comparison of 13 commercially available cardiac...

Comparison of 13 Commercially AvailableCardiac Troponin Assays in a Multicenter NorthAmerican Study

Robert H. Christenson,1* Ellis Jacobs,2,3 Denise Uettwiller-Geiger,4 Mathew P. Estey,5,6

Kent Lewandrowski,7 Thomas I. Koshy,8 Kenneth Kupfer,2 Yin Li,2 and James C. Wesenberg9,10

Background:We examined the concordance of 13 commercial cardiac troponin (cTn) assays [point-of-care, high-sensitivity (hs),

and conventional] using samples distributed across a continuum of results.

Methods: cTnI (11 assays) and cTnT (2 assays)weremeasured in 191 samples from128 volunteers. cTn assays includedAbbott

(iSTAT, STAT, and hs), Alere (Cardio 3), Beckman (AccuTnI+3), Pathfast (cTnI-II), Ortho (Vitros), Siemens (LOCI, cTnI-Ultra, Xpand,

Stratus CS), and Roche [4th Generation (Gen), hs]. Manufacturer-derived 99th percentile cutoffs were used to classify results as

positive or negative. Alternative 99th percentile cutoffs were tested for some assays. Correlation was assessed using Passing–

Bablok linear regression, bias was examined using Bland–Altman difference plots, and concordance/discordance of each

method comparison was determined using the McNemar method.

Results: Regression slopes ranged from 0.63 to 1.87, y-intercepts from 0.00 to 0.03 ng/mL, and r values from 0.93 to 0.99. The

cTnTmethods had a slopeof 0.93, y-intercept of 0.02 ng/mL, and r value of 0.99. For the cTnI assays, positive, negative, andoverall

concordance was 76.2%–100%, 66.0%–100%, and 82.9%–98.4%, respectively. Overall concordance between the 4th Gen cTnT

and hsTnT assays was 88.9%. A total of 30 of the 78 method comparisons showed significant differences in classification of

samples (P <0.001); the iSTAT showed10, hsTnT showed9, AccuTnI+3 showed5, Xpand showed5, and Stratus CS showed1. Using

alternative 99th percentile cutoffs to those listed by manufacturers lowered the method discordance by 6-fold, from 30 to 5 (all

involved iSTAT).

Conclusions: These data provide insight into characteristics of cTn methods and will assist the healthcare community in

setting expectations for relationships among commercial cTn assays.

IMPACT STATEMENTThis study demonstrates the analytical relationships among 13 commercial cTn assay systems that included 4 point-of-

care assays, 2 high-sensitivity (hs) assays, and 7 central laboratory systems in a multicenter setting. The data can be used to

set expectations for the relative differences between cTn assays in terms of classifying negative and positive results.

Alternative 99th percentile cutoffs improved agreement between most discordant assays. These data provide insight into

relationships between available commercial assays and will assist the laboratory and healthcare community in setting

expectations for comparisons among cTn assays.

1Department of Pathology, University of Maryland School of Medicine, Baltimore, MD; 2Alere, Waltham, MA; 3Department of Pathology, Mount SinaiSchool of Medicine, New York, NY; 4John T Mather Memorial Hospital, Port Jefferson, NY; 5DynaLIFEDx, Edmonton, Canada; 6Department of LaboratoryMedicine and Pathology, University of Alberta, Edmonton, Canada; 7Department of Pathology, Massachusetts General Hospital, Boston, MA; 8TheBinding Site Inc., San Diego, CA; 9Alberta Health Service, Red Deer, Alberta, Canada; 10Red Deer Regional Hospital Centre, Red Deer, Canada.

ARTICLESSC

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Copyright 2017 by American Association for Clinical Chemistry.

The diagnosis of acute myocardial infarction(MI)11 has evolved with an increasing focus on bio-markers for diagnosis and risk stratification of pa-tients with signs and symptoms of ischemic heartdisease and an increased emphasis on rapid andearly assessment of the disease process (1). Withover 8millionnontraumatic chest pain visits to emer-gency departments each year in the US (2), the highmortality associated with overcrowding, and longwaiting times in the emergency department, toolsare in high demand that assist in providing accurateand timely diagnosis or that help rule out patientswith a possible acuteMI presentation (3–7). Most pa-tients with acute MI do not have diagnostic electro-cardiogram changes upon presentation, so the useofmyocardial necrosis biomarkers to aid in the diag-nosis and risk stratificationof patientspresentingwithsuspicious signs and symptoms is essential (1, 8).Cardiac troponin (cTn) I and cardiac troponin T

(cTnT) are troponin isoforms that are unique to thecardiac myocyte, and measurement of either issensitive and specific for detecting cardiac injury.Over the years, several generations of cTn assayshave been developed, cleared by regulatory bod-ies, and made commercially available for patientcare. Modern clinical practice has focused on im-proved cTn assays for diagnosis of acute MI, asindicated by expert international task force guid-ance (8) and evidence-based guideline recommen-dations from professional societies worldwide(1, 9, 10). This guidance recommends use of cTnassays that are capable of quantifying and definingthe 99th percentile upper reference limit of a nor-mal control population. More sensitive cTn assaysallow for earlier MI detection and identify a higherpercentage of emergency department chest painpatients who are at risk for short-term major ad-verse cardiac events (1, 9, 11, 12).

There are a wide variety of laboratory-based andpoint-of-care (POC) systems that provide cTnmea-surements in whole blood and/or plasma. Despitethe fact that the results from these various testingplatform systems may yield similar clinical inter-pretation for diagnosis, i.e., above or below the99th percentile of the assaywith a rise and or fall ofcTn, there are considerable differences in the nu-merical cTn values between assays. This variabilitymay be due to differences in assay calibration, useof different antibodies, differences in assay design,instrument limitations, multiple detection technol-ogies, and differences in themeasurand, i.e., someassays measure cTnI and others cTnT.There is a paucity of resources available for di-

rectly comparing the commercially available cTnassays. We believe that such a resource would bevaluable to practicing laboratorians; therefore, wepresent here a multicenter study that examinedthe correlation and concordance of 13 commercialcTn assays using patient samples distributedacross a wide range of cTn results.

MATERIALS AND METHODS

Patient enrollment

A total of 191 blood samples with a continuum ofcTn results were collected from 128 adult patientsenrolled in the emergency department, medical in-tensive care unit, cardiac intensive care unit, cardiactelemetry, cardiac catheterization lab, and cardiacsurgery. The cTn assays used to identify and classifypotential subjectsat thecollectionsitewere theAlereTriage high-sensitivity (hs)-cTnI assay (Alere) andRoche Elecsys 4th Generation (Gen) TnT system(Roche Diagnostics). Consecutive samples meetingcriteria for the study were collected during workhours.

