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  • Original Article2022-03-01 Clinical Chemistry

    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

    Hyun Suk Yang , M.D., Ph.D., Mina Hur , M.D., Ph.D., Kyeong Ryong Lee , M.D., Ph.D., Hanah Kim , M.D., Ph.D., Hahn Young Kim , M.D., Ph.D., Jong Won Kim , M.D., Ph.D., Mui Teng Chua , M.D., Win Sen Kuan , M.D., Horng Ruey Chua , M.D., Chagriya Kitiyakara , M.D., Phatthranit Phattharapornjaroen , M.D., Anchalee Chittamma , Ph.D., Thiyapha Werayachankul , M.Sc., Urmila Anandh , M.D., Sanjeeva Herath , M.B., Ch.B., Zoltan Endre , M.D., Ph.D., Andrea Rita Horvath , M.D., Ph.D., Paola Antonini , M.D., and Salvatore Di Somma , M.D., Ph.D. on behalf of the GREAT Network

    Ann Lab Med 2022; 42(2): 178-187

    Abstract : 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

  • Original Article2022-03-01 Diagnostic Immunology

    Comparison of Non-Invasive Clinical Algorithms for Liver Fibrosis in Patients With Chronic Hepatitis B to Reduce the Need for Liver Biopsy: Application of Enhanced Liver Fibrosis and Mac-2 Binding Protein Glycosylation Isomer

    Mina Hur , M.D., Ph.D., Mikyoung Park , M.D., Ph.D., Hee-Won Moon , M.D., Ph.D., Won Hyeok Choe , M.D., Ph.D., and Chae Hoon Lee , M.D., Ph.D.

    Ann Lab Med 2022; 42(2): 249-257

    Abstract : Background: Non-invasive clinical algorithms for the detection of liver fibrosis (LF) can reduce the need for liver biopsy (LB). We explored the implementation of two serum biomarkers, enhanced liver fibrosis (ELF) and Mac-2 binding protein glycosylation isomer (M2BPGi), in clinical algorithms for LF in chronic hepatitis B (CHB) patients. Methods: Two clinical algorithms were applied to 152 CHB patients: (1) transient elastography (TE) followed by biomarkers (TE/ELF and TE/M2GPGi); (2) biomarker test followed by TE (ELF/TE and M2BPGi/TE). Using the cut-off value or index for the detection of advanced LF (TE≥F3; 9.8 in ELF and 3.0 in M2BPGi), LB was expected to be performed in cases with discordant TE and biomarker results. Results: In both algorithms, the expected number of LBs was lower when using M2BPGi than when using ELF (TE/ELF or ELF/TE, 13.2% [N=20]; TE/M2BPGi or M2BPGi/TE, 9.9% [N=15]), although there was no statistical difference (P=0.398). In the TE low-risk group (TE≤F2), the discordance rate was significantly lower in the TE/M2BPGi approach than in the TE/ELF approach (1.5% [2/136] vs. 11.0% [15/136], P=0.002). In the biomarker low-risk group, there was no significant difference between the ELF/TE and M2BPGi/TE approaches (3.9% [5/126] vs. 8.8% [13/147], P=0.118). Conclusions: Both ELF and M2BPGi can be implemented in non-invasive clinical algorithms for assessing LF in CHB patients. Given the lowest possibility of losing advanced LF cases in the low-risk group when using the TE/M2BPGi approach, this combination seems useful in clinical practice.

  • Original Article2022-01-01 Diagnostic Immunology

    Clinical Performance of Two Automated Immunoassays, EliA CTD Screen and QUANTA Flash CTD Screen Plus, for Antinuclear Antibody Screening

    Sumi Yoon , M.D., Hee-Won Moon , M.D., Ph.D., Hanah Kim , M.D., Ph.D., Mina Hur , M.D., Ph.D., and Yeo-Min Yun , M.D., Ph.D.

