A. Fortunato

A. Mercuri

C. Prontera

CLERICO, ALDO

EMDIN, MICHELE

G. Longombardo

G.C. Zucchelli

S. Storti

Archivio della ricerca della Scuola Superiore Sant'Anna

vidual variation in warfarin dosage.Prospective studies that incorporateboth gene testing and a variety ofethnic, clinical, pharmacological, andenvironmental variables, along withage, sex, and body weight, will berequired to demonstrate the realsafety, cost-effectiveness, and feasibil-ity of individualized dosing regimensaccording to the statistical models forwarfarin dose calculation.Grant/funding support: None declared.Financial disclosures: None declared.References1. Zhu Y, Shennan M, Reynolds KK, Johnson NA,Herrnberger MR, Valdes R Jr, et al. Estimation ofwarfarin maintenance dose based on VKORC1(1639 GA) and CYP2C9 genotypes. ClinChem May 17, 2007;[Epub ahead of print].2. Caldwell MD, Berg RL, Zhang KQ, Glurich I,Schmelzer JR, Yale SH, et al. Evaluation ofgenetic factors for warfarin dose prediction. ClinMed Res 2007;5:8–16.3. Brandin H, Myrberg O, Rundlof T, Arvidsson AK,Brenning G. Adverse effects by artificial grape-fruit seed extract products in patients on warfa-rin therapy. Eur J Clin Pharmacol 2007;63:565–70.4. Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A,Hylek E. The pharmacology and management ofthe vitamin K antagonists: the Seventh ACCPConference on Antithrombotic and ThrombolyticTherapy. Chest 2004;126(Suppl 3):204S–233S.5. Kealey C, Chen Z, Christie J, Thorn CF, White-head AS, Price M, et al. Warfarin and cytochromeP450 2C9 genotype: possible ethnic variation inwarfarin sensitivity. Pharmacogenomics 2007;8:217–25.Giuseppe Lippi*Gian Luca SalvagnoGian Cesare GuidiSezione di Chimica ClinicaDipartimento di ScienzeMorfologico-BiomedicheUniversita` degli Studi di VeronaVerona, Italy* Address correspondence to this au-thor at: Istituto di Chimica e Microsco-pia Clinica, Dipartimento di Scienze Mor-fologico-Biomediche, Universita` degliStudi di Verona, Ospedale PoliclinicoG.B. Rossi, Piazzale Scuro, 10, 37134 Ve-rona, Italy. Fax 0039-045-8201889; e-mailulippi@tin.it.DOI: 10.1373/clinchem.2007.092338Evaluation of Analytical Performanceof the Siemens ADVIA TnI UltraImmunoassayTo the Editor:In light of recommendations on thequality (1 ) and clinical use (2 ) oftroponin assays, we evaluated theanalytical performance of the AD-VIA Centaur and ADVIA CP® plat-forms (TnI-Ultra, Siemens MedicalSolutions Diagnostics SrL) for mea-surement of cardiac troponin I(cTnI). The chemiluminescent TnI-Ultra method uses 2 monoclonal cap-ture antibodies directed to epitopesat amino acids 41–49 and 87–91 anda tracer polyclonal goat antibody la-beled with acridinium ester, directedagainst amino acids 27–40 (1, 3, 4 ).Two clinical laboratories participatedin the study: the CNR Institute ofPhysiology in Pisa and the San Bor-tolo Hospital in Vicenza.The limit of detection (limit of theblank) for the TnI-Ultra method wascalculated as the concentration corre-sponding to a signal of 3 SD abovethe mean of 60 replicates (obtained in4 different runs and pooled together)for the calibrator in which cTnI wasabsent; a mean cTnI concentration of0.006 g/L was found. The total im-precision (CV%) of the TnI-Ultramethod, assessed according to theNCCLS EP5-A protocol over 20 con-secutive working days, was 11.6%,5.6%, and 4.4% for 3 plasma sampleswith cTnI concentrations of 0.05,0.25, and 2.68 g/L, respectively.From plots of CV vs log-transformedvalues of cTnI concentration in therange 0.006–0.20 g/L, the cTnI con-centrations that corresponded to 10%CVwere 0.064 g/L for ADVIA Cen-taur CP® and 0.07 g/L for ADVIACentaur.Blood samples, collected inpolypropylene tubes with lithiumheparin, were used in the study, ac-cording to the routine protocoladopted by both clinical laboratories.The 2 laboratories enrolled a whitepopulation including 418 apparentlyhealthy adult individuals (204 menand 214 women) with a mean (SD)age of 50.7 (16.6) years, range 