Desirable Specifications Research Articles

Development and workflow of a separation process for optimum design: A case of phenylenediamine

AbstractAn industrial project based upon the multi‐scale objective‐oriented process development (MOPD) method for developing an optimum process for separating phenylenediamine (PDA) isomers was executed. This article reports the first four (4) steps of that project. In the first step, the solution for this separation problem was conceptualized. It is a distillation‐crystallization‐hybrid process. The second step is to validate the concept experimentally from the thermodynamic point of view followed by kinetic considerations. It was found that a 2‐stage crystallization is required to purify the main product isomers to the desirable specification that is higher than 99.5 mol%. A heat and material balance model was then constructed for analyzing and optimizing various design variables, also used to understand the operability of the process. Finally, with proper HAZOP analysis and detailed engineering, the pilot unit was designed. Throughout the project, all exercises and efforts are well focused with clear objectives, hence there are minimum detours on the execution; furthermore, the clear objectives enhanced the communications among various disciplines tremendously. It is a valuable asset for senior management in the allocation of resources and budgets.

B-173 Cystine Analysis in Urine Sample Using the Laser Diode Thermal Desorption technique “LDTD”/Mass Spectrometry (Luxon)

Abstract Background Cystine is a polar amino acid found in the urine of healthy individuals; however, a genetic defect in renal transport can lead to cystine crystals and stones. A usual laboratory approach for diagnosing and monitoring cystinuria is to measure cystine concentration in 24-hour urine. The disease is rare, affecting around 1 in every 10,000 live births. The objective of this study was to develop a rapid assay using Tandem Mass Spectrometry methodology with an internal standard of Cystine derivatized in a urine sample, Luxon Ion Source®, Laser Diode Thermal Desorption (LDTD) technology. Methods The Luxon is a sample introduction and ionization source with a coupled laser diode, providing thermal uniformity, precision, accuracy and speed. Thermally desorbed neutral molecules are analyzed by mass spectrometry (MS). Initially, the sample was derivatized to make the cystine thermally vaporize, followed by liquid-liquid extraction assisted by salting out (SALLE). The isotope-labeled internal standard (Cystine-d4), homemade calibration curve and water quality controls were used for quantification. The analysis was performed using a Sciex 6500+ Triple Quad in APCI (Atmospheric Pressure Chemical Ionization) positive mode. The ratio of peak area to internal standard (ISTD) was used to normalize the signal. A linear regression model with 1/X2 weighting was used to obtain the calibration curve equation and determine the correlation coefficient (r2). Parallelism was assessed by comparing the (r2) of calibration curves prepared in water with six curves prepared with biological matrices. Intra- and interassay precision and accuracy were determined by measuring control samples ranging from low to high concentration in five replicates over 3 consecutive days. For urine analysis, aqueous calibration curves in the concentration range of 1 to 100 mg/L (n=3) showed excellent linearity. The following parameters were evaluated for quantitative analysis: linearity, precision, accuracy, carryover and parallelism.​ Results The calibration curve resulted in a linear response across the entire concentration range, the correlation coefficient (r) was 0.99. For each quality control concentration, CVs were <10%, meeting desirable imprecision and precision specifications. The intraassay CVs were 1.0-2.56% and the interassay CVs were 2.15-4.58% for precision, which reflects the agreement between repeated measurements. Precision results showed similar results, intra-assay CVs were 2.23-3.66% and inter-assay CVs were 1.0-2.77% Conclusions The new LDTD-MS/MS method for the determination of urinary Cystine was accepted after verification and validation of quality control parameters. The technique proved to be effective for reliably and quickly quantifying cystine in urinary samples from human patients, being a valuable tool in the diagnosis and prevention of cystine kidney stones. The assay developed, using the Luxon Ion Source®, based on LDTD (Laser Diode Thermal Desorption) technology, proved to be ultrafast for measuring derivatized cystine in urine

B-174 Quantification of vitamin C in serum as a biomarker using the Laser Diode Thermal Desorption technique “LDTD”/Mass Spectrometry (Luxon)

