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Quality control data of physiological and immunological biomarkers measured in

serum and plasma

Jansen, Eugène; Beekhof, Piet; Cremers, Johannes; Weinberger, Birgit; Fiegl, Simone;

Toussaint, Olivier; Bernhard, Jürgen; Gonos, Efstathios; Capri, Miriam; Franceschi, Claudio;

Sikora, Ewa; Moreno-Villanueva, María; Breusing, Nicolle; Grune, Tilman; Bürkle, Alexander;

Dollé, Martijn E T

Published in:

Mechanisms of Ageing and Development

DOI:

10.1016/j.mad.2015.06.004

Publication date:

2015

Document Version

Publisher's PDF, also known as Version of record

Link to publication

Citation for pulished version (HARVARD):

Jansen, E, Beekhof, P, Cremers, J, Weinberger, B, Fiegl, S, Toussaint, O, Bernhard, J, Gonos, E, Capri, M,

Franceschi, C, Sikora, E, Moreno-Villanueva, M, Breusing, N, Grune, T, Bürkle, A & Dollé, MET 2015, 'Quality

control data of physiological and immunological biomarkers measured in serum and plasma', Mechanisms of

Ageing and Development, vol. 151, pp. 54-59. https://doi.org/10.1016/j.mad.2015.06.004

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MechanismsofAgeingandDevelopment151(2015)54–59

ContentslistsavailableatScienceDirect

Mechanisms

of

Ageing

and

Development

j o ur na l h o me p a g e:w w w . e l s e v i e r . c o m / l o c a te / m e c h a g e d e v

Quality

control

data

of

physiological

and

immunological

biomarkers

measured

in

serum

and

plasma

Eugène

Jansen

a,∗

,

Piet

Beekhof

a

,

Johannes

Cremers

a

,

Birgit

Weinberger

b

,

Simone

Fiegl

c

,

Olivier

Toussaint

d

,

Jürgen

Bernhard

e

,

Efstathios

Gonos

f

,

Miriam

Capri

g

,

Claudio

Franceschi

g

,

Ewa

Sikora

h

,

María

Moreno-Villanueva

i

,

Nicolle

Breusing

j

,

Tilman

Grune

k

,

Alexander

Bürkle

l

,

Martijn

E.T.

Dollé

a

aCentreforHealthProtection,NationalInstituteforPublicHealthandtheEnvironment,POBox1,3720BABilthoven,TheNetherlands bLeopold-Franzens-UniversitätInnsbruck,InstituteforBiomedicalAgingResearch,Rennweg10,6020Innsbruck,Austria

cInstituteforNutritionalSciencesandPhysiology,UniversityforHealthSciences,MedicalInformaticsandTechnology,EduardWallnoefer-Zentrum1,6060 HallinTirol,Austria

dUnitofCellularBiochemistryandBiology,TheUniversityofNamur,RuedeBruxelles61,5000Namur,Belgium eBioTeSysGmbH,Schelztorstraße54-56,73,728Esslingen,Germany

fNationalHellenicResearchFoundation(NHRF)InstituteofBiologicalResearchandBiotechnology,48Vas.ConstantinouAve.,Athens11635,Greece gDIMES-DepartmentofExperimental,DiagnosticandSpecialtyMedicine,CIG-InterdepartmentallCentre“L.Galvani”,AlmaMaterStudiorum,Universityof Bologna,40,126Bologna,Italy

hNenckiInstituteofExperimentalBiology,PolishAcademyofSciences,St.Pasteura302-093Warsaw,Poland iMolecularToxicology,DepartmentofBiology,Box628,UniversityofKonstanz,78,457Konstanz,Germany jInstituteofNutritionalMedicine(180c),UniversityofHohenheim,Fruwirthstraße12,70,599Stuttgart,Germany

kGermanInstituteofHumanNutritionPotsdam-Rehbruecke(DIfE),Arthur-Scheunert-Allee114-116,14,558Nuthetal,Germany lMolecularToxicology,DeptofBiology,Box628,UniversityofKonstanz,78,457Konstanz,Germany

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received30January2015

Receivedinrevisedform29May2015 Accepted18June2015

Availableonline9July2015

Keywords: Biomarkers Qualitycontrol Hemolysis

a

b

s

t

r

a

c

t

IntwoworkpackagesoftheMARK-AGEproject,37immunologicalandphysiologicalbiomarkerswere measuredin3637serum,plasmaorbloodsamplesinfivebatchesduringaperiodof4years.

