Traceability in Laboratory Medicine: What is it and Why is it Important for Patients?

The between method variability of patient results is a source of uncertainty that can have adverse consequences for patient safety and clinical outcomes. Globalisation requires that laboratory medicine results should be transferable between methods. Traceability in laboratory medicine aims to reduce between method variability so that results are independent of time or location. Application of the metrological traceability chain facilitates a universal approach based around the preparation, adoption and use of higher order international commutable reference materials and reference measurement procedures, supported by expert reference laboratories. Global collaboration is required, involving several different stakeholder groups ranging from international experts to laboratory medicine specialists in routine clinical laboratories.

Role of laboratory medicine in collaborative healthcare.

Healthcare delivery and responsibility is changing. Patient-centered care is gaining international acceptance with the patient taking greater responsibility for his/her health and sharing decision making for the diagnosis and management of illness. Laboratory medicine must embrace this change and work in a tripartite collaboration with patients and with the clinicians who use clinical laboratory services. Improved communication is the key to participation, including the provision of educational information and support. Knowledge management should be targeted to each stakeholder group. As part of collaborative healthcare clinical laboratory service provision needs to be more flexible and available, with implications for managers who oversee the structure and governance of the service. Increased use of managed point of care testing will be essential. The curriculum content of laboratory medicine training programs will require trainees to undertake practice-based learning that facilitates interaction with patients, clinicians and managers. Continuing professional development for specialists in laboratory medicine should also embrace new sources of information and opportunities for collaborative healthcare.

Traceability in laboratory medicine: a global driver for accurate results for patient care.

Laboratory medicine results influence a high percentage of all clinical decisions. Globalization requires that laboratory medicine results should be transferable between methods in the interests of patient safety. International collaboration is necessary to deliver this requirement. That collaboration should be based on traceability in laboratory medicine and the adoption of higher order international commutable reference materials and measurement procedures. Application of the metrological traceability chain facilitates a universal approach. The measurement of serum cholesterol and blood HbA1c serve as examples of the process of method standardization where an impact on clinical outcomes is demonstrable. The measurement of plasma parathyroid hormone and blood HbA2 serve as examples where the current between-method variability is compromising patient management and method standardization and/or harmonization is required. Challenges to the widespread adoption of traceability in laboratory medicine include the availability of reference materials and methods, geographical differences, the use of variable units, complex analytes and limited global coordination. The global collaboration requires the involvement of several different stakeholder groups ranging from international experts to laboratory medicine specialists in routine clinical laboratories. A coordinated action plan is presented with actions attributable to each of these stakeholder groups.

Systems medicine, personalized health and therapy.

The 7th Santorini Conference was held in Santorini, Greece, and brought together 200 participants from 40 countries in several continents, including Europe, USA but also Japan, Korea, Brazil and South Africa. The attendees had the opportunity to: listen to 60 oral presentations; participate in two lunch symposia; look at 103 posters, which were divided in two groups ('systems medicine and environment' and 'pharmacogenomics and cancer') and attend a dedicated exhibition with six companies. The meeting was organized by the Institut National de la Santé et de la Recherche Médicale (INSERM) U1122; IGE-PCV and by 'Biologie Prospective' with the collaboration of the European Society of Pharmacogenomics and Theranostics (ESPT), under the auspices of international organizations (e.g., International Federation of Clinical Chemistry and Laboratory medicine [IFCC], European Federation of Clinical Chemistry and Laboratory Medicine [EFLM], European Diagnostic Manufacturers Association [EDMA], Federation of European Pharmacological Societies [EPHAR], European Science Foundation [ESF]). The 3 days of the conference stimulated intensive discussions on systems biology and the influence of omics technologies on personalized health. Sixty speakers were invited or selected from early abstracts and gave presentations on the following topics: From systems biology to systems medicine/pharmacology; Omics/translating pharmacogenomics/proteomic biomarkers/metabolomics; Human nutrition and health/personalized medicine. We are summarizing here the main topics and presentations, according to the successive sessions.

