Applying the Milan models to setting analytical performance specifications - considering all the information.

Analytical performance specifications (APS) are used for decisions about the required analytical quality of pathology tests to meet clinical needs. The Milan models, based on clinical outcome, biological variation, or state of the art, were developed to provide a framework for setting APS. An approach has been proposed to assign each measurand to one of the models based on a defined clinical use, physiological control, or an absence of quality information about these factors. In this paper we propose that in addition to such assignment, available information from all models should be considered using a risk-based approach that considers the purpose and role of the actual test in a clinical pathway and its impact on medical decisions and clinical outcomes in addition to biological variation and the state-of-the-art. Consideration of APS already in use and the use of results in calculations may also need to be considered to determine the most appropriate APS for use in a specific setting.

Outcome-based analytical performance specifications: current status and future challenges.

Analytical performance specifications (APS) based on outcomes refer to how 'good' the analytical performance of a test needs to be to do more good than harm to the patient. Analytical performance of a measurand affects its clinical performance. Without first setting clinical performance requirements, it is difficult to define how good analytically the test needs to be to meet medical needs. As testing is indirectly linked to health outcomes through clinical decisions on patient management, often simulation-based studies are used to assess the impact of analytical performance on the probability of clinical outcomes which is then translated to Model 1b APS according to the Milan consensus. This paper discusses the related key definitions, concepts and considerations that should assist in finding the most appropriate methods for deriving Model 1b APS. We review the advantages and limitations of published methods and discuss the criteria for transferability of Model 1b APS to different settings. We consider that the definition of the clinically acceptable misclassification rate is central to Model 1b APS. We provide some examples and guidance on a more systematic approach for first defining the clinical performance requirements for tests and we also highlight a few ideas to tackle the future challenges associated with providing outcome-based APS for laboratory testing.

Plasma arginine metabolites in health and chronic kidney disease.

BACKGROUND: Elevated plasma asymmetric and symmetric dimethylarginine (ADMA and SDMA) are risk factors for chronic kidney disease (CKD) and cardiovascular disease. Using plasma cystatin C (pCYSC)-based estimated glomerular filtration rate (eGFR) trajectories, we identified a cohort at high risk of poor kidney-related health outcomes amongst members of the Dunedin Multidisciplinary Health and Development Study (DMHDS). We therefore examined associations between methylarginine metabolites and kidney function in this cohort. METHODS: ADMA, SDMA, L-arginine and L-citrulline were measured in plasma samples from 45-year-olds in the DMHDS cohort by liquid chromatography-tandem mass spectrometry. RESULTS: In a healthy DMHDS subset (n = 376), mean concentrations were: ADMA (0.40 ± 0.06 µmol/L), SDMA (0.42 ± 0.06 µmol/L), L-arginine (93.5 ± 23.1 µmol/L) and L-citrulline (24.0 ± 5.4 µmol/L). In the total cohort (n = 857), SDMA correlated positively with serum creatinine (Pearson's r = 0.55) and pCYSC (r = 0.55), and negatively with eGFR (r = 0.52). A separate cohort of 38 patients with stage 3-4 CKD (eGFR 15-60 mL/min/1.73 m2) confirmed significantly higher mean ADMA (0.61 ± 0.11 µmol/L), SDMA (0.65 ± 0.25 µmol/L) and L-citrulline (42.7 ± 11.8 µmol/L) concentrations. DMHDS members classified as high-risk of poor kidney health outcomes had significantly higher mean concentrations of all four metabolites compared with individuals not at risk. ADMA and SDMA individually predicted high-risk of poor kidney health outcomes with areas under the ROC curves (AUCs) of 0.83 and 0.84, and together with an AUC of 0.90. CONCLUSIONS: Plasma methylarginine concentrations facilitate stratification for risk of CKD progression.

Lot-to-lot reagent verification: challenges and possible solutions.

Lot-to-lot verification is an important laboratory activity that is performed to monitor the consistency of analytical performance over time. In this opinion paper, the concept, clinical impact, challenges and potential solutions for lot-to-lot verification are exained.

Operational considerations and challenges of biochemistry laboratories during the COVID-19 outbreak: an IFCC global survey.

