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Challenges for International Standardization and Traceability - HORMONES - ______________________________________________ Lothar Siekmann Institute of Clinical Biochemisstry, University of Bonn Reference Institute of Bioanalysis, DGKL http://www.dgkl-rfb.de

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Target Concentrations for Steroid Hormones in a Commercial Control Serum __________________________________________________________________ Aldosterone Cortisol Progesterone Estradiol pmol/l nmo/lnmo/lpmol/l _________________________________________________________________________________________________________ ABBOTT121.9 AMERSHAM113.1 BAXTER DADE DIR104.8 2.16396.4 BAXTER DADE AG ER244.1 BAXTER DADE AD EXT196.0 BIOMERIEUX2.54539.6 BIOTEX PREMIX 99.4 70.63.72759.9 CAMBRID´GE MEDICAL120.80.86 CIBA CORNING110.3 CLINICAL ASSAYS 99.3 CYBERFLUOR FIAGEN 88.2 DIAGNOSTIC PRODUCTS113.13.12119.3 EURODIAGNOSTICS115.8 FARMOS DIAGN. 99.34.67394.9 IMMUNCHEM COV. COAT110.35.41348.7 LEECO113.12.99144.2 MALLINCKRODT 96.6 NMS PHARMACEUTICALS3.18205.5 PANTEX IMMUNO118.64.13190.8 PANTEX IMMUNOCOAT132.47.00154.9 PHARMACIA DELFIA 99.9790.0 RSL169.24.77117.4 SCLAVO LISO PHASE277.43.82 SERONO112.0 SIBAR ELISA121.31.27 SORIN165.9 68.92.86139.5 SYVA EMIT137.9 TECHLAND RIA4.77 VITEK SYSTEMS110.0

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In Vitro Diagnostica Directive European Union __________________________________________ “.... the traceability of values assigned to calibrators and control materials must be assured through available reference measurement procedures and/or reference materials of higher order...”

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Measurement Traceability _______________________________________ property of the result of a measurement or the value of a standard whereby it can be related to stated references, usually national or international standards, through an unbroken chain of comparisons all having stated uncertainties

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SI-Unit (definition) BIPM Primary calibrator Secondary calibrator Mf.´s working (master) calibrator Mf.´s product calibrator Secondary reference measurement procedure NMI, ACL Mf.´s selected measurement procedure Mf.´s standing measurement procedure End-user´s routine measurement procedure Routine sample RESULT NMI, ACL ACL, MCL ML Mf.-> End- user Mf. and/or End-user MCL Traceability BIPM: International Institute of Weights and Measures NMI: National Metrological Institute ACL: Accredited Calibration Laboratory MCL: Manufacturer´s Calibration Laboratory ML: Manufacturer´s Laboratory Mf: Manufacturer End-user Primary reference measurement procedure ML µ c (y)

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Reference Systems Laboratory Medicine _____________________________________________ Reference Materials Reference Measurement Procedures Reference Laboratories

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SERUM Addition of [ 14 C]Estradiol-17ß Extraction with Dichloromethane Column chromatography on Sephadex LH-20 Formation of the Heptafluorobutyric ester Selected Ion Recording at m/z 664 and 666 MEASUREMENT OF ESTRADIOL-17ß BY ISOTOPE DILUTION MASS SPECTROMETRY ___________________________________________________________ Calculation of the Estradiol-17ß Concentration from Isotope Ratios in Samples and Standard Mixtures

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M+ m/z Carrier gas InjectionVacuum Valve Ion Source Magnet Detector Mass Spectrum Mass Spectrometer min Selected ion recording Gas Chromatograph

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Implementation of the Traceability Concept ___________________________________________ by: - Diagnostic Kit Manufacturers - Organisers of External Quality Assessment Schemes

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DGKL Reference Procedures Electrolytes: Calcium Chloride Lithium Magnesium Potassium Sodium Metabolites and Substrates: Cholesterol Creatinine Glucose Total Glycerol Uric Acid Urea Bilirubine Lactate Enzmes; ASTGGT ALTAMYLASE CK Hormones: Aldosterone Cortisol Estradiol-17ß Estriol Progesterone 17-Hydroxy-progesterone Testosterone Thyroxine Drugs: Theophylline Digoxin Digitoxin Total Protein

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http://www.dgkl-rfb.de

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PROGESTERONE MEDIANS IN RING TRIALS y = 2,98 + 0,87 x n = 40, r = 0,681 Median (x) = 14,2 Median (y) = 15,75 Median (y-x)% = 10,3 PROGESTERONE PATIENT SAMPLES y = 1,84 + 0,96 x n = 42, r = 0.99 Median (x) = 19,2 Median (y) = 17,9 Median (y-x)% = 17,4

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PROGESTERONE MEDIANS IN RING TRIALS PROGESTERONE PATIENT SAMPLES

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http://www.dgkl-rfb.de

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y = 1,17 x + 6,04 n = 38, r = 0,998 Median (y-x)% = 18,4 y = 1,33 x - 7,25 n = 54, r = 0,98 Median (y-x)% = 30,1

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http://www.dgkl-rfb.de

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Aldosterone – Ring Trials - Method Comparison - Aldosterone – Patient Samples - Method Comparison - Y = 1.13 X + 0.09 n = 38, r = 0.939 Median (y-x)% = 32.3 Y = 1.97 X + 0.06 n = 50, r = 0.873 Median (y-x)% = 69.0

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Estriol, unconjugated DGKL -2005/01 Selected Participants: 54(93) Test – KIT 44 Ref.Values A: 44,3 nmol/l B: 35,4 nmol/l Limits A: 25.6 – 62.1 nmol/l B: 21,2 – 49,6 nmol/l http://www.dgkl-rfb.de

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Unconjugated Estriol in Serum of Pregnant Women Method Comparison

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http://www.dgkl-rfb.de

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SI-Unit (definition) BIPM Primary calibrator Secondary calibrator Mf.´s working (master) calibrator Mf.´s product calibrator Secondary reference measurement procedure NMI, ACL Mf.´s selected measurement procedure Mf.´s standing measurement procedure End-user´s routine measurement procedure Routine sample RESULT NMI, ACL ACL, MCL ML Mf.-> End- user Mf. and/or End-user MCL Traceability BIPM: International Institute of Weights and Measures NMI: National Metrological Institute ACL: Accredited Calibration Laboratory MCL: Manufacturer´s Calibration Laboratory ML: Manufacturer´s Laboratory Mf: Manufacturer End-user Primary reference measurement procedure ML µ c (y)

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http://www.dgkl-rfb.de

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Strategy to establish Reference Systems for non-SI Traceable Quantities ____________________________________________ Definition of the Analyte Development of a Reference Procedure Development of a Reference Material

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Definition of Proteo-Hormone Analytes __________________________________________ Decision on the sub-unit to be measured according to clinical relevance Decision on the epitope(s) to be detected by mono- or poli-clonal antibodies Decision on the glycosidic structure to be measured

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Y = 0.974 X + 14.6 n = 40, r = 0.998 Median (y-x)% = 0.7 Y = 1.064 X + 15.4 n = 40, r = 0.954 Median (y-x)% = 11.6

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Aldosterone – Ring Trials - Method Comparison - Aldosterone – Patient Samples - Method Comparison - Y = 1,127 X + 0.073 n = 40, r = 0.980 Median (y-x)% = 29 Y = 2.845 X - 0.042 n = 50, r = 0.831 Median (y-x)% = 165

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