Journal

The Effectiveness of Noninvasive Biomarkers to Predict
Hepatitis B-Related Significant Fibrosis and Cirrhosis: A

Systematic Review and Meta-Analysis of Diagnostic Test
Accuracy
Xue-Ying Xu1, Hong Kong2, Rui-Xiang Song3, Yu-Han Zhai1, Xiao-Fei Wu1, Wen-Si Ai1, Hong-Bo Liu1*
1 School of Public Health, China Medical University, Shenyang, PR China, 2 Department of Clinical Laboratory, Shengjing Hospital of China Medical University, Shenyang,
PR China, 3 Department of Urinary Surgery, Changhai Hospital, Shanghai, PR China
Abstract
Noninvasive biomarkers have been developed to predict hepatitis B virus (HBV)-related fibrosis owing to the significant
limitations of liver biopsy. Those biomarkers were initially derived from evaluation of hepatitis C virus (HCV)-related fibrosis,
and their accuracy among HBV-infected patients was under constant debate. A systematic review was conducted on records
in PubMed, EMBASE and the Cochrane Library electronic databases, up until April 1st, 2013, in order to systematically assess
the effectiveness and accuracy of these biomarkers for predicting HBV-related fibrosis. The questionnaire for quality
assessment of diagnostic accuracy studies (QUADAS) was used. Out of 115 articles evaluated for eligibility, 79 studies
satisfied the pre-determined inclusion criteria for meta-analysis. Eventually, our final data set for the meta-analysis contained
30 studies. The areas under the SROC curve for APRI, FIB-4, and FibroTest of significant fibrosis were 0.77, 0.75, and 0.84,
respectively. For cirrhosis, the areas under the SROC curve for APRI, FIB-4 and FibroTest were 0.75, 0.87, and 0.90,
respectively. The heterogeneity of FIB-4 and FibroTest were not statistically significant. The heterogeneity of APRI for
detecting significant fibrosis was affected by median age (P = 0.0211), and for cirrhosis was affected by etiology (P = 0.0159).
Based on the analysis we claim that FibroTest has excellent diagnostic accuracy for identification of HBV-related significant
fibrosis and cirrhosis. FIB-4 has modest benefits and may be suitable for wider scope implementation.
Citation: Xu X-Y, Kong H, Song R-X, Zhai Y-H, Wu X-F, et al. (2014) The Effectiveness of Noninvasive Biomarkers to Predict Hepatitis B-Related Significant Fibrosis
and Cirrhosis: A Systematic Review and Meta-Analysis of Diagnostic Test Accuracy. PLOS ONE 9(6): e100182. doi:10.1371/journal.pone.0100182
Editor: Anand S. Mehta, Drexel University College of Medicine, United States of America
Received December 3, 2013; Accepted May 22, 2014; Published June 25, 2014
Copyright: 2014 Xu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This research was supported by a National Natural Science Foundation Grant in China (No. 71073176) awarded to H.B.L. The funders had no role in
study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* Email: [email protected]
realize the importance of prediction of liver fibrosis by noninvasive

biomarkers.
Aspartate aminotransferase-to-platelet ratio index (APRI), the
fibrosis index based on the 4 factors (FIB-4) and FibroTest are
examples of noninvise biomarkers predicting liver fibrosis based on
routinely available clinical parameters [7]. They were initially used
in Western populations with hepatitis C virus (HCV) or HCV/
human immunodeficiency virus (HIV) co-infection [8] and had
good performance. The area under the receiver operating
characteristic (AUROC) curve of FibroTest for detecting significant fibrosis peaked out at 0.85 [9], and the AUROC curve of
APRI and FIB-4 reached 0.80 [10] and 0.81 [11] respectively. For
detecting cirrhosis, FibroTest also has the best result, and its
AUROC curve topped out at 0.90 [12]. The AUROC curve of
APRI and FIB-4 are 0.83 [13] and 0.89 [14], respectively. These
three markers can be considered as good, even better
markers, according to the criteria of Deeks JJ [15]. Consequently,
the researchers were regularly conducting those markers to predict
significant fibrosis and cirrhosis among HBV-infected patients.
APRI was first used to predict significant fibrosis or cirrhosis in
patients with HBeAg-negative chronic hepatitis B by Chrysanthos
et al. [16]. They found APRI was strongly correlated to the
Introduction
Chronic infection with hepatitis B virus (HBV) is an important
global health problem. Approximately 350 million people are
chronically infected with hepatitis B virus worldwide, especially in
developing countries, 25% of whom will die from long term
sequelae, such as cirrhosis, liver failure and hepatocellular
carcinoma, resulting in 600,000 to one million deaths annually
[1]. Patients who are suffering from significant hepatic inflammation and fibrosis are at high risk of those complications [2].
Assessment of liver significant fibrosis is critical to establishing
effective clinical practice. It could be of great help for a doctor to
determine patients suitability and the optimal time for antiviral
therapy to achieve the best curative effects as well as to prevent
excessive medication [3]. In addition, early prediction of cirrhosis
is beneficial to reducing complications in patients with chronic
viral hepatitis [4].
Liver biopsy, an invasive technique, is the gold standard for the
assessment of fibrosis. It has several disadvantages, such as
patients reluctance, pain, hemoperitoneum, and pneumothorax,
etc. [5]. In addition, its accuracy in assessing fibrosis is
questionable because of sampling errors and intra- and interobserver variations [6]. Therefore, many people are beginning to
PLOS ONE | www.plosone.org
June 2014 | Volume 9 | Issue 6 | e100182
The Effectiveness of Noninvasive Biomarkers
factors, FIB-4, FibroTest, hepatitis B virus, HBV, Chronic

