Home Current performance of C-reactive protein determination and derivation of quality specifications for its measurement uncertainty
Article
Licensed
Unlicensed Requires Authentication

Current performance of C-reactive protein determination and derivation of quality specifications for its measurement uncertainty

  • Francesca Borrillo EMAIL logo and Mauro Panteghini
Published/Copyright: February 13, 2023
Become an author with De Gruyter Brill
Submit Manuscript Author Information
Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 61 Issue 9

Abstract

From External Quality Assessment data, current harmonization of CRP measuring systems appears to be satisfactory, the inter-assay CV being well below 10%. The inter-method variability is even better (close to 3%) when the widely used measuring systems are compared at CRP concentrations employed as cut-off for detecting sub-clinical infection (i.e., 10.0 mg/L) and measurement variability estimated, according to ISO 20914:2019 Technical Specification, from the intermediate within-lab reproducibility of 6-month consecutive measurement data. According to the state-of-the-art model (which is better suited for CRP), the maximum allowable measurement uncertainty (MAU) for CRP measurement on clinical samples with 10.0 mg/L concentrations is 3.76% (desirable quality). As measurement uncertainty (MU) of the only available reference material (ERM-DA474/IFCC) is ∼3%, to fulfil desirable MAU on clinical samples, IVD manufacturers should work to keep the contribution of remaining MU sources (commercial calibrator and intermediate within-lab reproducibility) lower than 2.3%.

Keywords: analytical performance specifications; C-reactive protein; measurement uncertainty; metrological traceability
Corresponding author: Francesca Borrillo, UOC Patologia Clinica, ASST Fatebenefratelli-Sacco, Via GB Grassi 74, 20157 Milano, Italy; and Research Centre for Metrological Traceability in Laboratory Medicine (CIRME), and University of Milan, Milan, Italy, E-mail:

  1. Research funding: None declared.

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

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Not applicable.

  5. Ethical approval: Not applicable.

References

1. Whicher, JT, Ritchie, RF, Johnson, AM, Baudner, S, Bienvenu, J, Blirup-Jensen, S, et al.. New international reference preparation for proteins in human serum (RPPHS). Clin Chem 1994;40:934–8. https://doi.org/10.1093/clinchem/40.6.934.Search in Google Scholar

2. Whicher, JT. BCR/IFCC reference material for plasma proteins (CRM 470). Community Bureau of Reference. International Federation of Clinical Chemistry. Clin Biochem 1998;31:459–65. https://doi.org/10.1016/s0009-9120(98)00035-6.Search in Google Scholar PubMed

3. Johnson, AM, Whicher, JT, Ledue, TB, Carlström, A, Itoh, Y, Petersen, PH. Effect of a new international reference preparation for proteins in human serum (certified reference material 470) on results of the College of American Pathologists Surveys for plasma proteins. Arch Pathol Lab Med 2000;124:1496–501. https://doi.org/10.5858/2000-124-1496-eoanir.Search in Google Scholar

4. Merlini, G, Blirup-Jensen, S, Johnson, AM, Sheldon, J, Zegers, I. IFCC Committee on Plasma Proteins (C-PP). Standardizing plasma protein measurements worldwide: a challenging enterprise. Clin Chem Lab Med 2010;48:1567–75. https://doi.org/10.1515/CCLM.2010.314.Search in Google Scholar PubMed

5. Infusino, I, Valente, C, Dolci, A, Panteghini, M. Standardization of ceruloplasmin measurements is still an issue despite the availability of a common reference material. Anal Bioanal Chem 2010;397:521–5. https://doi.org/10.1007/s00216-009-3248-0.Search in Google Scholar PubMed

6. Rzychon, M, Zegers, I, Schimmel, H. Analysis of the physicochemical state of C-reactive protein in different preparations including two certified reference materials. Clin Chem 2010;56:1475–82. https://doi.org/10.1373/clinchem.2010.147124.Search in Google Scholar PubMed

