Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: APPENDICULAR ANATOMY OF THE ARTIOPOD EMERALDELLA BRUTONI FROM THE MIDDLE CAMBRIAN (DRUMIAN) OF WESTERN UTAH
Review round: 1
Reviewer: 3

Output:
Basic reporting: The manuscript presents a new specimen of Emeraldella brutoni, an arthropod from the early Cambrian of Utah. The new specimen is preserved in lateral view compared to the dorsal view on the holotype, and as such preserves much of the ventral morphology that was previously unknown from the species.

The manuscript is clear and unambiguous, with appropriate reference to the literature and suitable structure.
Experimental design: No comment.
Validity of the findings: The findings are supported by the available data, and the conclusions are well stated.
Additional comments: This is a solid manuscript, and I only have a couple of suggestions. The first is that it may be worthwhile to also re-figure the holotype, so that both specimens can be directly compared. Secondly, the preservation on the specimen does not appear to be such that you can state with certainty that there is only one articulation on the telson; the antennae, which are multiannulate, in places do not preserve the articulations and look fairly straight. The interpretation of articulations in the telson therefore should be treated with caution.

Otherwise, just a couple of typographic errors to correct:

Line 39: Presumably you mean 'improve' rather than 'improvise'.
Line 76: "End up in" rather than "End in"
Line 112: "Twice as thick" rather than "twice thicker"
Line 241: "of E. brocki that are exposed" instead of "of that E. brocki are exposed"
Line 362: "Sturmer" instead of "Surmer".


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: HIGH EXPRESSION OF HSP90 IS ASSOCIATED WITH POOR PROGNOSIS IN PATIENTS WITH COLORECTAL CANCER
Review round: 1
Reviewer: 1

Output:
Basic reporting: The manuscript is well written and easily understandable but still some corrections needed (ex line no 175). Good number of relevant literature references included. Article structure is fine. In the introduction, removing the second paragraph will not affect and will improve the flow of the manuscript. In the figure 1, I am suggesting to include error bars. Also it should be included that the number of samples/sequences considered in each cancer type to generate figure1
Experimental design: No comment
Validity of the findings: no comment
Additional comments: No comment


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: HIGH EXPRESSION OF HSP90 IS ASSOCIATED WITH POOR PROGNOSIS IN PATIENTS WITH COLORECTAL CANCER
Review round: 1
Reviewer: 2

Output:
Basic reporting: In this manuscript, the authors confirmed that HSP90 is expressed in higher level in colorectal cancer (CRC) tissues than para-cancer normal tissues, and they demonstrated that high expression of HSP90 is associated with poor prognosis of CRC patients. They also looked at 85 genes correlated with HSP90 in expression, and did GO analysis and KEGG analysis. This study looks simple, clear and straightforward.
Experimental design: no comment
Validity of the findings: no comment
Additional comments: Major comments:
1. Line 160 the definition 'Pearson corr. >= 0.04, P<0.0001' vs. Line 223 '|Pearson corr. coef.| > 0.4' for positively correlated genes are very different. Which one is actually used? And if absolute value of Pearson corr. coef. is used, it should be only described as 'correlated' but not 'positively correlated'.
2. Line 176-177, 'Further separated analysis ... also consistent with above results (Fig 1C)'. Fig 1A-1C seems to be all generated by GEPIA, thus they are based on exactly the same data source. Therefore, 'Further ... also consistent' might be a little misleading and impropriate here. Do the highlighted (in red) cancer types in Fig 1B all have statistically significant differences as shown in Fig 1C? What statistical test is used for Fig 1B and 1C?
3. Line 188, 'Statistical analysis showed', what statistical test is used here? Since the score index is set by multiplication and its distribution looks deviated from normal distribution, I suppose the authors should use the nonparametric Mann-Whitney U test (i.e. Wilcoxon rank-sum test) here.

Minor comments:
1. Line 39, abbreviation 'CRC' is not explained in its first appearance.
2. Line 42, 'colorectal cancer tissues (CRC)' might be better as 'colorectal cancer (CRC) tissues'
3. Line 52-54, 'Moreover, 85 genes ... assigned to ... xxx GO terms' looks of little meaning or information.
4. Line 144, since 'GEPIA' is actually used to generate all figures of Fig 1, it may deserve a better citation.
5. Line 175, 'Fog Fig 1B' might be typo of 'Fig 1B'.
6. Line 182, 'score index' might be better as 'HSP90 expression score index' for clarity.
7. Line 202, 'M category' might be better explained.
8. Line 223, '85 genes were positively correlated with the expression of HSP90' might be better listed in a (supplementary) table. The GO terms listed in Fig 5 and 6 look so general and thus with little information.
9. Line 252, 'TNM stage' seems to be equivalent to 'AJCC stage'; 'TNM' is only used once here, while 'AJCC' is used many times elsewhere. And both abbreviations are not explained.
10. Figure 1, the abbreviations of cancer types are not explained.
11. Figure 2B, y-axis label '-5' seems meaningless.
12. Figure 5, does the color legend for Pvalue mean the original (uncorrected) p-value? Why not show in q-value, just like that in Fig 6B? And in Fig 6B, because the color legend has most range of insignificant q-values, it is not clear whether the top two enriched terms are actually still statistically significant or not after multiple-test correction.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: HIGH EXPRESSION OF HSP90 IS ASSOCIATED WITH POOR PROGNOSIS IN PATIENTS WITH COLORECTAL CANCER
Review round: 1
Reviewer: 3

Output:
Basic reporting: No comment
Experimental design: This research work is covered within the Aims and Scope of the journal.

