DOI: 10.1111/tog.

12200

2015;17:16371

Review

The Obstetrician & Gynaecologist

http://onlinetog.org

Diagnosing adnexal tumours before surgery: a critical

appraisal of recent evidence
Jeroen Kaijser MD PhD,a,b,c Kirsten Van Hoorde PhD,d Ben Van Calster PhD,e
Tom Bourne PhD FRCOG FAIUM (hon),f,g,h Ignace Vergote MD PhD,g Dirk Timmerman

MD PhD FRCOG

f,g,

Consultant Gynaecologist, KU Leuven, Department of Development and Regeneration, Leuven, Belgium

Consultant Gynaecologist, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven,
Belgium
c
Consultant Gynaecologist, Department of Obstetrics and Gynaecology, Ikazia Hospital, Rotterdam, the Netherlands
d
Postdoctoral Researcher, KU Leuven, Department of Electrical Engineering (ESAT) and iMinds Medical Information Technologies,
Leuven, Belgium
e
Professor of Biostatistics, KU Leuven, Department of Development and Regeneration, Leuven, Belgium
f
Professor of Obstetrics and Gynaecology, KU Leuven, Department of Development and Regeneration, Leuven, Belgium
g
Professor of Obstetrics and Gynaecology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven,
Leuven, Belgium
h
Professor of Obstetrics and Gynaecology, Queen Charlottes & Chelsea Hospital, Imperial College, Du Cane Road, London W12 0HS, UK
*Correspondence: Professor Dirk Timmerman. Email: dirk.timmerman@uzleuven.be
b

Accepted on 9 March 2015

Key content

Introduction to preoperative classification of ovarian and

tubal neoplasms.
 A discussion of existing guidelines by professional societies.
 Updated evidence and new strategies for preoperative diagnosis of
ovarian cancer.
 Evidence-based recommendations for the diagnosis and
characterisation of adnexal masses.
 Areas of future interest in the field of adnexal tumour diagnosis.

Learning objectives

To understand the importance of accurate preoperative

discrimination of adnexal tumours to ensure optimal
patient management.

To critically appraise current guidelines by professional societies.

To discuss findings from a recent systematic review and
meta-analysis, and two diagnostic accuracy studies comparing
different types of prediction models for ovarian cancer diagnosis.
 To understand the advantages and disadvantages of different
International Ovarian Tumour Analysis (IOTA)
prediction models.
Ethical issues


Consequences of misclassification of ovarian and tubal masses.

Inappropriate use of IOTA prediction models.

Keywords: biomarkers / meta-analysis / ovarian neoplasm /

systematic review / ultrasonography

Please cite this paper as: Kaijser J, Van Hoorde K, Van Calster B, Bourne T, Vergote I, Timmerman D. Diagnosing adnexal tumours before surgery: a critical
appraisal of recent evidence. The Obstetrician & Gynaecologist 2015;17:16371.

Introduction
Ovarian or tubal masses are frequently observed in women of
all ages who seek gynaecological care,1 and are still a leading
indication to perform surgical treatment.2 However, most
affected women have benign disease as the incidence of
ovarian cancer remains low.3 Women only have a 1.4%
lifetime risk of developing this type of cancer, in comparison
to an estimated 510% lifetime risk of undergoing surgery
for a suspected ovarian neoplasm.2 In the UK the crude
incidence of ovarian cancer is approximately 22 new cases/
year for every 100 000 women.4

2015 Royal College of Obstetricians and Gynaecologists

While the risk of cancer associated with an ovarian or tubal

mass is low, it remains crucial to adequately characterise such
masses to ensure women are triaged appropriately and thus
receive optimal treatment. For most benign tumours this
may involve expectant non-surgical management or minimal
invasive surgery by a general gynaecologist. In this way,
patient morbidity and risks of compromising fertility are
minimised. For women with a high risk of ovarian cancer,
centralised, specialised multidisciplinary treatment by an
experienced gynaecological oncologist in a large volume
centre is warranted to improve survival.57 However,
currently less than 50% of women in Europe and the USA

163

Optimising the approach to characterise adnexal masses

with invasive ovarian cancer undergo appropriate surgical

treatment by gynaecological oncologists.8,9
Most tests that are used in clinical practice for the
preoperative diagnosis of ovarian cancer and to triage
women incorporate findings of transvaginal ultrasonography,
because evidence shows this is the most appropriate first-line
imaging technique for the preoperative assessment of women
with adnexal pathology.10 When ultrasonography fails to
provide a confident diagnosis, other imaging tests such as
magnetic resonance imaging (MRI) or novel biomarkers may
add value, but these areas are still largely unexplored.10
This review describes the recent improvements in
diagnostic tests for the preoperative characterisation of
ovarian masses and the diagnosis of ovarian cancer.

