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  • CONCURRENT10:

    THECOMPLETEBLOODCOUNTANDBEYOND:QUALITYISSUESANDREFERENCEMETHODS

    SaturdayMay14th 20161:30 3:00PM(13.30 15.00hrs)

    InternationalSocietyforLaboratoryHematology (ISLH)

  • CONCURRENT10:

    THECOMPLETEBLOODCOUNTANDBEYOND:QUALITYISSUESANDREFERENCEMETHODS

    CHAIRS:Dr.PieroCappelletti.SIPMEL,Pordenone, Italy

    Dr.AlbertHuisman,UMCUtrecht,Utrecht,Netherlands

    InternationalSocietyforLaboratoryHematology (ISLH)

  • VerificationandQualityControlofautomatedHematologyAnalyzers

    Dr.AlbertHuisman,UMCUtrecht,Utrecht,Netherlands

    InternationalSocietyforLaboratoryHematology (ISLH)

  • VerificationandQualityControlofautomatedHematologyAnalyzers

    Dr.AlbertHuisman,UMCUtrecht,Utrecht,Netherlands

    InternationalSocietyforLaboratoryHematology (ISLH)

  • Disclosure information:

    Dr AlbertHuisman:Nothing to disclose

    TheUMCUtrecht,department ofClinical ChemistryandHematology hasreceived fundingfor contractresearchfrom:

    Abbott DiagnosticsBeckman-CoulterDiagnostic GrifolsMechatronics

  • VerificationandqualitycontrolofautomatedHematologyAnalyzers AutomatedCellAnalysis(CompleteBloodCount(CBC))

    Including5partLeukocytedifferentialcount,reticulocytecountandnewparameters(ReticulocyteHemoglobincontentReticulatedPlatelets/ImmaturePlateletFraction,)

    Validationofanewanalyzer Verificationofanewanalyzer

    ISO15189 CLSI,ICSH,others Samples Precision Accuracyandcomparability Sensitivityandspecificity Referenceintervals

    Qualitycontrol Daily/internal ExternalQualityAssesment (EQA/Proficiencytesting)

  • Why?

    Why bother about verification and qualitycontrolofahighly automated analyzer?

  • Because:

    CBCresults formthe starting pointofnumerous diagnosticschedules,treatments and interventions,for example: Erytrocyte /Platelet transfusions Work upofanemia (irondeficiency /thalassemia /) Hematological malignancies Generalwork-upinvarious disease states Etctetera

  • Because:

    TheISO15189standard[Medicallaboratories Particularrequirementsforqualityandcompetence]requiresaverificationprocess

  • AdvantagesofAutomatedCellAnalysers:

    Excellentanalytical performance Closed-tubeanalysis Nointer-observer variability Noslidedistribution error Eliminate statistical variations Potential ofreflextesting Availabilityofextraparameterse.g.MCV,RDW,%rP, Moreefficient (>100analyses/hour)and cost effective than

    manualmethod .

  • Automatedcellcounters:

    CompleteBloodCount(CBC): Hemoglobin(Hb)concentration,RBCcount&RBCindices(MCV,

    MCH,MCHC),WBCcount,PLTcount WBCdifferentialcount(5normalWBCs) RDW,MPV Reticulocytecount NucleatedRBCcount(NRBCs) .Flagging,etc etc

    Newparameters: AdvancedRBCparameters:%microcyticRBCs,Reticulocyte

    Hemoglobincontent,.. ReticulatedPlatelets/ImmaturePlatelets .

  • Furtheradvancesinautomation

    Multipleinlineanalysers Built-inSlide-Maker-Stainer Auto-validationinLIS Automatedreflex/morphologyetc.

    Includingdigitalmorphologyorflow-cytometry solutions AllFullbloodanalysisinline(ESR,HbA1c,..)

    TotalLaboratoryAutomation DigitalMorphology

  • Validation ofanewanalyzer:goal

    Provision ofobjective evidence that ahematologyanalyzerfulfills specified requirements (where thespecifiedrequirements areadequatefor intended use).

    Validation isprimarily amanufacturersresponsibility toensure that designgoalsaremetand performanceclaimsarestated (including safety and effectiveness).

    Validation study (manufacturer): collectdatatosupportaregulatorysubmissionandtheregistrationofahematologyanalyzer.

  • Validation ofanewanalyzer:goal

    Provision ofobjective evidence that ahematologyanalyzerfulfills specified requirements (where thespecifiedrequirements areadequatefor intended use).

    Validation isprimarily amanufacturersresponsibility toensure that designgoalsaremetand performanceclaimsarestated (including safety and effectiveness).

    Validation study (manufacturer): collectdatatosupportaregulatorysubmissionandtheregistrationofahematologyanalyzer.