    Ann Lab Med 2022; 42(1): 63-70

    Abstract : Background: Recently, two fully automated immunoassays for antinuclear antibody (ANA) screening were introduced: EliA CTD Screen (Thermo Fisher Scientific, Freiburg, Germany) and QUANTA Flash CTD Screen Plus (Inova Diagnostics, San Diego, USA). We evaluated their clinical performance in comparison with the indirect immunofluorescence assay (IIFA) and analyzed samples with discrepant results. Methods: In total, 406 serum samples (206 from patients undergoing routine checkups and 200 from rheumatology clinic patients) were assayed using EliA, QUANTA Flash, and IIFA. We evaluated assay concordance and agreement and confirmed the presence of anti-extractable nuclear antigen (ENA) antibodies in samples with discrepant automated immunoassay and IIFA results. Additionally, we compared the clinical performance of each assay in diagnosing ANA-associated rheumatic disease (AARD) and adjusted the cut-off values. Results: In rheumatology clinic samples, the concordance and agreement were 91.5% and strong between EliA and QUANTA Flash, 79.0% and weak between EliA and IIFA, and 80.5% and moderate between QUANTA Flash and IIFA, respectively. In automated immunoassay-positive, IIFA-negative samples (N=15), all anti-ENA antibodies detected (6/15) were anti-Sjögren’s syndrome antigen A/Ro (Ro60) antibodies. The automated immunoassays and IIFA showed high accuracy for diagnosing AARD, and adjusted cut-off values improved their sensitivities (EliA with 0.56 ratio, 82.9% sensitivity; QUANTA Flash with 9.7 chemiluminescent units, 87.8% sensitivity). Conclusions: The two automated immunoassays showed reliable performance compared with IIFA and can be efficiently used with the IIFA in clinical immunology laboratories. Clinical cut-off values can be adjusted according to the workflow in each laboratory.

  • Original Article2021-11-01 Clinical Microbiology

    Disk Diffusion Susceptibility Testing for the Rapid Detection of Fluconazole Resistance in Candida Isolates

    Suhak Jeon , M.D., Jong Hee Shin , M.D., Ph.D., Ha Jin Lim , M.D., Min Ji Choi , Ph.D., Seung A Byun , M.S., Dain Lee , M.S., Seung Yeob Lee , M.D., Eun Jeong Won , M.D., Soo Hyun Kim , M.D., and Myung Geun Shin , M.D.

    Ann Lab Med 2021; 41(6): 559-567

    Abstract : Background: Given the increased fluconazole resistance (FR) among Candida isolates, we assessed the suitability of disk diffusion susceptibility testing (DDT) for the early detection of FR using well-characterized Candida isolates. Methods: In total, 188 Candida isolates, including 66 C. albicans (seven Erg11 mutants), 69 C. glabrata (33 Pdr1 mutants), 29 C. parapsilosis (15 Erg11 mutants), and 24 C. tropicalis (eight Erg11 mutants) isolates, were tested in this study. FR was assessed using DDT according to the standard CLSI M44-ED3 method, except that two cell suspensions, McFarland 0.5 (standard inoculum) and 2.5 (large inoculum), were used, and the inhibition zones were read at 2-hour intervals from 10 hours to 24 hours. Results: DDT results for the standard inoculum were readable after 14 hours (C. albicans, C. glabrata, and C. tropicalis) and 20 hours (C. parapsilosis) for >95% of the isolates, whereas the results for the large inoculum were readable after 12 hours (C. glabrata and C. tropicalis), 14 hours (C. albicans), and 16 hours (C. parapsilosis) for >95% of the isolates. Compared with the results produced using the CLSI M27-ED4 broth microdilution method, the first readable results from the DDT method for each isolate exhibited an agreement of 97.0%, 98.6%, 72.4%, and 91.7% for the standard inoculum and 100%, 98.6%, 96.6%, and 95.8% for the large inoculum for C. albicans, C. glabrata, C. parapsilosis, and C. tropicalis, respectively. Conclusions: DDT using large inoculum may detect FR rapidly and reliably in the four most common Candida species.

