International Journal of Gynecology and Obstetrics 132 (2016) 259–265

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International Journal of Gynecology and Obstetrics

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

REVIEW ARTICLE

Systematic reviews and meta-analyses of the accuracy of HPV tests, visual

inspection with acetic acid, cytology, and colposcopy
Reem A. Mustafa a,b, Nancy Santesso b, Rasha Khatib b,c, Ahmad A. Mustafa d, Wojtek Wiercioch b, Rohan Kehar b,
Shreyas Gandhi b, Yaolong Chen e, Adrienne Cheung f, Jessica Hopkins b, Bin Ma e, Nancy Lloyd b, Darong Wu g,
Nathalie Broutet h, Holger J. Schünemann b,i,⁎
a
Departments of Internal Medicine/Nephrology and Biomedical and Health Informatics, University of Missouri-Kansas City, Kansas City, MO, USA
b
Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada
c
Population Health Research Institute, McMaster University, Hamilton, ON, Canada
d
Faculty of Medicine, University of Science and Technology, Irbid, Jordan
e
Evidence-Based Medicine Centre, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
f
Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
g
Department of Clinical Epidemiology, 2nd Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
h
Reproductive Health and Research, World Health Organization, Geneva, Switzerland
i
Department of Medicine, McMaster University, Hamilton, ON, Canada

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

Article history: Background: Cervical cancer screening is offered to women to identify and treat cervical intraepithelial neoplasia
Received 22 January 2015 (CIN). Objectives: To support WHO guidelines, a systematic review was performed to compare test accuracy of
Received in revised form 25 June 2015 the HPV test, cytology (cervical smear), and unaided visual inspection with acetic acid (VIA); and to determine
Accepted 2 November 2015 test accuracy of HPV and colposcopy impression. Search strategy: Medline and Embase were searched up to
September 2012, and experts were contacted for references. Selection criteria: Studies of at least 100 nonpregnant
Keywords:
women (aged ≥18 years) not previously diagnosed with CIN were included. Data collection and analysis: Two in-
Cervical intraepithelial neoplasia
Cervical smear
vestigators independently screened and collected data. Pooled sensitivity and specificity, and absolute differences
Colposcopy were calculated, and the quality of evidence assessed using GRADE (Grading of Recommendations Assessment,
Cytology Development and Evaluation). Main results: High to moderate quality evidence was found. The greatest difference
HPV in overtreatment occurred with VIA instead of the cervical smear (58 more per 1000 women). Differences in
Meta-analysis missed treatment ranged from 2–5 per 1000 women. For 1000 women screened positive and then sent to colpos-
Review copy, 464 would be falsely diagnosed with CIN grade 2–3 and treated. Conclusions: Although differences in sensi-
Visual inspection with acetic acid tivity between tests could be interpreted as large, absolute differences in missed diagnoses were small. By contrast,
small differences in specificity resulted in fairly large absolute differences in overtreatment.
© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction
Cervical cancer is the fourth most common cancer in women world-
wide and the most common cancer in many low- and middle-income
countries [1]. For this reason, screening is typically offered to women
to identify precursors that can be treated to avoid progression to cervi-
cal cancer. Common screening methods widely used today include tests
for HPV, and tests to detect cervical lesions by cytology (cervical smear)
or unaided visual inspection with acetic acid (VIA). These tests can be
used alone or in a sequence (e.g. HPV test followed by a cervical
smear when HPV positive).
⁎ Corresponding author at: Department of Clinical Epidemiology and Biostatistics,
Room 2C16, Health Sciences Centre, McMaster University, 1280 Main Street West,
Hamilton, ON L8S 4L8, Canada. Tel.: +1 905 525 9140x24931; fax: +1 905 522 9507.
E-mail address: schuneh@mcmaster.ca (H.J. Schünemann).
There has been much debate about which screening tests should be
recommended. Ideally, reviews of studies comparing complete screen-
ing, diagnosis, and treatment strategies would provide high-quality ev-
idence to support clinical decision making [2]. However, this type of
direct evidence assessing the effect of providing a test followed by treat-
ment is frequently lacking and, when available, it usually does not pro-
vide information about important patient outcomes for decision
making. Instead, different decision makers—clinicians, program man-
agers, policy makers, and patients—have to rely on test accuracy data
(e.g. sensitivity and specificity of tests) together with data about the
consequences of treatment to decide which screening tests to provide.
In 2012, WHO committed to developing recommendations for
screen-and-treat strategies to prevent cervical cancer and commis-
sioned a series of reviews to inform those recommendations [3]. Given
the lack of studies directly testing complete screen-and-treat strategies,

