Standardization of Thyroid Function Tests, 05 05 - 2017
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Standardization of thyroid function tests is important to ensure comparable results across laboratories. For tests of total T3 and T4, a reference measurement system exists using primary calibrators and isotope dilution mass spectrometry. For free T3 and T4, a conventional reference measurement procedure was established using equilibrium dialysis and liquid chromatography tandem mass spectrometry. For TSH, the measurand was defined as intact total TSH accounting for glycosylation, and an "All Procedure Trimmed Mean" statistical approach using multiple commercial assays on patient samples was adopted as a surrogate reference measurement procedure.
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Standardization of Thyroid Function Tests, 05 05 - 2017
- 1. Standardization of Thyroid Function Tests Ola H. Elgaddar MD, PhD, MBA, CPHQ - Lecturer of Chemical Pathology Medical Research Institute - Alexandria University Ola.elgaddar@alexu.edu.eg
- 2. Clinical laboratory tests performed by different laboratories have comparable results
- 3. 1.Imprecision + 2.systematic differences in method results, which can arise from inherent differences in method design +++ (Very obvious in immunoassays)
- 4. Is this a problem?? Immunoassays are critical to many clinical decisions, and many parameters are present in several guidelines…..... Assuming that there is no difference between test results assayed in different settings!
- 5. UK NEQAS [Edinburgh], Department ofLaboratoryMedicine,Royal Infirmary ofEdinburgh,Edinburgh EH164SA,UK
- 6. Harmonization of Measurements Any process that enables the establishment of equivalence of reported values produced by different measurement procedures for the same measurand, (i.e. the quantity intended to be measured)
- 7. Harmonization is achieved via: 1) Method #1 = Standardization: The conventional approach which depends on the application of a well-understood reference measurement procedure (RMP) and commutable reference materials to establish the calibration for each available routine measurement procedure.
- 8. Commutability The ability of a reference material to have inter-assay properties comparable to the properties demonstrated by authentic clinical samples when measured by more than one measurement procedure
- 9. The core component of standardization is the “establishment of metrological traceability” which requires the availability of an ISO conform reference measurement system (RMS)
- 10. Components of ISO conform RMS: ØDefined measurand, ØUnits for expression of measurement results (ideally the Système International d’Unités or SI), ØDifferent hierarchical levels of materials and measurement procedures.
- 12. Accordingly, the provided lab results in the lower part of the hierarchy (routine IVD methods), will provide measurements traceable to the top of the hierarchy, within stated uncertainty constraints.
- 13. Joint Committee for Traceability in Laboratory Medicine (JCTLM)
- 14. Harmonization is achieved via: 2) Method #2: Considered only when RMPs are not available and is based on application of sound statistical methodology to produce arbitrary equivalence of otherwise disparate results generated by the various non- standardized routine measurement procedures (i.e: surrogate RMPs)
- 15. ØThyroid function tests (TFTs) are among the most commonly used tests in both primary and secondary healthcare settings ØMany factors affect the interpretation, and hence the clinical decision to be taken based on the TFTs results.
- 16. ØThese factors could be related to the physiology of the hypothalamic – pituitary – thyroid axis, and hence the distribution of TH in the the tissue. ØSome physiological / pathological / pharmacological cofounders could be present as well affecting TH results…. ØAnd finally, the difference in TH results could be attributed to the lab itself due to a standardization problem
- 19. Till the end of this presentation, all data is obtained either from the C-STFT official website, or from their progress reports released periodically!
- 20. Aim of the project The C-STFT aims at global standardization of thyroid function testing and works towards this with the international in vitro diagnostic (IVD) industry.
- 21. Aim of the project The overall expected benefit: ØProduce equivalent laboratory data so that common reference intervals and/or clinical practice decision limits can be used; ØInclude laboratory data in electronic patient records;
- 22. Aim of the project The overall expected benefit: ØDevelop evidence-based clinical practice guidelines for application of consistent standards of medical care; ØCombine laboratory data across studies to translate research into patient care & disease prevention activities.
- 23. Total T3 & T4
- 24. Standardization of TT4 and TT3 The mission was easy as there is an existing SI- traceable reference measurement system that could be recommended by the C-STFT to the IVD industry for implementation in accordance with the ISO 17511.
- 25. Such RMS is composed of: qPrimary calibrators (IRMM 468 & 469) qReference methods (isotope dilution-mass spectrometry, ID/MS) qReference laboratories offering measurement services The committee refers to the database of the Joint Committee for Traceability in Laboratory Medicine (JCTLM)
- 28. Free T3 & T4
- 29. Standardization of FT4 & FT3 When the C-STFT started its activities in 2005, no reference measurement system was available for free thyroid hormones (FT4, FT3). Therefore, the C-STFT started from scratch with defining the measurand, and proposing a reference measurement procedure (RMP)
- 30. Definition of the measurand According to the International Union of Pure and Applied Chemistry (IUPAC)/IFCC format, the component was ‘‘T4 that is not bound to proteins’’ (present in the water fraction of plasma or serum), the kind-of-quantity to measure the ‘‘amount-of- substance concentration’’ and the system ‘‘plasma or serum at physiological conditions (pH 7.40, temperature 37.0°C)’’. The preferred unit for expression of measurement results was pmol/L.
