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Date: May 15, 2020
To: "Sharon Jakus-Waldman"
From: "The Green Journal" [email protected]
Subject: Your Submission ONG-20-793
RE: Manuscript Number ONG-20-793
Risk Factors for Surgical Failure and Worsening Pelvic Floor Symptoms Up To 5 Years After Vaginal Prolapse Repair
Dear Dr. Jakus-Waldman:
Your manuscript has been reviewed by the Editorial Board and by special expert referees. Although it is judged not
acceptable for publication in Obstetrics & Gynecology in its present form, we would be willing to give further consideration
to a revised version.
If you wish to consider revising your manuscript, you will first need to study carefully the enclosed reports submitted by
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REVIEWER COMMENTS:
Reviewer #1: Abstract and introduction: well written, concise.
Methods:
1. As this is a sub-analysis of OPTIMAL using E-OPTIMAL data, it would be helpful clarify if "baseline" scores refer to
presurgical questionnaire scores or scores from the end of the OPTIMAL trial, prior to enrollment in E-OPTIMAL.
2. The definition of surgical failure includes anatomic, potentially asymptomatic, measures like descent of the apex 1/3
of the vaginal length with Valsalva, in addition to patient reported symptom measures on questionnaires and repeat
treatment for prolapse. It would be interesting to look at the primary and secondary outcomes in women who are
symptomatic vs. those who fall into the "surgical failure" category due to anatomic indicators only, who may be
asymptomatic. This could affect the outcomes of this analysis- as secondary outcomes are based on symptoms. Could the
authors please comment on their decision to analyze the data in this way and include it in the Discussion/limitations
section of the paper.
3. Why was an alpha of .2 selected for this analysis? All of the reported significant findings in the tables are <.05.
Results:
1. Was there a relationship between perineal body size and concomitant prolapse procedures like posterior repair or
perineorrhaphy, and whether this had an impact on surgical failure?
2. In text or as footnote in the tables please include what was adjusted for in each model.
Discussion
1. Could the authors discuss the possibility that one explanation for the increased surgical failure but decreased POPDI,
UDI and CRADI scores associated with higher baseline POPDI score could be related to the fact that there are non-
symptomatic criteria included in the "surgical failure" definition? One explanation could be that having an apex descend
1/3 of the length of the vagina counts as "failure" but the patient may have no other symptom findings that would be
reflected in the questionnaires. This is mentioned only briefly in 1 sentence in the discussion and merits further discussion.
2. The authors state that a longer perineal body may also correlate with a wider GH- was this the case in this study
population?
3. The authors mention a weak correlation between worsening UDI in participants who may have been peri-menopausal
but this information is not presented in the results section. Please mention this in the results or consider removing from
the discussion.
4. The authors suggest that the POPDI score may be a proxy for burden of other pelvic floor disorders that are not
addressed by the surgical intervention. In this study- the surgical intervention was aimed at POP and SUI, but the authors
suggest that other pelvic floor disorders not affected by the surgery (presumably UUI, FI, etc) explain their finding that
patients had symptomatic improvement but were not as likely to meet surgical success. However, one would assume that
this phenomenon would be reflected in the UDI scores or CRADI. This point is a little confusing would benefit from
clarification.
View Letter
1 of 5 6/16/2020, 4:51 PM
a. Could the authors discuss how their definition of surgical failure which includes asymptomatic measures could
affect their finding of higher POPDI scores being associated with lower surgical "success," but higher rates of symptomatic
improvement? (see point 1 of discussion)
b. Was there any change in outcome of final questionnaire scores in the patients who underwent BPMT prior to
surgery, as this could impact other pelvic floor disorders not addressed by surgery?
Reviewer #2: Objective (Abstract)To determine independent risk factors for surgical failure and worsening pelvic floor
symptoms within 5 years following vaginal prolapse surgery.
Objective (Introduction) multivariable modeling of independent risk factors for surgical failure and new or worsening pelvic
floor symptoms up to 5 years after transvaginal native tissue pelvic organ prolapse repair.
