Review Article2023-05-01 Clinical Chemistry

Biomarkers in Heart Failure: From Research to Clinical Practice

Alexander E. Berezin , M.D., Ph.D. and Alexander A. Berezin , M.D.

Ann Lab Med 2023; 43(3): 225-236

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Abstract : The aim of this narrative review is to summarize contemporary evidence on the use of circulating cardiac biomarkers of heart failure (HF) and to identify a promising biomarker model for clinical use in personalized point-of-care HF management. We discuss the reported biomarkers of HF classified into clusters, including myocardial stretch and biomechanical stress; cardiac myocyte injury; systemic, adipocyte tissue, and microvascular inflammation; cardiac fibrosis and matrix remodeling; neurohumoral activation and oxidative stress; impaired endothelial function and integrity; and renal and skeletal muscle dysfunction. We focus on the benefits and drawbacks of biomarker-guided assistance in daily clinical management of patients with HF. In addition, we provide clear information on the role of alternative biomarkers and future directions with the aim of improving the predictive ability and reproducibility of multiple biomarker models and advancing genomic, transcriptomic, proteomic, and metabolomic evaluations.

Review Article2023-01-01 Clinical Chemistry

Calibration Practices in Clinical Mass Spectrometry: Review and Recommendations

Wan Ling Cheng , M.Sc., Corey Markus , M.Sc., Chun Yee Lim , Ph.D., Rui Zhen Tan , Ph.D., Sunil Kumar Sethi , MBBS., and Tze Ping Loh , MB.BCh.BAO.; for the IFCC Working Group on Method Evaluation Protocols

Ann Lab Med 2023; 43(1): 5-18

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Abstract : Background: Calibration is a critical component for the reliability, accuracy, and precision of mass spectrometry measurements. Optimal practice in the construction, evaluation, and implementation of a new calibration curve is often underappreciated. This systematic review examined how calibration practices are applied to liquid chromatography-tandem mass spectrometry measurement procedures. Methods: The electronic database PubMed was searched from the date of database inception to April 1, 2022. The search terms used were “calibration,” “mass spectrometry,” and “regression.” Twenty-one articles were identified and included in this review, following evaluation of the titles, abstracts, full text, and reference lists of the search results. Results: The use of matrix-matched calibrators and stable isotope-labeled internal standards helps to mitigate the impact of matrix effects. A higher number of calibration standards or replicate measurements improves the mapping of the detector response and hence the accuracy and precision of the regression model. Constructing a calibration curve with each analytical batch recharacterizes the instrument detector but does not reduce the actual variability. The analytical response and measurand concentrations should be considered when constructing a calibration curve, along with subsequent use of quality controls to confirm assay performance. It is important to assess the linearity of the calibration curve by using actual experimental data and appropriate statistics. The heteroscedasticity of the calibration data should be investigated, and appropriate weighting should be applied during regression modeling. Conclusions: This review provides an outline and guidance for optimal calibration practices in clinical mass spectrometry laboratories.

Review Article2024-01-01 Clinical Chemistry

Bias in Laboratory Medicine: The Dark Side of the Moon

Abdurrahman Coskun , M.D.

Ann Lab Med 2024; 44(1): 6-20

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Abstract : Physicians increasingly use laboratory-produced information for disease diagnosis, patient monitoring, treatment planning, and evaluations of treatment effectiveness. Bias is the systematic deviation of laboratory test results from the actual value, which can cause misdiagnosis or misestimation of disease prognosis and increase healthcare costs. Properly estimating and treating bias can help to reduce laboratory errors, improve patient safety, and considerably reduce healthcare costs. A bias that is statistically and medically significant should be eliminated or corrected. In this review, the theoretical aspects of bias based on metrological, statistical, laboratory, and biological variation principles are discussed. These principles are then applied to laboratory and diagnostic medicine for practical use from clinical perspectives.

Review Article2024-03-01 Clinical Chemistry

Exploring Renal Function Assessment: Creatinine, Cystatin C, and Estimated Glomerular Filtration Rate Focused on the European Kidney Function Consortium Equation

Hans Pottel , Ph.D., Pierre Delanaye , M.D., Ph.D., and Etienne Cavalier , Ph.D.

Ann Lab Med 2024; 44(2): 135-143

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Abstract : Serum creatinine and serum cystatin C are the most widely used renal biomarkers for calculating the estimated glomerular filtration rate (eGFR), which is used to estimate the severity of kidney damage. In this review, we present the basic characteristics of these biomarkers, their advantages and disadvantages, some basic history, and current laboratory measurement practices with state-of-the-art methodology. Their clinical utility is described in terms of normal reference intervals, graphically presented with age-dependent reference intervals, and their use in eGFR equations.