- 31. The conventional Reference Measurement Procedure (cRMP) qIdeally, metrological traceability of assays should be established with a trueness-based RMP as key element qSince free thyroid hormones have to include a physical step for separation of the free from bound fraction (by equilibrium dialysis (ED) or ultrafiltration (UF), it is by no means possible to unequivocally demonstrate that the T4 concentration in dialysate or ultrafiltrate is identical to the true free hormone concentration in the original sample
- 32. The conventional Reference Measurement Procedure (cRMP) qTherefore, the C-STFT decided to propose an international “conventional” RMP (cRMP) qIt should be based on ED and be combined with direct determination of the T4 concentration in the dialysate with a trueness-based RMP utilizing ID-liquid chromatography/ tandem MS (ID- LC/tandem MS) as measurement principle.
- 33. The conventional Reference Measurement Procedure (cRMP) This implied that according to this proposal the measurand was operationally defined as “T4 in the dialysate from ED of serum prepared under defined conditions”. The convention did not apply to the ID-LC/tandem MS part of the cRMP, provided it is calibrated with the certified T4 primary calibrator IRMM 468, already available in the total T4 reference measurement system
- 35. No CRM present when you search for FT4
- 37. TSH
- 38. Harmonization of TSH qTSH is a glycoprotein circulating in the bloodstream as mixture of components comprising disease-specific glycoforms. qCurrent TSH immunoassays all are traceable to the same WHO IRP TSH 80/558, and express their measurements in mIU/L.
- 39. Harmonization of TSH qThe WHO IRP TSH 80/558 is from human cadaver pituitary and may comprise glycosylation forms that differ from those typically present in serum TSH. Therefore, the above issues of non commutability applies, and hence, IRP-traceable TSH measurements do not give equivalent or interchangeable results.
- 40. Before defining the TSH measurand TSH measurement is mixture analysis. This implies that each component in the mixture must contribute significantly to the diagnostic application of the assay used for mixture analysis, and that the latter should measure the components in the mixture in an “equimolar” way, but to the diagnostic relevant extent.
- 41. Before defining the TSH measurand qThis means that the important changes in overall concentration of the mixture in health and disease should outweigh the minor changes in composition of the mixture in individual samples. qThis requirement of equimolar measurement is of utmost relevance for TSH, since glycoforms are different in euthyroidism versus subclinical and overt hypothyroidism, and because there is evidence that immunoassays may be sensitive to the differences
- 42. Definition of TSH measurand The C-STFT defined the measurand as “TSH, intact, total, glycosylation encountered in diagnostic applications which should be specified”. This definition requires in first instance that TSH assays examined for harmonization deliver a measure for “total TSH”. It also implies that harmonization should be based on the glycoforms present in native samples.
- 43. The “All Procedure Trimmed Mean APTM” as surrogate RMP for TSH Ø Current TSH assays are expressed in IUs (concentrations in mIU/L). However, it is to expect that one day it will be possible to establish the relation between the IU and mass units (SI) for TSH. Ø From this point of view, the reference measurement system for TSH and its realization should be viewed as continuum from discovery of the analyte to final translation into the SI, with different needs at different stages of the continuum
- 44. The “All Procedure Trimmed Mean APTM” as surrogate RMP for TSH Ø Therefore, the C-STFT decided to preserve the traceability of TSH assays to the WHO IRP in their proposed harmonization process, and recommends the “All Procedure Trimmed Mean” (APTM, expressed in IU) as surrogate RMP. It is proposed to statistically derive the APTM from data of a dedicated method comparison study with native human samples, in which as many TSH assays as possible participate
- 45. The “All Procedure Trimmed Mean APTM” as surrogate RMP for TSH ØAccording to this proposal, the APTM targeted panel becomes the key tool in the harmonization process. ØIt has the big advantage that it is composed of samples that contain the typical glycoforms of TSH in the blood circulation, thus are as commutable as possible.
- 46. The “All Procedure Trimmed Mean APTM” as surrogate RMP for TSH ØAfter being assigned with the APTM (expressed in mIU/L) derived from the measurement values of the WHO traceable assays that participated in the method comparison study, the panel is intended to serve as a new measurement standard, in other words, at that point in the harmonization process, the IU of the WHO IRP is transferred to the panel.
- 47. The “All Procedure Trimmed Mean APTM” as surrogate RMP for TSH Note that for the process to be successful, proof of sufficient correlation of the concerned assays to the APTM is a prerequisite. Also the new standard should be sustainable. This requires that the IU is transferred from the first panel to the follow- up panels via analogous method comparison studies.