Acceptable Bias Research Articles

B-032 Evaluation of Assay Performance for Atellica CI 1900 analyzer in Routine Chemistry, Division of Laboratory Medicine, UMMC

Abstract Background The Atellica® CI 1900 (Siemens Healthiness) is a stand-alone, integrated clinical chemistry and immunoassay analyzer. Method verification has been done on this analyzer for 14 parameters based on the guideline of the Clinical and Laboratory Standard Institute (CLSI). Methods The method evaluation protocol consisted of determination of imprecision based CLSI EP 15-A3; CLSI EP06-A2 protocol was used for verification of linearity and method comparison was carry out in between Atellica® CI 1900 with our current Atellica® Solution based on CLSI EP09-A2 protocol. Method comparison data was analyzed by using statistical software, MedCalc. The data were used to calculate bias for Sigma metrics determination. Results Total of 14 analytes including sodium, potassium, chloride, creatinine, urea, alkaline phosphatase, total bilirubin, triglyceride, uric acid, glucose, thyroid stimulating hormone, free-thyroxine, human chorionic gonadotropin and carcinoembryonic antigen were tested. The results showed the repeatability and total imprecision were within acceptable limit as per manufacturer claims for all analytes. It was demonstrated that the analytical system operates within the claimed linearity ranges as stated in the information for use (IFU). Passing - Bablok analysis show the bias for all analytes were within our laboratory pre-set quality specification. The intercept and slope with 95% CI for Passing-Bablok analysis as shown in table 1. Sigma metrics were determined for each assay using the coefficient variation determined from precision study and bias obtained from the method comparison study. It showed that the Sigma for 14 analytes ranging from 3 to more than 6 with more than 93% assay has sigma scores more than 4. Conclusions Atellica® CI 1900 shows acceptable precision and bias for all analytes that evaluated. The analyser is fully comparable with Atellica® Solution. We conclude that Atellica® CI 1900 demonstrates good performance capabilities, making this analyzer suitable for low-to-medium volume laboratory.

A-212 Comparison of formulas for measuring LDL in cancer patients with hypertriglyceridemia

Abstract Background Treatments in recent years in cancer patients have been very favorable. However, some data suggest that dyslipidemia plays a role in carcinogenesis through the deregulation of the lipid signal, and this possibly leads to the development of cardiovascular diseases. A marker for the diagnosis and treatment of dyslipidemias is low density lipoproteins (LDL), and currently, the primary care level still calculates LDL due to the high costs of the direct method; Friedewald has been used since 1972, and in recent years, new equations have appeared such as Sampson and Martin - Hopkins (MH). These formulas use total cholesterol (TC), high-density lipoproteins (HDL), and triglycerides (TG). Objective was to compare the formulas for measuring LDL in cancer patients with hypertriglyceridemia. Methods It´s an observational, cross-sectional - and analytical study. The sample size was 880 lipid profiles processed in an automated dry chemistry analyzer between January and March 2023 at an Oncology Institute in Lima, Peru. The population was divided into several groups of triglyceride levels (<200 mg/dl, 200- 399 mg/dl, ≥ 400 mg/dl), and LDL was stratified according to ATP III to evaluate the classification of patients with respect to LDL formulas. The statistical analysis was performed by descriptive analysis of the categorical and numerical variables; The correlation was performed using Pearson, and a comparison of the LDL formulas was used by Bland Altman to determine the bias and percentage bias. To clinical relevance, it was compared with the biological variation of the Westgard table. A p-value <0.05 was considered significant, and the data were processed in MedCalc v20.027. Results The average age of the patients was 55.02 ± 13.92 years, and the frequency of female sex was 77.39% (n = 681). The average measured TC, HDL, and LDL were 208.95 ± 54.84 mg/dl, 41.53 ± 13.83 mg/dl, and 115.70 ±45.53 mg/dl, respectively, while the calculated average LDL in Friedewald was 120.40 ± 48.57, MH was 130.49 ± 44.15 mg/dl and Sampson was 125.97 ± 45.53 mg/dl. The correlations of measured versus calculated LDL were strong (r > 0.89) at different TG levels; Statistical (p<0.05) and clinical relevance was observed in the Friedewald formula when TG ≥ 400 mg/dl, while the MH and Sampson formulas presented clinical and significant relevance at all triglyceride levels. Patients with an LDL level between 130 and 159 mg/dl presented a more substantial classification error according to the Friedewald, MH, and Sampson formulas. Conclusions Friedewald formula presented a clinically acceptable bias up to 400 mg/dl, unlike the MH and Sampson formulas, which were affected by triglycerides ≥ 150 mg/dl.