16–89years; the mean (SD) age in womenwas 52.6 (17.5) years and in men 48.7(15.5) years. The presence of cardiacor other acute or chronic diseaseswas excluded by clinical examinationand laboratory tests. Informed con-cent was obtained by all individualsand patients before testing, and thestudy protocol was approved by thelocal ethics committee. The mea-sured cTnI values approximated alog-normal distribution with a calcu-lated 99th percentile of 0.087 g/L;therefore, the ratio of 10% CV con-centration to 99th percentile limit forthe TnI-Ultra method was 0.067:0.087  0.77 (1 ). In 82 samples, in-cluding 81 females and only 1 male,we found values 0.004 g/L (i.e.,undetectable cTnI concentration),and so an arbitrary concentration of0.001 g/L was attributed to thesesamples. A highly significant corre-lation was found between cTnI val-ues and age (R  0.268, P 0.0001 bySpearman rank correlation coeffi-cient test). Moreover, a significantdifference was found between thecTnI values found in men andwomen, respectively [mean (SD)0.015 (0.018) g/L, median 0.012g/L, range 0–0.196 g/L, n  204for men; 0.009 (0.014) g/L, 0.008g/L, 0–0.130 g/L, n  214 forwomen; P 0.0001 by Mann–Whit-ney U-test]. We found that both sex(as a dummy independent variablewith F  1 and M  2) and age (as acontinuous independent variable) in-dependently contributed to the re-gression with cTnI (as a dependentvariable after log transformation oforiginal values) by using a stepwisemultiple regression analysis (logcTnI  3.164  0.456 sex  0.007age; P 0.0001, F-value  71.962,R  0.508, n  416).A close linear relationship wasfound between cTnI values mea-sured by ADVIA TnI-Ultra with theCentaur CP® platform and the Ac-cess AccuTnI method on the Uni-Cell® DxI 800 platform (BeckmanCoulter) in 318 plasma samples of155 apparently healthy individualsand 163 cardiac patients (ADVIA0.016  1.272 Access; R  0.936). TheTnI-Ultra method showed highercTnI values than the Access AccuTnI1722 Lettersmethod (on average by 22.0%; P0.0001 by Wilcoxon signed-ranktest) and based on the 99th percentilevalues for each assay, 9 discordanceswere found between assays for val-ues within the reference interval vsincreased values.The ADVIA TnI-Ultra methodshowed no interference from dilu-tions with plasma samples that con-tained high concentration of triglyc-erides (6.6 g/L, final dilution 1:128;y  0.044  0.14x, n  8, R  0.99)or hemoglobin (1.47 g/L, final dilu-tion 1:4996; y 0.04 0.060x, n 13,R  0.99). No apparent positive in-terference was seen in 58 patientswith symptomatic rheumatoid ar-thritis [10 men and 48 women, mean(SD) age 60.8 (10.2) years] with amean concentration of rheumatoidfactor of 189.6 kIU/L (range 40–1280kIU/L), because the mean (SD) cTnIconcentration was not increased0.017 (0.023) g/L.The present study indicates thatthe ADVIA TnI-Ultra method meetsthe quality specifications recom-mended by NACB and IFCC Com-mittee for the Standardization ofCardiac Damage (5 ).Grant/funding support: None declared.Financial disclosures: None declared.References1. Panteghini M, Pagani F, Yeo KT, Apple FS, Chris-tenson RH, Dati F, et al. Committee on Standard-ization of Markers of Cardiac Damage of theIFCC. Evaluation of imprecision for cardiac tro-ponin assays at low-range concentrations. ClinChem 2004;50:327–32.2. Myocardial infarction redefined: a consensusdocument of The Joint European Society of Car-diology/American College of Cardiology Commit-tee for the redefinition of myocardial infarction.Eur Heart J 2000;21: 1502–13.3. Apple FS, Murakami MM. The diagnostic utility ofcardiac biomarkers in detecting myocardial in-farction. Clin Cornerstone 2005;7(Suppl 1):S25–30.4. Christenson RH, Duh SH, Apple FS, Bodor GS,Bunk DM, Dalluge J, et al. Standardization ofcardiac troponin I assays: round robin of tencandidate reference materials. Clin Chem 2001;47:431–7.5. Apple FS, Jesse RL, Newby LK, Wu AH, Christen-son RH. National Academy of Clinical