*Address correspondence to this author at: Laboratories of Pathology, University of Maryland Medical Center, 22 South Greene St.,Baltimore, MD 21201. Fax 410-328-5880; e-mail [email protected]: 10.1373/jalm.2016.022640© 2016 American Association for Clinical Chemistry11Nonstandard abbreviations:MI, myocardial infarction; cTn, cardiac troponin; POC, point-of-care; hs, high-sensitivity; Gen, generation.

13 Cardiac Troponin Assays Compared ARTICLES

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This study was approved by the InstitutionalReview Board at the collection site (New YorkMethodist Hospital, Brooklyn, NY). Study eligibilitywas confirmed and written informed consent wasobtained from all subjects before sample collec-tion. Basic demographic information (age, sex,race) was collected, along with date of collectionand the initial cTn concentration.

Sample collection

The total blood volume collected from each sub-ject was 23 mL into a total of 3 BD Vacutainer™tubes; 20 mL blood was collected into 2 10-mLsodium heparin anticoagulated tubes, and 3 mLblood was collected into 1 K2EDTA anticoagulatedtube. For patients having a change in cTn concen-trations within 12 h of the first blood draw, a sec-ond sample collection was permitted by theprotocol and Institutional Review Board; secondspecimens were handled independently fromthose obtained in the first draw.Blood samples were obtained by routine veni-

puncture and indwelling lines/catheters, in accor-dancewith the collection site's standardprocedures.Blood samples were inverted at least 10 times to en-sure complete dissolution and mixing of anticoagu-lant before centrifuging at 3000g for 10 min.Heparinized and EDTA plasmawas dispensedwithin1 h of collection into 0.5-mL aliquot tubes, whichwere then frozen and maintained at −70 °C. Speci-men aliquots were shipped on dry ice to the speci-men bank at Alere (San Diego, CA), where they werearchived at −70 ° C until shipment on dry ice to theperforming laboratories. Samples were stored at−70 °C at performing sites until measurement.

cTn assays

Table 1 lists the 13 commercial cTn assays in-cluded in this study, along with characteristics ofthe assays. The protocol for this study specifiedthat all measurements were performed in singli-cate and in accordance with manufacturers' rec-

ommendations. All assay runs that reportedresults were within laboratory-specified parame-ters, including Quality Control limits. cTn resultswere recorded on a Case Report Form and sent toAlere for data analysis by professional statisticians(coauthors K. Kupfer and Y. Li).

Sample testing

Samples were thawed, 1 set of 9 specimens at atime, by placing them in a water bath at room tem-perature (21 ± 3 °C) for approximately 30 min. Thethawed samples were mixed by gentle inversionand then centrifuged to remove particulate mat-ter. Samples were tested within 1 h of thawing.

Data analysis

Data analysis was performed in SAS version 9.3and Analyse-it version 2.22. A sample size of >180was determined to be sufficient for providing sig-nificant statistical power for the method compari-sons. With the sample size and data distributionassembled here, there is 96% power to detect adifference between a Pearson correlation of 0.93and 0.88 using a 2-sided test with a significancelevel of 0.05, or to achieve a 95% CI of 0.882–0.963when measuring a total agreement of 0.930. Thesample size chosen was sufficient to detect differ-ences in correlation coefficients and to estimatetotal agreement about the clinical decision point.

Assay correlation and assessment of bias

The Passing–Bablok method was performedfor all linear regression analyses that included dataabove the limit of detection for the assays.Spearman rank correlation coefficient andPearson r values were determined for all assaycomparisons. For bias, Bland–Altman differenceplots were constructed in 2 ways for each methodpair. The first was for the full set data, includingpoints below the assays' limit of detection (see Fig.1 in the Data Supplement that accompanies the

ARTICLES 13 Cardiac Troponin Assays Compared

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Table1.

Characteristicsof

the13

cTnassays

includ

edin

thisstud

y.

cTnassay

Ana

lyticalSystem

system

,man

ufacturer,

address

Date

approved

a,b

(anticoa

gulant)

cTnep

itop

estargeted

CVat

99th

percen

tile,

%99th

percen

tile,

packageinsert

Alterna

tive

value

for99th

percen

tile

Limitof

detection

Upp

erlim

itof

linearity,

ng/m

LPe

rforming

labo

ratory

Abbotti-STAT

CTnI

i-STATHandheld,Abbott

PointofCareInc.,

Princeton,NJ

2003

(Heparin)

Cc:41–49,88–91

16.5

0.08

0.04

(13,14)

0.02

50.0

RedDeerR

egional

HospitalCentre,Red

Deer,Alberta,

Canada

D:28–39,62–78

AlereTriage,

Cardio3cTnI

AlereTriage®MeterPro,

Alere

2011

@(EDTA)

C:27–39

17.0

0.02

—d

0.01

10.0

Alere,SanDiego,CA

D:83–93,190–196

AbbottARCH

ITECT

STAT

TnI

ARCH

ITECTi2000SR,

AbbottDiagnostics,

AbbottPark,IL

2007

(Heparin)

C:87–91,24–40

14.9

0.028

—0.01

50.0

DynaLIFE,Edmonton,

Alberta,Canada

D:41–49

AbbottARCH

ITECT,

High-Sensitivity

TnI

ARCH

ITECTi2000SR,

AbbottDiagnostics

2012

@(EDTA)

C:24–40

4.0

0.026

—0.001

50.0

DynaLIFE

D:41–49

Beckman

AccuTnI+3

Access2,Beckman

Coulter,Brea,CA

2013

(Heparin)

C:41–49

20.0

0.02

0.04

e(16)

0.01

100.0

JTMatherM

emorial

Hospital,Port

Jefferson,NY

D:24–40

XpandCTnIFlex

Dimension

XpandPlus,

Siem

ensHealthcare,

New

ark,DE

2001

(Heparin)

C:27–32

15–22

0.07

0.05

f0.04

40.0

RedDeerR

egional

HospitalCentre

D:41–56

StratusCS

Acute

CarecTnITestPak

StratusCS,Siemens

Healthcare

2005

(Heparin)

C:27–32

10.0

0.07

0.04

(14)

0.003

50.0

University

ofMaryland,

SchoolofMedicine,

Baltimore,MD

D:41–56

TnI-U

ltra

ADVIACentaur®

XP,

Siem

ensHealthcare

2005

(Heparin)

C:41–49,87–91

8.8

0.04

—0.006

50.0

MassachusettsGeneral

Hospital,Bo

ston,M

AD:27–40

LOCI®CTnI,

Dimension

Vista1500,

Siem

ensHealthcare

2001

(Heparin)

