TY  - JOUR
AB  - BACKGROUND: Recent advances in omics techniques have allowed detailed genetic characterization of cortisol-producing adrenal adenoma (CPA). In contrast, the pathophysiology of CPAs has not been elucidated in detail on the level of tumor metabolic alterations. METHODS: The current study conducted a comprehensive mass spectrometry imaging (MSI) map of CPAs in relation to clinical phenotypes and immunohistochemical profiles of steroidogenic enzymes. The study cohort comprised 46 patients with adrenal tumors including CPAs (n = 35) and nonfunctional adenomas (n = 11). RESULTS: Severity of cortisol hypersecretion was significantly correlated with 29 metabolites (adjusted P < 0.05). Adrenal androgens derived from the classic androgen pathway were inversely correlated with both cortisol secretion (rs = -0.41, adjusted P = 0.035) and CYP11B1 expression (rs = -0.77, adjusted P = 2.00E-08). The extent of cortisol excess and tumor CYP11B1 expression further correlated with serotonin (rs = 0.48 and 0.62, adjusted P = 0.008 and 2.41E-05). Tumor size was found to be correlated with abundance of 13 fatty acids (adjusted P < 0.05) and negatively associated with 9 polyunsaturated fatty acids including phosphatidic acid 38:8 (rs = -0.56, adjusted P = 0.009). CONCLUSIONS: MSI reveals novel metabolic links between endocrine function and tumorigenesis, which will further support the understanding of CPA pathophysiology.
AU  - Murakami, M.*
AU  - Sun, N.
AU  - Li, F.
AU  - Feuchtinger, A.
AU  - Gomez-Sanchez, C.*
AU  - Fassnacht, M.*
AU  - Reincke, M.*
AU  - Bancos, I.*
AU  - Walch, A.K.
AU  - Kroiss, M.*
AU  - Beuschlein, F.*
C1  - 67137
C2  - 53476
CY  - Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
SP  - 149-159
TI  - In situ metabolomics of cortisol-producing adenomas.
JO  - Clin. Chem.
VL  - 69
IS  - 2
PB  - Oxford Univ Press Inc
PY  - 2023
SN  - 0009-9147
ER  - 

TY  - JOUR
AU  - Ghini, V.*
AU  - Abuja, P.M.*
AU  - Polasek, O.*
AU  - Kozera, L.*
AU  - Laiho, P.*
AU  - Anton, G.
AU  - Zins, M.*
AU  - Klovins, J.*
AU  - Metspalu, A.*
AU  - Wichmann, H.-E.
AU  - Gieger, C.
AU  - Luchinat, C.*
AU  - Zatloukal, K.*
AU  - Turano, P.*
C1  - 62416
C2  - 50860
CY  - Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
SP  - 1153-1155
TI  - Metabolomic fingerprints in large population cohorts: Impact of preanalytical heterogeneity.
JO  - Clin. Chem.
VL  - 67
IS  - 8
PB  - Oxford Univ Press Inc
PY  - 2021
SN  - 0009-9147
ER  - 

TY  - JOUR
AB  - BACKGROUND: The Islet Autoantibody Standardization Program (IASP) aims to improve the performance of immunoassays measuring type 1 diabetes (T1D)-associated autoantibodies and the concordance of results among laboratories. IASP organizes international interlaboratory assay comparison studies in which blinded serum samples are distributed to participating laboratories, followed by centralized collection and analysis of results, providing participants with an unbiased comparative assessment. In this report, we describe the results of glutamic acid decarboxylase autoantibody (GADA) assays presented in the IASP 2018 workshop. METHODS: In May 2018, IASP distributed to participants uniquely coded sera from 43 new-onset T1D patients, 7 multiple autoantibody-positive nondiabetic individuals, and 90 blood donors. Results were analyzed for the following metrics: sensitivity, specificity, accuracy, area under the ROC curve (ROC-AUC), partial ROC-AUC at 95% specificity (pAUC95), and concordance of qualitative and quantitative results. RESULTS: Thirty-seven laboratories submitted results from a total of 48 different GADA assays adopting 9 different formats. The median ROC-AUC and pAUC95 of all assays were 0.87 [interquartile range (IQR), 0.83-0.89] and 0.036 (IQR, 0.032-0.039), respectively. Large differences in pAUC95 (range, 0.001-0.0411) were observed across assays. Of formats widely adopted, bridge ELISAs showed the best median pAUC95 (0.039; range, 0.036-0.041). CONCLUSIONS: Several novel assay formats submitted to this study showed heterogeneous performance. In 2018, the majority of the best performing GADA immunoassays consisted of novel or established nonradioactive tests that proved on a par or superior to the radiobinding assay, the previous gold standard assay format for GADA measurement.
AU  - Lampasona, V.*
AU  - Pittman, D.L.*
AU  - Williams, A.J.*
AU  - Achenbach, P.
AU  - Schlosser, M.*
AU  - Akolkar, B.*
AU  - Winter, W.E.*
C1  - 56872
C2  - 47405
SP  - 1141-1152
TI  - Islet autoantibody standardization program 2018 workshop: Interlaboratory comparison of glutamic acid decarboxylase autoantibody assay performance.
JO  - Clin. Chem.
VL  - 65
IS  - 9
PY  - 2019
SN  - 0009-9147
ER  - 