Professional guidelines in the UK

Current guidelines1113 of the Royal College of Obstetricians
and Gynaecologists (RCOG) and the National Institute for
Health and Care Excellence (NICE) stipulate that the risk of
malignancy index (RMI) should be used to evaluate ovarian
masses in secondary or tertiary care in both premenopausal and
postmenopausal women. A Scottish Intercollegiate Guidelines
Network (SIGN) clinical practice guideline on the management
of epithelial ovarian cancer in 2013 also supported use of RMI
as the benchmark test in secondary care (grade B evidence).14
The RMI classifies women as being at high or low risk of having
ovarian cancer based on a total score derived from a
combination of ultrasound findings (multilocularity, solid
components, bilaterality, ascites and the presence or absence of
intra-abdominal metastases), menopausal status and the serum
CA125 concentration.15 It does not provide clinicians with risk
estimates of cancer. A score above 200 is generally used to
define a positive test result for cancer, leading to the woman
being referred for specialist oncological treatment. Some
triaging protocols in UK hospitals advise second-line imaging
with MRI to obtain a confident diagnosis for tumours with an
intermediate RMI score (25200).16 The recommendation to
use RMI in all three organisations evidence-based practice
guidelines cited above1114 is based on the results of two
previous systematic reviews and meta-analyses that addressed
the test performance of various prediction models and scoring
systems for the diagnosis of ovarian cancer prior to surgery in
women with adnexal masses.17,18 However, these previous
meta-analyses and reviews only included evidence relating to
tests that had undergone external validation published up to
2009. Accordingly, these analyses and thus any guidance based
on them is now outdated.

New strategies
Until recently, novel strategies for diagnosing ovarian cancer
had not been subject to adequate review. These include the

164

Risk of Ovarian Malignancy Algorithm, OVA-1 and the risk

prediction models (LR1, LR2) and decision rules (Simple
Rules) developed by the International Ovarian Tumour
Analysis (IOTA) study.1921
The IOTA Simple Rules are based on five ultrasound
features of malignancy (M-features) and five ultrasound
features suggestive of a benign lesion (B-features)
(Figure 1).18 An adnexal mass is classified as malignant if
at least one M-feature and no B-features are present and vice
versa. When no B-features or M-features are present or if
both B-features and M-features are present, then simple rules
are considered inconclusive (uncertain) and in the
approximately 20% of masses where this is the case, a
secondary diagnostic test should be used to classify
these masses.20
The IOTA logistic regression model LR2 (Figure 2) uses
six variables:
(1) patient age (years)
(2) presence of ascites (yes = 1, no = 0)
(3) presence of blood flow within a papillary projection
(yes = 1, no = 0)
(4) maximum diameter of the solid component (expressed in
mm and truncated at 50 mm)
(5) irregular internal cyst walls (yes = 1, no = 0)
(6) presence of acoustic shadows (yes = 1, no = 0).
LR2 estimates the probability of malignancy for an adnexal
tumour as 1/(1 + exp( z)), where z = 5.3718 + 0.0354(1) +
1.6159(2)+ 1.1768(3) + 0.0697(4) + 0.9586(5) 2.9486(6).21
A probability of malignancy based on a cut-off of 10% has
been used to report test performance for the classification of
tumours as benign or malignant based on LR2 risk scores.21

Current evidence on preoperative

discrimination of adnexal tumours
Systematic review and meta-analysis by the
International Ovarian Tumour Analysis
(IOTA) group
In 2014 the IOTA group conducted and published a
systematic review and meta-analysis that aimed to
determine the optimal strategy currently available to
characterise adnexal tumours prior to surgery based on upto-date clinical evidence.22 Data were combined from both a
previous meta-analysis17 used as the basis of the RCOG,
NICE, and SIGN guidelines,1114 and from an extended
search strategy in PubMed and Embase (last date of search 1
October 2013).22 A total of 19 different prediction models,
externally validated in 96 studies on a total of 26 438 adnexal
masses, met the predefined criteria for quantitative data
synthesis.22 Seven of them had been previously subject to
detailed review: four morphological scoring systems
(Sassone, Lerner, DePriest and Ferrazzi), a logistic

2015 Royal College of Obstetricians and Gynaecologists

Kaijser et al.

