APS calculator: a data-driven tool for setting outcome-based analytical performance specifications for measurement uncertainty using specific clinical requirements and population data.

OBJECTIVES: According to ISO 15189:2022, analytical performance specifications (APS) should relate to intended clinical use and impact on patient care. Therefore, we aimed to develop a web application for laboratory professionals to calculate APS based on a simulation of the impact of measurement uncertainty (MU) on the outcome using the chosen decision limits, agreement thresholds, and data of the population of interest. METHODS: We developed the "APS Calculator" allowing users to upload and select data of concern, specify decision limits and agreement thresholds, and conduct simulations to determine APS for MU. The simulation involved categorizing original measurand concentrations, generating measured (simulated) results by introducing different degrees of MU, and recategorizing measured concentrations based on clinical decision limits and acceptable clinical misclassification rates. The agreements between original and simulated result categories were assessed, and values that met or exceeded user-specified agreement thresholds that set goals for the between-category agreement were considered acceptable. The application generates contour plots of agreement rates and corresponding MU values. We tested the application using National Health and Nutrition Examination Survey data, with decision limits from relevant guidelines. RESULTS: We determined APS for MU of six measurands (blood total hemoglobin, plasma fasting glucose, serum total and high-density lipoprotein cholesterol, triglycerides, and total folate) to demonstrate the potential of the application to generate APS. CONCLUSIONS: The developed data-driven web application offers a flexible tool for laboratory professionals to calculate APS for MU using their chosen decision limits and agreement thresholds, and the data of the population of interest.

Serum Calcium, Magnesium, and Phosphorus Levels in Patients with COVID-19: Relationships with Poor Outcome and Mortality.

In this retrospective study to assess the impact of serum corrected calcium (CorrCa), magnesium (Mg) and phosphorus (P) levels, all adult patients with laboratory-confirmed COVID-19 hospitalized during 2020 were included. Poor outcome was considered in patients who presented need for mechanical ventilation, intensive care unit (ICU) admission, or in-hospital mortality. We analyzed 2473 patients (956 females) aged (mean±SD) 63.4±15.9 years. During admission, 169 patients (6.8%) required mechanical ventilation, 205 (8.3%) were admitted to the ICU, and 270 (10.9%) died. Composite variable of poor outcome, defined as need for mechanical ventilation, ICU admission or death, was present in 434 (17.5%) patients. In univariate analysis, the need for mechanical ventilation was positively related to Mg levels (OR 8.37, 95% CI 3.62-19.33; p<0.001); ICU admission was related to CorrCa (OR 0.49, 95% CI 0.25-0.99; p=0.049) and Mg levels (OR 5.81, 95% CI 2.74-12.35; p<0.001); and in-hospital mortality was related to CorrCa (OR 1.73, 95% CI 1.14-2.64; p=0.011). The composite variable of poor outcome was only related to Mg (OR 2.68, 95% CI 1.54-4.68; p=0.001). However, in multivariate analysis only CorrCa was significantly related to the need for mechanical ventilation (OR 0.19, 95% CI 0.05-0.72; p=0.014) and ICU admission (OR 0.25; 95% CI 0.09-0.66; p=0.005), but not with in-hospital mortality or the composite variable. In conclusion, CorrCa can be used as a simple and reliable marker of poor outcome in patients with COVID-19, although not to predict the risk of in-hospital mortality.

ISO 15189 is a sufficient instrument to guarantee high-quality manufacture of laboratory developed tests for in-house-use conform requirements of the European In-Vitro-Diagnostics Regulation.

The EU In-Vitro Diagnostic Device Regulation (IVDR) aims for transparent risk-and purpose-based validation of diagnostic devices, traceability of results to uniquely identified devices, and post-market surveillance. The IVDR regulates design, manufacture and putting into use of devices, but not medical services using these devices. In the absence of suitable commercial devices, the laboratory can resort to laboratory-developed tests (LDT) for in-house use. Documentary obligations (IVDR Art 5.5), the performance and safety specifications of ANNEX I, and development and manufacture under an ISO 15189-equivalent quality system apply. LDTs serve specific clinical needs, often for low volume niche applications, or correspond to the translational phase of new tests and treatments, often extremely relevant for patient care. As some commercial tests may disappear with the IVDR roll-out, many will require urgent LDT replacement. The workload will also depend on which modifications to commercial tests turns them into an LDT, and on how national legislators and competent authorities (CA) will handle new competences and responsibilities. We discuss appropriate interpretation of ISO 15189 to cover IVDR requirements. Selected cases illustrate LDT implementation covering medical needs with commensurate management of risk emanating from intended use and/or design of devices. Unintended collateral damage of the IVDR comprises loss of non-profitable niche applications, increases of costs and wasted resources, and migration of innovative research to more cost-efficient environments. Taking into account local specifics, the legislative framework should reduce the burden on and associated opportunity costs for the health care system, by making diligent use of existing frameworks.

