Diagnostic Microbiology and Infectious Disease 88 (2017) 7–11

Contents lists available at ScienceDirect

Diagnostic Microbiology and Infectious Disease

journal homepage: www.elsevier.com/locate/diagmicrobio

Evaluation of the automated ADVIA centaur® XP syphilis assay for

serological testing
Sharon Saw ⁎, Huiqin Zhao, Phyllis Tan, Betty Saw, Sunil Sethi
Department of Laboratory Medicine, National University Hospital, National University Health System, Singapore

a r t i c l e i n f o a b s t r a c t

Article history: We evaluated the performance of the ADVIA Centaur XP Syphilis assay (Siemens Healthcare Diagnostics,
Received 30 September 2016 Tarrytown, NY, USA) using samples previously tested on the ARCHITECT i4000SR system (Abbott Diagnostics,
Received in revised form 1 February 2017 Lake Forest, IL, USA) and confirmed by the Treponema pallidum particle agglutination assay (TPPA) (SERODIA-
Accepted 15 February 2017
TPPA, Fujirebio Diagnostics Inc., Malvern, PA, USA). Clinical patient information was included to aid resolution
Available online 20 February 2017
of discordant samples where available. Precision, interference, and cross-reactivity were also assessed. Relative
Keywords:
to patient clinical status, the sensitivity of both the ADVIA Centaur XP and the ARCHITECT assays was 100%
Syphilis (95% CI, 93.9–100), and the specificity of the ADVIA Centaur XP assay was 95.5% (95% CI, 90.4–98.3), which
Treponema pallidum was slightly higher than that of the ARCHITECT assay at 93.9% (95% CI, 88.4–97.3). Overall agreement relative
Reverse testing algorithm to patient clinical status was 96.9% (95% CI, 93.3–98.8) for the ADVIA Centaur XP assay and 95.8% (95% CI,
Serology 91.9–98.2) for the ARCHITECT assay. Overall agreement between the two automated assays was 96.9% (95% CI,
93.3–98.8). ADVIA Centaur XP assay precision was b5% at all index values tested. No significant interference
was observed for lipemia or hemolysis; a small effect was seen with some samples for bilirubin. The assay
exhibited no significant cross-reactivity with a number of potential interfering factors. The ADVIA Centaur XP
Syphilis assay can be considered a sensitive and accurate assay for identification of treponemal antibodies in
screening populations as well as patients presenting with suspicion of syphilitic infection.
© 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction cultured using routine microbiological techniques. Treatment is avail-

Syphilis is a human disease of global importance with over 12 mil-
lion new infections every year, at least a million of them thought to
occur in pregnant women (Schmid, 2004; World Health Organization
(WHO), 2015). It is primarily a sexually transmitted disease caused by
the bacterium Treponema pallidum, subspecies pallidum. Infection is
classified into three main stages: primary, secondary, and latent. Left
untreated, approximately 30 percent of late-latent infections may pro-
ceed to tertiary disease, which is associated with significant morbidity
and mortality (Centers for Disease Control and Prevention NCfHA,
Viral Hepatitis, STD, and TB Prevention, Division of STD Prevention,
2013; Singh & Romanowski, 1999). Vertical transmission (mother to
child) represents a high risk to the developing embryo, commonly
resulting in either fetal demise or teratogenic defects (Centers for
Disease Control and Prevention NCfHA, Viral Hepatitis, STD, and TB
Prevention, Division of STD Prevention, 2012; Hawkes et al., 2011).
Laboratory analysis is often critical to a diagnosis of syphilis, as the
disease can mimic a range of clinical conditions and may sometimes
lack presenting signs or symptoms. The bacterial agent cannot be
⁎ Corresponding author. Tel.: +65-67725349; fax: +65-7751757.
E-mail address: Sharon_saw@nuhs.edu.sg (S. Saw).
able and efficacious (Workowski & Berman, 2010). Laboratory analysis
relies on two types of serological tests: treponemal and nontreponemal.
Nontreponemal tests such as the rapid plasma reagin (RPR) card test or
the Venereal Disease Research Laboratory (VDRL) test detect antibody
to lipoidal material such as cardiolipin released from the membranes
of damaged host cells and possibly the membrane of the treponeme it-
self (Larsen et al., 1995; Ratnam, 2005). Nontreponemal tests indicate
damage which may or may not be associated with syphilis. Treponemal
tests detect antibody to specific treponemal antigens associated with
the bacterial agent. Treponemal tests indicate infection (past or pres-
ent). Confirmation of syphilis typically requires the results of both
tests, indicating both exposure and active infection, though patients
with late-latent disease may convert to nonreactive with
nontreponemal assays (Ratnam, 2005), so medical history and risk
should always be considered.
Traditional testing typically involves screening with a nontreponemal
assay followed by confirmation with a treponemal test. In contrast,
reverse-sequence testing involves initial screening with a treponemal
assay. Because treponemal antibodies can persist for life (even with suc-
cessful treatment), nontreponemal tests aid assessment of current infec-
tion. Reverse sequence testing is becoming a common approach due to
advantages in both detection and workflow. In many countries, reverse

