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Item The EuBIVAS Project: Within- and Between-Subject Biological Variation Data for Serum Creatinine Using Enzymatic and Alkaline Picrate Methods and Implications for Monitoring(AMER ASSOC CLINICAL CHEMISTRY, 2017-01-01) Carobene, Anna; Marino, Irene; Coskun, Abdurrahman; Serteser, Mustafa; Unsal, Ibrahim; Guerra, Elena; Bartlett, William A.; Sandberg, Sverre; Aarsand, Aasne Karine; Sylte, Marit Sverresdotter; Roraas, Thomas; Solvik, Una Orvim; Fernandez-Calle, Pilar; Diaz-Garzon, Jorge; Tosato, Francesca; Plebani, Mario; Jonker, Niels; Barla, Gerhard; Ceriotti, Ferruccio; Variation, E.F.L.M. Working Grp BiolBACKGROUND: The European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) European Biological Variation Study (EuBIVAS) has been established to deliver rigorously determined biological variation (BV) indices. EuBIVAS determined BV for serum creatinine using the enzymatic and alkaline picrate measurement methods. METHOD: In total, 91 healthy individuals (38 males, 53 femalesItem The EuBIVAS: Within- and Between-Subject Biological Variation Data for Electrolytes, Lipids, Urea, Uric Acid, Total Protein, Total Bilirubin, Direct Bilirubin, and Glucose(AMER ASSOC CLINICAL CHEMISTRY, 2018-01-01) Aarsand, Aasne K.; Diaz-Garzon, Jorge; Fernandez-Calle, Pilar; Guerra, Elena; Locatelli, Massimo; Bartlett, William A.; Sandberg, Sverre; Roraas, Thomas; Ceriotti, Ferruccio; Solvik, Una Orvim; Sylte, Marit Sverresdotter; Coskun, Abdurrahman; Serteser, Mustafa; Unsal, Ibrahim; Tosato, Francesca; Plebani, Mario; Jonker, Niels; Barla, Gerhard; Carobene, Anna; Chem, European Federation ClinicalBACKGROUND: The European Federation of Clinical Chemistry and Laboratory Medicine European Biological Variation Study (EuBIVAS) has been established to deliver rigorously determined data describing biological variation (BV) of clinically important measurands. Here, EuBIVAS-based BV estimates of serum electrolytes, lipids, urea, uric acid, total protein, total bilirubin, direct bilirubin, and glucose, as well as their associated analytical performance specifications (APSs), are presented. METHOD: Samples were drawn from 91 healthy individuals (38 male, 53 femaleItem Biological Variation Estimates Obtained from 91 Healthy Study Participants for 9 Enzymes in Serum(AMER ASSOC CLINICAL CHEMISTRY, 2017-01-01) Carobene, Anna; Roraas, Thomas; Solvik, Una Orvim; Sylte, Marit Sverresdotter; Sandberg, Sverre; Guerra, Elena; Marino, Irene; Jonker, Niels; Barla, Gerhard; Bartlett, William A.; Fernandez-Calle, Pilar; Diaz-Garzon, Jorge; Tosato, Francesca; Plebani, Mario; Coskun, Abdurrahman; Serteser, Mustafa; Unsal, Ibrahim; Ceriottil, Ferruccio; Biological, E.F.L.M. Working GrpBACKGROUND: We sought to develop estimates of biological variation (BV) for 9 enzymes in blood serum as part of the European Biological Variation Study. METHODS: Ninety-one healthy study participants (38 male and 53 female, 21-69 years old) were phlebotomized in each of 10 consecutive weeks at 6 European laboratories. The same preanalytical sample-handling protocol was followed at each center before transport to San Raffaele Hospital, Milan, Italy, for analysis. Sera were stored at -80 degrees C before analysis in duplicate within a single run on an ADVIA 2400 Clinical Chemistry System (Siemens Healthcare) following a protocol designed to minimize analytical imprecision. Assay traceability was established using frozen sera with target values assigned by reference methods. The results were subjected to outlier analysis before CV-ANOVA to deliver valid BV estimates. Results for 9 enzymes were subsequently partitioned for graphical display allowing visual assessment of the effects of country of origin, sex, and age on BV estimates. RESULTS: We found no effect of country upon the observed variation, but overall sex-related differences were evident for alanine amino transferase (ALT), gamma-glutamyl transferase (GGT), and creatine kinase (CK). The following estimates for within-subject BV (CVI) and between-subject BV (CVG), respectively, were obtained: ALT: 9.3\%, 28.2\%Item Within- and between-subject biological variation data for serum zinc, copper and selenium obtained from 68 apparently healthy Turkish subjects(WALTER DE GRUYTER GMBH, 2022-01-01) Coskun, Abdurrahman; Carobene, Anna; Aarsand, Aasne K.; Aksungar, Fehime B.; Serteser, Mustafa; Sandberg, Sverre; Diaz-Garzon, Jorge; Fernandez-Calle, Pilar; Karpuzoglu, Fatma H.; Coskun, Cihan; Kizilkaya, Emine; Fidan, Damla; Jonker, Niels; Ugur, Esra; Unsal, Ibrahim; Chem, European Federation Clinical; Database, Task Grp Biol VariationObjectives Trace elements (TrEL) are nutritionally essential components in maintaining health and preventing diseases. There is a lack of reliable biological variation (BV) data for TrELs, required for the diagnosis