A-092 Siemens Healthineers Commitment to Quality - A Focus on Continuous Improvement and Customer Experience

Abstract Background It is necessary that each step of in vitro diagnostic assay development and manufacturing processes be documented and executed in alignment with established quality management systems. Here, we describe how Siemens Healthineers (SHS) maintains assay traceability and focus on continuous improvement using the Atellica® CH A-LYTE® Integrated Multisensor Technology (IMT) assays measuring electrolytes sodium (Na), potassium (K), and chloride (Cl) as a prime example. Methods Establishing an unbroken chain of comparison from the National Institute of Standards and Technology (NIST) higher standard references to the product calibrators ensures accurate value assignment within stated measurement uncertainties. Traceability and standardization are achieved by creating a panel of 10 serum anchor pools spanning the analytical measuring interval for each electrolyte: Na, K, and Cl. The concentrations of the anchor pools are determined at a reference laboratory using methods calibrated with standard solutions derived from NIST reference material. These serum anchor pools are used by SHS, assigning values to product calibrator material which maintains the chain of traceability to the primary reference methods. In addition to traceability, onboard stability for the A-LYTE® IMT multisensor is continuously monitored and evaluated against allowable drift limits for each electrolyte. Although observed drift was within allowable limits, a design change was implemented to improve recovery drift over the use life of the sensor. Results To ensure consistent, robust, and accurate performance of the A-LYTE IMT, a strict set of testing procedures are used to verify the accuracy of value assignments for each manufactured lot of master standards. The recovery of the NIST standard reference material must fall within manufacturer established acceptable bias limits. Consistency over nine master lots is shown with bias ranging from -0.9% to +1.9%, -2.4% to +1.8% and -1.8 to +0.5%, for Na, K and Cl, respectively. By further optimizing the amount of Na ionophore and the polymer matrix of the Na sensor, drift over the use life was minimized and onboard stability improved. Prior to making the sensor change, customer Na QC data at 116 mmol/L showed an SD of 1.1 mmol/L (n=585), whereas the precision improved to an SD of 0.6 mmol/L (n=470) post-optimization. As Manufacturers optimize assay performance, it may become necessary for laboratories to re-evaluate reference intervals for their patient populations. For example, one large integrated delivery network established a new reference interval for patient anion gap (AG). A re-evaluation of the historical AG reference interval which was 5-15 mmol/L identified the need for an update. AG values were calculated from 16,948 healthy patients and used to establish a new reference interval of 2-10 mmol/L. Conclusions Accurate clinical laboratory measurements are critical for diagnosing, monitoring, and treating diseases. A-LYTE assays have an unbroken chain of traceability to NIST reference material and minimal drift over the life of the multisensor. Continuous monitoring to identify improvement projects and rigorous control systems ensure sensor performance over time. This provides confidence that the patient results produced by the laboratory are accurate and consistent over time and across different laboratory locations.

Validity of the estimated core temperature algorithm during real-world prolonged walking exercise under warm ambient conditions

BackgroundNon-invasive methods to estimate core body temperature (TC) are increasingly available. We examined the group-level and individual participant-level validity of the Estimated Core Temperature (ECTemp™) algorithm to estimate TC based on sequential heart rate (HR) measurements during real-world prolonged walking exercise in warm ambient conditions. MethodsParticipants walked 30 (n = 3), 40 (n = 13) or 50 (n = 2) km on a self-selected pace during which TC was measured every minute using an ingestible temperature capsule. HR was measured every second and used to compute the estimated core temperature (TC-est) using the ECTemp™ algorithm. Bland-Altman analyses were performed to assess agreement between TC and TC-est. A systematic bias <0.1 °C was considered acceptable. Results18 participants (56 ± 16 years, 11 males) walked for 549 min (range 418–645 min), while ambient temperature increased from 22 °C to 29 °C. Average HR was 108 ± 13 bpm and TC ranged from 36.9 to 39.2 °C, whereas TC-est ranged from 36.8 to 38.9 °C (n = 8572 observations). Group level data revealed a systematic bias of 0.09 °C (p < 0.001) with limits of agreements of ±0.44 °C. A weak correlation was found between TC and TC-est (r = 0.28; p < 0.001). Large inter-individual differences in bias (range −0.45 °C to 0.62 °C) and correlation coefficients (range −0.09 to 0.95) were found, while only 3 participants (17%) had an acceptable systemic bias of <0.1 °C. ConclusionGroup level data showed that the ECTemp™ algorithm had an acceptable systematic bias during prolonged walking exercise in warm ambient conditions, but only 3 out of 18 participants had an acceptable systemic bias. Future studies are needed to improve the accuracy of the algorithm before individual users can rely on their estimated TC during real-world exercise.