TY  - JOUR
AB  - BACKGROUND: Adrenocortical carcinoma (ACC) is a rare tumor with variable prognosis even within the same tumor stage. Cancer-related sex hormones and their sulfated metabolites in body fluids can be used as tumor markers. The role of steroid sulfation in ACC has not yet been studied. MALDI mass spectrometry imaging (MALDI-MSI) is a novel tool for tissue-based chemical phenotyping.METHODS: We performed phenotyping of formalin-fixed, paraffin-embedded tissue samples from 72 ACC by MALDI-MSI at a metabolomics level.RESULTS: Tumoral steroid hormone metabolites-estradiol sulfate [hazard ratio (HR) 0.26; 95% CI, 0.10-0.69; P = 0.005] and estrone 3-sulfate (HR 0.22; 95% CI, 0.07-0.63; P = 0.003)-were significantly associated with prognosis in Kaplan-Meier analyses and after multivariable adjustment for age, tumor stage, and sex (HR 0.29; 95% CI, 0.11-0.79; P= 0.015 and HR 0.30; 95% CI, 0.10-0.91; P = 0.033, respectively). Expression of sulfotransferase SULT2A1 was associated with prognosis to a similar extent and was validated to be a prognostic factor in two published data sets. We discovered the presence of estradiol-17 beta 3,17-disulfate (E2S2) in a subset of tumors with particularly poor overall survival. Electron microscopy revealed novel membrane-delimited organelles in only these tumors. By applying duster analyses of metabolomic data, 3 sulfation-related phenotypes exhibited specific metabolic features unrelated to steroid metabolism.CONCLUSIONS: MALDI-MSI provides novel insights into the pathophysiology of ACC. Steroid hormone sulfation may be used for prognostication and treatment stratification. Sulfation-related metabolic reprogramming may be of relevance also in conditions beyond the rare ACC and can be directly investigated by the use of MALDI-MSI.
AU  - Sun, N.
AU  - Kunzke, T.
AU  - Sbiera, S.*
AU  - Kircher, S.*
AU  - Feuchtinger, A.
AU  - Aichler, M.
AU  - Herterich, S.*
AU  - Ronchi, C.L.*
AU  - Weigand, I.*
AU  - Schlegel, N.*
AU  - Waldmann, J.*
AU  - Fragoso, M.C.V.*
AU  - Whitsett, T.G.*
AU  - Gill, A.J.*
AU  - Fassnacht, M.*
AU  - Walch, A.K.
AU  - Kroiss, M.*
C1  - 56930
C2  - 47300
CY  - 2101 L Street Nw, Suite 202, Washington, Dc 20037-1526 Usa
SP  - 1276-1286
TI  - Prognostic relevance of steroid sulfation in adrenocortical carcinoma revealed by molecular phenotyping using high resolution mass spectrometry imaging.
JO  - Clin. Chem.
VL  - 65
IS  - 9
PB  - Amer Assoc Clinical Chemistry
PY  - 2019
SN  - 0009-9147
ER  - 

TY  - JOUR
AB  - BACKGROUND: Nonadherence to standard operating procedures (SOPs) during handling and processing of whole blood is one of the most frequent causes affecting the quality of serum and plasma. Yet, the quality of blood samples is of the utmost importance for reliable, conclusive research findings, valid diagnostics, and appropriate therapeutic decisions.METHODS: UHPLC-MS-driven nontargeted metabolomics was applied to identify biomarkers that reflected time to processing of blood samples, and a targeted UHPLC-MS analysis was used to quantify and validate these biomarkers.RESULTS: We found that (4E, 14Z)-sphingadienine-C181-phosphate (S1P-d18: 2) was suitable for the reliable assessment of the pronounced changes in the quality of serum and plasma caused by errors in the phase between collection and centrifugation of whole blood samples. We rigorously validated S1P-d18: 2, which included the use of practicality tests on >1400 randomly selected serum and plasma samples that were originally collected during single-and multicenter trials and then stored in 11 biobanks in 3 countries. Neither life-threatening disease states nor strenuous metabolic challenges (i.e., highintensity exercise) affected the concentration of S1P-d18: 2. Cutoff values for sample assessment were defined (plasma, <= 0.085 mu g/mL; serum, <= 0.154 mu g/mL).CONCLUSIONS: Unbiased valid monitoring to check for adherence to SOP-dictated time for processing to plasma or serum and/or time to storage of whole blood at 4 degrees C is now feasible. This novel quality assessment step could enable scientists to uncover common preanalytical errors, allowing for identification of serum and plasma samples that should be excluded from certain investigations. It should also allow control of samples before long-term storage in biobanks.
AU  - Liu, X.*
AU  - Hoene, M.*
AU  - Yin, P.*
AU  - Fritsche, L.
AU  - Plomgaard, P.*
AU  - Hansen, J.S.*
AU  - Nakas, C.T.*
AU  - Niess, A.M.*
AU  - Hudemann, J.*
AU  - Haap, M.*
AU  - Mendy, M.*
AU  - Weigert, C.*
AU  - Wang, X.*
AU  - Fritsche, A.
AU  - Peter, A.
AU  - Häring, H.-U.
AU  - Xu, G.*
AU  - Lehmann, R.
C1  - 54699
C2  - 45768
CY  - 2101 L Street Nw, Suite 202, Washington, Dc 20037-1526 Usa
SP  - 810-819
TI  - Quality control of serum and plasma by quantification of (4E, 14Z)-sphingadienine-C18-1-phosphate uncovers common preanalytical errors during handling of whole blood.
JO  - Clin. Chem.
VL  - 64
IS  - 5
PB  - Amer Assoc Clinical Chemistry
PY  - 2018
SN  - 0009-9147
ER  - 