A secondary analysis of the Operations and Pelvic Muscle Training in the Management of Apical Support Loss (OPTIMAL)
(n=374) and extended trial (E-OPTIMAL) (n=285) participants. The e-Optimal was recently published in JAMA 2018
Title and Precis are the same. I would think the findings are simple enough they could be stated in the Precis
Introduction: Well written, guides the reader through the logic. I would include the actual results of the E-Optimal trial
regarding surgical failure (high) not simply the statement of NO difference, because of their clinical significance
Methods takes the reader through the Optimal and E-optimal and then the secondary analysis
Discussion: Under strengths" Furthermore, a high percentage of participants contributed longitudinal follow-up data, and
the E-OPTIMAL cohort was similar to the OPTIMAL cohort" The women who opted to not participate in the e-cohort clearly
had earlier surgical failures This statement seems very contradictory to the great differences in the groups as you reported
in the first paragraph of Results.
Given that one of the significant findings were Hispanic (no known mechanism), Did you evaluate this subgroup in detail
regarding difference from the larger group: more babies? older?, significantly worsened symptoms at time of surgery and
higher POPDI ? Increased BMI? If they weren't different please state how you compared them. CAn you talk about the CI
for Hispanic race as it is close to 1 and the widest of all the findings
Can you talk about a normal Perineal body length is it known to be 3.4 cms +- 1 cms , what did the actual measurements
of a longer PB look like?
Given that you are looking at factors that contribute to long term failure. After Table 1 Comparing Optimal and E-Optimal I
would think Table 2 would be comparing women who failed surgically or anatomically and compared characteristics
between those two groups? It would help the reader with the storyline. You describe this in your methods section but the
only part the reader sees is the final product
Reviewer #3: 1. I found the wording in Abstract Results on page 8 to be confusing. Consider breaking up the one very
complex sentence into several. Replace perineal body with more descriptive verbiage for clarity: e.g. increased
preoperative perineal body measurement. The latter part of the sentence is so complex that it is difficult to read.
2. In the Introduction you state that patients had Stage 2-4 prolapse, even though you point out that these are POP-Q
measurements, it would be informative to add that information here.
3. On page 12, you state that a phone interview allowed inclusion in follow-up in e-OPTIMAL patients. I can see how a
phone interview is useful for validated questionnaires, how does a phone interview account for failure assessment, other
than subjectively?
4. On page 12 you note that in e-OPTIMAL the primary outcome was a time-to-event occurrence for failure (as defined in
the paper). Later, in the Discussion on page 17, there is a notation that fewer failure patients enrolled in e-OPTIMAL. Does
that mean you are analyzing a group that was more "non-failure" at 2 years, and if so, how might that change you analysis
and opinions? Could time-of-failure analysis further understanding of the complex statistical analysis you have presented in
this paper?
5. page 15 in the speculation regarding the surprising finding that an increased perineal body measurement is identified as
a risk factor for failure, there is mention that there may be perineal descent associated with damage to the levator
muscles. That finding is also present in apical disruption of the rectovaginal septum. You also mention a possible increase
in Genital Hiatus, is that data available? If GH is increased, and that results in a spuriously increased PB measurement,
what is the real association with failure? Does increased GH spuriously increase PB measurement during Valsalva and, if
so, what is the significance? To me, this is the finding of the paper that is most amenable to further analysis on a clinical
level.
6. On page 16, in the discussion of ideas regarding Hispanic patients, you use the term "biomechanical axis". More
clarification would be helpful, e.g. deep endopelvic connective tissue, variances in collagen-elasitin content and strength,
etc.
7. Does this paper suggest ideas for additional analysis (as with the perineal body genital hiatus comments above) or ideas
for future studies?
Overall an excellent and thought provoking paper.
View Letter
2 of 5 6/16/2020, 4:51 PM
STATISTICAL EDITOR COMMENTS:
The Statistical Editor makes the following points that need to be addressed:
1. General: In last line of paragraph 1 in Results, 13/28, the % is cited to 0.1% precision. In that instance and if there are
others with similar limited denominators, the % should be rounded to nearest integer %, not cited to 0.1% precision.
