Decision Limit Research Articles

Computer simulation approaches to evaluate the interaction between analytical performance characteristics and clinical (mis)classification: a complementary tool for setting indirect outcome-based analytical performance specifications.

Simulation-based approaches for setting indirect outcome-based analytical performance specifications (APS) predominantly involve test repetition through analytical reruns or resampling. These methodologies assess the agreement between original and simulated measurement results, determining the APS corresponding to pre-established performance thresholds. For APS related to imprecision and bias, both analytical performance characteristics (APCs) aretypically considered in simulations, whereas for APS regarding measurement uncertainty, bias is excluded in alignment with traceability standards. This paper introduces the "APS Simulator," a novel tool designed to complement the existing APS Calculator by simulating APS under various scenarios involving imprecision, bias, and measurement uncertainty. The APS Simulator facilitates simulations usingdistinct analytical rerun and resampling models, enabling laboratory professionals to explore a wide range of performance levels for their specific needs. While the APS Simulator provides valuable insights, significant challenges remain in the broader application of indirect outcome-based APS. These include incorporating sources of diagnostic uncertainty, setting appropriate thresholds for performance metrics, validating clinical decision limits, and accounting for population data characteristics. Addressing these limitations will be essential to enhancing the standardization and robustness of APS determination. The source code and desktop application for the APS Simulator are freely available at https://github.com/hikmetc/APS_Simulator, providing a user-friendly platform for researchers and clinicians to further explore these methodologies.

Accurate urine sodium measurements at home using Point of Care Testing in patients with Short Bowel Syndrome.

Measurement of the urine sodium concentration (USC) is a simple procedure that in many patients adequately indicates their hydration status. This is of particular importance in patients suffering from short bowel syndrome (SBS), who may very rapidly dehydrate and are at risk for permanently compromising their kidney function. A point of care test (POCT) that allows reliable measurement of USC would enable these patients to effectively evaluate their sodium- and water balance in the at home setting, thereby avoiding hospital visits and delayed test results. In this study, a POCT device to assess USC was first analytically validated after which it was applied for the at home evaluation of the hydration status in patients with SBS. First, we validated the imprecision, bias and limit of quantification of USC as measured with the Fisic Medimate POCT device in comparison to an automated routine chemistry system. Next, the device was used for monitoring USC at home in 21 patients with SBS, including an evaluation of user friendliness System Usability Scale (SUS) and accuracy for detecting low sodium levels as compared to the routine chemistry system. The imprecision of the POCT device at low USC was 6.1 %. In samples at the clinical decision threshold to identify patients at the verge of dehydration of 20 mmol/l as measured by routine chemistry USC, the POCT device demonstrated a mean estimation of USC of 20.6 mmol/l (95% CI 18.8-22.4). Dehydration was detected with a sensitivity of 95% when the medical decision limit for urinary sodium on the POCT device was set at a safe concentration of 30 mmol/l. Using the device was straightforward and easy to learn for patients with an overall System Usability Scale (SUS) score of 86. USC measurements using this POCT device can be safely integrated into daily practice for early detection of dehydration in patients with SBS. Clear patient instructions to ensure accurate drop dispensing and a higher clinical decision threshold of USC of 30 mmol/l will allow a high sensitivity for detecting dehydration in patients with short bowel syndrome.

Method development and validation for the simultaneous determination of 21 antiviral drugs by ultra-high performance liquid chromatography-tandem mass spectrometry in chicken muscle and liver.

The recent unauthorization of antiviral drugs in food-producing animals according to Commission Delegated Regulation (EU) 2022/1644 have increased the need for food control laboratories to develop analytical methods and perform official controls. In this work, a simple and fast analytical methodology was developed for the simultaneous determination of 21 antiviral drugs in chicken muscle and liver by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Chromatographic separation was achieved by an HILIC BEH amide column; followed by detection with a electrospray ionization source in positive and negative modes. Based on extraction efficiencies, critical parameters affecting sample treatment were optimized including the evaporation and clean up steps to extract the largest number of antiviral drugs and reduce interferences. The method was validated according to Commission Implementing Regulation (EU) 2021/808 in chicken muscle and liver. Most compounds showed a linearity of R2>0.9800, while decision limits were between 0.18 and 7.05 μg kg-1 and 0.19 and 36 μg kg-1 for chicken muscle and liver, respectively. Trueness and within-lab reproducibility were determined at three levels (n = 7) and the results showed values ranging from 81 to 133 % and 4.2-57 % for chicken muscle, and 71-136 % and 4.6-106 % for chicken liver, respectively. The applicability of the developed method was demonstrated by the analysis real samples. 20 samples from the National Residue Control Plan in the Netherlands were analyzed and although none of targeted compounds were detected it is important to continue the analysis of larger set of samples to address any possible food safety risks.

