ORIGINAL ARTICLE

Meta-analysis: Fecal Calprotectin for Assessment of Inammatory

Bowel Disease Activity
Jin-Feng Lin, MD, Jin-Min Chen, MD, Jun-Hua Zuo, MD, Allen Yu, BS, Zhu-Jun Xiao, MD,
Fei-Hong Deng, MD, Biao Nie, MD, PhD, and Bo Jiang, MD, PhD

Background: Fecal calprotectin (FC) is a promising biomarker for diagnosis of inammatory bowel disease (IBD). However, the utility of FC for
assessment of IBD activity has yet to be clearly demonstrated. The aim of our study was to evaluate the diagnostic accuracy of FC for differentiating
between patients with active IBD and those in remission.

Methods: We systematically searched the databases Medline, Web of Science, Cochrane Library, and EMBASE for eligible studies from December
2013 or earlier that evaluated activity in ulcerative colitis (UC) and Crohns disease (CD). A hierarchical summary receiver operating characteristic model
was performed to calculate the area under the curve to evaluate the overall diagnostic accuracy. The sensitivities and specicities of each commonly
applied cutoff value were pooled using a random effects model.

Results: We included 13 studies (744 patients with UC and 727 with CD) in the nal analysis. The area under the curve values were 0.89 (95% condence

interval, 0.860.92), 0.93 (0.890.97), and 0.88 (0.830.93) in the IBD, UC, and CD groups, respectively. For the IBD group at a cutoff value of 50 mg/g, the
pooled sensitivity was 0.92 (0.900.94) and specicity 0.60 (0.520.67). For a cutoff value at 100 mg/g, the pooled sensitivity was 0.84 (0.800.88) and
specicity was 0.66 (0.590.73). For a cutoff value at 250 mg/g, the pooled sensitivity was 0.80 (0.760.84) and specicity was 0.82 (0.770.86).

Conclusions: The FC test is a reliable marker for assessing IBD disease activity and may have greater ability to evaluate disease activity in UC
than CD.
(Inamm Bowel Dis 2014;20:14071415)
Key Words: inammatory bowel disease, Crohns disease, ulcerative colitis, fecal calprotectin, diagnostic accuracy

he incidence and prevalence of both ulcerative colitis (UC)

and Crohns disease (CD) is increasing worldwide. UC and
CD, the major forms of idiopathic inammatory bowel disease
(IBD), are chronic inammatory disorders of the gastrointestinal
tract that have been empirically dened by clinical, pathological,
endoscopic, and radiological features. The courses of these diseases are characterized by episodes of are-ups alternating with
periods of remission.14 Determination of inammatory activity is
essential to tailoring therapy and predicting prognosis. Symptoms
of colonic inammation are clearly manifested but unspecic and
poorly correlate with mucosal inammation.57 Serum biomarkers
Received for publication March 13, 2014; Accepted March 24, 2014.
From the Guangdong Provincial Key Laboratory of Gastroenterology, Department
of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou,
China.
The authors have no conicts of interest to disclose.
J.-F. Lin and J.-M. Chen contributed equally to this work.
B. Nie and B. Jiang were co-corresponding authors of the article. Supported by
the NanFang Hospital Fund for Distinguished Young Scholars, Grant 2013JQ03.
Reprints: Biao Nie, MD, PhD and Bo Jiang, MD, PhD, Department of
Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhoudadaobei
1838, Guangzhou, Guangdong 510515, China (e-mail: niebiao2@163.com;
drjiang@163.com).
Copyright 2014 Crohns & Colitis Foundation of America, Inc.
DOI 10.1097/MIB.0000000000000057
Published online 30 June 2014.

