Studies in health technology and informatics, 2020
Modern clinical laboratories have to confirm that the procedures used for specific tests are reli... more Modern clinical laboratories have to confirm that the procedures used for specific tests are reliable and valid. There are several sources of errors and interferences that can invalidate the results. Medical validation refers to the plausibility check of the test results. Implausible results indicate that something might went wrong with a sample retrieved from the patient, e.g., the blood sample got contaminated with another fluid, which requires re-examination. Here, we describe how an integrated R-based business intelligence (BI) tool can be developed that increase the efficiency of the medical validation at the Institute of Clinical Chemistry (ICC) of the University Hospital Zurich. A BI software environment allowed us to digitalize steps in the validation process that were manually done in Excel worksheets, e.g., importing the data, calculating percentiles, and producing graphical outputs.
Clinical Chemistry and Laboratory Medicine (CCLM), 2016
Background:Monitoring of plasma drug levels is mandatory in patients receiving high-dose methotre... more Background:Monitoring of plasma drug levels is mandatory in patients receiving high-dose methotrexate. This study evaluated the analytical performance of the novel Architect and the established ARK™ methotrexate immunoassay (running on the Roche CobasMethods:Imprecision and linearity were verified for the Architect and ARK assay according to CLSI EP15-A3 and EP6-A guidelines, respectively. The reported limit of quantitation (0.04 μmol/L) was tested for both assays according to the CLSI EP17-A2 guideline. Correlation and agreement between the different assays were evaluated using residual plasma samples (n=153).Results:Total imprecision was <6.3% and <9.5% for the Architect and ARK assay, respectively. The claimed linearity and limit of quantitation were confirmed for the Architect assay. For the ARK assay, imprecision at the limit of quantitation was <18% with a positive bias resulting in a high total error up to 58%, and hence the linearity could not be confirmed. Both ass...
Chronic granulomatous disease (CGD) is caused by a defect in both the host's defenses and its reg... more Chronic granulomatous disease (CGD) is caused by a defect in both the host's defenses and its regulation of inflammation normally provided by phagocytes and other leukocytes. As in the case described here, it is not uncommon that CGD patients are diagnosed late, only after organdamaging manifestations have already progressed. In this patient, we found that CGD arose due to a splice-supporting mutation in the last position of a cryptic exon towards the middle of intron 6 of the CYBB (gp91-phox) gene. The mutation led to the insertion of 56 bp into most of the CYBB mRNA of leukocytes causing a frame shift and a premature stop codon. The normal cryptic exon was also found to be mildly active in some tissues other than leukocytes in healthy donors, to be conserved in many primates, and to a lesser degree in other mammals. Some sequence similarity suggests that the cryptic exon may have originated from a mammalian interspersed repetitive (MIR) element. Taken together, we clarify an unusual disease-causing mutation, indicate its evolutionary background and emphasize the importance of a timely diagnosis of CGD.
Metal-responsive transcription factor-1 (MTF-1) is an evolutionarily conserved zinc finger protei... more Metal-responsive transcription factor-1 (MTF-1) is an evolutionarily conserved zinc finger protein that activates transcription in response to heavy metals such as Zn(II), Cd(II) and Cu(I). The DNA-binding domain of MTF-1 recognizes a specific DNA sequence termed the metal response element (MRE), located in the promoter/enhancer region of its target genes. Here we show that human MTF-1 forms homodimers in vivo via a conserved cysteine-rich cluster “CQCQCAC” located near the C-terminus that was previously shown by cell transfection experiments to be important for basal and especially metal-induced transcriptional activity. Using a mammalian two-hybrid system we find that dimerization is not further enhanced by zinc treatment, implying that dimerization via the cysteine cluster is required for metal-induced transcriptional activity but actual zinc sensing is mediated by another domain. By contrast copper, which on its own activates hMTF-1 only weakly, stabilizes the dimer by inducing ...
Zusammenfassung. Eine Erhöhung der Plasma-Vitamin-B12(=Cobalamin)-Spiegel findet sich unerwartet ... more Zusammenfassung. Eine Erhöhung der Plasma-Vitamin-B12(=Cobalamin)-Spiegel findet sich unerwartet häufig als asymptomatischer Zufallsbefund in der Routinelaboruntersuchung. Eine diagnostisch zielführende Klinik fehlt in der Regel. Der Cobalamin-Stoffwechsel und der Metabolismus seiner Transportproteine ist komplex, jedoch für das Verständnis der verschiedenen Differenzialdiagnosen einer Hypervitaminämie B12 von entscheidender Bedeutung. Neben der übermässigen Cobalaminzufuhr von aussen kann eine Vitamin-B12-Erhöhung auch bei soliden Neoplasien, hämatologischen Grunderkrankungen, Leber- und Nierenfunktionsstörungen und rheumatologischen Erkrankungen auftreten. Eine gezielte Anamnese verhindert dabei die Überdiagnostik. In diesem Artikel möchten wir auf Abklärungsstrategien und Differenzialdiagnosen einer Hypervitaminämie B12 eingehen.
