Analytical performance specifications for combined uncertainty budget in the implementation of metrological traceability.

In addition to the correct implementation of calibration traceability, the definition and fulfillment of maximum allowable measurement uncertainty (MAU) are essential in assuring that laboratory measurements are clinically usable. Across the entire calibration hierarchy, three major contributors to the measurement uncertainty (MU) budget are identified, starting with the higher-order reference providers, extending through the in vitro diagnostic (IVD) manufacturers and their processes for assigning calibrator values, and ending with medical laboratories generating the random variability of results reported to clinicians. To understand if it is possible to achieve MAU and, consequently, to fix the possible drawbacks, the definition of combined MU budget limits across the entire calibration hierarchy has a central role. In particular, quality specifications for MU of reference and commercial calibrator materials should be defined according to the MAU on clinical samples. All involved stakeholders (i.e., higher-order reference providers, IVD manufacturers, medical laboratories) should be prepared to improve their performance whenever the clinical application of the test is made questionable by the failure to achieve MAU.

Recommendations for Setting a Criterion and Assessing Commutability of Sample Materials Used in External Quality Assessment/Proficiency Testing Schemes.

It is important for external quality assessment materials (EQAMs) to be commutable with clinical samples; i.e., they should behave like clinical samples when measured using end-user clinical laboratory in vitro diagnostic medical devices (IVD-MDs). Using commutable EQAMs makes it possible to evaluate metrological traceability and/or equivalence of results between IVD-MDs. The criterion for assessing commutability of an EQAM between 2 IVD-MDs is that its result should be within the prediction interval limits based on the statistical distribution of the clinical sample results from the 2 IVD-MDs being compared. The width of the prediction interval is, among other things, dependent on the analytical performance characteristics of the IVD-MDs. A presupposition for using this criterion is that the differences in nonselectivity between the 2 IVD-MDs being compared are acceptable. An acceptable difference in nonselectivity should be small relative to the analytical performance specifications used in the external quality assessment scheme. The acceptable difference in nonselectivity is used to modify the prediction interval criterion for commutability assessment. The present report provides recommendations on how to establish a criterion for acceptable commutability for EQAMS, establish the difference in nonselectivity that can be accepted between IVD-MDs, and perform a commutability assessment. The report also contains examples for performing a commutability assessment of EQAMs.

Procalcitonin: Between evidence and critical issues.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated response of the host to infection. It represents one of the major health care problems worldwide. Unfortunately, the diagnosis of sepsis is challenging for many reasons, including a lack of a sufficiently sensitive and specific diagnostic test. When procalcitonin (PCT) was discovered, it was thought that it could become the best test for identifying patients with sepsis. From the evidence sources in the available literature, it is now clear that the power of PCT in differentiating infectious from non-infectious forms of systemic inflammatory response syndrome in adults, and in stratifying morbidity and mortality risk, is limited. Nevertheless, PCT determination can be a useful tool for diagnosing late-onset neonatal sepsis, bacterial meningitis and other forms of organ-related bacterial infections and, above all, it can be used for guiding antibiotic stewardship in critical patients. The real impact of this application of PCT testing, however, still needs to be clearly defined. Laboratories should offer unrestricted PCT testing only to intensive care units (as an aid in decision for continuing or stopping antibiotics) and pediatric wards. For all other clinical wards, the laboratory should guide PCT requests and give them support towards the most appropriate approach to testing.

[An alternative proposal for managing morphological examination of urinary sediment and increasing its appropriateness].

BACKGROUND: The morphological examination of urinary sediment (MEUS) is traditionally associated with urinalysis (UA), with workload implications and the need for automation of its execution. METHODS: Considering MEUS as a test requiring specialized knowhow and skill for its execution, since 2005 in our laboratory it is performed for inpatients only upon specific request. Eleven years after, we have analyzed the long-term impact of this approach on the provided service. We evaluated results in the 2009-2016 period, in which our hospital did not undergo any change both in the number of beds and in the clinical case-mix. RESULTS: From 2009 to 2013 an average of 2264 MEUS and 10,204 UA per year were ordered, respectively, with an average ratio of 22.2%. Since 2014, a change on computerized order entry involving MEUS caused a further decrease of its requests (in average, 923 per year), which was not associated to a decrease in UA (in average, 9810 per year) (in average, MEUS/UA 9.4%). MEUS requests came mainly from Paediatrics (47.8%), Nephrology (20.9%) and Rheumatology (18.3%) wards. By filling a satisfaction survey, clinical wards evaluated the provided service as satisfactory, while highlighting some critical issues, mainly referred to preanalytical phase. CONCLUSIONS: The alternative proposal for managing MEUS presented in this paper markedly reduces the number of requests and increases their appropriateness. This is achieved without any negative impact on patient care.