Inamm Bowel Dis
Volume 20, Number 8, August 2014

such as C-reactive protein, erythrocyte sedimentation rate, and

leukocytes reect a summation of systemic host responses rather
than being specic for intestinal inammation.8 Endoscopy is
currently considered the gold standard for evaluation of mucosal
inammation, and a number of endoscopic scoring systems exist
to assess inammatory activity in UC and CD.9,10 However,
endoscopy is invasive, time consuming, expensive, and uncomfortable. Furthermore, an endoscopic approach carries risks of
complications.11 Both patients and clinicians alike would benet
from a simple, reliable, and readily available test that enables
them to recognize an imminent are for timely intensication of
treatment and better disease control.
Fecal calprotectin (FC), a 36-kDa calcium and zincbinding protein, represents 60% of the cytosolic protein in the
granulocytes.12 The amount of calprotectin in feces is therefore
proportional to the amount of neutrophil migration from the
inamed bowel wall to the mucosa.13 Additionally, the FC
concentration is stable for up to 7 days at room temperature
and resistant to degradation.14 Compared with conventional
serum markers, FC is a more promising marker for assessing
intestinal activity with endoscopy as a reference standard.
Although its utility has been extensively studied, its exact role
has yet to be quantied. In this meta-analysis, we aim to assess
the overall diagnostic accuracy of FC in assessing IBD inammatory activity.
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Lin et al

MATERIALS AND METHODS

Literature Search
We comprehensively and systematically searched the databases Medline, Web of Science, Cochrane Library, and EMBASE
for eligible studies from December 2013 or earlier that evaluated
activity in UC and CD. Language restrictions were not used. The
search strategy used the following terms: (1) calprotectin: calprotectin, leukocyte L1 antigen complex, calgranulin; (2) IBD:
inammatory bowel disease, IBD, ulcerative colitis, UC,
crohns disease, CD, colitis, enteritis, intestinal inammation. References and reviews of related literature were searched
manually.

Study Selection
Articles were rst screened by 2 independent reviewers
(J.-F.L. and J.-M.C.) based on the title and abstract. The full text
of a potentially eligible study was then assessed independently.
Disagreements were resolved by discussion. A study was included
if it met the inclusion criteria as follows: (1) the study evaluated
FC for monitoring IBD activity; (2) an endoscopic scoring system
was used as reference standard to assess inammatory activity; (3)
the study provided sufcient details to construct a 2-by-2 table.
Studies were excluded if conducted in pediatric patients with IBD.

Data Extraction
General information extracted from each study was as
follows: rst author, publication year, country, age range of study
subjects, inclusion and exclusion criteria, and number of IBD
subjects (subdivided into UC and CD). Clinical data included the
details of the FC test (FC assay method, cutoff value), details
regarding the reference standard, prevalence of endoscopy-positive
cases in the study population (pretest probability), and 2-by-2 tables
in the IBD, UC, and CD groups. When more than 1 cutoff value
was reported in a study, we extracted all of them and their
corresponding 2-by-2 tables. The microgram per gram unit was
used for FC concentrations, except in 2 studies.15,16 One study15
used a previous FC assay kit with which FC was measured in
micrograms per milliliter. We multiplied the data by a factor of
5, after conrming with the authors17 and the kit manufacturers
(Calpro AS, Oslo, Norway). The author of another study,16 who
was contacted through e-mail, claimed that the milligram per liter
unit used in their study was equal to that of microgram per gram
unit and that the sensitivity needed to be corrected from 79.2% to
76.6% due to a printing mistake. We also contacted corresponding
authors through e-mail if further information was necessary for
analysis.

recommended against using scales yielding a summary score

because the interpretation of the summary score was problematic
and potentially misleading.19 Two reviewers evaluated the checklist independently. Disagreements were resolved by consensus.

Patients Spectrum
If the study consecutively recruited the diagnosed patients
with IBD without signs of overt clinical relapse, we marked yes
for the item. If the study recruited a group of healthy controls or
a portion of patients with IBD with overt disease activity, we
marked no for the item. If there was insufcient information
available to make a judgment, we marked unclear.

Reference Standard
The studies using endoscopy evaluation as reference
standard were marked with yes. If the reference standard
involved clinical indices or others, we marked no for the item.
An unclear reference standard was marked unclear.

Appropriate Time Between Reference

Standard and Index Test
Collection of fecal samples shortly before the endoscopy
examination was ideal. We marked yes for the studies that
collected stool samples within 1 week before endoscopic examination. This time frame was acceptable because the inammatory
condition was unlikely to change within such a short period of
time. A delay of over 1 week was considered unacceptable, and
we marked no for the item. If information on timing of tests was
not provided, the item was marked unclear.

Quality Assessment
Study quality was assessed using the QUADAS (QUality
Assessment of studies of Diagnostic Accuracy included in
Systematic reviews) tool. Each item should be answered yes,
no, or unclear. We chose all of the 11 items and followed the
guidelines for scoring each of them included in the tool.18 We

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FIGURE 1. Flow chart of study selection.