Abstract Background Ascorbic acid (AA) or vitamin C, is a crucial substance that is involved in numerous physiological processes in living beings, including collagen production and antioxidant activity. When ascorbic acid is exposed to moisture, air, heat, light and oxygen, it oxidizes and turns into dehydroascorbic acid (DHAA). Our objective is to describe the sample preparation procedure and total quantification of AA and DHAA in human serum sample based on LDTD-MS/MS, and demonstrate its efficiency in quantification, combined with analysis selectivity and rapidity. Methods The Luxon is a sample introduction and ionization source that used a fiber-coupled laser diode to thermally desorb neutral molecules and charge them using a corona needle so they can be analyzed by mass spectrometry. Due to the instability of ascorbic acid, plasma samples were enriched and stabilized with an acidic solution. Sample preparation utilized a phosphate-containing buffer to minimize interferents and help volatize the analyte, followed by a precipitation step using acetonitrile to further clean the extract. Stable isotope-labeled internal standard (13C6 ascorbic acid) and homemade calibration curve and water quality controls were used for quantification. The analysis was performed using a Sciex 6500+ Triple Quad in APCI (Atmospheric Pressure Chemical Ionization) negative mode. Calibration curves ranging from 1 to 100 μg/mL and QCs were prepared in ascorbic acid-depleted serum (kept at room temperature/exposed to light for 4 days). The peak area against the internal standard (IS) ratio was used to normalize the signal. The calibration curves were plotted using the peak area ratio and the nominal concentration of standards. The following parameters were assessed for quantitative analysis: linearity, precision, accuracy, carryover and parallelism. A linear regression model with 1/X2 weighting was used to obtain the calibration curve equation and determine the correlation coefficient (r2). Parallelism was assessed by comparing the correlation coefficient of calibration curves prepared in water to six curves prepared with biological matrixes. Intra and inter assay precision and accuracy were determined by measuring QC samples ranging from low to high concentration in five replicates for 3 consecutive days. Results Calibration curves (n=3) showed excellent linearity. The calibration curve resulted in a linear response throughout the concentration range, the correlation coefficient was 0.99. For each quality control concentrations CVs were <10% complying with desirable specifications for imprecision and accuracy. Intra-assay CVs were 3.0-8.89% and inter-assay CVs were 7.64-9.79% for precision which reflects the agreement between repeated measurements. The results for accuracy showed similar results, intra-assay CVs were 3.83-9.20% and inter-assay CVs were 5.0-9.7%. Conclusions The new LDTD-MS/MS method described here has been validated as an effective technique to reliably and rapidly quantify ascorbic acid. Simple sample preparation, rapid acid stabilization combined with high yield allow analysis without degradation responses.

Extent of Equivalence of Results for Urine Albumin among 3 Candidate Mass Spectrometry Reference Measurement Procedures.

Urine albumin (UA) is an important biomarker of chronic kidney disease. Current in vitro diagnostic medical devices (IVD-MDs) for measuring UA are not standardized, and median results among IVD-MDs differ by approximately 45%. Since fixed decision values are used to interpret UA, higher-order reference measurement procedures (RMPs) are needed for metrological traceability. Three candidate liquid chromatography-tandem mass spectrometry RMPs have been developed for UA. Eight single-donation human urine samples were measured by 3 candidate RMPs. Results were compared using t-test and variance component analysis. The mean results for each urine sample from each RMP laboratory were not statistically different from the overall mean value by t-test. The median total CV including contributions from bias and imprecision among the 3 RMP laboratories was 6.23% using variance component analysis for each sample. The allowable bias to the RMP for an end-user IVD-MD was ≦9.0% or ≦3.0% based on the desirable or optimal total allowable error of 30% or 24%, respectively. A maximum allowable standard uncertainty for an RMP result was determined to be 4.3% or 3.3% for desirable or optimal performance, respectively. The standard uncertainties for all of the RMP laboratories meet the desirable and optimal standard uncertainty specifications. The candidate RMPs for UA in these 3 laboratories have suitable agreement of results and uncertainties for use as higher-order RMPs in the metrological traceability of end-user IVD-MDs for measuring UA.