Multiresidue Method for Quantification of Nitroimidazoles, Anthelmintics, Amphenicols, and Dyes in Meat, Shrimp, and Fish by Using a Modified QuEChERS-type Extraction and Isotope Dilution Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry

This paper presents an analytical multiresidue method for the quantification of 7 nitroimidazoles, 19 anthelmintics, 3 amphenicols, and 4 dyes in poultry, pork, beef, horse, shrimp, and fish samples by isotope dilution ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) in a single 6 min run. Samples were prepared using a modified quick, easy, cheap, effective, rugged and safe (QuEChERS)-type extraction with ethyl acetate and Na2SO4-NaCl (2:1), concentration into dimethyl sulfoxide (DMSO), and defatting by liquid-liquid extraction (LLE) with n-hexane. No clean-up using solid-phase extraction (SPE) cartridges or dispersive solid-phase extraction (DSPE) was necessary. The linearity ranges (in μg kg−1) were 0.10-0.60 for chloramphenicol, 0.50-3.0 for dyes, 1.5-9.0 for nitroimidazoles, and 5.0-30.0 for the other drugs. The limits of quantitation (LOQ) were established at the lowest calibration curve levels. Except for chloramphenicol in the horse matrix, analyte recovery and reproducibility were satisfactory (recovery (fREC): 75.0 to 116.6%; coefficient of variation (CV): 1.2 to 29.9%). For the unapproved substances and the substances with a maximum residue level (MRL), respectively, the decision limits (CCα) were 0.14-4.10 and 5.28-1003.60 μg kg−1, while the detection capabilities (CCβ) were 0.13-3.33 and 5.46-11.56 μg kg−1.

Synovial fluid dual-biomarker algorithm accurately differentiates osteoarthritis from inflammatory arthritis.

Osteoarthritis (OA) prevalence increases as the population ages. Diagnosing osteoarthritis often occurs in the late stages when cartilage degradation is severe, making it difficult to distinguish from other types of arthritis. Accurate differentiation of primary osteoarthritis from other arthritic conditions is crucial for effective treatment planning. A new diagnostic test has been developed that uses a dual-biomarker algorithm to inform osteoarthritis diagnosis. Synovial fluid from patients with confirmed primary osteoarthritis showed elevated levels of cartilage oligomeric matrix protein. However, this biomarker alone could not distinguish primary osteoarthritis from other inflammatory conditions that also cause cartilage deterioration. Therefore, a combinatorial algorithm using cartilage oligomeric matrix protein and Interleukin-8 concentrations was developed to differentiate primary osteoarthritis from inflammatory arthritis. Clinical decision limits for cartilage oligomeric matrix protein concentration and the cartilage oligomeric matrix protein to Interleukin-8 ratio were established and validated using 171 human knee synovial fluid specimens. The osteoarthritis algorithm demonstrated clinical sensitivity and specificity of 87.0% and 88.9%, respectively. This is the first report of a biomarker test that can differentiate primary osteoarthritis from inflammatory arthritis with a high degree of accuracy.

Determination of clostebol residues in the urine of slaughter animals using liquid chromatography-tandem mass spectrometry.

