Bias in Laboratory Medicine: The Dark Side of the Moon
Abdurrahman Coskun 
, M.D.
Most Read (Last 3 years)
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Review Article2024-01-01 Clinical Chemistry
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.
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Review Article2023-05-01 Clinical Chemistry
Biomarkers in Heart Failure: From Research to Clinical Practice
Alexander E. Berezin
Ann Lab Med 2023; 43(3): 225-236, M.D., Ph.D. and Alexander A. Berezin , M.D.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.
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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
Ann Lab Med 2024; 44(2): 135-143, Ph.D., Pierre Delanaye , M.D., Ph.D., and Etienne Cavalier , Ph.D.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.
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Review Article2024-03-01 Clinical Chemistry
The Use of Bone-Turnover Markers in Asia-Pacific Populations
Samuel Vasikaran
Ann Lab Med 2024; 44(2): 126-134, 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 GroupAbstract : 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.
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Review Article2023-09-01 Clinical Chemistry
Artificial Intelligence in Point-of-Care Testing
Adil I. Khan
Ann Lab Med 2023; 43(5): 401-407, M.Sc., Ph.D., Mazeeya Khan , M.Sc., and Raheeb Khan , B.Sc.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.
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Original Article2023-05-01 Clinical Chemistry
Accuracy of the New Creatinine-based Equations for Estimating Glomerular Filtration Rate in Koreans
Tae-Dong Jeong
Ann Lab Med 2023; 43(3): 244-252, 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.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
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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
Ann Lab Med 2023; 43(3): 237-243, M.D., John Hoon Rim , M.D., Hyein Kang , M.D., Sang-Guk Lee , M.D., and Jong-Baeck Lim , M.D.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.
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Original Article2024-03-01 Clinical Chemistry
Predictive Performance of Neutrophil Gelatinase Associated Lipocalin, Liver Type Fatty Acid Binding Protein, and Cystatin C for Acute Kidney Injury and Mortality in Severely Ill Patients
Ayu Asakage
Ann Lab Med 2024; 44(2): 144-154, M.D., Shiro Ishihara , M.D., Louis Boutin , M.D., François Dépret , Ph.D., Takeshi Sugaya , Ph.D., Naoki Sato , Ph.D., Etienne Gayat , Ph.D., Alexandre Mebazaa , Ph.D., and Benjamin Deniau , Ph.D.Abstract : Background: Acute kidney injury (AKI) is a common condition in severely ill patients associated with poor outcomes. We assessed the associations between urinary neutrophil gelatinase-associated lipocalin (uNGAL), urinary liver-type fatty acid-binding protein (uLFABP), and urinary cystatin C (uCysC) concentrations and patient outcomes. Methods: We assessed the predictive performances of uNGAL, uLFABP, and uCysC measured in the early phase of intensive care unit (ICU) management and at discharge from the ICU in severely ill patients for short- and long-term outcomes. The primary outcome was the occurrence of AKI during ICU stay; secondary outcomes were 28-day and 1-yr allcause mortality. Results: In total, 1,759 patients were admitted to the ICU, and 728 (41.4%) developed AKI. Median (interquartile range, IQR) uNGAL, uLFABP, and uCysC concentrations on admission were 147.6 (39.9–827.7) ng/mL, 32.4 (10.5–96.0) ng/mL, and 0.33 (0.12–2.05) mg/L, respectively. Biomarker concentrations on admission were higher in patients who developed AKI and associated with AKI severity. Three hundred fifty-six (20.3%) and 647 (37.9%) patients had died by 28 days and 1-yr, respectively. Urinary biomarker concentrations at ICU discharge were higher in non-survivors than in survivors. The areas under the ROC curve (95% confidence interval) of uLFABP for the prediction of AKI, 28-day mortality, and 1-yr mortality (0.70 [0.67–0.72], 0.63 [0.59–0.66], and 0.57 [0.51–0.63], respectively) were inferior to those of the other biomarkers. Conclusions: uNGAL, uLFABP, and uCysC concentrations on admission were associated with poor outcomes. However, their predictive performance, individually and in combination, was limited. Further studies are required to confirm our results.