Assessing the stability of uncentrifuged serum and plasma analytes at various post-collection intervals

Abstract Objectives Our study aimed to assess the stability of 26 biochemistry analytes in serum or plasma samples separated from blood samples centrifuged at different time intervals after collection, simulating sample transport via despatch delivery systems. Methods Blood from forty-one volunteers were collected using five serum separator tubes (SST) and five fluoride oxalate tubes (FOT) for each volunteer following written informed consent. Each of the five tubes in both groups of SST and FOT was centrifuged at one of the time intervals: 0.5 h, 4 h, 8 h, 12 and 24 h after collection. These samples were left standing prior to centrifugation at room temperature. We calculated the percentage difference for each analyte between the 0.5 h and other time intervals to assess analyte stability. The percentage difference was compared to the desirable specification for bias and reference change value (RCV). Results Mean concentration of serum potassium showed a significant increase in the percentage RCV after 8 h, while CKMB showed an increase after 12 h of delayed centrifugation compared to the baseline (0.5 h). There were no significant percentage RCV for the other analytes at all timelines. Conclusions Serum potassium and CKMB were stable up to 8 and 12 h of delayed centrifugation respectively whilst all other analytes appear stable up to 24 h, suggesting that sample transport delay of up to 8 h, with the condition that room temperature is maintained, may not have a significant impact on accuracy of the biochemistry/immunochemistry test results.

Comparison of lipemia interference created with native lipemic material and intravenous lipid emulsion in emergency laboratory tests.

This study aimed to investigate the effects of lipemia on clinical chemistry and coagulation parameters in native ultralipemic (NULM) and intravenous lipid emulsion (IVLE) spiked samples. The evaluation of biochemistry (photometric, ion-selective electrode, immunoturbidimetric method), cardiac (electrochemiluminescence immunoassay method) and coagulation (the viscosity-based mechanical method for prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen and the immunoturbidimetric method for D-dimer) parameters were conducted. In addition to the main pools, five pools were prepared for both types of lipemia, each with triglyceride (TG) concentrations of approximately 2.8, 5.7, 11.3, 17.0 and 22.6 mmol/L. All parameters' mean differences (MD%) were presented as interferographs and compared with the desirable specification for the inaccuracy (bias%). Data were also evaluated by repeated measures of ANOVA. Prothrombin time and APTT showed no clinically relevant interference in IVLE-added pools but were negatively affected in NULM pools(P < 0.001 in both parameters). For biochemistry, the most striking difference was seen for CRP; it is up to 134 MD% value with NULM (P < 0.001) at the highest TG concentration, whereas it was up to - 2.49 MD% value with IVLE (P = 0.009). Albumin was affected negatively upward of 5.7 mmol/L TG with IVLE, while there was no effect for NULM. Creatinine displayed significant positive interferences with NULM starting at the lowest TG concentration (P = 0.028). There was no clinically relevant interference in cardiac markers for both lipemia types. Significant differences were scrutinized in interference patterns of lipemia types, emphasizing the need for careful consideration of lipemia interferences in clinical laboratories. It is crucial to note that lipid emulsions inadequately replicate lipemic samples.

Comparable analysis of six immunoassays for carcinoembryonic antigen detection

ObjectiveThis study aimed to assess the current status of carcinoembryonic antigen (CEA) detection. We evaluated the correlation, consistency, and comparability of CEA results among six automated immunoassays, and combined with the results of CEA trueness verification of the Beijing Center for Clinical Laboratories (BCCL) for further analysis. MethodsAbbott Architect i2000, Beckman DxI800, Roche Cobas E601, Diasorin Liaison XL, Maccura IS1200, and Autolumo A2000 were used to detect 40 individual serum CEA samples. Taking the optimal analytical quality specifications calculated from data on biological variation as the evaluation criterion. Passing-Bablok regression and Bland-Altman analysis were performed between each assay and all-assays median values to evaluate the correlation and relative difference. The concordance correlation coefficient (CCC) was used for consistency analysis. Additionally, the trueness verification program used samples at three concentration levels to assess the bias, coefficient of variation (CV), and total error (TE) between the average measured values and the target value. ResultsThe Spearman's rank correlation coefficient (rs) was ≥0.996 and the CCC ranged between 0.9448 and 0.9990 for each assay vs. all-assays median. Considering the all-assays median value of each sample as a reference, there were proportional and systematic differences according to the Passing-bablok regression analysis. The relative difference of the four assays (Abbott Architect i2000, Autolumo A2000, Diasorin Liaison XL, and Maccura IS1200) met the optimal analytical quality specifications. On the other hand, Beckman DxI800 (13.2 %) and Roche Cobas E601 (−9.0 %) were only able to fulfill the desirable analytical quality specifications. The average pass rates for bias, CV, and TE of the trueness verification program were 80 %, 98 %, and 96 %, respectively. ConclusionsThe six automated immunoassays vs. all-assays median have a good correlation in CEA detection. However, there is a lack of comparability of CEA results. Further improvements are needed in harmonization among CEA detections.

