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Permissible limits for uncertainty of measurement in laboratory medicine

  • Rainer Haeckel EMAIL logo , Werner Wosniok , Ebrhard Gurr and Burkhard Peil
Published/Copyright: January 23, 2015
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Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 53 Issue 8

Abstract

The international standard ISO 15189 requires that medical laboratories estimate the uncertainty of their quantitative test results obtained from patients’ specimens. The standard does not provide details how and within which limits the measurement uncertainty should be determined. The most common concept for establishing permissible uncertainty limits is to relate them on biological variation defining the rate of false positive results or to base the limits on the state-of-the-art. The state-of-the-art is usually derived from data provided by a group of selected medical laboratories. The approach on biological variation should be preferred because of its transparency and scientific base. Hitherto, all recommendations were based on a linear relationship between biological and analytical variation leading to limits which are sometimes too stringent or too permissive for routine testing in laboratory medicine. In contrast, the present proposal is based on a non-linear relationship between biological and analytical variation leading to more realistic limits. The proposed algorithms can be applied to all measurands and consider any quantity to be assured. The suggested approach tries to provide the above mentioned details and is a compromise between the biological variation concept, the GUM uncertainty model and the technical state-of-the-art.

Keywords: measurement uncertainty; permissible bias; permissible imprecision
Corresponding author: Rainer Haeckel, Bremer Zentrum für Laboratoriumsmedizin, Klinikum Bremen Mitte, 28305 Bremen, Germany, Phone: +49 412 273448, E-mail:

Acknowledgments

Suggestions from Dr W. J. Geilenkeuser, Referenzinstitut für Bioanalytik, are gratefully acknowledged.

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Financial support: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Appendix

Calculation of CVE in the case of a normal distribution

(17)sE=(RL2−RL1)/3.92 (17)
(18)CVE=sE·100/M (18)

In Equation (18), M is the arithmetic mean: (RL1+RL2)/2

Calculation of CVE* in the case of a log-normal distribution

a) for a RI covering a 95% interval (RL1=RL2.5and RL2=RL97.5are known)

On the logarithmic scale, sE and median (Med) can be calculated by the following equations:

(19)sE,ln=(lnRL2−lnRL1)/3.92Medln=(lnRL1+lnRL2)/2 (19)

CVE derived of sE,ln (CVE* ) can be calculated by equation (20) according to Aitchison [41].

(20)CVE∗=100  (exp  sE,ln2−1)0.5 (20)

b) if other information than RL2.5and RL97.5is given, e.g., RL2=RL99and Mln(which is identical to the median on the ln-scale),then RL2.5and RL97.5can be obtained by Equations (22) and (23)

(21)sE,ln=(lnRL99−Mln)/2.33 (21)
(22)lnRL2.5=Mln−sE,ln·1.96 (22)
(23)lnRL97.5=Mln+sE,ln·1.96 (23)

ln RL2.5 and ln RL97.5 [Equations (22) and (23)] are inserted in Equation (19) to obtain the standard deviation on the ln scale which is needed to calculate CVE* by Equation (20).

Permissible bias (pB) as fraction of analytical variation according to Fraser [10]

pB=0.25(sA2+sB2)0.5

In this equation sB means the inter-individual variation.

Assuming sA=0.5·sB or sB=2·sA

pB=0.25(sA2+4·sA2)0.5=0.25(5·sA2)0.5=0.56·sA

Calculation of the random variation uB of pB estimation [42]

The random variation of uB is derived from the estimation of a confidence interval (x) and amounts to:

uB=t1−α/2,n−1·psA/n0.5

If the mean value of a control material is determined from n=15 (or n=20) measurements, the t-value of the two-sided t-distribution (α=0.05) is 2.14 (2.09) and uB becomes 0.55·psA (or 0.47·psA). If 15–20 measurements are used, an average value of uB=0.5·psA is appropriate.