hepatitis B, CHB, fibrosis and cirrhosis (see Text S2 for full
search strategies). Additional studies were identified via a manual
search for the referenced studies and review articles. EndNote X5
software was used to manage the references.
fibrosis. Later FIB-4 and FibroTest were successively used to

predict HBV-related fibrosis.
However, due to the fact that those markers were initially
derived from evaluation of HCV-related fibrosis, their accuracy
for HBV patients was under constant debate among the
researchers. Some scholars indicated that all of those noninvasive
markers were able to predict significant fibrosis or cirrhosis among
HBV patients, and could potentially be used to decrease the
number of liver biopsies [7]. Others maintained that those markers
were not directly applicable to evaluation of HBV-related fibrosis
because of the small AUROC curve [17]. Therefore, we decided
to conduct this meta-analysis to assess the pooled performance of
these biomarkers for prediction of significant fibrosis and cirrhosis
among HBV-infected patients. It could provide the basis for future
research and clinical application.
Selection Criteria
Studies were included if they met the following inclusion
criteria: (a) The study evaluated the performance of the APRI
and/or FIB-4 and/or FibroTest for the prediction of fibrosis and/
or cirrhosis in HBV infected patients. Studies on patients with
other etiologies of liver disease were also included if data for HBVinfected patients could be independently extracted. In addition,
special populations of HBV patients (e.g., HBV/HIV coinfection,
HBV/HCV, and HBV/ hepatitis D virus [HDV]) were also
included. (b) Liver biopsy was used to diagnose liver fibrosis as a
golden standard. (c) Data could be extracted to construct at least
one 262 table of test performance, based on some cutoff points of
the APRI, FIB-4, and FibroTest for a fibrosis stage. (d) They
assessed the diagnostic accuracy for fibrosis stage F$2 or F$4
according to METAVIR or a comparable staging system. (e) The
study included at least 40 patients. Studies of smaller sample sizes
were excluded due to concerns on their applicability.
Methods
Literature Search
The review followed the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) guidelines
[18] (see Checklist S1 for PRISMA checklist). A protocol (see
Text S1) was developed and systematic methods were used to
identify relevant studies, assess study eligibility for inclusion, and
evaluate study quality. Online database search was completed on
PubMed, EMBASE and the Cochrane Library (01/2003-04/
2013) for terms including the following: aspartate aminotransferase-to-platelet ratio index, APRI, fibrosis index based on the 4
Data Extraction and Quality Assessment

Two reviewers (XYX and RXS) screened the downloaded titles
and abstracts against the inclusion criteria. Two reviewers (XYX
and HK) independently evaluated study eligibility, graded the
Figure 1. Flow diagram of article selection.

doi:10.1371/journal.pone.0100182.g001
factors, FIB-4, FibroTest, hepatitis B virus, HBV, Chronic

hepatitis B, CHB, fibrosis and cirrhosis (see Text S2 for full
search strategies). Additional studies were identified via a manual
search for the referenced studies and review articles. EndNote X5
software was used to manage the references.
fibrosis. Later FIB-4 and FibroTest were successively used to

predict HBV-related fibrosis.
However, due to the fact that those markers were initially
derived from evaluation of HCV-related fibrosis, their accuracy
for HBV patients was under constant debate among the
researchers. Some scholars indicated that all of those noninvasive
markers were able to predict significant fibrosis or cirrhosis among
HBV patients, and could potentially be used to decrease the
number of liver biopsies [7]. Others maintained that those markers
were not directly applicable to evaluation of HBV-related fibrosis
because of the small AUROC curve [17]. Therefore, we decided
to conduct this meta-analysis to assess the pooled performance of
these biomarkers for prediction of significant fibrosis and cirrhosis
among HBV-infected patients. It could provide the basis for future
research and clinical application.
Selection Criteria
Studies were included if they met the following inclusion
criteria: (a) The study evaluated the performance of the APRI
and/or FIB-4 and/or FibroTest for the prediction of fibrosis and/
or cirrhosis in HBV infected patients. Studies on patients with
other etiologies of liver disease were also included if data for HBVinfected patients could be independently extracted. In addition,
special populations of HBV patients (e.g., HBV/HIV coinfection,
HBV/HCV, and HBV/ hepatitis D virus [HDV]) were also
included. (b) Liver biopsy was used to diagnose liver fibrosis as a
golden standard. (c) Data could be extracted to construct at least
one 262 table of test performance, based on some cutoff points of
the APRI, FIB-4, and FibroTest for a fibrosis stage. (d) They
assessed the diagnostic accuracy for fibrosis stage F$2 or F$4
according to METAVIR or a comparable staging system. (e) The
study included at least 40 patients. Studies of smaller sample sizes
were excluded due to concerns on their applicability.
Methods
Literature Search
The review followed the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) guidelines
[18] (see Checklist S1 for PRISMA checklist). A protocol (see
Text S1) was developed and systematic methods were used to
identify relevant studies, assess study eligibility for inclusion, and
evaluate study quality. Online database search was completed on
PubMed, EMBASE and the Cochrane Library (01/2003-04/
2013) for terms including the following: aspartate aminotransferase-to-platelet ratio index, APRI, fibrosis index based on the 4
Data Extraction and Quality Assessment

Two reviewers (XYX and RXS) screened the downloaded titles
and abstracts against the inclusion criteria. Two reviewers (XYX
and HK) independently evaluated study eligibility, graded the
Figure 1. Flow diagram of article selection.

