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  • Review Article2022-03-01
    Clinical Chemistry

    Review of the Use of Liquid Chromatography-Tandem Mass Spectrometry in Clinical Laboratories: Part I-Development

    Brian A. Rappold , B.S.

    Ann Lab Med 2022; 42(2): 121-140

    Abstract : The process of method development for a diagnostic assay based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) involves several disparate technologies and specialties. Additionally, method development details are typically not disclosed in journal publications. Method developers may need to search widely for pertinent information on their assay(s). This review summarizes the current practices and procedures in method development. Additionally, it probes aspects of method development that are generally not discussed, such as how exactly to calibrate an assay or where to place quality controls, using examples from the literature. This review intends to provide a comprehensive resource and induce critical thinking around the experiments for and execution of developing a clinically meaningful LC-MS/MS assay.

  • Original Article2021-11-01
    Diagnostic Immunology

    Combination of a SARS-CoV-2 IgG Assay and RT-PCR for Improved COVID-19 Diagnosis

    Kotaro Aoki , Ph.D., Kunitomo Takai , M.H.E.S., Tatsuya Nagasawa , M.M.S., Katsuhito Kashiwagi , M.D., Nobuaki Mori , M.D., Ph.D., Keiji Matsubayashi , M.S., Masahiro Satake , M.D., Ph.D., Ippei Tanaka , Ph.D., Nanae Kodama , M.S., Takahiro Shimodaira , M.M.S, Yoshikazu Ishii , Ph.D., Taito Miyazaki , M.D., Toshiaki Ishii , M.M.S, Toshisuke Morita , M.D., Ph.D., Toru Yoshimura , Ph.D., and Kazuhiro Tateda , M.D., Ph.D.

    Ann Lab Med 2021; 41(6): 568-576

    Abstract : Background: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is generally diagnosed by reverse transcription (RT)-PCR or serological assays. The SARS-CoV-2 viral load decreases a few days after symptom onset. Thus, the RT-PCR sensitivity peaks at three days after symptom onset (approximately 80%). We evaluated the performance of the ARCHITECT® SARS-CoV-2 IgG assay (henceforth termed IgG assay; Abbott Laboratories, Lake County, IL, USA), and the combination of RT-PCR and the IgG assay for COVID-19 diagnosis. Methods: In this retrospective study, 206 samples from 70 COVID-19 cases at two hospitals in Tokyo that were positive using RT-PCR were used to analyze the diagnostic sensitivity. RT-PCR-negative (N=166), COVID-19-unrelated (N=418), and Japanese Red Cross Society (N=100) samples were used to evaluate specificity. Results: Sensitivity increased daily after symptom onset and exceeded 84.4% after 10 days. Specificity ranged from 98.2% to 100% for samples from the three case groups. Seroconversion was confirmed from 9 to 20 days after symptom onset in 18 out of 32 COVID-19 cases with multiple samples and from another case with a positive result in the IgG assay for the first available sample. Conclusions: The combination of RT-PCR and IgG assay improves the robustness of laboratory diagnostics by compensating for the limitations of each method.

  • Original Article2021-03-01

    Targeted Next-Generation Sequencing of Plasma Cell-Free DNA in Korean Patients with Hepatocellular Carcinoma

    Hyojin Chae , M.D., Ph.D., Pil Soo Sung , M.D., Ph.D., Hayoung Choi , M.S., Ahlm Kwon , M.S., Dain Kang , B.S.E., Yonggoo Kim , M.D., Ph.D., Myungshin Kim , M.D., Ph.D., and Seung Kew Yoon , M.D., Ph.D.