Development and Validation of a Predictive Model for Growth of Salmonella Infantis in Ground Turkey

Most retail samples (25 g) of ground turkey contain no or low levels of Salmonella. However, temperature abuse after retail can lead to spread and growth of Salmonella in the package. In addition, it can lead to levels that pose a significant risk of salmonellosis. This is especially true when the serotype is a top human clinical isolate, like Infantis. Therefore, the current study was undertaken to develop and validate a predictive model for growth of Salmonella Infantis in ground turkey subjected to temperature abuse. The purpose was to fill a gap for serotype-specific data and models in risk assessments for this pathogen and food combination. Storage trials with a low initial inoculum (0.85 log10) of Salmonella Infantis in commercial ground turkey samples (0.2 g) with native microflora were conducted at 16 to 40°C for 0 to 28 h. Salmonella was enumerated in ground turkey samples using an automated, whole sample enrichment, miniature, most probable number (MPN) assay. The MPN data were fitted to a three-phase linear primary model. Secondary models for primary model parameters were developed and used in the primary model to create a tertiary model that predicted growth of Salmonella Infantis in ground turkey as a function of time and temperature. Data and tertiary model predictions were evaluated using the test data, model performance, and model validation criteria of the Acceptable Prediction Zones method in the Validation Software Tool. The tertiary model predictions were considered to have acceptable bias and accuracy when the proportion of residuals (observed – predicted) in the partly and fully acceptable prediction zones (pAPZ) was ≥ 0.7. The overall pAPZ of the tertiary model was 0.866 for dependent data (n = 406) and 0.853 for independent data for interpolation (n = 177). However, there were local prediction problems that limited the validated prediction range to a region from 0 to 8 h at 16 to 40°C. Nonetheless, this validation range was sufficient to simulate temperature abuse of ground turkey during meal preparation in the consumers’ home. Thus, the model fills an important data and modeling gap in risk assessments for Salmonella and ground turkey. Additional data is needed to repair and fully validate the model.

WebMRT: An online tool to predict summertime mean radiant temperature using machine learning

Mean Radiant Temperature (Tmrt) is the most critical atmospheric variable influencing outdoor human thermal exposure and comfort in hot, dry environments. However, accurately quantifying Tmrt requires time-consuming field measurements with expensive equipment or complex, resource-intensive computations. We introduce WebMRT, an online tool to predict Tmrt using a data-driven approach. It features an intuitive interface using air temperature, shading status, and built environment features as predictors of Tmrt for a user-selected summer day, time, and location. Utilizing a tree-based ensemble model, WebMRT is trained on state-of-the-art human-biometeorological data collected by MaRTy using LightGBM after evaluating its performance against several candidate machine learning regressors. Feature engineering was applied to the day and time input, and two additional temporal features were derived: ‘Solar Altitude’ and ‘Minutes-from-Sunrise’. These inputs are integrated into the user interface, emphasizing simplicity and easy access for users at the frontend. After training the regressor on MaRTy datasets and employing k-fold cross-validation with ten folds, the model demonstrated strong predictive power (R2=0.92) with acceptable error (RMSE=3.43, MAPE=5.33) and bias (MBE=0.20). WebMRT also features optional fisheye photo uploads, processed using transfer learning techniques for image segmentation, further enhancing the tool's predictive accuracy, user experience, and applications towards climate action decision-making processes.