Review Article2024-03-01 Clinical Chemistry

The Use of Bone-Turnover Markers in Asia-Pacific Populations

Samuel Vasikaran , M.D., Subashini C. Thambiah , M.Path., Rui Zhen Tan , Ph.D., and Tze Ping Loh , M.B., B.ch., B.A.O.; APFCB Harmonization of Reference Interval Working Group

Ann Lab Med 2024; 44(2): 126-134

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Abstract : Bone-turnover marker (BTM) measurements in the blood or urine reflect the bone-remodeling rate and may be useful for studying and clinically managing metabolic bone diseases. Substantial evidence supporting the diagnostic use of BTMs has accumulated in recent years, together with the publication of several guidelines. Most clinical trials and observational and reference-interval studies have been performed in the Northern Hemisphere and have mainly involved Caucasian populations. This review focuses on the available data for populations from the Asia-Pacific region and offers guidance for using BTMs as diagnostic biomarkers in these populations. The procollagen I N-terminal propeptide and β-isomerized C-terminal telopeptide of type-I collagen (measured in plasma) are reference BTMs used for investigating osteoporosis in clinical settings. Premenopausal reference intervals (established for use with Asia-Pacific populations) and reference change values and treatment targets (used to monitor osteoporosis treatment) help guide the management of osteoporosis. Measuring BTMs that are not affected by renal failure, such as the bone-specific isoenzyme alkaline phosphatase and tartrate-resistant acid phosphatase 5b, may be advantageous for patients with advanced chronic kidney disease. Further studies of the use of BTMs in individuals with metabolic bone disease, coupled with the harmonization of commercial assays to provide equivalent results, will further enhance their clinical applications.

Original Article2023-01-01 Clinical Chemistry

Intuitive Modification of the Friedewald Formula for Calculation of LDL-Cholesterol

Jinyoung Hong , M.D., Hyunjung Gu , M.D., Juhee Lee , M.T., Woochang Lee , M.D., Sail Chun , M.D., Ki Hoon Han , M.D., and Won-Ki Min , M.D.

Ann Lab Med 2023; 43(1): 29-37

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Abstract : Background: High LDL-cholesterol (LDL-C) is an established risk factor for cardiovascular disease and is considered an important therapeutic target. It can be measured directly or calculated from the results of other lipid tests. The Friedewald formula is the most widely used formula for calculating LDL-C. We modified the Friedewald formula for a more accurate and practical estimation of LDL-C. Methods: Datasets, including measured triglyceride, total cholesterol, HDL-cholesterol, and LDL-C concentrations were collected and assigned to derivation and validation sets. The datasets were further divided into five groups based on triglyceride concentrations. In the modified formula, LDL-C was defined as total cholesterol − HDL-cholesterol − (triglyceride/adjustment factor). For each group, the adjustment factor that minimized the difference between measured LDL-C and calculated LDL-C using modified formula was obtained. For validation, measured LDL-C and LDL-C calculated using the modified formula (LDL-CM), Friedewald formula (LDL-CF), Martin-Hopkins formula (LDL-CMa), and Sampson formula (LDL-CS) were compared. Results: In the derivation set, the adjustment factors were 4.7, 5.9, 6.3, and 6.4 for the groups with triglyceride concentrations 300 mg/dL, respectively. In the validation set, the coefficient of determination (R²) between measured and calculated LDL-C was higher for LDL-CM than for LDL-CF (R²=0.9330 vs. 0.9206). The agreement according to the National Cholesterol Education Program Adult Treatment Panel III classification of LDL-C was 86.36%, 86.08%, 86.82%, and 86.15% for LDL-CM, LDL-CF, LDL-CMa, and LDL-CS, respectively. Conclusions: We proposed a practical, improved LDL-C calculation formula by applying different factors depending on the triglyceride concentration.

Review Article2023-09-01 Clinical Chemistry

Artificial Intelligence in Point-of-Care Testing

Adil I. Khan , M.Sc., Ph.D., Mazeeya Khan , M.Sc., and Raheeb Khan , B.Sc.

Ann Lab Med 2023; 43(5): 401-407

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Abstract : With the projected increase in the global population, current healthcare delivery models will face severe challenges. Rural and remote areas, whether in developed or developing countries, are characterized by the same challenges: the unavailability of hospitals, lack of trained and skilled staff performing tests, and poor compliance with quality assurance protocols. Point-of-care testing using artificial intelligence (AI) is poised to be able to address these challenges. In this review, we highlight some key areas of application of AI in point-of-care testing, including lateral flow immunoassays, bright-field microscopy, and hematology, demonstrating this rapidly expanding field of laboratory medicine.

Original Article2023-01-01 Clinical Chemistry

Clinical Usefulness of Ultraperformance Liquid Chromatography-Tandem Mass Spectrometry Method for Low Serum Testosterone Measurement

Sung-Eun Cho , M.D., Jungsun Han , M.S., Ju-Hee Park , B.S., Euna Park , M.T., Geun Young Kim , M.T., Jun Hyung Lee , M.D., Ahram Yi , M.D., Sang Gon Lee , M.D., Eun Hee Lee , M.D., and Yeo-Min Yun , M.D.