7. Zegers, I, Schreiber, W, Linstead, S, Lammers, M, McCusker, M, Muñoz, A, et al.. Development and preparation of a new serum protein reference material: feasibility studies and processing. Clin Chem Lab Med 2010;48:805–13. https://doi.org/10.1515/CCLM.2010.166.Search in Google Scholar PubMed

8. Panteghini, M, Braga, F, Camara, JE, Delatour, V, Van Uytfanghe, K, Vesper, HW, et al.. JCTLM Task Force on Reference Measurement System Implementation. Optimizing available tools for achieving result standardization: value added by Joint Committee on Traceability in Laboratory Medicine (JCTLM). Clin Chem 2021;67:1590–605. https://doi.org/10.1093/clinchem/hvab178.Search in Google Scholar PubMed

9. Secchiero, S, Sciacovelli, L, Plebani, M. Performance evaluation of 14 specific proteins measurement checked by an External Quality Assessment Scheme. Clin Chim Acta 2020;502:73–83. https://doi.org/10.1016/j.cca.2019.11.024.Search in Google Scholar PubMed

10. Braga, F, Panteghini, M. Derivation of performance specifications for uncertainty of serum C-reactive protein measurement according to the Milan model 3 (state of the art). Clin Chem Lab Med 2020;58:e263–5. https://doi.org/10.1515/cclm-2020-0532.Search in Google Scholar PubMed

11. International Organization for Standardization (ISO). Medical laboratories—practical guidance for the estimation of measurement uncertainty. ISO/TS 20914. Geneva, Switzerland: ISO; 2019.Search in Google Scholar

12. Infusino, I, Panteghini, M. Measurement uncertainty: friend or foe? Clin Biochem 2018;57:3–6. https://doi.org/10.1016/j.clinbiochem.2018.01.025.Search in Google Scholar PubMed

13. Braga, F, Panteghini, M. The utility of measurement uncertainty in medical laboratories. Clin Chem Lab Med 2020;58:1407–13. https://doi.org/10.1515/cclm-2019-1336.Search in Google Scholar PubMed

14. ISO 17511:2020. In vitro diagnostic medical devices—requirements for establishing metrological traceability of values assigned to calibrators, trueness control materials and human samples. Geneva, Switzerland: ISO; 2020.Search in Google Scholar

15. Braga, F, Panteghini, M. Verification of in vitro medical diagnostics (IVD) metrological traceability: responsibilities and strategies. Clin Chim Acta 2014;432:55–61. https://doi.org/10.1016/j.cca.2013.11.022.Search in Google Scholar PubMed

16. Braga, F, Infusino, I, Panteghini, M. Performance criteria for combined uncertainty budget in the implementation of metrological traceability. Clin Chem Lab Med 2015;53:905–12. https://doi.org/10.1515/cclm-2014-1240.Search in Google Scholar PubMed

17. Braga, F, Panteghini, M. Defining permissible limits for the combined uncertainty budget in the implementation of metrological traceability. Clin Biochem 2018;57:7–11. https://doi.org/10.1016/j.clinbiochem.2018.03.007.Search in Google Scholar PubMed

18. ISO15189:2012. Medical laboratories – requirements for quality and competence. Geneva, Switzerland: ISO; 2012.Search in Google Scholar

19. Thelen, M, Vanstapel, F, Brguljan, PM, Gouget, B, Boursier, G, Barrett, E, et al.. European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group Accreditation and ISO/CEN standards (WG-A/ISO). Documenting metrological traceability as intended by ISO 15189:2012: a consensus statement about the practice of the implementation and auditing of this norm element. Clin Chem Lab Med 2019;57:459–64. https://doi.org/10.1515/cclm-2018-1212.Search in Google Scholar PubMed

20. Panteghini, M. Implementation of standardization in clinical practice: not always an easy task. Clin Chem Lab Med 2012;50:1237–41. https://doi.org/10.1515/cclm.2011.791.Search in Google Scholar PubMed