Malignant features

Irregular solid
tumour

Presence of
ascites

4 papillary
projections

Irregular
multilocular-solid
tumour 100 mm

Colour score 4
(strong blood
flow)

Tumour with
largest solid
component <7 mm

Acoustic
shadows

Smooth
multilocular
tumour <100 mm

Colour score 1
(no blood flow)

Benign features

Unilocular cyst

Figure 1. Benign (B) and malignant (M) features used in the IOTA Simple Rules illustrated by ultrasound images.

Ascites (2)
Age (1)

Blood flow in
a papillary
structure (3)

Max size of
solid
component (4)

Irregular
internal cyst
walls (5)

Acoustic
shadows (6)

Figure 2. Variables used in the IOTA logistic regression model 2 (IOTA LR2). LR2 estimates the probability of malignancy for an adnexal tumour as
1/(1 + exp(z)), where z = 5.3718 + 0.0354(1) + 1.6159(2) + 1.1768(3) + 0.0697(4) + 0.9586(5) 2.9486(6). Risk 10% indicates malignancy.

regression model proposed by Tailor, and the RMI-1 and

RMI-2. The updated search identified an additional 12 new
diagnostic tests eligible for further analysis.22
Figure 3 and Table 1 show the main results of the metaanalysis with pooled sensitivity and specificity pairs with 95%
confidence intervals using the original cut-off level of each
included model. The IOTA LR2 model using a cut-off of 10%
had a pooled sensitivity of 92% (95% CI 8895%) and
specificity of 83% (95% CI 7788%) and Simple Rules had a
pooled sensitivity of 93% (95% CI 8995%) and specificity of

2015 Royal College of Obstetricians and Gynaecologists

81% (95% CI 7685%) when considering a strategy that

classifies inconclusive tumours as malignant.22 Both IOTA
models achieved the highest level of diagnostic accuracy and
performed significantly better than the RMI, which had
sensitivity of 72% (95% CI 6776%) and specificity of 92%
(95% CI 8993%) using the 200 cut-off.22 Furthermore,
when results were stratified for menopausal status, both
IOTA LR2 and Simple Rules had a higher sensitivity for
cancer than RMI in both premenopausal and
postmenopausal women (Table 2).22

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Optimising the approach to characterise adnexal masses

different centres and clinical environments.21,23 In favour of

the RMI is that it has been validated more frequently in the
literature than LR2 and Simple Rules.22 However, evidence
relating to the diagnostic accuracy of RMI is likely to be affected
by substandard methodological quality and a failure to report
potential sources of bias in many of its validation studies.22
Most studies that were included in the meta-analysis were
small, retrospective, single-centre studies that lack information
about adequate blinding of the index test (RMI) results to the
final outcome after surgery.22 Such blinding is pivotal in
retrospective diagnostic studies that assess relatively subjective
index tests such as transvaginal ultrasonography.24 A lack of
blinding in these circumstances can lead to over-optimistic
results of diagnostic test performance.24

International Ovarian Tumour Analysis

(IOTA) phase 3

Figure 3. Summary of pooled test performance of models included in

the meta-analysis. Reproduced from Kaijser J et al.22 2014, with
permission from Oxford University Press.

The RMI model was originally developed using a total of just

143 women, including 42 malignancies from a single unit.14 On
the other hand both the IOTA LR2 model and Simple Rules
were developed on a large dataset derived from a number of

In 2014 the IOTA group also reported its findings from IOTA
phase 3,25 a large (n=2403), prospective (20092012),
multicentre (18 centres), diagnostic accuracy study
comparing the test performance of different IOTA
strategies and the RMI in the hands of experienced level III
operators (according to European Federation of Societies for
Ultrasound in Medicine and Biology guidelines).26 All IOTA
methods showed better discrimination than RMI.23 These
results were in line with other validation studies in previous
phases (1, 1b and 2)21,2729 of IOTA (n=3511) and the 2014

Table 1. Pooled summary estimates of the expected operating point (sensitivity and specicity) of models included in the quantitative data synthesis.