Ann Lab Med 2023; 43(1): 19-28

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Abstract : Background: Mass spectrometry methods exhibit higher accuracy and lower variability than immunoassays at low testosterone concentrations. We developed and validated an ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay for quantifying serum total testosterone. Methods: We used an ExionLC UPLC (Sciex, Framingham, MA, USA) system and a Sciex Triple Quad 6500+ (Sciex) MS/MS system in electrospray ionization and positive ion modes with multiple reaction monitoring transitions to evaluate precision, accuracy, linearity, lower limit of quantitation (LLOQ), carryover, ion suppression, stability, and reference intervals. For method comparison, we measured serum testosterone concentrations using this method in 40 subjects whose testosterone concentrations ranged from 0.14 to 55.48 nmol/L as determined using the Architect i2000 immunoassay (Abbott Diagnostics, Abbott Park, IL, USA) and in an additional 160 sera with testosterone concentrations

Original Article2023-05-01 Clinical Chemistry

Associations of LDL Cholesterol, Non-HDL Cholesterol, and Apolipoprotein B With Cardiovascular Disease Occurrence in Adults: Korean Genome and Epidemiology Study

Shin Young Yun , M.D., John Hoon Rim , M.D., Hyein Kang , M.D., Sang-Guk Lee , M.D., and Jong-Baeck Lim , M.D.

Ann Lab Med 2023; 43(3): 237-243

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Abstract : Background: Despite the superiority of non-HDL cholesterol (non-HDL-C) and apolipoprotein B (ApoB) as lipid markers for atherosclerotic cardiovascular disease (ASCVD), these are only suitable as secondary markers. We compared LDL cholesterol (LDL-C), non-HDL-C, and ApoB concentrations with respect to the occurrence of cardiovascular disease in adults enrolled in the Korean Genome and Epidemiology Study (KoGES). Methods: We used information on age; sex; medical history; family history of ASCVD; current lipid-lowering therapy; current smoking status; and creatinine, total cholesterol, HDL-C, LDL-C, triglyceride, and ApoB concentrations from 5,872 KoGES participants without ASCVD. New ASCVD development was monitored during the 8-year follow-up period. Adjusted hazard ratios (aHRs) for ASCVD of LDL-C, non-HDL-C, and ApoB concentrations were calculated based on the multivariate Cox regression analyses. The participants were also grouped as low and high according to the median values for each lipid marker, and calculated aHRs of each group combined by two lipid makers. Results: ApoB showed the highest aHR per 1-SD for ASCVD (1.26; 95% confidence interval [CI], 1.11–1.43), followed by non-HDL-C (1.25; 95% CI, 1.11–1.41) and LDL-C (1.20; 95% CI, 1.06–1.37). The group with low LDL-C and high ApoB concentrations had a significantly higher aHR for ASCVD (1.61; 95% CI, 1.05–2.48) compared to the reference group values (low LDL-C and low ApoB concentrations). The aHR for the group with high LDL-C and low ApoB concentrations was not significant (1.30; 95% CI, 0.79–2.16). Conclusions: ApoB, non-HDL-C, and LDL-C are independent risk factors for ASCVD. Increases in the aHR per 1-SD for ASCVD were more strongly affected by ApoB, followed by non-HDL-C and LDL-C. Participants with low LDL-C and high ApoB concentrations showed increased ASCVD risk. For individuals with ASCVD risk factors, even those presenting normal LDL-C concentrations, measuring ApoB concentrations can provide useful information for better evaluation of ASCVD risk.

Original Article2023-05-01 Clinical Chemistry

Accuracy of the New Creatinine-based Equations for Estimating Glomerular Filtration Rate in Koreans

Tae-Dong Jeong , M.D., Ph.D., Jinyoung Hong , M.D., Woochang Lee , M.D., Ph.D., Sail Chun , M.D., Ph.D., and Won-Ki Min , M.D., Ph.D.

Ann Lab Med 2023; 43(3): 244-252

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Abstract : Background: New creatinine-based estimated glomerular filtration rate (eGFR) equations, including the 2021 Chronic Kidney Disease Epidemiology Collaboration (2021 CKD-EPI) and European Kidney Function Consortium (EKFC) equations, have been introduced recently. We assessed the performance of the 2021 CKD-EPI and EKFC equations in the Korean population. Methods: We analyzed 1,654 Korean patients aged ≥18 years who underwent chromium-51-ethylenediamine tetraacetic acid GFR measurements (mGFR). Bias (eGFR–mGFR), root mean square error (RMSE), and proportion of eGFR within 30% of mGFR (P30) of the 2009 CKD-EPI, 2021 CKD-EPI, and EFKC equations were compared. The concordance rate between eGFR and mGFR categories was evaluated. Both eGFR and mGFR categories were classified into six groups: ≥90, 89–60, 59–45, 44–30, 29–15, and