1. Method comparisons - what do we learn from the Nordic Reference Interval Project 2000 (NORIP) Pål Rustad Fürst Medical Laboratory Labquality Days 12/2-2005

2. NORIP Two important goals are about to be achieved in the Nordic countries for 25 common biochemical quantities: –Common Nordic reference intervals (see http://www.furst.no/norip) –Improvement in trueness of measurement systems using NFKK Reference Serum X

3. Can the laboratories use the proposed reference intervals??? Preanalytical aspects Analytical aspects NORIP reference intervals are traceable to target values of X irrespective of uncertainty and bias

4. NFKK Reference serum X Part of NOBIDA, purchase from DEKS Intention: Nordic laboratories may test trueness of their methods before implementing new reference intervals –Traceability Target values traceable to reference methods Exception: Some enzymes, HDL-cholesterol, TIBC –Commutability Frozen unprocessed serum pool Fresh donors blood, collected in dry bags and allowed to coagulate, pooled, filtered, mixed, dispensed in polypropylene vials, frozen at –80  C without further processing - i.e. interferences as for a mean patient sample –Durability Stored at -80 °C and sent to the laboratory on dry ice

5. Traceability Tranferred values Nordic Trueness Project 120 Nordic routine laboratories measured a ll materials in parallel during 5 days on 10 NORIP quantities Several ref. labs  IMEP 17, Material 1 (frozen unprocessed serumpool) HK02 (commercial/lyophilized) CAL (frozen unprocessed serumpool) transferred value X (frozen unprocessed serumpool) DGKC 2002  DGKC 1997  }

6. Traceability comparison Are transferred values achieved by using routine methods correct??

7. Traceability comparison Conclusions Transferred values by use of routine methods are only safe if both materials are commutable Agreement within uncertainty for all tested quantities for CAL is an indication of good commutability and correct target values Transferred values from Nordic Trueness Project are used as target values for CAL and for X (i.e. traceability for NORIP reference intervals for non-enzymes)

8. How to use X in the routine laboratory? Measurement protocol –Local calibrator and X measured in parallel ~ removed between run variation –10 replicates of each ~ removed within run variation Calculations (spreadsheet)spreadsheet Uncorrected and corrected relative bias: B u =(M x -T x )/T x B k =(T c /M c ·M x -T x )/T x Uncertainty: X, local calibrator, measurements, rounding Evaluation A measurement error is regarded as important if it is statistically significant and it exeeds a quality goal

9. Quality goal 0.375 x total biological variation

10. Protocol ensures that known sources of uncertainty are minimized to detect true bias! –Material Traceability, commutability, durability –Measurement protocol Minimized measurement uncertainty –Calculations Based on statistical and medical considerations –Evaluation Collection of data from several laboratories may reveal some important error sources

11. EQA with X in Norway Collected 39 spreadsheets from Norway –makes it possible to evaluate sources of error: »measurement system mean bias »local errors or robustness of measurement system May be difficult to argue with diagnostic industry if... –Uncertainty of target value for X is high »Ex: Albumin, sodium –Producer’s uncertainty on calibrator is high How will the diagnostic industry react? (… answer on last page!)

12. Measurement systems Potassium ProducerNumber Abbott Aeroset 2 Abbott Architect 3 Bayer Advia1650 7 DB Dimension RxL 1 Roche Cobas Integra 400 1 Roche Cobas Integra 700 3 Roche Cobas Integra 800 4 Roche Hitachi 911 2 Roche Hitachi 912 1 Roche Hitachi 917 4 Roche Modular 6 Vitros250 2 Vitros950 3

13. Target: 41.5 g/L (IMEP 17, RID/CRM 470) Albumin Target: 41.5 g/L (IMEP 17, RID/CRM 470) Generelly high Abbott Bayer Roche Roche Roche Ortho Aeroset Advia 1650 Cobas Hitachi Modular Vitros Architect Expect less dispersion between open than between filled squares Roche ref. lab.

