TY - JOUR
AU - Klingberg,, Sandra
AB - To the Editor: The recent article in Clinical Chemistry by Katzmann et al. (1) on screening panels to detect monoclonal gammopathies provided important information on the use of the free light chain (FLC)1 assay, and we commend the authors for this report. Apart from the selection bias inherent in the exclusion of 90% of cases of monoclonal gammopathy of uncertain significance (MGUS), we would like to address some aspects that, in our opinion, may enhance understanding of the role of various diagnostic strategies to detect monoclonal gammopathies in routine laboratories. Katzmann and coworkers did not make any statement regarding the statistical significance of their findings, nor did they provide CIs of the percentages in their Table 2. In deciding whether a particular diagnostic strategy is worthwhile to implement, it is useful to know whether any observed differences can be explained by chance; to do this, we calculated the 95% CIs of the proportions (2)(3)(4) reported by the authors. Our results are presented in Table 1 . When viewed in isolation, the FLC assay is clearly superior to serum immunofixation electrophoresis (IFE) for the detection of primary amyloidosis [88.3% (85.7%–90.9%) vs 73.8% (70.2%–77.4%)], but inferior as a stand-alone test for MGUS [42.2% (38.0%–46.4%) vs 92.8% (90.5%–95.15%)]. Table 1. Sensitivity of monoclonal gammopathy screening panels.1 . All 5 tests . Serum PEL, IFE, and uIFE2 . Serum PEL, IFE, and FLC . Serum PEL and FLC . Serum IFE . Serum PEL . Serum FLC . All 98.6 (98.1–99.2) 97.0 (96.2–97.8) 97.4 (96.7–98.1) 94.3 (93.2–95.4) 87.0 (85.5–88.5) 79.0 (77.2–80.8) 74.3 (72.3–76.3) MM 100.0 (99.4–100.0) 98.7 (97.5–99.9) 100.0 (99.4–100.0) 100.0 (99.4–100.0) 94.4 (92.3–96.5) 87.6 (84.6–90.6) 96.8 (95.1–98.5) Macroglobulinemia 100.0 (91.1–100.0) 100.0 (91.1–100.0) 100.0 (91.1–100.0) 100.0 (91.1–100.0) 100.0 (91.1–100.0) 100.0 (91.1–100.0) 73.1 (56.7–89.5) SMM 100.0 (98.6–100.0) 100.0 (98.6–100.0) 100.0 (98.6–100.0) 99.5 (97.8–100.0) 98.4 (96.2–100.0) 94.2 (90.7–97.7) 81.2 (75.6–86.8) MGUS 100.0 (99.5–100.0) 100.0 (99.5–100.0) 97.1 (95.6–98.6) 88.7 (86.0–91.4) 92.8 (90.5–95.1) 81.9 (78.6–85.2) 42.2 (38.0–46.4) Plasmacytoma 89.7 (77.5–100.0) 89.7 (77.5–100.0) 89.7 (77.5–100.0) 86.2 (73.0–99.4) 72.4 (56.7–88.1) 72.4 (56.7–88.1) 55.2 (38.2–72.2) POEMS 96.8 (87.5–100) 96.8 (87.5–100) 96.8 (87.5–100) 74.2 (57.4–89.2) 96.8 (87.5–100) 74.2 (57.4–89.2) 9.7 (0.0–21.3) Extramedullary plasmacytoma 20.0 (0.0–43.7) 20.0 (0.0–43.7) 10.0 (0.0–31.5) 10.0 (0.0–31.5) 10.0 (0.0–31.5) 10.0 (0.0–31.5) 10.0 (0.0–31.5) Primary amyloidosis 98.1 (96.9–99.3) 94.2 (92.3–96.15) 97.1 (95.7–98.5) 96.2 (94.6–97.8) 73.8 (70.2–77.4) 65.9 (62.1–69.7) 88.3 (85.7–90.9) LCDD 83.3 (65.8–100.0) 77.8 (59.2–96.4) 77.8 (59.2–96.4) 77.8 (59.2–96.4) 55.6 (34.8–76.4) 55.6 (34.8–76.4) 77.8 (59.2–96.4) . All 5 tests . Serum PEL, IFE, and uIFE2 . Serum PEL, IFE, and FLC . Serum PEL and FLC . Serum IFE . Serum PEL . Serum FLC . All 98.6 (98.1–99.2) 97.0 (96.2–97.8) 97.4 (96.7–98.1) 94.3 (93.2–95.4) 87.0 (85.5–88.5) 79.0 (77.2–80.8) 74.3 (72.3–76.3) MM 100.0 (99.4–100.0) 98.7 (97.5–99.9) 100.0 (99.4–100.0) 100.0 (99.4–100.0) 94.4 (92.3–96.5) 87.6 (84.6–90.6) 96.8 (95.1–98.5) Macroglobulinemia 100.0 (91.1–100.0) 100.0 (91.1–100.0) 100.0 (91.1–100.0) 100.0 (91.1–100.0) 100.0 (91.1–100.0) 100.0 (91.1–100.0) 73.1 (56.7–89.5) SMM 100.0 (98.6–100.0) 100.0 (98.6–100.0) 100.0 (98.6–100.0) 99.5 (97.8–100.0) 98.4 (96.2–100.0) 94.2 (90.7–97.7) 81.2 (75.6–86.8) MGUS 100.0 (99.5–100.0) 100.0 (99.5–100.0) 97.1 (95.6–98.6) 88.7 (86.0–91.4) 92.8 (90.5–95.1) 81.9 (78.6–85.2) 42.2 (38.0–46.4) Plasmacytoma 89.7 (77.5–100.0) 89.7 (77.5–100.0) 89.7 (77.5–100.0) 86.2 (73.0–99.4) 72.4 (56.7–88.1) 72.4 (56.7–88.1) 55.2 (38.2–72.2) POEMS 96.8 (87.5–100) 96.8 (87.5–100) 96.8 (87.5–100) 74.2 (57.4–89.2) 96.8 (87.5–100) 74.2 (57.4–89.2) 9.7 (0.0–21.3) Extramedullary plasmacytoma 20.0 (0.0–43.7) 20.0 (0.0–43.7) 10.0 (0.0–31.5) 10.0 (0.0–31.5) 10.0 (0.0–31.5) 10.0 (0.0–31.5) 10.0 (0.0–31.5) Primary amyloidosis 98.1 (96.9–99.3) 94.2 (92.3–96.15) 97.1 (95.7–98.5) 96.2 (94.6–97.8) 73.8 (70.2–77.4) 65.9 (62.1–69.7) 88.3 (85.7–90.9) LCDD 83.3 (65.8–100.0) 77.8 (59.2–96.4) 77.8 (59.2–96.4) 77.8 (59.2–96.4) 55.6 (34.8–76.4) 55.6 (34.8–76.4) 77.8 (59.2–96.4) 1 Adapted, with permission, from Katzmann et al. (1). Results are presented as % (95% CI), calculated with the modified Wald method [Motulsky (2)]. 2 uIFE, urine IFE; MM, multiple myeloma; SMM, smoldering MM; POEMS, polyneuropathy organomegaly endocrinopathy monoclonal gammopathy and skin changes syndrome; LCDD, light chain deposition disease. Open in new tab Table 1. Sensitivity of monoclonal gammopathy screening panels.1 . All 5 tests . Serum PEL, IFE, and uIFE2 . Serum PEL, IFE, and FLC . Serum PEL and FLC . Serum IFE . Serum PEL . Serum FLC . All 98.6 (98.1–99.2) 97.0 (96.2–97.8) 97.4 (96.7–98.1) 94.3 (93.2–95.4) 87.0 (85.5–88.5) 79.0 (77.2–80.8) 74.3 (72.3–76.3) MM 100.0 (99.4–100.0) 98.7 (97.5–99.9) 100.0 (99.4–100.0) 100.0 (99.4–100.0) 94.4 (92.3–96.5) 87.6 (84.6–90.6) 96.8 (95.1–98.5) Macroglobulinemia 100.0 (91.1–100.0) 100.0 (91.1–100.0) 100.0 (91.1–100.0) 100.0 (91.1–100.0) 100.0 (91.1–100.0) 100.0 (91.1–100.0) 73.1 (56.7–89.5) SMM 100.0 (98.6–100.0) 100.0 (98.6–100.0) 100.0 (98.6–100.0) 99.5 (97.8–100.0) 98.4 (96.2–100.0) 94.2 (90.7–97.7) 81.2 (75.6–86.8) MGUS 100.0 (99.5–100.0) 100.0 (99.5–100.0) 97.1 (95.6–98.6) 88.7 (86.0–91.4) 92.8 (90.5–95.1) 81.9 (78.6–85.2) 42.2 (38.0–46.4) Plasmacytoma 89.7 (77.5–100.0) 89.7 (77.5–100.0) 89.7 (77.5–100.0) 86.2 (73.0–99.4) 72.4 (56.7–88.1) 72.4 (56.7–88.1) 55.2 (38.2–72.2) POEMS 96.8 (87.5–100) 96.8 (87.5–100) 