The research questions are well defined, relevant & meaningful.

Rigorous investigations on the tissue biopsies were performed to a high technical & ethical standard.
Validity of the findings: Conclusions are well stated, linked to original research question & limited to supporting results.
Additional comments: This study designed to test the single gene HSP90 expression in CRC patients and healthy controls. Before performing this study, the authors tested in GEPIA databases, whether the HSP90 is the right target genes and identified that HSP90 is highly expressed in various cancers. The following questions need to be addressed.

1.	The P-values for 10 cancer types for hsp90 is missing in the results.
2.	Provide boxplot and correlation for HSP90 gene expression comparing the 99 CRC patients and 81 healthy controls. Are they significant between cases and controls?
3.	The authors performed the chi-squre test and fisher’s exact test to see the significant differences between clinicopathological characteristics of CRC patients. What about simple t-test between the groups and the HSP90 expression.
4.	The author selected 85 co-expressed genes from TCGA dataset and performed the pathway analysis. What about the co-expression of HSP90 in GEPIA? Does the author detect the same 85 genes that are co-expressed in HSP90 or those 85 genes are specific to TCGA?
5.	How significantly those 85 genes are enriched in Figure 5B-5C, are they significant by p-value?
6.	Figure legends were not provided


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: HIGH EXPRESSION OF HSP90 IS ASSOCIATED WITH POOR PROGNOSIS IN PATIENTS WITH COLORECTAL CANCER
Review round: 2
Reviewer: 1

Output:
Basic reporting: No comment
Experimental design: no comment
Validity of the findings: no comment
Additional comments: No additional comments


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: HIGH EXPRESSION OF HSP90 IS ASSOCIATED WITH POOR PROGNOSIS IN PATIENTS WITH COLORECTAL CANCER
Review round: 2
Reviewer: 2

Output:
Basic reporting: The authors addressed all the questions raised by the reviewer
Experimental design: The authors addressed all the questions raised by the reviewer
Validity of the findings: The authors addressed all the questions raised by the reviewer
Additional comments: The authors addressed all the questions raised by the reviewer.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: IDENTIFICATION OF KEY GENES AND PATHWAYS ASSOCIATED WITH CHOLANGIOCARCINOMA DEVELOPMENT BASED ON WEIGHTED GENE CORRELATION NETWORK ANALYSIS
Review round: 1
Reviewer: 1

Output:
Basic reporting: The language is in general good. The rules for the tables, datas, formatting are proper followed. However, the authors can improve the clarity of the paper.

The author wrote very general introduction about CCA. It will be relevant to review the current progress of the genetics and bioinformatic analysis for CCA.

The same with the discussion part. The novelty of WNT signaling is limited so please write it simple. It will be good to write on the secretion signaling and also discuss function of the genes.

I would like to see the authors illustrate the reason to use tan and salmon module in GO analysis.

Please write full name of any abbreviation when mentioned first time.  Please provide the full name and abbreviation of WGCNA in line 28. Same thing with “TCGA”.
Experimental design: The authors attempted to identify potential biomarkers highly associated with tumor progression. However, the results may only be biomarkers for late stages but not the early detectors for CCA due to the author’s design. Since they used the information after the tumor initiated, comparing Stage I-II with Stage III-IV, their result can be metastasis makers or late progression markers. The later only has limited clinical significance.

Biomarkers for metastasis is of great significance clinically. Nevertheless, the TNM system combined information of the metastasis and tumor orthotopic growth. The TNM system might not be the best trait to identify such markers. I will like to see the analysis to specifically identify genes with a more specific biological function, such as metastasis. This is better for follow-up studies too to link the genes with biological function.

The TCGA database need to be proper sited. There are at least two TCGA datasets. The author needs to specify the set.

Furthermore, the authors analysis 33 patients but there are additional samples in PanCancer Atlas or provisional sets. The author needs to list the reason for such selection or include all the samples.
Validity of the findings: Recently, a paper with the similar approach was published (Mao et al. Hepatology Res. June 2019). The originality is thus limited here. However, Mao et al. dissect the genome network by other bioinformatic tool to explore the protein-protein interaction. On the other hand, the authors adopted Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis to explore the biological functions for the tumor progression. The result putative gene list is very different within two papers. Therefore, Liu et al. still brought valuable information for cancer-driven genes of CCA.