2. The aORs give relative odds, but more data needs to be presented re: absolute risks associated with various factors.
3. Although from the standpoint of models, the various input variables are "predictors", by the nature of this study design,
what one can discern are associations. That distinction needs to made clearer in the exposition of results and discussion.
4. Table 1: Need units for age, BMI.
5. Table 2a: No necessary to include p-values, when the CIs are already included. Need to include the unadjusted ORs for
contrast, need to include in footnote a list of all variables included in the final model. Need to include (could be on-line
material), a list of all data citing counts of surgical failure, use of estrogen therapy, worsening MID etc.
6, Table 2b: Not necessary to include p-values, since the CIs are already included. Need to include a list of variable
s retained in final model.
7. General: Since the follow-up extended to variable time points after surgery up to 5 years, need to cite the n(%)
remaining of the original cohort at each time point and need to address how loss to follow-up might have biased the
results. Specifically, need to compare the demographic characteristics of those at baseline vs those with follow-up to
assure the reader that potential selection bias has been addressed.
MANUSCRIPT EDITOR COMMENTS:
1. Renumber your tables to avoid using "a" and "b." Please number them as Table 1, Table 2, and Table 3.
2. Would you describe why Table 2a cites reference 1 the table title?
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a. MID for "minimally important difference"
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June 14, 2020
Re: Submission of the revised manuscript “Risk Factors for Worsening Outcomes 5 Years After Vaginal Prolapse Repair”
The Editors
Obstetrics & Gynecology 409 12
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Dear Editors:
Thank you for the opportunity to submit a revised manuscript for further consideration by Obstetrics & Gynecology. We have made every effort to ensure that our revision is responsive to the thoughtful comments by the editors and reviewers. We confirm that we have reviewed the “Instructions for Authors” document and have provided a point-by-point response to each of the reviewer comments. All authors were given an opportunity to review and approve of this revised submission. We trust that our revised manuscript can be considered for acceptance by the journal.
Sincerely,
Sharon Jakus-Waldman, MD, MPH
REVIEWER COMMENTS:
Reviewer #1: Abstract and introduction: well written, concise.
Methods:
1. As this is a sub-analysis of OPTIMAL using E-OPTIMAL data, it would be helpful clarify if
"baseline" scores refer to presurgical questionnaire scores or scores from the end of the OPTIMAL trial, prior to enrollment in E-OPTIMAL.
Response: We appreciate this comment. The term “baseline” was changed to pretreatment where appropriate in the manuscript. Two statements were added to the methods section to clarify this point.
• Lines 107-110: “Secondary outcomes include quality of life measures. Subscales of the Pelvic Floor Distress Inventory (PFDI) (higher scores indicate worse symptoms)(14) were collected pretreatment, upon enrollment in the OPTIMAL trial, and during each of the follow-up assessments.”
• Lines 127-129: “Chi-square tests and t-tests were used to compare pretreatment PFDI subscale scores between surgical failures vs. successes and participants who did vs. did not report worsening of symptoms at each time point.”
2. The definition of surgical failure includes anatomic, potentially asymptomatic, measures like descent of the apex 1/3 of the vaginal length with Valsalva, in addition to patient reported symptom measures on questionnaires and repeat treatment for prolapse. It would be
interesting to look at the primary and secondary outcomes in women who are symptomatic vs.
those who fall into the "surgical failure" category due to anatomic indicators only, who may be asymptomatic. This could affect the outcomes of this analysis- as secondary outcomes are based on symptoms. Could the authors please comment on their decision to analyze the data in this way and include it in the Discussion/limitations section of the paper.
Response: We appreciate this comment. The following statements were added to the discussion:
• Lines 253-255: “The analysis plan for this secondary outcome paper was planned a priori when the OPTIMAL study was designed. This composite definition is consistent with the primary outcome measure for the OPTIMAL trial.”