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.

Adding value to laboratory medicine: a professional responsibility.

Laboratory medicine is a medical specialty at the centre of healthcare. When used optimally laboratory medicine generates knowledge that can facilitate patient safety, improve patient outcomes, shorten patient journeys and lead to more cost-effective healthcare. Optimal use of laboratory medicine relies on dynamic and authoritative leadership outside as well as inside the laboratory. The first responsibility of the head of a clinical laboratory is to ensure the provision of a high quality service across a wide range of parameters culminating in laboratory accreditation against an international standard, such as ISO 15189. From that essential baseline the leadership of laboratory medicine at local, national and international level needs to 'add value' to ensure the optimal delivery, use, development and evaluation of the services provided for individuals and for groups of patients. A convenient tool to illustrate added value is use of the mnemonic 'SCIENCE'. This tool allows added value to be considered in seven domains: standardisation and harmonisation; clinical effectiveness; innovation; evidence-based practice; novel applications; cost-effectiveness; and education of others. The assessment of added value in laboratory medicine may be considered against a framework that comprises three dimensions: operational efficiency; patient management; and patient behaviours. The profession and the patient will benefit from sharing examples of adding value to laboratory medicine.

Report of the IFCC Working Group for Standardization of Thyroid Function Tests; part 3: total thyroxine and total triiodothyronine.

BACKGROUND: Because total thyroid hormone testing is performed on many automated clinical chemistry instruments, the IFCC Scientific Division commissioned the Working Group for Standardization of Thyroid Function Tests to include total thyroxine (TT4) and total triiodothyronine (TT3) in its standardization efforts. METHODS: Existing SI-traceable reference measurement procedures (RMPs) were used to assign TT4 and TT3 values to 40 single-donor serum samples for subsequent use in a method comparison study with 11 TT4 and 12 TT3 immunoassays. Data from comparison of each immunoassay with the RMPs provided a basis for mathematical assay recalibration. RESULTS: Seven TT4 assays had a mean bias within 10% of the RMP, but 2 deviated by an average of -12% and another 2 by +17%. All TT3 assays showed positive biases, 4 within and 8 outside 10%, up to 32%. Mathematical recalibration effectively eliminated assay-specific biases, but sample-related effects remained, particularly for TT3. Correlation coefficients with the RMPs ranged from 0.82 to 0.97 for TT4 and from 0.32 to 0.92 for TT3. The within-run and total imprecision ranges for TT4 were 1.4% to 9.1% and 3.0% to 9.4%, respectively, and for TT3 2.1% to 7.8% and 2.8% to 12.7%, respectively. Approximately one-half of the assays matched the internal QC targets within approximately 5%; however, we observed within-run drifts/shifts. CONCLUSIONS: The study showed that of the assays we examined, only 4 TT4 but the majority of the TT3 assays needed establishment of calibration traceability to the existing RMPs. Most assays performed well, but some would benefit from improved precision, within-run stability, and between-run consistency.

Report of the IFCC Working Group for Standardization of Thyroid Function Tests; part 2: free thyroxine and free triiodothyronine.

