Traceability in routine clinical chemistry Stating or demonstrating?

Transcription

1 Traceability in routine clinical chemistry Stating or demonstrating? Dr. Solveig Linko HUSLAB Hunting for the true value

2 Topics of the presentation Facts about HUS and HUSLAB Normative documents and traceability Challenges of establishing traceability in routine clinical chemistry testing

3 Facts about HUS and HUSLAB HUS is divided into five hospital districts Hyvinkää Lohja Länsi Uusimaa Porvoo 100 km Helsinki 200 km

4 Facts about HUS and HUSLAB cont. 21 hospitals belong to HUS Population is 1.4 million HUSLAB offers lab services to hospitals and primary HC in Helsinki and the surrounding cities and communes 13 million lab tests in 2007, 70% on top20 list; six million accr. reports Approx clients

5 Challenges of HUSLAB HUSLAB covers with one quarter of all lab tests in Finland ( million yearly) Approx lab investigations included in the lab handbook,, 6400 in total 1500 employees in total Meilahti central lab (5.5 million tests yearly) plus 13 satellite labs Approx.. 80 sample taking sites 17 daily sample transporting routes

6 HUSLAB strategy includes inter alia offering fit for for purpose analytical quality reliable results in resonable time! maintaining active and consulting dialogue building a centralized production model developing and maintaining well designed laboratory processes choosing fit into into line analyzers maintaining an active and practical management system (accreditation)

7 Recent HUSLAB activities HUSLAB s s strong growth to east, west and north from 2004 Harmonized test and instrumentation concepts in clinical chemistry hospital lab automation and POC at the primary HC labs 168 accredited tests (accr( accr.. to EN ISO 15189) at the clinical chemistry and hematology section (T055)

8 Need for establishing traceability Stating... is a claim & Establishing... done in the lab & Demonstrating Proving... shown in the lab

9 Quality of measurement result common target Is to.. Assure the reliability of the results for reasonable decision making and improve the traceability to SI for better comparability. Validation ( method fit for purpose ) Quality of measurement result Uncertainty Budget (How well I know the result ) Traceability (my result is comparable common reference) 12 June 2005 Traceability 0 rev1 Slide 3

10 Characteristics of metrological traceability Uncertainty known in every point of traceability chain Well defined and documented measurement procedures used Demonstrated competence Adequate calibration frequency Accredited test procudeures

11 Characteristics of broken traceability Calibrations are not valid Too long calibration frequency Calibration program does not cover all instrumentation Traceability of the reference material unknown

12 Back to the basics...

13 Normative documents around traceability Basic standards and guides Documents obligating manufacturers Documents guiding and/or obligating medical labs

14 Basic standards and guides ISO/IEC Guide 99:2007, International vocabulary of metrology Basic and general concepts and associated terms (VIM) ISO 17511:2003 In vitro diagnostic medical devices Measurement of quantities in biological samples Metrological traceability of values assigned to calibrators and control materials

15 ISO/IEC Guide 99:2007, International vocabulary of metrology Basic and general concepts and associated terms (VIM)

16 ISO/IEC Guide 99:2007, International vocabulary of metrology Basic and general concepts and associated terms (VIM)

17 ISO 17511:2003 In vitro diagnostic medical devices Measurement of quantities in biological samples Metrological traceability of values assigned to calibrators and control materials

18 ISO 17511:2003 Calibration and transfer protocols five levels Level Cases with primary reference measurement procedure and primary calibrator(s) giving metrological traceability to SI measurable quantities with analytes such as electrolytes, metabolites,, glucose, cholesterol, steroid hormones and some thyroid hormones and drugs Primary reference measurement procedure eg.. For cortisol in blood plasma, gravimetry combined with assessment of impurities by chemical methods Primary calibrator eg. Cholesterol SRM 911b, NIST with given mass fraction and known uncertainty (k=2) Secondary reference measurement procedure eg.. for the concentration of cortisol in blood plasma, ID GC/MS Manufacturer s s working calibrator(s) ) as defined by the manufacturer and having value(s) assigned either by gravimetry,, measurement applying prim.. or sec. ref. meas.. procedure, manufacturer s standing meas.. procedure or product calibrator(s)

19 ISO 17511:2003 Calibration and transfer protocols five levels Level Cases with international conventional reference measurement procedure (which is not primary) and international conventional calibrator(s) ) without metrological traceability to SI International conventional reference measurement procedure eg.. for the amount of substance fraction of B HbA1c in blood,, a candidate HP LC/MS (Kobold U et al. Clin Chem:1997; 43: ) International conventional calibrator eg.. for the amount of substance concentration of Hb(Fe) ) in blood,, absorption spectrometry of its cyanide derivative is calibrated by CRM 522

20 ISO 17511:2003 Calibration and transfer protocols five levels Level Cases with international conventional reference measurement procedure (which is not primary) but no international conventional calibrator and without metrological traceability to SI Such parameters as HDL Cholesterol Cholesterol, blood cells and some haemostatic factors International Council for Standardization in Haematology (ICSH) for the measurement of the number concentration of erytrocytes and leukocytes in human blood (Clin Lab Haemat 1994; 16:131 8)

