformalcriteriafor:Offices,940WestValleyRoad,Suite1400,Wayne,PA•theauthorizationofaproject19087,USA.•thedevelopmentandopenreviewofdocumentsVOLUNTEERPARTICIPATION•therevisionofdocumentsinresponsetocommentsHealthcareprofessionalsinallspecialtiesareurgedtobyusersvolunteerforparticipationinNCCLSprojects.PleasecontacttheNCCLSExecutiveOfficesforadditional•theacceptanceofadocumentasaconsensusinformationoncommitteeparticipation.standardorguideline.EP17-AISBN1-56238-551-8Volume24Number34ISSN0273-3099ProtocolsforDeterminationofLimitsofDetectionandLimitsofQuantitation;ApprovedGuidelineDanielW.Tholen,M.S.KristianLinnet,M.D.,Ph.D.MarinaKondratovich,Ph.D.DavidA.Armbruster,Ph.D.,DABCC,FACBPatriciaE.Garrett,Ph.D.RobertL.Jones,Ph.D.MartinH.Kroll,M.D.RudolfM.Lequin,Ph.D.ThomasJ.Pankratz,Ph.D.G.A.Scassellati,Ph.D.HeinzSchimmel,Ph.D.JaneTsai,Ph.D.AbstractNCCLSdocumentEP17-A—ProtocolsforDeterminationofLimitsofDetectionandLimitsofQuantitation;ApprovedGuidelineprovidesprotocolsfordeterminingthelowerlimitofdetectionofclinicallaboratorymethods,forverifyingclaimedlimits,andfortheproperuseandinterpretationoftheselimits.Thisdocumentalsoprovidesguidancefordetermininglowerlimitsofquantitationbasedonalaboratory’sgoalsforperformanceatlow-levels.Thisappliestoallquantitativeprocedures,evenifthereportedresultisqualitative.EP17-Aisintendedforusebyclinicallaboratoriesandbymanufacturersofinvitrodiagnostictests.NCCLS.ProtocolsforDeterminationofLimitsofDetectionandLimitsofQuantitation;ApprovedGuideline.NCCLSdocumentEP17-A(ISBN1-56238-551-8).NCCLS,940WestValleyRoad,Suite1400,Wayne,Pennsylvania19087-1898USA,2004.THENCCLSconsensusprocess,whichisthemechanismformovingadocumentthroughtwoormorelevelsofreviewbythehealthcarecommunity,isanongoingprocess.Usersshouldexpectrevisededitionsofanygivendocument.Becauserapidchangesintechnologymayaffecttheprocedures,methods,andprotocolsinastandardorguideline,usersshouldreplaceoutdatededitionswiththecurrenteditionsofNCCLSdocuments.CurrenteditionsarelistedintheNCCLSCatalog,whichisdistributedtomemberorganizations,andtononmembersonrequest.Ifyourorganizationisnotamemberandwouldliketobecomeone,andtorequestacopyoftheNCCLSCatalog,contacttheNCCLSExecutiveOffices.Telephone:610.688.0100;Fax:610.688.0700;E-Mail:exoffice@nccls.org;Website:www.nccls.orgNumber34NCCLSThispublicationisprotectedbycopyright.Nopartofitmaybereproduced,storedinaretrievalsystem,transmitted,ormadeavailableinanyformorbyanymeans(electronic,mechanical,photocopying,recording,orotherwise)withoutpriorwrittenpermissionfromNCCLS,exceptasstatedbelow.NCCLSherebygrantspermissiontoreproducelimitedportionsofthispublicationforuseinlaboratoryproceduremanualsatasinglesite,forinterlibraryloan,orforuseineducationalprogramsprovidedthatmultiplecopiesofsuchreproductionshallincludethefollowingnotice,bedistributedwithoutcharge,and,innoevent,containmorethan20%ofthedocument’stext.Reproducedwithpermission,fromNCCLSpublicationEP17-A—ProtocolsforDeterminationofLimitsofDetectionandLimitsofQuantitation;ApprovedGuideline(ISBN1-56238-551-8).CopiesofthecurrenteditionmaybeobtainedfromNCCLS,940WestValleyRoad,Suite1400,Wayne,Pennsylvania19087-1898,USA.PermissiontoreproduceorotherwiseusethetextofthisdocumenttoanextentthatexceedstheexemptionsgrantedhereorundertheCopyrightLawmustbeobtainedfromNCCLSbywrittenrequest.Torequestsuchpermission,addressinquiriestotheExecutiveVicePresident,NCCLS,940WestValleyRoad,Suite1400,Wayne,Pennsylvania,19087-1898,USA.Copyright©2004.TheNationalCommitteeforClinicalLaboratoryStandards.SuggestedCitation(NCCLS.ProtocolsforDeterminationofLimitsofDetectionandLimitsofQuantitation;ApprovedGuideline.NCCLSdocumentEP17-A[ISBN1-56238-551-8].NCCLS,940WestValleyRoad,Suite1400,Wayne,Pennsylvania19087-1898USA,2004.)ProposedGuidelineMarch2004ApprovedGuidelineOctober2004ISBN1-56238-551-8ISSN0273-3099iiVolume24EP17-ACommitteeMembershipAreaCommitteeonEvaluationProtocolsJanS.Krouwer,Ph.D.KristianLinnet,M.D.,Ph.D.R.NeillCarey,Ph.D.ChairholderPsychiatricUniversityHospitalPeninsulaRegionalMedicalCenterKrouwerConsultingRisskov,DenmarkSalisbury,MarylandSherborn,MassachusettsKristenL.Meier,Ph.D.CarlC.Garber,Ph.D.,FACBLuannOchs,M.S.FDACenterforDevicesandQuestDiagnostics,IncorporatedVice-ChairholderRadiologicHealthLyndhurst,NewJerseyRocheDiagnosticsCorporationRockville,MarylandIndianapolis,IndianaPatriciaE.Garrett,Ph.D.MaxRobinowitz,M.D.BostonBiomedica,Inc.AndersKallner,M.D.,Ph.D.FDACenterforDevicesandWestBridgewater,MassachusettsKarolinskaHospitalRadiologicHealthStockholm,SwedenRockville,MarylandDonaldM.Powers,Ph.D.PowersConsultingServicesMartinH.Kroll,M.D.DanielW.Tholen,M.S.Pittsford,NewYorkDallasVAMedicalCenterDanTholenStatisticalConsultingDallas,TexasTraverseCity,MichiganGianAlfredoScassellati,Ph.D.Consultant,EnteNazionalItalianoJacob(Jack)B.Levine,M.B.A.AdvisorsDiUnificationeBayerCorporationTurin,ItalyTarrytown,NewYorkDavidA.Armbruster,Ph.D.,DABCC,FACBJackZakowski,Ph.D.,FACBAbbottLaboratoriesBeckmanCoulter,Inc.AbbottPark,IllinoisBrea,CaliforniaSubcommitteeonLimitsofDetectionDanielW.Tholen,M.S.MartinH.Kroll,M.D.StaffChairholderDallasVAMedicalCenterDanTholenStatisticalConsultingDallas,TexasLoisM.Schmidt,D.A.TraverseCity,MichiganStaffLiaisonKristianLinnet,M.D.,Ph.D.NCCLSPatriciaE.Garrett,Ph.D.PsychiatricUniversityHospitalWayne,PennsylvaniaBostonBiomedica,Inc.Risskov,DenmarkWestBridgewater,MassachusettsPatriceE.PolgarThomasJ.Pankratz,Ph.D.ProjectManagerRobertL.Jones,Ph.D.DadeBehringInc.-GlasgowNCCLSCentersforDiseaseControlandNewark,DelawareWayne,PennsylvaniaPreventionAtlanta,GeorgiaHeinzSchimmel,Ph.D.,DonnaM.Wilhelm(IFCCliaison)EditorMarinaKondratovich,Ph.D.IRMMNCCLSFDACenterforDevicesandRetieseweg,BelgiumWayne,PennsylvaniaRadiologicHealthRockville,MarylandMelissaA.LewisAssistantEditorNCCLSWayne,PennsylvaniaTheNCCLSAreaCommitteeonEvaluationProtocolsanditsSubcommitteeonLimitsofDetectiongratefullyacknowledgethevaluablecontributionsofthefollowingauthorsoftheguideline:DavidA.Armbruster,Ph.D.,DABCC,FACBGianAlfredoScasselatti,Ph.D.AbbottLaboratoriesConsultant,EnteNazionalItalianoDiUnificationeAbbottPark,IllinoisTurin,ItalyRudolfM.Lequin,Ph.D.JaneTsai,Ph.D.DiagnosticsConsultancyRocheDiagnosticsCorp.Eindhoven,TheNetherlandsIndianapolis,IndianaiiiNumber34NCCLSivVolume24EP17-AContentsAbstract....................................................................................................................................................iCommitteeMembership........................................................................................................................iiiForeword..............................................................................................................................................vii1Scope..........................................................................................................................................12Introduction................................................................................................................................12.1PathofDevelopmentandUse.......................................................................................22.2CommonPractices........................................................................................................22.3Terminology..................................................................................................................32.4DiscussionofLimitsofDetectionandtheTietoQualitativeTests.............................43Definitions.................................................................................................................................54ProceduresforDeterminingandVerifyingtheLimitofDetection(LoD)foraMeasurementProcedure...................................................................................................................................74.1Overview.......................................................................................................................74.2StudyDesign...............................................................................................................104.3ProceduretoDetermineandVerifytheLoBandLoD...............................................115LimitofQuantitation(LoQ)....................................................................................................175.1EstablishingtheLimitofQuantitation........