Transplantation Outcomes in Hepatitis C Virus-Positive Donor Hearts After Circulatory Death

Although the use of hepatitis C virus (HCV)-positive hearts has been shown to be safe and effective among donors with donation after brain death (DBD), it remains unknown whether such organs recovered after circulatory death (DCD) have similar outcomes. In contradistinction to recovery from DBD using cold static organ storage, DCD procurement processes typically use normothermic-perfusion transport strategies that necessitate the use of a large volume of donor blood and involve exposure to temperatures oscillating between cold to dominantly normothermic conditions. We performed a retrospective analysis of United Network for Organ Sharing (UNOS) registry data in the United States and found that clinical outcomes do not differ with respect to rates of treated allograft rejection, early and 1-year survival. Ideally, the organ-recovery source should not result in a bias in organ-offer acceptance from HCV-positive donors, although long-term outcome data are yet unavailable.

Commercially available tests for determining cefiderocol susceptibility display variable performance in the Achromobacter genus

BackgroundCefiderocol is a siderophore-conjugated cephalosporin increasingly used in the management of Achromobacter infections. Testing for cefiderocol susceptibility is challenging with distinct recommendations depending on the pathogens.ObjectivesWe evaluated the performance of commercial tests for testing cefiderocol susceptibility in the Achromobacter genus and reviewed the literature.MethodsDiffusion (disks, MIC gradient test strips [MTS], Liofilchem) and broth microdilution (BMD) methods (ComASP™, Liofilchem; UMIC®, Bruker) were compared with the BMD reference method according to the EUCAST guidelines on 143 Achromobacter strains from 14 species with MIC50/90 of ≤ 0.015/0.5 mg/L. A literature search was conducted regardless of method or species.ResultsNone of the methods tested fulfilled an acceptable essential agreement (EA). MTS displayed the lowest EA (30.8%) after UMIC® (49%) and ComASP™ (76.9%). All methods achieved an acceptable bias, with MICs either underestimated using MTS (-1.3%) and ComASP™ (-14.2%) or overestimated with UMIC® (+ 9.1%). Inhibition zone diameters ranged from 6 to 38 mm (IZD50/90=33/30 mm). UMIC® and ComASP™ failed to categorize one or the two cefiderocol-resistant strains of this study as resistant unlike the diffusion-based methods. The literature review highlighted distinct performance of the available methods according to pathogens and testing conditions.ConclusionsThe use of MTS is discouraged for Achromobacter spp. Disk diffusion can be used to screen for susceptible strains by setting a threshold diameter of 30 mm. UMIC® and ComASP™ should not be used as the sole method but have to be systematically associated with disk diffusion to detect the yet rarely described cefiderocol-resistant Achromobacter sp. strains.

A new Monte Carlo generator for BSM physics in B → K*ℓ+ℓ− decays with an application to lepton non-universality in angular distributions

Within the widely used EvtGen framework, we have added a new event generator model for B → K*ℓ+ℓ− with improved standard model (SM) decay amplitudes and possible BSM physics contributions, which are implemented in the operator product expansion in terms of Wilson coefficients. This event generator can then be used to estimate the statistical sensitivity of a simulated experiment to the most general BSM signal resulting from dimension-six operators. We describe the advantages and potential of the newly developed ‘Sibidanov Physics Generator’ in improving the experimental sensitivity of searches for lepton non-universal BSM physics and clarifying signatures. The new generator can properly simulate BSM scenarios, interference between SM and BSM amplitudes, and correlations between different BSM observables as well as acceptance bias. We show that exploiting such correlations substantially improves experimental sensitivity. As a demonstration of the utility of the MC generator, we examine the prospects for improved measurements of lepton non-universality in angular distributions for B → K*ℓ+ℓ− decays from the expected 50 ab−1 data set of the Belle II experiment, using a four-dimensional unbinned maximum likelihood fit. We describe promising experimental signatures and correlations between observables. The use of lepton-universality violating ∆-observables significantly reduces uncertainties in the SM expectations due to QCD and resonance effects and is ideally suited for Belle II with the large data sets expected in the next decade. Thanks to the clean experimental environment of an e+e− machine, Belle II should be able to probe BSM physics in the Wilson coefficients C7 and C7′\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ {C}_7^{\\prime } $$\\end{document}, which appear at low q2 in the di-electron channel.

