Title: Infertility Treatments and Risk of Breast Benign Diseases: a Case#Control Study
Version: 4 Date: 04 Sep 2024
Reviewer's report:
"PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses one or several
testable research questions? (Brief or other article types: is there a clear objective?)
No - there are minor issues
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
No - there are major issues
EXECUTION - Are the experiments and analyses performed with sufficient technical rigor to
allow confidence in the results?
No - there are major issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
No - there are issues with the statistics in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are major issues
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your concerns sufficiently
for you to now recommend the work as a technically sound contribution? If not, can further
revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: I read carefully the manuscript ""Infertility Treatments and Risk of
Breast Benign Diseases: a Case#Control Study"". Overall, despite the efforts of the authors are
clear, the manuscript needs extensive editing to be improved and to clarify several issues. For
the sake of clarity, I declare that I have evaluated the revised version of the manuscript (and of
the authors' answer), although I did not participate in the previous rounds of review.
REQUESTED REVISIONS:
I recommend to take into account the following suggestions:
- The text needs to be edited by a native speaker in order to improve grammar and style.
- Introduction: The introduction contains a broad range of topics, including BBDs, breast cancer
risk, infertility treatments, and the classification of these treatments. While the topics are related,
the connections between them could be more clearly articulated. Consider tightening the focus
to ensure that each paragraph builds logically toward the study's aims.
- Introduction: The introduction does a good job highlighting a gap in the literature regarding
the relationship between infertility treatments and BBDs. However, it could benefit from a more
structured presentation of the existing evidence. For instance, you could first establish what is
known about BBDs and their association with cancer risk, then discuss what is known about
infertility treatments and breast malignancies, and finally highlight the gap regarding BBDs
specifically.
- Introduction: There is some repetition in the text, such as the mention of BBDs' association
with breast cancer risk and the insufficient evidence regarding BBDs' etiology and risk factors.
Streamline these points to reduce redundancy and enhance the overall flow.
- Introduction: Certain terms, such as ""estrogen dominance,"" ""superovulation,"" and
""controlled ovarian stimulation (COS),"" are introduced without sufficient context or
explanation. It may help to briefly define these terms to ensure that readers without specialized
knowledge can understand them.
- Introduction: Some sentences are lengthy and contain multiple ideas, which can make them
difficult to follow. For example, the sentence beginning with ""Given the nature of infertility...""
contains several clauses and could be split into two or more sentences for clarity. Aim for
concise, direct sentences that convey a single idea at a time.
- Introduction: While the introduction covers several relevant points, the transitions between
paragraphs could be smoother. For instance, the shift from discussing the psychological burden
of benign lesions to discussing hormonal fluctuations and breast pathology could be more
seamlessly integrated.
- Introduction: The rationale for the study is provided towards the end, but it would benefit from
a clearer and earlier statement of why this study is necessary, what specific question it aims to
answer, and how it will contribute to the existing body of knowledge.
- Introduction: The section has a good number of citations, but it may benefit from grouping
related references together. For example, references discussing the same concept (e.g., the risk
associated with infertility treatments and breast cancer) could be clustered to improve readability
and avoid breaking the text flow.
- Introduction: Use more explicit signposting language to guide the reader through the
introduction's argument. For example, phrases like ""This study addresses..."" or ""However,
despite this evidence..."" can help clarify the logical progression of ideas.
- Introduction: Minor typographical errors need correction, such as the lowercase ""we"" in
the last sentence. Ensure that all sentences begin with a capital letter and that punctuation is
consistent throughout.
- Methods: The section contains many detailed descriptions, but the organization could
be improved for better readability. Consider dividing the methods into subheadings such
as ""Study Design,"" ""Participants and Recruitment,"" ""Data Collection,"" ""Infertility
Treatment Protocols,"" ""Study Variables,"" and ""Statistical Analysis."" This would help
readers quickly locate specific information.
- Methods: Some paragraphs are too long, particularly those detailing the infertility treatments.
Breaking them into smaller paragraphs will improve readability and comprehension.
- Methods: The eligibility criteria for the participants could be more clearly defined. For
example, ""infertile women aged 18-42 years old with a BMI between 18.5 and 29.9"" is a good
start, but additional details like specific exclusion criteria (e.g., other medical conditions) should
be made explicit early on.
- Methods: The section describing infertility treatments is comprehensive, but it would benefit
from simplification. Consider using bullet points or a table format to differentiate between OI,
ART, COS, and other treatments. Also, be more explicit in distinguishing between different drug
regimens and dosages for clarity.
- Methods: Clearly define how the primary and secondary outcomes were measured. For
instance, describe what constitutes a diagnosis of BBDs in more detail. The criteria for
confirming a BBD diagnosis (e.g., specific imaging results, histological confirmation) could be
better outlined.
- Methods: While it is noted that data were collected from medical records, questionnaires, and
interviews, more detail is needed on how data collection was standardized, who conducted the
interviews, and whether any specific tools or validated questionnaires were used.
- Methods: Explain how missing data were handled, especially since some participants may have
had incomplete records from external centers. Specify whether any imputation methods were
used or if certain cases were excluded from analysis due to missing information.
- Methods: You mention controlling for confounders like age, gravidity, parity, etc., but more
detail is needed on how these variables were selected for inclusion in the multivariate analysis.