Validacija epruveta male zapremine za prikupljanje krvi za rutinsko hematološko testiranje

Background: Low-volume blood tubes offer several advantages in facilitating blood collection, reducing iatrogenic anemia and spurious hemolysis, but their clinical reliability must be validated. We planned this investigation for establishing the reliability of routine hematologic testing in low-volume tubes before their implementation into clinical practice. Methods: Blood was drawn from 44 ostensibly healthy laboratory professionals into three blood tubes, as follows: 3.0 mL of blood into a 3.0 mL K2EDTA standard reference blood tube, 0.5 mL of blood into a second 3.0 mL K2EDTA standard blood tube, and 0.5 mL of blood into a 0.25-0.5 mL K2EDTA low-volume blood tube. Hematologic testing was performed on Sysmex XN-10 hematology analyzer. Results: Statistically significant differences were observed in total white blood cell count, neutrophil count, lymphocyte count, red blood cell count, platelet count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and mean platelet volume in both 0.5 mL-filled 3.0 mL standard blood tubes and 0.5 mL-filled low-volume blood tubes. Although none of these variations was found to be clinically significant in the 0.5 mL-filled low-volume blood tube compared to the desirable specifications, hematocrit, MCV and MCHC displayed a clinically significant bias in the 0.5 mL filled 3.0 mL K2EDTA standard blood tube. Conclusions: These results suggests that K2EDTA low-volume blood tubes could safely replace standard blood tubes for preventing the receipt of insufficient samples, but also for facilitating blood collection in patients with difficult veins and reducing the risk of iatrogenic anemia and spurious hemolysis.

Sigma Metrics in Thyroid Testing: Striving for Perfection- An Observational, Cross-sectional Study

Introduction: Six Sigma is a potent tool for evaluating the quality of the analytical phase by combining bias, imprecision, and Total Allowable Error (TEa). Considering the variation in TEa values from different sources, analysis on the sigma scale needs to be carefully monitored. Aim: To assess the performance of Thyroid Stimulating Hormone (TSH) and free Thyroxine (fT4) on the Sigma scale. Materials and Methods: The present observational, cross- sectional study Immunoassay laboratory at the Department of Biochemistry, IPGMER and SSKM Hospital, Kolkata, India, from February 2021 to January 2022. The study involves 12 months of tri-level (L1, L2, L3) Internal Quality (IQ) control data and External Quality Assessment (EQAS) data. The bias percentage was obtained from EQAS, and the Coefficient of Variation (CV%) was obtained from IQ Control (IQC) data run on Advia Centaur CP (CLIA) each month. Sigma (σ) was calculated applying TEa from the desirable biological variation database. Sigma values of L1, L2, L3 of TSH and fT4 have been calculated using Microsoft spreadsheet software version 2010, applying the formula σ= (TEa-bias)/CV. Results: The CV% and bias% were found to be within an acceptable range, always less than the cut-off percentage of imprecision (I%) and inaccuracy (B%) for TSH and fT4 in the desirable specifications for imprecision and inaccuracy (updated 2014). However, sigma levels are near the satisfactory mark, found to be &lt;5σ over 17 months for TSH and 23 months for fT4, considering all sigma values of L1, L2, and L3 IQ levels. Better sigma values (&gt;5σ) in tri-level IQ for TSH with a higher numeric TEa% value (23.7%) were obtained in more months, whereas for fT4 with a lower TEa% value (8%), better sigma values (&gt;5σ) were obtained in a lesser number of months. Conclusion: The present study establishes that Sigma values are affected by the numeric values of TEa% of a particular parameter taken from the source. Sigma values showed average performance despite satisfactory CV% and bias% for fT4 and TSH, creating chaos in the laboratory’s operational routine. The Sigma matrix is a good indicator, but it is difficult to maintain a good sigma value for parameters that have low TEa%. It becomes crucial to choose appropriate TEa to plan a quality control strategy for thyroid hormones.