Performance Evaluation of Open Channel Buhlmann Fecal Calprotectin Turbo Assay on Abbott Alinity C Analyzer.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal (GI) tract. Fecal calprotectin (fCAL) is a noninvasive laboratory test used in the diagnosis and monitoring of IBDs such as Crohn's disease and ulcerative colitis. The fCAL send-out test that our facility has been offering so far uses an ELISA-based method. In the current study, we sought to validate the performance of a Buhlmann fCAL turbo assay in an automated Abbott Alinity C analyzer (AFCAL) in our core laboratory. Five-day imprecision studies showed good performance for both within-run (5.3%) and between-day (2.5%) measurements. The reportable range was verified as 30-20,000 µg/g. Deming regression and Bland-Altman analysis indicated a strong correlation of r = 0.99 with a low, acceptable bias of 1.8% for AFCAL relative to the predicate Buhlmann fCAL ELISA results. AFCAL's clinical performance was determined retrospectively in 62 patients with ICD codes for IBD. Overall, the implementation of AFCAL in our routine clinical testing has improved our turnaround time, reduced the cost per test, and significantly increased our clinician satisfaction.

Performance evaluation and characterization of pre-analytical effects by sample types and storage conditions on tumor marker measurement by the point-of-care test platform IchromaTM II

Tumor markers should be measured regularly and accurately to prevent, diagnose, and monitor cancers efficiently. We aimed to characterize the pre-analytical factors effecting on the analytical performance of point-of-care test (POCT) platform IchromaTM II (Boditech Med Inc., Gangwon-do, Korea) for alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), and prostate specific antigen (PSA) and evaluate their consequences in clinical practice. Based on comprehensive evaluation for the analytical performance of IchromaTM II including precision, linearity, and method comparison performed according to CLSI guidelines, pre-analytical factors of sample types and conditions were extensively analyzed. A total of five sample types [serum, plasma (PL) and whole blood (WB) from EDTA tube, PL and WB from sodium heparin tube] from 40 patients were used for comparing among specimen types. Additionally, stability was assessed up to 21 h at room temperature, refrigerated for 8 days, and frozen for 16 weeks by using 4 levels of pooled patient samples which were measured in triplicate. Precision, linearity and correlation with central laboratory analyzers observed in all three tumor markers were within acceptable criteria. However, variable degrees of percent deviations were observed according to sample type and storage conditions. Only EDTA PL samples presented clinically acceptable percentage biases for all three tumor markers when stored at room temperature or refrigerated condition. Positive bias of CEA and PSA in storage duration until 16 weeks were observed when stored in frozen condition. While IchromaTM II showed an adequate analytical performance as a POCT platform with simple operating procedures for the measurement of tumor markers, clinical laboratories should be aware of stability issues when different types of blood specimens are practically utilized.

Impact of hematocrit levels on the accuracy of specific blood glucose meters: Ahospital-based study.

Blood glucose meters are commonly used at the bedside, but most of the meters used in Hung Vuong Hospital (Ho Chi Minh City, Vietnam) are built for self-monitoring and might not be suitable for determining glucose levels in patients. In this study, we aimed to validate the performance of six frequently used meters in our hospital using the Clinical & Laboratory Standards Institute (CLSI) standard, and investigate the hematocrit impact on the accuracy of these meters. A total of 135 pregnant women who underwent a 75-g oral glucose tolerance test consented to participate in the study at Hung Vuong Hospital. Whole blood glucose levels were measured in duplicate using meters, and hematocrit levels were measured using an Alinity h-series analyzer. Within 5 min, plasma glucose levels were measured twice in a row using the Cobas c502 reference analyzer. For accuracy and precision, the hematocrit effect was assed using CLSI POCT12-A3. Out of six evaluated meters, three meters qualified. For CLSI criterion at glucose concentration of 5.55 mmol/L, Accu-Chek Inform II, Accu-Chek Performa and OneTouch VerioVue achieved 97.31%, 98.08% and 99.62%, respectively. For CLSI criterion at 4.17 mmol/L, these three achieved 100%. Accu-Chek Inform II and Accu-Chek Performa showed an inverse correlation between glucose level and hematocrit with slopes of -0.500 (95% confidence interval -0.678 to -0.322) and -0.396 (95% confidence interval -0.569 to -0.224), whereas OneTouch VerioVue was not affected by hematocrit, with a slope of 0.207 (95% confidence interval -0.026 to 0.440). Blood glucose meters' measurements can be affected by hematocrit, and might provide readings not within an acceptable bias. Medical organizations need to verify or validate before using on patients.

Effect of hemolysis on D-dimer testing measured with the Improgen kit: is all manufacturer information correct?