 Besides, in the draft the authors need to mentioned the above paper and compare it with the author's study.
Additional comments: Weighted correlation network analysis (WGCNA) is an established gene co-expression analysis method. Liu et al. applied WGCNA to the data from The Cancer Genome Atlas (TCGA). They identified several genes as putative biomarkers for cholangiocarcinoma (CCA).


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: IDENTIFICATION OF KEY GENES AND PATHWAYS ASSOCIATED WITH CHOLANGIOCARCINOMA DEVELOPMENT BASED ON WEIGHTED GENE CORRELATION NETWORK ANALYSIS
Review round: 1
Reviewer: 2

Output:
Basic reporting: No issues
Experimental design: -"If the expression of genes showed limited variation, we regraded them as noise and discard these ones."; I'm unclear as to why this was done
-"We chose genes associated with prognosis as candidate genes"; Cant say I agree with this. I'd rather see it more open ended regarding the selection of genes. I'd rather see the prognostic of genes more frequently implicated in CCA, not necessarily genes we may / may not encounter
-I'm not sure how the tan and salmon modules were specifically made. This part is unclear in both the methods and results. The Gene Ontology and KEGG methods need to be better defined and described
Validity of the findings: -The concept of modules based on GO does not make much sense, given the epigenetic factors which may be at play and the lack of commonality between some of the genes in the same  modules. What would be better would be to report on the individual genes themselves. Additionally focusing on gene expression beyond the GO clusterings would be far more implicating. For example reporting on the frequency altered gene expression for major genes as BAP1, TP53, KRAS would be far more interesting and practical.
-If modules were to be used what would be needed would be the exact frequency of these mutations detailed in TCGA data. It is not clear how frequently mutations (ie SOX2, KIT)  and altered gene expression (of these proteins) are encountered in CCA to begin with.
-I would also be interested in knowing the prognostic and expression profiles other other modules such as DNA repair and immune based mechanisms. Given the therapeutic implications involved in these, these need to be described
Additional comments: -GO and KEGG analysis need to be better described. It is unclear based on the study exactly how the submodules were mapped
-Focus should be on protein expression of major genes which are more frequently implicated in CCA (ie TP53, BAP1). Unclear of the frequency of some of these mutations and through what means their expression is altered (ie epigenetic regulators)

Bottom Line: Overall interesting article. I'm not totally convinced of the findings, given the unclear frequency of some of these alterations and possible other factors contributing to altered gene expression in some of these cases. What I would be more interested in would be prognostic implications of genes tied to major mutations in CCA (ie KRAS, TP53, BAP1 etc) and gene expression signatures involving immune regulatory genes and DNA damage regulating genes, given potential therapeutic implications for both. I'm sure the data is there it just needs to be tailored to make an interesting case for prognosis and potential treatments for CCA.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: IDENTIFICATION OF KEY GENES AND PATHWAYS ASSOCIATED WITH CHOLANGIOCARCINOMA DEVELOPMENT BASED ON WEIGHTED GENE CORRELATION NETWORK ANALYSIS
Review round: 2
Reviewer: 1

Output:
Basic reporting: The writing is clear with professional English.

My comments for the intro and discussion section have been covered.
Experimental design: The author has explained the current knowledge gap. In the current version, the authors provide details about the methods, specifically about the GO and KEGG.
Validity of the findings: The authors have added more information about the current progress for the analysis of TCGA data of CCA. It is sufficient for publication
Additional comments: The authors have addressed all my comments. The paper meets the criteria of PeeJ Review


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: COMPARISON OF PREDICTION POWER OF THREE MULTIVARIATE CALIBRATIONS FOR ESTIMATION OF LEAF ANTHOCYANIN CONTENT WITH VISIBLE SPECTROSCOPY IN PRUNUS CERASIFERA
Review round: 1
Reviewer: 1

Output:
Basic reporting: The manuscript is well written with sufficient references and field background. In addition, sufficient data (figures and tables) were also provided.
Experimental design: - Research question well defined.
- Rigorous investigation performed to high technical and ethical standard
- However, method description should be improved (refer to my comments).
Validity of the findings: The findings are very useful for future research, however, supporting data should be provided (please refer to my comments).
Additional comments: Reviewer’s general comments: The manuscript reports on the application of multivariate data analysis to predict anthocyanin content in the leaf of Prunus cerasifera. It is quite interesting paper comparing three methods: PCR, PLSR, and BPNN modelling for their prediction capacity. However, there are some points need to be addressed