C:27–32

10.0

0.045

—0.015

40.0

RedDeerR

egional

HospitalCentre

D:41–56

Ortho

Vitros

TnIES

VITROS3600

Immuno-

diagnosticSystem

,Ortho

Clinical

Diagnostics,Raritan,NJ

2003

(Heparin)

C:24–40,41–49

10.0

0.034

—0.012

80.0

JTMatherM

emorial

Hospital

D:87–91

PathfastcTnI-II

Pathfast,M

itsubishi

Chem

icalMedienceCo

,Tokyo,Japan

2011

(EDTA)

C:41–49

5.0

0.029

—0.019

50.0

University

ofMaryland

SchoolofMedicine

D:71–116,163–209

4thGen

TnT

Elecsyse411,Roche

Diagnostics,

Indianapolis,IN

2005

(Heparin)

C:125–131

—0.010

—0.01

25.0


Hospital

D:136–147

hsTnT

Elecsyse411,Roche

Diagnostics

2010

@(Heparin)

C:125–131

10.0

0.014

0.028(15)

0.003

10.0


Hospital

D:136–147

aDatethateach

assaywas

approved

bytheU.S.FoodandDrugAdministration(FDA)or

theCo

nformité

Européene(CE)(EuropeanCo

nformity).

bAssaydateswith

the@

representproducts

arenotFD

Acleared,

anddate

indicatesCE

markapproval.The

third

througheighth

columns

wereexcerptedfrom

theIFCC

tableat

http://www.ifcc.org/m

edia/276664/IFCC

%20Troponin%20Tables%20ug_L_DRAFT%20Update%

20NOVEMBER%

202014.pdf.

cC,captureantibody;D,detectionantibody.

dEntryof“—

”indicates

thatthepackageinsertvaluewas

used

inthealternative99thpercentileanalysis(see

MaterialsandMethods).

eRecommendedBeckman

Access2TroponinDecisionpointinEuropean

Instructions

forU

se.

fThevalueof0.05

ng/m

Lwas

used

becauseitis0.01

ng/m

Labovethemethod'sdetectionlim

it.


March 2017 | 01:05 | 544–561 | JALM 547

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http://www.ifcc.org/media/276664/IFCC%20Troponin%20Tables%20ug_L_DRAFT%20Update%20NOVEMBER%202014.pdf

online version of this article at http://www.jalm.org/content/vol1/issue5). The second analysis fo-cused on cTn values near the respective 99thpercentile cutoffs by including samples with valuesfrom 0.01 ng/mL below the package insert 99thpercentile cutoffs to 0.5 ng/mL (see Fig. 2 in theonline Data Supplement).Method comparisons having a bias of ≤25% and

a scatter of ≤50%were identified. The rationale foruse of this bias and scatter criteria was 2-fold. First,thesemethod comparisons demonstrated the top16.7% of overall agreement. Second, the criteriawere convenient because, at a cutoff of 0.04ng/mL, bias of 0.01 ng/mL is 25% and scatter is0.02 ng/mL (i.e., 50%).

Concordance and manufacturers' 99thpercentile cutoff

Concordance was assessed by classifying eachassay result as either positive or negative accord-ing to the manufacturer's labeled 99th percentilecutoffs, regardless of the assays' 10% CV concen-tration. Results at or below the 99th percentilewere deemed negative. The statistical significanceof discordance between all assay pairs was evalu-ated by the McNemar analysis, without a correc-tion for continuity. Because of the multiplecomparisons performed, there was type I error in-flation. For a total of 78 comparisons, the signifi-cance level for each comparison was 0.05/78 =0.00064. Thus, McNemar P values <0.001 weredeemed to show significant discordance.

Concordance using alternative 99thpercentile cutoffs

Alternative cutoffs were applied to discordantmethods in a separate analysis to evaluate if thevariable interpretation between assays was pri-marily a function of the manufacturer prescribed99th percentile. Table 1 lists the alternative cutoffsapplied, which were selected as follows. A previ-ously reported lower cutoff of 0.04 ng/mL was

used for the Abbott iSTAT (13, 14) and the SiemensStratus CS assays (14). For the Dimension Xpand, alower cutoff of 0.05 ng/mL was used because thisconcentration is 0.01 ng/mL above the limit ofdetection for the method. Higher alternative cut-offs than themanufacturer specifiedwere used forthe Roche hsTnT assay at 0.028 ng/mL (15) and forthe Beckman Access 2 at 0.04 ng/mL, based on theassay's 10% CV (16). The alternative cutoff concor-dance analyses were performed with the McNemarmethod using a significance level of P <0.001.

RESULTS

A total of 191 samples were collected for thestudy. Demographics of the 128 subjects whowere enrolled in the study are listed in Table 1 inthe online Data Supplement. There were 65 sub-jects who had 1 specimen collected for the study;63 subjects had 2 specimens collected. Therewerea total of 2470 cTn measurements performed forthis study, of which 19 (0.78%) did not yield a validcTn result for 1 or more methods.Table 2 in the online Data Supplement shows all

Passing–Bablok regression data, including the 95%confidence limits for slope and y-intercept, as wellas the nonparametric Spearman rank correlationcoefficient. Table 2 summarizes the Passing–Bablock linear regression results for each cTn as-say comparison. For the cTnI assay comparisons,slopes ranged from 0.59 to 1.87; y-intercepts werelow, and overall cTnI correlation was good, as indi-cated by Pearson r values ranging from 0.83 to0.99. As expected, regression slopes for compari-sons between cTnT (y axis) and cTnI assays (x axis)were substantially lower. Correlation data havingPearson r values <0.80, all of which involved eitherthe Roche 4th Gen cTnT or hsTnT methods, arehighlighted in red in Table 2. However, correlationbetween the 2 cTnTmethodswas good, as indicatedby a slope of 0.94, 0 y-intercept of 0.02 ng/mL, andPearson r of 0.99.


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http://www.jalm.org/content/vol1/issue5

http://www.jalm.org/content/vol1/issue5

Table2.