http://dx.doi.org/10.1016/j.ijgo.2015.07.024
0020-7292/© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
260 R.A. Mustafa et al. / International Journal of Gynecology and Obstetrics 132 (2016) 259–265
the literature was reviewed for the accuracy of screening tests to pro-
vide essential information for decision making. The present paper pre-
sents a series of systematic reviews of test accuracy comparing the
three test options for screening to prevent cervical cancer: the HPV
test, the cervical smear, and VIA. Because screening can also be provided
as a sequence of tests (e.g. HPV followed by colposcopy), reviews of the
accuracy of HPV and of colposcopy impression were also performed.
2. Materials and methods
The series of systematic reviews was conducted in the course of
1 year. A search was performed for both previously published systemat-
ic reviews and for primary studies to conduct de novo reviews. A
Cochrane protocol was found that compared the HPV test with cytology,
which had a search date up to July 2010 [4]; the search was updated to
November 2011. For screening strategies related to an HPV test com-
pared with VIA, and to VIA compared with cytology, the Medline and
Embase online databases were searched up to February 2012. A search
for colposcopy was then conducted up to September 2012.
The search strategies consisted of keywords specific to the database
and text words for the screening options and cervical intraepithelial neo-
plasia (CIN) (Supplementary Material S1) without restrictions by study
design or language. Reference lists of relevant studies were also reviewed
and clinical experts in the specialty (e.g. members of the WHO Guideline
Development Group panel for the Recommendations on Treatment and
Screen and Treat Strategies for Cervical Cancer Prevention [3]) contacted
for additional references.
Two investigators independently screened titles, abstracts, and the
full text of relevant articles. A third investigator resolved disagreements.
Inclusion and exclusion criteria were defined a priori. Prospective or
cross-sectional observational studies that assessed and compared the
test accuracy of at least two screening tests in the same group of
women were included. Given that smaller studies of test accuracy
could result in increased imprecision and risk of bias, studies with a
minimum of 100 women were included [5]. Studies had to include non-
pregnant women aged 18 years or older who had not been previously
diagnosed with or treated for CIN, and women could have a positive,
negative, or unknown HIV status. The studies also had to be at low
risk of bias: all women who tested positive or negative (or a random
sample of at least 10% of the women who tested negative) had to receive
the reference standard. An acceptable reference standard for the tests
was colposcopy with or without biopsy when indicated, and the disease
threshold was CIN grade 2–3.
Two investigators independently collected data for patients’ charac-
teristics, diagnosis, setting, follow-up, and test accuracy results using a
pretested data abstraction form. The quality/risk of bias was assessed
for each study using the QUADAS tool (QUality Assessment for Diagnos-
tic Accuracy Studies) [6]. Data were pooled using Stata version 12
(StataCorp, College Station, TX, USA). A paired analysis was conducted
by pooling sensitivity and specificity for each of the test comparisons
using a hierarchical model. Specifically, HPV was compared with VIA,
VIA with cervical smear, and HPV with cervical smear; and the test accu-
racies of HPV and colposcopy impression were determined. Forest plots
and hierarchical summary receiver-operator curves were created for
each comparison. For the cervical smear, atypical squamous cells of un-
determined significance were used as the cutoff because the guideline
panel considered this cutoff as the least variable among cytologists’
reading and required the least quality assurance and continuous train-
ing. Moderate to high heterogeneity (I2 N 50%) would be explored. Sub-
group analyses for HIV status and age were planned, but studies did not
report data separately for these subgroups.