Line 114: How many gram is the leaf samples? Please mention
Line 115: Please add time of extraction (soaking)
Line 134: Where are the results for correlation analysis? I don’t find in the table or figure
Line 156: What is the software used to construct the PCR and PLSR models? Should be mentioned
Line 175-176: How to assign the samples as calibration set and validation set? Selection method?
Line 216: “RPDval values above 2.5 and the R2val values below 0.9 for the other 5 PCR models indicated that very good quantitative predictions”
Shouldn’t the higher value of R2 is the better? I suggest to change this statement to
“RPDval values above 2.5 and the R2val values in range of 0.80≤R2<0.90 for the other 5 PCR models indicated that very good quantitative predictions”
Line 279-281: Which results saying calibration and predicted of PCR and PLSR models were significantly different? Not clear. And then the comparison is between the same pretreatment in the same model or between the different pretreatments in the same model? Its better to show the sig value (pvalue) of this comparison data.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: COMPARISON OF PREDICTION POWER OF THREE MULTIVARIATE CALIBRATIONS FOR ESTIMATION OF LEAF ANTHOCYANIN CONTENT WITH VISIBLE SPECTROSCOPY IN PRUNUS CERASIFERA
Review round: 1
Reviewer: 2

Output:
Basic reporting: The manuscript describes a comparative study for evaluating three different chemometric models used for quantitative determination of anthocyanin content in Prunus cerasifera leaves based on their UV Vis measurements. Moreover, different preprocessing methods were also evaluated to determine the optimal spectral pretreatments. The manuscript is neat and well written however some points are needed to be considered:
In the introduction section, the authors should explain the importance of using the multivariate models and their potential to determination different chemical classes in plants and with special focus on coupling of UV Vis spectrophotometry with the multivariate analysis as this is the core of the manuscript.
Experimental design: no comment
Validity of the findings: My major concern is regarding non-linear neural network model that has been applied besides PCR/PLS models. Either the studied data is linear, and hence PCR/PLS should be the calibration tool of choices, or the data is not linear, in which case it might be justified to move to a non-linear calibration model. The lack of linearity could be checked in the multivariate case with suitable statistical tests [ Anal. Chim. Acta 552 (2005) 25-35; Anal. Chim. Acta 376 (1998) 153-168]. The results of these tests, combined with a statistically significant improvement in prediction error by applying non-linear models, might constitute a proof that the system behaves in a non-linear manner. One particularly appealing technique is based on the augmented partial residual plots (APARP) which can be constructed for PLS models [Detection of nonlinearity in multivariate calibration, Anal. Chim. Acta 376 (1998) 153-168]. The following is the recommended protocol: (1) model the multivariate data with A latent variables, (2) regress analyte concentrations against an augmented model including the A scores and the squared values of the first score, (3) plot the portion of the concentration data modelled by the first score and the squared first score vs. the first score, (4) compute the residuals of the linear regression of the latter plot, and finally (5) check for the presence of correlations in the residuals of the latter regression using a suitable statistical test. If significant trends are found in these APARP residuals, the data can be considered non-linear.
Another important issue is the poor optimization of the neural networks where the authors used just 10 nodes between the first and second layer based on a previous study on soil properties using visible and near infrared spectroscopy which is not acceptable. The machine learning algorithms usually suffer from over fitting which required careful optimization of the parameters which in case of ANN are number of nodes, learning rates, momentum, transfer function and the training algorithm.
Finally, the performance of these models should be carefully checked through suitable statistical procedures. It is necessary to check whether the RMSE for test samples is indeed smaller (statistically significantly or not).
Additional comments: No additional comments


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: COMPARISON OF PREDICTION POWER OF THREE MULTIVARIATE CALIBRATIONS FOR ESTIMATION OF LEAF ANTHOCYANIN CONTENT WITH VISIBLE SPECTROSCOPY IN PRUNUS CERASIFERA
Review round: 1
Reviewer: 3

Output:
Basic reporting: There are some typos and formatting that need amendment. We advise the author to care for tense throughout the manuscript. Also, references need to be revised for formatting and uniformity.
Experimental design: No comment
Validity of the findings: We would like to see more supporting literature on the idea of the and impact of the work. Are there valid problems for anthocyanin assessment? What value does the paper add? Does it save time? Solvents? Is it the software available for use? Are the results repeatable?
Additional comments: The work as presented deals with one species and optimizes or encourages the use of a certain chemometric model and preprocessing for predicting anthocyanin content spectrophotmetrically. But how can we make sure that this model is rigorous and repeatable if we used other species? If there were economic importance for the studied species, then I would understand the importance of the work. But since this is just a study of optimizing anthocyanin content using one example, emphasis has to be made on the importance of applying this method on other anthocyanin containing plants.
Also, why did the author select these 3 chemometric models for comparison?


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: WORLDWIDE INEQUALITY IN ACCESS TO FULL TEXT SCIENTIFIC ARTICLES: THE EXAMPLE OF OPHTHALMOLOGY
Review round: 1
Reviewer: 1

Output:
Basic reporting: See general comments. Article is well written in professional English. Some supplemental data files use French column names and documentation, although I imagine most users can deal with that.
Experimental design: See general comments.
Validity of the findings: See general comments.
Additional comments: The study compares fulltext access to 115 toll-access ophthalmology articles from 27 institutions around the world. In order to recruit participating institutions at a global scale, the organizers used an intriguing crowdsourcing approach by emailing corresponding authors of recent ophthalmology publications. The study found that alternative access methods (green OA combined with "online reprint request", i.e. requesting the PDF from an author) were able to access an average of 64% of the toll-access articles. Meanwhile, Sci-Hub provided access to 94% of the toll-access articles.