  • Original Article2021-11-01 Diagnostic Immunology

    Comparison of SARS-CoV-2 Antibody Responses and Seroconversion in COVID-19 Patients Using Twelve Commercial Immunoassays

    Sojeong Yun , B.S., Ji Hyeong Ryu , M.S., Joo Hee Jang , B.S., Hyunjoo Bae , M.S., Seung-Hyo Yoo , M.T., Ae-Ran Choi , M.T., Sung Jin Jo , M.D., Jihyang Lim , M.D., Jehoon Lee , M.D., Hyejin Ryu , M.D., Sung-Yeon Cho , M.D., Dong-Gun Lee , M.D., Jongmin Lee , M.D., Seok Chan Kim , M.D., Yeon-Joon Park , M.D., Hyeyoung Lee , M.D., and Eun-Jee Oh , M.D.

    Ann Lab Med 2021; 41(6): 577-587

    Abstract : Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody assays have high clinical utility in managing the pandemic. We compared antibody responses and seroconversion of coronavirus disease 2019 (COVID-19) patients using different immunoassays. Methods: We evaluated 12 commercial immunoassays, including three automated chemiluminescent immunoassays (Abbott, Roche, and Siemens), three enzyme immunoassays (Bio-Rad, Euroimmun, and Vircell), five lateral flow immunoassays (Boditech Med, SD biosensor, PCL, Sugentech, and Rapigen), and one surrogate neutralizing antibody assay (GenScript) in sequential samples from 49 COVID-19 patients and 10 seroconversion panels. Results: The positive percent agreement (PPA) of assays for a COVID-19 diagnosis ranged from 84.0% to 98.5% for all samples (>14 days after symptom onset), with IgM or IgA assays showing higher PPAs. Seroconversion responses varied across the assay type and disease severity. Assays targeting the spike or receptor-binding domain protein showed a tendency for early seroconversion detection and higher index values in patients with severe disease. Index values from SARS-CoV-2 binding antibody assays (three automated assays, one LFIA, and three EIAs) showed moderate to strong correlations with the neutralizing antibody percentage (r=0.517–0.874), and stronger correlations in patients with severe disease and in assays targeting spike protein. Agreement among the 12 assays was good (74.3%–96.4%) for detecting IgG or total antibodies. Conclusions: Positivity rates and seroconversion of SARS-CoV-2 antibodies vary depending on the assay kits, disease severity, and antigen target. This study contributes to a better understanding of antibody response in symptomatic COVID-19 patients using currently available assays.

  • Original Article2021-09-01 Clinical Chemistry

    Internal Quality Control Data of Urine Reagent Strip Tests and Derivation of Control Rules Based on Sigma Metrics

    Haeil Park , M.D., Ph.D. and Younsuk Ko , M.T.

    Ann Lab Med 2021; 41(5): 447-454

    Abstract : Background: Urine reagent strip test (URST) results are semi-quantitative; therefore, the precision of URSTs is evaluated as the proportion of categorical results from repeated measurements of a sample that are concordant with an expected result. However, URSTs have quantitative readout values before ordinal results challenging statistical monitoring for internal quality control (IQC) with control rules. This study aimed to determine the sigma metric of URSTs and derive appropriate control rules for IQC. Methods: The URiSCAN Super Plus fully automated urine analyzer (YD Diagnostics, Yongin, Korea) was used for URSTs. Change in reflectance rate (change %R) data from IQC for URSTs performed between November 2018 and May 2020 were analyzed. Red blood cells, bilirubin, urobilinogen, ketones, protein, glucose, leukocytes, and pH were measured from 2-3 levels of control materials. The total allowable error (TEa) for a grade was the difference in midpoints of a predefined change %R range between two adjacent grades. The sigma metric was calculated as TEa/SD. Sigma metric-based control rules were determined with Westgard EZ Rules 3 software (Westgard QC, Madison, WI, USA). Results: Seven out of the eight analytes had a sigma metric >4 in the control materials with a negative grade (-), which were closer to the cut-offs. Corresponding control rules ranged from 12.5s to 13.5s. Conclusions: Although the URST is a semi-quantitative test, statistical IQC can be performed using the readout values. According to the sigma metric, control rules recommended for URST IQC in routine clinical practice are 12.5s to 13.5s.