Model

Cut-off

Morphologic scoring systems

Sassone
>9
Lerner
>3
DePriest
>5
Ferrazzi
>9
Simple Rules
n/a
Risk of malignancy indexes
RMI I
200
RMI II
200
RMI III
200
RMI IV
450
Logistic regression models
Tailor
50%
LRa
25%
LRb
60%
mpeler
Pro
10%
Jokubkiene
12%
IOTA LR2
10%
Articial neural networks
ANN1
45%
ANN2
60%

Sensitivity %
(95% CI)

Specicity %
(95% CI)

Studies n

Centres n

19
9
8
7
5

19
17
8
7
17

85
80
90
86
93

(7790)
(7086)
(8195)
(7791)
(8995)

80
61
68
80
81

(7386)
(5368)
(5777)
(6689)
(7685)

23
15
9
3

41
32
19
13

72
75
70
68

(6776)
(6980)
(6078)
(5976)

92
87
91
94

(8993)
(8490)
(8893)
(9196)

6
3
4
2
2
3

24
20
21
10
20
13

35
76
82
61
77
92

(2449)
(7081)
(7786)
(4674)
(7182)
(8895)

96
87
78
81
87
83

(9498)
(8290)
(7383)
(7089)
(8389)
(7788)

3
4

20
21

77 (7182)
97 (9598)

86 (8090)
37 (3144)

ANN = articial neural network; IOTA LR2 = IOTA logistic regression model 2; LRa = logistic regression model a; LRb = logistic regression model b;
n/a = not applicable; RMI = risk of malignancy index.
Reproduced from Kaijser el al.22 2014, with permission from Oxford University Press.

166

2015 Royal College of Obstetricians and Gynaecologists

Kaijser et al.

Table 2. Pooled test performance of IOTA LR2, Simple Rules and Risk
of Malignancy Index in premenopausal and postmenopausal women
using a meta-analysis of centre-specic data from two multicentre
cohorts.
Premenopausal women

Postmenopausal women

Model

Sensitivity %
(95% CI)

Specicity %
(95% CI)

Sensitivity %
(95% CI)

Specicity %
(95% CI)

IOTA LR2
Simple Rules
RMI-1

85 (7591)
93 (8497)
44 (2862)

91 (8396)
83 (7390)
95 (9097)

94 (8997)
93 (8896)
79 (7285)

70 (6277)
76 (6982)
90 (8494)

IOTA LR2 = IOTA logistic regression model 2; RMI-1 = risk of

malignancy index-1.

meta-analysis as discussed previously.22 Irrespective of the

prevalence of malignancy, in all centres the sensitivity for
cancer was much higher for LR2 and Simple Rules than
for RMI.25

Test performance of International Ovarian Tumour

Analysis (IOTA) strategies by operators with varying
ultrasound expertise
The main IOTA strategies (IOTA LR2 and Simple Rules)
have also been subject to external validation by operators
with different training (doctors and sonographers) and levels
of ultrasound experience. In IOTA phase 4, a multicentre
diagnostic accuracy study, the performance of LR2, Simple
Rules and RMI were compared in the same patient group,
with the same equipment, by the same inexperienced
operators to minimise bias.30 Both IOTA tests had excellent
performance, and showed significantly better test
performance than RMI in their hands.30 Other research
groups have confirmed the results of IOTA phase 4, which
indicate that both IOTA LR2 and Simple Rules are reliable
tests to triage women in real world clinical practice.3134
A 2014 meta-analysis by Nunes et al.34 summarised the
currently available evidence concerning the accuracy of IOTA
Simple Rules for the diagnosis of ovarian cancer. In contrast
to the previous meta-analysis of the IOTA group,22 it
included additional validation studies of Simple Rules, and
only reported the accuracy of the rules in masses where they
are applicable (range: 7689% of all tumours).34 This metaanalysis showed that when applicable, the Simple Rules had
an excellent performance for the diagnosis of ovarian cancer
in the hands of ultrasound operators of varying levels of
expertise with a pooled sensitivity of 93% (95% CI 9096%)
and a pooled specificity of 95% (95% CI 9397%).34

Multiclass risk prediction of adnexal tumours

All existing diagnostic tests used for the preoperative
characterisation of adnexal tumours focus on the presence or
absence of cancer. However, various subtypes of malignant