Two investigators evaluated the quality of the evidence for each out-
come, including true positives (TPs), false positives (FPs), true negatives
(TNs), and false negatives (FNs), using the GRADE (Grading of Recom-
mendations Assessment, Development and Evaluation) approach, and
a third investigator helped to resolve any discrepancies [7]. The quality
of the evidence/confidence in the effect estimates of each outcome
were assessed as high, moderate, low, or very low. To better illustrate
the impact of the sensitivity and specificity, absolute differences in ef-
fects were calculated for each comparison as TPs, TNs, FPs, and FNs.
These effects were calculated for a population with a 2% prevalence of
CIN, and with a 20% prevalence for colposcopy impression because
women would receive colposcopy impression after a positive screening
test. These effects and quality of evidence are presented in GRADE
Evidence profiles.
3. Results
3.1. Search results
Among 3146 nonduplicate records (1925 for colposcopy and 1221 for
the other screening tests) identified from the electronic database search
and from other sources, 397 articles in full text were retrieved after title
and abstract screening (Fig. 1). After exclusion of articles that were not
relevant, 32 studies were included. Of those, 18 were conducted in low-
and middle-income countries, and most studies were of women aged
25–65 years of unknown HIV status. The overall risk of bias for each of
the comparisons was deemed not serious. However, many studies only
performed one biopsy of an abnormal lesion as a reference standard;
most studies did not report the uninterpretable results and withdrawals;
and it was unclear in most studies whether the results of the tests were
interpreted without knowledge of the results of the reference standard.
A summary of the test accuracy is presented below along with the
GRADE Evidence profiles; forest plots and hierarchical summary
receiver-operator curves are provided in Supplementary Material S2.
3.2. HPV test compared with VIA
The sensitivity and specificity estimates for HPV and VIA were pooled
from five studies, with a total number of participants of 8921 [8–12].
Fig. 2 shows a summary of the findings for this comparison. Sensitivity
estimates for HPV ranged from 0.64 to 0.97, and the sensitivity estimates
for VIA ranged from 0.41 to 0.87. Specificity estimates for HPV ranged
from 0.56 to 0.93, whereas specificity estimates for VIA ranged from
0.76 to 0.95. The pooled estimates for HPV sensitivity and specificity
were 0.95 (95% confidence interval [CI] 0.84–0.98) and 0.84 (95% CI
0.72–0.91), respectively. The pooled estimates for VIA sensitivity and
specificity were 0.69 (95% CI 0.54–0.81) and 0.87 (95% CI 0.79–0.92), re-
spectively. The quality of evidence for TP and FN was high, but moderate
for TN and FP because of inconsistency across the studies and impreci-
sion resulting in wide CIs.
3.3. VIA compared with cervical smear
Test accuracy data for VIA and cervical smears were pooled from 11
studies, with a total of 12 089 participants [8–10,12–19]. Fig. 3 shows a
summary of the findings for this comparison. Sensitivity estimates for
VIA ranged from 0.17 to 1.00, and the sensitivity estimates for cervical
smears ranged from 0.33 to 1.00. Specificity estimates for VIA ranged
from 0.08 to 0.95, whereas specificity estimates for cervical smears
ranged from 0.60 to 0.97. The pooled estimates for VIA sensitivity and
specificity were 0.77 (95% CI 0.66–0.85) and 0.82 (95% CI 0.67–0.91), re-
spectively. The pooled estimates for cervical smear sensitivity and spec-
ificity were 0.84 (95% CI 0.76–0.90) and 0.88 (95% CI 0.79–0.93),
respectively. The quality of evidence for TP and FN was high, but mod-
erate for TN and FP because of inconsistency across the studies and im-
precision resulting in wide confidence intervals.
3.4. HPV test compared with cervical smear
Eleven studies for HPV tests and cervical smears were pooled, with a
total of 39 050 participants [8,10,20–28]. Fig. 4 shows a summary of the
 R.A. Mustafa et al. / International Journal of Gynecology and Obstetrics 132 (2016) 259–265 261