http://dx.doi.org/10.1016/j.diagmicrobio.2017.02.009
0732-8893/© 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
8 S. Saw et al. / Diagnostic Microbiology and Infectious Disease 88 (2017) 7–11

screening has become a guideline-recommended method (Janier et al.,
2014; Kingston et al., 2008; Public Health England, 2015).
Accuracy in reporting is critical to minimize the reporting of false-
positive results and to appropriately identify individuals likely to benefit
from treatment. Other factors that can affect assay performance include
interferences associated with hemolysis, icterus, and lipemia; and cross-
reactivity due to other disease states, including those resulting from
infection with other pathogens. Autoimmune issues may also lead to
false-positive as well as false-negative results. To assess any impact on re-
ported values caused by common interferences or cross-reactivity, sam-
ples were tested under a range of conditions using the ADVIA Centaur
XP Syphilis assay (Siemens Healthcare Diagnostics, Tarrytown, NY, USA).
2. Materials and methods
Archived patient or blood donor serum samples (n = 190) which
were previously tested on the ARCHITECT i4000SR (Abbott Diagnostics,
Lake Forest, IL, USA) platform and confirmed with TPPA (SERODIA-
TPPA, Fujirebio Diagnostics Inc., Malvern, PA, USA) were tested with
the ADVIA Centaur XP Syphilis assay. Sample selection of laboratory
samples was based on the initial screening results from ARCHITECT
and with confirmation with TPPA when initially reactive results were
obtained. Final adjudication of discordant samples was reviewed by a
clinician to establish syphilis infection. All samples were de-identified
to ensure confidentiality. Samples were stored for up to 6 months
at −20 °C and thawed immediately prior to analysis. All samples were
run on the ADVIA Centaur XP platform following the manufacturer's
instructions. For ARCHITECT the initial screening results were used for
the comparison.
The ADVIA Centaur XP Syphilis assay is a chemiluminometric, fully au-
tomated, antigen sandwich assay. The ancillary pack reagent, containing
acridinium-ester-labeled Treponema pallidum recombinant antigens
(TpN15, TpN17), are added to the sample and they bind Treponema
pallidium antibodies–if present in the sample. Subsequent addition of
biotinylated Treponema pallidum recombinant antigens, bound to
streptavidin-coated magnetic latex particles in the solid phase, capture
Treponema pallidium antibody–antigen complexes. There is a direct
relationship between the level of Treponema pallidum antibodies in the
sample and the amount of relative light units (RLUs) generated and
detected. Results are determined as reactive, nonreactive, or equivocal.
For the purpose of calculating sensitivity, specificity, and overall
agreement relative to patient syphilis status, the patient status was
inferred using these criteria:
Samples with reactive Centaur or Architect results were confirmed
with TPPA (n = 70). Clinical status was defined as: the Centaur or
Architect qualitative status if they are the same, or the TPPA result,
always followed up with a clinician.
1. Samples that were nonreactive according to all 3 treponemal assays
were considered clinical negatives.
2. For the discordant samples between the ADVIA Centaur XP assay and
the ARCHITECT assay or between one of these 2 assays and TPPA,
available patient clinical information was considered. Samples that
showed TPPA reactivity or subsequently repeat reactive TPPA or
samples from patients for whom the clinical information was highly
suggestive of infection were considered “positive” (see Table 1).
Samples that were not “positive” were considered as “negative”.
3. Samples for which all results were reactive according to all three
assays were considered “positive.”
Assay precision was assessed using 3 patient serum pools with index
values of 0.4, 1.2, and 10, respectively. These serum pools were analyzed
using within-day (n = 4) and between-day duplicates for 20 days.
Interference studies to determine the effect of hemolysis, icterus, or
triglycerides were evaluated using the three patient serum pools with
index values of 0.4, 1.2, and 10, respectively. Aliquots of the serum
pools were spiked with hemoglobin (118–553 mg/dL); lipemia
(896–2296 mg/dL) and bilirubin (5.9–40.1 mg/dL). Samples with and
without interferent were assayed and the difference in recovery report-
ed as a percentage of spiked/unspiked.
Samples known to be positive for analytes previously identified as
potential sources of cross-reactivity were tested. These include samples
for hepatitis B surface antibody or antigen, hepatitis C antibody HIV
antigen–antibody, measles IgG, mumps IgG, leptospira IgM, anti-
nuclear antibody, anti-ds-DNA antibody, anti-mitochondrial antibody,
anti–parietal cell antibody, anti–smooth muscle antibody, anti-
neutrophil cytoplasmic antibodies, anti–intrinsic factor antibody; and
with antenatal screening samples.
2.1. Statistical methods
For comparisons of either ADVIA Centaur XP or ARCHITECT with
clinical status, standard definitions are used. 95% Clopper–Pearson con-
fidence intervals are calculated using the Microsoft Excel spreadsheet
function BetaInv. It should be noted that because this is an archived
study, the observed study prevalence may not reflect the prevalence
in a target population.
3. Results
Out of the 190 samples tested in this study, the ADVIA Centaur XP
and ARCHITECT assays yielded congruent results for 185 samples: 126
nonreactive samples and 59 reactive samples. The overall agreement
between these two assays was 96.9% (95% CI, 93.3–98.8). Five samples
that yielded discordant results between ADVIA Centaur XP and