D-dimer is a fibrin degradation product and its measurement is affected by hemolysis. This study was designed to reveal the value of hemolysis affecting D-dimer in our laboratory. In this study, hemolysate samples obtained by both mechanical and freezing methods were used. D-dimer levels of all plasmas were measured with Improgen Diagnostic kit by immune-turbidimetric method. Numerical change in hemolyzed samples was evaluated by calculating the percentage difference, and clinically significant differences were evaluated by calculating the maximum acceptable bias (MAB). In the hemolysate study prepared by both freeze-thaw and mechanical methods, it was observed that low D-dimer levels did not exceed the total allowable error (TAE) (30%) up to +2 hemolysis (corresponds to hemoglobin = 1.01-2 g/l) and did not exceed the MAB (65%) even at +4 hemolysis (corresponds to hemoglobin = 1.01-2 g/l). High D-dimer levels did not exceed the limit values of both TAE (30%) and MAB (68%) even in +4 hemolysis. The D-dimer test was affected by lower levels of hemolysis compared to both other studies and the values in the kit insert (hemoglobin >5 g/l corresponds to +4 hemolysis index). We verified the hemolysis interference in the D-dimer test, which we thought was not compatible with the kit insert, under our own laboratory conditions. This is the first hemolysis interference study performed with the Improgen brand d-dimer kit. In samples with a hemolysis rate of +2 and above, it would be more accurate to reject the D-dimer result as a 'hemolyzed sample'.

Consistency analysis of two fingertip capillary blood sampling methods for complete blood count

This study was performed to analyze fingertip capillary blood sampling in pediatric patients using microcapillary blood collection tubes and microhematocrit tubes and to compare the blood cell analysis results obtained via these two blood collection methods. Finger capillary blood was collected from 110 outpatients using microcapillary blood collection tubes and microhematocrit tubes and complete blood count analysis was performed with a Sysmex XS-900i hematology analyzer and manual microscopy for blood cell morphology. Paired data was evaluated for agreement and bias using the microhematocrit samples as the reference group and the samples from the microcapillary blood collection tubes as the observation group. The two blood collection methods demonstrated good agreement for measuring red blood cell (RBC) parameters (i.e., RBC, Hb, Hct, MCV, MCH and MCHC), wherein the relative bias was > allowable total error (TEa) in 0.91%, 1.82%, 11.82%, 1.82%, 0.91% and 8.18% of the parameter measures, respectively. According to industry requirements, the proportion of samples meeting the acceptable bias level should be > 80%. Additionally, the estimated biases at each medical decision level were within clinically acceptable levels for RBC, Hb, Hct, and MCV. However, the proportion of WBC and PLT counts with relative bias > TEa was 25.45% and 35.45%, respectively. Furthermore, the relative bias of the WBC count at the medical decision level of 0.5 × 109/L and that of the PLT counts at the medical decision levels of 10 × 109/L and 50 × 109/L were clinically significant. Bland–Altman analysis further showed a mean bias of 0.66 × 109/L (95% LoA, − 0.79 to 2.11) for the WBC count and 39 × 109/L (95% LoA, − 46 to 124) for the PLT count from the blood samples collected in the microcapillary blood collection tubes compared with the counts of those collected in the microhematocrit tubes. Neutrophil, monocyte, lymphocyte, eosinophil, and PLT counts increased significantly in the microcapillary blood collection tubes compared with those in the microhematocrit tubes, along with an elevated number of instrument false alarms (P < 0.05). The two capillary blood collection devices exhibit performance differences. Therefore, clinicians should pay attention to the variation in results caused by different blood collection methods.

A computational approach to understanding effort-based decision-making in depression.

Motivational dysfunction is a core feature of depression, and can have debilitating effects on everyday function. However, it is unclear which disrupted cognitive processes underlie impaired motivation, and whether impairments persist following remission. Decision-making concerning exerting effort to collect rewards offers a promising framework for understanding motivation, especially when examined with computational tools which can offer precise quantification of latent processes. Effort-based decision-making was assessed using the Apple Gathering Task, in which participants decide whether to exert effort via a grip-force device to obtain varying levels of reward; effort levels were individually calibrated and varied parametrically. We present a comprehensive computational analysis of decision-making, initially validating our model in healthy volunteers (N=67), before applying it in a case-control study including current (N=41) and remitted (N=46) unmedicated depressed individuals, and healthy volunteers with (N=36) and without (N=57) a family history of depression. Four fundamental computational mechanisms that drive patterns of effort-based decisions, which replicated across samples, were identified: an overall bias to accept effort challenges; reward sensitivity; and linear and quadratic effort sensitivity. Traditional model-agnostic analyses showed that both depressed groups showed lower willingness to exert effort. In contrast with previous findings, computational analysis revealed that this difference was driven by lower effort acceptance bias, but not altered effort or reward sensitivity. This work provides insight into the computational mechanisms underlying motivational dysfunction in depression. Lower willingness to exert effort could represent a trait-like factor contributing to symptoms, and might represent a fruitful target for treatment and prevention.