3. Why was an alpha of .2 selected for this analysis? All of the reported significant findings in the tables are <.05.
Response: Thank you for this comment. A significance level of p<0.2 was used to identify
characteristics that might be associated with the outcome in either unadjusted or adjusted
analysis. If a stricter cut-off such as p<0.05 was used, we would risk missing important factors
that could be associated with the outcome after controlling for other covariates.
Results:
1. Was there a relationship between perineal body size and concomitant prolapse
procedures like posterior repair or perineorrhaphy, and whether this had an impact on surgical failure?
Response: We appreciate this comment. The decision to perform concomitant procedures was at the discretion of the surgeon and there was no analysis of the likelihood of performing a posterior repair or perineorrhaphy based on the baseline perineal body measurement. The focus of the surgical modeling was on presurgical risk factors. An analysis of the association between concomitant procedures and surgical success is outside the scope of this paper.
We have modified the manuscript in response to this comment by adding these statements to the discussion:
• Lines 213-220: “The decision to perform concomitant procedures such as a posterior repair or perineorrhaphy were at the discretion of the operating surgeon. The length of the perineal body at baseline may have impacted the decision to perform a concomitant procedure. A previously published secondary analysis paper of the OPTIMAL trial
determined that the performance of a posterior repair at the time of apical suspension was not independently associated with surgical success. Preoperative genital hiatus was prognostic of prolapse recurrence regardless of concomitant posterior repair.” (Sutkin, G., et al)
Reference:
Sutkin G, Zyczynski HM, Sridhar A, et al. Association between adjuvant posterior repair and success of native tissue apical suspension. Am J Obstet Gynecol. 2020 Feb;222(2):161.e1- 161.e8.
2. In text or as footnote in the tables please include what was adjusted for in each model.
Response: Thank you for this comment. We have modified the manuscript in response to this comment with new table footnotes. Footnotes listing the variables included in each model have been added to the tables.
Discussion
1. Could the authors discuss the possibility that one explanation for the increased surgical
failure but decreased POPDI, UDI and CRADI scores associated with higher baseline POPDI score
could be related to the fact that there are non-symptomatic criteria included in the "surgical
failure" definition? One explanation could be that having an apex descend 1/3 of the length of
the vagina counts as "failure" but the patient may have no other symptom findings that would
be reflected in the questionnaires. This is mentioned only briefly in 1 sentence in the discussion
and merits further discussion.
Response: Thank you for this comment. We have modified the manuscript by adding the following statements to the discussion:
• Lines 281-285: “Despite meaningful improvement in symptoms, participants with higher presurgical symptom scores may still have been classified as surgical failures based on anatomic criteria alone. Further research is needed to clarify the patient-preference and values for surgical outcomes of reconstructive prolapse procedures.”
2. The authors state that a longer perineal body may also correlate with a wider GH- was this the case in this study population?
Response: Thank you for this comment. In this study population, the Pearson correlation between preoperative PB and GH was 0.69 (weak correlation). We have not modified the manuscript in response to this comment.
3. The authors mention a weak correlation between worsening UDI in participants who may have been peri-menopausal but this information is not presented in the results section.
Please mention this in the results or consider removing from the discussion.
Response: Thank you for this comment. We wish to draw attention to existing text that is in the results section.
• Lines 166-8: “…worsening of the UDI score in the small number of participants that categorized themselves as unsure of their menopausal status and were presumably perimenopausal at the start of the study (Table 3).”
4. The authors suggest that the POPDI score may be a proxy for burden of other pelvic floor disorders that are not addressed by the surgical intervention. In this study- the surgical intervention was aimed at POP and SUI, but the authors suggest that other pelvic floor disorders not affected by the surgery (presumably UUI, FI, etc) explain their finding that patients had symptomatic improvement but were not as likely to meet surgical success.
However, one would assume that this phenomenon would be reflected in the UDI scores or CRADI. This point is a little confusing would benefit from clarification.
Response: Thank you for this comment. This statement refers to the impact of the POPDI subscale score (prolapse symptoms specifically) on the composite definition of surgical success.
The other pretreatment subscale scores (UDI and CRADI) did impact post-treatment scores but were not independent risk factors for surgical success.