TY  - JOUR
AB  - For decades, glucose, hemoglobin A1c, insulin, and C peptide have been the laboratory tests of choice to detect and monitor diabetes (1). However, these tests do not identify individuals at risk for developing type 2 diabetes (T2Dm)4 (so-called prediabetic individuals and the subphenotypes therein), which would be a prerequisite for individualized prevention. Nor are these parameters suitable to identify T2Dm subphenotypes, a prerequisite for individualized therapeutic interventions. The oral glucose tolerance test (oGTT) is still the only means for the early and reliable identification of people in the prediabetic phase with impaired glucose tolerance (IGT). This procedure, however, is very time-consuming and expensive and is unsuitable as a screening method in a doctor′s office. Hence, there is an urgent need for innovative laboratory tests to simplify the early detection of alterations in glucose metabolism.
AU  - Lehmann, R.
C1  - 28148
C2  - 32964
SP  - 1294-1296
TI  - Diabetes subphenotypes and metabolomics: The key to discovering laboratory markers for personalized medicine?
JO  - Clin. Chem.
VL  - 59
IS  - 9
PB  - Amer. Assoc. Clinical Chemistry
PY  - 2013
SN  - 0009-9147
ER  - 

TY  - JOUR
AB  - BACKGROUND: Metabolomics is a powerful tool that is increasingly used in clinical research. Although excellent sample quality is essential, it can easily be compromised by undetected preanalytical errors. We set out to identify critical preanalytical steps and biomarkers that reflect preanalytical inaccuracies. METHODS: We systematically investigated the effects of preanalytical variables (blood collection tubes, hemolysis, temperature and time before further processing, and number of freeze-thaw cycles) on metabolomics studies of clinical blood and plasma samples using a nontargeted LC-MS approach. RESULTS: Serum and heparinate blood collection tubes led to chemical noise in the mass spectra. Distinct, significant changes of 64 features in the EDTA-plasma metabolome were detected when blood was exposed to room temperature for 2, 4, 8, and 24 h. The resulting pattern was characterized by increases in hypoxanthine and sphingosine 1-phosphate (800% and 380%, respectively, at 2 h). In contrast, the plasma metabolome was stable for up to 4 h when EDTA blood samples were immediately placed in iced water. Hemolysis also caused numerous changes in the metabolic profile. Unexpectedly, up to 4 freeze-thaw cycles only slightly changed the EDTA-plasma metabolome, but increased the individual variability. CONCLUSIONS: Nontargeted metabolomics investigations led to the following recommendations for the preanalytical phase: test the blood collection tubes, avoid hemolysis, place whole blood immediately in ice water, use EDTA plasma, and preferably use nonrefrozen biobank samples. To exclude outliers due to preanalytical errors, inspect the biomarker signal intensities reflecting systematic as well as accidental and preanalytical inaccuracies before processing the bioinformatics data.
AU  - Yin, P.*
AU  - Peter, A.
AU  - Franken, H.*
AU  - Zhao, X.*
AU  - Neukamm, S.S.
AU  - Rosenbaum, L.*
AU  - Lucio, M.
AU  - Zell, A.*
AU  - Häring, H.-U.
AU  - Xu, G.*
AU  - Lehmann, R.
C1  - 26256
C2  - 32147
SP  - 833-845
TI  - Preanalytical aspects and sample quality assessment in metabolomics studies of human blood.
JO  - Clin. Chem.
VL  - 59
IS  - 5
PB  - Amer. Assoc. Clinical Chemistry
PY  - 2013
SN  - 0009-9147
ER  - 