Patients
(UC/
CD)
FC Assay

Test Results (Total/UC/CD)

Study

Country

Age (yr)

Total
IBD

Cutoff
(mg/g)

Sipponen et al29

Finland

1970

106

0/106

PhiCal

Langhorst et al15

Germany

1570

85

42/43

ELISA

50
100
200a
30

1880

78

40/38

PhiCal

Schoepfer et al27

Switzerland

1879

134

134/0

PhiCal

50a

Schoepfer et al28

Switzerland

1885

140

0/140

PhiCal

Finland

1869

126

0/126

PhiCal

The Netherlands

3064

126

39/87

PhiCal

Turkey

49.7 6 10.7

60

60/0

PhiCal

Spain

1885

146

146/0

ELISA

160

PhiCal

250a
50

ELISA

57a
100

ELISA
ELISA

250a
140
274

Vieira et al

af Bjokesten et al22
DHaens et al23

Onal et al16
Lobaton et al24

26

Schoepfer et al

Nancey et al25

Switzerland

France

www.ibdjournal.org |

31

Yamamoto et al
Lobaton et al32
Total IBD

Japan
Spain

1874

1879

32 6 1.6
3258

228

133

20
89
1471

228/0

55/78

0/20
0/89
744/727

100
50
70a
94a
100
250

99.5

CDEIS $ 3

Endoscopy-based
classication of
inammation . 0
Mayo endoscopic
score . 0/CDEIS
$3
Rachmilewitz
endoscopic activity
index $ 4
SES-CD $ 3
SES-CD $ 3
Mayo endoscopic
score . 0/SES-C
$2
Rachmilewitz index
$4
Mayo endoscopic
score . 0
Modied Baron
score $ 2
Rachmilewitz index
$ 3/SES-CD $ 3
Rutgeerts score $ 2
CDEIS $ 3

Prevalence of
Active
Disease (%)

TP

FP

FN

TN

64
57
49
60/27/33

20
11
3
21/14/7

6
13
21
0/0/0

16
25
33
4/1/3

71

49/22/27
39

6/4/2
1

11/5/6
5

19/11/8
33

56

93

10

24

74

86
101
101
87
83
51/22/29

4
11
7
6
6
8/0/8

14
13
13
16
20
28/9/19

30
15
19
17
17
39/8/31

63

23

23

50

93

12

17

24

75

70
160

18
8

8
14

50
46

76

158
68/35/33

5
34/9/25

16
5/0/5

49
26/11/15

55

59/32/27
7
36

12/3/9
3
11

14/3/11
3
1

48/17/31
7
41

50
42
66

66

81
82

1409

a
The cutoff value that showed the highest diagnostic accuracy in study of multiple cutoff values.
CDEIS, Crohns disease index of severity; ELISA, enzyme-linked immunosorbent assay produced by unknown company (no mention in article); FN, false negative; FP, false positive; Phical, a quantitative enzyme linked
immunosorbent assay produced by the Calprotectin Company; SES-CD, simple endoscopic score for Crohns disease; TN, ture negative; TP, ture positive.

Fecal Calprotectin for Assessment of IBD Activity

Brazil

240a
200

30

Reference Standard
(UC/CD)

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TABLE 1. Study Characteristics of Included Studies

Lin et al

Partial Verication
If all the study patients who received an FC test went on to
receive verication of their disease status using the endoscopic
evaluation, we marked yes for this item. If not, we marked it
with no. If this information was not reported by the study, we
marked it unclear.

Differential Verication
If the same type of endoscopy was performed in all patients
of a study to assess the inammation condition, we marked yes
for this item. If the choice of endoscopy varied between individuals in one study, we marked no for the item. If it was unclear
whether different reference standards were used, then the item
was marked unclear.

Index Test Incorporation

If the reference standard was independent of the index test,
then we marked yes for this item. In all the included studies in
our meta-analysis, the FC test and endoscopic evaluation were
independent of each other, so all of the items were marked with
yes.

Index Test Results Blinded/Reference

Standard Results Blinded
These 2 items were used to check whether a double-blinded
method was used in the study or not. If endoscopy performers were
blinded for the results of index test or the technicians of FC test
were blinded for the results of reference standard, then we marked
yes for the item. If blinding was not used or was unclear, we
marked no or unclear for the item, respectively.