Synthetic anabolic hormones, which may pose a potential risk to human health, should not be used in fattening food-producing animals. Because of the hormonal effects they cause, growth-promoting compounds are banned by legislation in the EU for use in animal husbandry. Consequently, all EU member states are required to conduct monitoring tests on the content and residues of these compounds in prescribed biological matrices to ensure the safety of food consumers. The aim of this research was to develop a liquid chromatography-tandem mass spectrometry method for the detection of the residue of one such anabolic hormone, clostebol in food animal urine. Clostebol and its marker metabolite residues were determined by a method involving enzymatic hydrolysis, isolation of compounds from urine on a C18 solid-phase extraction (SPE) column, purification of the extract by liquid-liquid extraction using n-pentane and a NH2 SPE column, and detection by liquid chromatography-tandem mass spectrometry. No traces of this anabolic steroid hormone or its metabolites were found in any of the samples tested. The method was validated in accordance with the current requirements for confirmatory methods, and the determined parameters of the decision limits necessary for assessing sample compliance met the specified criteria. In 2023, the method was introduced for testing under the National Control Plan in Poland. Up to July 19, 2024, 53 urine samples from different animal species had been tested.

Development of a Low-Cost Reflectance Visible Spectrophotometer with Chemometrics for Curcuma xanthorrhiza Roxb. Quality Control

A simple, portable visible reflectance spectrophotometer was developed for classifying the quality of Curcuma xanthorrhiza Roxb. The device was assembled using consumer electronic components: an LED as the light source, a DVD optical layer as the diffraction grating, and a webcam as the detector, with web-based software (Spectral Workbench) as the signal processor. The spectrophotometer's performance was evaluated using standard Sudan III samples and powdered C. xanthorrhiza samples from two quality classes (A and B). Spectral data were analysed using principal component analysis (PCA) and partial least squares (PLS) regression. PCA successfully grouped Sudan III samples by concentration and classified C. xanthorrhiza by curcuminoid content. A PLS regression model was developed for quantifying Sudan III, yielding R² values of 0.9909 for both calibration and cross-validation, with RMSEs of 0.3821% and 0.4152%, respectively. The results closely matched those from a commercial spectrophotometer. A PLS-discriminant analysis (PLS-DA) classification model for C. xanthorrhiza was also developed, achieving sensitivity and specificity values of 1. Additionally, semi-quantitative parameters such as decision limit (26.15% B), detection capability (41.06% B), and unreliability range (26.15–41.06% B) were calculated. The classification model showed strong sensitivity, specificity, and detection capabilities within acceptable limits. These findings suggest that this low-cost reflectance spectrophotometer, combined with chemometric methods, holds promise as a practical tool for the quality control of raw herbal materials.

Reference TSH intervals in children and adolescents

The determination of thyroid-stimulating hormone (TSH) is a reliable test in the diagnosis of thyroid dysfunction. When interpreting the results of quantitative studies, clinicians and laboratory specialists most often resort to assessing the compliance of the result with reference intervals (RI). At the same time, each laboratory must determine them for the analytes being measured itself, based on the characteristics of the examined contingent, the characteristics of the analytical systems used, achieving the necessary diagnostic effectiveness of the methodology, and its own practical and economic capabilities. A retrospective analysis of TSH results obtained from patients under the age of 19 years was performed for 54970 patients without hypothyroidism, thyrotoxicosis and pituitary disorders. For this work, reagent kits “Roche Cobas”, “Mindray” and “Beckman Coulter” (ICLA) were used. As a result, RI was established for the study of TSH for three sets of reagents with appropriate equipment and for four age groups: 1 day – 6 months, 6 months – 7 years, 7–14 years, 14–19 years. This makes it possible to use RI as a screening for possible developmental pathology in childhood and to determine the limits of clinical decisions.

Interpretation of reference intervals and clinical decision limits

Reference intervals (RI) and clinical decision limits (CDL) are an important part of th e medical information needed to interpret the results of a laboratory tests. The emphasis is on the need to distinguish between the two concepts. RI allows to assess the compliance of the patient’s result with the values detected in a healthy population with a certain probability. CDL is associated with specific diseases and medical risks and may be more significant for clinical decision-making than RI. When interpreting RI and CDL, it is necessary to take into account the possibility of divergence of results on different analytical systems as a potential source of erroneous medical decisions.

Spatiotemporal gait characteristics post-total hip arthroplasty and its impact on locomotive syndrome: a before-after comparative study in hip osteoarthritis patients.