Thequalityoftheserumandplasmasampleswasverygoodasjudgedbythelownumberofbiomarker measurements(only0.2%)thatwererejectedbecauseofahighhemolysis,icteriaorlipemiaofthe samples.

Usingqualitycontrolsamples,day-to-dayandbatchvariationsweredetermined.Themeaninter-assay variationofthefivebatcheswereallbelow8%,withanaverageinter-assaycoefficientofvariationofall biomarkersof4.0%.Alsotheprecisionofthemeasurementswasverygood,becauseallmeasurements werebetween90%and115%ofthedefinedtargetvalues.

Apossiblemix-upofsampleswasdeterminedbycomparisonoftheextremetestosteronelevelsof menandwomen.Itwasconcludedthat3%ofthesampleidentificationcouldbemixed-up.

Consideringthecomplexprocedurefromcollectiontoanalysis,includingpreparation,handling, ship-mentandstorage,ofthesamplesintheMARK-AGEproject,boththequalityofthesamplesandthe qualityofthemeasurementsareverygood.

©2015TheAuthors.PublishedbyElsevierIrelandLtd.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

∗ Correspondingauthor.

E-mailaddresses:eugene.jansen@rivm.nl(E.Jansen),piet.beekhof@rivm.nl

(P.Beekhof),hans.cremers@rivm.nl(J.Cremers),birgit.weinberger@uibk.ac.at

(B.Weinberger),simone.fiegl@umit.at(S.Fiegl),olivier.toussaint@fundp.ac.be

(O.Toussaint),j.bernhardt@biotesys.de(J.Bernhard),sgonos@eie.gr(E.Gonos),

miriam.capri@unibo.it(M.Capri),claudio.franceschi@unibo.it(C.Franceschi),

e.sikora@nencki.gov.pl(E.Sikora),maria.moreno-villanueva@uni-konstanz.de

(M.Moreno-Villanueva),breusing@uni-hohenheim.de(N.Breusing),

scientific.director@dife.de(T.Grune),alexander.buerkle@uni-konstanz.de

(A.Bürkle),martijn.dolle@rivm.nl(M.E.T.Dollé).

1. Introduction

MARK-AGEisalarge-scaleintegratedprojectsupportedbythe

EuropeanCommission.Themajoraimofthisprojectistoconduct

apopulationstudyinordertoidentifyasetofbiomarkersofageing

which,asacombinationofparameterswithappropriateweighting,

wouldmeasurebiologicalagebetterthananymarkerinisolation.

Atotalof37immunologicalandphysiologicalbiomarkerswere

measuredin3637serum, plasmaorblood samplesat the

Cen-http://dx.doi.org/10.1016/j.mad.2015.06.004

0047-6374/©2015TheAuthors.PublishedbyElsevierIrelandLtd.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/ by-nc-nd/4.0/).

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56 E.Jansenetal./MechanismsofAgeingandDevelopment151(2015)54–59

Table1

Listofallphysiologicalandimmunologicalbiomarkers,measuredbytheNationalInstituteforPublicHealthandtheEnvironmentinBilthoven,theNetherlandsandthe materialandmethodofanalysis.