Correlationstatistics

from

Passing–Ba

blok

linearregression

analysisof

paired

metho

dcompa

risons.a

Y2X¡

Alere

Cardio3

Abb

ott

ARC

HITECT

Abb

ott

ARC

HITECThs

Abb

ott

i-STA

TBe

ckman

Access2

Mitsubishi

PathFast

Ortho

Vitros

3600

Roche

4thGen

TnT

Roche

hsTn

TSiem

ens

Centau

rSiem

ens

Xpan

dSiem

ens

Stratus

AbbottARCH

ITECT

1.60

Orderof

regression

parameters:

Slope

0.03

y-intercept

0.92

Pearsonr

0.85

Pearsonr2

AbbottARCH

ITECThs

1.41

0.92

0.00

0.00

0.88

0.96

0.77

0.92

Abbotti-STAT

1.00

0.59

0.66

0.01

0.00

0.00

0.87

0.96

0.88

0.76

0.92

0.77

Beckman

Access2

1.18

0.75

0.81

1.23

0.03

0.00

0.01

0.01

0.87

0.96

0.95

0.97

0.76

0.92

0.90

0.94

MitsubishiPathFast

1.26

0.81

0.81

1.30

1.05

0.00

0.00

0.01

0.00

−0.02

0.83

0.93

0.85

0.97

0.95

0.69

0.86

0.72

0.94

0.90

Ortho

Vitros

3600

1.23

0.76

0.80

1.16

1.03

0.96

0.03

0.00

0.02

0.01

0.00

0.02

0.91

0.95

0.87

0.99

0.96

0.96

0.83

0.90

0.76

0.98

0.92

0.92

Roche4thGen

TnT

0.26

0.13

0.19

0.22

0.16

0.15

0.14

0.06

0.05

0.01

0.05

0.05

0.08

0.08

0.54

0.63

0.60

0.70

0.76

0.62

0.72

0.29

0.40

0.36

0.49

0.58

0.38

0.52

RochehsTnT

0.23

0.17

6.96

0.33

0.22

0.15

0.17

0.94

0.05

0.01

−0.50

0.01

0.01

0.06

0.04

0.02

0.55

0.66

0.60

0.71

0.78

0.60

0.72

0.99

0.30

0.44

0.36

0.50

0.61

0.36

0.52

0.98

Continuedon

page

550


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Table2.

Correlationstatistics

from

Passing–Ba

blok

linearregression

analysis

ofpa

ired

metho

dcompa

risons.a(Continu

edfrom

page

549)

Y2X¡

Alere

Cardio3

Abb

ott

ARC

HITECT

Abb

ott

ARC

HITECThs

Abb

ott

i-STA

TBe

ckman

Access2

Mitsubishi

PathFast

Ortho

Vitros

3600

Roche

4thGen

TnT

Roche

hsTn

TSiem

ens

Centau

rSiem

ens

Xpan

dSiem

ens

Stratus

Siem

ensCentaur

1.87

1.05

1.17

1.82

1.44

1.52

1.60

9.29

6.41

0.00

0.00

0.00

0.01

−0.01

−0.02

−0.04

−0.51

−0.10

0.90

0.96

0.89

0.99

0.96

0.98

0.98

0.61

0.63

0.81

0.92

0.79

0.98

0.92

0.96

0.96

0.37

0.40

Siem

ensXpand

1.19

0.77

0.77

1.18

1.00

0.96

0.96

6.78

6.68

0.63

0.01

−0.01

0.03

0.00

0.00

0.02

−0.01

−0.60

−0.47

0.03

0.94

0.96

0.98

0.89

0.94

0.88

0.89

0.54

0.54

0.91

0.88

0.92

0.96

0.79

0.88

0.77

0.79

0.29

0.29

0.83

Siem

ensStratus

1.33

0.82

0.81

1.27

1.13

1.00

1.05

6.96

6.81

0.67

1.05

0.02

0.00

0.01

0.01

−0.02

0.02

−0.01

−0.50

−0.43

0.02

0.00

0.96

0.98

0.97

0.92

0.95

0.91

0.92

0.58

0.58

0.94

0.99

0.92

0.96

0.94

0.85

0.90

0.83

0.85

0.34

0.34

0.88

0.98

Siem

ensVISTA

1.57

0.99

1.04

1.51

1.32

1.24

1.27

9.24

9.03

0.83

1.27

1.20

0.03

0.00

0.02

0.01

−0.01

0.04

0.00

−0.95

−0.56

0.03

0.02

0.01

0.92

0.93

0.98

0.85

0.94

0.85

0.85

0.54

0.54

0.89

0.99

0.97

0.85

0.86

0.96

0.72

0.88

0.72

0.72

0.29

0.29

0.79

0.98

0.94

aAssaysarecTnIunlessotherwiseindicated.Thedescending

ordero

fregressionresults

isslope,y-intercept,Pearsoncoefficient(r),and

Pearsonr2.Pearson

rvalues<0.8areinred.Thefull

complem

entoflinearregressionvariables,including

95%CIsforslope

andy-interceptsarelistedinTable2intheonlineDataSupplement.


550 JALM | 544–561 | 01:05 | March 2017

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All 78 Bland–Altman plots of the data, including95% CIs, are displayed in Fig. 1 in the online DataSupplement and for the concentrations near the99th percentile cutoff for the methods in Fig. 2 inthe online Data Supplement. Table 3 lists theBland–Altman proportional mean bias and SD datafor all method pairs at concentrations near the 99thpercentile cutoff. These data show that proportionalmean bias using this limited region ranged from alow of 0.4% to a high of 80.3%; the SD of the propor-tional bias demonstrated scatter between 33.6%and 118.5%. The difference plots for method com-parisons having both ≤25% mean proportional biasand ≤50% SD of scatter in proportional bias repre-sented the best 16.7% of the total comparison andare displayed in red type in Table 3.Table 3A in the online Data Supplement shows

concordance (agreement) data for themethod com-parisons. Here, the sample results were classified aspositive or negative according to the respectiveman-ufacturers' listed 99th percentile cutoffs. There are158 comparisons in this approach because the neg-ative and positive agreements are calculated witheach of the 13 assays as the reference method. Theclassification of samples as method 1 or method 2,and their designation of positive or negative wassolely on the basis of the manufacturers' cutoffs.Comparisons were relative, and there was no goldstandard. It is important to note when interpretingthese data that the purpose of this effort was limitedto examining agreement of themethodswith regardto their respective cutoffs. As such, this analysis ex-amined the extent of discordance between themethods and did not to determine which methodcorrectly classified patients clinically. As an example,Table 3B in the online Data Supplement shows thedetermination of positive, negative, and overallagreementwhenmethod1 is theRochehsTnTassayand method 2 is Roche 4th Gen assay. The hsTnTassay was positive for all 4th Gen cTnT positive re-sults, thus yielding 100% for positive agreement (i.e.,no 4th Gen cTnT samples were negative when thematchinghsTnT resultwaspositive)where theRoche

Table3.