96.8 (87.5–100) 74.2 (57.4–89.2) 96.8 (87.5–100) 74.2 (57.4–89.2) 9.7 (0.0–21.3) Extramedullary plasmacytoma 20.0 (0.0–43.7) 20.0 (0.0–43.7) 10.0 (0.0–31.5) 10.0 (0.0–31.5) 10.0 (0.0–31.5) 10.0 (0.0–31.5) 10.0 (0.0–31.5) Primary amyloidosis 98.1 (96.9–99.3) 94.2 (92.3–96.15) 97.1 (95.7–98.5) 96.2 (94.6–97.8) 73.8 (70.2–77.4) 65.9 (62.1–69.7) 88.3 (85.7–90.9) LCDD 83.3 (65.8–100.0) 77.8 (59.2–96.4) 77.8 (59.2–96.4) 77.8 (59.2–96.4) 55.6 (34.8–76.4) 55.6 (34.8–76.4) 77.8 (59.2–96.4) . All 5 tests . Serum PEL, IFE, and uIFE2 . Serum PEL, IFE, and FLC . Serum PEL and FLC . Serum IFE . Serum PEL . Serum FLC . All 98.6 (98.1–99.2) 97.0 (96.2–97.8) 97.4 (96.7–98.1) 94.3 (93.2–95.4) 87.0 (85.5–88.5) 79.0 (77.2–80.8) 74.3 (72.3–76.3) MM 100.0 (99.4–100.0) 98.7 (97.5–99.9) 100.0 (99.4–100.0) 100.0 (99.4–100.0) 94.4 (92.3–96.5) 87.6 (84.6–90.6) 96.8 (95.1–98.5) Macroglobulinemia 100.0 (91.1–100.0) 100.0 (91.1–100.0) 100.0 (91.1–100.0) 100.0 (91.1–100.0) 100.0 (91.1–100.0) 100.0 (91.1–100.0) 73.1 (56.7–89.5) SMM 100.0 (98.6–100.0) 100.0 (98.6–100.0) 100.0 (98.6–100.0) 99.5 (97.8–100.0) 98.4 (96.2–100.0) 94.2 (90.7–97.7) 81.2 (75.6–86.8) MGUS 100.0 (99.5–100.0) 100.0 (99.5–100.0) 97.1 (95.6–98.6) 88.7 (86.0–91.4) 92.8 (90.5–95.1) 81.9 (78.6–85.2) 42.2 (38.0–46.4) Plasmacytoma 89.7 (77.5–100.0) 89.7 (77.5–100.0) 89.7 (77.5–100.0) 86.2 (73.0–99.4) 72.4 (56.7–88.1) 72.4 (56.7–88.1) 55.2 (38.2–72.2) POEMS 96.8 (87.5–100) 96.8 (87.5–100) 96.8 (87.5–100) 74.2 (57.4–89.2) 96.8 (87.5–100) 74.2 (57.4–89.2) 9.7 (0.0–21.3) Extramedullary plasmacytoma 20.0 (0.0–43.7) 20.0 (0.0–43.7) 10.0 (0.0–31.5) 10.0 (0.0–31.5) 10.0 (0.0–31.5) 10.0 (0.0–31.5) 10.0 (0.0–31.5) Primary amyloidosis 98.1 (96.9–99.3) 94.2 (92.3–96.15) 97.1 (95.7–98.5) 96.2 (94.6–97.8) 73.8 (70.2–77.4) 65.9 (62.1–69.7) 88.3 (85.7–90.9) LCDD 83.3 (65.8–100.0) 77.8 (59.2–96.4) 77.8 (59.2–96.4) 77.8 (59.2–96.4) 55.6 (34.8–76.4) 55.6 (34.8–76.4) 77.8 (59.2–96.4) 1 Adapted, with permission, from Katzmann et al. (1). Results are presented as % (95% CI), calculated with the modified Wald method [Motulsky (2)]. 2 uIFE, urine IFE; MM, multiple myeloma; SMM, smoldering MM; POEMS, polyneuropathy organomegaly endocrinopathy monoclonal gammopathy and skin changes syndrome; LCDD, light chain deposition disease. Open in new tab The statement by Katzmann et al. (1) that use of a simplified screening panel led to a reduction in sensitivity for detecting plasmacytoma does not appear to be substantiated by their data, because the 95% CIs of the 2 approaches clearly overlap [86.2% (73.0%–99.4%) for serum protein electrophoresis (PEL) plus FLC vs 89.7% (77.5%–100%) for all 5 tests]. Katzmann et al. reported that when they compared serum PEL and serum IFE with either FLC or urine IFE, the FLC assay appeared to offer a marginal increase in sensitivity over urine IFE in detecting