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Review Article2023-09-01 Clinical Chemistry
Functional Reference Limits: Describing Physiological Relationships and Determination of Physiological Limits for Enhanced Interpretation of Laboratory Results
Tyng Yu Chuah
Ann Lab Med 2023; 43(5): 408-417, M.B., B.Ch., B.A.O., Chun Yee Lim , Ph.D., Rui Zhen Tan , Ph.D., Busadee Pratumvinit , M.B., B.S, Tze Ping Loh , M.B., B.Ch., B.A.O., Samuel Vasikaran , M.B., B.S., and Corey Markus , M.Sc. for the APFCB Harmonization of Reference Intervals Working GroupAbstract : Functional reference limits describe key changes in the physiological relationship between a pair of physiologically related components. Statistically, this can be represented by a significant change in the curvature of a mathematical function or curve (e.g., an observed plateau). The point at which the statistical relationship changes significantly is the point of curvature inflection and can be mathematically modeled from the relationship between the interrelated biomarkers. Conceptually, they reside between reference intervals, which describe the statistical boundaries of a single biomarker within the reference population, and clinical decision limits that are often linked to the risk of morbidity or mortality and set as thresholds. Functional reference limits provide important physiological and pathophysiological insights that can aid laboratory result interpretation. Laboratory professionals are in a unique position to harness data from laboratory information systems to derive clinically relevant values. Increasing research on and reporting of functional reference limits in the literature will enhance their contribution to laboratory medicine and widen the evidence base used in clinical decision limits, which are currently almost exclusively contributed to by clinical trials. Their inclusion in laboratory reports will enhance the intellectual value of laboratory professionals in clinical care beyond the statistical boundaries of a healthy reference population and pave the way to them being considered in shaping clinical decision limits. This review provides an overview of the concepts related to functional reference limits, clinical examples of their use, and the impetus to include them in laboratory reports.
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Original Article2024-01-01 Clinical Chemistry
Comparison of Direct and Extraction Immunoassay Methods With Liquid Chromatography-Tandem Mass Spectrometry Measurement of Urinary Free Cortisol for the Diagnosis of Cushing’s Syndrome
Danni Mu
Ann Lab Med 2024; 44(1): 29-37, B.S., Jiadan Fang , M.S., Songlin Yu , M.S., Yichen Ma , B.S., Jin Cheng , M.S., Yingying Hu , B.S., Ailing Song , B.S., Fang Zhao , B.S., Qi Zhang , M.S., Zhihong Qi , M.S., Kui Zhang , B.S., Liangyu Xia , M.S., Ling Qiu , M.S., Huijuan Zhu , Ph.D., and Xinqi Cheng , Ph.D.Abstract : Background: Twenty-four-hour urinary free cortisol (UFC) measurement is the initial diagnostic test for Cushing’s syndrome (CS). We compared UFC determination by both direct and extraction immunoassays using Abbott Architect, Siemens Atellica Solution, and Beckman DxI800 with liquid chromatography-tandem mass spectrometry (LC-MS/MS). In addition, we evaluated the value of 24-hr UFC measured by six methods for diagnosing CS. Methods: Residual 24-hr urine samples of 94 CS and 246 non-CS patients were collected. A laboratory-developed LC-MS/MS method was used as reference. UFC was measured by direct assays (D) using Abbott, Siemens, and Beckman platforms and by extraction assays (E) using Siemens and Beckman platforms. Method was compared using Passing–Bablok regression and Bland–Altman plot analyses. Cut-off values for the six assays and corresponding sensitivities and specificities were calculated by ROC analysis. Results: Abbott-D, Beckman-E, Siemens-E, and Siemens-D showed strong correlations with LC-MS/MS (Spearman coefficient r=0.965, 0.922, 0.922, and 0.897, respectively), while Beckman-D showed weaker correlation (r=0.755). All immunoassays showed proportionally positive bias. The areas under the curve were 0.975 for Abbott-D, 0.972 for LC-MS/MS, 0.966 for Siemens-E, 0.948 for Siemens-D, 0.955 for Beckman-E, and 0.877 for Beckman-D. The cut-off values varied significantly (154.8–1,321.5 nmol/24 hrs). Assay sensitivity and specificity ranged from 76.1% to 93.2% and from 93.0% to 97.1%, respectively. Conclusions: Commercially available immunoassays for measuring UFC show different levels of analytical consistency compared to LC-MS/MS. Abbott-D, Siemens-E, and Beckman-E have high diagnostic accuracy for CS.
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