A Compact Microwave Quadrature Hybrid Coupler Using Capacitive Composite Lines and Meandered Stubs

In this paper, a new structure of the quadrature hybrid coupler (QHC) with compact size is proposed using capacitive composite lines and meandered open stubs. The proposed coupler works at 1.6 GHz with a 0.4 GHz bandwidth, which shows 25% fractional bandwidth (FBW). The proposed QHC occupies only 15 mm × 15 mm (0.12 λ × 0.12 λ), while the typical QHC size is 32 mm × 32 mm (0.25 λ × 25 λ) at the same working frequency. In the designed structure, two symmetric meandered stubs and two symmetric π-shaped composite networks including capacitors and microstrip lines are applied together. The designed QHC has a small size and occupies only 22% of the area of the conventional QHC, resulting in a 78% size reduction. The designed prototype has been analyzed, fabricated and tested, and the experimental results verify the simulated and analysis results. The results show a better than 27 dB return loss, more than 28 dB isolation between the output ports and less than 0.4 dB insertion loss at the working frequency of 1600 MHz. With the achieved desirable specifications, the fabricated QHC is a suitable choice for wireless microwave applications.

Biological variation of serum neopterin concentrations in apparently healthy individuals.

The aims of this study were to determine the biological variation (BV), reference change value (RCV), index of individuality (II), and quality specifications for serum neopterin concentrations; a measurand provided by clinical laboratories as an indicator of cellular immunity. The study delivered serum samples collected for 10 consecutive weeks from 12 apparently healthy individuals (3 male, 9 female). Serum neopterin concentrations were measured using high-performance liquid chromatography with fluorometric detection. The data analysis was performed using an online statistical tool and addressed published criteria for estimation of biological variation. The mean neopterin concentration was 5.26 nmol/L. The within-subject biological variation (CVI) with 95 % confidence interval (CI) of neopterin serum concentrations was 11.54 % (9.98-13.59), and the between-subject biological variation (CVG) with 95 % CI was 43.27 % (30.52-73.67). The neopterin asymmetrical RCV was-24.9 %/+33.1 %, and the II was 0.27. The desirable quality specifications for neopterin were <5.77 % for precision, <11.20 % for bias, and <20.72 % for total allowable error (TEa). When analytical variation was used instead of CVI to calculate TEa, the desirable TEa was <18.39. This study determined BV data for neopterin, an indicator of cell-mediated immune response. Asymmetric RCV values, of 24.9 % decrease or a 33.1 % increase between consecutive measurements indicate significant change. The II of 0.27 indicates a high degree of individuality, therefore that it is appropriate to consider the use of personal reference data and significance of change rather than the reference interval as points of reference for the evaluation of neopterin serum concentrations.

A-161 Analytical Performance of Reagents for Determination of Activated Partial Thromboplastin Time: A Sigma Metric Perspective

Abstract Background Sigma Metric (SM) assesses the degree of deviation of lab. tests from established specifications, combining Total Acceptable Error (ETa), imprecision and analytical bias. Quality criteria, defined by models of desirable specification, are used to determine the analytical performance of lab. tests. The concepts of biological variation are used as the preferred approach for establishing specifications. Reagents (RE) for the determination of activated partial thromboplastin time (APTT) use thromboplastin obtained from different tissue extracts and activation factors, being standardized to reduce the variability of the tests, and ensure equivalence of clinical diagnosis. This work evaluated three RE for APTT and the fulfillment of the desirable specifications of analytical quality, using the SM as an analysis tool. Material &amp; methods APTT determinations were performed on the Sysmex®CS-2500 (Siemens Healthineers) with Actin®FS (AFS), Actin®FSL (FSL), and Pathromtin®SL (PSL) RE and bi-level Control Plasma N (CN) and Ci-Trol®2 Control (CI). Two different lots were used for each RE and control (CT), and the results were analyzed in RE-CT combination. We determined (a)analytical bias (Bias), from intra-assay imprecision determined by 30 repetitions in a single analytical run and by comparison with manufacturer's data, and (b)analytical coefficient of variation (CVa), from inter-assay imprecision, by triplicate in 3 periods each 3 h, for the 2 CT levels. Analytical quality specifications for APTT were selected in the literature, adopting desirable ETa values of 4.5% and minimum of 6.7%, obtained from a database for biological variation and acceptable limit of 15%, based on CLIA-CAP. SM was calculated with formula: Sigma = ETa–Bias/CVa, with graphic representation adapted from the Westgard’s model. Results For CVa, AFS and FSL results with CN and CI were &amp;lt;1.0%. PSL presented results above 1.0% for CN and CI. All RE presented results lower than those recommended by the manufacturer, respectively 4.0% for AFS; 3.0% for FSL; and 2.8% for PSL. For bias, a greater variation was observed for the combinations of RE and CT, ranging from 1.16% to 4.07%, being related to the differences between the averages obtained and the values defined in the leaflets. For the desirable specification of ETa (4.5%), 3 combinations of RE and CT level AFS-CN, FSL-CN and PSL-CI presented Sigma values &amp;gt;3 (respectively, 3.61, 3.87 and 3.33). When using the minimum specification (6.7%), the PSL-CN combination presented a Sigma = 2.06. With the CLIA-CAP specification, all RE and CT combinations had Sigma &amp;gt;6. Discussion All RE showed similar analytical performance when compared by SM, demonstrating that different commercial formulations for APTT determination do not show differences in analytical Bias and CVa determinations. The graphical representation by SM allows you to visually compare analytical imprecision and inaccuracy values. Conclusion All RE showed no differences in analytical performance, with SM being a visual tool for analyzing and comparing RE performance.