Biomarker Abbreviation Matrix Methodofanalysis Companyofassay Assayproductnr

25hydroxy-vitaminD 25OHVitD EDTA EIA IDS AC57F1

␣2-macroglobulin AMG Serum Autoanal Dialab A00505

Alanineaminotransferase ALT EDTA Autoanal Beckman 476826

Albumin ALB EDTA Autoanal Beckman 442765

IgGabagainst8nuclearantigens ANA-8 Serum EIA Dialab R99419

IgGabagainstcytomegalovirus CMV-ab Serum EIA DRG EIA-3468

Thyroglobulinautoantibodies TG-ab EDTA Immunoanal Beckman A32898

Ceruloplasmin CER Serum Autoanal Dialab A00531

Cholesterol CHOL Serum Autoanal Beckman 467825

Creatinine CREA EDTA Autoanal Beckman 442760

Dehydroepiandrosteronesulphate DHEA-S EDTA Immunoanal Beckman A10826

Totaliron Fe Serum Autoanal Beckman 467910

Ferritin FER Serum Immunoanal Beckman 33020

Fibrinogen FIB EDTA Autoanal Dialab A00517

Freefattyacids FFA Serum Autoanal Wako NEFA-HR

ϒ-Glutamyltransferase GGT Serum Autoanal Beckman 476846

Glucose GLU Serum Autoanal Beckman 442640

Hemoglobin Hb Blood Autoanal Beckman A17836

Glycatedhemoglobin HbA1c Blood Autoanal Beckman A17836

Homocysteine HCy EDTA Autoanal Dialab 908520

High-densitylipoproteincholesterol HDL-C Serum Autoanal Beckman 650207 High-sensitiveC-reactiveprotein HS-CRP Li-Hep Autoanal Beckman 378020

ImmunoglobulinA IgA Serum Autoanal Beckman 467920

ImmunoglobulinE IgE Serum Immunoanal Beckman 35000

ImmunoglobulinG IgG Serum Autoanal Beckman 467925

ImmunoglobulinM IgM Serum Autoanal Beckman 467930

Insulin INS EDTA immunoanal Beckman 33410

Low-densitylipoproteincholesterol LDL-C Serum Autoanal Beckman 969706

Prostatespecificantigen PSA Serum Immunoanal Beckman 37200

Serotonin SER Serum EIA Biosource 10-0900

Testosterone TEST Serum immunoanal Beckman 33560

Totalproteinofserum s-TP Serum Autoanal Beckman 442740

Totalproteinofplasma p-TP EDTA Autoanal Beckman 442740

Transferrin TFN Serum Autoanal Beckman 467942

Triglycerides TG Serum Autoanal Beckman 445850

Urea UREA EDTA Autoanal Beckman 442820

Uricacid UA EDTA Autoanal Beckman 442785

Abbreviations:EDTA=EDTA-plasma;Li–hep=lithium–heparinplasma;autoanal=autoanalyzer;immunoanal=immunoanalyzer;EIA=enzymeimmunoassay.

terforHealthProtectionoftheDutchNationalInstituteforPublic HealthandtheEnvironmentwithinWorkpackage4: “Immunolog-icalmarkers”andWorkpackage5:“Clinicalchemistry,hormones andmarkersofmetabolism”.

Inthispaperwepresentqualitycontroldata,day-to-dayand batchvariationsandapossiblenumberofsampleexchangesfor thewhole4-yearperiod.

2. Materialsandmethods

IntheMARK-AGEprojectintotal3637samplesweredistributed amongstthevariouslaboratoriesfromthecoordinationcentreat theUniversityofHohenheim.IntheCenterforHealthProtectionof theDutchNationalInstituteforPublicHealthandtheEnvironment inBilthoven,37biomarkershavebeenmeasured.Thebiomarkers weremeasuredinserum,EDTA-plasma,citrateplasmaand ery-throcytesin5batches(1444,775,685,354and379samples)over a4-yearperiod.

Foreachbiomarker, tworeferencesampleswereincludedin thedailyroutine.Eachdayabout100samplesweremeasured.In addition,eachsamplewascheckedforhemolytic(H),icteric(I)and lipemic(L)disturbancesbymeasuringtheH-,I-andL-indexonthe clinicalauto-analyzer(LX20-Pro,Beckman–Coulter,Woerden,The Netherlands).

AllassaysmeasuredontheLX20autoanalyzerwereobtained fromBeckman–Coulter,except HCyand AMG (Dialab,Neudorf, Austria),FFA(Wako Diagnostics,Neuss, Germany). Mostof the assaysontheLX20wereenzymaticassaywithacolorimetric

end-point.TheassaysforAMG,CER,FIB,HbA1c,HDL-C,LDL-C,HS-CRP, IgA,IgG,IgMand transferrinwereperformedusing turbidimet-ricassays(immunoprecipitation).Anextensivedescriptionofthe LX20autoanlyzerincludingthedifferentassayswasdescriberdby Mikolaenkoetal.,(2000).

Seven biomarkers have been measured with an

immuno-analyzer(Access-2,Beckman–Coulter,Woerden,TheNetherlands).