21 ISO 17511:2003 Calibration and transfer protocols five levels Level Cases with international conventional calibrator (which is not primary) but no international conventional reference measurement procedure and without metrological traceability to SI Such parameter as HBsAg and hcg as well as antibodies (international protocol for value assignment of international scientific organization, WHO)

22 ISO 17511:2003 Calibration and transfer protocols five levels Level Cases with manufacturer s selected measurement procedure but neither international conventional reference measurement procedure nor international conventional calibrator and without metrological traceability to SI. Such parameters as fibrin degradation products (D dimer), and tumor markers (CA 12 5), antibodies towards antigens such as Chlamydia.

23 Documents obligating manufacturers IVD Directive 98/79/EC Annex I ESSENTIAL REQUIREMENTS A 3. The devices must be designed... The traceability of values assigned to calibrators and/or control materials must be assured through available reference measurement procedures and/or available reference materials of a higher order.

24 Documents guiding and/or obligating medical labs EN ISO 15189:2003 Medical laboratories. Particular requirements for quality and competence In Finland medical laboratory accreditation is on voluntary basis 25 laboratories accredited in Finland, only HUSLAB acc. to ISO 15189

25 EN ISO 15189: Assuring quality of examination procedures A programme for calibration of measuring systems and verification of trueness shall be designed and performed so as to ensure that results are traceable to SI units or by reference to a natural constant or other stated reference. Where none of these are possible or relevant, other means for providing confidence in the results shall be applied, including but not limited to the following: EQA ( eg. Labquality 2 level EQA samples with traceable values) RM s (certified) documentation (statements and establishments!) etc.

26 What are we hunting for? Huckleberry Finn, illustration by E. W. Kemble from the original 1884 edition of the book by Mark Twain

27 Some key numbers and facts about diabetes in Finland More than Finnish people affected by diabetes The treatment covers 15 % of health care costs A doubled incidence is probable in yrs. according to recent predictions T2D undiagnosed systematic screening of high risk groups is important Specific guidelines for diabetes care are available for T1D and T2D

28 The Finnish Current Care guideline Diabetes Published Working group appointed by the Finnish Medical Society Duodecim and the Medical Advisory Board of the Finnish Diabetes Society Current Care Diabetes concerns with prevention, diagnosis,, treatment and follow up of adult diabetes (86 guidelines available, first guideline in 1994)

29 Main routine tests in diagnosis and follow up of diabetes fp Gluk ( HUSLAB tests in 2007), fp Gluk Gluk O O ( t.) B GHbA1c ( t) fp Kol LDL, indirect ( t.)

30 1. Criteria in diagnosing An elevated fasting plasma glucose fp Gluk no less than 7.0 mmol/l > > Diabetes or A two hour value in the oral glucose test Pt Gluk Gluk R1 > 11.0 mmol/l > > Diabetes (HUSLAB criteria fp Gluk Gluk 0 < 7.0 mmol/l tested at primary health care labs with POC) Repeated tests, if abnormal results

31 1. Criteria in diagnosing cont. fp Gluk mmol/l > Impared Fasting Glucose, IFG or A two hour value in the oral glucose test Pt Gluk Gluk R mmol/l > Impared Glucose Tolerance,, IFG

32 2. Goals in treatment of glucose & lipid balance and blood pressure Measure HbA1c (%) fb Gluk (mmol( mmol/l) Goal < Obs. unless no severe hypoglycemias SMBG fb Gluk after 2 h from last meal (mmol/l) fp Kol Kol LDL (mmol/l) Blood pressure (mmhg) < 8 < 2.5 < 1.8 < 130/80 SMBG among T2D and T1D with microalbuminuria coronary heart disease detected

33 I HUSLAB Glucose setup Lab Meilahti Automation, Reference lab Meilahti Emergency Instrumentation Modular 1 Modular 2 Cobas Integra Cobas Integra Test * accredited Roche Diagnostics, Gluco quant * Glucose HK (GLUC2) * Glucose/HK Areal satellites (10) Olympus AU 640/400 GLUCOSE, Olympus til.no OSR6121 * Glucose Hexokinase Women s Clinic Children s Clinic Health Care Center Labs Biosen C_Line sport s HemoCue s Calibration by lot EKF diagnostic no. # * Amperometric, gluc ox Calibration by batch HemoCue Cuvettes,, GDH Factory calibration

34 Stated traceability of glucose applications Level 1 ISO Prim. ref. meas. proc.. & prim. cal s trac.. to SI Manufacturer Calibrator Statement of the traceability Roche Roche Diagnostics, Calibrator for automated systems, No NIST SRM 965a levels 1 41 ID GC/MS Olympus Diagnostics Olympus System Calibrator NIST SRM 965a levels 1 4 EKF diagnostic EKF system calibrator NIST SRM 917b Health Care Center Labs Factory calibration, fixed level over time ID GC/MS

