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[Special Reports] National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for Use of Tumor Markers in Clinical Practice: Quality Requirements
Sturgeon, C. M., Hoffman, B. R., Chan, D. W., Ch'ng, S.-L., Hammond, E., Hayes, D. F., Liotta, L. A., Petricoin, E. F., Schmitt, M., Semmes, O. J., Soletormos, G., van der Merwe, E., Diamandis, E. P. Mon, 28 Jul 2008 00:00:00 -0000
Background: This report presents updated National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines summarizing quality requirements for the use of tumor markers. Methods: One subcommittee developed guidelines for analytical quality relevant to serum and tissue-based tumor markers in current clinical practice. Two other subcommittees formulated recommendations particularly relevant to the developing technologies of microarrays and mass spectrometry. Results: Prerequisites for optimal use of tumor markers in routine practice include formulation of the correct clinical questions to ensure selection of the appropriate test, adherence to good clinical and laboratory practices (e.g., minimization of the risk of incorrect patient and/or specimen identification, tube type, or timing), use of internationally standardized and well-characterized methods, careful adherence to manufacturer instructions, and proactive and timely reactions to information derived from both internal QC and proficiency-testing specimens. Highly desirable procedures include those designed to minimize the risk of the reporting of erroneous results attributable to interferences such as heterophilic antibodies or hook effects, to facilitate the provision of informative clinical reports (e.g., cumulative and/or graphical reports, appropriately derived reference intervals, and interpretative comments), and when possible to integrate these reports with other patient information through electronic health records. Also mandatory is extensive validation encompassing all stages of analysis before introduction of new technologies such as microarrays and mass spectrometry. Provision of high-quality tumor marker services is facilitated by dialogue involving researchers, diagnostic companies, clinical and laboratory users, and regulatory agencies. Conclusions: Implementation of these recommendations, adapted to local practice, should encourage optimization of the clinical use of tumor markers.
[Editorials] There's Nothing to Winning, Really
Bennett, S. T. Mon, 28 Jul 2008 00:00:00 -0000

[Endocrinology and Metabolism] Within-Subject Variability and Analytic Imprecision of Insulinlike Growth Factor Axis and Collagen Markers: Implications for Clinical Diagnosis and Doping Tests
Nguyen, T. V., Nelson, A. E., Howe, C. J., Seibel, M. J., Baxter, R. C., Handelsman, D. J., Kazlauskas, R., Ho, K. K. Mon, 28 Jul 2008 00:00:00 -0000
Background: The utility of insulinlike growth factor (IGF) axis and collagen markers for a growth hormone (GH) doping test in sport depends on their stability and reproducibility. We sought to determine short-term within-subject variability of these markers in a large cohort of healthy individuals. Methods: We measured IGF-I, IGF binding protein 3 (IGFBP-3), acid labile subunit (ALS), and the collagen markers N-terminal propeptide of type I procollagen (PINP), C-terminal telopeptide of type I collagen (ICTP), and N-terminal propeptide of type III procollagen (PIIINP) in serum samples obtained on multiple occasions (median 3 per participant) over a 2- to 3-week period from 1103 elite athletes (699 men, 404 women) ages 22.2 (5.2) years [mean (SD)]. We estimated between-subject and within-subject variances by mixed–effects ANOVA. Results: Within-subject variance accounted for 32% to 36% and 4% to 13% of the total variance in IGF markers and collagen markers, respectively. The within-subject CV ranged from 11% to 21% for the IGF axis markers and from 13% to 15% for the collagen markers. The index of individuality for the IGF axis markers was 0.66–0.76, and for the collagen markers, 0.26–0.45. For each marker, individuals with initial extreme measured values tended to regress toward the population mean in subsequent repeated measurements. We developed a Bayesian model to estimate the long-term probable value for each marker. Conclusions: These results indicate that in healthy individuals the within-subject variability was greater for IGF-I than for the collagen markers, and that where a single measurement is available, it is possible to estimate the long-term probable value of each of the markers by applying the Bayesian approach. Such an application can increase the reliability and decrease the cost of detecting GH doping.