Table 1
Clinical assessment of samples with discordance between ADVIA Centaur XP, ARCHITECT and TPPA results.

Sample ADVIA Centaur ARCHITECT TPPA Clinical assessment

1 Nonreactive Reactive Nonreactive No clinical evidence of syphilis

2
3
4
5 Reactive Nonreactive Nonreactive No clinical evidence of syphilis
6 Reactive Reactive Indeterminate Positive: Antenatal screening. Subsequent TPPA repeatedly reactive
(likely too early for TPPA to detect at the first blood draw)
7 Positive: HSV reactive. TPPA subsequently reactive (likely too early for TPPA to detect at the first blood draw)
8 Reactive Reactive Nonreactive Positive: HIV+ with syphilis
9 Positive: Resolving vertical syphilis of newborn (titer might be too low to be detected by TPPA)
10 Reactive Reactive Indeterminate Negative: HBV carrier,#
11 Negative: Health screening, no signs of syphilis, likely false positive
12 Reactive Reactive Nonreactive Negative: Health screening, no signs of syphilis, likely false positive
13 Negative: Elderly patient, neurological investigation negative; no further review of syphilis, assumed false positive
14 Negative: End-stage renal disease. Follow-up screen with ARCHITECT assay clearly negative
#
No cross-reactivity or interference from hepatitis B was found in this study; however, there remains a possibility that it may cross-react in some patients.
 S. Saw et al. / Diagnostic Microbiology and Infectious Disease 88 (2017) 7–11 9

ARCHITECT were then compared to TPPA results; 4 of the 5 ADVIA Table 3

Centaur XP results and 1 of the 5 ARCHITECT results agreed with TPPA Precision of the ADVIA Centaur XP syphilis assay.