Basar, 2013, Turkey
Wang, 2012, China
Liu, 2011, china
Sebastiani, 2011, Italy
Sebastiani, 2007, Italy
Bonnard, 2010, France
APRI/FIB-4
APRI/FIB-4
APRI/FT
APRI/FT
APRI/FIB-4/
FibroTest
Prospective, one center
Retrospective, one center
Retrospective, multicenter
Retrospective, multicenter
Retrospective, 2 centers
Cohort, multicenter
Prospective, 2 centers
Study/Center
Description
59
110
253
623
349
76
58
73
231
78
175
114
237
170
100
330
48
194
108
59
209
212
668
117
250
444
205
346
264
48
146
Same time
Same time
Same time
,1 week
Same time
Same time
Unclear
Same time
Same time
Unclear
,7 days
Same time
Same time
Same time
Same time
Same time
,6 months
Same time
,6 months
Unclear
,6 months
Unclear
,2 days
Unclear
Unclear
,1 week
Same time
Same time
Unclear
Unclear
Same time
Interval Between
Biopsy&Predictive index
35(69%)
43(73%)
44(73%)
32(55%)
37(92%)
45(45%)
41(57%)
45(64%)
34(68%)
33(85%)
37(78%)
38(80%)
32(67%)
45(60%)
35(78%)
44(61%)
37(73%)
47(61%)
42(90%)
43(84%)
39(70%)
31(88%)
39(66%)
41(54%)
39(58%)
30(71%)
51(75%)
34(90%)
28(87%)
56(83%)
35(84%)
Mean Age
(%male)
METAVIR
METAVIR
Scheuer
Batts Ludwing
METAVIR
Ishak
Scheuer
Ishak
Batts Ludwing
METAVIR
METAVIR
Scheuer
Liver biopsy
System
HBV
HBV
HBV+HDV
HBV
HBV(eAg-)
HBV
HBV
HBV
HBV
HBV
HBV
HBV
HBV
HBV
HBV
HBV
HBV
HBV
METAVIR
METAVIR
METAVIR
METAVIR
Scheuer
METAVIR
Ishak
METAVIR
Scheuer
METAVIR
METAVIR
China hospital
Ishak
Batts Ludwing
Ishak
Batts Ludwing
METAVIR
Batts Ludwing
HBV+HIV/HDV METAVIR
HBV+HIV
HBV+HDV
HBV
HBV
HBV
HBV
HBV
HBV(eAg-)
HBV
HBV
HBV
HBV
Etiology
2166 mm
$15 mm
Unclear
$10 mm
$10 mm
$10 mm
$20 mm
Unclear
$15 mm
18.263.4 mm
.15 mm
1520 mm
1520 mm
$20 mm
$15 mm
$20 mm
$20 mm
$20 mm
17.067.3 mm
58%$15 mm
Unclear
20 mm
$15 mm
$15 mm
Unclear
.10 mm
$15 mm
Unclear
22 mm
Unclear
.15 mm
length of liver
specimen
70%,24%
68%,20%
58%,8%
35%,6%
60%,7%
67%,17%
17%,NA
56%,11%
29%,7%
41%,12%
45%,17%
51%,11%
32%,2%
71%,28%
39%,12%
80%,24%
46%,10%
85%,39%
56%,15%
61%,20%
29%,9%
76%,21%
79%,34%
62%,3%
26%,16%
29%,6%
60%,27%
75%,23%
53%,3%
NA,38%
58%,10%
Prevalence
F2-4/F4
14
12
13
14
13
14
13
14
14
13
14
14
13
12
14
13
12
14
10
14
14
11
12
13
11
14
12
13
13
12
13
QUADAS
Score
APRI, aspartate aminotransferase-to-platelet ratio index; FIB-4, fibrosis index based on the 4 factors; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; QUADAS, The quality assessment of diagnostic accuracy
studies.
doi:10.1371/journal.pone.0100182.t001
Gumusay, 2011, Turkek
Wu, 2010, China
APRI/FIB-4
APRI/FIB-4
Zhu, 2011, China
APRI/FIB-4
APRI/FIB-4
Liu, 2012, China
APRI/FIB-4
Ucar, 2013, Turkey
Seto, 2011, China
APRI/FIB-4
APRI/FIB-4
Kim, 2012, Korea
FibroTest
Wang, 2012, China
Gui, 2008, China
APRI/FIB-4
Park, 2013, Korea
FibroTest
FibroTest
Myers, 2003, France
FIB-4
FibroTest
Zhang, 2010, China
FIB-4
Stibbe, 2011, The