21. Sandberg, S, Fraser, CG, Horvath, AR, Jansen, R, Jones, G, Oosterhuis, W, et al.. Defining analytical performance specifications: consensus Statement from the 1st Strategic Conference of the European Federation of Clinical Chemistry and Laboratory Medicine. Clin Chem Lab Med 2015;53:833–5. https://doi.org/10.1515/cclm-2015-0067.Search in Google Scholar PubMed

22. Ceriotti, F, Fernandez-Calle, P, Klee, GG, Nordin, G, Sandberg, S, Streichert, T, et al.. EFLM Task and Finish Group on Allocation of laboratory tests to different models for performance specifications (TFG-DM). Criteria for assigning laboratory measurands to models for analytical performance specifications defined in the 1st EFLM Strategic Conference. Clin Chem Lab Med 2017;55:189–94. https://doi.org/10.1515/cclm-2016-0091.Search in Google Scholar PubMed

23. Panteghini, M, Ceriotti, F, Jones, G, Oosterhuis, W, Plebani, M, Sandberg, S. Task Force on Performance Specifications in Laboratory Medicine of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM). Strategies to define performance specifications in laboratory medicine: three years on from the Milan Strategic Conference. Clin Chem Lab Med 2017;55:1849–56. https://doi.org/10.1515/cclm-2017-0772.Search in Google Scholar PubMed

24. Braga, F, Panteghini, M. Performance specifications for measurement uncertainty of common biochemical measurands according to Milan models. Clin Chem Lab Med 2021;59:1362–8. https://doi.org/10.1515/cclm-2021-0170.Search in Google Scholar PubMed

25. Braga, F, Pasqualetti, S, Borrillo, F, Capoferri, A, Chibireva, M, Rovegno, L, et al.. Definition and application of performance specifications for measurement uncertainty of 23 common laboratory tests: linking theory to daily practice. Clin Chem Lab Med 2023;61:213–23. https://doi.org/10.1515/cclm-2022-0806.Search in Google Scholar PubMed

26. Braga, F, Panteghini, M. Biologic variability of C-reactive protein: is the available information reliable? Clin Chim Acta 2012;413:1179–83. https://doi.org/10.1016/j.cca.2012.04.010.Search in Google Scholar PubMed

27. Braga, F, Ferraro, S, Szöke, D, Lanzoni, M, Panteghini, M. Estimate of intraindividual variability of C-reactive protein: a challenging issue. Clin Chim Acta 2013;419:85–6. https://doi.org/10.1016/j.cca.2013.02.004.Search in Google Scholar PubMed

28. Alexander, KS, Kazmierczak, SC, Snyder, CK, Oberdorf, JA, Farrell, DH. Prognostic utility of biochemical markers of cardiovascular risk: impact of biological variability. Clin Chem Lab Med 2013;51:1875–82. https://doi.org/10.1515/cclm-2012-0750.Search in Google Scholar PubMed PubMed Central

29. Franzini, C. Need for correct estimates of biological variation: the example of C-reactive protein. Clin Chem Lab Med 1998;36:131–2. https://doi.org/10.1515/cclm.1998.024.Search in Google Scholar

30. Braga, F, Ferraro, S, Ieva, F, Paganoni, A, Panteghini, M. A new robust statistical model for interpretation of differences in serial test results from an individual. Clin Chem Lab Med 2015;53:815–22. https://doi.org/10.1515/cclm-2014-0893.Search in Google Scholar PubMed

31. Carobene, A, Aarsand, AK, Guerra, E, Bartlett, WA, Coşkun, A, Díaz-Garzón, J, et al.. European Federation of Clinical Chemistry and Laboratory Medicine Working Group on Biological Variation. European Biological Variation Study (EuBIVAS): within- and between-subject biological variation data for 15 frequently measured proteins. Clin Chem 2019;65:1031–41. https://doi.org/10.1373/clinchem.2019.304618.Search in Google Scholar PubMed