An approach for determining allowable between reagent lot variation.

Clinicians trust medical laboratories to provide reliable results on which they rely for clinical decisions. Laboratories fulfil their responsibility for accurate and consistent results by utilizing an arsenal of approaches, ranging from validation and verification experiments to daily quality control procedures. All these procedures verify, on different moments, that the results of a certain examination procedure have analytical performance characteristics (APC) that meet analytical performance specifications (APS) set for a particular intended use. The APC can in part be determined by estimating the measurement uncertainty component under conditions of within-laboratory precision (uRw), which comprises all components influencing the measurement uncertainty of random sources. To maintain the adequacy of their measurement procedures, laboratories need to distinguish aspects that are manageable vs. those that are not. One of the aspects that may influence uRw is the momentary significant bias caused by shifts in reagent and/or calibrator lots, which, when accepted or unnoticed, become a factor of the APC. In this paper, we postulate a model for allocating a part of allowable uRw to between-reagent lot variation, based on the need for long-term consistency of the measurement variability for that specific measurand. The allocation manages the ratio between short-term and long-term variation and indicates laboratories when to reject or correct certain variations due to reagent lots.

Effect of Expanded Hemodialysis with Theranova® in Patients with COVID-19.

INTRODUCTION: Cytokine storm control is the main target for improving severe COVID-19 by using immunosuppressive treatment. Effective renal replacement therapy (RRT) could give us an advantage removing cytokines in patients with RRT requirements superimposed on COVID-19. METHODS: This is a prospective observational study in COVID-19 patients who required hemodialysis (HD). Patients were assigned to online hemodiafiltration (OL-HDF) and expanded HD (HDx) according to Brescia group recommendations. We measured several cytokines, ß2 microglobulin and albumin levels pre/post-dialysis and on 1st-2nd week. We compared levels among both techniques and control group (HD without COVID-19). RESULTS: We included 26 patients: 18 with COVID-19 on RRT (5 of them had acute kidney injury [AKI]) and 8 controls. We confirm higher cytokine levels in COVID-19 patients than controls and even higher in patients with AKI than in those with chronic kidney disease. Most cytokines raised during HD session, except IL-10 and TNFα. IL-10 was eliminated by any dialysis technique, while clearance of TNFα was higher in the HDx group. HDx achieved a deeper normalization of cytokines and ß2 microglobulin reduction. Mortality was higher in the OL-HDF group than the HDx group. DISCUSSION: Not all cytokines behave equally along HD session. The following characteristics should be taken into account, such as intrinsic kinetic profile during a HD session. HDx seems to get better performance, probably due to the combination of different factors; however, we did not reach statistical significance due to the small sample size, dropout, and reduction of AKI incidence during the 2nd pandemic wave. CONCLUSION: HDx appears to provide better clearance for TNFα and ß2 microglobulin during HD session and associates lower mortality. We propose the HDx technique for COVID-19 patients with RRT requirements since it seems to be safe and more effective than OL-HDF. Further studies are still needed, but we hope that our preliminary data may help us in future pandemic waves of SARS-CoV-2 or other viruses still to come.

Accreditation process in European countries - an EFLM survey.