Netherlands
Kim, 2009, Korea
APRI
Kim, 2012, Korea
Lesmana, 2011, Indonesia
APRI
FibroTest
Guzelbulut, 2011, Turkey
APRI
FibroTest
Liu, 2007, China
APRI
Miailhes, 2011, France
Chrysanthos, 2005, Greece
APRI
Bottero, 2009, France
Kim, 2007, Korea
APRI
FibroTest
Shin, 2008, Korea
APRI
FibroTest
Zhou, 2010, China
Lin, 2008, TaiWan
APRI
Author, Year, Regin
Test
Table 1. Characteristics of the 31 Studies Included in the Meta-analysis.
Figure 2. Meta-analysis of Hepatitis B-Related significant fibrosis. (A) SROC curve of the APRI; (B) Diagnostic odds ratio of the APRI.
Table 2. Diagnostic Accuracy of APRI for the Prediction of Significant Fibrosis in Various Studies.
Author,Year
Cutoff
Sensitivity
Specificity
PPV
NPV
AUROC(95%CI)
Sebastiani, 2011
1.5
36%
98%
96%
53%
0.64(0.580.70)
Seto, 2011
0.5
89%
41%
42%
89%
0.71(0.630.80)
1.5
29%
88%
55%
72%
Bonnard, 2010
56%
50%
72%
33%
0.61(0.460.76)
Zhou, 2010
0.5
82%
38%
54%
71%
0.72
1.5
48%
86%
75%
66%
0.5
97%
34%
63%
91%
87%
66%
75%
82%
1.4
78%
83%
84%
77%
1.5
75%
83%
83%
74%
58%
89%
86%
65%
0.5
84%
35%
47%
76%
1.5
46%
80%
63%
68%
Wang, 2012
0.5
58%
79%
54%
82%
0.77(0.710.84)
Ucar, 2013
0.54
73%
59%
70%
63%
0.66
Chrysanthos, 2005
0.5
79%
35%
65%
53%
NA
1.5
33%
83%
75%
45%
Shin, 2008
Wu, 2010
0.86(0.820.91)
0.71(0.590.83)
Liu, 2007
0.4
72%
75%
54%
87%
0.77
Guzelbulut, 2011
0.5
87%
45%
36%
91%
0.78(0.720.84)
1.5
38%
91%
60%
81%
Lesmana, 2011
0.24
64%
70%
78%
54%
0.69(0.600.79)
Gumusay, 2011
0.7
70%
87%
54%
93%
0.82
Basar, 2013
0.43
62%
68%
80%
47%
0.67(0.550.79)
Wang, 2012
0.5
53%
86%
86%
56%
0.78
1.5
22%
98%
95%
46%
Liu, 2011
0.3
69%
71%
56%
82%
0.76(0.730.8)
Sebastiani, 2007
0.5
70%
85%
91%
58%
0.72(0.580.86)
1.5
26%
94%
91%
38%
APRI, aspartate aminotransferase-to-platelet ratio index; AUROC, area under the receiver operating characteristic; PPV, positive predictive value; NPV, negative predictive
value; 95%CI, 95% confidence interval.
study quality, and extracted data from the study. Any disagreements between the reviewers were resolved with detailed
discussions between them together with a third reviewer (HBL).
The parameters in our literature search included author, year of
publication, region, method, patient gender, age, number of
patients, underlying chronic liver disease etiology, histological
scoring system, average length of liver specimen, time interval
between biopsy and laboratory tests, prevalence of the fibrosis
stage, as well as cutoff values to identify the fibrosis stage [13].
The quality of included studies was independently appraised by
two reviewers (XYX and YHZ) using the quality assessment of
diagnostic accuracy studies (QUADAS) questionnaire [19] (see
Text S3). It could estimate the internal and external validity of
diagnostic accuracy studies used in systematic reviews.
F6. This gauge was chosen because significant fibrosis is often

considered a threshold for the initiation of antiviral therapy [24].
We also assessed cirrhosis (METAVIR, Batts and Ludwig, and
Scheuer F4, and Ishak F5-6). In order to provide clinically
meaningful results, the metrics of diagnostic test accuracy were
examined.
The SROC curve, generated using linear regression, represents
the relationship between the true positive rate and false positive
rate across these studies, albeit they may have used different test
thresholds [25]. In this analysis, the area under SROC curve was
examined according to Moses et al. [26], and each study was
weighted with its sample size and with adjustment for the number
of thresholds within each study [27].
The diagnostic odds ratio (DOR) describes the odds of a positive
test in true disease cases compared with cases of no disease [15].
The summary DOR was calculated using a DerSimonian and
Laird random-effects model on a logarithmic scale with a
corresponding test of heterogeneity [28]. Because such analyses
require a single measure of accuracy for each study and many
studies reported multiple test thresholds, we calculate the average
DOR among all thresholds for a given study [29]. We also
calculated summary sensitivities and specificities using the
Statistical Analysis and Data Synthesis

We extracted and tabulated the data in a series of 262 tables,
which included sensitivity, specificity, positive predictive value
(PPV) and negative predictive value (NPV) at each threshold value.
The primary outcome was the identification of significant fibrosis,
defined by METAVIR [20], Batts and Ludwig [21], and Scheuer
[22] for stages F2 through F4, and Ishak [23] for stages F3 through
Figure 3. Meta-analysis of Hepatitis B-Related significant fibrosis. (A) SROC curve of the FIB-4; (B) Diagnostic odds ratio of the FIB-4.
Figure 4. Meta-analysis of Hepatitis B-Related significant fibrosis. (A) SROC curve of the FibroTest; (B) Diagnostic odds ratio of the FibroTest.
bivariate meta-analytic approach [30]. Pairs of sensitivity and

specificity for diagnostic thresholds are jointly analyzed, with any
correlation that might exist between those two measures taken into
account using a random-effects approach.
The heterogeneity (or the lack of homogeneity) of the results

between studies was assessed statistically using the Cochran-Q and
the quantity I2. I2 value describes the percentage of total variation
across studies that is attributable to heterogeneity rather than
Figure 5. Meta-analysis of Hepatitis B-Related cirrhosis. (A) SROC curve of the APRI; (B) Diagnostic odds ratio of the APRI.
chance [31]. A meta-regression was conducted to further explore