Biochemis-try; IFCC Committee for Standardization of Markersof Cardiac Damage. National Academy of ClinicalBiochemistry and IFCC Committee for Standardiza-tion of Markers of Cardiac Damage LaboratoryMedicine Practice Guidelines: analytical issues forbiochemical markers of acute coronary syn-dromes. Circulation 2007;115:e352–5.Concetta Prontera1Antonio Fortunato2Simona Storti1Antonella Mercuri1Giovanni Longombardo3Gian Carlo Zucchelli1Michele Emdin1Aldo Clerico1,4*1 CNR Institute of ClinicalPhysiology of PisaPisa, Italy2 Clinical Chemistry LaboratorySan Bortolo HospitalVicenza, Italy3 Clinical Immunology UnitDepartment of Internal MedicineUniversity of PisaPisa, Italy4 Scuola Superiore Sant’Anna,Pisa, Italy* Address correspondence to this au-thor at: Laboratory of Cardiovascular En-docrinology and Cell Biology, C.N.R. In-stitute of Clinical Physiology, Via Trieste41, 56126 Pisa, Italy. Fax 39-0585-493601;e-mail clerico@ifc.cnr.it.DOI: 10.1373/clinchem.2007.089995Midtrimester Amniotic FluidAdiponectin in Normal PregnancyTo the Editor:Adiponectin is an adipose tissue–derived protein with important met-abolic effects and a strong correlationwith insulin sensitivity. In pregnancythere is a progressive increase of in-sulin resistance, whereas plasma adi-ponectin concentrations decrease inthe 2nd half of gestation (1 ). In con-trast, cord plasma adiponectin con-centrations increase throughout ges-tation (2 ). Nothing is known aboutthe concentration, origin, or role ofamniotic fluid adiponectin, particu-larly in relation to amniotic insulin.Therefore we evaluated adiponectinand insulin concentrations in themidtrimester amniotic fluid ofwomen with normal pregnancies.Beginning January 1, 2006, we se-lected the first 50 pregnant womenwho underwent a midtrimester am-niocentesis for prenatal diagnosis(15–18 weeks gestation) and werefound to have a normal pregnancy,defined as an uncomplicated preg-nancy with full-term delivery of aninfant of adequate size for gesta-tional age. The study was approvedby the institutional review board,and all women gave written in-formed consent.Amniotic fluid samples were ob-tained by transabdominal amnio-centesis and collected in 15 mL drytubes. All samples were free of bloodcontamination, as estimated by mi-croscopic inspection. The sampleswere immediately centrifuged for 10min at 3000g and stored at –70 °C.Plasma EDTA samples were centri-fuged for 15 min at 1000g within 30min of collection and stored at –70 °C.Plasma samples required 200-fold di-lution before assay. The adiponectinconcentration was measured by im-munoenzymatic assay (R&D Systems).The intra- and interassay imprecision(CVs) for adiponectin at a concentra-tion of 15.0 g/L were 3.5% and 5.5%,respectively. The intra- and interassayimprecision values (CVs) for insulin ata concentration of 4.0 mIU/L were3.3% and 5.6%, respectively.Amniotic and plasma adiponectinand amniotic insulin concentrationsare presented as the median and the25th–75th percentile range; all othervariables are presented as the mean(SD). The Mann–Whitney U-test wasused to compare continuous variablesbetween the 2 groups. Univariate cor-relations between amniotic fluid adi-ponectin and all the other variableswere assessed using the Spearmantest. The statistical analysis was per-formed using SPSS 13.0 (SPSS Inc.). Alltests were 2-sided; a P value0.05wasconsidered statistically significant.The clinical characteristics of preg-nant women are reported in Table 1.Median adiponectin amniotic fluidvalues were 26.8 (13.9–37.3) g/L,but when we dichotomized for sex,there was a significant difference(P  0.01) between female 34.8 (18.2–48.7) g/L and male fetuses 18.2(13.4–26.8) g/L. Univariate analysisClinical Chemistry 53, No. 8, 2007 1723

Evaluation of Analytical Performance of the Siemens ADVIA TnI Ultra Immunoassay

Evaluation of Analytical Performance of the Siemens ADVIA TnI Ultra Immunoassay

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