    Ann Lab Med 2021; 41(2): 198-206

    Abstract : Background: Hepatocellular carcinoma (HCC) is the second-most-common cause of cancer-related deaths worldwide, and an accurate and non-invasive biomarker for the early detection and monitoring of HCC is required. We assessed pathogenic variants of HCC driver genes in cell-free DNA (cfDNA) from HCC patients who had not undergone systemic therapy. Methods: Plasma cfDNA was collected from 20 HCC patients, and deep sequencing was performed using a customized cfDNA next-generation sequencing panel, targeting the major HCC driver genes (TP53, CTNNB1, TERT) that incorporates molecular barcoding. Results: In 13/20 (65%) patients, we identified at least one pathogenic variant of two major HCC driver genes (TP53 and CTNNB1), including 16 variants of TP53 and nine variants of CTNNB1. The TP53 and CTNNB1 variants showed low allele frequencies, with median values of 0.17% (range: 0.06%–6.99%) and 0.07% (range: 0.05%–0.96%), respectively. However, the molecular coverage of variants was sufficient, with median values of 5,543 (range: 2,317–9,088) and 7,568 (range: 2,400–9,633) for TP53 and CTNNB1 variants, respectively. Conclusions: Our targeted DNA sequencing successfully identified low-frequency pathogenic variants in the cfDNA from HCC patients by achieving high coverage of unique molecular families. Our results support the utility of cfDNA analysis to identify somatic gene variants in HCC patients.

  • Original Article2021-03-01

    Laboratory Diagnostic Methods for Clostridioides difficile Infection: the First Systematic Review and Meta-analysis in Korea

    Hae-Sun Chung , M.D., Ph.D., Jeong Su Park , M.D., Ph.D., and Bo-Moon Shin , M.D., Ph.D.

    Ann Lab Med 2021; 41(2): 171-180

    Abstract : Background: Various methods are used for the diagnosis of Clostridioides difficile infection (CDI). We systematically analyzed and investigated the performance of current laboratory diagnostic methods for CDI. Methods: We performed systematic review and meta-analysis of studies in PubMed, Web of Science, Cochrane Library, and KoreaMed. The following methods were evaluated: glutamate dehydrogenase (GDH) enzyme immunoassays (GDH EIAs), toxin A and B detection by enzyme immunoassays (toxin AB EIAs), and nucleic acid amplification tests (NAATs) for C. difficile toxin genes. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each method were calculated. Results: Based on 39 studies, the pooled sensitivities/specificities were 92.7%/94.6%, 57.9%/97.0%, and 90.0%/95.8% for GDH EIAs, toxin AB EIAs, and NAATs, respectively, compared with those of toxigenic culture. The pooled sensitivities of automated EIAs were significantly higher than those of non-automated EIAs for both GDH and toxins A and B. The pooled sensitivity of Xpert C. difficile was significantly higher than those of other NAATs. PPVs increased as CDI prevalence increased, and NPVs were excellent when CDI prevalence was low; at CDI prevalence of 5%, PPV=37%–65% and NPV=97%–100%; at CDI prevalence of 50%, PPV=92%–97% and NPV=65%–98%. Conclusions: Toxin AB EIAs still show unsatisfactory sensitivity, whereas GDH EIAs and NAATs show relatively high sensitivity. However, toxin AB EIAs are the most specific tests. This study may provide useful information for CDI diagnosis.

  • Review Article2022-05-01
    Transfusion Medicine

    Current State of Blood Management Services in Korea

    Hyun Ok Kim , M.D., Ph.D.

    Ann Lab Med 2022; 42(3): 306-313

    Abstract : Blood is lifesaving; however, it can neither be limitlessly acquired nor artificially produced. The supply and use of blood, as an invaluable biological commodity, necessitate systematic and rational management under governmental guidance to ensure safe and reliable transfusions. Despite Korea’s blood donation rate of 5.04%, which is higher than the 3.15% in high-income countries as reported by the WHO, the demand for blood exceeds the availability. This is due to the birthrate decline, dearth of young donors, and growing and aging recipient population. This review outlines the Korean blood management system, with a focus on blood service data from 2020, with the aim to delineate the current state of Korea’s blood management system and the policies established to address the imminent blood shortage. Each policy is described in detail to provide helpful information for blood management services in other countries.

  • Original Article2022-01-01
    General Laboratory Medicine

    Economic Evaluation of Total Laboratory Automation in the Clinical Laboratory of a Tertiary Care Hospital

    KyungYi Kim , M.S., Sang-Guk Lee , M.D., Ph.D., Tae Hyun Kim , Ph.D., and Sang Gyu Lee , M.D., Ph.D., M.B.A.