the covariates that may induce heterogeneity, according to the
following predefined characteristics: (a) study design (retrospective
or prospective); (b) etiology (HBV, HBV[HBeAg negative], or coinfection with other virus); (c) length of liver specimen ($10 mm,
$15 mm, $20 mm, or not); (d) liver biopsy scoring system
8
Table 3. Summary Sensitivities and Specificities of the APRI at Different Diagnostic Thresholds for the Prediction of Cirrhosis.
Test Threshold
Number of Studies
SROC
Summary Sensitivity(95%CI)
Summary Specificity(95%CI)
,1.0
5(1,228)
0.76
84% (79%88%)
54% (51%58%)
6(1,471)
0.76
62% (55%68%)
75% (72%77%)
6(1,409)
0.79
29% (23%35%)
89% (87%91%)
APRI, aspartate aminotransferase-to-platelet ratio index; 95%CI, 95% confidence interval.

liver biopsy scoring system used to classify the histology varied. Six
studies used a METAVIR score, three studies used a Scheuer
score, two studies used an Ishak score, one study used a Batts and
Ludwig score, and one study used the Chinese Hospital System.
Seven studies met all 14 requirements of the QUADAS scale, 4
studies met 13, 1 study met 12, and one study met 11.
There were 1,640 patients (median age 42 yr, 69% male) used
to assess the performance of FibroTest in eleven studies. The
overall prevalence of significant fibrosis and cirrhosis were 63%
(ranged 39%85%) and 20% (8%39%), respectively. Seven of
these studies (N = 1,011) included HBV-infected patients without
comorbid conditions [47,48,5458]. The four remaining studies
included special populations with HBV/HDV-coinfected patients
(N = 462) [49,51], HBV/HIV-coinfected patients (N = 59) [52],
and HBV/HDV/HIV-coinfected patients (N = 108) [53]. According to the Quality Assessment of Diagnostic Accuracy Studies
scale, we can see that 5 studies met all 14 requirements of this
scale, 2 study met 13, 3 studies met 12, and 1 study met 10.
(METAVIR, Ishak, Scheuer, Batts and Ludwig, and the Chinese

Hospital System); (e) QUADAS score; (f) sample size; (g) median
age (#30, 3140,4150, or .50); (h) percentage of males; (i)
location of study (Europe or Asia); (j) prevalence of significant
fibrosis/cirrhosis.
The potential publication bias was assessed using the Deeks
funnel plots (the logarithm of the DOR plotted against
p
1= ESS
) [32].
p
1= ESS
is proportional to the square root of (1/n1+1/n2), where n1 is the
number diseased and n2 not diseased. Data analyses were
performed using the Meta-Disc software (v. 1.4).
Results
Diagnostic Accuracy for the Prediction of Significant

Fibrosis
Search Results
In the seventeen studies assessing the APRI (N = 3,573), the

AUROC curve ranged from 0.61 to 0.86. When combined, the
area under the SROC curve was 0.77 08 (SE = 0.0172) (Figure 2A).
The Pooled DOR was 5.41 (95% confidence interval [CI] 3.98
7.35) (Figure 2B). The Cochran-Q and I2 value of all measures
were 38.32 and 58.2%, indicating significant heterogeneity across
the included studies (P = 0.001) (Figure 2B). The pooled sensitivities and specificities could not be assessed. Instead, the sensitivities
and specificities of the APRI at various diagnostic thresholds in the
seventeen studies are listed in Table 2. We used the metaregression analysis to explore the heterogeneity of the APRI
accuracy for detecting significant fibrosis, which was mainly
affected by median age (P = 0.0211, see Text S4 for metaregression). There was no significant correlation between other
covariates and the DOR.
In the ten studies assessing the FIB-4 for the prediction of
significant Fibrosis (N = 1,996), the AUROC curve ranged from
0.69 to 0.77. When combined, the area under the SROC curve
was 0.75 (SE = 0.0168) (Figure 3A). The summary DOR was 5.3
(95% CI 4.36.6), and the score of Cochran-Q is 7.54 (P = 0.581)
(Figure 3B). The result from the analysis of the heterogeneity was
statistically insignificant. The summary sensitivities and specificities of the FIB-4 were 65.8% (95% CI 62.4%69.1%) and 73.6%
(95% CI 70.8%76.3%), respectively (Figure S1S2).
The AUROC curve ranged from 0.69 to 0.90 in the 11 studies
assessing the FibroTest (N = 1.640). When combined, the area
under the SROC curve was 0.84 (SE = 0.0227) (Figure 4A). The
summary DOR was 13.73 (95% CI 8.6121.90), and the score of
Cochran-Q is 22.52, indicating significant heterogeneity across the
included studies (P = 0.0127) (Figure 4B). We didnt find the cause
of the heterogeneity of FibroTest accuracy according to the
The study selection process is presented with a flow chart in

Figure 1. 306 studies were retrieved with the described search
strategies, of which 196 were excluded following title and abstract
screening. The full texts of 110 potentially eligible reports were
obtained for further assessment. Of those, 30 papers were included
in the review following full-text screening (Table 1); 20 studies
were related to the APRI [3,16,17,33-49], 13 studies related to the
FIB-4 [3,7,17,3946,48,50], and 11 studies related to the
FibroTest [4749,5158].
Characteristics of the Included Studies