BACKGROUND: Accreditation is a valuable resource for medical laboratories. The development of quality systems based on ISO 15189 has taken place in many laboratories in the European countries but data about accreditation remain scarce. The EFLM Working Group "Accreditation and ISO/CEN standards" conducted a survey that reviews the current state of the accreditation process in European countries. METHODS: An on-line questionnaire was addressed to delegates of 39 EFLM scientific societies in March 2014. One answer by country was taken into account. The survey was dealing with mandatory status, number of accredited medical laboratories in each country, possibility of flexible scope and concerned medical fields. The status of point-of-care testing (POCT) in each country was also studied. RESULTS: Twenty-nine responses (74%) were registered. All the assessed countries (100%) have begun an accreditation process in various ways. All the national accreditation bodies (NAB) offer or are working to offer an ISO 15189 accreditation. The accreditation process most often concerns all phases of the examination and various medical fields. Medical laboratories are responsible for POCT in 20 (69%) countries. The accreditation process for POCT, according to ISO 15189 and ISO 22870, is also developing. CONCLUSIONS: While there are several variations in the approaches to accreditation of medical laboratories in the European countries, the ISO 15189 accreditation project has been widely accepted. The use of a unique standard and the cooperation among countries due to scientific societies, EFLM, accreditation bodies and EA enable laboratory professionals to move toward uniform implementation of the accreditation concept.

EFLM Working Group Accreditation and ISO/CEN standards on dealing with ISO 15189 demands for retention of documents and examination objects.

Many aspects of the activity of a medical laboratory have to be documented so as to facilitate the maintenance of the ongoing quality of service. As a consequence, many documents, forms and reports are generated. The retention time for each of these has to be specified. In addition to medical laboratory reports as part of the patient's medical record, the medical laboratory has to retain many documents and specimens according to national legislation or guidance from professional organizations, if these exist. If not, the laboratory management needs to define a retention schedule, which shall define the storage conditions and period of storage, according to ISO 15189:2022 requirements for retention of general quality management documents and records. The EFLM Working Group on Accreditation and ISO/CEN standards provides here a proposal on retention periods of documentation and specimens based on a failure-mode-effects-analysis (FMEA) risk-based approach, a concept of risk reduction that has become an integral part of modern standards.

Thyroid dysfunction in patients older than 75 years: an analysis of inadequacy of treatment and therapeutic control.

PURPOSE: Suboptimal control of thyroid dysfunction may carry harmful health consequences, especially in older population. We aimed to estimate the inadequacy of thyroid dysfunction treatment and control in people aged 75 years and over. METHODS: A cross-sectional analysis of all serum thyrotropin (TSH) determinations carried out by the Biochemistry laboratory of the Hospital Universitario Puerta de Hierro Majadahonda during 2019 was performed. All samples from outpatients over age 75 years were selected. In patients with serum TSH out of the range of reference (0.35-5.0 mU/l), we calculated the proportions of patients with inadequate control and inadequate treatment. RESULTS: Of a total of 15,255 patients (mean (SD) age, 82.9 ± 6.1 years; 62.1% females), 13,796 had normal serum TSH (82.8 ± 6.1 years; 61.1% females), 398 low TSH (83.3 ± 6.7 years; 75.6% females), and 1061 high TSH (83.0 ± 4.0 years; 69.5% females). Inadequate control of thyroid function was found in 45.2% (95% CI 40.0-51.0) of patients with low TSH and in 6.93% (95% CI 5.40-8.85) of patients with high TSH. Furthermore, 39.7% (95% CI 34.1-45.6) of patients with low TSH and 27.5% (95% CI 24.5-30.6) of patients with high TSH were not adequately treated. Inadequacy of control was higher in women and patients over 82 years with elevated TSH. Inadequacy of therapy was higher in women. CONCLUSIONS: Inadequacy in both treatment and control of thyroid dysfunction is found in a significant number of aged patients. Clinicians should strive to improve thyroid medication prescription and closely monitor older patients with thyroid dysfunction.

Effects of the COVID-19 pandemic on the activity of clinical laboratories in Spain, evolution in the 2019-2021 period.