Objectives: The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on COVID-19 conducted a global survey to understand how biochemistry laboratories manage the operational challenges during the coronavirus disease 2019 (COVID-19) pandemic. Materials and methods: An electronic survey was distributed globally to record the operational considerations to mitigate biosafety risks in the laboratory. Additionally, the laboratories were asked to indicate the operational challenges they faced. Results: A total of 1210 valid submissions were included in this analysis. Most of the survey participants worked in hospital laboratories. Around 15% of laboratories restricted certain tests on patients with clinically suspected or confirmed COVID-19 over biosafety concerns. Just over 10% of the laboratories had to restrict their test menu or services due to resource constraints. Approximately a third of laboratories performed temperature monitoring, while two thirds of laboratories increased the frequency of disinfection. Just less than 50% of the laboratories split their teams. The greatest reported challenge faced by laboratories during the COVID-19 pandemic is securing sufficient supplies of personal protective equipment (PPE), analytical equipment, including those used at the point of care, as well as reagents, consumables and other laboratory materials. This was followed by having inadequate staff, managing their morale, anxiety and deployment. Conclusions: The restriction of tests and services may have undesirable clinical consequences as clinicians are deprived of important information to deliver appropriate care to their patients. Staff rostering and biosafety concerns require longer-term solutions as they are crucial for the continued operation of the laboratory during what may well be a prolonged pandemic.

Laboratory practices to mitigate biohazard risks during the COVID-19 outbreak: an IFCC global survey.

Objectives: A global survey was conducted by the IFCC Task Force on COVID-19 to better understand how general biochemistry laboratories manage the pre-analytical, analytical and post-analytical processes to mitigate biohazard risks during the coronavirus disease 2019 (COVID-19) pandemic. Methods: An electronic survey was developed to record the general characteristics of the laboratory, as well as the pre-analytical, analytical, post-analytical and operational practices of biochemistry laboratories that are managing clinical samples of patients with COVID-19. Results: A total of 1210 submissions were included in the analysis. The majority of responses came from hospital central/core laboratories that serve hospital patient groups and handle moderate daily sample volumes. There has been a decrease in the use of pneumatic tube transport, increase in hand delivery and increase in number of layers of plastic bags for samples of patients with clinically suspected or confirmed COVID-19. Surgical face masks and gloves are the most commonly used personal protective equipment (PPE). Just >50% of the laboratories did not perform an additional decontamination step on the instrument after analysis of samples from patients with clinically suspected or confirmed COVID-19. A fifth of laboratories disallowed add-on testing on these samples. Less than a quarter of laboratories autoclaved their samples prior to disposal. Conclusions: The survey responses showed wide variation in pre-analytical, analytical and post-analytical practices in terms of PPE adoption and biosafety processes. It is likely that many of the suboptimal biosafety practices are related to practical local factors, such as limited PPE availability and lack of automated instrumentation.

Setting analytical performance specifications based on outcome studies - is it possible?

The 1st Strategic Conference of the European Federation of Clinical Chemistry and Laboratory Medicine proposed a simplified hierarchy for setting analytical performance specifications (APS). The top two levels of the 1999 Stockholm hierarchy, i.e., evaluation of the effect of analytical performance on clinical outcomes and clinical decisions have been proposed to be replaced by one outcome-based model. This model can be supported by: (1a) direct outcome studies; and (1b) indirect outcome studies investigating the impact of analytical performance of the test on clinical classifications or decisions and thereby on the probability of patient relevant clinical outcomes. This paper reviews the need for outcome-based specifications, the most relevant types of outcomes to be considered, and the challenges and limitations faced when setting outcome-based APS. The methods of Model 1a and b are discussed and examples are provided for how outcome data can be translated to APS using the linked evidence and simulation or decision analytic techniques. Outcome-based APS should primarily reflect the clinical needs of patients; should be tailored to the purpose, role and significance of the test in a well defined clinical pathway; and should be defined at a level that achieves net health benefit for patients at reasonable costs. Whilst it is acknowledged that direct evaluations are difficult and may not be possible for all measurands, all other forms of setting APS should be weighed against that standard, and regarded as approximations. Better definition of the relationship between the analytical performance of tests and health outcomes can be used to set analytical performance criteria that aim to improve the clinical and cost-effectiveness of laboratory tests.