Relevant Clinical Information

Because the result of FC assay was generated by an
objective measurement enzyme-linked immunosorbent assay,

FIGURE 2. Summary of the methodological assessment of the

included studies basing on the Cochrane handbook. +, low risk; 2,
high risk; ?, unclear.

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Inamm Bowel Dis
Volume 20, Number 8, August 2014

which was unaltered by clinical information, this item was

marked yes.

Uninterpretable Results Reported

In our study, because the number of results reported agreed
with that of patients recruited in the primary studies, this item was
marked yes.

Withdrawals Explained
A yes indicated that clear outcomes were reported for all
patients, including withdrawals and bad or missing results. A no
meant that some of the patients who entered the studies did not
complete the study and the withdrawals were not explained. If it
was unclear how many patients entered and hence whether there
were any withdrawals, this item was marked unclear.

Statistical Analysis
The standard methods were used in this meta-analysis as
recommended in the Cochrane handbook for systematic reviews
of diagnostic test accuracy.20 The pretest probability of active
disease, namely prevalence of active disease, was calculated
according to the formula: reference-positive subjects/total patients. For the data analysis, we estimated both hierarchical summary receiver operating characteristic (HSROC) curves at
different cutoff values and average operating points with each
commonly applied threshold value, as they may complement each
other in providing clinically useful summaries and powerful ways
of detecting effects. An HSROC curve with 95% condence
region and 95% prediction region was performed to examine
the interaction between sensitivity and specicity. Diagnostic
odds ratio (DOR) and the area under the HSROC curve (AUC)
were calculated to evaluate the diagnostic performance of FC over
the IBD group and UC and CD subgroups. The DOR was calculated using the following formula: (sensitivity/[1 2 sensitivity])/
([1 2 specicity]/specicity). A DOR of 1 indicates that the test
cannot discriminate between patients with active and inactive
IBD. A higher value indicates better test performance. AUC
equals 1 for a perfect test and 0.5 for a completely uninformative
test.20 Pooled sensitivity, specicity, and their corresponding 95%
condence intervals were calculated using a random effects model
at each threshold. The heterogeneity was detected by a chi-square
test or Q-statistic and Higgins I-squared statistic (I2). A P value of
less than 0.1 was considered statistically signicant heterogeneity
for the chi-square or Q-statistics. The percentage of I2 represented
the degree of heterogeneity. I2 percentages of 25%, 50%, and 75%
indicated a low, moderate, and high degree of heterogeneity,
respectively.21 The source of heterogeneity was explored using
threshold analysis, meta-regression, and sensitivity analysis.
Meta-regression covariate analysis included pretest probability,
blinded design, and sample size. Sensitivity analysis was undertaken to assess the impact of a high pretest probability (pretest
probability more than overall average pretest probability) and
small sample studies (sample sizes ,100). Publication bias was
assessed using Deeks test. P , 0.05 was considered to indicate

Inamm Bowel Dis
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Fecal Calprotectin for Assessment of IBD Activity

statistically signicant publication bias. We performed statistical

analysis on Meta-Disc (version 1.4 for Windows; XI Cochrane,
Colloquium, Barcelona, Spain) and Stata (version 12; Stata Corp.,
College Station, TX).

RESULTS
Characteristics and Quality of the
Included Studies
As Figure 1 shows, 603 articles are available after the
initial search. After reading the titles and abstracts and reviewing
the full texts, 13 publications15,16,2232 (1471 patients with IBD;
744 with UC and 727 with CD) were included in the nal analysis. Two studies33,34 were excluded because their patients overlapped with the included study conducted by Sipponen et al.29
The clinical characteristics of these studies are listed in Table 1.
All studies used a prospective study design and enrolled patients
with diagnosed IBD. Ten of the studies were conducted in Europe and the other 3 were in Brazil, Turkey, and Japan. Three
studies by Schoepfer et al2628 and 2 studies by Lobaton et al24,32
performed analysis using different cohorts (conrmed by details
of primary articles). In the 5 included studies,22,24,2729 endoscopies and FC tests were performed more than once in 1 patient
as independent samples. Yamamoto et al31 recruited patients
with postoperative quiescent CD, af Bjorkestenf et al22 recruited
patients with CD who received anti-TNF therapy and Onal
et al16 recruited a number of clinical remission patients with
UC for investigation. The rest of the 10 studies consecutively
recruited patients referred for endoscopy. All the reference
standards of included studies were based on endoscopy, including
the Mayo endoscopic activity index, Rachmilewitz endoscopic
activity index, Modied Baron Score, Endoscopy-based classication of inammation in UC disease evaluation, Crohns disease
index of severity, simple endoscopic score for Crohns disease,
Rutgeerts score, and endoscopy-based classication of inammation in CD. Figure 2 shows our opinions on each bias risk item for
the included studies.