Understanding the gait pattern of patients eligible for total hip arthroplasty (THA) due to hip osteoarthritis (OA) offers valuable information for improving locomotive syndrome (LS). This study aims to measure the gait patterns of THA-eligible patients using an optical motion capture system and to analyze these patterns using principal component analysis (PCA). Additionally, this study examines the relationship between THA-induced gait patterns and LS. This before-after study included 237 patients who underwent unilateral primary THA due to hip OA. The primary outcome measures were spatiotemporal gait parameters. Secondary outcome measures included three LS risk tests: a stand-up test, a two-step test, a 25-question Geriatric Locomotive Function Scale (GLFS-25), and total clinical decision limits stages. PCA was performed using 16 spatiotemporal gait parameters collected before and three months after THA. Principal components (PC) were selected to achieve a cumulative contribution rate of 90% (0.9) or higher. Each summarized PC was compared using a paired t-test before and three months after THA. Furthermore, multiple regression analysis was conducted to determine how changes in each PC between before and three months after THA related to changes in the four LS evaluation items. PCA identified three principal components (PC1, PC2, PC3) that accounted for a cumulative contribution rate of 0.910 using 16 spatiotemporal gait parameters. When comparing before and three months after THA for all three PCs, significant differences were observed in each PC (p<0.001), with overall walking ability and stance phase being higher three months after THA than before THA, while the asymmetry of support time was lower three months after THA. The results of multiple regression analysis revealed that PC1, PC2, and PC3 were the most influential factors in total clinical decision limits stage. For each LS risk test, the factors related to the stand-up test were identified as PC1, PC2, and PC3, while the factors related to the two-step test were identified as PC1 and PC2. The factors related to the GLFS-25 were also identified as PC1 and PC2. The most important findings of this study indicate that the three PCs represent over 90% of the 16 spatiotemporal gait parameters, which are associated with total clinical decision limits stage and LS risk tests. The present results suggest that PC1 represents overall walking ability, PC2 represents the stance phase, and PC3 represents asymmetry of support time. Gait pattern characteristics, such as overall walking ability, stance phase, and asymmetry of support time, were clearly defined by these PCs. Regarding the relationship between PC and LS, all three PCs are related to total clinical decision limits stage. In addition, PC1 and PC2 related to all three LS risk tests, and PC3 related only to the stand-up test.

Defining Gestational Thyroid Dysfunction Through Modified Nonpregnancy Reference Intervals: An Individual Participant Meta-analysis.

Establishing local trimester-specific reference intervals for gestational TSH and free T4 (FT4) is often not feasible, necessitating alternative strategies. We aimed to systematically quantify the diagnostic performance of standardized modifications of center-specific nonpregnancy reference intervals as compared to trimester-specific reference intervals. We included prospective cohorts participating in the Consortium on Thyroid and Pregnancy. After relevant exclusions, reference intervals were calculated per cohort in thyroperoxidase antibody-negative women. Modifications to the nonpregnancy reference intervals included an absolute modification (per .1 mU/L TSH or 1 pmol/L free T4), relative modification (in steps of 5%) and fixed limits (upper TSH limit between 3.0 and 4.5 mU/L and lower FT4 limit 5-15 pmol/L). We compared (sub)clinical hypothyroidism prevalence, sensitivity, and positive predictive value (PPV) of these methodologies with population-based trimester-specific reference intervals. The final study population comprised 52 496 participants in 18 cohorts. Optimal modifications of standard reference intervals to diagnose gestational overt hypothyroidism were -5% for the upper limit of TSH and +5% for the lower limit of FT4 (sensitivity, .70, CI, 0.47-0.86; PPV, 0.64, CI, 0.54-0.74). For subclinical hypothyroidism, these were -20% for the upper limit of TSH and -15% for the lower limit of FT4 (sensitivity, 0.91; CI, 0.67-0.98; PPV, 0.71, CI, 0.58-0.80). Absolute and fixed modifications yielded similar results. CIs were wide, limiting generalizability. We could not identify modifications of nonpregnancy TSH and FT4 reference intervals that would enable centers to adequately approximate trimester-specific reference intervals. Future efforts should be turned toward studying the meaningfulness of trimester-specific reference intervals and risk-based decision limits.