This study is impactful as a comparative analysis of institutional fulltext access across the globe. However, the analyses and visualziations do not present the findings of the survey to the fullest possible extent. Specifically, I was surprised not to see any plots of access rates by continent, income category, and Hinari access. A simple dot plot with access rate on the x-axes and category on the y-axis would provide important comparative summaries of the findings. Scatterplots may also be an option for comparing multiple continuous varaibles, with extra dimensions encoded by point color, size, or other attributes.

In addition, I was interested in discussion of the access rate of Hinari. It seems that this study should provide an answer to the question: "What percent of toll-access ophthalmology articles does Hinari provide access to?"

The discussion seems to imply that these analyses are not performed because of the low number of countries as well as the unequal selection. However, I still think it is important to visaualize access rates versus different factors, even in the absense of striking differences.

The study does not provide confidence intervals for proportions. There are many [existing, widely-implemented options](https://www.statsmodels.org/0.9.0/generated/statsmodels.stats.proportion.proportion_confint.html) to compute a confidence interval for a binomial proportion. In the [Sci-Hub Coverage Study](https://greenelab.github.io/scihub-manuscript/), we used the Jeffreys interval. It is essential that confidence intervals be reported, such that the reader can determine the uncertainty introduced by the small sample size of toll-access articles (n = 115). An example of a finding that demands a confidence interval is: "Used alone, Sci-hub allows the recovery of 108 full texts (93.9%) of 115." Presenting confidence intervals will likely illustrate that it would have been preferable to assess a larger number of toll-access articles (perhaps on the order of 500 articles). I do think the small sample size is a shortcoming of this study, but understand that increasing the sample size may not be possible at this stage. Confidence intervals are important to convey the uncertainty due to low sample size. It would be ideal to also present confidence intervals for the mean of access rates accross institutions. However, this is more complicated and may require a meta-analysis based approach.

Personally, I think "online reprint request" should not be grouped with Green OA availability into a single alternative access category. Specifically, ORR does not immediately provide access and is a laborious proceedure. It is also highly dependent on many factors that vary between invididuals. It is difficult to assess and control. So on one hand, it's helpful that the study analyzed ORR. On the other hand, it is not a reliable or controled method of article access. I understand that it may be too late to change this aspect of the study, but wanted to comment on it.

I wanted to point the authors attention to the 2016 study titled "[Correlating the Sci-Hub data with World Bank Indicators and Identifying Academic Use](https://doi.org/10.15200/winn.146485.57797)." I am not sure whether the authors were aware of this study, but it correlates Sci-Hub downloads to socioeconomic factors. These findings may provide interesting context for the fulltext access rates observed in this study.

In conclusion, the present work investigates a timely and important topic. The study design is innovative and reliable. The available of supplemental data is comprehensive. The main areas that need improvement are visualization of the findings and presentation of uncertainty.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: WORLDWIDE INEQUALITY IN ACCESS TO FULL TEXT SCIENTIFIC ARTICLES: THE EXAMPLE OF OPHTHALMOLOGY
Review round: 1
Reviewer: 2

Output:
Basic reporting: The manuscript is well structured and well written and I have only minor comments:

- The main body frequently refers to Sci-Hub being illegal. My understanding is that the legality of Sci-Hub depends on the jurisdiction in which the user accesses its services. The warning that's cited from Himmelstein et al 2018 in lines 381ff is more nuanced in that it points this out.
Unless the authors checked that using Sci-Hub is indeed illegal in all countries surveyed in this study, I'd encourage them to adopt a similarly nuanced language in the rest of the manuscript. If the authors checked and Sci-Hub is indeed illegal in all countries included in this study, it would be great if this could be pointed out too.

- I hate being the person who suggests adding one of their papers as a citation, but maybe http://dx.doi.org/10.15200/winn.146485.57797 could be useful to cite. In it I investigate global usage of Sci-Hub on a per-country level and correlate it with indicators such as GDP. This seems to fit well with the theme of this manuscript. But of course that addition is just a suggestion and by no means mandatory! :-)

- In some cases there are spaces missing to separate citations from the text (e.g. lines 105-108). It would be good to double check the references to see that they their formatting in the main body of the manuscript is correct.
Experimental design: Overall, the experimental design is well done, with a clearly outlined research question and appropriate methods to investigate it. The authors also do a great job in pointing out the limitations of their comparatively small random sample (200 journal articles out of 11,103 articles matching their search criteria). Given the large amount of manual labor involved in trying to access the paywalled proportion of these, the size of the subset is defensible.

