IOTA Three-Step Strategy for Classifying Adnexal Masses: A Systematic Review and Meta-Analysis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Based on the article, here are the original contributions and the specific gap it addresses within the field of adnexal mass diagnosis. While other IOTA models have been thoroughly evaluated in systematic reviews and meta-analyses, the three-step strategy introduced in 2012 had not yet been comprehensively assessed.

1. There was moderate to high heterogeneity in sensitivity and specificity. More rigorous subgroup or sensitivity analyses (country, patient age) to explore causes of heterogeneity.
2. Follow-up for benign masses was inconsistent (some used 60 days, others 1 year). Apply a minimum standardized follow-up period (ideally ≥12 months) for non-surgically managed benign cases to confirm classification accuracy.
3. Majority of studies were from Europe, particularly Spain, with limited diversity in settings. Encourage inclusion of more diverse populations to enhance generalizability.

Implementing these improvements and controls would enhance the study's rigor, validity, and policy implications.

Author Response

Comment 1: There was moderate to high heterogeneity in sensitivity and specificity. More rigorous subgroup or sensitivity analyses (country, patient age) to explore causes of heterogeneity.

Response 1: Thanks for this comment. We have performed a new meta-regression analysis including other co-variables in the analysis (country and number of centers) (see line116). Patient's age could no be used because not all studies reported this data. However, no new information was obtained.

Comment 2: Follow-up for benign masses was inconsistent (some used 60 days, others 1 year). Apply a minimum standardized follow-up period (ideally ≥12 months) for non-surgically managed benign cases to confirm classification accuracy.

Response 2: Thanks for this comment. There is a misunderstanding. In all studies a minimum 12 months of follow-yp was required for considering as benign for reference standard (all studies were from Spain). No study used less than 12 months. 120 days or 60 days, as reported in table 3, is the maximun time ellapsed between US exam and surgery as reproted by tha authors in their respective papers. Obviusly, in those masses managed conservatively with at least 12 months follow-up, this data is not applicable. We clarify this in table 3 and add some data in the text (see line 216)

Comment 3: Majority of studies were from Europe, particularly Spain, with limited diversity in settings. Encourage inclusion of more diverse populations to enhance generalizability.

Response 3: Thanks for this comment. We agree with the reviewer. We have added a sentence as a limitation in the Discussion

Reviewer 2 Report

Comments and Suggestions for Authors

I read the study presented by the authors. The study concerns a very very important topic and the conduct of the study was excellent. With great competence the authors conducted an extremely excellent and complete statistical analysis.
What I am not convinced by is the electronic research, which identified 448 citations. After the first analysis, 233 citations remained. After reading titles 187 and abstracts, 203 citations were excluded. Full text of the remaining 30 articles were examined. Of these, only 7 remained.
Well, frankly, performing an analysis that has very valid results for the scientific community is quite difficult to sustain.
What can the authors say about this great bias?

Author Response

Comment 1: What I am not convinced by is the electronic research, which identified 448 citations. After the first analysis, 233 citations remained. After reading titles 187 and abstracts, 203 citations were excluded. Full text of the remaining 30 articles were examined. Of these, only 7 remained. Well, frankly, performing an analysis that has very valid results for the scientific community is quite difficult to sustain. What can the authors say about this great bias?

Response 1. Thanks for this comment. We agree with the reviewer. The main limitation of our study is the small number of studies included in the meta-analysis. We stress this in the Discussion. In fact, we add a new sentence (see line 294)

Reviewer 3 Report

Comments and Suggestions for Authors

Dear authors,

Thanks very much for your well-designed and presented work

 

There are only a few comments to be noted.

• Why did the search stop in 2020?
• What was the date of the last search?
• Please define more clearly what is meant by "where no data were available for constructing a 2 × 2 table." and mention if any articles were excluded for this exact cause
• Please add a paragraph in the discussion comparing this strategy with other suggested or commonly used strategies
• Please mention the study limitations
• A few language errors (ex: "being" instead of "benign" in line 68)

Best regards

Author Response

Comment 1: Why did the search stop in 2020?

Response 1: Thanks for this comment. There is a misunderstanding. Actually, the search was up to June 2024 (see line 105). However, the most recent paper included was published in 2020. No change made in the manuscript.

Comment 2: What was the date of the last search?

Response 2: As stated above, search was conducted up to June 2024.

Comment 3: Please define more clearly what is meant by "where no data were available for constructing a 2 × 2 table." and mention if any articles were excluded for this exact cause

Response 3: This information has been added (see lines 124 and 193)

Comment 4: Please add a paragraph in the discussion comparing this strategy with other suggested or commonly used strategies.

Response 4: Thanks for this comment. We already comment and compare the three-step strategy with other IOTA proposals (See Discussion). However, a sentence has been added (See lines 308-311)

Comment 5: Please mention the study limitations

Response 5: Thanks for this comment. This is already mentioned in the Discussion. No change made in the manuscript.

Comment 6: A few language errors (ex: "being" instead of "benign" in line 68)

Response 6: Thanks for this comment. Text has been revised and amended

Reviewer 4 Report

Comments and Suggestions for Authors

This is an interesting study. However, some important relative references are missing. Example: A new risk malignancy index to predict ovarian cancer: a bicentric preliminary study. J BUON. 2018 Sep-Oct;23(5):1380-1383.

Author Response

Comment 1: This is an interesting study. However, some important relative references are missing. Example: A new risk malignancy index to predict ovarian cancer: a bicentric preliminary study. J BUON. 2018 Sep-Oct;23(5):1380-1383.

Response 1: Dear reviewer, thanks for this comment. But, with all respect, the citation mentioned is a study that has nothing to do with our study. The study mentioned by the reviewer is related to a new malignancy index based on old Jacob's RMI, published in 2018, as a preliminary report. IOTA models clearly overcome and are superior to RMI for discriminating benign from malignant adnexal masses. Our study is focusing on IOTA three-step strategy. We do not think this study is actully relevant to our study. We did no change in the manuscript.