These 7 biomarkers were dedicated assays on the Access-2

andobtainedfromBeckman–Coulter.TheAccess-2systemisan

automated immunoanalyzerbased of the principle of

chemilu-minescence detection using acridinium esters. The assays are

performed in a homogenous format without the necessity of

pretreatment of the samples. An extensive description of the

immunoanalyzerandthededicated assayshave beendescribed

by Patterson et al., (1994). Four biomarkers have been

mea-sured with enzyme immunoassays (EIA): 25OHVitD (OCTEIA,

AC57F1, IDS, Boldon, UK), SER (KAPL10-0900, Biosource,

Niv-elles, Belgium), CMV-ab (EIA-3468, DRG Diagnostics, Marburg,

Germany), ANA-8(ANA Screen 8 IgG, R99419,Dialab, Neudorf,

Austria).Technicalinformationaboutthebiomarkerscanbefound

inTable1.

3. Results

Ineachserumandplasmasample,afirstqualitycontrolcheck

wasdonebythedetermination oftheextentofhemolysis,high

levelsof bilirubin or lipids, expressedas hemolytic, ictericand

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automaticprocedureontheclinicalauto-analyzer.Eachofthese

threeindicesisexpressedinarbitraryunitsfrom0to10.Formost

ofthebiomarkers,thresholdvaluesareknownforeachofthethree

indices(Vermeeretal.,2007).Ifoneofthethreeindicesofthe

sam-pleishigherthantheestablishedthresholdvaluesforaparticular

biomarker,thedeterminedvalueofthebiomarkerisprobableto

deviatefromanormalsampleconditionandthereforethe

respec-tivebiomarkervalueshouldbediscarded.

ForEDTA–plasmathethreeindicesweredeterminedin3637

samplesandcomparedwiththethresholdvaluesthatwereknown

for12biomarkers.Theresultofthisqualitycheckwasthatof43,644

biomarkervalues,only49(0.11%)usedshouldbeexcludedfor

anal-ysis(Table2).Fortheserumsamples,thethresholdvaluesoftheH-,

I-,andL-indexwereknownfor20biomarkers.Inthiscase,fromthe

72,740determinations,171(0.24%)shouldbeexcluded(Table3).

Anotherinterestingobservationwasdonefromacomparison

betweentheH-,I- andL-indicesin serumand EDTAplasmaof

thesameindividuals.Itappearedthatthecorrelationbetweenthe

H-indicesofserumandEDTA-plasmaisratherlow(0.11),whereas

thecorrelationoftheI-andL-indicesbetweenserumandplasma

is0.83 and 0.74,respectively (resultsnotshown).The

explana-tionisthaticteriaandlipemiaareaninherentpropertypresent

inthebloodoftheindividual,whereashemolysisiscausedbythe

preparationofserumandplasma.

Fig.2.Histogramofthetestosteroneconcentrationsinallmen(uppergraph)andwomen(lowergraph).Theparticipantsthathaveextremetestosteroneconcentrations havebeenindicatedwithwhitebars.

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58 E.Jansenetal./MechanismsofAgeingandDevelopment151(2015)54–59

Table2

ThethresholdvaluesoftheH-,I-andL-indicesforthebiomarkersthathavebeen measuredinserumsamplesandthecorrespondingnumberofdatathathavebeen excludedfromthedatabase.

Serum H-index I-index L-index Excluded

s-TP 10 10 3 22 GLU 7 7 9 9 Fe 2 10 10 36 TRF 10 10 10 5 CER 10 10 10 5 GGT 5 10 10 8 CHOL 10 10 10 6 TG 10 3 X 7 HDL-C 10 10 10 5 LDL-C 9 10 10 5 FFA 5 10 10 8 IgG 10 10 10 5 IgA 10 10 10 5 IgM 10 10 6 9 FER 7 5 10 7 IgE 10 8 10 6 PSA 10 10 10 5 TEST 10 8 10 6 AMG 4 8 10 7 ANA-8 10 10 10 5 Total171 0.21%

SampleswithahighH-indexdidnotcorrelatetoageorgender oftheindividuals.Weobservedhoweverthatmostofthehemolytic samplesoriginatefromonecenterandthattwocentershadalmost nohemolyticserumsamples.