    Ann Lab Med 2022; 42(1): 89-95

    Abstract : Background: Total laboratory automation (TLA) is an innovation in laboratory technology; however, the high up-front costs restrict its widespread adoption. To examine whether the capital investment for TLA is worthwhile, we analyzed its clinical- and cost-effectiveness for the expected payback period. Methods: Clinical chemistry tests and immunoassays performed in the clinical laboratory of a tertiary care hospital were divided into a post-TLA group, including 1,182,419 tests performed during December 2019, and a pre-TLA group, including 1,151,501 tests performed during December 2018. Laboratory information system data were used to measure clinical effectiveness, and depreciation data were used to calculate TLA costs. Results: Laboratory performance improved after TLA adoption in all four key performance indicators: mean turn-around time (TAT), representing the timeliness of result reporting, decreased by 6.1%; the 99th percentile of TAT, representing the outlier rate, decreased by 13.3%; the TAT CV, representing predictability, decreased by 70.0%; and weighted tube touch moment (wTTM), representing staff safety, improved by 77.6%. Based on these effectiveness results, economic evaluation was performed using two approaches. First, the incremental cost-effectiveness ratio and wTTM were used as the most cost-effective performance indicators. Second, the expected payback period was calculated. Considering only staff cost reduction, it was anticipated that 4.75 yrs would be needed to payback the initial investment. Conclusions: TLA can significantly enhance laboratory performance, has a relatively quick payback period, and can reduce total hospital expenses in the long term. Therefore, the capital investment for TLA adoption is considered to be worthwhile.

  • Original Article2022-03-01
    Clinical Microbiology

    Clinical Differences in Patients Infected with Fusobacterium and Antimicrobial Susceptibility of Fusobacterium Isolates Recovered at a Tertiary-Care Hospital in Korea

    Myungsook Kim , Ph.D., Shin Young Yun , M.D., Yunhee Lee , B.D., Hyukmin Lee , M.D., Dongeun Yong , M.D., Kyungwon Lee , M.D.

    Ann Lab Med 2022; 42(2): 188-195

    Abstract : Background: Fusobacterium species are obligately anaerobic, gram-negative bacilli. Especially, F. nucleatum and F. necrophorum are highly relevant human pathogens. We investigated clinical differences in patients infected with Fusobacterium spp. and determined the antimicrobial susceptibility of Fusobacterium isolates. Methods: We collected clinical data of 86 patients from whom Fusobacterium spp. were isolated from clinical specimens at a tertiary-care hospital in Korea between 2003 and 2020. In total, 76 non-duplicated Fusobacterium isolates were selected for antimicrobial susceptibility testing by the agar dilution method, according to the Clinical and Laboratory Standards Institute guidelines (M11-A9). Results: F. nucleatum was most frequently isolated from blood cultures and was associated with hematologic malignancy, whereas F. necrophorum was mostly prevalent in head and neck infections. Anti-anaerobic agents were more commonly used to treat F. nucleatum and F. varium infections than to treat F. necrophorum infections. We observed no significant difference in mortality between patients infected with these species. All F. nucleatum and F. necrophorum isolates were susceptible to the antimicrobial agents tested. F. varium was resistant to clindamycin (48%) and moxifloxacin (24%), and F. mortiferum was resistant to penicillin G (22%) and ceftriaxone (67%). β-Lactamase activity was not detected. Conclusions: Despite the clinical differences among patients with clinically important Fusobacterium infections, there was no significant difference in the mortality rates. Some Fusobacterium spp. were resistant to penicillin G, ceftriaxone, clindamycin, or moxifloxacin. This study may provide clinically relevant data for implementing empirical treatment against Fusobacterium infections.

  • Original Article2022-01-01
    Diagnostic Immunology

    Performance Comparison of Five SARS-CoV-2 Antibody Assays for Seroprevalence Studies

    Younhee Park , M.D., Ki Ho Hong , M.D., Su-Kyung Lee , M.S., Jungwon Hyun , M.D., Eun-Jee Oh , M.D., Jaehyeon Lee , M.D., Hyukmin Lee , M.D., Sang Hoon Song , M.D., Seung-Jung Kee , M.D., Gye Cheol Kwon , M.D., Su Hwan Kim , B.S., Hyeon-Nam Do , M.S., Ah-Ra Kim , M.S., June-Woo Lee , Ph.D., Sung Soon Kim , Ph.D., and Hyun Soo Kim , M.D., Ph.D.