Creatinine-based formulas are not ideal to estimate glomerular filtration rate in selected pediatric patients: data from a tertiary pediatric nephrology center.

Evaluating glomerular filtration rate (GFR) remains challenging in pediatrics; new formulas were developed to increase performance of GFR estimation (eGFR). We aimed to evaluate the recently published formulas as applied to another pediatric population. A retrospective study was conducted in a cohort of 307 patients with a "kidney risk" (mean age 12.1 ± 4.5 years, sex ratio 1/1) assessed in a tertiary pediatric nephrology center and a mean measured GFR (mGFR) using plasma iohexol clearance of 85.5 ± 25.3 mL/min/1.73 m2; creatinine levels were measured by IDMS-standardized enzymatic method and cystatin C by immunonephelometry. The following eGFRs were calculated: Schwartz2009, Schwartz-Lyon, CKiDU25creat, and EKFC for eGFR using creatinine (eGFR-creat), CKiDU25cys and FAScys for eGFR using cystatin (eGFR-cys) as well as combined SchwartzCreat-Cys, average (CKiDU25creat-CKiDU25cys), and average (EKFC-FAScys) for eGFR using both biomarkers. The performance of the different formulas was evaluated compared to mGFR by absolute bias measurement and accuracy (p10%, p30%). Results are expressed as mean ± SD. Creatinine-based formulas and especially the new CKiDU25 and EKFC overestimate GFR, even in children with normal kidney function. However, the bias is constant with these two formulas whatever the age group or gender, contrary to the previously published formulas. In contrast, cystatin C-based equations and combined formulas showed good performance in all age groups and all medical conditions with an acceptable bias and p30%. In our pediatric population, the performance of all creatinine-based formulas is inadequate with significant GFR overestimation, mainly in subjects with mGFR > 75 mL/min/1.73 m2. Conversely, cystatin C-based or combined formulas have acceptable performance in patients followed in a tertiary pediatric nephrology unit.

Kinetic modeling of the monoamine oxidase-B radioligand [18F]SMBT-1 in human brain with positron emission tomography.

This paper describes pharmacokinetic analyses of the monoamine-oxidase-B (MAO-B) radiotracer [18F](S)-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline ([18F]SMBT-1) for positron emission tomography (PET) brain imaging. Brain MAO-B expression is widespread, predominantly within astrocytes. Reactive astrogliosis in response to neurodegenerative disease pathology is associated with MAO-B overexpression. Fourteen elderly subjects (8 control, 5 mild cognitive impairment, 1 Alzheimer's disease) with amyloid ([11C]PiB) and tau ([18F]flortaucipir) imaging assessments underwent dynamic [18F]SMBT-1 PET imaging with arterial input function determination. [18F]SMBT-1 showed high brain uptake and a retention pattern consistent with the known MAO-B distribution. A two-tissue compartment (2TC) model where the K1/k2 ratio was fixed to a whole brain value best described [18F]SMBT-1 kinetics. The 2TC total volume of distribution (VT) was well identified and highly correlated (r2∼0.8) with post-mortem MAO-B indices. Cerebellar grey matter (CGM) showed the lowest mean VT of any region and is considered the optimal pseudo-reference region. Simplified analysis methods including reference tissue models, non-compartmental models, and standard uptake value ratios (SUVR) agreed with 2TC outcomes (r2 > 0.9) but with varying bias. We found the CGM-normalized 70-90 min SUVR to be highly correlated (r2 = 0.93) with the 2TC distribution volume ratio (DVR) with acceptable bias (∼10%), representing a practical alternative for [18F]SMBT-1 analyses.

Performance of the non-invasive point-of-care device, EzeCheck, for haemoglobin assessment in adults and children in community and institutional care settings.