Setting Bias Specifications Based on Qualitative Assays With a Quantitative Cutoff Using COVID-19 as a Disease Model.

OBJECTIVES: Automated qualitative serology assays often measure quantitative signals that are compared against a manufacturer-defined cutoff for qualitative (positive/negative) interpretation. The current general practice of assessing serology assay performance by overall concordance in a qualitative manner may not detect the presence of analytical shift/drift that could affect disease classifications. METHODS: We describe an approach to defining bias specifications for qualitative serology assays that considers minimum positive predictive values (PPVs) and negative predictive values (NPVs). Desirable minimum PPVs and NPVs for a given disease prevalence are projected as equi-PPV and equi-NPV lines into the receiver operator characteristic curve space of coronavirus disease 2019 serology assays, and the boundaries define the allowable area of performance (AAP). RESULTS: More stringent predictive values produce smaller AAPs. When higher NPVs are required, there is lower tolerance for negative biases. Conversely, when higher PPVs are required, there is less tolerance for positive biases. As prevalence increases, so too does the allowable positive bias, although the allowable negative bias decreases. The bias specification may be asymmetric for positive and negative direction and should be method specific. CONCLUSIONS: The described approach allows setting bias specifications in a way that considers clinical requirements for qualitative assays that measure signal intensity (eg, serology and polymerase chain reaction).

Biomarker Rule-in or Rule-out in Patients With Acute Diseases for Validation of Acute Kidney Injury in the Emergency Department (BRAVA): A Multicenter Study Evaluating Urinary TIMP-2/IGFBP7.

Background: Urine tissue inhibitor of metalloproteinases-2/insulin-like growth factor-binding protein 7 (TIMP-2/IGFBP7) (NephroCheck, Ortho Clinical Diagnostics, Raritan, NJ, USA) is a US Food and Drug Administration-approved biomarker for risk assessment of acute kidney injury (AKI) in critically ill adult patients in intensive care units; however, its clinical impact in the emergency department (ED) remains unproven. We evaluated the utility of NephroCheck for predicting AKI development and short-term mortality in the ED. Methods: This was a prospective, observational, five-center international study. We consecutively enrolled ED patients admitted with ≥30% risk of AKI development (assessed by ED physician: ED score) or acute diseases. Serum creatinine was tested on ED arrival (T0), day 1, and day 2 (T48); urine for NephroCheck was collected at T0 and T48. We performed ROC curve and reclassification analyses. Results: Among the 529 patients enrolled (213 females; median age, 65 years), AKI developed in 59 (11.2%) patients. The T0 NephroCheck value was higher in the AKI group than in the non-AKI group (median 0.77 vs. 0.29 (ng/m)2/1,000, P=0.001), and better predicted AKI development than the ED score (area under the curve [AUC], 0.64 vs. 0.53; P=0.04). In reclassification analyses, adding NephroCheck to the ED score improved the prediction of AKI development (P<0.05). The T0 NephroCheck value predicted 30-day mortality (AUC, 0.68; P<0.001). Conclusions: NephroCheck can predict both AKI development and short-term mortality in at-risk ED patients. NephroCheck would be a useful biomarker for early ruling-in or ruling-out of AKI in the ED.

Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus.

BACKGROUND: Multiple laboratory tests are used to diagnose and manage patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these tests varies substantially. APPROACH: An expert committee compiled evidence-based recommendations for the use of laboratory testing for patients with diabetes. A new system was developed to grade the overall quality of the evidence and the strength of the recommendations. Draft guidelines were posted on the Internet and presented at the 2007 Arnold O. Beckman Conference. The document was modified in response to oral and written comments, and a revised draft was posted in 2010 and again modified in response to written comments. The National Academy of Clinical Biochemistry and the Evidence Based Laboratory Medicine Committee of the AACC jointly reviewed the guidelines, which were accepted after revisions by the Professional Practice Committee and subsequently approved by the Executive Committee of the American Diabetes Association. CONTENT: In addition to long-standing criteria based on measurement of plasma glucose, diabetes can be diagnosed by demonstrating increased blood hemoglobin A(1c) (Hb A(1c)) concentrations. Monitoring of glycemic control is performed by self-monitoring of plasma or blood glucose with meters and by laboratory analysis of Hb A(1c). The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of autoantibodies, urine albumin, insulin, proinsulin, C-peptide, and other analytes are addressed. SUMMARY: The guidelines provide specific recommendations that are based on published data or derived from expert consensus. Several analytes have minimal clinical value at present, and their measurement is not recommended.