Incomplete filling of spray-dried K2EDTA evacuated blood tubes: impact on measuring routine hematological parameters on Sysmex XN-10.

Because there is little published evidence on the effects of incomplete filling of K2EDTA evacuated blood tubes on routine hematological testing, this original study aimed to provide updated information on this preanalytical aspect. The study population consisted of 17 ostensibly healthy volunteers. Blood was drawn by venipuncture with a 10 mL syringe and dispensed in varying amounts (0.2, 0.5, 1.0, 2.0, and 3.0 mL) into 3.0 mL blood tubes containing spray-dried 5.4 mg K2EDTA. All tubes were gently mixed and used to perform routine hematology tests on the Sysmex XN-10. Clinically significant variations were defined when the limits of desirable specifications of bias derived from biologic variation were exceeded. The desirable bias was exceeded in 33 % filled tubes (1.0 mL) for hematocrit and MCV (increased values) and for MCHC (decreased values), while it was exceeded in 17 % filled tubes (0.5 mL) for hemoglobin, hematocrit and MCV (increased values), and for MCHC (decreased values). Finally, the variation of values was higher than the desirable bias for RBC, hemoglobin, hematocrit and MCV (increase), and for MCHC and MPV (decrease) in 7 % filled tubes (0.2 mL). No clinically significant variations were observed in tubes filled up to 67 % of their nominal volume (i.e.,2.0 mL). Consideration should be given to reject spray-dried K2EDTA blood tubes that contain a blood volume <67 % of the nominal fill volume, as biased laboratory data in these samples may interfere with clinical decision making and care management.

Design of a robust and practicable SSI damping controller using H[formula omitted] technique for series compensated DFIG-based wind farms

This paper designs a robust and practicable subsynchronous interaction (SSI) damping controller using H∞ technique for the safe operation of series capacitor compensated wind farms (WFs) with doubly-fed induction generator (DFIG) wind turbines (WTs). Mixed sensitivity control design together with pole placement are formulated into a set of linear matrix inequalities (LMIs) to obtain the controller parameters. The LMI technique allows to include both desirable frequency and time domain specifications. The proposed damping controller is integrated into the WT controller (WTC) and receives the DFIG converter currents as inputs. The implementation of the proposed controller does not require any communication links between the WTs and WF secondary control layer. The controller output signals are applied to the inner control loops of DFIG converters and are dynamically limited for the desired fault-ride-through (FRT) performance. The effectiveness of the damping controller is verified through detailed electromagnetic transient (EMT) simulations. In these simulations, the complete medium-voltage (MV) collector grid is modeled with all details, and it is assumed that the wind speed at the location of each turbine follows a Gaussian distribution. The collected results confirm the accuracy of the modeling of the entire WF as an aggregated WT with the average wind speed.

Electrochemical Ionic Synapses: Progress and Perspectives.

Artificial neural networks based on crossbar arrays of analog programmable resistors can address the high energy challenge of conventional hardware in artificial intelligence applications. However, state-of-the-art two-terminal resistive switching devices based on conductive filament formation suffer from high variability and poor controllability. Electrochemical ionic synapses are three-terminal devices that operate by electrochemical and dynamic insertion/extraction of ions that control the electronic conductivity of a channel in a single solid-solution phase. They are promising candidates for programmable resistors in crossbar arrays because they have shown uniform and deterministic control of electronic conductivity based on ion doping, with very low energy consumption. Here, the desirable specifications of these programmable resistors are presented. Then, an overview of the current progress of devices based on Li+ , O2- , and H+ ions and material systems is provided. Achieving nanosecond speed, low operation voltage (≈1V), low energy consumption, with complementary metal-oxide-semiconductor compatibility all simultaneously remains a challenge. Toward this goal, a physical model of the device is constructed to provide guidelines for the desired material properties to overcome the remaining challenges. Finally, an outlook is provided, including strategies to advance materials toward the desirable properties and the future opportunities for electrochemical ionic synapses.