results and final clinical determination (Table 1).
Of the 59 samples that were reactive by both the ADVIA Centaur XP
and the ARCHITECT assays, TPPA was indeterminate (a specimen
showing (−) with unsensitized particles (1:40 final dilution) and
demonstrating (±) with sensitized particles (1:80 final dilution) is
interpreted as indeterminate) (n = 4) or nonreactive (n = 5) for 9 of
these samples (Table 1). Of the 4 samples that were TPPA indetermi-
nate, 2 (samples 6 and 7) were from patients subsequently diagnosed
with syphilis. Of the 5 TPPA-nonreactive samples, final clinical assess-
ment determined 2 to be true positives, with one sample from a patient
identified with syphilis with HIV coinfection, and the other sample asso-
ciated with a case of vertical transmission to a newborn (samples 8 and
9). The 3 remaining TPPA-nonreactive samples (samples 12–14) had no
evidence of syphilis.
Relative to patient clinical status, that is, clinical diagnosis extrapo-
lated from all serological results and patient history, the sensitivity of
both the ADVIA Centaur XP and the ARCHITECT assays was 100% (95%
CI, 93.9–100); the specificity of the ADVIA Centaur XP assay was 95.5%
(95% CI, 90.4–98.3), slightly higher than that of the ARCHITECT assay
at 93.9% (95% CI, 88.4–97.3). Overall agreement relative to patient clin-
ical status was 96.9% (95% CI, 93.3–98.8) for the ADVIA Centaur XP assay
vs. 95.8% (95% CI, 91.9–98.2) for the ARCHITECT assay (Table 2).
Precision of the ADVIA Centaur XP syphilis assay was evaluated
using patient serum pools with defined index values. The coefficients
of variation (CVs) relative to the mean values were assessed for both
within-day and between-day results (Table 3). Total imprecision was
b5.0% at all index values tested.
Table 4 lists results of the influence on ADVIA Centaur XP assay
values obtained with pooled samples in the presence of defined concen-
trations of triglycerides, hemoglobin, and bilirubin. Recoveries were cal-
culated using previously determined values.
Cross-reactivity was assessed using a range of clinical samples
representing both infectious and autoimmune etiologies. Samples
were tested using both the ADVIA Centaur XP and the ARCHITECT as-
says (Table 5). No significant cross-reactivity was observed for either
assay, and between-assay correlation was 100%.
4. Discussion
Advantages of newer treponemal assays on automated platforms in-
clude increased sensitivity, and thus improved detection, over both
manual treponemal (TPPA, FTA-ABS) and nontreponemal (RPR) assays.
In addition, automated assays provide non-subjective programmed re-
sults reporting. (Binnicker, 2012; Binnicker et al., 2012; Castro et al.,
2013) Questions have however been raised regarding the specificity of
treponemal assays when used in a reverse-sequence screening algo-
rithm (Centers for Disease Control & Prevention (CDC), 2008, 2011),
Within-run Between-run Total
Patient pool Mean index CV (%) CV (%) CV (%)
1 0.393 2.15 4.38 4.65
2 1.182 2.60 4.33 3.38
3 9.808 0.53 3.82 3.58
and agreement among treponemal assays can vary.(Binnicker et al.,
2011) In the present study, the 3 samples that were reactive by both
the ADVIA Centaur XP and the ARCHITECT assays but nonreactive by
TPPA(samples 12–14), from patients without evidence of clinical syph-
ilis, may represent false-positive screening results.
Confirmation may involve use of a second (and often manual) trep-
onemal assay with good specificity such as TPPA. When using an algo-
rithm involving a nontreponemal assay to confirm a reactive
treponemal result, discordant results also often require assessment
with an alternative treponemal assay. Use of a second immunoassay
versus TPPA is supported by studies showing good correlation to TPPA
(or to the Treponema pallidum hemagglutination assay [TPHA] or to
fluorescent treponemal antibody absorption [FTA-ABS]) (Binnicker
et al., 2011; Ebel et al., 1998). A recently published study that investigat-
ed three treponemal assays, including the ADVIA Centaur XP assay, also
noted excellent agreement and high specificity for the assays tested,
leading the authors to suggest that initially reactive treponemal screens
could be confirmed with a second treponemal immunoassay versus
TPPA (Donkers et al., 2014). Our data suggest a similarly good
correlation between the ADVIA Centaur XP and ARCHITECT assays
(though the ADVIA Centaur XP assay demonstrated slightly higher
specificity).The slightly lower specificity we observed for ARCHITECT
is consistent with recent comparative studies which also noted good
sensitivity but reduced relative specificity for the ARCHITECT syphilis
assay (Li et al., 2015; Malm et al., 2015). Specificity differences could
be associated with assay design, as the Siemens assay detects both
Tp15 and Tp17 antibodies while the ARCHITECT also detects Tp47 anti-
body. Studies suggest that detection of TpN47 antibody is not necessary
for sensitive and early detection (though the ability to detect Tp17 does
appear to be an important factor) (Malm et al., 2015; Marangoni et al.,
2013; Miranda & Sato, 2008). Our findings also support similar sensitiv-
ity between these assays, though analysis of the specific antibodies de-
tected was not included in this study.
Interfering factors represent a potential source of reporting error
with any immunoassay. Positive or negative bias could adversely impact
reporting accuracy, leading to possible patient mismanagement. No sig-
nificant interference was found for lipemia or hemolysis, consistent
with what was reported in the manufacturer's insert. (Anonymous,
2017) A small effect was seen with some samples for bilirubin, with
over-recovery of up to 111.9% in both negative and equivocal samples.