14. Creatinine Reference limits Original suggestion: female: 50-90, male 60-100 Corrected methods: female: 45-90, male 60-105 Jaffé-methods corrected: Y = (Yo-I)·Tc/(Tc-I) Vitros corrected (enz): Y=1.02 · Yo -8.1  mol/L Enzymatic methods Yn = (Yo-I)·Tc/(Tc-I) i.e. Slope = Tc/(Tc-I) Intercept = -I·TC/(Tc-I)

15. Target: 73.9 µmol/L (IMEP 17, IDMS) Creatinine Target: 73.9 µmol/L (IMEP 17, IDMS) Abbott Bayer Cobas Hitachi Modular Vitros

16. Target 140.65 mmol/L (IMEP 17, gravimetry/FAES)) Sodium Target 140.65 mmol/L (IMEP 17, gravimetry/FAES)) Abbott Bayer Cobas Hitachi Modular Vitros

17. Target: 2.325 mmol/L (IMEP 17, IDMS) Calcium Target: 2.325 mmol/L (IMEP 17, IDMS) Abbott Bayer Cobas Hitachi Modular Vitros

18. Target: 0.810 mmol/L (IMEP 17, IDMS) Magnesium Target: 0.810 mmol/L (IMEP 17, IDMS) Abbott Bayer Cobas Hitachi Modular Vitros

19. Target: 20.0 µmol/L (IMEP 17, IDMS) Iron Target: 20.0 µmol/L (IMEP 17, IDMS) Abbott Bayer Cobas Hitachi Modular Vitros

20. Target: 68.7 g/L (NORIP, biuret) Protein Target: 68.7 g/L (NORIP, biuret) Abbott Advia 1650 Cobas Hitachi Modular Vitros

21. Target: 4.405 mmol/L (IMEP 17, IDMS) Glucose Target: 4.405 mmol/L (IMEP 17, IDMS) Abbott Bayer Cobas Hitachi Modular Vitros

22. Target: 5.22 mmol/L (IMEP 17, IDMS) Cholesterol Target: 5.22 mmol/L (IMEP 17, IDMS) Abbott Bayer Cobas Hitachi Modular Vitros

23. Target: 309.9 µmol/L (IMEP 17, IDMS) Urate Target: 309.9 µmol/L (IMEP 17, IDMS) Abbott Bayer Cobas Hitachi Modular Vitros

24. Target: 4.910 mmol/L (IMEP 17, IDMS) Carbamide (urea) Target: 4.910 mmol/L (IMEP 17, IDMS) Generally high Abbott Bayer Cobas Hitachi Modular Vitros

25. Target: 147.8 U/L (NORIP consensus, Roche Modular) Lactate dehydrogenase (LD) Target: 147.8 U/L (NORIP consensus, Roche Modular) Abbott Bayer Cobas Hitachi Modular Vitros

26. Suggestions for follow up Collect spreadsheets from all Nordic countries Discuss discovered deviations with diagnostic industry Agree with diagnostic industry on possible national/Nordic corrections

27. Reactions from diagnostic industy Abbott Norway took initiative to collect spreadsheets from ”their” laboratories in Norway –National factor for magnesium –Will consider correction of their creatinine Jaffé method Roche measured X in their reference lab. –Changed their reference method from atomic absorption to IDMS for calcium –Consider changing calcium routine method Ortho (Vitros) measured X in their reference lab. Konelab ordered X

28. Thank you for your attention!

29. Effect of correction

30. Target: 3.732 mmol/L (IMEP 17, IDMS) Potassium Target: 3.732 mmol/L (IMEP 17, IDMS) Abbott Bayer Cobas Hitachi Modular Vitros

31. Target: 1.043 mmol/L (NORIP, ion chromatography, scintillation counting) Phosphate Target: 1.043 mmol/L (NORIP, ion chromatography, scintillation counting) Abbott Bayer Cobas Hitachi Modular Vitros

32. Target: 68.9 µmol/L(NORIP consensus) Total iron binding capacity (TIBC) Target: 68.9 µmol/L(NORIP consensus) Abbott Advia 1650 Cobas Hitachi Modular Vitros

33. Target: 8.97 µmol/L (NORIP, Jendrassik) Bilirubin Target: 8.97 µmol/L (NORIP, Jendrassik) Abbott Bayer Cobas Hitachi Modular Vitros

34. Target: 1.387 mmol/L (NORIP consensus, direct methods) HDL-cholesterol Target: 1.387 mmol/L (NORIP consensus, direct methods) Abbott Bayer Cobas Hitachi Modular Vitros

35. Target: 1.287 mmol/L (NORIP, GC/IDMS) Triglycerides Target: 1.287 mmol/L (NORIP, GC/IDMS) Abbott Bayer Cobas Hitachi Modular Vitros