Evaluation of the first immunosuppressive drug assay available on a fully automated LC-MS/MS-based clinical analyzer suggests a new era in laboratory medicine

Hörber, Sebastian; Peter, Andreas; Lehmann, Rainer; Hoene, Miriam

doi:10.1515/cclm-2020-0848

Cited by 27 publications

(12 citation statements)

References 17 publications

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“…In a smaller study that included only 21 patient samples, the observed bias against the LC-MS/MS system was not detectable. 17 This was attributed to the low number of samples tested. Having a bias of −9% in the case of CSA could result in a certain number of patient results not being detected as above therapeutic range, and thus, dose correction may be missed out for those patients.…”

Section: Discussionmentioning

confidence: 99%

Immunosuppressant Monitoring—Performance of the First Mass Spectrometry–Based Automated Clinical Analyzer Cascadion

Grote-Koska

Czajkowski

Antje

et al. 2023

Therapeutic Drug Monitoring

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Background: Automatic analyzers simplify processes and may help improve standardization. The first automated analyzer based on mass spectrometry is available and offers a panel for monitoring cyclosporin A, tacrolimus, sirolimus, and everolimus. Method comparisons and evaluation tests are presented to verify the capability of the Cascadion system for use in a clinical laboratory.Methods: Sample preparation and measurements were performed using the Cascadion clinical analyzer. More than 1000 measurement values of patient samples were compared with an in vitro diagnosticcertified assay run on a liquid chromatography tandem mass spectrometry instrument. Precision and accuracy were determined using commercial quality control and external quality assessment (EQA) samples.Results: A good correlation between the 2 instruments was observed (Pearson correlation r = 0.956-0.996). Deming regression revealed 95% confidence intervals of slopes and intercepts covering the values 1 and 0, for sirolimus and everolimus, respectively, indicating equivalence of both measuring systems. However, for cyclosporin A, a bias was observed and confirmed using a Bland-Altman plot (29.1%). Measurement repeatability and intermediate measurement precision were appropriate showing coefficients of variation of 0.9%-6.1% and 2.0%-5.3%, respectively. Accuracy according to internal quality controls was 85%-111% and 81%-100% in the EQA samples of Reference Institute of Bioanalytics and Laboratory of the Government Chemist, respectively. High robustness was found with regard to the linearity of the calibration lines (linear regression coefficient r 2 . 0.99). Carryover was negligible (0.1%). Conclusions:The Cascadion automatic analyzer produced convincing results in the measurement of patient, control, and EQA samples. The throughput was sufficient for routine use. Overall, it can be used as an alternative to open liquid chromatography tandem mass spectrometry instruments for immunosuppressant monitoring, simplifying processes without the need for specially trained personnel.

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Section: Discussionmentioning

confidence: 99%

Immunosuppressant Monitoring—Performance of the First Mass Spectrometry–Based Automated Clinical Analyzer Cascadion

Grote-Koska

Czajkowski

Antje

et al. 2023

Therapeutic Drug Monitoring

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“…Thirdly, the metabolites described here can be analyzed in a single LC-MS run. Recently a fully automatic LC-MS system, suitable for 24/7 use, was introduced into routine diagnostics ( 74 ). This instrument, which is easy to operate and does not call for specific LC-MS expertise ( 74 ), not only opens up perspectives for every routine diagnostic laboratory to apply LC-MS, but also analyzes complex diagnostic patterns in a fully automatic, high-throughput manner in the future.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic Performance of Sex-Specific Modified Metabolite Patterns in Urine for Screening of Prediabetes

Zhang

Hoene

et al. 2022

Front. Endocrinol.

