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- Aakre, K. M., et al.
(författare)
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Analytical Considerations in Deriving 99th Percentile Upper Reference Limits for High-Sensitivity Cardiac Troponin Assays: Educational Recommendations from the IFCC Committee on Clinical Application of Cardiac Bio-Markers
- 2022
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Ingår i: Clinical chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 68:8, s. 1022-1030
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Tidskriftsartikel (refereegranskat)abstract
- The International Federation of Clinical Chemistry Committee on Clinical Application of Cardiac Bio-Markers provides evidence-based educational documents to facilitate uniform interpretation and utilization of cardiac biomarkers in clinical laboratories and practice. The committee's goals are to improve the understanding of certain key analytical and clinical aspects of cardiac biomarkers and how these may interplay in clinical practice. Measurement of high-sensitivity cardiac troponin (hs-cTn) assays is a cornerstone in the clinical evaluation of patients with symptoms and/or signs of acute cardiac ischemia. To define myocardial infarction, the Universal Definition of Myocardial Infarction requires patients who manifest with features suggestive of acute myocardial ischemia to have at least one cTn concentration above the sex-specific 99th percentile upper reference limit (URL) for hs-cTn assays and a dynamic pattern of cTn concentrations to fulfill the diagnostic criteria for MI. This special report provides an overview of how hs-cTn 99th percentile URLs should be established, including recommendations about prescreening and the number of individuals required in the reference cohort, how statistical analysis should be conducted, optimal preanalytical and analytical protocols, and analytical/biological interferences or confounds that can affect accurate determination of the 99th percentile URLs. This document also provides guidance and solutions to many of the issues posed.
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| 2. |
- Aakre, Kristin M, et al.
(författare)
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Lower Limits for Reporting High-Sensitivity Cardiac Troponin Assays and Impact of Analytical Performance on Patient Misclassification.
- 2024
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Ingår i: Clinical chemistry. - 0009-9147 .- 1530-8561. ; 70:3, s. 497-505
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Tidskriftsartikel (refereegranskat)abstract
- Cardiac troponin measurements are indispensable for the diagnosis of myocardial infarction and provide useful information for long-term risk prediction of cardiovascular disease. Accelerated diagnostic pathways prevent unnecessary hospital admission, but require reporting cardiac troponin concentrations at low concentrations that are sometimes below the limit of quantification. Whether analytical imprecision at these concentrations contributes to misclassification of patients is debated.The International Federation of Clinical Chemistry Committee on Clinical Application of Cardiac Bio-Markers (IFCC C-CB) provides evidence-based educational statements on analytical and clinical aspects of cardiac biomarkers. This mini-review discusses how the reporting of low concentrations of cardiac troponins impacts on whether or not assays are classified as high-sensitivity and how analytical performance at low concentrations influences the utility of troponins in accelerated diagnostic pathways. Practical suggestions are made for laboratories regarding analytical quality assessment of cardiac troponin results at low cutoffs, with a particular focus on accelerated diagnostic pathways. The review also discusses how future use of cardiac troponins for long-term prediction or management of cardiovascular disease may require improvements in analytical quality.Clinical guidelines recommend using cardiac troponin concentrations as low as the limit of detection of the assay to guide patient care. Laboratories, manufacturers, researchers, and external quality assessment providers should extend analytical performance monitoring of cardiac troponin assays to include the concentration ranges applicable in these pathways.
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| 6. |
- El-Khoury, Joe M., et al.
(författare)
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Time to Reevaluate the 95% Inclusion Criteria for Defining Reference Intervals?
- 2024
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Ingår i: Clinical Chemistry. - : OXFORD UNIV PRESS INC. - 0009-9147 .- 1530-8561.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- When test results fall outside the reference intervals in healthy individuals, it often leads to frustration and unnecessary investigations for potential diseases. These anomalies can be attributed to matrix effects or lack of selectivity but more commonly are due to the strict criteria we use when designing reference intervals that ultimately could be narrow for some tests (1–3).The central question we raise here is whether it is time to reevaluate and redesign our approach to creating reference intervals to reduce the occurrence of false positives while minimizing false negatives. Here we provide a condensed overview of the history, theory, and practical considerations regarding reference intervals and why we firmly believe we need to update our approach for some tests.
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| 7. |
- Filges, Stefan, 1991, et al.