Executive summary: guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus.

BACKGROUND: Multiple laboratory tests are used in the diagnosis and management of patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially. APPROACH: An expert committee compiled evidence-based recommendations for the use of laboratory analysis in patients with diabetes. A new system was developed to grade the overall quality of the evidence and the strength of the recommendations. A draft of the guidelines was posted on the Internet, and the document was modified in response to comments. The guidelines were reviewed by the joint Evidence-Based Laboratory Medicine Committee of the AACC and the National Academy of Clinical Biochemistry and were accepted after revisions by the Professional Practice Committee and subsequent approval by the Executive Committee of the American Diabetes Association. CONTENT: In addition to the long-standing criteria based on measurement of venous plasma glucose, diabetes can be diagnosed by demonstrating increased hemoglobin A(1c) (Hb A(1c)) concentrations in the blood. Monitoring of glycemic control is performed by the patients measuring their own plasma or blood glucose with meters and by laboratory analysis of Hb A(1c). The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of autoantibodies, urine albumin, insulin, proinsulin, C-peptide, and other analytes are addressed. SUMMARY: The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are found to have minimal clinical value at the present time, and measurement of them is not recommended.

Electrochemotherapy of cutaneous metastases of melanoma--a case series study and systematic review of the evidence.

OBJECTIVES: Electrochemotherapy (ECT) is a novel therapeutic option for the treatment of cutaneous and subcutaneous metastases of malignant melanoma. During the treatment, electric pulses are applied to tumor nodules to deliver nonpermeant or poorly permeant chemotherapeutic agents into the cells, increasing local cytotoxicity of anticancer drugs. We compared the clinical effectiveness of ECT as an alternative palliative treatment option for unresectable metastatic lesions of malignant melanoma with a systematic review of reported outcomes. METHODS: One hundred fifty-eight cutaneous and subcutaneous metastases of nine patients were treated with ECT. All treatments were performed under general anesthesia using intravenous bleomycin injection. Median follow-up was 195 days. RESULTS: In our case series, complete response rate was 23%, and partial response rate was 39%. We observed no change in 30% and progressive disease in 8% of cases. CONCLUSIONS: ECT is a simple and effective treatment of single or multiple cutaneous and subcutaneous metastases of melanoma with minimal side effects. Our results provide further data for the growing body of evidence in recently published studies that ECT used for palliation has clinical benefit. The authors have indicated no significant interest with commercial supporters.

[Controversial issues in colorectal screening in Hungary: conflict of clinical and public health viewpoints]. / A vastag- és végbéldaganatok szurésének vitatott kérdései: klinikai és népegészségügyi nézopontok ütközése.

In Hungary, mortality rates from colorectal cancer are dramatically high, therefore the reduction by population screening as a public health measure is considered as one of the priorities of National Public Health Program. In the beginning, a human-specific immunological test was applied in the "model programs", as a screening tool, to detect the occult blood in the stool; compliance was 32% in average. However, the objectives of the model programs have not been achieved, because, among other reasons, a debate on the method of choice and the strategy to follow have divided the professional public opinion. In this study the debated issues are critically discussed, being convinced that, at present, population screening seems to be the most promising way to alleviate the burden of colorectal cancer.

The potential for overdiagnosis and underdiagnosis because of blood pressure variability: a comparison of the 2017 ACC/AHA, 2018 ESC/ESH and 2019 NICE hypertension guidelines.