Were they chosen based on prior studies, theoretical considerations, or statistical criteria?
- Methods: While the statistical tests used are listed (e.g., Student’s t-test, chi-square test, logistic
regression), provide a brief justification for choosing these specific tests. Explain why certain
tests were selected based on data distribution or study design.
- Methods: Describe in more detail how the odds ratios (ORs) and confidence intervals (CIs)
were calculated and interpreted. Additionally, clarify if any adjustments were made for multiple
comparisons.
- Methods: While it is mentioned that written informed consent was obtained, consider adding a
brief statement about how participant confidentiality and data privacy were ensured throughout
the study, especially given the sensitive nature of infertility treatments and breast disease.
- Methods: A few grammatical issues and typos need correction, such as “the 2nd the 3rd day
of the menstrual cycle,” which should read “the 2nd or 3rd day.”
- Methods: Strengthen the connection between the methods and the study's overall aims. For
example, more clearly justify why certain infertility treatments were included and how they
relate to the study’s objectives regarding BBDs.
- Results: The ""Results"" section lacks a clear structure. Consider breaking it down into
subheadings such as ""Baseline Characteristics,"" ""Infertility Treatment History,"" and
""Univariate Analysis Results"" to help readers follow the findings more easily.
- Results: The current order of presenting the results could be improved. It might be more logical
to first present the baseline characteristics and differences between groups before discussing the
infertility treatments and statistical analysis results. This would provide a clearer context for
interpreting the findings.
- Results: The discussion on stratification by age, gravidity, parity, etc., is not clearly presented.
More information should be provided on how stratifying by these factors affected the results or
why this analysis was conducted.
- Results: The text states that ""the results of univariate analysis showed that the odds of BBDs
increased with age,"" but the follow-up statement seems contradictory or lacks clarity. Make it
clearer whether age was a significant factor in multivariate analysis or not and why.
- Results: There is a discrepancy in the reporting of the odds ratios (OR) after controlling
for certain factors. While the text suggests that controlling for these factors eliminates the
association between age and BBDs, the reported adjusted OR (1.23) still seems elevated. Further
clarification is needed to explain this finding, including why the association is not statistically
significant (P = 0.125).
- Results: Some grammatical and typographical errors need correction, such as ""an equal
participants in control and case group"" should be ""an equal number of participants in the
control and case groups.""
- Discussion: Some sentences and points are repeated, particularly around the findings related
to the lack of association between BBDs and infertility treatments. Streamline the text to avoid
redundancy and enhance clarity.
- Discussion: The discussion of the main findings is somewhat superficial. The text should delve
deeper into the possible reasons why no significant association was found between BBDs and
infertility treatments. Consider providing more hypotheses, potential biological mechanisms, or
explanations based on existing literature.
- Discussion: The discussion mentions interesting findings (e.g., lower rates of nulliparity and
nulligravidity in infertile women with BBDs, and the lower prevalence of menstrual disorders
in the case group) that contradict existing literature but does not adequately explain or explore
these discrepancies. Consider discussing possible explanations, such as sample size, population
differences, or methodological considerations, that could account for these unexpected results.
- Discussion: While the section briefly compares the findings to other studies, these comparisons
are not well-developed. Include more details on how your findings align or differ from similar
studies, particularly those examining hormonal factors and BBDs or infertility treatments and
breast cancer risk.
- Discussion: When mentioning studies that show conflicting results (e.g., studies on the
association between infertility and breast cancer risk), provide more context. Explain the
possible reasons for the discrepancies, such as differences in study design, population, or sample
size.
- Discussion: While some limitations are mentioned (e.g., retrospective design, small sample
size), the text does not adequately discuss how these limitations might affect the study's
conclusions. Consider elaborating on how these factors could introduce bias or affect the
generalizability of the results.
- Discussion: The discussion of strengths appears overly optimistic and lacks balance. While the
study's standardized treatment protocols are a strength, it is important to acknowledge that this
might limit the applicability of the findings to other settings where different protocols are used.
- Discussion: The suggestion for further research is too broad and vague. Provide more specific
recommendations, such as the type of study design (e.g., prospective cohort studies), larger
sample sizes, or the inclusion of specific variables that could help clarify the association between
infertility treatments and BBDs.
- Discussion: The discussion does not clearly outline the clinical or public health implications
of the findings. Explain how the results could influence clinical practice, patient counseling, or
future research directions.
- Discussion: Some sentences are lengthy or have grammatical errors that make them difficult
to follow. For example, the sentence ""However, the total number of OI cycles was marginally
higher in the case group..."" could be simplified for clarity.
- Discussion: When discussing findings, such as the lack of significant association, provide
more statistical context to help readers interpret the results. For instance, mention the confidence
intervals, effect sizes, or P-values where relevant.
- Discussion: The discussion mentions nonsignificant findings (e.g., ""statistically
nonsignificant higher number of total OI cycles"") but could clarify the clinical importance or
relevance of these findings. Explain why these results might still be worth considering, despite
their lack of statistical significance.
- Conclusion: The conclusion reiterates the lack of significant association found in the study but
could be more concise and focused. Additionally, emphasize the need for further research to
clarify the potential associations, considering the study's limitations."