Towards high throughput analysis using 96-well plate solid phase extraction to determine sedatives and β-blocker residues in food control monitoring

BackgroundVeterinary drugs are widely used in animal production to prevent infections and treat diseases but, this may cause a risk to consumers. Due to the high number of food samples required to monitor yearly, simple, fast, sensitive and selective analytical methods are needed in control laboratories to ensure consumers safety. Nevertheless, many analytical methodologies available in these laboratories include multiple steps and therefore are time-consuming and hinder the analysis throughput requiring significant amounts of solvents and reagents. ResultsThis work developed a 96-well plate solid phase extraction (SPE) method for the extraction of seven sedatives and a β-blocker in animal kidney by ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC−MS/MS). The developed method was validated based on Implementing Regulation (EU) 2021/808 in kidney, meat and fish. The performance characteristics of the validation (1–5 μg kg−1) showed good linearity (R2 > 0.998) while decision limits (CCα) were between 1 and 1.2 μg kg−1. Trueness and precision were determined at three levels (n = 7) and the results showed values ranging from 85 to 103 % and from 1 to 9 %, respectively. The feasibility of the method was demonstrated for the residue control requirement established by EU. Method was applied to 201 samples of kidney, meat and fish. SignificanceThis study is the first to present an optimized and validated holistic method for sedatives and β-blocker using 96-well plate SPE and UHPLC−MS/MS. The method showed good performance in kidney, meat and fish samples being an universal method for any species along the same type of sample. The fast, easy, efficient, reliable and universal method showed high throughput and so reduced the analysis time by nine-fold and the required solvent amount by four times fulfilling the green chemistry principals.

Inconsistency in ferritin reference intervals across laboratories: a major concern for clinical decision making.

Iron deficiency anemia is a significant global health concern, diagnosed by measuring hemoglobin concentrations in combination with plasma ferritin concentration. This study investigated the variability in ferritin reference intervals among laboratories in the Netherlands and examined how this affects the identification of iron-related disorders. Ferritin reference intervals from 52 Dutch ISO15189-certified medical laboratories were collected. Ferritin, hemoglobin and mean corpuscular volume data of non-anemic apparently healthy primary care patients, measured by four laboratory platforms (Beckman, Abbott, Siemens, and Roche), were collected (n=397,548). Median ferritin levels were determined per platform, stratified by sex and age. The proportion of ferritin measurements outside of the reference interval was calculated using the reference intervals from the 52 laboratories (using a total of n=1,093,442 ferritin measurements). Lastly, ferritin data from 3,699 patients as captured in general practitioner (GP) data from the PHARMO Data Network were used to assess the variation of abnormal ferritin measurements per GP. Median plasma ferritin concentrations were approximately four times higher in men and twice as high in postmenopausal women compared to premenopausal women. Moreover, there are substantial differences in the median plasma ferritin concentration between the four platforms. However, even among laboratories using the same platform, ferritin reference intervals differ widely. This leads to significant differences in the percentages of measurements classified as abnormal, with the percentage of ferritin measurements below the reference limit in premenopausal women ranging from 11 to 53 %, in postmenopausal women from 3 to 37 %, and in men from 2 to 19 %. The percentage of ferritin measurements above the reference limit in premenopausal women ranged from 0.2 to 11 %, in postmenopausal women from 3 to 36 % and in men from 7 to 32 %. The lack of harmonization in ferritin measurement and the disagreement in plasma ferritin reference intervals significantly impact the interpretation of the iron status of patients and thereby the number of iron disorder diagnoses made. Standardization or harmonization of the ferritin assays and establishing uniform reference intervals and medical decision limits are essential to reduce the substantial variability in clinical interpretations of ferritin results.

Clinical implications of opioid parent-metabolite ratios

BackgroundThe opioid epidemic has underscored the importance of urine drug testing in the management of chronic pain. However, interpreting test results can be challenging, especially in scenarios where medications may have been directly added to urine samples to simulate compliance. MethodsWe conducted a retrospective analysis of 9,690 opioid testing results using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The study aimed to define the expected ratios between parent drugs and metabolites for eight commonly prescribed opioids. Cases with a parent-metabolite ratio above the 95th percentile were subjected to chart review. ResultsA total of 13 cases appeared likely consistent with simulated compliance with buprenorphine, 2 with methadone, 14 with oxycodone, and one with hydrocodone. The unusual patterns of parent-metabolite ratio can also be associated with hyperacute drug exposures/use, pharmaceutical impurity, or underlying liver enzyme deficiency. Furthermore, patients who failed the decision limits could exhibit other illicit use or aberrant behaviors. ConclusionLaboratories conducting LC-MS/MS-based opioid testing can more objectively identify anomalies by analyzing parent-metabolite ratios. When in consultation with providers, laboratories can point to these data when suggesting the possibility of simulated compliance and help identify cases warranting further investigation.

