DOI QR코드

DOI QR Code

Robust Reference Intervals for Serum Kappa and Lambda Free Light Chains from a Multi Centre Study Population from Hyderabad, India: Myeloma Diagnostic Implications

  • Mohammed, Noorjahan (Institute of Medical Sciences) ;
  • Chandran, Priscilla Abraham (Institute of Medical Sciences) ;
  • Kandregula, Madhavi (Institute of Medical Sciences) ;
  • Mattaparthi, Ratna Deepika (Institute of Medical Sciences) ;
  • Gundeti, Sadasivudu (Department of Medical Oncology, Nizam's Institute of Medical Sciences) ;
  • Volturi, Jyotsna (Department of Laboratory Medicine, Basavatarakam IndoAmerican Cancer Hospital and Research Institute) ;
  • Darapuneni, Radhika (Department of Lab Medicine, Krishna Institute of Medical Sciences, Omega Hospitals) ;
  • Raju, Sree Bhushan (Department of Nephrology, Nizam's Institute of Medical Sciences) ;
  • Dattatreya, Palanki Satya (Oncology, Omega Hospitals)
  • Published : 2016.05.01

Abstract

The International Myeloma Working Group considers the serum free light chain (SFLC) assay to be an adjunct to traditional tests. Apart from the FLC ratio, the absolute values of individual free light chains also are gaining importance as they appear to be more relevant in certain clinical settings. Automated assays are available for their determination. As laboratories put new test systems into use catering to different disease populations, they are required by accreditation and certification bodies to verify or establish performance specifications, including reference intervals (RIs) representative of their population. Our aim was to establish local RIs for SFLC in a multicentre representative healthy population using a robust method. There was no significant relationship between SFLC levels and age, gender and creatinine levels. The 95% RI for ${\kappa}SFLC$ was 4.81 to 33.86mg/L, for ${\lambda}$ SFLC was 5.19 to 23.67mg/L and for ${\kappa}/{\lambda}SFLC$ was 0.36 to 2.33, significantly higher than the values given by the manufacturer. The ${\kappa}/{\lambda}$ SFLC ratio at 2.23, covering 100% of the data, showed 72% sensitivity (95% CI=39.0 - 94.0), 100% specificity (95% CI=71.5 - 100.0), 100% PPV (95% CI=21.5 - 100.0), 95% NPV (95% CI=75.4 - 99.9), and 79% accuracy (95% CI=56.0 - 93.0). In the patient group, kit RI for ${\kappa}/{\lambda}$ SFLC ratio classified 45.5% (n=5) as positive vs 9.1% (n=1) positive by the study RI, while the kit RI for kappa FLC classified 90.9% (n=10) as positive vs 54.5% (n=6), indicating increased probability of false positive test results with the kit RI when applied to our patient population. Appropriate and specific reference intervals and criteria values result in fewer false-positive and false-negative results which means fewer wrong or missed diagnoses.

Keywords

Robust reference intervals;serum;free kappa light chains;free lambda light chains;myeloma