Diagnostic Accuracy

FIGURE 3. The HSROC plot for the utility of FC assay in assessing IBD,
UC, and CD activity, with summary point, 95% condence region, and
95% prediction region. The condence region indicates the precision
with estimation, which consists of the most likely values of true summary sensitivity and specicity. The prediction region predicts the true
sensitivity and specicity of a future study. Individual study estimates
are represented as circles, with size proportional to study weight.
HSROC plot for IBD (A), HSROC plot for UC (B), HSROC plot for CD (C).

We chose the cutoff value that showed the highest diagnostic

accuracy from each study and extracted their corresponding 2-by-2
tables to construct the HSROC model for evaluating IBD disease
activity. The formula of diagnostic accuracy was ture positive +
ture negative/total patients, with the higher values indicating better
test performance. In Figure 3A, the HSROC curve of the IBD
group is near the upper left corner, the DOR and AUC were
22.72 (14.2436.25) and 0.89 (0.860.92), indicating a relatively
high overall level of accuracy. The HSROC model generated a summary point represented by a dot, surrounded by a 95% condence
region and a 95% prediction region. The sensitivity and specicity
of this point were 0.85 (0.820.87) and 0.81 (0.770.84). The
Cochrane Q values detecting heterogeneity across studies are presented in Table 2.
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Lin et al

TABLE 2. Different Groups

IBD
AUC (95% CI)
Summary sensitivity (95% CI)
Heterogeneitya (P, I2)
Summary specicity (95% CI)
Heterogeneitya (P, I2)
Patients

0.89
0.85
55.20
0.81
23.10

(0.860.92)
(0.820.87)
(0.0000, 78.3%)
(0.770.84)
(0.0269, 48.1%)
1471

UC
0.93
0.88
15.07
0.82
20.91

(0.890.97)
(0.850.91)
(0.0351, 53.5%)
(0.770.86)
(0.0039, 66.5%)
744

CD
0.88
0.81
35.53
0.81
14.26

(0.830.93)
(0.770.84)
(0.0000, 77.5%)
(0.760.86)
(0.0752, 43.9%)
727

a
Q-value.
AUC, area under the curve; CI, condence interval.

On the basis of the HSROC curve and pooled sensitivity

and specicity, positive likelihood ratio (PLR) and negative
likelihood ratio (NLR) were pooled and applied to estimate
posttest probability. The PLR and NLR were 3.92 (3.174.85)
and 0.20 (0.140.28), respectively, in the IBD group. As Figure 4
shows, active IBD is conrmed in 66% (n 972) of the total
included patients (n 1471). The use of the FC test changes the
posttest probability of IBD activity, allowing us to illustrate the
result in a more reasonable way: with a pretest probability of 66%,
a positive FC test result increases the probability of active IBD to
90% and the negative FC result decreases the probability of active
IBD to 26%. It is worth noting that the pretest probability of 66%

