Verification of Harmonization of Serum Total and Free Prostate-Specific Antigen (PSA) Measurements and Implications for Medical Decisions.

BACKGROUND: Previous studies have shown that the harmonization of prostate-specific antigen (PSA) assays remained limited even after the introduction of WHO International Standards. This information needs updating for current measuring systems (MS) and reevaluation according to established analytical performance specifications (APS) and the characteristics of antibodies used. METHODS: Total (tPSA) and free (fPSA) PSA were measured in 135 and 137 native serum samples, respectively, by Abbott Alinity i, Beckman Access Dxl, Roche Cobas e801, and Siemens Atellica IM MSs. Passing-Bablok regression and difference plots were used to compare results from each MS to the all-method median values. Agreement among methods was evaluated against APS for bias derived from biological variation of the 2 measurands. RESULTS: The median interassay CV for tPSA MSs (11.5%; 25-75th percentiles, 9.2-13.4) fulfilled the minimum APS goal for intermethod bias (15.9%), while the interassay CV for fPSA did not [20.4% (25-75th percentiles, 18.4-22.7) vs goal 17.6%]. Considering the all-method median value of each sample as reference, all tPSA MSs exhibited a mean percentage bias within the minimum goal. On the other hand, Alinity (+21.3%) and Access (-24.2%) were out of the minimum bias goal for fPSA, the disagreement explained only in minimal part by the heterogeneity of employed antibodies. CONCLUSIONS: The harmonization among tPSA MSs is acceptable only when minimum APS are applied and necessitates further improvement. The marked disagreement among fPSA MSs questions the use of fPSA as a second-level test for biopsy referral.

Percentile transformation and recalibration functions allow harmonization of thyroid-stimulating hormone (TSH) immunoassay results.

Background The comparability of thyroid-stimulating hormone (TSH) results cannot be easily obtained using SI-traceable reference measurement procedures (RPMs) or reference materials, whilst harmonization is more feasible. The aim of this study was to identify and validate a new approach for the harmonization of TSH results. Methods Percentile normalization was applied to 125,419 TSH results, obtained from seven laboratories using three immunoassays (Access 3rd IS Thyrotropin, Beckman Coulter Diagnostics; Architect System, Abbott Diagnostics and Elecsys, Roche Diagnostics). Recalibration equations (RCAL) were derived by robust regressions using bootstrapped distribution. Two datasets, the first of 119 EQAs, the second of 610, 638 and 639 results from Access, Architect and Elecsys TSH results, respectively, were used to validate RCAL. A dataset of 142,821 TSH values was used to derive reference intervals (RIs) after applying RCAL. Results Access, Abbott and Elecsys TSH distributions were significantly different (p < 0.001). RCAL intercepts and slopes were -0.003 and 0.984 for Access, 0.032 and 1.041 for Architect, -0.031 and 1.003 for Elecsys, respectively. Validation using EQAs showed that before and after RCAL, the coefficients of variation (CVs) or among-assay results decreased from 10.72% to 8.16%. The second validation dataset was used to test RCALs. The median of between-assay differences ranged from -0.0053 to 0.1955 mIU/L of TSH. Elecsys recalibrated to Access (and vice-versa) showed non-significant difference. TSH RI after RCAL resulted in 0.37-5.11 mIU/L overall, 0.49-4.96 mIU/L for females and 0.40-4.92 mIU/L for males. A significant difference across age classes was identified. Conclusions Percentile normalization and robust regression are valuable tools for deriving RCALs and harmonizing TSH values.

A multicenter study for the evaluation of the reference interval for TSH in Italy (ELAS TSH Italian Study).

Background The aims of this study were: (1) to calculate reliable thyroid stimulating hormone (TSH) reference intervals using laboratory databases; (2) to evaluate the relationship between TSH, sex and age values in different large Italian populations. Methods The TSH values stored in the laboratory information system of clinical laboratories of four Italian city hospitals, including 146,801 TSH measurements (with the respective age and sex data of individuals) were taken in consideration. Assuming a log-normal distribution, to log-transformed TSH values were applied the Dixon's iterative principle in order to exclude the outliers. At the end of this iterative process 142,821 log-transformed TSH results remained. The four clinical laboratories measured serum TSH concentrations using the same TSH immunoassay method (Access TSH 3rd IS, using UniCel DxI platform). Results The TSH reference interval calculated in the present study (0.362-5.280 mIU/L) is similar to that suggested by the manufacturer for the Access TSH 3rd IS assay (0.45-5.33 mIU/L). TSH values in females were significantly higher than in males (females: mean=2.06 mIU/L; standard deviation [SD]=1.26 mIU/L; n=101,243; males: mean=1.92 mIU/L; SD=1.19 mIU/L; n=41,578; p<0.0001). Moreover, a negative linear relationship was observed between TSH throughout all interval age values (from 0 to 105 years). Conclusions The results of the present multicenter study confirm that data mining techniques can be used to calculate clinically useful reference intervals for TSH. From a pathophysiological point of view, our results suggest that some Northern populations of Italy might still suffer some harmful effects on the thyroid gland due to mild to moderate iodine intake deficiency. Specific clinical trials are needed to confirm these results.