The following explanation was added to the discussion section and further clarifies this point:
• Lines 281-285: “Despite meaningful improvement in symptoms, participants with higher
presurgical symptom scores may still have been classified as surgical failures based on
anatomic criteria alone. Further research is needed to clarify the patient-preference
and values for surgical outcomes of reconstructive prolapse procedures.”
a. Could the authors discuss how their definition of surgical failure which includes asymptomatic measures could affect their finding of higher POPDI scores being associated with lower surgical "success," but higher rates of symptomatic improvement? (see point 1 of discussion)
Response: Thank you for this comment. Participants with higher presurgical POPDI scores had more potential for improvement in symptoms than women with lower presurgical scores or less bother.
We have modified the manuscript in response to this comment by adding text to the discussion.
• Lines 281-285: “Despite meaningful improvement in symptoms, participants with higher presurgical symptom scores may still have been classified as surgical failures based on anatomic criteria alone. Further research is needed to clarify the patient-preference and values for surgical outcomes of reconstructive prolapse procedures.”
b. Was there any change in outcome of final questionnaire scores in the patients who underwent BPMT prior to surgery, as this could impact other pelvic floor disorders not addressed by surgery?
Response: Thank you for this comment. The aim of this study was to identify pre-treatment risk factors associated with surgical success. The effect of BPMT is outside the scope of this analysis.
The primary OPTIMAL and EOPTIMAL papers did not find a significant effect of BPMT on postoperative questionnaire scores.
Reviewer #2: Objective (Abstract)To determine independent risk factors for surgical failure and worsening pelvic floor symptoms within 5 years following vaginal prolapse surgery.
Objective (Introduction) multivariable modeling of independent risk factors for surgical failure and new or worsening pelvic floor symptoms up to 5 years after transvaginal native tissue pelvic organ prolapse repair.
A secondary analysis of the Operations and Pelvic Muscle Training in the Management of Apical Support Loss (OPTIMAL) (n=374) and extended trial (E-OPTIMAL) (n=285) participants. The e-Optimal was
recently published in JAMA 2018 Title and Precis are the same. I would think the findings are simple enough they could be stated in the Precis
Introduction: Well written, guides the reader through the logic. I would include the actual results of the E-Optimal trial regarding surgical failure (high) not simply the statement of NO difference, because of their clinical significance Methods takes the reader through the Optimal and E-optimal and then the secondary analysis
Response: Thank you for this comment. The following text (seen in itaalics) was added to clarify this point.
Lines 45-47: “Clinically and statistically significant improvements were seen in quality of life,
sexual function, and body image without significant differences between groups in anatomic
and functional outcomes; however surgical success rates were suboptimal.”
Lines 51-53: “Given the undesirable rate of surgical failure, additional research is needed to understand the risk factors associated with recurrence and re-operation for pelvic organ prolapse.”
Discussion: Under strengths "Furthermore, a high percentage of participants contributed longitudinal follow-up data, and the E-OPTIMAL cohort was similar to the OPTIMAL cohort" The women who opted to not participate in the e-cohort clearly had earlier surgical failures This statement seems very contradictory to the great differences in the groups as you reported in the first paragraph of Results.
Response: Thank you for this comment. The statement regarding the similarity between the OPTIMAL and E-OPTIMAL cohorts referred to similarity in pre-treatment characteristics. We have modified the manuscript by adding this clarification, seen below in itaalics to the discussion.
• Lines 269-271: “Furthermore, a high percentage of participants contributed longitudinal follow-up data, and the E-OPTIMAL cohort was similar to the OPTIMAL cohort with respect to pretreatment characteristics.”
1) Given that one of the significant findings were Hispanic (no known mechanism), Did you evaluate this subgroup in detail regarding difference from the larger group: more babies?
older?, significantly worsened symptoms at time of surgery and higher POPDI ? Increased BMI?
If they weren't different please state how you compared them.
Response: Thank you for this comment. The following statement were added to the discussion.