In the twenty APRI studies, a total of 4,208 patients (median
age 36 yr, 72% male) were included. The overall prevalence of
significant fibrosis and cirrhosis were 47% (ranged 17%70%) and
11% (7%27%), respectively. The liver biopsy scoring system used
to classify the histology varied. 10 studies used a METAVIR score,
4 studies used an Ishak score, 4 studies used a Scheuer score, 1
study used a Batts and Ludwig score, and 1 study used the Chinese
Hospital System. Nineteen of these studies (N = 3,955) included
HBV-infected patients without comorbid conditions [3,16,17,33
48]. The one remaining study included special populations of
patients such as HBV/HDV-coinfected patients (N = 253) [59].
According to the QUADAS scale, eight studies met all 14
requirements of this scale, nine studies met 13, two studies met 12,
and one study met 11.
A total of 2,953 patients (median age 36 yr, 70% male) were
included in the thirteen studies on FIB-4. The overall prevalence
of significant fibrosis and cirrhosis were 53% (ranged 17%76%)
and 15% (11%34%), respectively. All those studies (N = 2,953)
included HBV-infected patients without comorbid conditions. The
Figure 6. Meta-analysis of Hepatitis B-Related cirrhosis. (A) SROC curve of the FIB-4; (B) Diagnostic odds ratio of the FIB-4.
10
Figure 7. Meta-analysis of Hepatitis B-Related cirrhosis. (A) SROC curve of the FibroTest; (B) Diagnostic odds ratio of the FibroTest.
predefined characteristics. But center description might affect

heterogeneity beyond the predefined design (See Text S5).
Diagnostic Accuracy for the Prediction of Cirrhosis

There were 11 studies on assessing the APRI for the predication
of cirrhosis (N = 2,083). The AUROC curve of these studies
ranged from 0.50 to 0.83. When combined, the area under the
11
Table 4. Diagnostic Accuracy of FibroTest for the Prediction of Significant Fibrosis and Cirrhosis in Various Studies.
Author,Year
Cutoff
Sensitivity
Specificity
PPV
NPV
AUROC(95%CI)
Sebastiani, 2011
0.48
54%
83%
81%
57%
0.69(0.630.75)
Myers, 2003
0.2
89%
52%
43%
92%
0.78(0.740.82)
0.4
54%
80%
52%
81%
0.6
34%
93%
68%
78%
0.8
18%
99%
92%
75%
8%
100%
100%
73%
Miailhes, 2011
0.38
77%
85%
89%
72%
Bottero, 2009
0.48
70%
72%
77%
65%
0.77(0.680.86)
Bonnard, 2010
0.37
78%
78%
89%
61%
0.79(0.660.91)
Kim, 2012
0.32
79%
93%
98%
45%
0.90(0.840.97)
Stibbe, 2011
0.31
86%
69%
70%
86%
NA
Park, 2013
0.32
75%
77%
93%
43%
NA
Gui, 2008
0.31
79%
79%
70%
86%
0.84(0.750.93)
0.4
74%
92%
85%
85%
0.84(0.750.93)
0.72
28%
98%
92%
68%
0.84(0.750.93)
Kim, 2012
0.31
75%
96%
98%
61%
0.9(0.850.94)
Sebastiani, 2007
F2
80%
91%
95%
68%
0.85(0.750.95)
Sebastiani, 2011
0.75
42%
91%
51%
88%
0.68(0.630.73)
Miailhes, 2011
0.58
100%
81%
56%
100%
0.92(0.850.99)
Bottero, 2009
0.73
75%
85%
46%
95%
0.87(0.790.94)
Bonnard, 2010
0.5
86%
82%
60%
95%
0.85(0.740.96)
Kim, 2012
0.68
80%
92%
87%
87%
0.87(0.820.92)
Stibbe, 2011
0.75
100%
7%
11%
100%
NA
Gui, 2008
0.55
83%
84%
42%
97%
0.86(0.711.00)
Kim, 2012
0.67
91%
85%
85%
91%
0.88(0.830.94)
Sebastiani, 2007
F4
55%
97%
80%
89%
0.76(0.670.85)
Significant Fibrosis
0.86(0.750.96)
Cirrhosis
under the SROC curve was 0.87 (SE = 0.0307) (Figure 6A). The
summary DOR was 12.97 (95% CI 6.9124.35) and the score of
Cochran-Q is 10.01 (P = 0.07) (Figure 6B). The analysis showed
that the heterogeneity was statistically insignificant. The summary
sensitivities and specificities of the FIB-4 were 44.7% (95% CI
39.4%50.2%) and 86.6% (95% CI 84.3%88.7%), respectively
(Figures S7S8).
In the nine studies assessing the FibroTest (N = 1101), the
AUROC curve ranged from 0.68 to 0.92. When combined, the
area under the SROC curve was 0.90 (SE = 0.0250) (Figure 7A).
The summary DOR was 23.75 (95% CI 11.8847.48) and the
score of Cochran-Q is 20.25 (P = 0.0094) (Figure 7B). The
heterogeneity was statistically significant. The pooled sensitivities
and specificities could not be assessed. Instead, the sensitivities and
specificities of the FibroTest at various diagnostic thresholds in the
nine studies are listed in Table 4.
According to the meta-regression analysis, the heterogeneity of
FibroTest accuracy for detecting cirrhosis was mainly affected by
sample size (P = 0.0385) and median age (P = 0.0436) (Text S7),
whereas the other covariates were not significant.
SROC curve was 0.75 (SE = 0.0174) (Figure 5A). The summary
DOR was 4.4 (95% CI 2.96.8). The heterogeneity occurred in
the meta-analysis for the twelve studies assessing the APRI for the
predication of cirrhosis, which was statistically significant
(Q = 23.10, P = 0.01; I2 = 56.7%, Figure 5B). However, when we
further conducted the meta-analysis at the different thresholds of
,1.0, 1.0, and 2.0, we found that the heterogeneity wasnt
statistically significant (Figure S3). The summary sensitivity and
specificity of the APRI at different diagnostic thresholds are listed
in Table 3.
According to the meta-regression analysis, the heterogeneity of
APRI accuracy for detecting cirrhosis was mainly affected by
etiology (P = 0.0159) (See Text S6), whereas the other covariates
were not significant. After excluding the only one study which
included HBV/HDV-coinfected patients, the pooled DOR was
5.03 (95% CI 3.457.35) and heterogeneity was no longer
significant (Q = 14.05, P = 0.1204; I2 = 36.0%).(Figure S4) According to the meta-analysis, the pooled sensitivity and specificity were
60.9% (95% CI 55.066.6%) and 74.8% (72.477.1%), respectively (Figures S5S6).
The AUROC curve in the six studies assessing the FIB-4
(N = 1,304) ranged from 0.74 to 0.93. When combined, the area
12
Figure 8. Funnel plot of publication bias. (A) APRI to predict significant fibrosis; (B) FIB-4 to predict significant fibrosis; (C) FibroTest to predict
significant fibrosis; (D) APRI to predict cirrhosis; (E)FIB-4 to predict cirrhosis; (F) FibroTest to predict cirrhosis.
cirrhosis should be considered for antiviral therapy, which can