indicated that a relatively large proportion of recruited patients

with IBD were endoscopically active.
Of the 13 eligible studies, there were 8 studies evaluating
UC and 9 evaluating CD. HSROCs were constructed for both of
the diseases (Fig. 3B, C). The summary point of sensitivity, specicity, and AUC are also listed in Table 2. AUC of the UC group
were higher than those of the CD group. Overall results suggested
that the FC test appeared to have greater ability to evaluate disease
activity in UC than in CD.
The cutoff values for testing positive in the FC assay varied
between studies, ranging from 30 to 274 mg/g. Pooled sensitivity
and specicity were calculated at commonly applied thresholds (50,
100, and 250 mg/g). In 5 studies, the manufacturers recommended
value (50 mg/g, including 30 mg/g) was used to obtain the following values: pooled sensitivity of 0.92, specicity of 0.60, PLR of
2.33, and NLR of 0.13. In 5 studies, 100 mg/g (including 99.5 mg/
g) was used as an adjusted cutoff value, and the results were sensitivity 0.84, specicity 0.66, PLR 2.95, and NLR 0.23.
With cutoff values of 250 mg/g (including 200 and 274 mg/g) in 7
of the studies, the corresponding values were 0.80, 0.82, 4.17, and
0.22, respectively. The pooled estimates with 95% condence interval and their corresponding heterogeneity values are shown in
Table 3. As the cutoff value increases, sensitivity became lower
and specicity became higher.

Heterogeneity Analysis

FIGURE 4. Fagans nomogram for showing posttest probability of IBD

activity after FC-positive result (upper line) and FC-negative result
(lower line).

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Our results were heterogeneous. We rst explored heterogeneity through threshold analysis by nding the logarithm of truepositive rates of FC assay detection and the logarithm of falsepositive rates. We then performed a Spearmans correlation between
those 2 values. The coefcient was 0.113 (P 0.714), indicating that
the threshold effect difference was not statistically signicant. Secondly, a meta-regression model failed to demonstrate a statistically
signicant difference as well. Restricted by the number of available
studies, we did not determine a reference standard in the
meta-regression model. Lastly, sensitivity analysis showed that
the result of large sample studies was stable, with summary DORs
ranging from 22.72 to 22.75. In the low pretest probability (,66%)

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Fecal Calprotectin for Assessment of IBD Activity

TABLE 3. Different Cutoff Values

50 mg/g
Sensitivity (95% CI)
Heterogeneitya (P, I2)
Specicity (95% CI)
Heterogeneitya (P, I2)
PLR (95% CI)
Heterogeneitya (P, I2)
NLR (95% CI)
Heterogeneitya (P, I2)
Patients

0.92
11.72
0.60
42.19
2.33
71.9
0.13
5.17

(0.900.94)
(0.0195, 65.9%)
(0.520.67)
(0.0000, 90.5%)
(1.184.61)
(0.0000, 94.4%)
(0.090.19)
(0.2698, 22.7%)
693

100 mg/g
0.84
8.12
0.66
24.27
2.95
21.58
0.23
4.10

250 mg/g

(0.800.88)
(0.0873, 50.7%)
(0.590.73)
(0.0001, 83.5%)
(1.685.17)
(0.0002, 81.5%)
(0.180.29)
(0.3931, 2.4%)
559

0.80
32.09
0.82
14.29
4.17
7.98
0.22
26.62

(0.760.84)
(0.0000, 81.3%)
(0.770.86)
(0.0266, 58.0%)
(3.155.52)
(0.2399, 24.8%)
(0.140.35)
(0.0002, 77.5%)
763

a
Q-value.
CI, condence interval.

studies, there was variation with summary DORs ranging from

22.72 to 20.02. These data showed that prevalence of active disease
among the different study populations may have contributed to
overall heterogeneity.

Publication Bias
Although the funnel plot of publication bias showed some
asymmetry due to the limited number of studies (Fig. 5), the
Deeks test showed a statistically nonsignicant value (P
0.425), indicating no publication bias among the included studies.

DISCUSSION
FC is an indirect indicator of intestinal mucosa condition.
To date, 3 meta-analyses have shown that FC is useful for
discriminating IBD from other diseases17,35 and predicting relapse
of patients with IBD at remission.36 But IBD activity requires
timely assessment by conventional endoscopy to aid clinicians
in developing a personalized therapeutic regimen and predicting
outcomes to avoid complications and death resulting from IBD.
Furthermore, considering the complications and contraindications
of endoscopy, clinicians and patients need a simple noninvasive