Derivation of Russian-specific reference intervals for complete blood count, iron markers and related vitamins.

This study aimed to establish reference intervals (RIs) for Russian adults for hematological parameters including related iron markers and vitamins. Sources of variation of reference values (RVs) and needs for secondary exclusion were explored for proper derivations of RIs. Following the harmonized protocol of the IFCC Committee on Reference Intervals and Decision Limits (C-RIDL), 506 healthy Russians (age 18-80; 46% male) were recruited. Complete blood counts (CBC) and leukocyte differentials, iron markers, vitamin B12, and folate were measured by Beckman Coulter's analyzers. Sources of variation were analyzed by multiple regression analysis, and ANOVAs, and the need for partitioning RVs was decided accordingly. Two schemes of excluding latent anemia were compared: (1) latent abnormal values exclusion method (LAVE) based on associations among CBC parameters, or (2) explicit exclusion of individuals with either ferritin or iron below the respective lower limit of the manufacturer. RIs were determined by the parametric method using two-parameter Box-Cox formula. Gender-specific RIs were required for most analytes, while age-specific RIs were set only for ferritin in females. A BMI-related increase in RVs was prominently observed for reticulocyte parameters, hence we chose to exclude individuals with BMI>28 kg/m2 when establishing the RIs. The LAVE method was more effective in excluding individuals with latent anemia, than exclusion based on low ferritin and/or iron values. International comparison revealed that Russian RIs featured a lower side shift of platelet counts. Similar to African countries, Russian RIs for total leukocyte and neutrophil counts were lower compared to most of other countries. RIs for the Russian population for 34 hematological and related parameters were established using up-to-date methods proposed by C-RIDL. Reducing the influences of latent anemia and obesity on RIs was crucial for erythrocyte parameters. Low levels of Russian RIs observed for platelet and neutrophil counts need further investigation.

Diagnosis Based on Population Data versus Personalized Data: The Evolving Paradigm in Laboratory Medicine.

The diagnosis of diseases is a complex process involving the integration of multiple parameters obtained from various sources, including laboratory findings. The interpretation of laboratory data is inherently comparative, necessitating reliable references for accurate assessment. Different types of references, such as reference intervals, decision limits, action limits, and reference change values, are essential tools in the interpretation of laboratory data. Although these references are used to interpret individual laboratory data, they are typically derived from population data, which raises concerns about their reliability and consequently the accuracy of interpretation of individuals' laboratory data. The accuracy of diagnosis is critical to all subsequent steps in medical practice, making the estimate of reliable references a priority. For more precise interpretation, references should ideally be derived from an individual's own data rather than from population averages. This manuscript summarizes the current sources of references used in laboratory data interpretation, examines the references themselves, and discusses the transition from population-based laboratory medicine to personalized laboratory medicine.

Zilpaterol in bovine liver, meat, heart, and kidney, determined by liquid chromatography–quadrupole-orbitrap high-resolution mass spectrometry

ABSTRACT An analytical method was developed for identification and quantification of zilpaterol in bovine liver, meat, heart, and kidney, using liquid chromatography coupled to quadrupole-Orbitrap high-resolution mass spectrometry (LC-Q-Orbitrap HRMS). It was validated in accordance with Commission Implementing Regulation (CIR) EU 2021/808 at six different concentrations, ranging from 0.1 to 5 μg/kg. The mean recoveries ranged from 71% to 99%, while the decision limit (CCα) and detection capability (CCβ) ranges were 0.11–0.12 μg/kg and 0.13–0.15 μg/kg, respectively. The method demonstrated good linearity (R2 > 0.9996) and the limits of detection (LODs) and of quantification (LOQs) were in the range of 0.015–0.061 μg/kg and 0.025–0.091 μg/kg, respectively. Out of 200 samples collected from local markets in Egypt, 17 contained zilpaterol residues. Liver samples revealed the highest detection frequency (26%), followed by meat (6%), at mean concentrations of 2.64 and 1.93 μg/kg, respectively.