Prop

ortion

al(%

)bias

andCV

(%)from

Blan

d–Altman

analysisof

metho

dcompa

risonin

thearea

ofthe99th

percen

tile

cutoff.a

Y2X¡

Alere

Cardio3

Abb

ott

ARC

HITECT

Abb

ott

ARC

HITECThs

Abb

ott

i-STA

TBe

ckman

Access2

Mitsubishi

PathFast

Ortho

Vitros

3600

Roche

4thGen

TnT

Roche

hsTn

TSiem

ens

Centau

rSiem

ens

Xpan

dSiem

ens

StratusCS

AbbottARCH

ITECT

64.7%(56.2)

AbbottARCH

ITECThs

44.2%(44.8)

−37.1%

(37.8)

Abbotti-STAT

−4.3%(90.3)

−82.4%

(58.4)

−55.9%

(74.4)

Beckman

Access2

47.2%(53.2)

−28.2%

(34.0)

10.2%(33.6)

57.7%(69.6)

MitsubishiPathFast

35.0%(63.0)

−22.3%

(74.0)

−2.2%(71.4)

45.6%(87.0)

−5.8%(67.1)

Ortho

Vitros

3600

45.7%(72.8)

−35.1%

(41.3)

−1.0%(52.2)

45.9%(63.2)

−7.4%(50.0)

−7.1%(83.0)

Roche4thGen

TnT

37.7%(107.9)

−37.8%

(97.5)

−9.8%(103.6)

18.6%(100.7)

−13.4%

(99.3)

−13.1%

(118.5)

−22.3%

(102.0)

RochehsTnT

24.8%(106.0)

−35.3%

(77.9)

−0.4%(89.0)

51.8%(90.5)

−6.7%(81.1)

−23.0%

(105.9)

−4.8%(76.0)

31.4%(46.6)

Siem

ensCentaur

50.4%(66.7)

−25.0%

(42.7)

12.6%(39.3)

65.6%(59.9)

1.8%

(38.3)

9.6%

(72.7)

20.4%(47.0)

21.6%(102.7)

12.2%(84.7)

Siem

ensXpand

44.1%(41.2)

−20.5%

(48.4)

2.5%

(38.7)

41.6%(69.1)

1.9%

(37.2)

5.3%

(64.4)

6.6%

(62.4)

9.2%

(110.1)

19.3%(98.4)

−5.3%(58.7)

Siem

ensStratus

38.3%(50.9)

−25.2%

(43.0)

1.0%

(45.9)

49.3%(73.4)

−2.7%(41.8)

0.5%

(67.6)

2.2%

(54.2)

15.8%(111.0)

20.7%(94.0)

−5.6%(57.3)

−11.9%

(35.4)

Siem

ensVISTA

80.3%(33.6)

12.7%(58.8)

37.0%(44.0)

69.6%(67.5)

32.3%(44.9)

43.8%(68.0)

31.1%(64.4)

29.3%(111.7)

42.0%(100.7)

23.5%(60.3)

39.5%(33.8)

46.8%(42.6)

aSeeBland–Altm

andifferenceplotsforeachcomparison

inFigure2intheonlineDataSupplement.Methodpairs

displayedinredhave

proportionalm

eanbias

≤25%

andSD

(≤50%).


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4thGenassay is the referencemethod.On theotherhand, thenegative agreementwas72.0%;of interest,28% of negative results for the 4th Gen cTnT assaydid not have amatching hsTnT negative result. Over-all, 88.9% of the 4th Gen and hsTnT results agreed[i.e., concordant results/(concordant + discordant)results]. In the entire data set, 72.5%–98.4% ofthe positive and negative results were concordant;agreement among positive samples ranged from68.4% to 100%, and agreement of the negativesample results ranged from 56.1% to 100% (Table

3A in the online Data Supplement). Restrictingthis analysis to cTnI assays, the range of total, pos-itive, and negative agreement was 82.9%–98.4%,74.4%–100%, and 66.0%–100%, respectively.Fig. 1 displays all study data arranged as a “heat

map” in which each sample measurement is clas-sified as either negative, i.e., equal to or less thanthe respective package insert's stated 99th per-centile value (green cells), or positive, i.e., greaterthan the respective assay's package insert 99thpercentile value (red cells). Here, the cTn assays

Fig. 1. Heat map format showing agreement of classification of sample results as either equal to orbelow the specified 99th for the assay (green) or greater than the 99th percentile for the assay (red).There were 3 regions: region 1, in which all samples (except 1) were negative for 8 or more methods; region 2, in which allsamples (except 2)were positive (ormissing data) for 6–10methods; and region 3, inwhich all samples (except 1) hadpositiveresults for 11 or more methods.

Continued on page 553


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are arranged in alphabetical order with results dis-played from the lowest to the highest according toAbbott ARCHITECT cTnI values, with correspondingresults for the sample from the other 12 cTn as-says included in the same data row. For conve-nience, the heat map is divided into 3 regions:region 1, in which all samples (except 1) were neg-ative for 8 or more methods (n = 74 samples); re-gion 2, in which all samples (except 2) were positive

(or missing data) for 6–10 methods (n = 19 sam-ples); and region 3, in which all samples (except 1)had positive results for 11 or more methods (n =98 samples). Of the measurements in region 1,there were discordant results for 54 (5.7% of re-gion 1 total) samples. Two assays had 10 or morediscordant measurements; the Roche hsTnT assayhad 20 (37.0% of total noncordant results), andthe Beckman Access 2 assay had 10 (18.5% of

Fig. 1. Continued.Continued on page 554


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discordant results). In region 3, there were 13 dis-cordant negative measurements (1.0% of region 3total). No assay hadmore than 5 discordant resultsin region 3. In region 2, 163 (68.2%) of the resultswere positive, and the remaining 76 results (31.8%)were negative. As seen in Fig. 1, in region 2, most ofthe negative measurements were with the iSTAT(n = 19; 25.0% of negatives), Siemens Stratus CS(n = 16; 21.1% of negatives), and Siemens Xpand

(n = 14; 18.4% of negatives). It is noteworthy thatfor unknown reasons, the Abbott iSTAT and OrthocTnI assays had undetectable results for the samesamples that were significantly positive by theother 11 assays. The reason for this observationwas not clear but is likely specimen related.Concordance data with McNemar analysis for all

78 of the paired cTnI method comparisons are pre-sented in Table 4 in the online Data Supplement.

Fig. 1. Continued.Continued on page 555


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Table 4 displays the 30 (39%) total comparisons thatwere significantly biased in the distribution ofnonconcordant results in the McNemar analysis(P <0.001). The Abbott iSTAT method showed a sig-nificant difference, with 10 of its 12 (83.3%) pairedcomparisons; the Roche hsTnT assay showed a sig-nificant difference with 9 (75.0%) of its paired com-parisons; both the Beckman Access 2 and SiemensXpandmethods showed a significant difference with5othermethods (41.7%); and theAbbott ARCHITECTshowed a significant difference with the Siemens

Stratus CS (8.5%). Note that all of the discordantpaired comparisons for both the Abbott iSTAT andSiemensXpandwerenegativeby thesemethodsandpositive by the other methods. On the other hand,thesignificantlydifferentdiscordant comparisons fortheRochehsTnT andBeckmanAccess 2 assayswerepositive by thesemethods and negative by the com-parison methods.Reanalysis of the concordance data with alterna-

tive cutoffs listed in Table 1 was performed for themethod comparisons; the results of this analysis are

Fig. 1. Continued.