  • Validationofanewanalyzer(manufacturer)

    Objectives ofavalidation study: Generate datato assess safety and clinical efficacy from amedical perspective Develop performanceinformationfor labelingandmarketingpurposes Validate appropriate operationalperformancecharacteristics ofthe

    hematology analyzerinatypical end-usersetting Develop datathat areused to supportsubmissionoftheproductfor approval

    orclearanceby regulatory bodies

    Source:CLSIH26A2

  • Validationofanewanalyzer(manufacturer)

    Validation performancespecifications: Limitofblank(LoB,background) Carryover Imprecision (reproducibility),shorttermand long-term Analytical measuring interval(AMI)(linearity) Lower limitofdetection (LLoD)and lower limitofquantitation (LLoQ) Comparibility (correlation) Interferences Frequency and typeofdatainvalidations

    Source:CLSIH26A2

  • Validationofanewanalyzer(manufacturer)

    Performancespecifications:current referencemethods*: Selective microscopy for WBCdifferential RBCcount andWBCcount (impedance) Selective microhematocrit (PCV)for hematocrit (HCT) Hemoglobin by hemiglobincyanidemethod Selective PLTmonoclonalantibody (contemporary referencemethod) Reticulocytes by flowcytometry

    Source:CLSIH26A2

    *Standardized and independent ofmanufacturer

  • Validationofanewanalyzer(manufacturer)

    Performancespecifications:current referencemethods: When noreferencemethod isavailable:usually comparisonwith previous

    generation instrument

    Source:CLSIH26A2

  • Validationofanewanalyzer(manufacturer)

    Current referencemethods,problems,need for improvement: Current referencemethods aremoreorless outdated

    e.g.:microscopic 400cell WBCdifferential count:elaborative and imprecise

    Huismanetal.Clin LabMed 2015

  • Validationofanewanalyzer(manufacturer)

    Current referencemethods,problems,need for improvement: Current referencemethods aremoreorless outdated

    e.g.:microscopic 400cell WBCdifferential count:elaborative and imprecise Noreferencemethods available for clinically relevantparameters*:

    MCV ExtendedRBCparameters Reticulocyte Hb content MPV Reticulated platelets/immatureplatelet fraction .

    *Clinically relevantparametersarenot standardized! This may leadto differences between differentHematology analyzers:

    Differences inclinical interpretation (confusion for clinicians) Mayprevent wider use Invalid aggregation ofdata

    Huismanetal.Clin LabMed 2015

  • Validationofanewanalyzer(manufacturer)

    Current referencemethods,problems,need for improvement: Current referencemethods aremoreorless outdated

    e.g.:microscopic 400cell WBCdifferential count:elaborative and imprecise Noreferencemethods available for clinically relevantparameters:

    MCV ExtendedRBCparameters Reticulocyte Hb content MPV Reticulated platelets/immatureplatelet fraction .

    Urgentneed for improvement,role for professionalsocieties

    Huismanetal.Clin LabMed 2015

  • Verification

  • InstrumentVerification by the enduserlaboratory

    Theendusershould asseswhether the manufacturers claimsonperformanceofthe specific instrumentalso apply to theintended use criteriasetby the laboratory:Verification

    Huismanetal.Clin LabMed 2015

  • InstrumentVerification by the enduserlaboratory

    Theverification process includes performanceanalysisof: Accuracy Precision Reportable rangeoftestresults and reference intervals (normal ranges) Background(limitofblank) Carryover (sample) Lower limits ofdetection Quantitation Clinically reportable intervals (CRIs)

    Huismanetal.Clin LabMed 2015

  • InstrumentVerification by the enduserlaboratory

    Accordingto ISO15189acertain levelofverification ofanynew(hematology)analyzerhasto be done (preferably)according toaprofessionalstandard.

    ISO15189also stimulates laboratories to takepatient riskfactorsinto consideration tomeetthesestandards

    There arecurrenly 2internationaldocuments available forverification ofahematology analyzer: Consensusdocuments with recommendations (not based onstrong

    evidence butrather onexpertopinion).

    Huismanetal.Clin LabMed 2015

  • InstrumentVerification by the enduserlaboratory

    Accordingto ISO15189acertain levelofverification ofanynew(hematology)analyzerhasto be done (preferably)according toaprofessionalstandard.

    ISO15189also stimulates laboratories to takepatient riskfactorsinto consideration tomeetthesestandards

    There arecurrenly 2internationaldocuments available forverification ofahematology analyzer: Clinical Laboratory StandardsInstitute (CLSI)(standardH26A2)

    published in2010 InternationalCouncilonStandardisation inHematology (ICSH)

    guidelinepublished in2014.

    Huismanetal.Clin LabMed 2015

  • Consensusdocuments with recommendations

    CLSI ICSH(publishedintheInternationalJournalofLaboratoryHematology,theofficialISLH journal

  • InstrumentVerification by the enduserlaboratory

    CLSI ICSHVerification Thelaboratory(enduser)

    should followtheproceduresofmanufacturervalidation,buttheverificationmaybeabbreviated;thegoalistoverifythatthemanufacturersstatedperformance iscorrect

    Verification isconformationoftheevaluationperformedbythemanufacturerorpublished intheliterature;theverificationmaybeabbreviated(ie,focusedtomeetspecificrequirementsatthetestsite)

    Precision/imprecision(within-run reproducibility,closeness ofagreementbetween testresults

    Should be performed withnormal samplesand samplesatmedical decision levelsavailable inclinicallaboratories.Nospecifications for number ofmeasureme

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