  • Original Article2021-07-01 Diagnostic Genetics

    Accuracy and Performance Evaluation of Triplet Repeat Primed PCR as an Alternative to Conventional Diagnostic Methods for Fragile X Syndrome

    Hyunjung Gu , M.D., Man Jin Kim , M.D., Dahae Yang , M.D., Ji Yun Song, M.T., Sung Im Cho , M.T., Sung Sup Park , M.D., Ph.D., and Moon-Woo Seong , M.D., Ph.D.

    Ann Lab Med 2021; 41(4): 394-400

    Abstract : Background: Conventional diagnosis of fragile X syndrome (FXS) is based on a combination of fragment analysis (FA) and Southern blotting (SB); however, this diagnostic approach is time- and labor-intensive and has pitfalls such as the possibility of missing large number alleles. Triplet repeat primed PCR (TP-PCR) is a current alternative used to overcome these limitations. We evaluated the diagnostic usefulness of TP-PCR compared with the conventional diagnostic protocol consisting of FA and/or SB in terms of allele categorization, repeat number correlation, and zygosity concordance in female genetic carriers. Methods: From November 2013 to March 2018, 458 patients (326 males, 132 females) were simultaneously examined using FA and/or SB and TP-PCR by detecting CGG repeat numbers in FMR1 gene and diagnosed as per American College of Medical Genetics guidelines. Results: The TP-PCR results showed high concordance with the FA and/or SB results for all three aspects (allele categorization, repeat number correlation, and zygosity concordance in female genetic carriers). TP-PCR detected CGG expansions ≥200 in all full mutation (FM) allele cases in male patients, as well as both the normal allele (NL) and FM allele in female carriers. In premutation (PM) allele carriers, the TP-PCR results were consistent with the FA and/or SB results. In terms of zygosity concordance in female genetic carriers, 12 NL cases detected by TP-PCR showed a merged peak consisting of two close heterozygous peaks; however, this issue was resolved using a 10-fold dilution. Conclusions: TP-PCR may serve as a reliable alternative method for FXS diagnosis.

  • Brief Communication2021-07-01 Clinical Microbiology

    Laboratory Aspects of Donor Screening for Fecal Microbiota Transplantation at a Korean Fecal Microbiota Bank

    Hyun Soo Seo , M.S., Hyung Sun Chin , B.S.N., Yeon-Hee Kim , M.S., Hye Su Moon , B.S., Kyungnam Kim , B.S., Le Phuong Nguyen , M.D., and Dongeun Yong , M.D., Ph.D.

    Ann Lab Med 2021; 41(4): 424-428

    Abstract : Fecal microbiota transplantation (FMT) is a widely accepted alternative therapy for Clostridioides difficile infection and other gastrointestinal disorders. Thorough donor screening is required as a safety control measure to minimize transmission of infectious agents in FMT. We report the donor screening process and outcomes at a fecal microbiota bank in Korea. From August 2017 to June 2020, the qualification of 62 individuals as FMT donors was evaluated using clinical assessment and laboratory tests. Forty-six (74%) candidates were excluded after clinical assessment; high body mass index (>25) was the most common reason for exclusion, followed by atopy, asthma, and allergy history. Four of the remaining 16 (25%) candidates failed to meet laboratory test criteria, resulting in a 19% qualification rate. FMT donor re-qualification was conducted monthly as an additional safety control measure, and only three (5%) candidates were eligible for repeated donation. As high prevalence of multidrug-resistant organisms (55%) and Helicobacter pylori (44%) were detected in qualified donors during the screening, a urea breath test was added to the existing protocol. The present results emphasize the importance of implementing a donor re-qualification system to minimize risk factors not identified during initial donor screening.