The decision to limit the search to articles published in 2017-2018 could be a bit better motivated though. As the authors state (line 230f), recent articles are embargoed and will be found less frequently in the alternative access routes for that reason. My feeling is that sampling a bit older articles would avoid this issue and lead to numbers which are more 'stable' in time. I assume the focus on recent articles is done deliberately, as it's assumed that those articles are of most value to researchers who look for the latest findings to inform their own work. Pointing this out more clearly would be helpful.
Validity of the findings: All data are provided and the conclusions are well stated, supported and linked to the data and research questions. One minor thing:

The abstract states 'We found that complementary use of “alternative ways” and Sci-Hub leads to 95.5% of full text “paywalled articles”, and also divides by 14 the extra costs needed to obtain all full texts on publishers’ websites using pay-per-view.'

In the main body of the manuscript all I could find is 'Interestingly, complementary use of Sci-Hub reduces the average extra cost of unavailable full texts even more, dividing the maximum extra cost of unavailable full texts by 12.9'.

I could not fully understand whether this is based because of using different baselines for the calculations or because of a typo. It would be good to clear this up, as I couldn't find any reference to the 'dividing the cost by 14' anywhere but the abstract.
Additional comments: This is a really interesting manuscript about the impact of paywalls and alternative ways of accessing paywalled content. I think it will be a valuable addition for many people working in the field. All my comments above were really just minor changes that could make the argument a bit stronger. Well done!


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: WORLDWIDE INEQUALITY IN ACCESS TO FULL TEXT SCIENTIFIC ARTICLES: THE EXAMPLE OF OPHTHALMOLOGY
Review round: 2
Reviewer: 1

Output:
Basic reporting: See general comments
Experimental design: See general comments
Validity of the findings: See general comments
Additional comments: The authors addressed most of comments from my review of version 1.

The addition of Figure 2 is a major improvement. Figure 2b provides a striking finding: outside of the high-income bracket for countries, institutional + Hinari access is often below 50%. The two low income countries have particularly bad access. These findings suggests programs like Hinari are not succeeding in providing widespread access to countries that are not in the top income bracket.

I do have some remaining issues, regarding Figure 2 and the calculation of confidence intervals.

In Figure 2, rather than have the y-axis represent number of accessed articles out of 115, it would be clearer to plot the percent of articles accessed, such that the y-axis goes from 0% to 100%. The font size of the y-axis labels should be increased (currently they are practically illegible).

Regarding the confidence intervals / margins of error, I believe there are problems. The rebuttal letter states:

> In our case (sample size of 200), the confidence level is 85% (with a margin of error of 5%). We added at the end of Table 2, the confidence levels corresponding to the mean values. We also added, the sentence in Materials and Methods: “Confidence intervals were calculated taking into consideration the sample size studied (200), with a margin of error of 5%.”

I haven't verified the first quoted sentence, but let's assume that it is correct. This would mean that the _maximum margin of error_ is ±5% for a proportion with a sample size of 200 at 85% confidence. This statement is close to being relevant, except that most proportions reported in the manuscript have a sample size of 115 and not 200. I'd recommend computing the maximum margin of error with 95% confidence for a proportion with sample size of 115. This value could then be reported in the manuscript (not just the rebuttal letter) because it provides an upper bound on the margin of error for any reported proportion with sample size 115 (at the standard 95% confidence). In short, there are three variables here: the sample size (115), the confidence level (generally 95%), and then the margin of error / confidence interval. Usually, you choose a confidence level (generally 95%) and then calculate the margin of error **or** the confidence interval.

Note that the maximum margin of error is the radius of the largest-possible confidence interval given the sample size. The Wikipedia description is [not too dense](https://en.wikipedia.org/w/index.php?title=Margin_of_error&oldid=904288519#Maximum_and_specific_margins_of_error). In other words, for any specific proportion you can report a confidence interval. For any possible proportion of a given denominator (sample size), you can report a margin of error. For example, a (maximum) margin of error applies to any proportion computed from 115 samples. On the other hand, a confidence interval applies to a specific proportion like 70 / 115 and will generally be tighter than the maximum margin of error at the same confidence level.

Now let's turn our attention to "Confidence intervals were calculated taking into consideration the sample size studied (200), with a margin of error of 5%." First, the sample size of the proportions is 115, not 200. Second, the confidence interval and margin of error are the same thing: they are both ways of summarizing the output of an uncertainty assessment. Perhaps the authors mean  "at 95% confidence" rather than "margin of error of 5%"?

In Table 2, the authors add a confidence interval row with the following caption: "confidence intervals were calculated considering the sample size studied (200), with a margin of error of 5%." Note that this description makes the same mistakes as the sentence added to Methods. Furthermore, the confidence intervals are presented (in the rebuttal letter only) as "corresponding to the mean values". However, the mean proportions across institutions cannot be computed with simple confidence intervals for proportions because they combine many individual proportions. The authors seem aware of this when they write: "Concerning the confidence intervals for the mean access rates across institutions, as mentioned, it is a more complicated approach which was not planned in our initial protocol and seems difficult to initiate now." Therefore, it doesn't make sense to report a margin of error / confidence interval for the mean proportion.