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Received: 2014-9-1
Accepted: 2014-11-13
Published Online: 2015-1-23
Published in Print: 2015-7-1

©2015 by De Gruyter

Articles in the same Issue

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  2. Editorials
  3. Once upon a time: a tale of ISO 15189 accreditation
  4. A new integrated tool for assessing and monitoring test comparability and stability
  5. Liver-FibroSTARD checklist and glossary: tools for standardized design and reporting of diagnostic accuracy studies of liver fibrosis tests
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https://doi.org/10.1515/cclm-2014-0874
Keywords for this article
measurement uncertainty; permissible bias; permissible imprecision

Articles in the same Issue

  1. Frontmatter
  2. Editorials
  3. Once upon a time: a tale of ISO 15189 accreditation
  4. A new integrated tool for assessing and monitoring test comparability and stability
  5. Liver-FibroSTARD checklist and glossary: tools for standardized design and reporting of diagnostic accuracy studies of liver fibrosis tests
  6. Reviews
  7. Thromboembolic risk in hematological malignancies
  8. A review of the cut-off points for the diagnosis of vitamin B12 deficiency in the general population
  9. Opinion Paper
  10. Permissible limits for uncertainty of measurement in laboratory medicine
  11. EFLM Position Paper
  12. Flexible scope for ISO 15189 accreditation: a guidance prepared by the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group Accreditation and ISO/CEN standards (WG-A/ISO)
  13. Genetics and Molecular Diagnostics
  14. Evaluation of a low-cost procedure for sampling, long-term storage, and extraction of RNA from blood for qPCR analyses
  15. Application of real-time PCR of sex-independent insertion-deletion polymorphisms to determine fetal sex using cell-free fetal DNA from maternal plasma
  16. General Clinical Chemistry and Laboratory Medicine
  17. The Empower project – a new way of assessing and monitoring test comparability and stability
  18. Comparison of four automated serum vitamin B12 assays
  19. Combined indicator of vitamin B12 status: modification for missing biomarkers and folate status and recommendations for revised cut-points
  20. INR vs. thrombin generation assays for guiding VKA reversal: a retrospective comparison
  21. Determination of dabigatran in plasma, serum, and urine samples: comparison of six methods
  22. Simple high-throughput analytical method using ultra-performance liquid chromatography coupled with tandem mass spectrometry to quantify total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in urine
  23. Revival of physostigmine – a novel HPLC assay for simultaneous determination of physostigmine and its metabolite eseroline designed for a pharmacokinetic study of septic patients
  24. Relationship between antiphosphatidylserine/prothrombin and conventional antiphospholipid antibodies in primary antiphospholipid syndrome
  25. Reference Values and Biological Variations
  26. Relevance of EDTA carryover during blood collection
  27. Reference intervals for renal injury biomarkers neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in young infants
  28. Cardiovascular Diseases
  29. NT-proBNP levels and their relationship with systemic ventricular impairment in adult patients with transposition of the great arteries long after Mustard or Senning procedure
  30. Letters to the Editors
  31. Troponin T measured with highly sensitive assay (hsTnT) on admission does not reflect infarct size in ST-elevation myocardial infarction patients receiving primary percutaneous coronary intervention
  32. Analytical challenges related to the use of biomarker ratios for the biological diagnosis of Alzheimer’s disease
  33. Serum brain injury biomarkers as predictors of mortality after severe aneurysmal subarachnoid hemorrhage: preliminary results
  34. Tumor markers assay by the Lumipulse G
  35. Real-world costs of laboratory tests for non-small cell lung cancer
  36. Impact of stopping vitamin K antagonist therapy on concentrations of dephospho-uncarboxylated Matrix Gla protein
  37. Practicability of fetal scalp blood sampling during labor using microtubes and a point-of-care (POC) lactate testing device: difficulty assessment, sampling time and failure rates
  38. Establishing objective analytical quality requirements in the IgE specific assay: a message in a bottle
  39. Bacteria on a peripheral blood smear as presenting sign of overwhelming post-splenectomy infection in a patient with secondary acute myeloid leukemia
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