2015 Royal College of Obstetricians and Gynaecologists

disease in the ovary each have their own implications regarding

the optimal management.35 In 2014 the IOTA group developed
and validated a multiclass risk prediction model, ADNEX
(Assessment of Different NEoplasias in the adneXa), using
prospectively collected data from almost 6000 patients from 24
centres in 10 countries.35 The ADNEX model enables more
specific subtyping of cancer (borderline, early stage I invasive
ovarian cancer, stage IIIV invasive ovarian cancer and
secondary tumours that have metastasised to the ovaries such
as breast or gastrointestinal cancer). The model offers risk
estimates, and provides similar diagnostic accuracy to IOTA
LR2 and Simple Rules for the standard dichotomous
discrimination between the benign and malignant nature of a
mass.35 The ADNEX model (area under the receiver operating
characteristics curve [AUC] = 0.94) also had better
discrimination than the RMI (AUC = 0.88)25 when validated
on data from IOTA phase 3.35 ADNEX offered fair to excellent
discrimination (AUCs ranging 0.710.95) between the four
different types of ovarian malignancy.35 This model contains
three clinical predictors (age, serum CA125 level, type of
centre: oncology centre versus other hospital), and six
ultrasound predictors (maximum diameter of lesion,
proportion of solid tissue, more than ten cyst locules,
number of papillary projections, acoustic shadows and
ascites; Figure 4).35 These ultrasound variables are very
similar and perhaps simpler to obtain than variables used in
both the IOTA LR2 model and Simple Rules. Accordingly,
ADNEX is a test that should be straightforward to use by any
competent ultrasound examiner.

Discussion
In recent years, diagnostic tests for the preoperative diagnosis
of ovarian cancer have been published that perform better
than those previously available. Their use are likely to
improve the existing management, guidance and triage of
women with adnexal tumours. Consequently, there should be
no reason for women at high risk of cancer not to have
surgery carried out in the right place, by the right surgeon.36
Based on current evidence, the IOTA LR2 and Simple
Rules offer the optimal approach to discriminate between
benign and malignant disease of the ovary or tube prior to
surgery. This assertion is based on a comprehensive
systematic review of the most recent available evidence.22
These conclusions were based on methodologically sound
and high-quality evidence when applying Quality Assessment
of Diagnostic Accuracy Studies criteria. The ADNEX model
has not yet been subject to external validation but it seems
likely that it will further improve management decisions.
The meta-analysis by the IOTA group focused on a
comparison of pooled sensitivity and specificity at the
original cut-off level used for each model.22 While this is
valid from a methodological point of view, to recommend a

167

Optimising the approach to characterise adnexal masses

(1) maximum diameter

of lesion (mm)

(2) proportion of solid

tissue

(3) more than 10 cyst

locules (yes vs no)

(4) number of papillary

projections (0, 1, 2, 3,
more than 3)

(5) acoustic shadows

(yes vs no)

(6) ascites (yes vs no)

Figure 4. Ultrasound variables used in the IOTA ADNEX model.

clinical test only on these criteria is not always correct in

practice.37 Using different cut-off values for different
prediction models (that is, 10% for LR2, 200 for RMI)
does complicate interpretation of the results.37 However, in
both IOTA phase 3 and phase 4, the LR2 model had better
overall discrimination (AUC) than RMI.25,30
In general, for any test to diagnose ovarian malignancy, a
high sensitivity (preferably over 90%) is essential because
correctly identifying women with cancer is key to appropriate
triage to specialists in high-volume oncology centres.38 When
using a score of 200 to indicate malignant disease, RMI misses
one in three patients with ovarian cancer. This is not an
appropriate cut-off to triage women. Likewise, as shown in
IOTA phase 3, a negative test result for RMI is associated with a
disproportionately high risk of cancer (of around 50%).25
IOTA 4 and other studies have demonstrated that nonexpert operators are perfectly capable of identifying the
ultrasound variables required for IOTA LR2 or Simple
Rules.3034 While these promising and reassuring findings
were derived mainly from well-controlled units, adequate
knowledge of IOTA standardised terminology and
definitions39 remains essential for any operator who would
like to use IOTA LR2 or Simple Rules in clinical practice. In
contrast to these strategies, the ADNEX model has included
more objective ultrasound features and does not necessitate
the use of colour Doppler ultrasonography.35 Interestingly, it
also shows a resemblance to the RMI;14 the RMI requires the
operator to identify whether a mass is multilocular or has
solid areas, while ADNEX asks the examiner to record the
number of locules and the size of the solid area if

168

present.14,35,36 This should not be beyond the capability of

any ultrasound examiner currently using the RMI.36
In accordance with the findings of the meta-analysis,22 and
more recent diagnostic studies,25,35 professional societies
should adopt IOTA models into their existing triaging
protocols in order to improve patient management for
women with ovarian or tubal masses eligible for surgical
management (Figure 5). In the UK this process has started, as
the RCOG has already incorporated the Simple Rules into its
guidance for the assessment of premenopausal women with
known adnexal pathology.12