    Ann Lab Med 2022; 42(1): 71-78

    Abstract : Background: Seroprevalence studies of coronavirus disease 2019 (COVID-19) cases, including asymptomatic and past infections, are important to estimate the scale of the disease outbreak and to establish quarantine measures. We evaluated the clinical performance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody assays available in Korea for use in seroprevalence studies. Methods: The sensitivity, specificity, cross-reactivity, and interference of five SARS-CoV-2 antibody assays were evaluated using the following: 398 serum samples from confirmed COVID-19 patients, 510 negative control samples from before 2018 (pre-pandemic), 163 serum samples from patients with SARS, Middle East respiratory syndrome (MERS), and other viral infections, and five samples for the interference study. Results: The sensitivities of the five assays ranged from 92.2% to 98%, and their specificities, including cross-reactivity and interference, ranged from 97.5% to 100%. The agreement rates were excellent (kappa >0.9). Adjustment of the cutoff values could be considered through ROC curve analysis. The positive predictive values of the individual assays varied from 3.5% to 100% at a 0.1% prevalence but were as high as ≥95% when two assays were combined. Conclusions: The prevalence of COVID-19 in Korea is considered to be exceptionally low at present; thus, we recommend using a combination of two or more SARS-CoV-2 antibody assays rather than a single assay. These results could help select SARS-CoV-2 antibody assays for COVID-19 seroprevalence studies in Korea.

  • Brief Communication2021-07-01

    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 Article2021-07-01
    Clinical Chemistry

    Predictive Value of Plasma NGAL:Hepcidin-25 for Major Adverse Kidney Events After Cardiac Surgery with Cardiopulmonary Bypass: A Pilot Study

    Christian Albert , M.D., Michael Haase , M.D., Annemarie Albert , M.D., Martin Ernst , M.D., Siegfried Kropf , Ph.D., Rinaldo Bellomo , M.D., Sabine Westphal , M.D., Rüdiger C. Braun-Dullaeus, M.D., Anja Haase-Fielitz , Pharm.D., and Saban Elitok , M.D.

    Ann Lab Med 2021; 41(4): 357-365

    Abstract : Background: Neutrophil gelatinase-associated lipocalin (NGAL) and hepcidin-25 are involved in catalytic iron-related kidney injury after cardiac surgery with cardiopulmonary bypass. We explored the predictive value of plasma NGAL, plasma hepcidin-25, and the plasma NGAL:hepcidin-25 ratio for major adverse kidney events (MAKE) after cardiac surgery. Methods: We compared the predictive value of plasma NGAL, hepcidin-25, and plasma NGAL:hepcidin-25 with that of serum creatinine (Cr) and urinary output and protein for primary-endpoint MAKE (acute kidney injury [AKI] stages 2 and 3, persistent AKI >48 hours, acute dialysis, and in-hospital mortality) and secondary-endpoint AKI in 100 cardiac surgery patients at intensive care unit (ICU) admission. We performed ROC curve, logistic regression, and reclassification analyses. Results: At ICU admission, plasma NGAL, plasma NGAL:hepcidin-25, plasma interleukin-6, and Cr predicted MAKE (area under the ROC curve [AUC]: 0.77, 0.79, 0.74, and 0.74, respectively) and AKI (0.73, 0.89, 0.70, and 0.69). For AKI prediction, plasma NGAL:hepcidin-25 had a higher discriminatory power than Cr (AUC difference 0.26 [95% CI 0.00–0.53]). Urinary output and protein, plasma lactate, C-reactive protein, creatine kinase myocardial band, and brain natriuretic peptide did not predict MAKE or AKI (AUC <0.70). Only plasma NGAL:hepcidin-25 correctly reclassified patients according to their MAKE and AKI status (category-free net reclassification improvement: 0.82 [95% CI 0.12–1.52], 1.03 [0.29–1.77]). After adjustment to the Cleveland risk score, plasma NGAL:hepcidin-25 ≥0.9 independently predicted MAKE (adjusted odds ratio 16.34 [95% CI 1.77–150.49], P=0.014). Conclusions: Plasma NGAL:hepcidin-25 is a promising marker for predicting postoperative MAKE.

Journal Information March, 2023
Vol.43 No.2
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