32. Braga, F, Pasqualetti, S, Aloisio, E, Panteghini, M. The internal quality control in the traceability era. Clin Chem Lab Med 2021;59:291–300. https://doi.org/10.1515/cclm-2020-0371.Search in Google Scholar PubMed

33. Panteghini, M. Redesigning the surveillance of in vitro diagnostic medical devices and of medical laboratory performance by quality control in the traceability era. Clin Chem Lab Med 2023;61:759–68. https://doi.org/10.1515/cclm-2022-1257.Search in Google Scholar PubMed

Received: 2023-01-18
Accepted: 2023-01-31
Published Online: 2023-02-13
Published in Print: 2023-08-28

© 2023 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Developments in reference measurement systems for C-reactive protein and the importance of maintaining currently used clinical decision-making criteria
  4. Review
  5. Why C-reactive protein is one of the most requested tests in clinical laboratories?
  6. Mini Reviews
  7. C-reactive protein and clinical outcome in COVID-19 patients: the importance of harmonized measurements
  8. Current performance of C-reactive protein determination and derivation of quality specifications for its measurement uncertainty
  9. Opinion Papers
  10. Implementing metrological traceability of C-reactive protein measurements: consensus summary from the Joint Committee for Traceability in Laboratory Medicine Workshop
  11. Analytical performance specifications for the measurement uncertainty of 24,25-dihydroxyvitamin D examinations
  12. A new door to a different world: opportunities from the metaverse and the raise of meta-medical laboratories
  13. Guidelines and Recommendations
  14. Point-of-care testing performed by healthcare professionals outside the hospital setting: consensus based recommendations from the IFCC Committee on Point-of-Care Testing (IFCC C-POCT)
  15. General Clinical Chemistry and Laboratory Medicine
  16. Effects of storage conditions on the stability of blood-based markers for the diagnosis of Alzheimer’s disease
  17. Long-term stability of thyroid peroxidase antibody (anti-TPO) in serum in the Danish General Suburban Population Study
  18. Exploration of suitable external quality assessment materials for serum C-peptide measurement
  19. Description and validation of an equilibrium dialysis ID-LC-MS/MS candidate reference measurement procedure for free thyroxine in human serum
  20. Evaluation of testosterone, estradiol and progesterone immunoassay calibrators by liquid chromatography mass spectrometry
  21. Lack of comparability of immunoassays for rheumatoid factor isotypes
  22. Validation of ELISA assays for the calculation of FLC indices for the diagnosis of intrathecal immunoglobulin synthesis
  23. First-trimester screening for Down syndrome using quadruple maternal biochemical markers
  24. Dipeptidyl peptidase 4 (DPP4) in fecal samples: validation of the extraction methodology and stability in short-term storage conditions
  25. Cardiovascular Diseases
  26. Interlaboratory variation for NT-proBNP among Swedish laboratories in an external quality program 2011–2021
  27. Infectious Diseases
  28. SARS-CoV-2 specific T-cell humoral response assessment after COVID-19 vaccination using a rapid direct real-time PCR amplification
  29. Efficiency evaluation of a SARS-CoV-2 diagnostic strategy combining high throughput quantitative antigen immunoassay and real time PCR
  30. Peri-infection titers of neutralizing and binding antibodies as a predictor of COVID-19 breakthrough infections in vaccinated healthcare professionals: importance of the timing
  31. Letters to the Editor
  32. Pooled analysis of laboratory-based SARS-CoV-2 antigen immunoassays
  33. Cost-effectiveness analysis of different COVID-19 screening strategies based on rapid or laboratory-based SARS-CoV-2 antigen testing
  34. Early kinetics of cellular immunity in recipients of bivalent BNT162b2 vaccine: a proof-of-concept study
  35. Impact of switching total bilirubin assays on the classification of neonates at high risk for hyperbilirubinemia
  36. Discrepancies in PSA values among laboratories: the case of a traveling patient
  37. Measurement of amyloid-β 1–42 in cerebrospinal fluid: a comparison of the second generation Elecsys and INNOTEST
https://doi.org/10.1515/cclm-2023-0069
Keywords for this article
analytical performance specifications; C-reactive protein; measurement uncertainty; metrological traceability