  • Original Article2021-03-01 Clinical Chemistry

    Quantification of Thioguanine in DNA Using Liquid Chromatography-Tandem Mass Spectrometry for Routine Thiopurine Drug Monitoring in Patients With Pediatric Acute Lymphoblastic Leukemia

    Rihwa Choi , M.D., Mi Ryung Chun , M.S., Jisook Park , Ph.D., Ji Won Lee , M.D., Ph.D., Hee Young Ju , M.D., Hee Won Cho , M.D., Ju Kyung Hyun , M.D., Hong Hoe Koo , M.D., Ph.D., Eun Sang Yi , M.D., and Soo-Youn Lee , M.D., Ph.D.

    Ann Lab Med 2021; 41(2): 145-154

    Abstract : Background: We developed an assay to measure DNA-incorporated 6-thioguanine (DNA-TG) and validated its clinical applicability in Korean pediatric patients with acute lymphoblastic leukemia (ALL) in order to improve individualized thiopurine treatment and reduce the life-threatening cytotoxicity. Methods: The DNA-TG assay was developed based on liquid chromatography-tandem mass spectrometry, with isotope-labeled TG-d3 and guanine-d3 as internal standards. This method was applied to 257 samples of pediatric ALL patients. The DNA-TG level was compared with erythrocyte TG nucleotide (RBC-TGN) level in relation to the TPMT and NUDT15 genotypes, which affect thiopurine metabolism, using Spearman’s rank test and repeated measure ANOVA. Results: For DNA-TG quantification, a linearity range of 10.0-5,000.0 fmol TG/μg DNA; bias for accuracy of –10.4% –3.5%; coefficient of variation for intra- and inter-day precision of 3.4% and 5.8% at 80 fmol TG/μg DNA and of 4.9% and 5.3% at 800 fmol TG/μg DNA, respectively; and recovery of 85.7%–116.2% were achieved without matrix effects or carry-over. The median DNA-TG level in the 257 samples was 106.0 fmol TG/μg DNA (interquartile range, 75.8–150.9). There was a strong correlation between DNA-TG and RBC-TGN levels (ρ=0.68, P

  • Original Article2021-01-01 Clinical Chemistry

    Effectiveness of Plasma and Urine Neutrophil Gelatinase-Associated Lipocalin for Predicting Acute Kidney Injury in High-Risk Patients

    Ahram Yi , M.D., Chang-Hoon Lee , M.D., Ph.D., Yeo-Min Yun , M.D., Ph.D., Hanah Kim , M.D., Ph.D., Hee-Won Moon , M.D., Ph.D., and Mina Hur , M.D., Ph.D.

    Ann Lab Med 2021; 41(1): 60-67

    Abstract : Background: Neutrophil gelatinase-associated lipocalin (NGAL) is a useful biomarker for acute kidney injury (AKI) prediction. However, studies on whether using both plasma NGAL (PNGAL) and urine NGAL (UNGAL) can improve AKI prediction are limited. We investigated the best approach to predict AKI in high-risk patients when using PNGAL and UNGAL together. Methods: We enrolled 151 AKI suspected patients with one or more AKI risk factors. We assessed the diagnostic performance of PNGAL and UNGAL for predicting AKI according to chronic kidney disease (CKD) status by determining the areas under the receiver operating curve (AuROC). Independent predictors of AKI were assessed using univariate and multivariate logistic regression analyses. Results: In the multivariate logistic regression analysis for all patients (N=151), Model 2 and 3, including PNGAL (P=0.012) with initial serum creatinine (S-Cr), showed a better AKI prediction power (R2=0.435, both) than Model 0, including S-Cr only (R2=0.390). In the non-CKD group (N=135), the AuROC of PNGAL for AKI prediction was larger than that of UNGAL (0.79 vs 0.66, P=0.010), whereas in the CKD group (N=16), the opposite was true (0.94 vs 0.76, P=0.049). Conclusions: PNGAL may serve as a useful biomarker for AKI prediction in high-risk patients. However, UNGAL predicted AKI better than PNGAL in CKD patients. Our findings provide guidance for selecting appropriate specimens for NGAL testing according to the presence of CKD in AKI high-risk patients.

Annals of Laboratory Medicine
Journal Information September, 2024
Vol.44 No.5
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