BACKGROUND: Free thyroxine (FT4) and free triiodothyronine (FT3) measurements are useful in the diagnosis and treatment of a variety of thyroid disorders. The IFCC Scientific Division established a Working Group to resolve issues of method performance to meet clinical requirements. METHODS: We compared results for measurement of a panel of single donor sera using clinical laboratory procedures based on equilibrium dialysis-isotope dilution-mass spectrometry (ED-ID-MS) (2 for FT4, 1 for FT3) and immunoassays from 9 manufacturers (15 for FT4, 13 for FT3) to a candidate international conventional reference measurement procedure (cRMP) also based on ED-ID-MS. RESULTS: For FT4 (FT3), the mean bias of 2 (4) assays was within 10% of the cRMP, whereas for 15 (9) assays, negative biases up to -42% (-30%) were seen; 1 FT3 assay was positively biased by +22%. Recalibration to the cRMP eliminated assay-specific biases; however, sample-related effects remained, as judged from difference plots with biologic total error limits. Correlation coefficients to the cRMPs ranged for FT4 (FT3) from 0.92 to 0.78 (0.88 to 0.30). Within-run and total imprecision ranged for FT4 (FT3) from 1.0% to 11.1% (1.8% to 9.4%) and 1.5% to 14.1% (2.4% to 10.0%), respectively. Approximately half of the manufacturers matched the internal QC targets within approximately 5%; however, within-run instability was observed. CONCLUSIONS: The study showed that most assays had bias largely correctable by establishing calibration traceability to a cRMP and that the majority performed well. Some assays, however, would benefit from improved precision, within-run stability, and between-run consistency.

Report of the IFCC Working Group for Standardization of Thyroid Function Tests; part 1: thyroid-stimulating hormone.

BACKGROUND: Laboratory testing of serum thyroid-stimulating hormone (TSH) is an essential tool for the diagnosis and management of various thyroid disorders whose collective prevalence lies between 4% and 8%. However, between-assay discrepancies in TSH results limit the application of clinical practice guidelines. METHODS: We performed a method comparison study with 40 sera to assess the result comparability and performance attributes of 16 immunoassays. RESULTS: Thirteen of 16 assays gave mean results within 10% of the overall mean. The difference between the most extreme means was 39%. Assay-specific biases could be eliminated by recalibration to the overall mean. After recalibration of singlicate results, all assays showed results within the biological total error goal (22.8%), except for 1 result in each of 4 assays. For a sample with a TSH concentration of 0.016 mIU/L, 6 assays either did not report results or demonstrated CVs >20%. Within-run and total imprecision ranged from 1.5% to 5.5% and 2.5% to 7.7%, respectively. Most assays were able to match the internal QC targets within 5%. Within-run drifts and shifts were observed. CONCLUSIONS: Harmonization of TSH measurements would be particularly beneficial for 3 of the 16 examined assays. These data demonstrate that harmonization may be accomplished by establishing calibration traceability to the overall mean values for a panel of patient samples. However, the full impact of the approach must be further explored with a wider range of samples. Although a majority of assays showed excellent quality of performance, some would benefit from improved within-run stability.

Prospective, double blind, randomized, controlled trial of simvastatin in human fracture healing.

Although statins are widely prescribed as cholesterol-lowering drugs, a number of studies suggest that these compounds may have anabolic effects on bone. Our aim was to assess whether simvastatin affects the rate of fracture healing in humans. A prospective, double-blind, randomized controlled trial was performed. Individuals who had sustained an undisplaced, extra-articular fracture of the distal radial metaphysis were recruited from a trauma clinic. Patients were randomized to receive simvastatin 20 mg once daily or a placebo. Regular clinical and radiological follow-up was undertaken for a 12 week period. Dual-energy X-ray absorptiometry assessment of bone mineral density was conducted at 2 and 12 weeks postinjury. Biochemical markers of bone turnover were assayed during the study period. Time to fracture union was defined as the time to cortical bridging in four cortices on plain radiographs. In addition, the rate of trabecular union was assessed. Eighty patients were recruited, of which 62 completed the study (31 in each group). Study cohorts were matched for age and gender. For patients receiving simvastatin therapy, the mean time to fracture union was 71.6 days (SD 22.2 days, SEM 3.8 days). This compared to 71.3 days (SD 21.3, SEM 4.1 days) for the control cohort (p = 0.6481). There was no significant difference between bone mineral density or bone biochemical markers between groups (p > 0.05). Despite promising results from in vivo and in vitro animal studies, simvastatin at a treatment dose of 20 mg once daily does not affect the rate of fracture healing in humans.