Defining permissible limits for the combined uncertainty budget in the implementation of metrological traceability.

In addition to the correct implementation of calibration traceability, the definition and the achievement of an appropriate analytical performance specification for the total uncertainty budget (GU) is essential to ensure that laboratory measurements are clinically usable. To understand if it is possible to fulfil these specifications, limits for combined uncertainty across the entire metrological traceability chain should be defined. We recommended that no more than one third of GU should be consumed by the uncertainty of higher order references and ≤50% of GU by the combined measurement uncertainty at the manufacturer's calibration level. The remaining allowable uncertainty should be available for random sources, i.e. for the imprecision of the commercial measuring system (including the reagent batch-to-batch variation) and the individual laboratory performance, as a safety margin to fulfil GU. Based on this approach, it is of interest to assess for each analyte measured in the clinical laboratory the status of the uncertainty budget of its measurement associated with the selected metrological traceability chain. Accordingly, we report three didactic cases that could occur in the clinical practice. This approach is very helpful to identify those analytes for which further technological improvements are probably needed to reduce uncertainty associated with their measurement.

The role of external quality assessment in the verification of in vitro medical diagnostics in the traceability era.

Once an in-vitro diagnostic (IVD) measuring system has been marketed and introduced into daily practice, the possible sources of degradation of its performance are numerous. It is therefore essential to put in place a continuous post-market surveillance of the quality of performance of the IVD system and of the laboratories that perform measurements in clinical setting. The participation to external quality assessment (EQA) schemes that meet specific metrological criteria is central to the evaluation of performance of clinical laboratories in terms of standardization and clinical suitability of their measurements. In addition to the use of commutable materials, in this type of EQA it is necessary to assign values (and uncertainty) to them with reference procedures and to define and apply clinically permissible analytical performance specifications to substantiate the suitability of laboratory measurements in the clinical setting. Unfortunately, there are still few permanent EQA programs fully covering these requirements because some practical constraints, including technical and economic aspects, which limit their introduction. It is, however, clear that these issues should be quickly overcome, since EQA schemes are in a unique position to add substantial value to the practice of laboratory medicine, by identifying analytes that need improved harmonization and by stimulating and sustaining standardization initiatives that are needed to support clinical practice. Importantly, this will definitively help those manufacturers that produce superior products to demonstrate the superiority of those products and oblige end users (and consequently industry) to abandon assays with demonstrated insufficient quality.

Analytical performance specifications for external quality assessment - definitions and descriptions.

External Quality Assurance (EQA) is vital to ensure acceptable analytical quality in medical laboratories. A key component of an EQA scheme is an analytical performance specification (APS) for each measurand that a laboratory can use to assess the extent of deviation of the obtained results from the target value. A consensus conference held in Milan in 2014 has proposed three models to set APS and these can be applied to setting APS for EQA. A goal arising from this conference is the harmonisation of EQA APS between different schemes to deliver consistent quality messages to laboratories irrespective of location and the choice of EQA provider. At this time there are wide differences in the APS used in different EQA schemes for the same measurands. Contributing factors to this variation are that the APS in different schemes are established using different criteria, applied to different types of data (e.g. single data points, multiple data points), used for different goals (e.g. improvement of analytical quality; licensing), and with the aim of eliciting different responses from participants. This paper provides recommendations from the European Federation of Laboratory Medicine (EFLM) Task and Finish Group on Performance Specifications for External Quality Assurance Schemes (TFG-APSEQA) and on clear terminology for EQA APS. The recommended terminology covers six elements required to understand APS: 1) a statement on the EQA material matrix and its commutability; 2) the method used to assign the target value; 3) the data set to which APS are applied; 4) the applicable analytical property being assessed (i.e. total error, bias, imprecision, uncertainty); 5) the rationale for the selection of the APS; and 6) the type of the Milan model(s) used to set the APS. The terminology is required for EQA participants and other interested parties to understand the meaning of meeting or not meeting APS.

The role of laboratory in ensuring appropriate test requests.

This review highlights the role of laboratory professionals and the strategies to be promoted in strict cooperation with clinicians for auditing, monitoring and improving the appropriateness of test request. The introduction of local pathways and care maps in agreement with international and national guidelines as well as the implementation of reflex testing and algorithms have a central role in guiding test request and in correcting the overuse/misuse of tests. Furthermore, removing obsolete tests from laboratory menu and vetting of restricted tests is recommended to increase cost-effectiveness. This saves costs and permits to introduce new biomarkers with increased diagnostic accuracy with a better impact on patient outcome. An additional issue is concerning the periodicity of (re)testing, accounting that only a minority of tests may be ordered as often as necessary. In the majority of cases, a minimum retesting interval should be introduced. The availability of effective computerised order entry systems is relevant in ensuring appropriate test requests and in providing an aid by automated rules that may stop inappropriate requests before they reach the laboratory.