(författare)
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Digital Quantification of Chemical Oligonucleotide Synthesis Errors
- 2021
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 67:10, s. 1384-1394
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Chemically synthesized oligonucleotides are vital to most nucleic acids-based technologies and several applications are sensitive to oligonucleotide sequence errors. However, it is challenging to identify and quantify the types and amount of errors in synthetic oligonucleotides. METHODS: We applied a digital sequencing approach using unique molecular identifiers to quantify errors in chemically synthesized oligonucleotides from multiple manufacturers with different synthesis strategies, purity grades, batches, and sequence context. RESULTS: We detected both deletions and substitutions in chemical oligonucleotide synthesis, but deletions were 7 times more common. We found that 97.2% of all analyzed oligonucleotide molecules were intact across all manufacturers and purity grades, although the number of oligonucleotide molecules with deletions ranged between 0.2% and 11.7% for different types. Different batches of otherwise identical oligonucleotide types also varied significantly, and batch effect can impact oligonucleotide quality more than purification. We observed a bias of increased deletion rates in chemically synthesized oligonucleotides toward the 5'-end for 1 out of 2 sequence configurations. We also demonstrated that the performance of sequencing assays depends on oligonucleotide quality. CONCLUSIONS: Our data demonstrate that manufacturer, synthesis strategy, purity, batch, and sequence context all contribute to errors in chemically synthesized oligonucleotides and need to be considered when choosing and evaluating oligonucleotides. High-performance oligonucleotides are essential in numerous molecular applications, including clinical diagnostics.
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| 8. |
- Johansson, Gustav, et al.
(författare)
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Ultrasensitive DNA Immune Repertoire Sequencing Using Unique Molecular Identifiers.
- 2020
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Ingår i: Clinical chemistry. - : Oxford University Press (OUP). - 1530-8561 .- 0009-9147. ; 66:9, s. 1228-1237
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Tidskriftsartikel (refereegranskat)abstract
- Immune repertoire sequencing of the T-cell receptor can identify clonotypes that have expanded as a result of antigen recognition or hematological malignancies. However, current sequencing protocols display limitations with nonuniform amplification and polymerase-induced errors during sequencing. Here, we developed a sequencing method that overcame these issues and applied it to γδ T cells, a cell type that plays a unique role in immunity, autoimmunity, homeostasis of intestine, skin, adipose tissue, and cancer biology.The ultrasensitive immune repertoire sequencing method used PCR-introduced unique molecular identifiers. We constructed a 32-panel assay that captured the full diversity of the recombined T-cell receptor delta loci in γδ T cells. The protocol was validated on synthetic reference molecules and blood samples of healthy individuals.The 32-panel assay displayed wide dynamic range, high reproducibility, and analytical sensitivity with single-nucleotide resolution. The method corrected for sequencing-depended quantification bias and polymerase-induced errors and could be applied to both enriched and nonenriched cells. Healthy donors displayed oligoclonal expansion of γδ T cells and similar frequencies of clonotypes were detected in both enrichment and nonenriched samples.Ultrasensitive immune repertoire sequencing strategy enables quantification of individual and specific clonotypes in a background that can be applied to clinical as well as basic application areas. Our approach is simple, flexible, and can easily be implemented in any molecular laboratory.
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| 10. |
- Kavsak, P. A., et al.
(författare)
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Cardiac Troponin Testing in Patients with COVID-19: A Strategy for Testing and Reporting Results
- 2021
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 67:1, s. 107-113
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged late in 2019 causing COVID-19 (coronavirus disease-2019) may adversely affect the cardiovascular system. Publications from Asia, Europe, and North America have identified cardiac troponin as an important prognostic indicator for patients hospitalized with COVID-19. We recognized from publications within the first 6 months of the pandemic that there has been much uncertainty on the reporting, interpretation, and pathophysiology of an increased cardiac troponin concentration in this setting. CONTENT: The purpose of this mini-review is: a) to review the pathophysiology of SARS-CoV-2 and the cardiovascular system, b) to overview the strengths and weaknesses of selected studies evaluating cardiac troponin in patients with COVID-19, and c) to recommend testing strategies in the acute period, in the convalescence period and in long-term care for patients who have become ill with COVID-19. SUMMARY: This review provides important educational information and identifies gaps in understanding the role of cardiac troponin and COVID-19. Future, properly designed studies will hopefully provide the much-needed evidence on the path forward in testing cardiac troponin in patients with COVID-19.
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