Areas of uncertainty and future interest

Value of MRI for difficult tumours
There are studies indicating that MRI may have a role to play
in the presurgical assessment of adnexal masses that are
difficult to classify with transvaginal ultrasonography.10
However, most have lacked uniformity in describing the
exact criteria used to define such difficult masses.10 A
benefit of using the IOTA strategies is they offer
straightforward criteria that can be used to define a
difficult mass (that is, when Simple Rules do not apply or
when LR2 risk scores are between 5% and 25%).10 In
addition, LR2-based triage would also substantially reduce
the number of second-stage tests for difficult tumours
compared with RMI-based triage.40 Future studies should
evaluate the performance of MRI compared with expert
ultrasound assessment for difficult tumours.10 To date there
are no data relating to the performance of MRI for masses

2015 Royal College of Obstetricians and Gynaecologists

Kaijser et al.

Women
presenting with
adnexal tumours
prior to surgery

IOTA
Simple
Rules

IOTA LR2 risk

model

Benign

Malignant

Surgery by
general
gynaecologist

Referral for
specialised
treatment in
oncology clinic

Subjective
expert
assessment

Inconclusive

Benign

Malignant

Surgery by
general
gynaecologist

Referral for
specialised
treatment in
oncology clinic

Classify
inconclusive
tumours as
malignant

Benign

Surgery by
general
gynaecologist

Malignant

Referral for
specialised
treatment in
oncology clinic

Referral for
specialised
treatment in
oncology clinic

Figure 5. An evidence-based approach to the use of ultrasonography in the assessment of women with adnexal tumours to estimate risk of
malignancy prior to surgical intervention. Adapted and reproduced from Kaijser J et al.38 2013, with permission from John Wiley and Sons.

that cannot be classified with IOTA Simple Rules or are close

to the decision boundary with IOTA LR2. Until such data are
available, the subjective interpretation of ultrasound images
by an expert clinician with a special interest in
gynaecological ultrasonography offers the best available
second-stage test in this group of masses.27

Expectant non-surgical management of

ovarian tumours
The majority of validation studies of diagnostic tests and
models designed to predict malignancy in ovarian tumours
that have been subject to detailed review use final histology
after surgery as a clear endpoint to verify the index test results.
The percentage of women with benign-looking tumours that
can be safely treated conservatively to date is largely unknown
because the natural history of masses that do not undergo
surgery is not known. The result is that we do not know the risk
of potential complications such as torsion, rupture, bleeding or

2015 Royal College of Obstetricians and Gynaecologists

malignant transformation. In the absence of evidence to

provide clear guidance, the management of these masses in
clinical practice is highly variable and many are surgically
removed because evidence from long-term follow-up studies is
missing, and because of a fear of missing ovarian cancer even
if the mass does not manifest any features of malignancy. This is
clearly not an optimal approach, and such unnecessary
intervention may lead to increased patient morbidity and
may even jeopardise fertility in women of reproductive age.
Developing new insights into the outcome of benign-looking
ovarian masses that are being conservatively managed would
potentially change the management of thousands of women, by
avoiding surgery or even further surveillance for some and
detecting cancer earlier or even preventing it for others.

Contribution of authorship
JK, BVC, TB and DT drafted the manuscript. KVH and BVC
conducted the analysis. All authors revised and commented

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Optimising the approach to characterise adnexal masses

on subsequent drafts and approved the final version

for submission.

Disclosure of interests

13

The authors report no conflict of interest

14

Acknowledgements

15

Dirk Timmerman is Senior Clinical Investigator of the

Research Foundation - Flanders (Belgium) (FWO). Kirsten
Van Hoorde was supported by a PhD grant of the Flanders
Agency for Innovation by Science and Technology (IWT
Vlaanderen). Ben Van Calster is supported by a fellowship
from the Research Foundation Flanders (FWO). Tom
Bourne is supported by the National Institute for Health
Research (NIHR) Biomedical Research Centre based at
Imperial College Healthcare NHS Trust and Imperial
College London. The views expressed are those of the
author(s) and not necessarily those of the NHS, the NIHR or
the Department of Health. The IOTA studies are supported
by the Flemish Government: Research Foundation Flanders
(FWO) project G049312N, and Flanders Agency for
Innovation by Science and Technology (IWT) project
IWT-TBM 070706-IOTA3, and iMinds 2013.

16

17

18

19

20

21

22

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