For26ofthe33biomarkersmeasuredwiththeauto-analyzeror theimmuno-analyzer,thereferencesampleshadwell-defined tar-getvalues.Fromthe5seriesofmeasurements80%ofthebiomarker measurementswerebetween95%and105%ofthetargetvaluesand allmeasurementswerebetween90%and115%ofthetargetvalues. Inallmeasuringsessions(usually100samplesperday),atleast onequalitycontrolsamplewasincluded.InFig.1theinter-assay

coefficientsofvariation(CVs)ofonequalitycontrolsample(with

referencevaluesinthenormalphysiologicalrange)foreachofthe

fiveseriesofmeasurementshavebeenplotted.TheCVshavebeen

expressedaspercentageofthestandarddeviationdividedbythe

meanvalue).TheassayforANA-8wasonlysemi-quantitativeand

thereforenoquantitativedataofthequalitycontrolisavailable.

Oftheremaining36biomarkersand180seriesofmeasurements,

almostallCVs werebelow10%,withtheexception ofonlyfive

measurements.TheaverageCVs,beingthemeansofthefive

mea-surementserieswereallbelow7–8%.Theaverageinter-assayCV

Table3

ThethresholdvaluesoftheH-,I-andL-indicesforthebiomarkersthathavebeen measuredinEDTA-plasmaandthecorrespondingnumberofdatathathavebeen excludedfromthedatabase.The“x”inthetableforTGmeansthattheLipemicindex infactisareflectionoftheTGconcentrationinthesample,sonoindexnumbercan begiven.

EDTA-pl H-index I-index L-index Excluded

p-TP 10 10 3 24 ALB 10 10 10 2 UREA 10 10 10 2 CREA 10 10 10 2 ALT 2 10 9 2 FIB 10 10 10 2 DHEAS 10 10 10 2 INS 10 8 10 2 Tg-ab 10 10 10 2 UA 3 5 10 5 Hcy 10 10 10 2 25OHVifD 10 10 10 2 Total49 0.11%

ofallbiomarkerswasabout4%,whereastheclinicalauto-analyzer showedlowerCVsthantheimmuno-analyzerandtheELISAs.

Upon completion of the measurements, gender information wasreleased for 2871 analysed samples,allowing theanalysis oftestosterone concentrationrangesforboth menand women. Thenormalrangefortestosteroneinwomenandmendoesnot overlap,being0.06–0.86ng/mLand2.69–10.70ng/mLforwomen and men,respectively (Kratz et al., 2004).In Fig.2 histograms

areshownofboththetestosteroneconcentrationsofmen(upper

graph)and women (lowergraph).We noticed that 44samples

fromfemale participantswere in a concentrationrange that is

characteristic for men (whitebars), while an identical number

of male samples, i.e. 44, had concentrations typically found in

women (white bars).Furthermore it is observed that 18 of 19

women(94%)withPSA>1ng/mlareamongthe44womenwith

mostextremetestosteroneconcentrations.Together,theseresults

suggestthat88sampleswereexchangedbetweengenders,being

3%.

4. Conclusions

In therecruiter centers of theMARK-AGE project, the

sam-pling was performed according a very strict protocol (see

Moreno–Villanueva,Caprietal.,thisissue).Asaresult,the

qual-ity ofthe serumand plasma sampleswas verygood. This was

judgedby thethreeindices thatweredetermined onthe

clini-calauto-analyzer. Boththehemolytic, ictericandlipemicindex

showingeneralverylowlevels,indicatingthatonlyasmallpart

ofthebiomarkerscouldnotbeusedforthefinalanalysis.Fromthe

intotal116,384biomarkersmeasured,only130(0.2%)cannotbe

usedbecauseofatoohighindex.Thispercentageiscomparable

withthefindingofanotherEuropeanstudyonaging(seeBoffetta

etal.,2014).Bycorrelationanalysisitappearedthatespeciallythe

hemolyticindexdeterminesthequalityofthesamplepreparation

andnottheictericorlipemicindex.

Thequalitycontroloftheanalyseswasperformedbyincluding

controlsamplesatthebeginningandendofeachanalysissession.