References

  1. Anonymous (2000). How to define and determine reference intervals in the clinical laboratory; approved guideline. Pennsylvania NCCLS, 28-22.
  2. Anonymous (2008). Revised document, Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory. Approved Guideline-Third Edition, published in November.
  3. Anonymous (2015). "MedCalc Software bvba, Ostend, Belgium; https://www.medcalc.org."
  4. Altman DG, Chitty LS (1993). Design and analysis of studies to derive charts of fetal size. Ultrasound Obstet Gynecol, 3, 378-84. https://doi.org/10.1046/j.1469-0705.1993.03060378.x
  5. Antony J (2008). Graham the clinical biochemist. Reviews Australian Associat Clin Biochem, 29, 93-7.
  6. Barai SS, Gambhir N, Prasad, RK, et al (2008). Levels of GFR and protein-induced hyperfiltration in kidney donors: a single-center experience in India. Am J Kidney Diseases, 51, 407-14. https://doi.org/10.1053/j.ajkd.2007.11.008
  7. Callis M, Garcia L, Gironella M, et al (2008). Serum free light chain reference intervals. A study of 133 blood donors. Haematologica, 93, 1332.
  8. Clerk C, Solberg HE (1987). Petit Approved recommendation on the theory of reference values. Part 2 Selection of individuals for the production of reference values. Chem Clin Biochem, 25, 639-44.
  9. Dispenzieri A, Lacy MQ, Katzmann JA (2005). Absolute values of immunoglobulin free light chains are prognostic in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood, 107, 3378-83.
  10. Efron R (1993). Scientific misconduct: undue process. Accountability Res, 3, 223-38. https://doi.org/10.1080/08989629308573853
  11. GD (1993). Altman of age-related reference centiles using absolute residuals. Statistics Med, 12, 917-24. https://doi.org/10.1002/sim.4780121003
  12. Hernandez J, Bonnedahl J, Eliasson I, et al (2010). Globally disseminated human pathogenic Escherichia coli of O25b-ST131 clone, harbouring blaCTX-M-15, found in Glaucous-winged gull at remote Commander Islands, Russia. Environ Microbiol Rep, 2, 329-32. https://doi.org/10.1111/j.1758-2229.2010.00142.x
  13. Horn PS, Lesce AJ, Washington DC (2005). Reference Intervals s Guide, 47-57.
  14. Horn PS, Pesce AJ, Copeland BE (1998). A robust approach to reference interval estimation and evaluation. Clin Chem 44, 622-31.
  15. Horowitz GL (2008). , eJIFCC, Reference Intervals: Practical Aspects. 19.
  16. Jenner E (2014). Serum free light chains in clinical laboratory diagnostics. Clin Chim Acta, 427, 15-20. https://doi.org/10.1016/j.cca.2013.08.018
  17. Jolliff CR, Cost KM, Stivrins PC, et al (1982). Reference intervals for serum IgG, IgA, IgM, C3, and C4 as determined by rate nephelometry. Clin Chem, 28, 126-8.
  18. Katzmann JA, Clark RJ, Abraham RS, et al (2002). Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. Clinical Chem, 48, 1437-44.
  19. Katzmann JA, Dispenzieri A, Kyle RA, et al (2006). Elimination of the need for urine studies in the screening algorithm for monoclonal gammopathies by using serum immunofixation and free light chain assays. Mayo Clinic proceedings, 81, 1575-8. https://doi.org/10.4065/81.12.1575
  20. Liang YF, Chen WM, Wang QT, et al (2014). Establishment and validation of serum free light chain reference intervals in an ethnic Chinese population. Clinical Laboratory, 60, 193-8.
  21. Mahajan S, Mukhiya GK, R. Singh, et al (2005). Assessing glomerular filtration rate in healthy Indian adults: a comparison of various prediction equations. J Nephrol, 18, 257-61.
  22. Marshall G, Tate J, Mollee P (2009). Borderline high serum free light chain kappa/lambda ratios are seen not only in dialysis patients but also in non-dialysis-dependent renal impairment and inflammatory states. Am J Clin Pathol, 132, 309. https://doi.org/10.1309/AJCP8VOT5TVLAQBQ
  23. Mead GP, Carr-Smith HD, Drayson MT, et al (2004). Serum free light chains for monitoring multiple myeloma. British J Haematol, 126, 348-54. https://doi.org/10.1111/j.1365-2141.2004.05045.x
  24. Miettinen TA, Kekki M (1967). Effect of impaired hepatic and renal function on Bence Jones protein catabolism in human subjects. Clin Chim Acta, 18, 395-407. https://doi.org/10.1016/0009-8981(67)90036-8
  25. Rajkumar SV, Kyle RA, Connor RF (2011). Recognition of monoclonal proteins. In eds Waltham UpToDate.
  26. Reed AH, Henry RJ, Mason WB (1971). Influence of statistical method used on the resulting estimate of normal range. Clin Chem, 17, 275-84.
  27. Sanchorawala V, Seldin DC, Magnani B, Skinner M, Wright DG (2005). Serum free light-chain responses after high-dose intravenous melphalan and autologous stem cell transplantation for AL (primary) amyloidosis. Bone Marrow Transplantation, 36, 597-600. https://doi.org/10.1038/sj.bmt.1705106
  28. Solberg HE, Petit Clerc C (1988). Approved recommendation (1988) on the theory of reference values. Part 3. Preparation of individuals and collection of specimens for the production of reference values. Clin Chim Acta; Int J Clin Chem, 177, 3-11. https://doi.org/10.1016/0009-8981(88)90074-5
  29. Sv R (2011). Clinical features, laboratory manifestations, and diagnosis of multiple myeloma. In eds Waltham UpToDate.
  30. Waldmann TA, Strober W, Mogielnicki RP (1972). The renal handling of low molecular weight proteins. II. Disorders of serum protein catabolism in patients with tubular proteinuria, the nephrotic syndrome, or uremia. J Clin Investigat, 51, 2162-74. https://doi.org/10.1172/JCI107023
  31. Wright EM, Royston P (1997). Simplified estimation of age-specific reference intervals for skewed data. Statistics Med, 16, 2785-803. https://doi.org/10.1002/(SICI)1097-0258(19971230)16:24<2785::AID-SIM797>3.0.CO;2-Z
  32. Zemlin AE, Rensburg MA, Ipp H, et al (2013). Verification of serum reference intervals for free light chains in a local South African population. J Clin Pathol, 66, 992-5. https://doi.org/10.1136/jclinpath-2013-201511