................................................................185.2VerifyingaClaimedLoQ...........................................................................................186ReportingResults.....................................................................................................................236.1ReportingIntervalsforQuantitativeResults..............................................................236.2ExampleofaClaiminLabeling.................................................................................25References.............................................................................................................................................26AppendixA.StandardErrorofLoDandEstimationofSampleSize...................................................27AppendixB.EstimationofSDS............................................................................................................28AppendixC.Example...........................................................................................................................29SummaryofDelegateCommentsandSubcommitteeResponses.........................................................36TheQualitySystemApproach..............................................................................................................38RelatedNCCLSPublications................................................................................................................39vNumber34NCCLSviVolume24EP17-AForewordLaboratorymethodshavemanyperformancecharacteristicsthatmustbeunderstoodandassessedfortheirappropriateuse.Theperformancecharacteristicsforanymethoddescribethemethod’scapabilitytoreliablymeasuretheamountofananalyteinasubject’ssample(althoughforsomeanalytes,reliabledetectionissufficient).Twosuchcriticalperformancecharacteristicsaredefinedatthelowerendofthemeasurementscale.Thefirstisthesmallestamountthatthemethodcanreliablydetecttodeterminepresenceorabsenceofananalyte.Thisisthelimitofdetection(LoD).Thesecondcharacteristicisthesmallestamountthemethodcanreliablymeasurequantitatively.Thisisthelimitofquantitation(LoQ).Thelimitsofdetectionandquantitationarecriticalbecausedetectingextremelysmallamountsofananalytecanbenecessarytodefinediseasestates,screenfordisease,identifysignificantexposure,ortorevealthepresenceorabsenceoftoxins,pollutants,carcinogens,contaminants,infectiousagents,andillicitdrugs.Someoftheseapplicationsmayeffectivelyusetheexaminationmethodasaqualitativeorsemiquantitative(ordinalscale)procedure.Althoughthediscriminationpoint,orcutoffvalue,foraqualitativemethodisrarelydesignatedbythedevelopertobeequivalenttothelowestdetectableamountsoftheanalyte,knowledgeofthelimitofdetectioninformsthechoiceofacutoff,sotheproceduresinthisdocumentshouldbeapplicable.TheLoDandLoQarealsoimportantinlaboratoryexaminationsfortumormarkers,hormones,agentsofinfectiousdiseases,therapeuticdrugs,andothertestswherelowvaluesseparatesubjectsintodifferentdiseaseorexposurecategories.Becauseofthestatisticalsophisticationoftheseprotocols,itisexpectedthatthisdocumentwillbeusedprimarilybymanufacturersandclinicallaboratorysupervisors.ANoteonTerminologyNCCLS,asagloballeaderinstandardization,isfirmlycommittedtoachievingglobalharmonizationwhereverpossible.Harmonizationisaprocessofrecognizing,understanding,andexplainingdifferenceswhiletakingstepstoachieveworldwideuniformity.NCCLSrecognizesthatmedicalconventionsintheglobalmetrologicalcommunityhaveevolveddifferentlyintheUnitedStates,Europe,andelsewhere;thatthesedifferencesarereflectedinNCCLS,ISO,andCENdocuments;andthatlegallyrequireduseofterms,regionalusage,anddifferentconsensustimelinesareallobstaclestoharmonization.Inlightofthis,NCCLSrecognizesthatharmonizationoftermsfacilitatestheglobalapplicationofstandardsanddeservesimmediateattention.Implementationofthispolicymustbeanevolutionaryandeducationalprocessthatbeginswithnewprojectsandrevisionsofexistingdocuments.TheSubcommitteeonLimitsofDetectionhasmadeeveryefforttousegloballyacceptedtermswhereverpossible.ThesearedescribedinSections2.3.1and2.3.2whichdiscusssomecommonlyusedtermsthatarenotemployedinthisdocument,andinSection3.Usersareencouragedtocommentonthechoicesmadebythesubcommittee,inthehopeofeventuallyreachingfullinternationalharmonizationofthesetermsandconcepts.KeyWordsLimitofblank,limitofdetection,limitofquantitation,nonparametricstatisticsAcknowledgementThisguidelinewaspreparedbyNCCLS,aspartofacooperativeeffortwithIFCCtoworktowardtheadvancementanddisseminationoflaboratorystandardsonaworldwidebasis.NCCLSgratefullyacknowledgestheparticipationofIFCCinthisproject.viiNumber34NCCLSviiiVolume24EP17-AProtocolsforDeterminationofLimitsofDetectionandLimitsofQuantitation;ApprovedGuideline1ScopeNCCLSdocumentEP17specifiesrecommendationsfordeterminingthelowerlimitofdetectionofclinicallaboratorymethods,forverifyingclaimedlimits,andfortheproperuseandinterpretationofthelimits.Italsoprovidesguidancefordetermininglowerlimitsofquantitationbasedonalaboratory’sgoalsforperformanceatlow-levels.EP17maybeappliedtoallmeasurementprocedures(evenifthereportedresultisqualitative),mostnotablythoseforwhichthemedicaldecisionlevelislow(i.e.,approachingzero).Theintendedusersofthisguidelineareclinicallaboratorysupervisorsandmanufacturersofinvitrodiagnostictests.2IntroductionTherehavebeenagreatnumberofproceduresproposedforestablishingthelowerlimitsofdetectionandquantitation(LoDandLoQ)inlaboratorymeasurementprocedures.Thisdocumentdoesnotintendtoreviewthemall,nordoesitattempttofindagreementamongthem.Theneedsoftheclinicallaboratoryareuniqueinthattherecommendedproceduremustapplytoanalyticaldevicesastheyareusedinthelaboratorysetting.Usually,thismeansusingthedeviceasitis,oftenassetupandmaintainedbyamanufactureroritsrepresentatives.ThemostcommonlyrecommendedstatisticalprotocolsforLoDandLoQ,includingtheISOprotocol11843,Parts1to4,1-4assumethattherawinstrumentoutputatlowlevelscanresultinnegativeconcentrations.Theseprotocolsalsoassumethatthesignalsforblanksamplesarenormallydistributedaroundsomelowaveragevalue(usuallyzero).However,manycommonclinicallaboratoryinstrumentsreportanalytelevelsinpositivenumbersonly,andbasicinstrumentanalyticalsignalsarenotretrievable,sothepreferredparametricmodelsarenotappropriate.Thisprotocolisintendedforusewithmethodsthatreportinmassorconcentrationunits,and,inparticular,inwhichthereisclinicalneedorinterestinverylowconcentrations(approachingzero).EP17isintendedforallmethods,butitwasdesignedspecificallyforusewithmethodsthatreport“zero”orpositivevaluesonly.ManufacturersordevelopersofmethodswhohaveaccesstothebasicinstrumentresponseshouldconsideruseofISO11843-11andeither11843-22or11843-3,3dependingonwhetherornotlinearcalibrationdataareavailable;thesedocumentsdescribetheinternationallyrecognizedproceduresfordeterminingtheLoD.Usually,theexpectedlimitsofdetectionfortheEP17protocolarethesameasfortheISOmodel,buttheISOprocedureshouldreturnvalueswithloweruncertainty.However,itisimportanttorememberthattheuseoftheparametricISOproceduresrequiresthevalidityoftheassumptionsofnormality(Gaussian)atalltestedlevels,includingtheblankmaterial.ProperuseoftheISOprotocolwillalsorequirestatisticalsophisticationthatisoftenbeyondthecapabilitiesofmostlaboratories.TheEP17protocolisintendedtobeappliedandunderstoodwithoutstrainingtheresourcesavailabletomostclinicallaboratories.TheproceduresarebasedontheconceptsusedinconventionalLoDprocedures,butarepracticalforusewithcommonclinicallaboratorydevices.Thisprotocolrequiresknowledgeofthetrue(oraccepted)levelsofthemeasurandinsamplesbeingtested.Thereislittleutilityinestimatesofprecisionaroundanunknownvalue.Itisalsoimportanttorecognizethatmodernelectronicinstrumentsdonotpossesscontinuousfunctionsrelatingsensorandvoltageorcurrentoutput.Therandomerrormeasuredintheregionofablankmaybetrulyrandom,butitAnNCCLSglobalconsensusguideline.©NCCLS.Allrightsreserved.1Number34NCCLScouldalsobeduetoexplainablefactors.Beforespendingmucheffortpursuingstatisticaldescriptionsofresultsonablankmaterial,itisimportanttofirstdefinetheissuesrelatedtotheanalyzersthemselvesandtheenvironmentinwhichtheyareused.5ThefollowingNCCLSdocumentsEP5—EvaluationofPrecisionPerformanceofClinicalChemistryDevices,EP6—EvaluationoftheLinearityofQuantitativeMeasurementProcedures:AStatisticalApproach,EP7—InterferenceTestinginClinicalChemistry,andEP9—Meth