Tackling serum folate test in European countries within the health technology assessment paradigm: request appropriateness, assays and health outcomes.

Several authors have recently claimed an excess in serum folate test ordering, suggesting phasing out it from clinical use. According to studies performed in countries undergoing folic acid fortification policies, it is indeed no more cost-effective to test folate in the face of deficiency prevalence <1%. In this paper, we sought to evaluate request appropriateness, analytical issues, and cost-effectiveness of serum folate determination for clinical purposes in the European context, considering if evidence retrieved in fortified countries may be generalized. Studies performed in non-fortified countries have generally reported a suboptimal folate intake and suggest a remarkable prevalence of folate deficiency. Our internal data suggest that ~20%-25% of the subjects undergoing serum folate test are at risk for deficiency. However, a reliable evaluation of the risk for deficiency implies the knowledge of all issues related to the total testing process of folate measurement as well as the identification of the appropriate population in which to perform the test. The cost-effectiveness of the test is maximized when the request is oriented to subjects suggestive/at risk for deficiency, becoming low if the test is used as a screening tool or for monitoring of vitamin intake/supplementation. Because the individual folate status has a key role in ensuring normal development, physiologic growth, and maintenance of optimal health, the evaluation of its serum levels has to be retained in the clinical use in non-fortified countries, boosting for more appropriate request, and evidence from countries following fortification policies should be cautionary interpreted.

Performance criteria for combined uncertainty budget in the implementation of metrological traceability.

The measurement uncertainty budget should combine the uncertainty of higher order references, the uncertainty of commercial system calibration, the system imprecision and individual laboratory performance in terms of variability. Here we recommend that no more than one third of the total uncertainty budget, established by appropriate analytical performance specifications, is consumed by the uncertainty of references and approximately 50% of the total budget consumed by the manufacturer's calibration and value transfer protocol. The remaining 50% should be available for the commercial system imprecision (including the batch to batch variation of the reagents) and individual laboratory performance in order to fulfil the uncertainty goal. For commercial systems to work properly, in vitro diagnostics (IVD) manufacturers will need to take more responsibility and ensure the traceability of the combination of platform, reagents, calibrators and control materials for system alignment verification that only as such (as a whole) are certified ("CE marked") by the manufacturer itself in terms of traceability to the selected reference measurement system. Particularly, IVD manufacturers should report the combined (expanded) uncertainty associated with their calibrators when used in conjunction with other components of their analytical system (platform and reagents). This is more than what they are currently providing as traceability and uncertainty information.

Harmonization of automated hemolysis index assessment and use: Is it possible?

The major source of errors producing unreliable laboratory test results is the pre-analytical phase with hemolysis accounting for approximately half of them and being the leading cause of unsuitable blood specimens. Hemolysis may produce interference in many laboratory tests by a variety of biological and analytical mechanisms. Consequently, laboratories need to systematically detect and reliably quantify hemolysis in every collected sample by means of objective and consistent technical tools that assess sample integrity. This is currently done by automated estimation of hemolysis index (HI), available on almost all clinical chemistry platforms, making the hemolysis detection reliable and reportable patient test results more accurate. Despite these advantages, a degree of variability still affects the HI estimate and more efforts should be placed on harmonization of this index. The harmonization of HI results from different analytical systems should be the immediate goal, but the scope of harmonization should go beyond analytical steps to include other aspects, such as HI decision thresholds, criteria for result interpretation and application in clinical practice as well as report formats. With regard to this, relevant issues to overcome remain the objective definition of a maximum allowable bias for hemolysis interference based on the clinical application of the measurements and the management of unsuitable samples. Particularly, for the latter a recommended harmonized approach is required when not reporting numerical results of unsuitable samples with significantly increased HI and replacing the test result with a specific comment highlighting hemolysis of the sample.

Tracing a roadmap for vitamin B12 testing using the health technology assessment approach.

In our hospital, we are currently working to manage the appropriateness of vitamin B12 (B12) testing. Unfortunately, the classic evidence-based approach is unhelpful in this process and meta-analyzing data on the accuracy of this marker for cobalamin deficiency detection is misleading due to the lack of reference diagnostic methods. The approach currently proposed by the Health Technology Assessment (HTA) enables us to tackle the issue of B12 requests as a "healthcare" problem by considering the position of stakeholders involved in ordering, performing, interpreting the test, and receiving its results. Clinical expectations, methodological issues, and ethical aspects concerning the performance of the test can aid us in providing more guidance on the use of this marker. By building such structured information, hemodialysis patients and pregnant women have emerged as those groups preferentially requiring B12 testing, as it may potentially improve the clinical outcome. To avoid misinterpretation of B12 results more care should be taken in considering its biochemical and biological features, as well as the analytical issues. Spurious values obtained by current automated immunoassays may reflect suboptimal pre-analytical steps as well as known interfering conditions. Furthermore, the harmonization of results by available methods is still a far-reaching goal and the approach to interpret an individual's results should be improved. Tracing a roadmap for B12 testing by exploiting the HTA model to balance the stakeholders' claims and maximizing the patient's outcome may help to manage the marker demand.