TY  - JOUR
AB  - Platelet glycoprotein VI (pGPVI) expression is increased in acute coronary syndrome (ACS), reflecting platelet activation. There is no reliable method available to measure pGPVI. Our aim was to develop a bead-based sandwich immunoassay to measure soluble GPVI (sGPVI). METHODS: Based on antibodies for sGPVI developed earlier, we established and validated a bead-based sandwich immunoassay in 2438 consecutive patients with stable angina pectoris (SAP; n = 1371), non-ST-elevation myocardial infarction (NSTEMI; n = 724), and ST-elevation MI (STEMI; n = 343). In a subgroup (n = 1011), we measured surface expression of pGPVI using flow cytometry. RESULTS: The assay revealed a working range of 8-500 ng/L. Intra- and interassay imprecision was <7% and <14%, respectively. Patients with NSTEMI and STEMI showed significantly lower mean sGPVI concentrations than patients with SAP [mean (SD), 8.4 (3.6) μg/L and 8.6 (4.1) μg/L vs 9.8 (4.8) μg/L; P = 0.002], whereas subgroup analysis revealed significantly enhanced pGPVI in NSTEMI (n = 276) and STEMI (n = 80) patients compared with SAP (n = 655) [mean fluorescence intensity (SD), 21.2 (8.1) and 19.8 (6.8) vs 18.5 (7.7); P = 0.002 and P = 0.018]. pGPVI and sGPVI were inversely correlated (r = -0.076; P = 0.023). Area under the ROC curve was 0.716, 95% CI 0.681-0.751, for sGPVI, distinguishing patients with SAP from those with ACS, and was superior (P = 0.044) to the curve of subgroup analysis for pGPVI (0.624, 95% CI 0.586-0.662). sGPVI (P = 0.023) and pGPVI (P = 0.028) had better association with the development of ACS than troponin I (P = 0.055) in the very early stage of disease, based on logistic regression analysis. CONCLUSIONS: This sandwich immunoassay reliably measures sGPVI and may help to identify patients with ACS earlier than other laboratory markers.
AU  - Bigalke, B.*
AU  - Pötz, O.*
AU  - Kremmer, E.
AU  - Geisler, T.*
AU  - Seizer, P.*
AU  - Puntmann, V.O.*
AU  - Phinikaridou, A.*
AU  - Chiribiri, A.*
AU  - Nagel, E.*
AU  - Botnar, R.M.*
AU  - Joos, T.*
AU  - Gawaz, M.*
C1  - 6237
C2  - 28652
SP  - 898-904
TI  - Sandwich immunoassay for soluble glycoprotein VI in patients with symptomatic coronary artery disease.
JO  - Clin. Chem.
VL  - 57
IS  - 6
PB  - Amer Assoc Clinical Chemistry
PY  - 2011
SN  - 0009-9147
ER  - 

TY  - JOUR
AB  - PURPOSE: Copeptin, a stable peptide derived from the AVP precursor, has been linked to presence and severity of myocardial ischemia. We sought to evaluate the predictive value of copeptin and its incremental value beyond that of high-sensitivity cardiac troponin T (hs-cTnT) in patients with acute chest pain and low to intermediate risk for acute coronary syndrome (ACS). METHODS: We recruited patients who presented with acute chest pain to the emergency department and had a negative initial conventional troponin T test (<0.03 μg/L). In all patients, hs-cTnT and copeptin measurements were taken. Each patient also underwent cardiac computed tomography (CT) and coronary angiography.RESULTS:Baseline copeptin concentrations, in contrast to hs-cTnT, were not significantly higher in patients with ACS than in those without (P = 0.24). hs-cTnT showed an earlier rise in patients with ACS than copeptin, when analyses were stratified by time. A copeptin concentration ≥7.38 pmol/L had a negative predictive value (NPV) of 94% and a sensitivity of 51%, whereas hs-cTnT (≥13.0 pg/mL) had a NPV of 96% and a sensitivity of 63%. The combination of copeptin and hs-cTnT resulted in a lower diagnostic accuracy than hs-cTnT alone. Finally, on cardiac CT, copeptin concentrations were not associated with coronary artery morphology, although they were related to the presence of left ventricular dysfunction (P = 0.02). CONCLUSIONS: Among patients with acute chest pain and low to intermediate risk for ACS, copeptin concentrations are not independently predictive of ACS and do not add diagnostic value beyond that of hs-cTnT measurements.
AU  - Karakas, M.*
AU  - Januzzi, J.L. Jr.*
AU  - Meyer, J.
AU  - Lee, H.*
AU  - Schlett, C.L.*
AU  - Truong, Q.A.*
AU  - Rottbauer, W.*
AU  - Bamberg, F.*
AU  - Dasdemir, S.*
AU  - Hoffmann, U.*
AU  - Koenig, W.*
C1  - 6719
C2  - 29301
SP  - 1137-1145
TI  - Copeptin does not add diagnostic information to high-sensitivity troponin T in low- to intermediate-risk patients with acute chest pain: Results from the Rule Out Myocardial Infarction by Computed Tomography (ROMICAT) study.
JO  - Clin. Chem.
VL  - 57
IS  - 8
PB  - American Assoc. for Clinical Chemistry
PY  - 2011
SN  - 0009-9147
ER  - 