Harmonization protocols for TSH immunoassays: a multicenter study in Italy.

BACKGROUND: Systematic difference between thyroid-stimulating hormone (TSH) immunoassays may produce misleading interpretation when samples of the same patients are measured with different methods. The study aims were to evaluate whether systematic differences are present among TSH immunoassays, and whether it is possible to obtain a better harmonization among TSH methods using results obtained in external quality assessment (EQA) schemes. METHODS: Seven Italian clinical laboratories measured TSH in 745 serum samples of healthy subjects and patients with thyroid disorders. These samples were also re-measured by two reference laboratories of the study with the six TSH immunoassays most popular in Italy after 2 months of storage at -80 °C. Moreover, these data were compared to 53,823 TSH measurements, obtained by laboratories participant to 2012-2015 EQA annual cycles in 72 quality control samples (TSH concentrations from about 0.1 mIU/L to 18.0 mIU/L). TSH concentrations were recalibrated using a mathematical approach based on the principal component analysis (PCA). RESULTS: Systematic differences were found between the most popular commercially available TSH immunoassays. TSH concentrations measured by the clinical laboratories were very closely correlated to those measured with the same method by reference laboratories after 2 months of storage at -80 °C. After recalibration using the PCA approach the variation of TSH values significantly decreased from a median pre-calibration value of 13.53% (10.79%-16.53%) to 9.63% (6.90%-13.21%) after recalibration. CONCLUSIONS: Our data suggest that EQA schemes are useful to improve harmonization among TSH immunoassays and also to produce some mathematical formulas, which can be used by clinicians to better compare TSH values measured with different methods.

Evaluation of 99th percentile and reference change values of the hs-cTnI method using ADVIA Centaur XPT platform: A multicenter study.

BACKGROUND: According to quality specifications required by international guidelines, the evaluation of the 99th URL value is a very difficult task that is usually beyond the capacity of a single laboratory. The aims of this article are to report and discuss the results of a multicenter study concerning the evaluation of the 99th percentile URL and reference change (RCV) of the ADVIA Centaur High-Sensitivity Troponin I (TNIH), recently distributed to the Italian clinical laboratories. MATERIALS AND METHODS: The reference population evaluated with ADVIA XPT method for the calculation of cTnI reference distribution parameters consisted of 1325 healthy adults subjects (age range from 18 to 86 years), including 653 women (mean age 50.7 years, SD 14.5 years) and 672 men (mean age 50.9 years, SD 13.8 years), well matched for both age (P = .8112) and sex (F/M = 0.97). RESULTS: cTnI distribution values of reference population was highly skewed, while log-transformed cTnI values roughly approximated a log-normal distribution. Men have higher cTnI values than women throughout all the adult lifespan. Moreover, the subjects with age ≤ 55 years had significantly lower cTnI values than those with age > 55 years (p < .0001). Of note, 62% of women and 77% of men had equal or higher than cTnI values than the LoD value of the method (i.e., 2.2 ng/L). CONCLUSIONS: The results of the present study demonstrate that the ADVIA Centaur High-Sensitivity Troponin I using the XPT automated platform fits both the criteria and quality specifications required by the most recent international guidelines for high-sensitivity methods for cTnI assay.

Evaluation of 99th percentile and reference change values of a high-sensitivity cTnI method: A multicenter study.