Clinical Decision-Making Suffers from Inequivalent Measurement Results and Inadequate Reference Intervals.

Appropriate clinical decision-making relies on the interpretation of equivalent measurement results in the context of valid clinical decision limits. Besides guideline-based decision limits, reference intervals (RIs) are commonly used to discriminate between abnormal results and results from "healthy" individuals. This study evaluated the suitability of RIs in light of the analytical bias for laboratories in the Netherlands using one standardized, one harmonized, and one unharmonized measurand (creatinine, hemoglobin, and ferritin, respectively). Three types of data were collected: (a) external quality assessment (EQA) performance data from the Dutch Foundation for Quality Assurance in Laboratory Medicine (SKML); (b) the RIs reported by laboratories for a 55-year-old female; and (c) harmonized RIs established by using unique routine patient results using RefineR. Routinely used RIs (b) were compared to the harmonized RIs (c) and evaluated in combination with the analytical bias at the lower and upper reference limits. Laboratories reported a variety of routinely used RIs that were inconsistent with the analytical bias, with differences between measurement procedures. The use of assays that perform within allowable bias limits does not automatically guarantee that the appropriate RI is used, allowing potential for structural misinterpretation of important diagnoses in patients. The use of RIs that are inconsistent with the analytical bias causes unnecessary between-laboratory differences in clinical decision-making. Adopting harmonized RIs facilitates similar interpretation of results across facilities. Harmonized RIs can be adopted immediately if the observed bias is acceptable or eliminated, or after standardization/harmonization of measurands without complete metrological traceability.

Laboratory Aspects of Using the Results of NT-Probnp Concentration Immunochemical Determination in the Management of Patients With Heart Failure: Support For Clinical Decision-Making

The burden of heart failure (HF) has been increasing worldwide in recent decades. Early diagnosis of HF based on the outpatient measurement of natriuretic peptide (NP) concentration will allow timely initiation of the treatment and reducing the incidence of adverse outcomes in HF. Unfortunately, the frequency of NP testing remains low worldwide. At the online expert meeting held on March 15, 2024, the features of the N-terminal pro-brain natriuretic peptide (NT-proBNP) test (Elecsys proBNP by Roche) were discussed along with the interpretation of test results and presentation of results in laboratory reports. The experts addressed the features of the Elecsys proBNP test in patients with suspected HF in various clinical scenarios (chronic and acute HF). The limits of clinical decision for the NT-proBNP test were established depending on the clinical scenario. Changes in the Elecsys proBNP test results depending on the comorbidities were addressed. The experts suggested ways to optimize the format of the Elecsys proBNP test result reports in the Russian Federation, which will accelerate the implementation of the test in clinical practice and optimize the management of HF patients.

Diagnostic Performance of Serum Erythropoietin to Discriminate Polycythemia Vera from Secondary Erythrocytosis through Established Subnormal Limits.

Serum erythropoietin (sEPO) is an initial screening tool for distinguishing polycythemia vera (PV) from secondary erythrocytosis (SE), but defining 'subnormal' sEPO levels for PV diagnosis remains contentious, complicating its clinical utility. This study compares the diagnostic performance of sEPO across established subnormal limits, including reference interval (RI), clinical decision limit (CDL), and functional reference limit. sEPO levels were analyzed in 393 healthy donors (HDs) and 90 patients (41 PV and 49 SE), who underwent bone marrow biopsy and genetic tests due to erythrocytosis. The RI (2.5-97.5 percentile from HDs) of sEPO was 5.3-26.3 IU/L. A CDL of 3.1 IU/L, determined by ROC analysis in erythrocytosis patients, had a sensitivity of 80.5% and specificity of 87.8% for diagnosing PV. A functional reference limit of 7.0 IU/L, estimated based on the relationship between sEPO and hemoglobin, hematocrit, and WBC, increased sensitivity to 97.6% but decreased specificity to 46.7%. Using 5.3 IU/L as a 'subnormal' limit identified all three JAK2-negative PV cases, increasing the sensitivity and negative predictive value to 97.6% and 97.0%, respectively. Combining the RI, CDL, and functional reference limit may improve PV diagnostic accuracy.