Objectives: To assess the impact of the COVID-19 pandemic on the activity of clinical laboratories in Spain. Methods: A descriptive, observational, retrospective, multicenter study. Results: Between March and December 2020, there was a statistically significant decrease in the number of test requests (-17.7%, p=<0.001) and total tests performed (-18.3%, p<0.001) with respect to the same period in 2019. A decrease was observed in the number of requests from primary care (-37.4%) (p<0.001) and in the number of foecal occult blood (-45.8%); qualitative urine (-30.1%); PSA (-28.5%); TSH (-27.8%); total cholesterol (-27.2%) and HbA1c (-24.7%) tests performed, p<0.001. A significant increase was found in the number of requests from ICUs (76.6%, p<0.001) and number of IL-6 (+22,350.9), D-dimer (+617.2%), troponin (+46.8%) and arterial blood gas (+3.9%) tests carried out, p<0.001. During the first months of 2021, there were significant changes in the number of requests for qualitative urine (-8.7%, p<0.001), PSA (-6.3%, p=0.009), IL-6 (+66,269.2, p<0.001), D-dimer (+603.6%, p<0.001), troponin (+28.7%, p<0.001), arterial blood gas (+26,2%, p=0.014) and ferritin (+16.0%, p=0.002) tests performed. Conclusions: There were changes in the origin and number of test requested to clinical laboratories in Spain. The number of requests for the evaluation and monitoring of COVID-19 patients increased, whereas requests for the control of non-COVID patients and for population screening decreased. Long-term analysis reveals that the volume of tests performed for the control of chronic diseases returned to normal over time, whereas the increase observed in the volume of tests performed for the management of COVID-19 patients is maintained.

IL-6 and Other Biomarkers associated with Poor Prognosis in a Cohort of Hospitalized Patients with COVID-19 in Madrid.

OBJECTIVES: There are several published works on the prognostic value of biomarkers in relation to the severity or fatal outcome of coronavirus disease 2019 (COVID-19). In Spain, the second European country in incidence of the disease at the time of data collection, there are few studies that include both laboratory parameters and clinical parameters. Our aim is to study the relationship of a wide series of biomarkers with admission to intensive care and death in a hospital in the Autonomous Community of Madrid (Spain), with special attention to IL-6 due to its role in the systemic inflammatory response associated with a worse prognosis of the disease. METHODS: Data were collected from 546 hospitalized patients with COVID-19. All of them had IL-6 results, in addition to other biochemical and haematological parameters. The difference of the medians for the selected parameters between the groups (ICU vs non-ICU, dead vs survivors) was studied using a Mann-Whitney analysis. The independent variables that predicted death were studied using a Cox proportional hazard regression model. RESULTS: Higher age and blood concentrations of ALT, creatinine, CK, cTnI, LDH, NT-proBNP, CRP, IL-6, leucocyte count and D-dimer together with lower blood concentrations of albumin and lymphocyte count were associated with mortality in univariate analysis. Age, LDH, IL-6 and lymphocyte count remained associated with death in multivariate analysis. CONCLUSIONS: Age, LDH, IL-6 and lymphocyte count, as independent predictors of death, could be used to establish more aggressive therapies in COVID-19 patients.

Comparison of three methods for determining anti-thyrotropin receptor antibodies (TRAb) for diagnosis of Graves' disease: a clinical validation.

Objectives: Graves' disease is secondary to the presence of anti-thyrotropin receptor antibodies (TRAb), which stimulate thyroid hormones. TRab determination is crucial for etiological diagnosis. The objectives of this study were (i) to compare two methods for determining TRab by chemoluminiscence vs. standard TRACE-immunofluorescence; (ii) to determine the diagnostic validity of the three methods. Methods: A retrospective study in 194 patients with a TRAb determination request. TRAb were determined by immunofluorescence (Kryptor, ThermoFisher) and chemiluminescence (Immulite, Siemens and Maglumi, Snibe). Clinical validation: medical records were reviewed and categorized according to thyroid function. Statistical analysis: Differences in quantitative variables were assessed by intraclass correlation coefficient, Bland-Altman plot, and mean differences (mD). Qualitative variables were dichotomized by cut-off points; Kappa coefficient was calculated. Correlations were evaluated by Pearson's coefficient and Passing-Bablok regression analysis. The diagnostic validity of the three methods was investigated. Results: Kryptor-Immulite: mD: 1.2 (95%CI: -16 to >18). Passing-Bablok: Constant error (95%CI: -0.8349 to -0.5987). Proportional error (95%CI: 0.7862-1.0387). ICC: 0.86 (95%CI: 0.82-0.89). Kappa coefficient: 0.68 (95%CI 0.59-0.78). Kryptor-Maglumi: mD: -0.3 (95%CI: -12 to >12). Passing-Bablok: Constant error (95%CI: -0.7701 to >0.1621. Proportional error (95%CI: 0.8571 to 1.3179. ICC: 0.93 (95%CI: 0.89-0.97). Kappa coefficient: 0.53 (95%CI: 0.32-0.74). Diagnosis of Graves' disease was confirmed in 113 patients (Kryptorf showed better specificity and positive predictive value, whereas Immulite demonstrated better sensitivity and negative predictive value). Conclusions: The three methods have a good diagnostic performance for Graves' disease, with superimposable results on Bland-Altman plot. Interchangeability was not confirmed on the regression and agreement analysis, with the presence of biases.