Without more advanced statistical expertise, I see a couple of options for the authors. The easiest option would be to report the maximum margin of error for a proportion with 115 samples at 95% confidence. Another option would be to report confidence intervals for each individual proportion (like 77 / 115), but not for the mean of proportions because that is more complicated. Both options can coexist. Hopefully, my explanation will help the authors determine how to proceed.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: WORLDWIDE INEQUALITY IN ACCESS TO FULL TEXT SCIENTIFIC ARTICLES: THE EXAMPLE OF OPHTHALMOLOGY
Review round: 2
Reviewer: 2

Output:
Basic reporting: no comment
Experimental design: no comment
Validity of the findings: no comment
Additional comments: The authors have fully addressed all my comments and concerns regarding the experimental design and validity and also clarified the language in the suggested places. I recommend accepting this manuscript in its revised version.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: WORLDWIDE INEQUALITY IN ACCESS TO FULL TEXT SCIENTIFIC ARTICLES: THE EXAMPLE OF OPHTHALMOLOGY
Review round: 3
Reviewer: 1

Output:
Basic reporting: no comment
Experimental design: no comment
Validity of the findings: no comment
Additional comments: The revised manuscript addresses my remaining concerns. The margin of error is now only referenced in a single location as "9,14%". I presume this value should use a decimal separator of a period not a comma for consistency in the published version, i.e. "9.1%". I can confirm that ±9.1% is the proper maximum margin of error for a proportion with a sample size of 115.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: SERUM-DEPRIVED DIFFERENTIATED NEUROBLASTOMA F-11 CELLS EXPRESS FUNCTIONAL DORSAL ROOT GANGLION NEURON PROPERTIES
Review round: 1
Reviewer: 1

Output:
Basic reporting: The paper describes a basic electrophysiological characterization of low serum differentiated F11 cells that induces them to fire action potentials and express some channels that are missing in the undifferentiated cells.

Figure 1 is not helpful it should be removed. The images in 2AB are sufficient.

I suggest adding a table that compares the characteristics (voltage-gated and ligand-gated channel responses, Av cell capacitance, etc), including the % responding cells measured in
-       high and low serum F11 cells and,
-	isolated DRG neurons,
-	F11 cells differentiated in other ways and,
-	one or two other key sensory-model cell lines.

This will have the advantage of clearly placing this study in the context of published data and remove the need for the many bar graphs reporting the % of responding cells.

Thank you for providing the raw data, Make sure there is a short explanation in the raw data file that describes what each data table is and notes the corresponding figure in the paper.

The article is generally well presented and easy to read, however there are a few sections that require improvements to the phrasing. Be careful particularly when reporting the results as it is sometime becomes difficult to follow.

Line 32, “…the most (significant?) differences (when compared?) with DRGs….
Line 35, Revise, The use of  “consistence” is incorrect
Line 143, unclear sentence
Line 146, Unclear
Line 161, “even if low.. “ unclear
Line 190, delete “any”
Line 200, 100% of cells and is all the cells responsive to capsaicin is obsolete
Line 203, What is the “sustained component at pH5”
Line 252, what is the significance of N-type Cav currents?
Line 284-285 unclear section.
Line 293, unclear “It promoted small inward currents and depolarised 23% of differentiated F11 cells"?
Experimental design: - Figure 2 – Include a figure illustrating the resting membrane potential in high and low serum cells. Was only tonic firing patterns observed? Are they compatible with isolated DRGs?
- Figure 3, DRG neurons should not be mentioned in the figure title. Indicate what each figure symbols is. Indicated what the inlay-ed trace under the "TTX-sensitive Na current" is.
- Please show data demonstrating that NavCh are TTX-sensitivity, KvCh (including ERG) are sensitivity to TEACl and CsCl.
- Figure 3E, Confirm these barium currents are inhibited by cadmium. Why hasn’t Fluoride inhibited the IBa(high) current?  Are these the best recordings you have? The noise of the left trace and shape of the right trace is unusual. Indicated the resting current.
- Figure 4. Include a bar graph of peak current and a measure of AP change in frequency in 10 and 1% FBS.
- The currents recorded in response to capsaicin and SP are very small (25 and 14pA) – comment on their expression levels and what sort of studies they will be useful for.
- Figure 5, Line 228, you cannot make any conclusions about the relative expression of NMDA and AMPAR from the described experiment. Please show the AP5 sensitive component in figure 5B.
Validity of the findings: The data seems largely consistent with the conclusions. However, it needs to be strengthened by demonstrating that the voltage gated Na+, K+ and Ca2+ channel currents are sensitive to TTX,  Cs/TEA and Cadmium respectively. TRPV1, SP and acid- currents should also be confirmed with appropriate antagonist.
Additional comments: No additional comments


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: SERUM-DEPRIVED DIFFERENTIATED NEUROBLASTOMA F-11 CELLS EXPRESS FUNCTIONAL DORSAL ROOT GANGLION NEURON PROPERTIES
Review round: 1
Reviewer: 2

Output:
Basic reporting: This study shows that serum deprivation produces differentiation of F-11 cells which change their membrane electrical properties. The changes increase their similarities to DRG neurons. Although it has been demonstrated in the literature that serum deprivation changes cell properties and may provide strategies to enhance cell lines use, this seems to be the first report of its use in F-11 cells.