[Endocrinology and Metabolism] Effects of Hemoglobin (Hb) E and HbD Traits on Measurements of Glycated Hb (HbA1c) by 23 Methods
Little, R. R., Rohlfing, C. L., Hanson, S., Connolly, S., Higgins, T., Weykamp, C. W., D'Costa, M., Luzzi, V., Owen, W. E., Roberts, W. L. Mon, 28 Jul 2008 00:00:00 -0000
Background: Glycohemoglobin (GHB), reported as hemoglobin (Hb) A1c, is a marker of long-term glycemic control in patients with diabetes and is directly related to risk for diabetic complications. HbE and HbD are the second and fourth most common Hb variants worldwide. We investigated the accuracy of HbA1c measurement in the presence of HbE and/or HbD traits. Methods: We evaluated 23 HbA1c methods; 9 were immunoassay methods, 10 were ion-exchange HPLC methods, and 4 were capillary electrophoresis, affinity chromatography, or enzymatic methods. An overall test of coincidence of 2 least-squares linear regression lines was performed to determine whether the presence of HbE or HbD traits caused a statistically significant difference from HbAA results relative to the boronate affinity HPLC comparative method. Deming regression analysis was performed to determine whether the presence of these traits produced a clinically significant effect on HbA1c results with the use of ±10% relative bias at 6% and 9% HbA1c as evaluation limits. Results: Statistically significant differences were found in more than half of the methods tested. Only 22% and 13% showed clinically significant interference for HbE and HbD traits, respectively. Conclusions: Some current HbA1c methods show clinically significant interferences with samples containing HbE or HbD traits. To avoid reporting of inaccurate results, ion-exchange chromatograms must be carefully examined to identify possible interference from these Hb variants. For some methods, manufacturers’ instructions do not provide adequate information for making correct decisions about reporting results.
[Endocrinology and Metabolism] Low Vitamin D Status in a Representative Sample of Youth From Quebec, Canada
Mark, S., Gray-Donald, K., Delvin, E. E., O'Loughlin, J., Paradis, G., Levy, E., Lambert, M. Mon, 28 Jul 2008 00:00:00 -0000
Background: Adequate vitamin D status is important for bone growth and mineralization and has been implicated in the regulation of autoimmunity, metabolic function, and cancer prevention. There are no reports of population-based studies on the vitamin D status of Canadian youth, a population with mandatory fortification of foods. Methods: We measured plasma 25-hydroxyvitamin D [25(OH)D], the best indicator of vitamin D status, in a school-based cross-sectional sample of representative French Canadian youth (n = 1753) ages 9, 13, and 16 years living in Québec (latitude: 45°–48°N). Blood samples were collected from January to May 1999. We defined 25(OH)D deficiency as ≤27.5 nmol/L, hypovitaminosis as ≤37.5 nmol/L, and optimal as >75.0 nmol/L. Results: More than 93% of youth in each age and sex group had suboptimal 25(OH)D concentrations. The prevalence of 25(OH)D deficiency increased with age in both sexes (P < 0.0001). It was 2%, 3%, and 13% in 9-, 13-, and 16-year-old boys and 2%, 8%, and 10% in 9-, 13-, and 16-year-old girls. Girls with higher body mass index and girls from households with lower income had lower 25(OH)D concentrations. These effects were not observed in boys. Conclusions: Inadequate vitamin D status is a potentially serious public health problem among children and adolescents in Québec. Youth living at high latitudes in countries with and without mandatory fortification of vitamin D are likely at heightened risk of 25(OH)D deficiency. These results call for renewed efforts to ensure adequate vitamin D intake among growing children and adolescents.
[Endocrinology and Metabolism] State-of-the-Art of Serum Testosterone Measurement by Isotope Dilution-Liquid Chromatography- Tandem Mass Spectrometry
Thienpont, L. M., Van Uytfanghe, K., Blincko, S., Ramsay, C. S., Xie, H., Doss, R. C., Keevil, B. G., Owen, L. J., Rockwood, A. L., Kushnir, M. M., Chun, K. Y., Chandler, D. W., Field, H. P., Sluss, P. M. Mon, 28 Jul 2008 00:00:00 -0000
Background: The recent interest of clinical laboratories in developing serum testosterone assays based on isotope dilution–liquid chromatography–tandem mass spectrometry (ID-LC-MS/MS) stems from the lack of accuracy of direct immunoassays. In this study, we assessed the accuracy and state of standardization (traceability) of 4 published ID-LC-MS/MS procedures in a method comparison with an ID–gas chromatography (GC)–MS reference measurement procedure listed in the database of the Joint Committee for Traceability in Laboratory Medicine. Methods: The study used 58 specimens from different patient categories. Each specimen was measured in triplicate (ID-LC-MS/MS) and quadruplicate (ID-GC-MS) in independent runs. Results: The testosterone concentrations by ID-GC-MS were 0.2–4.4 nmol/L (women), 0.2–2.0 nmol/L (hypogonadal man), and 10.1–31.3 nmol/L (normogonadal men). For ID-GC-MS, the CV was nearly constant, with a median of 1.0%; for ID-LC-MS/MS, it was concentration-dependent, with a median of up to 8%. Weighted Deming regression gave mean slopes, intercepts, and correlation coefficients of 0.90–1.11, –0.055–0.013 nmol/L, and 0.993–0.997, respectively. The % difference plot showed between 7% and 26% of the results outside a total error limit of 14%, with median deviations from ID-GC-MS between –9.6 and 0.4%. Conclusions: This study demonstrated fairly good accuracy and standardization of the tested ID-LC-MS/MS procedures. Performance differences between procedures were evident in some instances, due to improper calibration and between-run calibration control. This emphasizes the need for thorough validation, including traceability, of new ID-LC-MS/MS procedures.

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