35 Demonstrated traceability of HUSLAB glucose automated methods HUSLAB total uncertainty U (k=2), CV lab included Allowed bias + 3 % (demonstrated with NIST SRM 965a) Glucose U target Level I 4.9 mmol/l 7.81 % 8 % 9 % 7 % 11 % 8 % Level II 15.3 mmol/l 8.05 % 8 % 9 % 5 % 7 % 8 %

36 II HUSLAB GHbA setup 1c Lab Instrumentation Test * accredited Meilahti Automation, Reference lab Bio Rad Variant TM II Turbo 4 setups * Bio Rad Variant TM II Turbo Hemoglobin A 1c HPLC Children s Diabetes Clinic Afinion TM instrumentation Afinion TM / GHbA1c Boronic acid affinity test principle Total and glycated hemoglobin are measured

37 Stated traceability of GHbA 1c applications Level 2 ISO Int. conv. ref. meas. proc.. & int. conv. cal s without trac.. to SI Manufacturer Bio Rad Calibrator Set of system calibrators level 1 and level2 Statement of the traceability The approved IFCC reference method is used to assign IFCC values to the secondary reference materials. These secondary materials are used to value assign product calibrators and determine product calibration parameters through use of the IFCC/NGSP master equation. AXIS SHIELD SHIELD Factory calibration Afinion TM AS100 is traceable to the IFCC Reference method Calibration of the Analyzer established using Reference Materials from ERL Conversion factors for the Designated comparison metrohd (NGSP/DCCT, Mono S and JDS)

38 Demonstrated traceability of HUSLAB GHbA 1c HUSLAB CV tot (k=2), CV lab included Allowed repeatability 3 % GHbA1c Bio Rad Variant TM II Turbo U target Level I 5.7 % 5.1 % 4 % 5 % 5 % n.a. 10 % Level II 9.6 % 4.5 % 5 % 6 % 6 % n.a 10 % Afinion TM AS100 Level I and II 5.0 %

39 Demonstrated traceability of the reference material according to WG HbA 1c Mosca et. al. Global standardization of glycated hemoglobin measurement: the position of the IFCC Working Group Clin Chem Lab Med 2007; 45(8):

40 Approved IFCC Reference Method for the Measurement of HBA1c in Human Blood by Jeppsson et al. Clin Chem Lab Med 2002; 40(1):78 89 Measurement uncertainty of the primary reference material Purity of the HbA 0 and HbA 1c preparations Uncertainty of the target values for the Hb concentratio of these two materials Uncertainty resulting from mixing HbA 1c ja HbA 0 materials to defined concentrations u cal = 0.63% for the primary calibrator ( % HbA 1c ) Secondary reference material, calibrators and controls: Primary calibrator u cal (0.63%) Uncertainty of the value assignment u va 1.0% lab n=4; duplicates in two batches) Combined standard uncertainty u total = ca. 1.2% In practice with a commercial 7.0 % calibrator =>HbA 1c range %

41 III HUSLAB LDL Chol preliminary testing* Lab Instrumentation Test not accredited Meilahti Automation, Reference lab Modular 1 Modular 2 Roche Diagnostics LDL C C plus 2nd generation* Areal satellites (4) Olympus AU 640/400 Calibration according to manufacturer s instructions

42 Stated traceability of LDL Chol applications Level 2 ISO Int. conv. ref. meas. proc.. & int. conv. cal s without traceability to SI Manufacturer Calibrator Statement of the traceability Roche C.f.a.s.. Lipids calibrator Calibration against the beta quantification method as defined in the recommendations in the LDL Cholesterol Method Certification Protocol for Manufacturers (National Reference System for Cholesterol. Cholesterol Reference Method Laboartory Network. October 1997).

43 Stated traceability of LDL Chol applications Level 2 u = 0.76 %

44 Demonstrated traceability of fp Kol Kol LDL in preliminary testing Roche HUSLAB total uncertainty U (k=2), Allowed bias 3 % (demonstrated with NIST SRM 1915b) level I bias 1.73 % level II bias 2.34 % 2008 U target Level I 3.0 mmol/l 4.9 % 10 %? Level II 4.0 mmol/l 5.7 % 10 %?

45 How good is good enough? Glucose level 7.0 mmol/l U = 8 % mmol/l acceptable? GHbA 1c level 7 % U = 6 % % acceptable? LDL Chol Chol* level 2.5 mmol/l U = 5 % mmol/l acceptable? * in preliminary testing

46 Summary Traceability statements available for user calibrators from manufacturers (IVDD) Demonstrating traceability necessary at labs for assuring proper quality and comparability of results Safe ground under the methods of diabetes diagnosis and follow up if proper QA Right course in many tests, not to be ruined with incompetent analysing systems International co operation operation needed in laboratory medicine (JCTLM)

47 Still hunting or tracking...?

48 Thanks to HUSLAB clinical biochemists and specializing chemists Aija Helin Pirjo Juutilainen Leena Riittinen Hannele Kangas Jarkko Salo