Table 2
Sensitivity and specificity of the ADVIA Centaur XP and ARCHITECT assays determined using clinical status and agreement

Syphilis study: method comparison results

Test method Centaur Architect Centaur Centaur Architect

Predicate method Clinical status Clinical status Architect TPPA TPPA

100.0 100.0 94.0 100.0 100.0

Sensitivity vs. clinical status or positive agreement of test method with predicate method
(93.9–100.0) (93.9–100.0) (85.4–98.3) (93.7–100.0) (93.7–100.0)
95.5 93.9 98.4 38.5 23.1
Specificity vs. clinical status or negative agreement of test method with predicate method
(90.4–98.3) (88.4–97.3) (94.3–99.8) (13.9–68.4) (5.0–53.8)
96.9 95.8 96.9 88.6 85.7
Apparent overall agreement
(93.3–98.8) (91.9–98.2) (93.3–98.8) (78.7–94.9) (75.3–92.9)
90.8 88.1 96.9 87.7 85.1
Apparent positive predictive value or positive agreement of predicate method with test method
(81.0–96.5) (77.8–94.7) (89.3–99.6) (77.2–94.5) (74.3–92.6)
100.0 100.0 96.8 100.0 100.0
Apparent negative predictive value or negative agreement of predicate method with test method
(97.1–100.0) (97.1–100.0) (92.1–99.1) (47.8–100.0) (29.2–100.0)

Note: Comparisons with TPPA (n = 70), and All Others (n = 190) sample pairs. Clopper-Pearson 95% confidence intervals in parentheses.
10 S. Saw et al. / Diagnostic Microbiology and Infectious Disease 88 (2017) 7–11

Table 4 the clinical picture for patients with discrepant findings. Importantly,
Cross-reactivity for the ADVIA Centaur XP assay in the presence of triglycerides, up to 40 percent of patients with latent, untreated infections (including
hemoglobin, and bilirubin. Unspiked samples are represented by (−); spiked samples
are represented by (+).
those in HIV patients) may become negative with nontreponemal tests,
(Larsen et al., 1995; Mishra et al., 2011; Singh et al., 2008) confounding
Triglyceride (mg/dL) (−) (+) Recovery perception of the need to treat and challenging clinical interpretation.
Index 0.4 2210 0.44 0.45 102.27% In summary, the Siemens ADVIA Centaur XP syphilis assay showed
Index 1.2 2259 1.22 1.22 100.00% excellent sensitivity and good specificity for detection of treponemal an-
Index 10.0 2296 10.22 10.18 99.61%
tibodies, and excellent precision with minimal cross-reactivity to poten-
Index 0.4 896 0.44 0.44 100.00%
Index 1.2 921 1.22 1.26 103.28% tial interferences. Though icterus interference may be associated with a
Index 10.0 906 10.22 10.340 101.17% modest increase in over-recovery, use of simultaneous indices measure-
ment could help ensure that no incorrect results are reported. The assay
Hemoglobin (mg/dL) (−) (+) Recovery
Index 0.4 553 0.39 0.37 94.87% demonstrated good correlation to the Abbott ARCHITECT syphilis assay
Index 1.2 517 1.16 1.10 94.83% but greater specificity relative to TPPA. This study supports the perfor-
Index 10.0 546 9.72 8.95 92.08% mance of the ADVIA Centaur XP syphilis assay for the routine evaluation
Index 0.4 274 0.39 0.38 97.44% of samples, including those with potential interfering factors.
Index 1.2 266 1.16 1.11 95.69%
Index 10.0 272 9.72 9.44 97.12%
Index 0.4 118 0.39 0.39 100.00% Acknowledgment
Index 1.2 119 1.16 1.14 98.28%
Index 10.0 118 9.72 9.58 98.56%
We thank Siemens for writing support, which in no way influenced
Bilirubin (mg/dL) (−) (+) Recovery our conclusions; and Paul Dillon, PhD, for statistical support. All reagents
Index 0.4 40.1 0.42 0.47 111.90% were provided by Siemens Healthcare Diagnostics for this study.
Index 1.2 39.8 1.21 1.34 110.74%
Index 10.0 38.3 10.08 10.97 108.83%
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