OBJECTIVE: To estimate the extent that BP measurement variability may drive over- and underdiagnosis of 'hypertension' when measurements are made according to current guidelines. METHODS: Using data from the National Health and Nutrition Examination Survey and empirical estimates of within-person variability, we simulated annual SBP measurement sets for 1 000 000 patients over 5 years. For each measurement set, we used an average of multiple readings, as recommended by guidelines. RESULTS: The mean true SBP for the simulated population was 118.8 mmHg with a standard deviation of 17.5 mmHg. The proportion overdiagnosed with 'hypertension' after five sets of office or nonoffice measurements using the 2017 American College of Cardiology guideline was 3-5% for people with a true SBP less than 120 mmHg, and 65-72% for people with a true SBP 120-130 mmHg. These proportions were less than 1% and 14-33% using the 2018 European Society of Hypertension and 2019 National Institute for Health and Care Excellence guidelines (true SBP <120 and 120-130 mmHg, respectively). The proportion underdiagnosed with 'hypertension' was less than 3% for people with true SBP at least 140 mmHg after one set of office or nonoffice measurements using the 2017 American College of Cardiology guideline, and less than 18% using the other two guidelines. CONCLUSION: More people are at risk of overdiagnosis under the 2017 American College of Cardiology guideline than the other two guidelines, even if nonoffice measurements are used. Making clinical decisions about cardiovascular prediction based primarily on absolute risk, minimizes the impact of blood pressure variability on overdiagnosis.

Setting analytical performance specifications using HbA1c as a model measurand.

Analytical performance specifications (APS) for measurands describe the minimum analytical quality requirements for their measurement. These APS are used to monitor and contain the systematic (trueness/bias) and random errors (precision/imprecision) of a laboratory measurement to ensure the results are "fit for purpose" in informing clinical decisions about managing a patient's health condition. In this review, we highlighted the wide variation in the setting of APS, using different levels of evidence, as recommended by the Milan Consensus, and approaches. The setting of a priori defined outcome-based APS for HbA1c remains challenging. Promising indirect alternatives seek to link the clinical utility of HbA1c and APS by defining statistical confidence for interpreting the laboratory values, or through simulation of clinical performance at varying levels of analytical performance. APS defined based on biological variation estimates in healthy individuals using the current formulae are unachievable by nearly all routine laboratory methods for HbA1c testing. On the other hand, the APS employed in external quality assurance programs have been progressively tightened, and greatly facilitate the improved quality of HbA1c testing. Laboratories should select the APS that fits their intended clinical use and should document the data and rationale underpinning those selections. Where possible common APS should be adopted across a region or country to facilitate the movement of patients and patient data across health care facilities.

Staff rostering, split team arrangement, social distancing (physical distancing) and use of personal protective equipment to minimize risk of workplace transmission during the COVID-19 pandemic: A simulation study.

BACKGROUND: The recent global survey promoted by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Taskforce on COVID-19 (coronavirus disease 2019) described staff rostering and organization as significant operational challenges during the COVID-19 pandemic. METHOD: A discrete event simulation was used to explore the impact of different permutations of staff roster, including the number of shifts per day, the number of staff on duty per shift, overall number of staff accessible to work in the laboratory (i.e. overall staff pool), the frequency of shift changes (i.e. number of consecutive days worked), fixed work-rest days and split team arrangement on workplace transmission of COVID-19 by a simulated index staff who acquired the infection from the community over 21 days. Additionally, the impact of workplace social distancing (physical distancing) and use of personal protective equipment (PPE) were investigated. RESULTS: A higher rate of transmission was associated with smaller overall staff pool (expressed as multiples of the number of staff per shift), higher number of shifts per day, higher number of staff per shift, and longer consecutive days worked. Having fixed work-rest arrangement did not significantly reduce the transmission rate unless the workplace outbreak was prolonged. Social distancing and PPE use significantly reduced the transmission rate. CONCLUSION: Laboratories should consider organizing the staff into smaller teams/shift and reduce the number of consecutive days worked. Additionally, our observation aligns with the IFCC biosafety recommendation of monitoring staff health (to detect early infection), split team arrangement, workplace social distancing and use of PPE.