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Seven Direct Methods for Measuring HDL and LDL Cholesterol Compared with Ultracentrifugation Reference Measurement Procedures
Open accessAbstract
Background: Methods from 7 manufacturers and 1 distributor for directly measuring HDL cholesterol (C) and LDL-C were evaluated for imprecision, trueness, total error, and specificity in nonfrozen serum samples. Methods: We performed each direct method according to the manufacturer’s instructions, using a Roche/Hitachi 917 analyzer, and compared the results with those obtained with reference measurement procedures for HDL-C and LDL-C. Imprecision was estimated for 35 runs performed with frozen pooled serum specimens and triplicate measurements on each individual sample. Sera from 37 individuals without disease and 138 with disease (primarily dyslipidemic and cardiovascular) were measured by each method. Trueness and total error were evaluated from the difference between the direct methods and reference measurement procedures. Specificity was evaluated from the dispersion in differences observed. Results: Imprecision data based on 4 frozen serum pools showed total CVs <3.7% for HDL-C and <4.4% for LDL-C. Bias for the nondiseased group ranged from −5.4% to 4.8% for HDL-C and from −6.8% to 1.1% for LDL-C, and for the diseased group from −8.6% to 8.8% for HDL-C and from −11.8% to 4.1% for LDL-C. Total error for the nondiseased group ranged from −13.4% to 13.6% for HDL-C and from −13.3% to 13.5% for LDL-C, and for the diseased group from −19.8% to 36.3% for HDL-C and from −26.6% to 31.9% for LDL-C. Conclusions: Six of 8 HDL-C and 5 of 8 LDL-C direct methods met the National Cholesterol Education Program total error goals for nondiseased individuals. All the methods failed to meet these goals for diseased individuals, however, because of lack of specificity toward abnormal lipoproteins.
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“Most discordances in dyslipidemic samples are observed at lower concentration ranges of LDLC (< 1.8 mmol/L) and HDLC (< 1.0 mmol/L) [42].”
From Quantifying atherogenic lipoproteins for lipid-lowering strategies: Consensus-based recommendations from EAS and EFLM (2020) · cites this paper as [42]
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“Direct measurements of dLDLC and dHDLC in normolipidemic samples usually meet the National Cholesterol Education Program (NCEP) total error goals of ≤12% and ≤13%, respectively, but total error ranged from -26% to +32% for dLDLC and -20% to +36% for dHDLC in a comprehensive study of different assays in dyslipidemic samples [42].”
From Quantifying atherogenic lipoproteins for lipid-lowering strategies: Consensus-based recommendations from EAS and EFLM (2020) · cites this paper as [42]
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“It is important to note that direct LDL-C measurements also have limitations, including systematic bias and inaccuracy in patients with dyslipidaemia, especially for high TG levels [88-90].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [89]
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“LDL-C was measured via the direct homogenized method [15, 16].”
MethodDysfunctional high-density lipoprotein: an updated review
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Commutability and traceability in EQA programs
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Dietary vitamin E and fat intake are related to Beck's depression score
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“Serum lipid and fasting blood glucose (FBG) concentrations were measured by enzymatic methods [16].”
MethodBanach, M., Burchardt, P., Chlebus, K., Dobrowolski, P., Dudek, D., Dyrbuś, K., Gąsior, M., Jankowski, P., Jozwiak, J. J., Kłosiewicz−Latoszek, L., et al. (2021) · Diagnostyka Laboratoryjna · doi:10.5604/01.3001.0015.4805 · Cited by 36
Evaluation of twelve formulas for LDL-C estimation in a large, blinded, random Italian population.
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LDL cholesterol performance of beta quantification reference measurement procedure
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Self-citationStatin use and all-cause and cancer mortality: BioBank Japan cohort
Yokomichi, H., Nagai, A., Hirata, M., Tamakoshi, A., Kiyohara, Y., Kamatani, Y., Muto, K., Ninomiya, T., Matsuda, K., Kubo, M., et al. (2017) · Journal of Epidemiology · doi:10.1016/j.je.2016.12.011 · Cited by 34
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“Ultracentrifugation following by betaquantification is the gold standard for measurement of LDL-C [12] but special equipment requirement, expensiveness and time-consuming of this method make it inconvenient for most routine clinical laboratories [13].”
Methodvon Eckardstein, A., & Rohrer, L. (2016) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000294 · Cited by 33
“LDL-cholesterol) are notoriously inaccurate especially in dyslipidemic samples [64,65].”
BackgroundKorzun, W. J., Nilsson, G., Bachmann, L. M., Myers, G. L., Sakurabayashi, I., Nakajima, K., Nakamura, M., Shamburek, R. D., Remaley, A. T., & Miller, W. G. (2015) · Clinical Chemistry · doi:10.1373/clinchem.2015.240861 · Cited by 33
Self-citationProgress in the care of common inherited atherogenic disorders of apolipoprotein B metabolism
Ellis, K. L., Hooper, A. J., Burnett, J. R., & Watts, G. F. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.69 · Cited by 33
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“[8] Miller WG, Myers GL, Sakurabayashi I, Bachman LM, Caudill SP, Dziekonski A, et al.”