Theaverageinter-assayvariationofallbiomarkerswas4.0%.Asis

showninFig.1,theCVsoftheimmunochemicalmethods(EIAand

immunoanalyzer)aresomewhathigherthantheCVsofthe

colori-metricassaysoftheautoanalyzer,becauseofthemorecomplicated

assaysoftheimmunochemicalmethods.

Sampleexchangesordatabaseerrorsaredifficulttoavoidin

complexlarge-scaleprojects.Sampleordataexchangecouldhave

occurredatseveralstages,includingrecruiting,storageand

rela-belingofsamples,samplesanalysisincludingreportinganddata

storage, all done at different sites (see Bürkle et al.;

Moreno-Villanueva,Caprietal.;Capri,Moreno-Villanuevaetal.;Bauretal.,

thisissue). Onepossiblecheckofsamplemix-upis the

correla-tionbetweentheparticipant’sgenderandthetestosteronelevels.

Anequalnumberofdesignatedmaleandfemalesamplesshowed

testosteronelevelsintherangeoftheoppositegender,withalmost

halfofthedesignatedsamplesfromfemales havingthehighest

PSAvaluesmeasuredin thisgroup.Possibly,thesesamples(3%

oftotal)gotexchangedanywhereinthechainfromsample

col-lection to data analysis. Aspotential sample exchangeswithin

sexesgounnoticedinthis analysisbasesonsexdifferences,the

estimated exchange rate for all sample sets may be twice as

high.

In the MARK-AGE project, both the quality of the serum

and plasma samples and the quality of the biomarkers

measurementsareexcellent,consideringthecomplicated

proce-duresinthislarge-scaleproject.Thequalityincludespreparation,

handling,shipments, (re)numbering, storageconditions, quality

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Conflictofinterest

All authors approved the final manuscript and none of the

authorshadanypersonalorfinancialconflictofinterest.

Acknowledgements

Wethankallparticipantsfromthedifferentstudycenterswithin

theMARK-AGE study.We thankthe EuropeanCommission for

financialsupportthroughtheFP7large-scaleintegratingproject

‘EuropeanStudytoEstablishBiomarkersofHumanAgeing’

(MARK-AGE;grantagreementno.200880).

References

Boffetta,P.,Trichopoulos,D.,Bobak,M.,Borsch-Supan,A.,Brenner,H.,Eriksson,S., Grodstein,F.,Jansen,E.,Jenab,M.,Jurges,H.,Kampman,E.,Kee,F.,Kuulasmaa,

K.,Park,Y.,Tjonneland,A.,vanDuijn,C.,Wilsgaard,T.,Wolk,A.,Bamia,C., Trichopoulou,A.,onbehalfoftheCHANCESConsortium,2014.TheConsortium onHealthandAgeing:NetworkofCohortsinEuropeandtheUnitedStates (CHANCES)project:design,populationanddataharmonizationofa large-scale,internationalstudy.Eur.J.Epidemiol.29,929–936.

Kratz,A.,Ferraro,M.,Sluss,P.M.,Lewandrowski,K.B.,2004.Laboratoryreference values.N.Engl.J.Med.351,1548–1563.

Mikolaenko,I.,Benson,E.,Konrad,R.J.,Chaffin,C.,Robinson,C.A.,Hardy,R.W., 2000.EvaluationoftheBeckmanCoulterLX20clinicalchemistryanalyzer.Lab. Med.31,387–393.

Patterson,W.,Werness,P.,Payne,W.J.,Matsson,P.,Leflar,C.,Melander,T.,Quast, S.,Stejskal,J.,Carlson,A.,Macera,M.,etal.,1994.Randomand

continuous-accessimmunoassayswithchemiluminescentdetectionbyAccess automatedanalyzer.Clin.Chem.40,2042–2045.

Vermeer,H.J.,Steen,G.,Naus,A.J.M.,Goevaerts,B.,Agricola,P.T.,Schoenmakers, C.H.H.,2007.CorrectionofpatientresultsforBeckmanCoulterLX-20assays affectedbyinterferenceduetohemoglobin,bilirubinorlipids:apractical approach.Clin.Chem.LabMed.45,114–119.

Figure

Fig. 2. Histogram of the testosterone concentrations in all men (upper graph) and women (lower graph)

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