Stiekma 2014.

Study characteristics
Patient Sampling	Country: the Netherlands Centres: single Study design: within‐person comparison Recruitment: retrospective cross‐sectional study Method of patient selection: convenience Inappropriate exclusions (all stages, all ages, included comorbidities such as infertility or endometriosis): BOT and non‐EOC excluded
Patient characteristics and setting	Clinical setting: tertiary Study entry criteria: histologically confirmed EOC or benign ovarian disease referred to the institute Sample size: 181 Age range: not reported Mean age: benign 47 years, malignant 57 years Median age: not reported Percentage postmenopausal (n): 79% (143) Comments: none
Index tests	ROMA Prior test: unclear Threshold for test positivity predefined: no Threshold for test positivity: ROMA; premenopausal 0.129, postmenopausal 0.278 Type of ultrasound (TAS, TVS or both): N/A Operator experience of sonographer (generalist, specialist or trainee): N/A Type of technology or manufacturer of biomarker test: CA125 and HE4 (both Abbott) Comments: N/A
Target condition and reference standard(s)	Only surgical patients included Histology (n): benign 34, borderline excluded, malignant 147, metastatic and others not reported Staging: early 24, late 123
Flow and timing
Comparative
Notes
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	No
Was a case‐control design avoided?	Yes
Did the study avoid inappropriate exclusions?	No
A) Includes all ages regardless of menopausal status or justify restrictions	Unclear
B) Includes all stages and types of ovarian cancer	No
C) Includes comorbidities such as infertility and endometriosis	Unclear
Could the selection of patients have introduced bias?		High risk
A) All patients are symptomatic or symptomatic and asymptomatic can be disaggregated
B) Prior test in primary care: self‐reported symptoms
C) Prior test secondary care: self‐reported symptoms or self‐reported symptoms plus one or more biochemical markers and ultrasound
Are there concerns that the included patients and setting do not match the review question?			Unclear
DOMAIN 2: Index Test (ADNEX)
Were the index test results interpreted without knowledge of the results of the reference standard?
If a threshold was used, was it pre‐specified?
Were all components and thresholds of composite index test (including multivariable model) prespecified before their application?
If a composite index test was used, were components of a composite index test/model defined and assessed in a similar way (e.g. in the same healthcare setting) for all participants?
Could the conduct or interpretation of the index test have introduced bias?
A) Was ultrasound performed in all patients by non‐specialised sonographers
B) i. Were symptoms interpreted without the knowledge of ultrasound and biomarkers; ii: was ultrasound interpreted without the knowledge of biomarkers
Are there concerns that the index test, its conduct, or interpretation differ from the review question?
DOMAIN 2: Index Test (RMI)
Were the index test results interpreted without knowledge of the results of the reference standard?
If a threshold was used, was it pre‐specified?
Were all components and thresholds of composite index test (including multivariable model) prespecified before their application?
If a composite index test was used, were components of a composite index test/model defined and assessed in a similar way (e.g. in the same healthcare setting) for all participants?
Could the conduct or interpretation of the index test have introduced bias?
A) Was ultrasound performed in all patients by non‐specialised sonographers
B) i. Were symptoms interpreted without the knowledge of ultrasound and biomarkers; ii: was ultrasound interpreted without the knowledge of biomarkers
Are there concerns that the index test, its conduct, or interpretation differ from the review question?
DOMAIN 2: Index Test (ACOG)
Were the index test results interpreted without knowledge of the results of the reference standard?
If a threshold was used, was it pre‐specified?
Were all components and thresholds of composite index test (including multivariable model) prespecified before their application?
If a composite index test was used, were components of a composite index test/model defined and assessed in a similar way (e.g. in the same healthcare setting) for all participants?
Could the conduct or interpretation of the index test have introduced bias?
A) Was ultrasound performed in all patients by non‐specialised sonographers
B) i. Were symptoms interpreted without the knowledge of ultrasound and biomarkers; ii: was ultrasound interpreted without the knowledge of biomarkers
Are there concerns that the index test, its conduct, or interpretation differ from the review question?
DOMAIN 2: Index Test (ROMA)
Were the index test results interpreted without knowledge of the results of the reference standard?	Unclear
If a threshold was used, was it pre‐specified?	Yes
Were all components and thresholds of composite index test (including multivariable model) prespecified before their application?	Unclear
If a composite index test was used, were components of a composite index test/model defined and assessed in a similar way (e.g. in the same healthcare setting) for all participants?	Yes
Could the conduct or interpretation of the index test have introduced bias?		Unclear risk
A) Was ultrasound performed in all patients by non‐specialised sonographers
B) i. Were symptoms interpreted without the knowledge of ultrasound and biomarkers; ii: was ultrasound interpreted without the knowledge of biomarkers
Are there concerns that the index test, its conduct, or interpretation differ from the review question?			Low concern
DOMAIN 2: Index Test (LR2)
Were the index test results interpreted without knowledge of the results of the reference standard?
If a threshold was used, was it pre‐specified?
Were all components and thresholds of composite index test (including multivariable model) prespecified before their application?
If a composite index test was used, were components of a composite index test/model defined and assessed in a similar way (e.g. in the same healthcare setting) for all participants?
Could the conduct or interpretation of the index test have introduced bias?
A) Was ultrasound performed in all patients by non‐specialised sonographers
B) i. Were symptoms interpreted without the knowledge of ultrasound and biomarkers; ii: was ultrasound interpreted without the knowledge of biomarkers
Are there concerns that the index test, its conduct, or interpretation differ from the review question?
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Yes
Were the reference standard results interpreted without knowledge of the results of the index tests?	Yes
Could the reference standard, its conduct, or its interpretation have introduced bias?		Low risk
Can borderline tumours be grouped with primary ovarian cancer for the purposes of analysis?
Are there concerns that the target condition as defined by the reference standard does not match the question?			Unclear
DOMAIN 4: Flow and Timing
Was there an appropriate interval between index test and reference standard?	Unclear
Did all patients receive the same reference standard?	Yes
Were all patients included in the analysis?	No
Could the patient flow have introduced bias?		High risk
DOMAIN 5: Comparative
For studies comparing two or more index tests or testing strategies in different populations, were the selection criteria for participants receiving one or other index test or testing strategy the same?
For within‐study comparisons of index tests: was the interval between application of index test less than 3 months?
For within‐study comparison of individual index tests: were index tests interpreted blind to the results of other index test results?
Could the conduct of the comparative studies have introduced bias?
Is there concern that included patients have been selected in a different way to participants in non‐comparative studies?