• Lines 199-205: “Although we did not examine the characteristics of Hispanic participants, age, BMI, and number of deliveries were all considered in the model building process; none of these factors were associated with surgical failure. Thus, it is unlikely that those characteristics account for the effect of Hispanic ethnicity. Hispanic ethnicity and higher baseline POPDI score were both associated with surgical failure in the final model, indicating that each was independently associated with the outcome even after controlling for the other.”
2) Can you talk about the CI for Hispanic race as it is close to 1 and the widest of all the findings Response: Thank you for this comment. The point estimate for the adjusted odds ratio for Hispanic ethnicity is 1.92, and the 95% CI is 1.17 to 3.15. The distance of the lower bound from 1, and the width of the 95% CI, are consistent with the statistical significance of the AOR which is 0.01. If the p value was closer to 0.05, the lower bound of the 95% CI would be closer to 1 and the width of the CI would be wider. The widths of the CIs for the other significant risk factors are narrower, consistent with the more significant p values. We have not modified the manuscript in response to this query.
3) Can you talk about a normal Perineal body length is it known to be 3.4 cms +- 1 cms , what
did the actual measurements of a longer PB look like?
Response
Thank you for this comment. The best available data for average perineal body length in patients being evaluated for pelvic floor disorders is 3.34 +/- 0.9cm and does not significantly vary across prolapse stages (Dunivan, G. et al).
In our data, the median preoperative PB was 3 cm, the 75
th percentile was 4 cm, and the
maximum was 7 cm. In the model results, the adjusted OR for PB is interpreted as the increased odds of surgical failure for every 1 cm increase in baseline PB. We have not modified the
manuscript in response to this query.
Reference:
Dunivan, G., Lyons, KE., Jeppson, PC., et al. Pelvic organ prolapse stage and the relationship to genital hiatus and perineal body measurements. Fem Pel Med REconstr Surg 2016 Nov-Dec;
22(6):497-500
4)Given that you are looking at factors that contribute to long term failure. After Table 1
Comparing Optimal and E-Optimal I would think Table 2 would be comparing women who failed surgically or anatomically and compared characteristics between those two groups? It would help the reader with the storyline. You describe this in your methods section but the only part the reader sees is the final product
Response: Thank you for this comment. Since a participant may be a success at some timepoints and a failure at others, it is not straightforward to present a table comparing the baseline characteristics of successes and failures. Respectfully, we believe that the tables presenting the results of the statistical models, which longitudinally model outcomes from 6 months through 5 years, are the most informative way of showing the associations between baseline characteristics and outcomes. We have not modified the Table or manuscript in response to this suggestion.
Reviewer #3: 1. I found the wording in Abstract Results on page 8 to be confusing. Consider breaking up the one very complex sentence into several. Replace perineal body with more descriptive verbiage for clarity: e.g. increased preoperative perineal body measurement. The latter part of the sentence is so complex that it is difficult to read.
Response: We appreciate this comment and have revised the abstract.
• Lines 18-24: “Statistically significant baseline risk factors for surgical failure were
Hispanic ethnicity (adjusted odds ratio [AOR]1.92, 95%CI 1.17, 3.15), perineal body (AOR 1.34, 95%CI 1.09,1.63), and baseline POPDI (AOR 1.16, 95%CI 1.05,1.28). Risk factors for worsening of pelvic floor symptoms were baseline POPDI (AOR 0.75, 95%CI 0.60,0.94) for worsening POPDI; vaginal deliveries (AOR 1.26, 95%CI 1.10,1.44) and baseline UDI (AOR 0.86, 95%CI 0.80,0.93) for worsening UDI; age (AOR 1.03, 95%CI 1.01,1.05) and baseline CRADI (AOR 0.95, 95%CI 0.92,0.98) for worsening CRADI.”
2. In the Introduction you state that patients had Stage 2-4 prolapse, even though you point out
that these are POP-Q measurements, it would be informative to add that information here.
Response: We appreciate this suggestion and have modified the manuscript by adding the following text to the Methods.
• Lines 67-70: “Participants had stage 2-4 apical prolapse (determined by baseline POPQ exam) with symptomatic stress urinary incontinence and underwent a vaginal
suspension surgery with a planned hysterectomy (in participants with a uterus) and retropubic mid urethral sling.”