Evaluation of four automated clinical analyzers for the determination of total 25(OH)D in comparison to a certified LC-MS/MS.

The aim of this study was to compare the results of five methods for the determination of total 25(OH)D. For that purpose, two mass spectrometry and three immunoassay methods were used. A total of 124 serum samples were analyzed on five different methods (i.e.,a reference LC-MS/MS, Cascadion, Lumipulse, Roche Elecsys II and Roche Elecsys III). Analytical performance against LC-MS/MS was evaluated and compared to the Milan models 1 (analytical performance based on the clinical outcome using thresholds of 12,20 and 30ng/mL) and 2 (analytical performance based on biological variation). Additionally, imprecision studies and accuracy using NIST SRM972a samples were carried out. Compared to the reference LC-MS/MS method, theLumipulse and the Roche Elecsys III assays reached theoptimal criterion for bias, while the Cascadion met the desirable one. The Roche Elecsys II was not able to reach theminimal criteria. The proportion of correctly classified patients was higher using the Cascadion (95.2%) compared to the three immunoassays. In addition to its better precision, the Cascadion was not impacted by a high concentration of3-epi-25(OH)D3 compared to the three immunoassays. Compared to the LC-MS/MS reference method, the Cascadion presented the highest level of concordance atmedical decision cut-offs for total 25(OH)D and reached the desirable specification for bias. Moreover, the presence of 3-epi-25(OH)D3 in enriched samples was only problematic in immunoassay methods, and especially considering Roche Elecsys methods. The release of performant fully automated mass spectrometry assays with high throughput might therefore facilitate the wide scale adoption of LC-MS/MS, even in non-specialized clinical laboratories.

Evaluation of Measurement Performance of Routine Chemistry Analytes by Application of Sigma Metrics, Method Evaluation Decision (MEDx) Charts and Quality Goal Index (QGI)

Objective: To evaluate performance of routine chemistry analytes in a tertiary care hospital laboratory by the application of sigma metrics. Introduction: Six sigma (6σ) is a popular Quality Management System (QMS) tool. Laboratories are increasingly using the six sigma method for the objective assessment and comparison of the analytical methods and instrument performance. Six sigma is about measuring or counting the number of defects. It quantifies the performance of a process as a rate of Defects-Per-Million-Opportunities (DPMO or DPM). The aim is to assess the performance and to eliminate or reduce the variation in a process. Materials and Methods: This prospective study was conducted over a period of six months duration. Sigma metrics were calculated using coefficient of variation (%CV), %Bias and total allowable error (%TEa). For %CV we used Internal Quality Control (IQC) samples, at two levels L1 and L2. Daily IQC results of L1 and L2 for 25 routine chemistry analytes were recorded in an excel sheet and %CV was calculated for each analyte for the period of study. For each analyte %Bias was calculated based on values obtained from monthly RIQAS-EQA program data. The total allowable error (%TEa) values for each analyte were extracted from various sources like Clinical Laboratories Improvement Amendment act (CLIA), Canadian Fixed Limits from the College of Physicians and Surgeons of Saskatchewan (CFX) and Spanish Society of Clinical Chemistry and Molecular Pathology (SEQC) table of Desirable Quality Specifications based on Biological Variation (BV) criteria for acceptable performance. Sigma values were calculated. The minimal acceptable performance criteria was considered as 3 sigma. Normalized MEDx charts were used to plot sigma metrics to visually present the performance. Quality Goal Index (QGI) analysis was carried out as a part of Root Cause Analysis (RCA). Results: Highest sigma value of 16.7 was noted for HDL-C and the lowest of 2.08 for chloride at level L1. Many analytes like ALP, Amylase, AST, CK, GGT, HDL-C, Magnesium and Uric Acid attained world class quality performance at both levels L1 and L2 with sigma levels of &gt;6. Many other analytes showed satisfactory performance with sigma levels of &gt;3. Sodium, potassium, chloride and urea did not show a satisfactory performance. Conclusion: Sigma metrics evaluation of analytical performance of our laboratory showed an acceptable performance for a wide range of analytes in patient samples.