Fig. 1. Flow diagram.

findings for this comparison. Sensitivity estimates for HPV ranged from
0.69 to 1.00, and the sensitivity estimates for cervical smears ranged
from 0.43 to 0.94. Specificity estimates for HPV ranged from 0.79 to
0.97, whereas specificity estimates for cervical smears ranged from
0.78 to 0.98. The pooled estimates for HPV sensitivity and specificity
were 0.94 (95% CI 0.89–0.97) and 0.90 (95% CI 0.86–0.93), respectively.
The pooled estimates for cervical smear sensitivity and specificity were
0.70 (95% CI 0.57–0.80) and 0.95 (95% CI 0.92–0.97), respectively. The
quality of the evidence for TP and FN was high, but moderate for TN
and FP when considering inconsistency and some imprecision.
findings for the diagnostic test accuracy of the HPV test. Sensitivity
estimates for HPV ranged from 0.64 to 1.00 and the specificity
ranged from 0.56 to 0.97. The pooled estimates for HPV sensitivity
and specificity were 0.94 (95% CI 0.89–0.97) and 0.88 (95% CI
0.84–0.92), respectively. The quality of the evidence for TP and FN
was high, but moderate for TN and FP due to inconsistency
across the studies and imprecision resulting in wide confidence
intervals.
3.6. Colposcopy impression

3.5. HPV test (from comparisons) There are 12 reports of 11 studies [8,30–39] that provided test
accuracy data for colposcopy impression among 6370 participants.
HPV test accuracy data were pooled from 15 studies, with a total Fig. 6 provides a summary of the findings for the diagnostic test
of 45 783 participants [8–12,20–29]. Fig. 5 shows a summary of the accuracy of colposcopy impression. Sensitivity estimates for colposcopy
262 R.A. Mustafa et al. / International Journal of Gynecology and Obstetrics 132 (2016) 259–265

Fig. 2. Summary of findings for diagnostic test accuracy of HPV test versus VIA. Abbreviations: VIA, visual inspection with acetic acid; CI, confidence interval; GRADE, Grading of Recom-
mendations Assessment, Development, and Evaluation; CIN, cervical intraepithelial neoplasia.

impression ranged from 0.29 to 1.00, and the specificity ranged from
0.12 to 0.88. The pooled estimates for HPV sensitivity and specificity
were 0.95 (95% CI 0.86–0.98) and 0.42 (95% CI 0.26–0.61), respectively.
The quality of the evidence for TP and FN was high, but moderate for TN
and FP because of inconsistency across the studies and imprecision
resulting in wide confidence intervals.
4. Discussion
The present review gives the results of a series of systematic reviews
and meta-analyses of test accuracy data for screening tests in the pre-
vention of cervical cancer. High to moderate quality evidence was
found of test accuracy for direct comparisons between the HPV test

Fig. 3. Summary of findings for diagnostic test accuracy of VIA versus cervical smears. Abbreviations: VIA, visual inspection with acetic acid; CI, confidence interval; GRADE, Grading of
Recommendations Assessment, Development, and Evaluation; CIN, cervical intraepithelial neoplasia.
 R.A. Mustafa et al. / International Journal of Gynecology and Obstetrics 132 (2016) 259–265 263

Fig. 4. Summary of findings for diagnostic test accuracy of HPV tests versus cervical smears. Abbreviations: CI, confidence interval; GRADE, Grading of Recommendations Assessment, De-
velopment, and Evaluation; CIN, cervical intraepithelial neoplasia.

and VIA, VIA and cervical smears, and the HPV test and cervical smears,
as well as for pooled estimates for the HPV test and for colposcopy im-
pression. For the direct comparisons, the absolute differences between
the outcomes of TP, FN, TN, and FP were calculated to provide a clearer
representation of the impact of sensitivity and specificity on diagnosis
and subsequent treatment [40]. For example, the differences in sensitiv-
ity of HPV when compared with VIA (95% compared to 69%) could be
interpreted as large. However, for a given prevalence, the absolute dif-
ferences in the number of women correctly identified with CIN grade
2–3 was five more per 1000 tested with the HPV test, and five fewer
women per 1000 tested falsely identified as negative for CIN grade
2–3. Decision makers would need to consider whether missing five in
every 1000 women when using VIA is acceptable for CIN grade 2–3 le-
sions, of which 70% could progress with time.
By contrast, small differences in the specificity for all comparisons re-
sulted in fairly large absolute differences between tests for TN and FP for a
given disease prevalence. In particular, the difference between VIA and
cervical smears was 58 more FPs; this means that 58 more women
would receive treatment unnecessarily if VIA alone (instead of the cervi-
cal smear) was used to screen women for CIN grade 2–3 lesions. Again,
decision makers, including those making recommendations, would
need to consider the downstream consequences of these differences
when choosing to provide these tests in a screening program followed
by treatment. The small variation in the absolute differences between
FN values and the large variation between the FP values among the differ-
ent tests is primarily due to the fairly low prevalence of CIN 2–3 of 2%. Col-
poscopy impression has also been used in screening programs after a
screen positive test. However, the present results show that its use