potentially reverse cirrhosis and reduce complications [60].
Considering the limitations and risks of biopsy, the researchers
make persistent efforts in exploring some noninvasive markers in
order to more accurately identify patients with significant fibrosis
or cirrhosis. APRI, FIB-4 and FibroTest are such noninvasive
markers gaining increasing acceptance in clinical practice. Those
markers may reduce the need for liver biopsy and may help to
monitor the efficacy of treatment [47].
In our systematic review, the diagnostic accuracy of the APRI,
FIB-4 and FibroTest for HBV-related significant fibrosis and
cirrhosis has been comprehensively evaluated and summarized on
Publication Bias
Funnel plots of these three markers for assessing possible
publication bias are illustrated in Figure 8. Mild asymmetry was
noted in the funnel plots of the FIB-4 and FibroTest.
Discussion
Liver fibrosis progression is commonly found in HBV-infected
patients. Cirrhosis develops in approximately one third of those
cases, usually after an extensive period of time during which liver
biochemical indices are found to be predominantly or even
persistently abnormal [1]. Patients with significant fibrosis or
13
widely noninvasive tool, was not considered in this meta-analysis,

because our focus was to compare the serum markers calculated
by biochemical examination.
In summary, the FibroTest has excellent diagnostic accuracy for
the identification of HBV-related significant fibrosis and cirrhosis.
But FibroTest is seldom applied in clinical practice as a result of
expensive cost. FIB-4, a relatively moderate marker, has better
summary diagnostic accuracy and could be measured and
calculated relatively easily. Furthermore, APRI shows some
limited value in identifying hepatitis B-related significant fibrosis
and cirrhosis. All of them have their own advantages and
disadvantages. Future studies of novel fibrosis markers are needed
to demonstrate improved accuracy and cost-effectiveness compared with those simple, economical, and widely available indeces.
a large scale, and we confirmed the results of many individual