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Developments in reference measurement systems for C-reactive protein and the importance of maintaining currently used clinical decision-making criteria
  4. Review
  5. Why C-reactive protein is one of the most requested tests in clinical laboratories?
  6. Mini Reviews
  7. C-reactive protein and clinical outcome in COVID-19 patients: the importance of harmonized measurements
  8. Current performance of C-reactive protein determination and derivation of quality specifications for its measurement uncertainty
  9. Opinion Papers
  10. Implementing metrological traceability of C-reactive protein measurements: consensus summary from the Joint Committee for Traceability in Laboratory Medicine Workshop
  11. Analytical performance specifications for the measurement uncertainty of 24,25-dihydroxyvitamin D examinations
  12. A new door to a different world: opportunities from the metaverse and the raise of meta-medical laboratories
  13. Guidelines and Recommendations
  14. Point-of-care testing performed by healthcare professionals outside the hospital setting: consensus based recommendations from the IFCC Committee on Point-of-Care Testing (IFCC C-POCT)
  15. General Clinical Chemistry and Laboratory Medicine
  16. Effects of storage conditions on the stability of blood-based markers for the diagnosis of Alzheimer’s disease
  17. Long-term stability of thyroid peroxidase antibody (anti-TPO) in serum in the Danish General Suburban Population Study
  18. Exploration of suitable external quality assessment materials for serum C-peptide measurement
  19. Description and validation of an equilibrium dialysis ID-LC-MS/MS candidate reference measurement procedure for free thyroxine in human serum
  20. Evaluation of testosterone, estradiol and progesterone immunoassay calibrators by liquid chromatography mass spectrometry
  21. Lack of comparability of immunoassays for rheumatoid factor isotypes
  22. Validation of ELISA assays for the calculation of FLC indices for the diagnosis of intrathecal immunoglobulin synthesis
  23. First-trimester screening for Down syndrome using quadruple maternal biochemical markers
  24. Dipeptidyl peptidase 4 (DPP4) in fecal samples: validation of the extraction methodology and stability in short-term storage conditions
  25. Cardiovascular Diseases
  26. Interlaboratory variation for NT-proBNP among Swedish laboratories in an external quality program 2011–2021
  27. Infectious Diseases
  28. SARS-CoV-2 specific T-cell humoral response assessment after COVID-19 vaccination using a rapid direct real-time PCR amplification
  29. Efficiency evaluation of a SARS-CoV-2 diagnostic strategy combining high throughput quantitative antigen immunoassay and real time PCR
  30. Peri-infection titers of neutralizing and binding antibodies as a predictor of COVID-19 breakthrough infections in vaccinated healthcare professionals: importance of the timing
  31. Letters to the Editor
  32. Pooled analysis of laboratory-based SARS-CoV-2 antigen immunoassays
  33. Cost-effectiveness analysis of different COVID-19 screening strategies based on rapid or laboratory-based SARS-CoV-2 antigen testing
  34. Early kinetics of cellular immunity in recipients of bivalent BNT162b2 vaccine: a proof-of-concept study
  35. Impact of switching total bilirubin assays on the classification of neonates at high risk for hyperbilirubinemia
  36. Discrepancies in PSA values among laboratories: the case of a traveling patient
  37. Measurement of amyloid-β 1–42 in cerebrospinal fluid: a comparison of the second generation Elecsys and INNOTEST
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 7.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/cclm-2023-0069/html
Scroll to top button