FIGURE 5. Deeks funnel plot for evaluating publication bias. It shows the correlation between the lnDOR and the effective sample size. Individual
study estimates are represented as circles, with size proportional to study weight.
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Lin et al

test to evaluate disease activity. Therefore, the role of FC assay in

detecting IBD activity merits further evaluation. To our knowledge, this is the rst meta-analysis of assessment of IBD activity
using an FC assay.
Our meta-analysis showed a pooled DOR of 22.72 and
AUC of 0.89, indicating a relatively high level of overall accuracy
in discriminating active from inactive IBD. DOR summarizes test
accuracy in a single number, which makes it easy to use for metaanalysis, but it has little direct clinical relevance and can be
difcult to apply directly in clinical practice.37 Compared with
DOR, sensitivity and specicity may be more meaningful for
clinicians. As shown in Table 3, we summarized the pooled statistics of 3 commonly applied thresholds. Although those statistics
were objectively illustrated, the optimal cutoff value may be different depending on their use as either a triage tool or as the nal
assessment for active disease; clinicians should use those data
soundly according to the proper clinical scenario. We suggest
50 mg/g as a screening cutoff value for further endoscopy examination in clinical practice, with specicity of 60% and pooled
sensitivity of 92%, which is the highest sensitivity among the 3
commonly applied cutoff values. This suggestion will result in 8%
of endoscopy-positive patients being unable to receive timely
intensive treatment, but the numbers are acceptable when FC is
introduced as a screening test. However, 40% of endoscopynegative patients will undergo an unnecessary invasive procedure
when this low cutoff is used. Ultimately, when contemplating
escalating therapy if there is active disease, higher specicity will
be desired. According to our meta-analysis, we suggest the cutoff
value at 250 mg/g as a conrmed test to contemplate escalating
therapy with pooled sensitivity of 80% and specicity of 82%, the
highest specicity among the 3 commonly applied cutoff values.
Clinicians should be aware, however, that 18% of those without
active disease would be identied as false positives and receive
excessive treatment. Meanwhile, treatment will be delayed in 20%
of patients with active IBD.
In this meta-analysis, the result suggested that the diagnostic
performance of the FC assay in the UC group appeared to be
superior to that in the CD group. However, we cannot exclude that
in some patients with CD, some intestinal lesions of the
gastrointestinal tract were not reached by ileocolonoscopy. Patients
with high FC levels but apparently low ileocolonoscopy disease
activity may need further examination to assess the condition of the
upper gastrointestinal tract and/or small bowel. In addition, we
cannot exclude selection bias that may play a role here. Severe
disease activity in UC manifested by gross blood in the stools is
easier to recognize for both clinicians and patients than severe
disease activity in CD, which is subtle in presentation.
This meta-analysis successfully avoided the risk of partial
verication bias through excluding studies that did not apply an
endoscopy index as a reference standard. However, this metaanalysis has several limitations. First, the study was limited in part
by a large portion of patients with active IBD (overall pretest
probability, 66%) being enrolled in the primary studies because
most of the studies were conducted in tertiary centers. This

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Inamm Bowel Dis
Volume 20, Number 8, August 2014

spectrum bias limited the usage of FC test in primary cares with

a lower activity probability. Furthermore, some studies2527,29
might include a considerable proportion of patients with overt
clinical relapse and therefore have overestimated the accuracy
of the FC assay. More multicenter large sample studies and strict
patient access systems are required to precisely investigate the
diagnostic accuracy of the FC test. Second, although we used
endoscopic evaluation as reference standard, a consensus between
endoscopic scoring systems is still absent for both UC and CD.
The nonuniform endoscopic scoring systems may be the reason for
the heterogeneous data. Due to the limited number of available
studies, we did not perform meta-regression with respect to a reference standard. Third, we could not reach most of the corresponding
authors for further information about clinical characteristics of patients, hindering us from investigating sources of heterogeneity by
disease severity (e.g., mild, moderate, or severe disease) and disease
location (e.g., distal or proximal involvement).
During quality assessment, data extraction, and analysis
process, we encountered many obstacles, highlighting the methodological aws in the current studies. It is hoped that more
widespread multicenter large samples and implementation of the
Standards for the Reporting of Diagnostic Accuracy studies will
enable readers to directly extract desired information. These can
be emphasized as factors that should be considered and improved
in future studies in the area.
In conclusion, our results indicate that FC is a simple,
reliable, and readily available test to measure IBD activity,
appearing to have greater ability to evaluate disease activity in
UC than in CD.

ACKNOWLEDGMENTS
The authors would like to thank Dr. brahim Koral nal
(Department of Gastroenterology, Yuksek Ihtisas Teaching and
Research Hospital, Ankara, Turkey) for providing additional
information.

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