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listed in Table 4. All previously discordant pairedcomparisons showing significant bias (McNemarP <0.001) were no longer significant except for 5paired comparisons with the Abbott iSTAT; thesespecific comparisons are displayed in Table 5 in redtype.

DISCUSSION

Here we present a descriptive study of 13 com-mercial cTn assays performed in accordance with

manufacturers' recommendations. The purpose ofthis studywas toprovidea transparent aid for settingexpectations when evaluating and comparing vari-ous cTn assays. Although comparison studies havebeen performed previously (16–23), this was amulti-Center, North American study that used a commoncohort of samples designed to span the range of cTnmeasurements. There were several POC assays in-cluded in this study, and as has been reported previ-ously (17, 23), the data show substantial variability

Table 4. McNemar analysis table.a

Paired comparisonNumber ofsamples PPb PN NP NN

McNemarP value

Abbott i-STAT (X) vs Beckman Access 2 (Y) 187 93 0 32 62 <0.001Abbott i-STAT (X) vs Mitsubishi PathFast (Y) 191 92 1 23 75 <0.001Abbott i-STAT (X) vs Ortho Vitros 3600 (Y) 187 90 0 17 80 <0.001Abbott i-STAT (X) vs Roche 4th Gen TnT (Y) 189 92 1 22 74 <0.001Abbott i-STAT (X) vs Roche hsTnT (Y) 191 93 0 43 55 <0.001Abbott i-STAT (X) vs Siemens Centaur (Y) 189 93 0 23 73 <0.001Abbott i-STAT (X) vs Siemens VISTA (Y) 191 93 0 23 75 <0.001Abbott i-STAT (X) vs Alere Cardio 3 (Y) 187 93 0 19 75 <0.001Abbott i-STAT (X) vs Abbott ARCHITECT (Y) 189 93 0 29 67 <0.001Abbott i-STAT (X) vs Abbott ARCHITECT hs (Y) 190 93 0 24 73 <0.001Roche hsTnT (X) vs Siemens Centaur (Y) 189 115 21 1 52 <0.001Roche hsTnT (X) vs Siemens Xpand (Y) 191 101 35 1 54 <0.001Roche hsTnT (X) vs Siemens Stratus CS (Y) 189 100 35 2 52 <0.001Roche hsTnT (X) vs Siemens VISTA (Y) 191 113 23 3 52 <0.001Roche hsTnT (X) vs Roche 4th Gen TnT (Y) 189 114 21 0 54 <0.001Roche hsTnT (X) vs Mitsubishi PathFast (Y) 191 112 24 3 52 <0.001Roche hsTnT (X) vs Ortho Vitros 3600 (Y) 187 107 25 0 55 <0.001Roche hsTnT (X) vs Alere Cardio 3 (Y) 187 110 24 2 51 <0.001Roche hsTnT (X) vs Abbott ARCHITECT hs (Y) 190 115 21 2 52 <0.001Beckman Access 2 (X) vs Ortho Vitros 3600 (Y) 184 106 16 1 61 <0.001Beckman Access 2 (X) vs Siemens Xpand (Y) 187 100 25 0 62 <0.001Beckman Access 2 (X) vs Siemens Stratus CS (Y) 185 99 25 2 59 <0.001Beckman Access 2 (X) vs Siemens VISTA (Y) 187 114 11 0 62 <0.001Beckman Access 2 (X) vs Alere Cardio 3 (Y) 183 111 13 0 59 <0.001Siemens Xpand (X) vs Abbott ARCHITECT (Y) 189 102 0 20 67 <0.001Siemens Xpand (X) vs Abbott ARCHITECT hs (Y) 190 101 1 16 72 <0.001Siemens Xpand (X) vs Mitsubishi PathFast (Y) 191 101 1 14 75 <0.001Siemens Xpand (X) vs Siemens Centaur (Y) 189 101 0 15 73 <0.001Siemens Xpand (X) vs Siemens VISTA (Y) 191 102 0 14 75 <0.001Abbott ARCHITECT (X) vs Siemens Stratus CS (Y) 187 99 22 3 63 <0.001

a Package insert 99th percentile cutoffs are displayed in Table 1.b PP, X value positive, Y value positive; PN, X value positive, Y value negative; NP, X value negative, Y value positive; NN, X value negative, Y value negative.


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among these assays. Althoughmeasurements in thecurrent studywereperformedby laboratory person-nel using plasma samples rather than a whole bloodmatrix, some of the POC assays show no significantdifference from the central laboratory-based assaysin concordance in this study or previously (17, 23).Evidence indicates that there is indeed substantialvariability among POC assays, and these assays

should be considered individually, rather than assimply a homogeneous class of assays, as was sug-gested in recent guidelines that state “[clinical]sensitivity [of point-of-care troponin assays] issubstantially below that of central laboratorymethods” (1).An important aimof this studywas to provide data

for thecomparisonandevaluationof cTnassaysand,

Table 5. Comparison data when alternative 99th percentile cutoffs (Table 1) for several of themethods were used.a