and monitoring of TrEL disturbances. In this study, we aimed to provide updated within- and between-subject BV estimates for zinc (Zn), copper (Cu) and selenium (Se). Methods Weekly serum samples were drawn from 68 healthy subjects (36 females and 32 males) for 10 weeks and stored at -80 degrees C prior to analysis. Serum Zn, Cu and Se levels were measured using inductively-coupled plasma mass spectrometry (ICP-MS). Outlier and variance homogeneity analyses were performed followed by CV-ANOVA (Roraas method) to determine BV and analytical variation estimates with 95\% CI and the associated reference change values (RCV) for all subjects, males and females. Results Significant differences in mean concentrations between males and females were observed, with absolute and relative (\%) differences for Zn at 0.5 mu mol/L (3.5\%), Cu 2.0 mu mol/L (14.1\%) and Se 0.06 mu mol/L (6.0\%). The within-subject BV (CVI {[}95\% CI]) estimates were 8.8\% (8.2-9.3), 7.8\% (7.3-8.3) and 7.7\% (7.2-8.2) for Zn, Cu and Se, respectively. Within-subject biological variation (CVI) estimates derived for male and female subgroups were similar for all three TrELs. Marked individuality was observed for Cu and Se. Conclusions The data of this study provides updated BV estimates for serum Zn, Cu and Se derived from a stringent protocol and state of the art methodologies. Furthermore, Cu and Se display marked individuality, highlighting that population based reference limits should not be used in the monitoring of patients.Item Personalized reference intervals - statistical approaches and considerations(WALTER DE GRUYTER GMBH, 2022-01-01) Coskun, Abdurrahman; Sandberg, Sverre; Unsal, Ibrahim; Yavuz, Fulya G.; Cavusoglu, Coskun; Serteser, Mustafa; Kilercik, Meltem; Aarsand, Aasne K.For many measurands, physicians depend on population-based reference intervals (popRI), when assessing laboratory test results. The availability of personalized reference intervals (prRI) may provide a means to improve the interpretation of laboratory test results for an individual. prRI can be calculated using estimates of biological and analytical variation and previous test results obtained in a steady-state situation. In this study, we aim to outline statistical approaches and considerations required when establishing and implementing prRI in clinical practice. Data quality assessment, including analysis for outliers and trends, is required prior to using previous test results to estimate the homeostatic set point. To calculate the prRI limits, two different statistical models based on `prediction intervals' can be applied. The first model utilizes estimates of `within-person biological variation' which are based on an individual's own data. This model requires a minimum of five previous test results to generate the prRI. The second model is based on estimates of `within-subject biological variation', which represents an average estimate for a population and can be found, for most measurands, in the EFLM Biological Variation Database. This model can be applied also when there are lower numbers of previous test results available. The prRI offers physicians the opportunity to improve interpretation of individuals' test results, though studies are required to demonstrate if using prRI leads to better clinical outcomes. We recommend that both popRIs and prRIs are included in laboratory reports to aid in evaluating laboratory test results in the follow-up of patients.Item A Simple Method for Quantification of Five Urinary Porphyrins, Porphobilinogen and 5-Aminolevulinic Acid, Using Liquid Chromatography Tandem Mass Spectrometry(SPRINGER INDIA, 2019-01-01) Dogan, Ozlem; Serdar, Muhittin A.; Murat, Koza; Sonmez, Cigdem; Ispir, Emre; Serteser, Mustafa; Unsal, IbrahimAnalysis of porphyrins and 5-aminolevulinic acid (ALA), porphobilinogen (PBG) in physiological liquids is required for diagnosis and follow-up of porphyrias. High performance liquid chromatography (HPLC) and liquid chromatography tandem mass spectrometry (LC-MS) methods with higher specificity and sensitivity have been developed. The major disadvantage of those methods is that they require longer extraction times due to their matrix effects. The present study suggests a simple, fast, sensitive, and specific assay for determination of Coproporphyrin, 5-carboxylporphyrin, 6-carboxylporphyrin, 7-carboxylporphyrin, Uroporphyrin I and ALA, PBG in urine sample by direct injection without sample pre-treatment using LC-MS. For the purposes of the present study LC-MS device was set to multiple reaction monitoring (MRM) and positive ion mode. Porphyrins and ALA, porphobilinogen were characterized by their MS/MS product ion, spectra. ALA, PBG and 5 porphyrins were detected simultaneously. Limit of detection for Coproporphyrin, 5-carboxylporphyrin, 6-carboxylporphyrin, 