TY  - JOUR
AB  - Oxidative stress plays a critical role in the initiation and progression of atherosclerosis. Oxidized LDL (oxLDL) is a marker of oxidative stress. We prospectively investigated whether increased serum oxLDL concentrations are associated with incident coronary heart disease (CHD.We conducted a prospective population-based case-cohort study within the MONICA/KORA Augsburg studies. Serum oxLDL concentrations were measured in 333 case individuals with incident CHD and in 1727 noncase individuals selected from a source population of 9300 middle-aged, healthy men and women. The mean (SD) follow-up time was 10.8 (4.6) years. Baseline oxLDL concentrations were higher in case individuals than in noncase individuals (P < 0.001). After adjustment for age, sex, survey, smoking status, systolic blood pressure, physical activity, diabetes, body mass index, parental history of myocardial infarction, and alcohol consumption, the hazard ratio (HR) for comparing the first and third tertiles was 1.87 (95% CI, 1.33-2.64; P < 0.001). Additional adjustment for lipid parameters, inflammatory markers, and markers of endothelial dysfunction attenuated the association (HR, 1.29; 95% CI, 0.88-1.89; P = 0.087). We observed no significant interactions between oxLDL and sex or being overweight. Increased oxLDL concentrations were associated with an increased risk for incident CHD. Nevertheless, because this effect became nonsignificant after adjustment for covariates, particularly the ratio of total cholesterol to HDL cholesterol, it may be mediated primarily by lipid parameters. Further studies are warranted to clarify this issue.
AU  - Koenig, W.*
AU  - Karakas, M.*
AU  - Zierer, A.
AU  - Herder, C.*
AU  - Baumert, J.J.
AU  - Meisinger, C.
AU  - Thorand, B.
C1  - 6531
C2  - 28914
CY  - Washington, DC, USA
SP  - 1196-1200
TI  - Oxidized LDL and the risk of coronary heart disease: Results from the MONICA/KORA Augsburg study.
JO  - Clin. Chem.
VL  - 57
IS  - 8
PB  - American Assoc. for Clinical Chemistry
PY  - 2011
SN  - 0009-9147
ER  - 

TY  - JOUR
AB  - BACKGROUND: Zinc transporter 8 (ZnT8) is a recently identified major autoantigen in type 1 diabetes, and autoantibodies to ZnT8 (ZnT8A) are new markers for disease prediction and diagnosis. Here we report the results of the first international proficiency evaluation of ZnT8A assays by the Diabetes Antibody Standardization Program (DASP). METHODS: After a pilot workshop in 2007, an expanded ZnT8A workshop was held in 2009, with 26 participating laboratories from 13 countries submitting results of 63 different assays. ZnT8A levels were measured in coded sera from 50 patients with newly diagnosed type 1 diabetes and 100 blood donor controls. Results were analyzed comparing area under the ROC curve (ROC-AUC), sensitivity adjusted to 95% specificity (AS95), concordance of sample ZnT8A positive or negative designation, and autoantibody levels. RESULTS: ZnT8A radio binding assays (RBAs) based on combined immunoprecipitation of the 2 most frequent ZnT8 COOH-terminal domain polymorphic variants showed a median ROC-AUC of 0.848 [interquartile range (IQR) 0.796-0.878] and a median AS95 of 70% (IQR 60%-72%). These RBAs were more sensitive than assays using as antigen either 1 ZnT8 variant only or chimeric constructs joining NH(2)- and COOH-terminal domains, assays based on immunoprecipitation and bioluminescent detection, or assays based on immunofluorescent staining of cells transfected with full-length antigen. CONCLUSIONS: The DASP workshop identified immunoprecipitation-based ZnT8A assays and antigen constructs that achieved both a high degree of sensitivity and specificity and were suitable for more widespread clinical application.
AU  - Lampasona, V.*
AU  - Schlosser, M.*
AU  - Mueller, P.W.*
AU  - Williams, A.J.*
AU  - Wenzlau, J.M.*
AU  - Hutton, J.C.*
AU  - Achenbach, P.
C1  - 6855
C2  - 29358
CY  - Washington, DC
SP  - 1693-1702
TI  - Diabetes antibody standardization program: First proficiency evaluation of assays for autoantibodies to zinc transporter 8.
JO  - Clin. Chem.
VL  - 57
IS  - 12
PB  - American Assoc. for Clinical Chemistry
PY  - 2011
SN  - 0009-9147
ER  - 