Management of postanalytical processes in the clinical laboratory according to ISO 15189:2012 Standard requirements: considerations on the review, reporting and release of results.

The objective of this paper is to share some considerations about the management of postanalytical processes in relation to the review, reporting and release of test results in accordance with UNE-EN ISO 15189:2013 Standard requirements. The scope of this paper includes postanalytical activities and the personnel involved (laboratory management and staff). We describe the criteria and information required to review and validate analytical results and ensure that clear reports are sent to requesters. These criteria also guarantee that results are transcribed in a reliable way and that all necessary information is provided for the correct interpretation of results. Likewise, the requirements for the correct release of laboratory results are described, with special emphasis on the release of alarming or critical results. In some European countries, clinical laboratories are required to hold partial or full ISO 15189 accreditation, which is a global trend. Therefore, understanding ISO 15189 requirements is imperative for a progressive and more effective implementation of the Standard.

Management of post-analytical processes in the clinical laboratory according to ISO 15189:2012. Considerations about the management of clinical samples, ensuring quality of post-analytical processes, and laboratory information management.

ISO 15189:2012 establishes the requirements for clinical sample management, ensuring quality of process and laboratory information management. The accreditation authority, ENAC in Spain, established the requirements for the authorized use of the label in reports issued by accredited laboratories. These recommendations are applicable to the postanalytical processes and the professionals involved. The Standard requires laboratories to define and document the duration and conditions of sample retention. Laboratories are also required to design an internal quality control scheme to verify whether postanalytical activities attain the expected standards. Information management requirements are also established and laboratories are required to design a contingency plan to ensure the communication of laboratory results. Instructions are finally provided about the correct use of the accreditation label in laboratory reports. A range of nations and scientific societies support that clinical laboratories should be required to obtain accreditation. With ISO 15189 being the most specific standard for demonstrating technical performance, a clear understanding of its requirements is essential for proper implementation.

Improving the laboratory result release process in the light of ISO 15189:2012 standard.

The ISO 15189:2012 standard section 5.9.1 requires laboratories to review results before release, considering quality control, previous results, and clinical information, if any, and to issue documented procedures about it. While laboratory result reporting is generally regarded as part of the post-analytical phase, the result release process requires a general view of the total examination process. Reviewing test results may follow with troubleshooting and test repetition, including reanalyzing an individual sample or resampling. A systematic understanding of the result release may help laboratory professionals carry out appropriate test repetition and ensure the plausibility of laboratory results. In this paper, we addressed the crucial steps in the result release process, including evaluation of sample quality, critical result notification, result reporting, and recommendations for the management of the result release, considering quality control alerts, instrument flags, warning messages, and interference indexes. Error detection tools and plausibility checks mentioned in the present paper can support the daily practice of results release.

Impact of a Barcode Medication Administration System on Patient Safety
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OBJECTIVES: To determine the impact of barcode medication administration (BCMA) on the incidence of medication administration errors among patients in an onco-hematology day hospital and to identify the characteristics of medication errors in that setting.
. SAMPLE & SETTING: 715 patients treated in the onco-hematology day unit at the Príncipe de Asturias University Hospital in Madrid, Spain.
. METHODS & VARIABLES: A between-groups, pre-/postintervention study was conducted. Administration errors observed in patients with solid tumors (intervention group) were compared with those in patients with hematologic cancer (control group) before and after the introduction of BCMA. Error incidence, type, and severity were assessed, as was length of stay for treatment.
. RESULTS: Use of a BCMA system reduced the incidence and severity of errors in medication administration in the onco-hematology day hospital.
. IMPLICATIONS FOR NURSING: BCMA is a useful technology to check the five rights of medication administration in the onco-hematology day hospital and could help nurses increase the time spent on direct patient care activities. 
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