Seasonal Changes in Serum Thyrotropin Concentrations Observed from Big Data Obtained During Six Consecutive Years from 2010 to 2015 at a Single Hospital in Japan.

BACKGROUND: This study analyzed big data for serum thyrotropin (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) concentrations in patients who had attended the outpatient clinic of Ito Hospital (Tokyo, Japan) during a recent six-year period (between January 1, 2010, and December 31, 2015) in order to investigate for seasonal changes. METHODS: The serum TSH concentrations were reviewed for all 135,417 patients aged >20 years. Patients with any thyroid diseases were included, irrespective of whether they were receiving drug therapy. In total 1,637,721 serum samples were analyzed for TSH, 1,626,269 for fT3, and 1,669,381 for fT4. RESULTS: It was observed that the TSH concentrations showed annual changes during the six-year period. They decreased during the summer, while they increased during the winter. The TSH concentrations were negatively correlated with the daily temperatures (Spearman rank correlation coefficient -0.4486; p < 0.0001). The same applied for the correlation between fT3 concentrations and daily temperatures. CONCLUSIONS: The fact that the TSH concentrations show annual changes in areas where the temperature ranges during the year are rather wide should be borne in mind for interpretation of results.

Standardization of Free Thyroxine Measurements Allows the Adoption of a More Uniform Reference Interval.

BACKGROUND: The IFCC Committee for Standardization of Thyroid Function Tests intended to standardize free thyroxine (FT4) immunoassays. We developed a Système International d'Unités traceable conventional reference measurement procedure (RMP) based on equilibrium dialysis and mass spectrometry. We describe here the latest studies intended to recalibrate against the RMP and supply a proof of concept, which should allow continued standardization efforts. METHODS: We used the RMP to target the standardization and reference interval (RI) panels, which were also measured by 13 manufacturers. We validated the suitability of the recalibrated results to meet specifications for bias (3.3%) and total error (8.0%) determined from biological variation. However, because these specifications were stringent, we expanded them to 10% and 13%, respectively. The results for the RI panel were reported as if the assays were recalibrated. We estimated all but 1 RI using parametric statistical procedures and hypothesized that the RI determined by the RMP was suitable for use by the recalibrated assays. RESULTS: Twelve of 13 recalibrated assays had a bias, meeting the 10% specification with 95% confidence; for 7 assays, this applied even for the 3.3% specification. Only 1 assay met the 13% total error specification. Recalibration reduced the CV of the assay means for the standardization panel from 13% to 5%. The proof-of-concept study confirmed our hypothesis regarding the RI but within constraints. CONCLUSIONS: Recalibration to the RMP significantly reduced the FT4 immunoassays' bias, so that the RI determined by the RMP was suitable for common use within a margin of 12.5%.

Value Assignment of Vitamin D Metabolites in Vitamin D Standardization Program Serum Samples.

Assay variability has been cited as an obstacle to establishing optimal vitamin D exposure. As part of the Vitamin D Standardization Program (VDSP) effort to standardize the measurement of total 25-hydroxyvitamin D [25(OH)D], the value assignment of total 25(OH)D in 50 single-donor serum samples was performed using two isotope-dilution LC with tandem MS methods. Both methods are recognized as reference measurement procedures (RMPs) by the Joint Committee for Traceability in Laboratory Medicine. These samples and their assigned values serve as the foundation for several aspects of the VDSP. To our knowledge, this is the first time that two RMPs have been used to assign 25(OH)D values to such a large number of serum samples.

Harmonization of Serum Thyroid-Stimulating Hormone Measurements Paves the Way for the Adoption of a More Uniform Reference Interval.

BACKGROUND: The IFCC Committee for Standardization of Thyroid Function Tests developed a global harmonization approach for thyroid-stimulating hormone measurements. It is based on a multiassay method comparison study with clinical serum samples and target setting with a robust factor analysis method. Here we describe the Phase IV method comparison and reference interval (RI) studies conducted with the objective to recalibrate the participating assays and demonstrate the proof-of-concept. METHODS: Fourteen manufacturers measured the harmonization and RI panel; 4 of them quantified the harmonization and first follow-up panel in parallel. All recalibrated their assays to the statistically inferred targets. For validation, we used desirable specifications from the biological variation for the bias and total error (TE). The RI measurements were done with the assays' current calibrators, but data were also reported after transformation to the new calibration status. We estimated the pre- and postrecalibration RIs with a nonparametric bootstrap procedure. RESULTS: After recalibration, 14 of 15 assays met the bias specification with 95% confidence; 8 assays complied with the TE specification. The CV of the assay means for the harmonization panel was reduced from 9.5% to 4.2%. The RI study showed improved uniformity after recalibration: the ranges (i.e., maximum differences) exhibited by the assay-specific 2.5th, 50th, and 97.5th percentile estimates were reduced from 0.27, 0.89, and 2.13 mIU/L to 0.12, 0.29, and 0.77 mIU/L. CONCLUSIONS: We showed that harmonization increased the agreement of results from the participating immunoassays, and may allow them to adopt a more uniform RI in the future.

Monitoring the stability of the standardization status of FT4 and TSH assays by use of daily outpatient medians and flagging frequencies.