TY  - JOUR
AB  - BACKGROUND: Among the numerous emerging biomarkers, high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) have received widespread interest, and a large database has been accumulated on their potential role as predictors of cardiovascular risk. The concentrations of inflammatory biomarkers, however, are influenced, among other things, by physiological variation, which is the natural within-individual variation occurring over time. Implementation of hsCRP and IL-6 measurement into clinical practice requires data on the reliability of such measurements. METHODS: We serially measured hsCRP and IL-6 concentrations in up to 6 blood samples taken at monthly intervals from 200 post-myocardial infarction patients who participated in the AIRGENE study. RESULTS: The mean (SD) of the ln-transformed plasma concentrations (in milligrams per liter for hsCRP and nanograms per liter for IL-6) for all participants over all samples was 0.16 (1.04) for hsCRP and 0.76 (0.57) for IL-6, with no significant differences between men and women. The within-individual and analytical variance component for the ln-transformed hsCRP data was 0.37, and the between-individual variance component was 0.73. For the ln-transformed IL-6 data, these values were 0.11 and 0.22, respectively. A substantial part of the total variation in plasma hsCRP and IL-6 concentrations was explained by the between-individual variation (as a percentage of the total variance, 66.1% for the ln-transformed hsCRP data and 66.2% for the ln-transformed IL-6 data). For both markers, 2 measurements were needed to reach a sufficient reliability. CONCLUSIONS: Our results demonstrate considerable stability and good reproducibility for serial hsCRP and IL-6 measurements. Thus, there should be no major concern about misclassification in clinical practice if at least 2 subsequent measurements are taken.
AU  - Karakas, M.*
AU  - Baumert, J.J.
AU  - Greven, S.*
AU  - Rückerl, R.
AU  - Peters, A.
AU  - Koenig, W.*
C1  - 4660
C2  - 27551
SP  - 861-864
TI  - Reproducibility in serial C-reactive protein and interleukin-6 measurements in post-myocardial infarction patients: Results from the AIRGENE study.
JO  - Clin. Chem.
VL  - 56
IS  - 5
PB  - American Assoc. of Clinical Chemistry
PY  - 2010
SN  - 0009-9147
ER  - 

TY  - JOUR
AB  - Background: C-reactive protein (CRP), a sensitive marker of the acute-phase response, has been associated with future cardiovascular endpoints independently of other risk factors. A joint analysis of the role of risk factors in predicting mean concentrations and variation of high-sensitivity CRP (hsCRP) in serum has not been carried out previously. Methods: We used data from 1003 myocardial infarction (MI) survivors who had hsCRP measured monthly up to 8 times and multivariate mixed effects statistical models to study the role of time-variant and -invariant factors on the geometric mean of and the intraindividual variation in hsCRP concentrations. Results: Patients with ≥6.5% glycosylated hemoglobin (HbA1c) had 26.2% higher hsCRP concentrations (95% CI, 7.2% 48.6%) and 20.7% greater variation in hsCRP values (P = 0.0034) than patients with lower baseline Hb A1c values (<6.5%). Similar but less pronounced differences were seen in patients with a self-reported diagnosis of type 2 diabetes. hsCRP concentrations showed less variation in patients who reported angina pectoris, congestive heart failure, or emphysema (11.0%, 24.9%, and 41.6%, respectively, vs patients without these conditions) but greater variation in males and smokers (+24.8% and +27.3%, respectively, vs females and nonsmokers). Exposures in the 24 h before blood sampling, including exposure to environmental tobacco smoke, alcohol consumption, and extreme stress, did not have a major impact. Conclusions: One or 2 hsCRP measurements may not be sufficient to adequately characterize different patient groups after MI with similar precisions. We found hsCRP concentrations to be especially variable in males, smokers, and patients with increased Hb A1c values.
AU  - Rückerl, R.
AU  - Peters, A.
AU  - Khuseyinova, N.*
AU  - Andreani, M.*
AU  - Koenig, W.*
AU  - Meisinger, C.
AU  - Dimakopoulou, K.*
AU  - Sunyer, J.*
AU  - Lanki, T.*
AU  - Nyberg, F.*
AU  - Schneider, A.E.
C1  - 1081
C2  - 26691
SP  - 322-335
TI  - Determinants of the acute-phase protein C-reactive protein in myocardial infarction survivors: The role of comorbidities and environmental factors.
JO  - Clin. Chem.
VL  - 55
IS  - 2
PY  - 2009
SN  - 0009-9147
ER  - 

TY  - JOUR
AB  - Of the numerous emerging biomarkers for coronary heart disease (CHD), lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), an enzyme involved in lipid metabolism and inflammatory pathways, seems to be a promising candidate. Implementation of Lp-PLA(2) measurement into clinical practice, however, requires data on the reliability of such measurements. METHODS: We measured Lp-PLA(2) concentrations by ELISA in blood samples drawn from 200 post-myocardial infarction patients (39-76 years) at 6 monthly intervals between May 2003 and February 2004, for a total of 1143 samples. We estimated analytical, within-individual, and between-individual variation, the critical difference, and the intraclass correlation coefficient of reliability (ICC) to assess the reliability of serial Lp-PLA(2) measurements. RESULTS: The mean (SD) plasma Lp-PLA(2) concentration for the study participants was 188.7 (41.8) microg/L, with no significant difference between men and women. The analytical CV for Lp-PLA(2) was 4.4%, the within-individual biological CV was 15%, and the between-individual CV was 22%. The ICC was 0.66. An important part of the total variation in plasma Lp-PLA(2) concentration was explained by the between-individual variation (as a percentage of the total variance, 66.1%), whereas the within-individual variance was 31.3%. The analytical variance was as low as 2.6%. CONCLUSIONS: Between-individual variation in Lp-PLA(2) concentration was substantially greater than within-individual variation. In general, our data demonstrate considerable stability and good reproducibility of serial Lp-PLA(2) measurements, results that compared favorably with those for the more commonly measured lipid markers.
AU  - Khuseyinova, N.*
AU  - Greven, S.
AU  - Rückerl, R.
AU  - Trischler, G.*
AU  - Löwel, H.
AU  - Peters, A.
AU  - König, W.*
C1  - 2444
C2  - 25179
SP  - 124-130
TI  - Variability of serial lipoprotein-associated phospholipase A2 measurements in post myocardial infarction patients: Results from the AIRGENE Study Center Augsburg.
JO  - Clin. Chem.
VL  - 54
IS  - 1
PB  - American Assoc. for Clinical Chemistry
PY  - 2008
SN  - 0009-9147
ER  - 