3. On page 12, you state that a phone interview allowed inclusion in follow-up in e-OPTIMAL patients. I can see how a phone interview is useful for validated questionnaires, how does a phone interview account for failure assessment, other than subjectively?
Response: Thank you for this insightful comment. As the reviewer points out, only subjective outcomes were assessed for E-OPTIMAL participants who were followed up only by phone. The manuscript was not modified in response to this comment.
4. On page 12 you note that in e-OPTIMAL the primary outcome was a time-to-event
occurrence for failure (as defined in the paper). Later, in the Discussion on page 17, there is a notation that fewer failure patients enrolled in e-OPTIMAL. Does that mean you are analyzing a group that was more "non-failure" at 2 years, and if so, how might that change your analysis and opinions? Could time-of-failure analysis further understanding of the complex statistical analysis you have presented in this paper?
Response: Thank you for the opportunity to clarify. We have modified the methods portion of the manuscript in response to this comment. This analysis included all women who were randomized in OPTIMAL, and outcomes from 6 months through 5 years were included in the models. The manuscript was not modified in response to this comment.
5. page 15 in the speculation regarding the surprising finding that an increased perineal body measurement is identified as a risk factor for failure, there is mention that there may be
perineal descent associated with damage to the levator muscles. That finding is also present in apical disruption of the rectovaginal septum. You also mention a possible increase in Genital Hiatus, is that data available? If GH is increased, and that results in a spuriously increased PB measurement, what is the real association with failure? Does increased GH spuriously increase PB measurement during Valsalva and, if so, what is the significance? To me, this is the finding of the paper that is most amenable to further analysis on a clinical level.
Response: We, too, were intrigued by this finding. Although our data cannot address these
thoughtful questions directly, we agree that there is much to consider for future studies as our
model results indicate that PB is associated with surgical success after controlling for GH; that
is, for two women with the same GH, the woman with the longer PB had higher odds of surgical
failure. We have not modified the manuscript in response to this comment and hope that
readers will be similarly engaged in thinking about the possible explanations for our findings.
6. On page 16, in the discussion of ideas regarding Hispanic patients, you use the term
"biomechanical axis". More clarification would be helpful, e.g. deep endopelvic connective tissue, variances in collagen-elasitin content and strength, etc.
Response: We agree that this statement is confusing and there is insufficient evidence to support it. The following sentence was removed from the paper: “It is certainly plausible that there are biological factors within the musculo-skeletal, neuronal or biomechanical axis that could detract from longer-term surgical success.”
7. Does this paper suggest ideas for additional analysis (as with the perineal body genital hiatus comments above) or ideas for future studies?
Response: Thank you for this comment. We believe that readers will be stimulated to consider further research ideas. We have not listed potential study approaches, as it is beyond the scope of a discussion of our findings.
Overall an excellent and thought provoking paper.
Response: Thank you – we appreciate the opportunity to share our work.
STATISTICAL EDITOR COMMENTS:
The Statistical Editor makes the following points that need to be addressed:
1. General: In last line of paragraph 1 in Results, 13/28, the % is cited to 0.1% precision. In that instance and if there are others with similar limited denominators, the % should be rounded to nearest integer %, not cited to 0.1% precision.
Response: We have modified the manuscript in response to this comment. In the text and tables, percentages have been rounded to integers where the denominator is less than 100.
2. The aORs give relative odds, but more data needs to be presented re: absolute risks associated with various factors.
Response: We have modified the manuscript in response to this comment. Unadjusted results have been added for comparison with the model results in Tables 2 and 3 (see responses to items #5 and #6 below).
3. Although from the standpoint of models, the various input variables are "predictors", by the
nature of this study design, what one can discern are associations. That distinction needs to
made clearer in the exposition of results and discussion.
Response: We appreciate this helpful suggestion. The results and discussion section refer to
“associations” between baseline characteristics and outcomes as opposed to stating that they
“predict” outcomes.
4. Table 1: Need units for age, BMI.
Response: We have modified the manuscript in response to this comment by adding units as requested.