studies. Our meta-analysis also included the description of multiple
measures of test performance using confirmed meta-analytic
techniques and formal assessment for publication bias and
heterogeneity, as well as exploratory analysis. All results should
be valid and reasonably reliable.
FibroTest had the best result in not only significant fibrosis but
also cirrhosis. The area under the SROC curve of FibroTest is
bigger and even reaches the standard of better on cirrhosis [15],
and the summary sensitivity and specificity have reached 84% and
82%, respectively. A meta-analysis about HCV-infected patients
showed that the area under the SROC curve of significant fibrosis
and cirrhosis are 0.81 and 0.90 [12]. Evidently, the performance of
FibroTest in evaluating HBV-related fibrosis is no worse than
HCV-related. Therefore, FibroTest could be considered as a
better marker in assessing fibrosis and cirrhosis of HBV-infected
patients. The FibroTest, however, is calculated with alpha2
macroglobulin, alpha2 globulin (or haptoglobin), gamma globulin,
apolipoprotein A1, GGT and total bilirubin [61]. Alpha2
macroglobulin and alpha2 globulin (or haptoglobin) are not
routine clinical measurements, and those two indicators are not
tested for patients in most hospitals. Furthermore they cost more
than conventional indicators. Those factors may bring restrictions
to the wider application of the FibroTest in clinical practice.
The calculation method of FIB-4 is simpler than that of
FibroTest. The area under the SROC curve of FIB-4 predicting
HBV-related significant fibrosis and cirrhosis are 0.75 and 0.87,
respectively. FIB-4 also has a better performance of predicting
fibrosis [7]. Its test items are easy to obtain in clinical practice,
although its predictive results are not as good as FibroTest [11,14].
APRI shows lower diagnostic accuracy than FibroTest and Fib-4
to identify HBV-related significant fibrosis and cirrhosis. It has
been introduced to assess HBV-related fibrosis the earliest because
of its simple and easy practice. Presently, APRI is widely utilized in
identifying the degree of fibrosis and cirrhosis of patients with
hepatitis C and hepatitis B, particularly in regions with limited
healthcare resources. Some scholars argue that the calculation
method of APRI did not consider the factor of spleen size [35]. If
patients were grouped by spleen size, the performance of APRI in
predicting HBV-related fibrosis would be improved. Our metaanalysis revealed that the area under the SROC curve of APRI
was small and the accuracy of the evaluation of HBV-related
fibrosis was poor. Our results showed similar performance of
APRI for staging of significant fibrosis and cirrhosis [62].
Meta-regression method was convenient and reliable to screen
the factors of heterogeneity. The strength of our study is that metaregression analysis has been used to explore several factors that
may be responsible for heterogeneity. Liver biopsy scoring systems
and percentage of males emerged from many relevant factors to
provide heterogeneity to summary test result on APRI to predict
significant fibrosis [62]. On the other hand, etiology of cirrhosis
was found to be significantly associated with the heterogeneity on
APRI to predict cirrhosis. But the heterogeneity of the metaanalysis of the FIB-4 and FibroTest to predict significant fibrosis
and cirrhosis was not statistically significant. FIB-4 and FibroTest
to predict fibrosis had better consistency, and summary test results
were reasonably reliable.
However, there are several limitations in our systematic review.
Firstly, we only focused our analysis on those patients with HBVrelated fibrosis, without distinguishing between HBeAg negative
and positive cases, or considering the virus replication rate due to
the limited number of publications. Secondly, we included studies
published in English and Chinese languages only, so the language
bias may influence the results to some extent. Lastly, Fibroscan, a
Supporting Information
Figure S1
Sensitivity of FIB-4 detecting significant
fibrosis.
(TIF)
Figure S2 Specificity of FIB-4 detecting significant
fibrosis.
(TIF)
Figure S3
DOR of APRI cirrhosis (subgroup).
(TIF)
Figure S4 DOR of APRI cirrhosis excluded patients with
HBV and HDV coinfected.
(TIF)
Figure S5 Sensitivity of APRI cirrhosis excluded patients with HBV and HDV coinfected.
(TIF)
Figure S6 Specificity of APRI cirrhosis excluded patients with HBV and HDV coinfected.
(TIF)
Figure S7
Sensitivity of Fib-4 detecting cirrhosis.
(TIF)
Figure S8
Specificity of Fib-4 detecting cirrhosis.
(TIF)
Checklist S1 PRISMA checklist of items.
(DOC)
Text S1 Systematic review protocol.
(DOC)
Text S2 Search strategies.
(DOC)
Text S3 Quadas checklist.
(DOC)
Text S4 Meta-regression of APRI detecting significant
fibrosis.
(DOC)
Text S5 Meta-regression of FibroTest detecting significant fibrosis.
(RTF)
Text S6 Meta-regression of APRI detecting cirrhosis.
(RTF)
Text S7 Meta-regression of FibroTest detecting cirrho-
sis.
(RTF)
14
XFW WSA. Data collection: XYX HK RXS YHZ. First draft of the
manuscript: XYX HBL.
Author Contributions
Conceived and designed the experiments: HBL XYX. Analyzed the data:
XYX WSA XFW HBL. Wrote the paper: HBL XYX HK RXS YHZ
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The Effectiveness of Noninvasive Biomarkers to Predict

Hepatitis B-Related Significant Fibrosis and Cirrhosis: A

realize the importance of prediction of liver fibrosis by noninvasive

June 2014 | Volume 9 | Issue 6 | e100182

The Effectiveness of Noninvasive Biomarkers

factors, FIB-4, FibroTest, hepatitis B virus, HBV, Chronic

fibrosis. Later FIB-4 and FibroTest were successively used to

Data Extraction and Quality Assessment

Figure 1. Flow diagram of article selection.

PLOS ONE | www.plosone.org

June 2014 | Volume 9 | Issue 6 | e100182

The Effectiveness of Noninvasive Biomarkers

factors, FIB-4, FibroTest, hepatitis B virus, HBV, Chronic

fibrosis. Later FIB-4 and FibroTest were successively used to

Data Extraction and Quality Assessment

Figure 1. Flow diagram of article selection.

PLOS ONE | www.plosone.org

June 2014 | Volume 9 | Issue 6 | e100182

PLOS ONE | www.plosone.org

Basar, 2013, Turkey

Wang, 2012, China

Liu, 2011, china

Sebastiani, 2011, Italy

Sebastiani, 2007, Italy

Bonnard, 2010, France

Prospective, one center

Retrospective, one center

Retrospective, one center

Retrospective, one center

Prospective, one center

Retrospective, one center

Retrospective, one center

Retrospective, one center

Retrospective, one center

Prospective, one center

Retrospective, one center

Retrospective, one center

Retrospective, one center

Retrospective, one center

Retrospective, one center

Retrospective, one center

Retrospective, one center

Retrospective, one center

Retrospective, one center

Retrospective, one center

Retrospective, one center

Retrospective, one center

Gumusay, 2011, Turkek

Wu, 2010, China

Zhu, 2011, China

Liu, 2012, China

Ucar, 2013, Turkey

Seto, 2011, China

Kim, 2012, Korea

Wang, 2012, China

Gui, 2008, China

Park, 2013, Korea

Myers, 2003, France

Zhang, 2010, China