TY  - JOUR
AB  - C-reactive protein (CRP), an exquisitely sensitive systemic marker of inflammation, has emerged as an independent predictor of cardiovascular diseases (CVD). Because other chronic diseases are also associated with an inflammatory response, we sought to assess the association of high-sensitivity CRP (hsCRP) with total and cause-specific mortality in a large cohort of middle-aged men. METHODS: We measured hsCRP at baseline in 3620 middle-aged men, randomly drawn from 3 samples of the general population in the Augsburg area (Southern 0Germany) in 1984-85, 1989-90, and 1994-95. Outcome was defined as all deaths, fatal CVD, fatal coronary heart disease (CHD) including sudden cardiac deaths, and cancer deaths. RESULTS: During an average follow-up of 7.1 years, 408 deaths occurred (CVD 196, CHD 129, cancer 127). In multivariable Cox regression analysis, subjects with hsCRP >3 mg/L at baseline showed an almost 2-fold increased risk to die vs those with hsCRP <1 mg/L [hazard ratio (HR) 1.88, 95% CI 1.41-2.52]. HRs were 2.15 (95% CI 1.39-3.34) for fatal CVD, 1.74 (1.04-2.92) for fatal CHD, and 1.65 (1.01-2.68) for cancer mortality. In contrast, neither total nor HDL cholesterol significantly predicted all-cause or cancer mortality, and cholesterol had only modest effects on CVD mortality. CONCLUSIONS: Our results suggest that increased circulating hsCRP concentrations are associated with an increased risk of death from several widespread chronic diseases. Persistently increased hsCRP is a sensitive and valuable nonspecific indicator of an ongoing disease process that deserves serious and careful medical attention.
AU  - Koenig, W.*
AU  - Khuseyinova, N.*
AU  - Baumert, J.J.
AU  - Meisinger, C.
C1  - 638
C2  - 25286
SP  - 335-342
TI  - Prospective study of high-sensitivity C-reactive protein as a determinant of mortality: Results from the MONICA/KORA Augsburg Cohort Study, 1984-1998.
JO  - Clin. Chem.
VL  - 54
IS  - 2
PB  - American Assoc. for Clinical Chemistry
PY  - 2008
SN  - 0009-9147
ER  - 

TY  - JOUR
AU  - Koenig, W.*
AU  - Meisinger, C.
C1  - 2268
C2  - 25259
SP  - 231-233
TI  - Uric acid, type 2 diabetes, and cardiovascular diseases: Fueling the common soil hypothesis?
JO  - Clin. Chem.
VL  - 54
IS  - 2
PB  - American Assoc. for Clinical Chemistry
PY  - 2008
SN  - 0009-9147
ER  - 

TY  - JOUR
AB  - An increased plasma concentration of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) predicts adverse clinical outcome in patients with coronary heart disease. We investigated the association between plasma concentrations of ADMA and risk in initially healthy smoking and nonsmoking men. METHODS: Participants for this nested case-control study came from the population-based Monitoring of Trends and Determinants in Cardiovascular Disease/Kooperative Gesundheitsforschung in der Region Augsburg study. ADMA was measured by liquid chromatography-tandem mass spectrometry in 88 men with incident coronary events (fatal and nonfatal myocardial infarction and sudden cardiac death) and 254 age-matched controls, with a median (interquartile range) follow-up of 6.2 (3.3-7.9) years. RESULTS: After adjustment for potential confounders, the relative risk for a future coronary event was 2.00 [95% confidence interval (CI) 1.27-3.16; P = 0.003] for smokers compared with nonsmokers and 1.35 (95% CI 0.78-2.33; P = 0.282) for the top vs the bottom tertile of the ADMA distribution. In cases and controls, lower ADMA plasma concentrations were observed in smokers. Analysis of ADMA-associated risk in smokers and nonsmokers separately revealed substantial differences: the adjusted relative risk for future coronary events (top vs bottom tertile of the ADMA distribution) was 0.48 (95% CI 0.16-1.46; P = 0.198) in smokers and 2.40 (95% CI 1.14-5.08; P = 0.021) in nonsmokers. Exposure of human endothelium-derived EAhy 926 cells to tobacco smoke enhanced expression of the ADMA metabolizing enzyme dimethylarginine dimethylaminohydrolase 2 and reduced ADMA concentration. CONCLUSIONS: In apparently healthy men, increased ADMA predicts the risk for coronary events in nonsmokers, but not in smokers. This may be explained in part by an alteration of ADMA metabolism by tobacco smoke.
AU  - Maas, R.*
AU  - Schulze, F.*
AU  - Baumert, J.J.
AU  - Löwel, H.
AU  - Hamraz, K.*
AU  - Schwedhelm, E.*
AU  - Koenig, W.*
AU  - Boger, R.H.*
C1  - 2939
C2  - 24615
SP  - 693-701
TI  - Asymmetric dimethylarginine, smoking, and risk of coronary heart disease in apparently healthy men: Prospective analysis from the population-based Monitoring of Trends and Determinants in Cardiovascular Disease/Kooperative Gesundheitsforschung in der Region Augsburg study and experimental data
JO  - Clin. Chem.
VL  - 53
IS  - 4
PB  - American Assoc. for Clinical Chemistry
PY  - 2007
SN  - 0009-9147
ER  - 