Anaemia is a major public health problem, especially in resource constrained settings. Dependency on assessment of blood hemoglobin (Hgb) concentration impedes anemia detection, risk stratification and intervention. Thus, valid, frugal and scalable technologies are needed. EzeCheck is a noninvasive portable device developed in India for predicting hemoglobin levels in human beings aged 4 years and above using a finger-tip biosensor. In this assessment, we aimed to: (i) evaluate EzeCheck's performance with an automated whole blood hemato-analyzer (Sysmex XN 1000) as the gold standard, and (ii) estimate EzeCheck's agreement with Sahli's method and HemoCue (Hb-301) in real-world primary and higher care facilities. Paired assessments were done at five sites across India i.e., Bhubaneshwar, Shimla, Solan and Mashobra and Ulhasnagar. Participants across all age groups (4 years and above) were assessed. We used a range of statistical tests to evaluate the performance of EzeCheck. It was found that EzeCheck performed well across age and gender categories with convincing validity, concordance, precision and accuracy, and acceptable bias. While comparing EzeCheck with Hemato-analyzer, no statistically significant systematic bias was found. However, EzeCheck showed significant systematic bias when compared to Sahli's method and HemoCue. We concluded that EzeCheck could detect anemia (as per WHO Hgb cut-offs) in 'real-world settings' and 'across age and gender categories', with high sensitivity, specificity and accuracy, and can serve as a replacement to traditional methods of hemoglobin assessment. Further, for countries with higher prevalence of anemia where universal screening may be mandated, the positive predictive value of EzeCheck will be higher. The likelihood ratios also indicated that the device had moderate-to-good utility. EzeCheck is suitable for embedment into program and out-patient health care settings in resource constrained contexts as a spot-check hemoglobinometer.

The role of analytical performance specifications in international guidelines and standards dealing with metrological traceability in laboratory medicine.

The goal of metrological traceability is to have equivalent results for a measurand in clinical samples (CSs) irrespective of the in-vitro diagnostic medical device (IVD-MD) used for measurements. The International Standards Organization standard 17511 defines requirements for establishing metrological traceability of values assigned to calibrators, trueness control materials and human samples used with IVD-MDs. Each step in metrological traceability has an uncertainty associated with the value assigned to a material. The uncertainty at each step adds to the uncertainty from preceding steps such that the combined uncertainty gets larger at each step. The combined uncertainty fora CS result must fulfil an analytical performance specification (APS) for the maximum allowable uncertainty (umax CS). The umax CS can be partitioned among the steps in a metrological traceability calibration hierarachy to derive the APS for maximum allowable uncertainty at each step. Similarly, the criterion for maximum acceptable noncommutability bias can be derived from the umax CS. One of the challenges in determining if umax CS is fulfilled is determining the repeatability uncertainty (u Rw) from operating an IVD-MD within a clinical laboratory. Most of the current recommendations for estimating u Rw from internal quality control data do not use a sufficiently representative time interval to capture all relevant sources of variability in measurement results. Consequently, underestimation of u Rw is common and may compromise assessment of how well current IVD-MDs and their supporting calibration hierarchies meet the needs of clinical care providers.

Understanding the limitations of your assay using EQA data with serum creatinine as an example.

Laboratories need to take into consideration the specificity and imprecision of assays not only in verification, but also of quality assessment. This study investigates the composition of serum used in EQA materials by comparing material from a single and multiple donors (pooled material), across multiple methods, using creatinine as an example. Sixteen different serum matrices were distributed as 36 specimens through the UK NEQAS for Acute and Chronic Kidney Disease Scheme from March 2022 to March 2023. Male-only and female-only serum was used as single donations, pooled donations, unmanipulated or with addedexogenous creatinine. Specimens were distributed to primarily UK participants (approximately n=500) for creatinine analysis. Data has been reviewed by method compared to the enzymatic creatinine method principle mean. From the 16 different matrices, only the enzymatic creatinine assay systems from Roche Cobas and Siemens Atellica met the minimum acceptable bias goal, from biological data, of 5.6 %, in all specimens. Pooled material showed less variation in bias across all methods. Since Laboratories invest a lot of time and money in quality management, they need to know the limitations of their assays so that they are not investigating 'apparent' EQA/IQC problems which are purely due to non-specific, imprecise assay, rather than an analytical issuein their laboratory. When large numbers of individual donations are combined, interferents are essentially diluted out. Therefore, if EQA material is of this type it will be very difficult to determine the actual assay's bias and variability.