7-carboxylporphyrin, Uroporphyrin I were 2nmol/L, where it was 5mol/L for ALA and 2mol/L for porphobilinogen. The present study suggests that the present method is very effective compared to many other available methods for it does not require pre-treatment, provides simultaneous results of ALA, PBG and 5 porphyrins quantitatively in a shorter span of time, and has suitable sensitivity and selectivity. LC-MS technique was used clinically for the determination of urine porphyrin levels.Item Reference interval of pregnancy-associated plasma protein-A in healthy men and non-pregnant women(ELSEVIER, 2013-01-01) Coskun, Abdurrahman; Serteser, Mustafa; Duran, Sadik; Inal, Tamer C.; Erdogan, Birsen E.; Ozpinar, Aysel; Can, Ozge; Unsal, IbrahimObjective: The serum pregnancy-associated plasma protein-A (PAPP-A) concentration is a predictor of ischemic cardiac events and renal impairment. However, the reference interval of PAPP-A has not been determined. This study determined the reference interval of PAPP-A in men and non-pregnant women. Methods: The study enrolled 126 apparently healthy individuals (52 males and 74 females). The mean age of the men and women was 34.7 (range 20-66) years and 34.6 (range 18-65) years, respectively. Serum PAPP-A concentrations were determined using an ultrasensitive enzyme-linked immunoassay kit. Reference intervals were calculated using the bootstrap method. Results: The results for three subjects were outliers, so the reference interval of PAPP-A was calculated using the data for 123 subjects. PAPP-A was undetectable in 26 subjects. The reference interval of PAPP-A for men and women (with the 90\% confidence interval) was <22.9 ng/mL (19.7-23.3) and <33.6 ng/mL (25.2-36.7), respectively. In male subjects, serum PAPP-A levels of smokers {[}3.10 (UD, 7.30) ng/mL] were significantly lower than that of non-smokers {[}11.00 (UD, 24.4) ng/mL] (p < 0.001) and there was a positive correlation between serum PAPP-A levels and subjects' age (r=0.439Item Association Between Serum Pregnancy-Associated Plasma Protein-A and Bicarbonate in Hemodialysis Patients(JOHN WILEY \& SONS INC, 2014-01-01) Bicik, Zerrin; Coskun, Abdurrahman; Serteser, Mustafa; Bulur, Atilla; Mese, Meral; Unsal, IbrahimBackground Acidosis is associated with protein-energy malnutrition, inflammation, and bone disease, and low bicarbonate levels have been implicated in higher mortality rates in chronic kidney disease. Recently, the concentration of serum pregnancy-associated plasma protein-A (PAPP-A) has become accepted as a prognostic marker in hemodialysis patients. This study determined the relationship between PAPP-A and bicarbonate levels in these patients. Methods The study enrolled 65 hemodialysis patients (41 males, 24 females) and 26 control subjects (11 males, 15 females). Serum PAPP-A, intact parathormone (iPTH), calcium, phosphorus (P), and bicarbonate levels were measured. Correlations between PAPP-A and bicarbonate, iPTH, calcium, and phosphorus were evaluated. Results Median PAPP-A levels were significantly higher in hemodialysis patients {[}15.1 (<0.03-158.8) ng/ml] than in control subjects {[}6.6 (<0.03-16.4) ng/ml] (P < 0.05). There were statistically significant correlations between serum PAPP-A and bicarbonate, iPTH, and P in hemodialysis patients but not in control subjects. Conclusion Elevation of serum PAPP-A has been found in hemodialysis patients and its significant correlation with bicarbonate suggests that it may be a prognostic factor.Item Hepatitis C virus positive patient diagnosed after detection of atypical cryoglobulin(BAISHIDENG PUBLISHING GROUP INC, 2016-01-01) Ongen, Belkiz; Aksungar, Fehime Benli; Cicek, Bahattin; Akyar, Isin; Coskun, Abdurrahman; Serteser, Mustafa; Unsal, IbrahimA 60-year-old male patient presented with jaundice and dark urine for three days, icteric sclerae and skin rash on his legs for six months. Laboratory inves-tigations revealed an atypical cryoglobulinemia with high hepatitis C virus (HCV)-RNA levels. Imaging studies showed cholestasis was accompanying HCV. Capillary zone electrophoresis using immunosubtraction method revealed a polyclonal immunoglobulin G and immunoglobulin A (IgA) monoclonal cryoglobulin and that IgA lambda was absent in immu-nofixation electrophoresis. After a liver biopsy, chronic hepatitis C, HCV related mixed cryoglobulinemia and cryoglobulinemic vasculitis were diagnosed and antiviral therapy was initiated. Our HCV patient presented with cryoglobulinemic symptoms with an atypical cryoglobulinemia that was detected by an alternative method: Immunosubtraction by capillary electrophoresis. Different types of cryoglobulins may therefore have a correlation with clinical symptoms and prognosis. Therefore, the accurate immunotyping of cryoglobulins with alternative methods may provide more information about cryoglobulin-generated pathology.