Target organ damage in a population at intermediate cardiovascular risk, with adjunctive major risk factors: CArdiovascular PREvention Sacco Study (CAPRESS).

The objective of the study is to assess the prevalence of target organ damage (TOD) at carotid, cardiac, renal and peripheral vascular levels in a population at intermediate cardiovascular risk, with adjunctive major risk factors (AMRF). From March 2007 to July 2009 we examined 979 subjects at intermediate cardiovascular risk, as indicated by the Italian algorithm "Progetto Cuore"; the patients were aged 40-69 years, sensitized by one or more AMRF such as family history for cardiovascular disease (CVD), being overweight or obese, and smoking habit (more than 10 cigarettes/day). We measured common carotid intima-media thickness (cc-IMT) and plaque at any level, left ventricular mass index (LVMI), urine albumin/creatinine ratio (UACR), and ankle-brachial index (ABI). The prevalence of at least one TOD was 63% (617 subjects), cc-IMT was high in 48.2% (472), UACR abnormal in 14.1% (138), LVMI high in 12.6% (117) and ABI pathological in 9.1% (89). In those with carotid damage 423 had a plaque, amounting to 43.2% of the total population. Of note, carotid damage was present in all subjects with 3 TODs, and in 92% of subjects with 2 TODs. A multivariate logistic regression model including conventional factors and AMRF indicated that age 50-69 years, systolic blood pressure, relevant smoking and CV risk score ≥15 were independently and significantly associated with at least one TOD, and at least, with carotid damage. Among the AMRF, peripheral arterial disease was associated with relevant smoking, with an odds ratio (OR) of 3 [confidence interval (CI) 1.80-4.97, p < 0.0001]; overweight and obesity both had selective associations with cardiac damage with OR 2.75 (CI 1.2-6.3, p < 0.01) and OR 3.89 (CI 1.61-9.73, p < 0.01). A substantial proportion of people at intermediate risk, with at least one AMRF have at least one TOD, a major predictor of cardiovascular outcomes.

Cardiac: is this biomarker ready for the prime time?

Today, the increase of the blood concentration of cardiac troponins is designated as surrogate for cardiac necrosis and myocardial infarction, when an appropriate clinical and/or instrumental situation is present. As cardiac troponins reflect myocyte death, biomarkers of reversible myocardial damage in the absence of necrosis are, however, still needed to detect the presence of damage even before the irreversible injury is induced and identify "vulnerable" patients before major events occur, permitting adequate treatment. Markers of plaque destabilization and/or markers of myocardial ischemia could be enormously valuable in the emergency department setting if shown to contribute additional independent diagnostic information. However, a new cardiac biomarker is of definitive clinical value only if adequate assays for its measurement are available, its predictive value is defined in the right clinical context, optimal cut-off and release kinetics are known, demonstration of the marker incremental value is clear, there is consistency of marker performance across different settings, and, more importantly, there are data on the effect on patient management and outcome and on cost-effectiveness. Despite the emergence of multiple candidates, sufficient evidence for any of these has yet been demonstrated to recommend their adoption into clinical practice.

Reference intervals for serum creatinine concentrations: assessment of available data for global application.

BACKGROUND: Reference intervals for serum creatinine remain relevant despite the current emphasis on the use of the estimated glomerular filtration rate for assessing renal function. Many studies on creatinine reference values have been published in the last 20 years. Using criteria derived from published IFCC documents, we sought to identify universally applicable reference intervals for creatinine via a systematic review of the literature. METHODS: Studies were selected for inclusion in the systematic review only if the following criteria were met: (a) reference individuals were selected using an "a priori" selection scheme, (b) preanalytical conditions were adequately described; (c) traceability of the produced results to the isotope dilution-mass spectrometry (IDMS) reference method was demonstrated experimentally, and (d) the collected data received adequate statistical treatment. RESULTS: Of 37 reports dealing specifically with serum creatinine reference values, only 1 report with pediatric data and 5 reports with adult data met these criteria. The primary reason for exclusion of most papers was an inadequate demonstration of measurement traceability. Based on the data of the selected studies, we have collated recommended reference intervals for white adults and children. CONCLUSION: Laboratories using methods producing traceable results to IDMS can apply the selected reference intervals for serum creatinine in evaluating white individuals.