Clinicians diagnose thyroid dysfunction based on TSH and FT4 testing. However, the current lack of comparability between assays limits the optimal use of laboratory data. The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) gave a mandate to the Committee for Standardization of Thyroid Function Tests (C-STFT) to resolve this limitation by standardization. Recently, the Committee members and their partners felt ready to set the step towards the technical recalibration. However, before implementation, they were furthered by the Food and Drugs Administration (FDA) to develop a tool to assess the sustainability of the new calibration basis. C-STFT began to use 2 online applications, i.e., the "Percentiler" and "Flagger", with the intention to assess their utility for this purpose. The tools monitor the course of instrument-specific moving medians of outpatient results (Percentiler) and flagging rates (Flagger) from data of individual laboratories grouped by instrument/assay peer. They additionally document the mid- to long-term medians, hence, are quality indicators of stability of performance of both laboratories and peers/assays. Here, the first experiences built up in the pre-standardization phase are reported. They suggest the suitability of both applications to document the sustainability of the calibration basis in the post-standardization phase.

Standardization of FT4 and harmonization of TSH measurements - a request for input from endocrinologists and other physicians.

Given the prevalence of thyroid disorders and the subtle signs and symptoms that may accompany subclinical disease, reliable laboratory testing for serum TSH and free thyroid hormones is important for both primary care physicians and endocrinologists. The laboratory community has recognized the need for standardization of thyroid function tests to achieve comparability of measurement results between methods. This applies in particular to tests for free T4 (FT4), which may be considered controversial in terms of clinical and analytical validity. However, variability is also observed with TSH testing - a fact which has not been emphasized in ongoing discussions regarding lowering the upper limit of normal and/or common decision limits to start treatment for hypothyroidism. In response to this need, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Committee for Standardization of Thyroid Function Tests worked over the years towards the goal of standardization of FT4 and TSH testing.

Monitoring laboratory data across manufacturers and laboratories--A prerequisite to make "Big Data" work.

BACKGROUND: "The Percentiler" project provides quasi real-time access to patient medians across laboratories and manufacturers. This data can serve as "clearinghouse" for electronic health record applications, e.g., use of laboratory data for global health-care research. METHODS: Participants send their daily outpatient medians to the Percentiler application. After 6 to 8weeks, the laboratory receives its login information, which gives access to the user interface. Data is assessed by peer group, i.e., 10 or more laboratories using the same test system. Participation is free of charge. RESULTS: Participation is global with, to date, >120 laboratories and >250 instruments. Up to now, several reports have been produced that address i) the general features of the project, ii) peer group observations; iii) synergisms between "The Percentiler" and dedicated external quality assessment surveys. Reasons for long-term instability and bias (calibration- or lot-effects) have been observed for the individual laboratory and manufacturers. CONCLUSIONS: "The Percentiler" project has the potential to build a continuous, global evidence base on in vitro diagnostic test comparability and stability. As such, it may be beneficial for all stakeholders and, in particular, the patient. The medical laboratory is empowered for contributing to the development, implementation, and management of global health-care policies.

The Empower project - a new way of assessing and monitoring test comparability and stability.

BACKGROUND: Manufacturers and laboratories might benefit from using a modern integrated tool for quality management/assurance. The tool should not be confounded by commutability issues and focus on the intrinsic analytical quality and comparability of assays as performed in routine laboratories. In addition, it should enable monitoring of long-term stability of performance, with the possibility to quasi "real-time" remedial action. Therefore, we developed the "Empower" project. METHODS: The project comprises four pillars: (i) master comparisons with panels of frozen single-donation samples, (ii) monitoring of patient percentiles and (iii) internal quality control data, and (iv) conceptual and statistical education about analytical quality. In the pillars described here (i and ii), state-of-the-art as well as biologically derived specifications are used. RESULTS: In the 2014 master comparisons survey, 125 laboratories forming 8 peer groups participated. It showed not only good intrinsic analytical quality of assays but also assay biases/non-comparability. Although laboratory performance was mostly satisfactory, sometimes huge between-laboratory differences were observed. In patient percentile monitoring, currently, 100 laboratories participate with 182 devices. Particularly, laboratories with a high daily throughput and low patient population variation show a stable moving median in time with good between-instrument concordance. Shifts/drifts due to lot changes are sometimes revealed. There is evidence that outpatient medians mirror the calibration set-points shown in the master comparisons. CONCLUSIONS: The Empower project gives manufacturers and laboratories a realistic view on assay quality/comparability as well as stability of performance and/or the reasons for increased variation. Therefore, it is a modern tool for quality management/assurance toward improved patient care.

A Progress Report of the IFCC Committee for Standardization of Thyroid Function Tests.

BACKGROUND: The IFCC Committee for Standardization of Thyroid Function Tests aims at equivalence of laboratory test results for free thyroxine (FT4) and thyrotropin (TSH). OBJECTIVES: This report describes the phase III method comparison study with clinical samples representing a broad spectrum of thyroid disease. The objective was to expand the feasibility work and explore the impact of standardization/harmonization in the clinically relevant concentration range. METHODS: Two sets of serum samples (74 for FT4, 94 for TSH) were obtained in a clinical setting. Eight manufacturers participated in the study (with 13 FT4 and 14 TSH assays). Targets for FT4 were set by the international conventional reference measurement procedure of the IFCC; those for TSH were based on the all-procedure trimmed mean. The manufacturers recalibrated their assays against these targets. RESULTS: All FT4 assays were negatively biased in the mid- to high concentration range, with a maximum interassay discrepancy of approximately 30%. However, in the low range, the maximum deviation was approximately 90%. For TSH, interassay comparability was reasonable in the mid-concentration range, but worse in the pathophysiological ranges. Recalibration was able to eliminate the interassay differences, so that the remaining dispersion of the data was nearly entirely due to within-assay random error components. The impact of recalibration on the numerical results was particularly high for FT4. CONCLUSIONS: Standardization and harmonization of FT4 and TSH measurements is feasible from a technical point of view. Because of the impact on the numerical values, the implementation needs careful preparation with the stakeholders.