BackgroundIto, T., Arima, H., Fujiyoshi, A., Miura, K., Takashima, N., Ohkubo, T., Kadota, A., Hayakawa, T., Kita, Y., Miyagawa, N., et al. (2016) · International Journal of Cardiology · doi:10.1016/j.ijcard.2016.06.021 · Cited by 32
“However, reagents for the homogeneous assay have not been standardized, and values are not consistent between the assay reagents, particularly for subjects with elevated levels of intermediate-density lipoprotein.(15) Non-high-density lipoprotein (HDL) cholesterol level, however, is less affected by fasting status or…”
BackgroundEstimation of low-density lipoprotein cholesterol by machine learning methods
Tsigalou, C., Panopoulou, M. I., Papadopoulos, C., Karvelas, A., Tsairidis, D., & Anagnostopoulos, K. P. (2021) · Clinica Chimica Acta · doi:10.1016/j.cca.2021.02.020 · Cited by 33
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Comparability of 11 different equations for estimating LDL cholesterol on different analysers
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The Sampson-NIH Equation Is the Preferred Calculation Method for LDL-C
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Self-citationCalculated Low Density Lipoprotein-Cholesterol: Friedewald's Formula versus Other Modified Formulas
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“…the ability of direct methods to specifically measure the cholesterol contents of one lipoprotein class in presence of other types of lipoproteins [35], (ii) only 5 of 8 direct method for LDLc measurement met NCEP total error goals for non diseased individuals but all the 8 method failed in…”
Advances in quantifying apolipoproteins using LC-MS/MS technology: implications for the clinic
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Design of Smart Aggregates: Toward Rapid Clinical Diagnosis of Hyperlipidemia in Human Blood
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ADLM Guidance Document on the Measurement and Reporting of Lipids and Lipoproteins
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Self-citationLeptin and Adiponectin Serum Levels from Infancy to School Age: Factors Influencing Tracking
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“Nevertheless, ultracentrifugation remains the classic comparison method and is the basis for the accepted reference methods [16, 17, 21].”
BackgroundMethodPotential role of anti-inflammatory HDL subclasses in metabolic unhealth/obesity
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“Homogeneous direct assays are now available to isolate LDL by chemical means [59,79].”
BackgroundUse of Apolipoprotein B in the Era of Precision Medicine: Time for a Paradigm Change?
Cole, J., Zubirán, R., Wolska, A. T., Jialal, I., & Remaley, A. T. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12175737 · Cited by 23
Self-citationFibre Intake Is Associated with Cardiovascular Health in European Children
Larrosa, S., Luque, V., Grote, V., Closa‐Monasterolo, R., Ferré, N., Koletzko, B. V., Verduci, E., Gruszfeld, D., Xhonneux, A., & Escribano, J. (2020) · Nutrients · doi:10.3390/nu13010012 · Cited by 27
“Total cholesterol (mg/dL), LDL cholesterol (mg/dL), HDL cholesterol (mg/dL), triglycerides (mg/dL), and glucose (mg/dL) were assessed in the clinical chemistry laboratories of study centres with routine methods used for clinical diagnosis [33].”
Method
Metadata
- Authors
- Miller, W. G., Myers, G. L., Sakurabayashi, I., Bachmann, L. M., Caudill, S. P., Dziekonski, A., Edwards, S., Kimberly, M. M., Korzun, W. J., Leary, E. T., Nakajima, K., Nakamura, M., Nilsson, G., Shamburek, R. D., Vetrovec, G. W., Warnick, G. R., & Remaley, A. T.
- Affiliations
- Virginia Commonwealth University (US)
- Centers for Disease Control and Prevention (US)
- Jichi Medical University (JP)
- Virginia Commonwealth University, Richmond, VA
- Pacific Biomarkers (United States) (US)
- Otsuka (Japan) (JP)
- Osaka Medical Center for Health Science and Promotion, Osaka, Japan
- Nilsson Measurement Quality, Uppsala, Sweden
- National Institutes of Health (US)
- Health Diagnostics Laboratory, Richmond, VA
- Corresponding author
- Miller, W Greg
- ORCID
- Venue
- Clinical Chemistry
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-06-01
- Volume
- 56
- Issue
- 6
- Pages
- 977-986
- ISSN
- 0009-9147 (ISSN-L)
- 1530-8561
- PMC
- PMC4687457
- OpenAlex
- W2130132335
- Cited by
- 386
- References
- 23
- Citations by year
- 2026: 22 · 2025: 31 · 2024: 25 · 2023: 31 · 2022: 30 · 2021: 30 · 2020: 31 · 2019: 26 · 2018: 22 · 2017: 21 · 2016: 15 · 2015: 14 · 2014: 27 · 2013: 16 · 2012: 17
- FWCI
- 13.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Clinical Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Merck
- Pfizer
- Abbott
- NIH
- Topics
- Health Sciences › Health Professions › Medical Laboratory Technology › Clinical Laboratory Practices and Quality Control
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Physical Sciences › Physics and Astronomy › Instrumentation › Scientific Measurement and Uncertainty Evaluation
- Keywords
- HDL cholesterol, LDL cholesterol, direct measurement method, method comparison, total error, imprecision, trueness, specificity, dyslipidemia, cardiovascular disease
- MeSH terms
- Blood Chemical Analysis, Humans, Cholesterol, HDL, Cholesterol, LDL, Reference Standards, Sensitivity and Specificity, Ultracentrifugation
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