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Aims/HypothesisLarge-scale prediabetes screening is still a challenge since fasting blood glucose and HbA1c as the long-standing, recommended analytes have only moderate diagnostic sensitivity, and the practicability of the oral glucose tolerance test for population-based strategies is limited. To tackle this issue and to identify reliable diagnostic patterns, we developed an innovative metabolomics-based strategy deviating from common concepts by employing urine instead of blood samples, searching for sex-specific biomarkers, and focusing on modified metabolites.MethodsNon-targeted, modification group-assisted metabolomics by liquid chromatography–mass spectrometry (LC-MS) was applied to second morning urine samples of 340 individuals from a prediabetes cohort. Normal (n = 208) and impaired glucose-tolerant (IGT; n = 132) individuals, matched for age and BMI, were randomly divided in discovery and validation cohorts. ReliefF, a feature selection algorithm, was used to extract sex-specific diagnostic patterns of modified metabolites for the detection of IGT. The diagnostic performance was compared with conventional screening parameters fasting plasma glucose (FPG), HbA1c, and fasting insulin.ResultsFemale- and male-specific diagnostic patterns were identified in urine. Only three biomarkers were identical in both. The patterns showed better AUC and diagnostic sensitivity for prediabetes screening of IGT than FPG, HbA1c, insulin, or a combination of FPG and HbA1c. The AUC of the male-specific pattern in the validation cohort was 0.889 with a diagnostic sensitivity of 92.6% and increased to an AUC of 0.977 in combination with HbA1c. In comparison, the AUCs of FPG, HbA1c, and insulin alone reached 0.573, 0.668, and 0.571, respectively. Validation of the diagnostic pattern of female subjects showed an AUC of 0.722, which still exceeded the AUCs of FPG, HbA1c, and insulin (0.595, 0.604, and 0.634, respectively). Modified metabolites in the urinary patterns include advanced glycation end products (pentosidine-glucuronide and glutamyl-lysine-sulfate) and microbiota-associated compounds (indoxyl sulfate and dihydroxyphenyl-gamma-valerolactone-glucuronide).Conclusions/InterpretationOur results demonstrate that the sex-specific search for diagnostic metabolite biomarkers can be superior to common metabolomics strategies. The diagnostic performance for IGT detection was significantly better than routinely applied blood parameters. Together with recently developed fully automatic LC-MS systems, this opens up future perspectives for the application of sex-specific diagnostic patterns for prediabetes screening in urine.

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“…Examples of automated systems that are currently available are the Shimadzu CLAM System 145 and ThermoFisher Scientific's Cascadion™ SM Clinical Analyzer 146 . The latter has been tested and compared with routine tests for Vitamin D and immunosuppressive drugs (cyclosporine A, sirolimus, tacrolimus, and everolimus) and showed excellent analytical performance 147,148 . For Vitamin D, all samples were within 10% of the reference concentrations, and for the immunosuppressive drugs, the mean deviation from the immunoassays was 17%–19%, 147,148 suggesting that automated LC–MS provides robust clinical data.…”

Section: Techniques and Challenges For Tdmmentioning

confidence: 99%

Utility, promise, and limitations of liquid chromatography‐mass spectrometry‐based therapeutic drug monitoring in precision medicine

et al. 2021

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Therapeutic drug monitoring (TDM) is typically referred to as the measurement of the concentration of drugs in patient blood. Although in the past, TDM was restricted to drugs with a narrow therapeutic range in order to avoid drug toxicity, TDM has recently become a major tool for precision medicine being applied to many more drugs. Through compensating for interindividual differences in a drug's pharmacokinetics, improved dosing of individual patients based on TDM ensures maximum drug effectiveness while minimizing side effects. This is especially relevant for individuals that present a particularly high intervariability in pharmacokinetics, such as newborns, or for critically/severely ill patients. In this article, we will review the applications for and limitations of TDM, discuss for which patients TDM is most beneficial and why, examine which techniques are being used for TDM, and demonstrate how mass spectrometry is increasingly becoming a reliable and convenient alternative for the TDM of different classes of drugs. We will also highlight the advances, challenges, and limitations of the existing repertoire of TDM methods and discuss future opportunities for TDM‐based precision medicine.

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Evaluation of the first immunosuppressive drug assay available on a fully automated LC-MS/MS-based clinical analyzer suggests a new era in laboratory medicine

Cited by 27 publications

References 17 publications

Immunosuppressant Monitoring—Performance of the First Mass Spectrometry–Based Automated Clinical Analyzer Cascadion

Immunosuppressant Monitoring—Performance of the First Mass Spectrometry–Based Automated Clinical Analyzer Cascadion

Diagnostic Performance of Sex-Specific Modified Metabolite Patterns in Urine for Screening of Prediabetes

Utility, promise, and limitations of liquid chromatography‐mass spectrometry‐based therapeutic drug monitoring in precision medicine

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