Fig. 5. Summary of findings for diagnostic test accuracy of HPV tests. Abbreviations: CI, confidence interval; GRADE, Grading of Recommendations Assessment, Development, and
Evaluation; CIN, cervical intraepithelial neoplasia.
264 R.A. Mustafa et al. / International Journal of Gynecology and Obstetrics 132 (2016) 259–265
Fig. 6. Summary of findings for diagnostic test accuracy of colposcopy impressions. Abbreviations: CI, confidence interval; GRADE, Grading of Recommendations Assessment, Develop-
ment, and Evaluation; CIN, cervical intraepithelial neoplasia.
resulted in 464 false positives in every 1000. In other words, for every
1000 women screened positive and then sent to colposcopy, 464 would
be falsely diagnosed as CIN grade 2–3 positive and subsequently treated.
Confidence in the present estimates was high to moderate. Given the
unknown degree of influence of risk of bias on test accuracy estimates,
only studies at low risk of bias were included and paired analyses were
conducted for direct comparisons. Many studies were excluded that
have been included in other reviews of test accuracy data, because the
women who screened negative in these studies did not receive the refer-
ence standard. This means that there would be little to no data to deter-
mine FNs and TNs. Also excluded were studies that did not provide the
two screening tests to all women. By including studies providing at least
two tests, it was possible to make a direct comparison of the results in
the same women within studies. In addition, a paired analysis of studies
was conducted that had a direct comparison of the tests within the
same group of women. Not only does this provide more rigorous esti-
mates of the effects [6], but it also provides relevant data for decision
makers who will almost always be faced with a decision to provide one
test over another. However, two analyses without comparisons were in-
cluded: HPV and colposcopy impression. Because these tests are often
used as part of a sequence of tests (e.g. HPV test followed by colposcopy
impression), the overall test accuracy of each test was calculated sepa-
rately. For these analyses, only studies that had a low risk of bias were
pooled. In particular, data were used only from studies that included
women who were screened positive and screened negative, thus ensuring
appropriate calculations of the TN and FN, and reducing verification bias.
There are few limitations of the present review. One could argue that
other important information has been omitted that has been included in
other published reviews of these tests, because the analyses were limit-
ed to studies of low risk of bias. However, adding in studies with high
risk of bias would substantially reduce the confidence—i.e. the quality
of the evidence—in the effects we found. In addition, although well de-
veloped, the methods for pooling test accuracy data and exploring het-
erogeneity continue to improve. It was not possible to explore or
explain the high heterogeneity in many of the analyses. Instead, the
range of sensitivity and specificity from the included studies has been
presented in addition to the confidence intervals.
In conclusion, the ideal studies to inform decision making about a
screen-and-treat strategy for screening for precancerous cervical lesions
would be direct comparisons between use of one screening test and an-
other, and measuring the effect on important patient outcomes. Instead,
recommendations are typically based on the accuracy of a test, which is
determined by calculating the sensitivity and specificity of the test.
However, these data do not address the consequences of screening—
treatment and the subsequent outcomes. When deciding on a screen-
and-treat strategy, it is critical to consider the downstream consequences
after treatment (for a positive test) or no treatment (for a negative test),
such as cervical cancer and related mortality, recurrence of CIN grade
2–3, adverse effects of treatment (and overtreatment), and use of re-
sources. Therefore, the differences in sensitivity and specificity of the
test comparisons found in the present review should not be considered
as standalone figures, but should be considered in the context of treat-
ment and patient outcomes. In fact, the sensitivity and specificity results
were used in a model to determine the effects of different strategies to
screen and treat women. Using the model, the outcomes due to treatment
or missed treatment were calculated and then used to make recommen-
dations about the use of the strategies. Ideally, rigorous studies comparing
highly relevant screen-and-treat strategies and following up all women to
assess effect on important outcomes need to be conducted to inform
decision makers.
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.ijgo.2015.07.024.
Acknowledgments
The present review was commissioned and funded by WHO as an in-
dependent review.
Conflict of interest
The authors have no conflicts of interest.
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