Studies in health technology and informatics, 2020
Modern clinical laboratories have to confirm that the procedures used for specific tests are reli... more Modern clinical laboratories have to confirm that the procedures used for specific tests are reliable and valid. There are several sources of errors and interferences that can invalidate the results. Medical validation refers to the plausibility check of the test results. Implausible results indicate that something might went wrong with a sample retrieved from the patient, e.g., the blood sample got contaminated with another fluid, which requires re-examination. Here, we describe how an integrated R-based business intelligence (BI) tool can be developed that increase the efficiency of the medical validation at the Institute of Clinical Chemistry (ICC) of the University Hospital Zurich. A BI software environment allowed us to digitalize steps in the validation process that were manually done in Excel worksheets, e.g., importing the data, calculating percentiles, and producing graphical outputs.
Clinical Chemistry and Laboratory Medicine (CCLM), 2016
Background:Monitoring of plasma drug levels is mandatory in patients receiving high-dose methotre... more Background:Monitoring of plasma drug levels is mandatory in patients receiving high-dose methotrexate. This study evaluated the analytical performance of the novel Architect and the established ARK™ methotrexate immunoassay (running on the Roche CobasMethods:Imprecision and linearity were verified for the Architect and ARK assay according to CLSI EP15-A3 and EP6-A guidelines, respectively. The reported limit of quantitation (0.04 μmol/L) was tested for both assays according to the CLSI EP17-A2 guideline. Correlation and agreement between the different assays were evaluated using residual plasma samples (n=153).Results:Total imprecision was <6.3% and <9.5% for the Architect and ARK assay, respectively. The claimed linearity and limit of quantitation were confirmed for the Architect assay. For the ARK assay, imprecision at the limit of quantitation was <18% with a positive bias resulting in a high total error up to 58%, and hence the linearity could not be confirmed. Both ass...
Chronic granulomatous disease (CGD) is caused by a defect in both the host's defenses and its reg... more Chronic granulomatous disease (CGD) is caused by a defect in both the host's defenses and its regulation of inflammation normally provided by phagocytes and other leukocytes. As in the case described here, it is not uncommon that CGD patients are diagnosed late, only after organdamaging manifestations have already progressed. In this patient, we found that CGD arose due to a splice-supporting mutation in the last position of a cryptic exon towards the middle of intron 6 of the CYBB (gp91-phox) gene. The mutation led to the insertion of 56 bp into most of the CYBB mRNA of leukocytes causing a frame shift and a premature stop codon. The normal cryptic exon was also found to be mildly active in some tissues other than leukocytes in healthy donors, to be conserved in many primates, and to a lesser degree in other mammals. Some sequence similarity suggests that the cryptic exon may have originated from a mammalian interspersed repetitive (MIR) element. Taken together, we clarify an unusual disease-causing mutation, indicate its evolutionary background and emphasize the importance of a timely diagnosis of CGD.
Metal-responsive transcription factor-1 (MTF-1) is an evolutionarily conserved zinc finger protei... more Metal-responsive transcription factor-1 (MTF-1) is an evolutionarily conserved zinc finger protein that activates transcription in response to heavy metals such as Zn(II), Cd(II) and Cu(I). The DNA-binding domain of MTF-1 recognizes a specific DNA sequence termed the metal response element (MRE), located in the promoter/enhancer region of its target genes. Here we show that human MTF-1 forms homodimers in vivo via a conserved cysteine-rich cluster “CQCQCAC” located near the C-terminus that was previously shown by cell transfection experiments to be important for basal and especially metal-induced transcriptional activity. Using a mammalian two-hybrid system we find that dimerization is not further enhanced by zinc treatment, implying that dimerization via the cysteine cluster is required for metal-induced transcriptional activity but actual zinc sensing is mediated by another domain. By contrast copper, which on its own activates hMTF-1 only weakly, stabilizes the dimer by inducing ...
Zusammenfassung. Eine Erhöhung der Plasma-Vitamin-B12(=Cobalamin)-Spiegel findet sich unerwartet ... more Zusammenfassung. Eine Erhöhung der Plasma-Vitamin-B12(=Cobalamin)-Spiegel findet sich unerwartet häufig als asymptomatischer Zufallsbefund in der Routinelaboruntersuchung. Eine diagnostisch zielführende Klinik fehlt in der Regel. Der Cobalamin-Stoffwechsel und der Metabolismus seiner Transportproteine ist komplex, jedoch für das Verständnis der verschiedenen Differenzialdiagnosen einer Hypervitaminämie B12 von entscheidender Bedeutung. Neben der übermässigen Cobalaminzufuhr von aussen kann eine Vitamin-B12-Erhöhung auch bei soliden Neoplasien, hämatologischen Grunderkrankungen, Leber- und Nierenfunktionsstörungen und rheumatologischen Erkrankungen auftreten. Eine gezielte Anamnese verhindert dabei die Überdiagnostik. In diesem Artikel möchten wir auf Abklärungsstrategien und Differenzialdiagnosen einer Hypervitaminämie B12 eingehen.
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