BACKGROUND: The Italian Society of Clinical Biochemistry (SIBioC) and the Italian Section of the European Ligand Assay Society (ELAS) have recently promoted a multicenter study (Italian hs-cTnI Study) with the aim to accurately evaluate analytical performances and reference values of the most popular cTnI methods commercially available in Italy. The aim of this article is to report the results of the Italian hs-cTnI Study concerning the evaluation of the 99th percentile URL and reference change (RCV) values around the 99th URL of the Access cTnI method. MATERIALS AND METHODS: Heparinized plasma samples were collected from 1306 healthy adult volunteers by 8 Italian clinical centers. Every center collected from 50 to 150 plasma samples from healthy adult subjects. All volunteers denied the presence of chronic or acute diseases and had normal values of routine laboratory tests (including creatinine, electrolytes, glucose and blood counts). An older cohort of 457 adult subjects (mean age 63.0 years; SD 8.1 years, minimum 47 years, maximum 86 years) underwent also ECG and cardiac imaging analysis in order to exclude the presence of asymptomatic cardiac disease. RESULTS AND CONCLUSIONS: The results of the present study confirm that the Access hsTnI method using the DxI platform satisfies the two criteria required by international guidelines for high-sensitivity methods for cTn assay. Furthermore, the results of this study confirm that the calculation of the 99th percentile URL values are greatly affected not only by age and sex of the reference population, but also by the statistical approach used for calculation of cTnI distribution parameters.

Head-to-head comparison of plasma cTnI concentration values measured with three high-sensitivity methods in a large Italian population of healthy volunteers and patients admitted to emergency department with acute coronary syndrome: A multi-center study.

BACKGROUND: The study aim is to compare cTnI values measured with three high-sensitivity (hs) methods in apparently healthy volunteers and patients admitted to emergency department (ED) with acute coronary syndrome enrolled in a large multicentre study. METHODS: Heparinized plasma samples were collected from 1511 apparently healthy subjects from 8 Italian clinical institutions (mean age: 51.5 years, SD: 14.1 years, range: 18-65 years, F/M ratio:0.95). All volunteers denied chronic or acute diseases and had normal values of routine laboratory tests. Moreover, 1322 heparinized plasma sample were also collected by 9 Italian clinical institutions from patients admitted to ED with clinical symptoms typical of acute coronary syndrome. The reference study laboratory assayed all plasma samples with three hs-methods: Architect hs-cTnI, Access hs-cTnI and ADVIA Centaur XPT methods. Principal Component Analysis (PCA) was also used to analyze the between-method differences among hs-cTnI assays. RESULTS: On average, a between-method difference of 31.2% CV was found among the results of hs-cTnI immunoassays. ADVIA Centaur XPT method measured higher cTnI values than Architect and Access methods. Moreover, 99th percentile URL values depended not only on age and sex of reference population, but also on the statistical approach used for calculation (robust non-parametric vs bootstrap). CONCLUSIONS: Due to differences in concentrations and reference values, clinicians should be advised that plasma samples of the same patient should be measured for cTnI assay in the same laboratory. Specific clinical studies are needed to establish the most appropriate statistical approach to calculate the 99th percentile URL values for hs-cTnI methods.

Multicenter evaluation of the new immunoassay method for TSH measurement using the automated DxI platform.

AIM OF THE STUDY: Recently, Beckman Coulter Diagnostics set up a new TSH immunoassay for the automated DxI platform. The aim of this study was to evaluate and compare the analytical performance and clinical results of this method with those of previous method. MATERIAL AND METHODS: A multicenter study (named TSH ELAS Study) was organized using 593 serum samples, collected from healthy subjects and patients with thyroid disorders, and 13 control samples, circulated in an External Quality Assessment (EQA) scheme. RESULTS: The values of LoB and LoD, and LoQ at 20% CV were 0.0004mIU/L, 0.001mIU/L and 0.0023mIU/L, respectively. Moreover, TSH concentrations >0.01mIU/L actually show imprecision values lower than 5% CV. This new TSH assay showed a systematic underestimation (on average of 6.25%) compared to old method, which is mainly due to larger differences between methods for samples with low TSH concentrations, related to the better analytical sensitivity of new compared to old method. In a reference population, including 279 apparently healthy adult subjects, Caucasian volunteers (mean age 43.6years, age 20-63years, 138 women and 141 males) the distribution of TSH concentrations was: mean (CI 95%) 1.694mIU/L (1.588-1.779), median 1.495mIU/L (1.412-1.588mIU/L), 97.5th percentile 3.707mIU/L. CONCLUSIONS: The new TSH immunoassay for DxI platform shows some relevant improvements compared to the previous one: use of the most recent WHO 3rd IRP 81/563 standard and monoclonal antibodies (instead of polyclonal antibodies of the old method), and better analytical sensitivities and reproducibility.