Paired comparisonbNumber ofsamples PPc PN NP NN

McNemarP value

Abbott i-STAT (X) vs Beckman Access 2 (Y) 187 103 0 10 74 0.002Abbott i-STAT (X) vs Mitsubishi PathFast (Y) 191 103 1 12 75 0.002Abbott i-STAT (X) vs Ortho Vitros 3600 (Y) 187 100 0 7 80 0.008Abbott i-STAT (X) vs Roche 4th Gen TnT (Y) 189 100 3 14 72 0.008Abbott i-STAT (X) vs Roche hsTnT (Y)c 191 103 1 20 67 <0.001Abbott i-STAT (X) vs Siemens Centaur (Y) 189 104 0 12 73 <0.001Abbott i-STAT (X) vs Siemens VISTA (Y) 191 104 0 12 75 <0.001Abbott i-STAT (X) vs Alere Cardio 3 (Y) 187 102 2 10 73 0.021Abbott i-STAT (X) vs Abbott ARCHITECT (Y) 189 103 0 19 67 <0.001Abbott i-STAT (X) vs Abbott ARCHITECT hs (Y) 190 104 0 13 73 <0.001Roche hsTnT (X) vs Siemens Centaur (Y) 189 112 11 4 62 0.071Roche hsTnT (X) vs Siemens Xpand (Y)d 191 107 16 6 62 0.033Roche hsTnT (X) vs Siemens Stratus CS (Y) 189 104 18 8 59 0.050Roche hsTnT (X) vs Siemens VISTA (Y) 191 110 13 6 62 0.108Roche hsTnT (X) vs Roche 4th Gen TnT (Y) 189 114 8 0 67 0.005Roche hsTnT (X) vs Mitsubishi PathFast (Y) 191 108 15 7 61 0.088Roche hsTnT (X) vs Ortho Vitros 3600 (Y) 187 105 15 2 65 0.002Roche hsTnT (X) vs Alere Cardio 3 (Y) 187 107 14 5 61 0.039Roche hsTnT (X) vs Abbott ARCHITECT hs (Y) 190 112 11 5 62 0.134Beckman Access 2 (X) vs Ortho Vitros 3600 (Y) 184 104 6 3 71 0.317Beckman Access 2 (X) vs Siemens Xpand (Y)e 187 109 4 2 72 0.414Beckman Access 2 (X) vs Siemens Stratus CS (Y) 185 106 6 4 69 0.527Beckman Access 2 (X) vs Siemens VISTA (Y) 187 113 0 1 73 0.317Beckman Access 2 (X) vs Alere Cardio 3 (Y) 183 109 4 2 68 0.414Siemens Xpand (X) vs Abbott ARCHITECT (Y) 189 112 0 10 67 0.002Siemens Xpand(X) vs Abbott ARCHITECT hs (Y) 190 111 2 6 71 0.157Siemens Xpand(X) vs Mitsubishi PathFast (Y) 191 111 2 4 74 0.414Siemens Xpand(X) vs Siemens Centaur (Y) 189 110 2 6 71 0.157Siemens Xpand (X) vs Siemens VISTA (Y) 191 112 1 4 74 0.180Abbott ARCHITECT (X) vs Siemens Stratus CS (Y) 187 108 13 4 62 0.029

a Significance was determined with theMcNemar Analysis. Adjusted 99th percentile cutoffs are listed in Table 1. Bold red type indicates a significantdifference between the methods.b The first character represents (X) and second character represents (Y).c PP, X value positive, Y value positive; PN, X value positive, Y value negative; NP, X value negative, Y value positive; NN, X value negative, Y value negative.


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in thatwaywould, helpassist practitionersandstake-holders in the field. One question that will likely berelevant involves the expectations that users mayhave when switching their current central laboratoryassays to the next generation of hs-cTn assays. As anexample of switching from Roche's 4th Gen assay tothe Roche hsTnT test, a report by Saenger et al. (19)demonstrated in amulticenter study that the regres-sion equationwas as follows: hsTnT = 1.02 × 4thGencTnT + 18.4 ng/L; r = 0.99. In the current study, Table2 shows that the relationship observed was quiteclose: hsTnT = 0.94 × 4th Gen + 0.02 ng/mL; r = 0.99.A different examplemay involve expectations for im-plementing Abbott's hsTnI for users of the AbbottARCHITECT cTnI assay. Rezvanpour et al. (20) com-pared these assays in over 7000measurements per-formed at 3 Canadian sites. For the 5509 points inthe 10–100 ng/L range, the overall relationship was:hsTnI = 1.12 × cTnI + (−5ng/L); r = 0.85. In the currentstudy, Table 2 (and Table 2 in theonlineData Supple-ment) shows that for the full cohort studiedhere, therelationship was somewhat different: hsTnI = 0.92 ×cTnI +0.00ng/mL; r=0.96. Further, information fromthe Rezvanpour et al. (20) contribution showedslopes for linear regression over the entire range ofmeasurements that differed by 0.26, from 1.18 (site1) to 1.44 (site 3). Of interest, the difference betweenthe lowest slope from the full cohort at their site 1 of1.18 (20) was also 0.26 different from the slope of0.92 from the Abbott hsTnI vs TnI comparison in thecurrent study. Thus, many interesting examinationsand comparisons are possible using data from thisstudy and available literature.The Passing–Bablok regression analyses showed

slopes and y-intercept values that indicate stronglinear relationships between the cTnI assays exam-ined here. The correlation coefficients (r values) forthe comparisons were high, indicating that therank order and direction of the measurement-pairs was consistent. Further, the r2 values indicatethat the comparison data were close to the fittedregression line. As expected, the cTnI and cTnTcomparisons had lower slopes and values for r and

r2; this may be, at least in part, because theseassays target distinctly different measurands.However, the 2 cTnT assays, which are both man-ufactured by the same vendor and use the sameantibodies for capture and detection, demon-strated good correlation.Bland–Altman difference plots showed bias that

varied substantially among the methods. Also, thescatter (SD) between method comparisons variedand was substantial for a number of comparisonsexamined. Approximately 15% of the cTn compar-isons demonstrated ≤25% bias and ≤50% scatter.These criteria may be interpreted as a convenientstarting point for assessing method agreementand potential for harmonization. The bias andscatter data are transparently displayed in Table 2in the online Data Supplement so that readers canexamine other criteria according to their interestand practice needs.It must be noted that this study was not designed

to address the issue of harmonization or standard-ization of cTnI assays, although others have exam-ined this possibility in similar investigations (21, 22).Tate et al. (21) examined 16 cTnI assays formeasure-ment equivalence and their standardization capabil-ity. Their study concluded that the methodsdemonstrated a significantly higher degree of mea-surement equivalence after mathematical recalibra-tion, indicating that measurement harmonization orstandardization would be effective at reducing inter-assay bias (21). Also, Clerico et al. (22) recently con-ducted a pilot study that included patient samples,external quality assessment controls, and plasmapools from MI patients and healthy subjects. Thesesamples were run on the ARCHITECT High hsTnI,Centaur cTnI, ST AIA-Pack cTnI Third Generation(Tosoh Bioscience), and Beckman Access 2. Aftermathematical recalibrationof theassays, theauthorsfound that the between-method cTnI variability de-creased significantly. The authors suggested that,based on these results, they were able to evaluatebetween-method variability and produce reliablerecalibration and harmonization of results (22).