5. Table 2a: No necessary to include p-values, when the CIs are already included. Need to include the unadjusted ORs for contrast, need to include in footnote a list of all variables included in the final model. Need to include (could be on-line material), a list of all data citing counts of surgical failure, use of estrogen therapy, worsening MID etc.
Response: Thank you for this comment. We have modified the manuscript in response to this
comment. Unadjusted ORs and 95% CIs for each follow-up time point have been added to a
Supplemental Table 1. A footnote has been added to Table 2 which lists the independent
variables included in the model. Consistent with the comment below, p values have been
removed from the table. Counts of participants with estrogen therapy and other baseline
characteristics are provided in Table 1. Another supplementary table (Supplemental Table 2)
has been added with counts of each outcome, including surgical failure, at time points through
5 years.
Supplemental Table 2. Counts of Each Outcome at Timepoints Through 5 Years
Outcome Timepoint Events (n) % Total (N)
Surgical Failure 6 months 51 19.2% 266
1 year 74 27.4% 270
2 years 81 29.3% 276
3 years 81 34.0% 238
4 years 82 40.0% 205
5 years 74 34.9% 212
POPDI worsening MID 6 months 9 2.8% 327
1 year 3 1.0% 312
2 years 14 4.8% 294
3 years 11 4.7% 236
4 years 9 4.2% 216
5 years 9 4.2% 216
UDI Worsening MID 6 months 10 3.1% 327
1 year 8 2.6% 311
2 years 19 6.5% 292
3 years 13 5.7% 228
4 years 14 6.6% 211
5 years 14 6.6% 211
CRADI Worsening MID 6 months 24 7.3% 328
1 year 27 8.7% 312
2 years 42 14.3% 293
3 years 35 15.1% 232
4 years 46 21.4% 215
5 years 46 21.4% 215
6. Table 2b: Not necessary to include p-values, since the CIs are already included. Need to include a list of variable s retained in final model.
Response: We have modified the manuscript in response to this comment. P values have been removed from the table, and a footnote has been
added which lists the independent variables included in the model.
7. General: Since the follow-up extended to variable time points after surgery up to 5 years, need to cite the n(%) remaining of the original cohort at each time point and need to address how loss to follow-up might have biased the results. Specifically, need to compare the
demographic characteristics of those at baseline vs those with follow-up to assure the reader that potential selection bias has been addressed.
Response: We have modified the manuscript in response to this comment. We have included a supplementary table with counts of each
outcome at time points through 5 years which also shows the number of the original cohort with follow up at each time point. Table 1 compares the baseline characteristics of the OPTIMAL and E-OPTIMAL cohorts to demonstrate their similarity.
The italicized text has also been added to the discussion section:
• Lines 273-8: “there is potential bias due to loss of participants from OPTIMAL especially as the participants with surgical failures by 2 years were less likely to enroll in E-OPTIMAL (6). However, the statistical modeling methods used in this study assume that missing outcomes are “missing at random,” thus the model results take into account that the unobserved outcomes at 3 to 5 years among participants who did not enroll in E-OPTIMAL may be related to the data collected through 2 years.”
MANUSCRIPT EDITOR COMMENTS:
Renumber your tables to avoid using "a" and "b." Please number them as Table 1, Table 2, and Table 3.
Response: We have modified the manuscript in response to this comment and renumbered the tables as requested.
Would you describe why Table 2a cites reference 1 the table title?
Response: We have removed the cited reference.
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Precis: 21 words Abstract: 286 words
Total word count: 5,500 words (excluding references)
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Response: This is a short title that can be used: Risk factors for failure after prolapse repair
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b. PB for "perineal body"
c. BPMT for "behavioral therapy with pelvic floor muscle training"
d. "SSLF for sacrospinous ligament fixation"
e. ULS for uterosacral ligament suspension"
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Response: We do not believe the revised version of our manuscript has any instances of the use of the virgule in any sentence with words.
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Response: We have modified the manuscript to make the suggested changes.
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Response: This does not apply for our manuscript.
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