multiple myeloma, but when the CIs are considered this apparent benefit disappears [100.0% (99.4%–100%) vs 98.7% (97.5%–99.9%)]. In the report by Katzmann et al., an additional column in Table 2 showing the results of serum PEL and serum IFE as a combination would allow for a more meaningful comparison with PEL and FLC as components of an alternative testing strategy. Without these results the information provided by Katzmann et al. does not make possible the accurate estimation of the yield of serum PEL and serum IFE as a stand-alone strategy. Therefore it is not possible to verify the statement by Katzmann et al. that “serum PEL and/or IFE should be used in combination with either urine IFE and/or serum FLC.” Presenting the findings of complex comparisons with limited space can be challenging, but the use of appropriate statistical analysis and relevant CIs aids in the interpretation of data and allows readers to judge the validity of conclusions reached (4)(5). In our opinion, the usefulness of the data in the report by Katzmann and coworkers will be enhanced by the addition of the information discussed above. 1 Nonstandard abbreviations: FLC, free light chains; MGUS, monoclonal gammopathy of uncertain significance; IFE, immunofixation electrophoresis; PEL, protein electrophoresis. Author Contributions:Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article. Authors’ Disclosures of Potential Conflicts of Interest:No authors declared any potential conflicts of interest. Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript. References 1 Katzmann JA, Kyle RA, Benson J, Larson DR, Snyder MR, Lust JA, et al. Screening panels for the detection of monoclonal gammopathies. Clin Chem 2009 ; 55 : 1517 -1522. Crossref Search ADS PubMed 2 Motulsky HJ. Prism 4 statistics guide—statistical analyses for laboratory and clinical researchers. Section 12, The confidence interval of a proportion 2003 : p 96 -98 Graphpad Software San Diego. . 3 Agresti A, Coull BA. Approximate is better than “exact” for intervals of binomial proportions. Am Stat 1998 ; 52 : 119 -126. 4 Newcombe RG. Confidence for proportions: the Cinderella of statistical analysis. Clin Oncol 2008 ; 20 : 92 -93. Crossref Search ADS 5 Boyd JC, Rifai N, Anesley TM. Preparation of manuscripts for publication: improving your chances for success. Clin Chem 2009 ; 55 : 1259 -1264. Crossref Search ADS PubMed © 2010 The American Association for Clinical Chemistry This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Screening Panels for Detection of Monoclonal Gammopathies: Confidence Intervals
JF - Clinical Chemistry
DO - 10.1373/clinchem.2009.139097
DA - 2010-04-01
UR - https://www.deepdyve.com/lp/oxford-university-press/screening-panels-for-detection-of-monoclonal-gammopathies-confidence-kcyMYfxCvt
SP - 677
VL - 56
IS - 4
DP - DeepDyve
ER -