TY  - JOUR
AU  - Meisinger, C.
AU  - Koletzko, B.*
AU  - Heinrich, J.
C1  - 4999
C2  - 23694
SP  - 897-898
TI  - Metabolic syndrome: Older than usually assumed, but still too young to die.
JO  - Clin. Chem.
VL  - 52
PY  - 2006
SN  - 0009-9147
ER  - 

TY  - JOUR
AU  - Ollert, M.*
AU  - Weissenbacher, S.*
AU  - Rakoski, J.*
AU  - Ring, J.
C1  - 2747
C2  - 22878
SP  - 1241-1249
TI  - Allergen-specific IgE measured by a continous random-access immunoanalyzer: Interassay comparison and agreement with skin testing.
JO  - Clin. Chem.
VL  - 51
PY  - 2005
SN  - 0009-9147
ER  - 

TY  - JOUR
AU  - Fröhlich, M.*
AU  - Sund, M.
AU  - Thorand, B.
AU  - Hutchinson, W.L.*
AU  - Pepys, M.B.
AU  - Koenig, W.*
C1  - 10264
C2  - 20136
SP  - 575-577
TI  - Lack of Seasonal Variation in C-Reactive Protein.
JO  - Clin. Chem.
VL  - 48
PB  - Assoc.
PY  - 2002
SN  - 0009-9147
ER  - 

TY  - JOUR
AB  - Background: Children are at particular risk for selenium deficiency, which has potentially serious medical implications. Reliable age-specific reference values for serum selenium concentrations in children are sparse, but are essential for the identification of selenium deficiency and decisions regarding selenium supplementation.Methods: Using electrothermal atomic absorption spectrometry we analyzed serum selenium concentrations from 1010 apparently healthy children (age range, 1 day to IS years) and from 60 patients on a protein-restricted diet because of inborn errors of metabolism. Reference intervals were defined according to recommended guidelines.Results: Medians for serum selenium concentrations showed a statistically significant age dependency: a decrease from the age <1 month (0.64 mumol/L) to 4 months (0.44 mumol/L); an increase to 0.62 mumol/L in the 4-12 months age group; constant values in children between I and 5 years of age (0.90 mumol/L); and an additional slight increase to reach a plateau between 5 and IS years (0.99 mumol/L). Of 43 children older than 1 year and on a protein-restricted diet, 87% showed serum selenium concentrations below the 2.5 percentile.Conclusions: Because of nutritional changes, serum selenium concentrations are significantly higher in older children than in infants under 1 year of age. The application of age-adjusted reference values may provide more specific criteria for selenium supplementation. Long-term protein restriction in children is reflected by a failure to achieve higher serum selenium concentrations with increasing age.
AU  - Muntau, A.C.*
AU  - Streiter, M.*
AU  - Kappler, M.*
AU  - Röschinger, W.*
AU  - Schmid, I.*
AU  - Rehnert, A.*
AU  - Schramel, P.
AU  - Roscher, A.A.*
C1  - 10265
C2  - 20232
SP  - 555-560
TI  - Age-related Reference Values for Serum Selenium Concentrations in Infants and Children.
JO  - Clin. Chem.
VL  - 48
PB  - American Assoc. for Clinical Chemistry
PY  - 2002
SN  - 0009-9147
ER  - 

TY  - JOUR
AU  - Hutchinson, W.L.*
AU  - Koenig, W.*
AU  - Fröhlich, M.*
AU  - Sund, M.
AU  - Lowe, G.D.O.*
AU  - Pepys, M.B.*
C1  - 21482
C2  - 19603
SP  - 934-938
TI  - Immunoradiometric assay of circulating c-reactive protein: Age-related values in the adult general population.
JO  - Clin. Chem.
VL  - 46
PY  - 2000
SN  - 0009-9147
ER  -