Evaluation of analytical performance of homocysteine LC-MS/MS assay and design of internal quality control strategy.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has become a common technique in clinical laboratories in recent years. Because most methods are laboratory-developed tests (LDTs), their reproducibility and quality control (QC) have been controversial. In this study, Westgard Sigma Rules were used to evaluate the analytical performance and establish an individualised internal QC (IQC) strategy for these LDTs. Taking the LC-MS/MS LDT method for homocysteine (Hcy) as an example, the 'desirable specifications' from the Biological Variation Database were used as quality goals. Based on the external quality assessment (EQA) samples, bias was calculated and the coefficient of variation (CV) was also calculated by IQC measurements for six consecutive months. The analytical performance was evaluated by calculated sigma metrics and an IQC strategy was designed using the Westgard Sigma Rules with run size. Over 116days within 6months, a total of 850 data points were collected for each of IQC 1 and IQC 2. The monthly coefficient of variation CV% was 2.57-4.01%, which was non-significant (p-value: 0.75). The absolute bias% for IQC1 and IQC2 was 1.23 and 1.87%, respectively. The allowable total error (TEa) was selected as 15.5%, Sigma metrics were 4.02 and 4.30, and the analytical performance was 'Good'. The 13s/22s/R4s/41s multi rules (n=4, r=1) with a run size of 200 samples were suggested for the Hcy IQC scheme. The quality goal index (QGI) values were over 1.2, indicating that trueness needed to be improved. The analytical performance of the Hcy LC-MS/MS LDT conformed to the Six Sigma rating level, achieving 'good' (four Sigma). Clinical practice indicated that calibration bias was the primary factor affecting trueness.

Evaluation laboratory prenatal screening performance based on biological variation of risk assessment in second trimester in China

Abstract Objectives This study intends to evaluate prenatal screening risk assessment performance based on biological variation to help clinical laboratories realize their own screening performance and set the appropriate performance specifications for prenatal screening risk assessment in China. Methods Fifteen samples with detailed clinical information were distributed to participants and the prenatal screening Down syndrome risk assessment of each sample were submitted. Three levels of performance specification (optimum, desirable, minimum) derived from biological variation were used to evaluate laboratory prenatal screening risk assessment performance. Results A total of 797 laboratories participated in the survey project. There are 216 laboratories using serological double-marker test and 581 laboratories using serological triple-marker test. For each screening protocol, more than 92.00% laboratories meet minimum performance specifications, more than 84.00% laboratories meet desirable performance specifications, and only about 62.50%laboratories meet optimum performance specifications. The Feltz and Miller test indicated that there were no significant statistical differences in the RCV for double-marker screening in 5 platforms and triple-marker screening in 6 platforms. Conclusions The risk assessment of prenatal screening in the second trimester in China can be improved further. It is appropriate to choose desirable performance specifications for external quality assurance organizations to evaluate the risk assessment performance.

Managing ethylenediaminetetraacetic acid (EDTA) interference in EDTA contaminated samples - selectivity in reporting analytes.

The widely accepted practice of not reporting any results from ethylenediaminetetraacetic acid (EDTA) contaminated samples necessitates repeat phlebotomy and could delay clinical management decisions. EDTA, however, interferes variably or not at all in assays. EDTA concentration in contaminated samples, like serum indices, therefore, could be used to selectively report the result of analytes not affected at measured EDTA concentration. A serum pool, level 1 and level 3 internal quality control materials were spiked with tripotassium-EDTA to create samples with EDTA concentration up to 6.0mmol/L. EDTA and 45 common and critically important analytes were measured on Abbott Architect to identify EDTA concentrations for analytes where the change in concentration exceeded their respective reference change value (RCV) for unidirectional change at 95% probability. Serum potassium increased and calcium decreased exceeding RCV at 0.17mmol/L EDTA. Alkaline phosphatase (ALP) decreased exceeding RCV at EDTA >1.86mmol/L. The decrease in iron did not exceed a wide RCV of 61.9% until maximum spiked EDTA but exceeded the desirable specification for allowable total error (30.7%) at EDTA >1.86mmol/L. The small decrease in magnesium did not exceed RCV. EDTA up to the concentration in blood collection tubes did not affect the results of any other measured analyte. Only serum potassium, calcium, ALP and iron studies, of the 45 analytes studied, should not be reported in EDTA contaminated samples. EDTA concentration cut-offs for selective reporting would further facilitate reporting of these analytes in EDTA contaminated samples.