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The 99th percentile cutoff values from the re-spective manufacturers' package inserts wereused to classify samples as either negative or pos-itive, i.e., less than or equal to or greater than the99th percentile. The Abbott i-STAT and SiemensXpand cTnI assays demonstrated a high rate ofnegative disconcordant results, and the RochehsTnT and Beckman Access 2 cTnI assays demon-strated a high rate of positive discordant results.Inspection of region 2 of the heat map (Fig. 1) sug-gests that these differences may to be related tothe diagnostic sensitivity of the respective assays,differences in populations used to establish the99th percentile, and/or other factors.Inspection of the epitope targets for the various

cTnI assays (Table 1) show that the amino acidrange of 24–49 is a common epitope target forvirtually all cTnI assays examined here. Althoughthe assays may be targeting similar measurands,the significant differences may reflect variationin the populations used for determining the as-says' 99th percentile cutoffs for classifying samplesas positive or negative. To investigate this issue, weused alternative 99th percentile cutoffs for theAbbott iSTAT, Siemens Xpand, and Stratus CS as-says to lower feasible values, and the Roche hsTnTassay and the Beckman Access 2 assays were in-creased to higher feasible values. This exercisecorrected much of the discordance betweenmethods, reducing the overall number of discor-dant comparisons by about 83%. However, resultsfrom the Abbott iSTAT assay were still discordantwhen compared to results from 5 other methods.The Abbott iSTAT assay, therefore, appears to havegreater variability compared to any of the othermethods included; this variability was not cor-rected by simply changing the 99th percentile cut-off. These data further highlight the variability andheterogeneity among POC devices, some of whichshowed the same characteristics as laboratoryquality assays. These data support the use of acommon set of normal reference samples for es-tablishing the 99th percentile for the assays, which

may be effective in improving, at least in part, thesignificant discordance observed in about 40% ofcomparisons presented here.Further to this point, methodological differences

in the 99th percentile and their impact on patientclassification have been documented. For exam-ple, a recent study by Ungerer et al. (16) includedmeasurements with the Abbott cTnI, Beckman Ac-cess 2 TnI, and Roche hsTnT assays in a commonset of 2004 samples. This study found that 50% to70% of the subjects having cTn values above the99th percentile cutoffs were unique to individualassays, and that only 4 out of 20 individuals abovethe cutoff for all 3 assays (16). Use of a commonsamplebankmaybeof assistance indetermining thediagnostic concordance and discordance amongcTn assays. It is noteworthy that sample banks havebeen reported previously, including the aforemen-tioned 2004-person (16). Also, this point was exam-ined in a cohort of 524 presumably healthy adultsassembled by Apple et al. (14), which also found vari-ations in a number of previously “established” 99thpercentile values. Another set of samples consists of875 presumably healthymales and females andwasassembled through the American Association forClinical Chemistry. This sample bank is unique in thatall samples were tested for creatinine, hemoglobinA1c, and amino-terminal proB-type natriuretic pep-tide to assess health; the number of males and fe-males recruited is in compliance with the IFCC TaskForce on Clinical Applications of Cardiac Bio-Markers(24); and, perhaps most importantly, this samplebank can be purchased by anymanufacturer or indi-vidual for their use, whereas to our knowledge thereis no other properly banked cohort available for gen-eral use.For the Abbott iSTAT andOrtho cTnI assays, a num-

ber of measurements were undetectable (negative),whereas the other assays produced significantly posi-tive results. The reason for this observation was notclear, but is likely specimen-related.There are several limitations to this study. One

is that the samples were run in singlicate, and


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therefore discordant results could not be confirmedor refuted as outliers. However, the participatingsiteswereblinded toother results, and thestudywasdesigned to reflect what practitioners would experi-ence in “real-life” performance of the respective as-says. We used the Passing–Bablok regressiontechnique because it assumes error in both the XandYmethods.Withuseof thePassing–Bablok tech-nique, however, onemustbecautionednot to simplysquare the correlation coefficient to calculate the co-efficient of determination because it is calculatedfrom the residuals of the fit. Generally, statisticiansdonot calculate thecoefficientofdetermination for aPassing–Bablok fit because the fit is nonparametricand the coefficient of determination is sensitive tooutliers. Also, because there are no clinical data forthe specimens analyzed in this study, the data can-not be used to reflect clinical comparison of the as-says. In addition, the only sample types used witheach assay in this study are listed in Table 1. There-fore, different sample types may yield different re-sults and comparisons may be different. Also, somecTn results are reported to 2decimal places andoth-ers to 3. Therefore, roundingmay have had an effecton the data. Initial and then later samples were col-lected from some individual patients, which mayhave had an impact on the study. Finally, the assays

includedherehaddifferent characteristics regardingimprecision at low concentrations, which may alsohaveaneffect.However, in theBland–Altmanplots inTable 3 in the online Data Supplement, we compen-sated for this by only including data exceeding thedetection limit for each assay.In conclusion, this study demonstrates the ana-

lytical relationship between 13 cTn assay systems,4 POC assays, 2 hs assays, and 8 central laboratorysystems. This study provides transparent aware-ness of the relative differences expected for cTnassays in terms of classification of results as eithernegative or positive relative to the manufacturerspecified 99th percentile cutoff of a reference pop-ulation. Adjusting the 99th percentile cutoffs forthe assays greatly improved concordance be-tween the assays for all systems and revealedpotential issues with patient selection for deter-mining the 99th percentile of an assay. Althoughcorrelation between the cTn assays included wasgood, correlation between cTnI and cTnT mea-surements varied substantially. There was bothbias and scatter among the methods, as demon-strated by difference plots. In large health systemswhere standardization to a single platform is notpossible, these data may provide insights and ex-pectations of relationships for various assays.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4requirements: (a) significant contributions to the conceptionanddesign, acquisition of data, or analysis and interpretationof data; (b) draftingor revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects ofthearticle thus ensuring thatquestions related to theaccuracyor integrity of anypart of thearticle areappropriately investigatedand resolved.

Authors’ Disclosures or Potential Conflicts of Interest:Uponmanuscript submission, all authors completed the author disclosureform. Employment or Leadership: E. Jacobs, T.I. Koshy, K. Kupfer, Y. Li, Alere. Consultant or Advisory Role: R.H. Christenson,Roche Diagnostics, Seimens Healthcare Diagnostics, and Becton Dickinson; D. Uettwiller-Geiger, K. Lewandrowski, T.I. Koshy,Alere. StockOwnership: T.I. Koshy, Alere.Honoraria:R.H. Christenson, RocheDiagnostics; T.I. Koshy, Alere. Research Funding:R.H. Christenson, T.I. Koshy, J.C. Wesenberg, Alere. Expert Testimony: None declared. Patents: None declared.Other Remu-neration: R.H. Christenson, Roche Diagnostics and Siemens Healthcare Diagnostics.

Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review andinterpretation of data, or preparation or approval of manuscript.

Acknowledgments:We thank Alere for financial support of this study. The authors also gratefully acknowledge Dr. Robert Birkahnand Paris Datillo, New York Methodist Hospital, for the enrollment of subjects and specimen collection and handling for this study.


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comparison of 13 commercially available cardiac...

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