The text needs an extensive revision. The abstract needs a special improvement. Some expressions like “to investigate endogenous properties” and “the sub-type of interest” could be replaced by more precise descriptions.

In general, the results section makes many claims without providing the necessary references.

The discussion repeats the results presentation. It would be interesting to discuss, for example, the similarity of the differentiated F-11 cells with specific sub-types of DRG neurons. Also, why and how their findings are relevant for the research in the area.
Experimental design: The experiments were conducted in a small number of cells. It is necessary to state the number of cells in every group, and the number of cultures they used. When reporting the percentage, it would be interesting to report, in the figures, the number of cells that responded to a specific stimulus over the total number of cells tested.

The protocols for current isolation are adequate.

Line 106 WAY-123,398

The complex geometry of the differentiated cells will make voltage clamp more difficult. Literature results from DRG neurons are often based on data from cell bodies with few or no processes, exactly to avoid space clamp issues. Authors should include a paragraph in their discussion evaluating if and how the morphological changes may affect their data.

Line 77 – please provide details for staining with DiI.

Line 128 Excel (Microsoft)

Line 191 – It would be difficult to measure a mean of 14 pA with a noise of about 10 pA (figure 4). Please review this data.
Validity of the findings: The scientific question is clear, although the rationale is not well described.

The rationale for conducting this study is not because DRG neurons are heterogeneous and change their properties in culture, so we need an alternative that also change their properties in culture.

Regarding to heterogeneity, lines 171-173 report the expression of LVA Ca2+ channels in 4 cells tested, and the lack of expression in the other 7 cells. This result indicates heterogeneity in this regard in their system. Although similar heterogeneity is observed in different classes of DRG neurons, what difference may exist in their culture from cell-to-cell? Similar question for the sensitivity to capsaicin (lines 174-183).
Additional comments: line 125 – The expression “to study pain response” referring to the use of capsaicin is inadequate. Pain is a subjective sensation. In animals, the term nociception is used. In isolated cells, potential nociceptive stimulus produces response through nociceptive transducing receptors.
Line 143 “cells with electrical activity” – a more specific parameter would be appropriate.
Line 146 – it is not clear what authors mean by “intrinsic cues”
Line 147 The subtitle needs a complement “Expression of voltage dependent sodium and potassium channels in differentiated cells”
Line 149 present in some classes of DRG neurons
Lines 161-163 are unclear. Does it mean that all calcium currents sub-types are present, but low threshold is only observed in medium and small cells?
Line 168 should state first the % of cells with currents, to compare with control, then give details of mean current density. Use the same criteria to report the variables in different groups.
Line 189 “depolarized the cells by 23±7%”, “No any cell tested…” change to: No cells tested…
Line 193 – “such as for capsaicin” is incorrect and unnecessary
Line 284 – Change “cells which manifest…” to: Differentiation of F11 cells produced 44% increase in response to capsaicin.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: SERUM-DEPRIVED DIFFERENTIATED NEUROBLASTOMA F-11 CELLS EXPRESS FUNCTIONAL DORSAL ROOT GANGLION NEURON PROPERTIES
Review round: 2
Reviewer: 1

Output:
Basic reporting: There are some sections that need improvement.
Please fix typing errors, revise the phrasing/clarity at the following places: Lines 43,48,169,177,212,249 (remove capsaicin line it has no meaning), 293-295, 302,205-14,335,397.
Avoid using phrases like line 51, “perform functions of nociceptive and non-nociceptive sensory neurons”; Line 155, “to study nociception”; Line 386 “…include neurons with nonnociceptive and nociceptive functions respectively”.  They are inaccurate.
Please use consistent language around 1 and 10% serum grown F-11 cells. (Differentiated, 1% FBS, high/low serum, serum deprived etc). eg. I don’t think differentiated cells has the same meaning at line 170 vs line 60 & 63.
Line 395 is overstated.
Experimental design: The identity of the cells being sampled and compared in Fig. 2 and throughout the paper still needs to be clarified in the text. The statistics comments about comparison from the editor is valid and should be taken into account.
I believe you only recorded from 1% FBS cells with neuronal morphology and from cells chosen at random in the 10% FBS condition. Are the 1% FBS cells without neuronal morphology different from the ones with neuronal morphology? What proportion of 1% FBS cells have neuronal morphology? This is of interest to anyone who is considering using this model. Report a type of current occurs in x% of sampled cells.
Given NMDA receptors are inhibited by pore Mg2+ most of the time. Without membrane depolarisation/Mg2+ free solutions would you expect to see an AP5 effect even if NMDAR were highly expressed?
Validity of the findings: Stated aim: "characterization of the electrophysiological properties of F-11 cells differentiated by serum deprivation and investigate if differentiated F-11 cells manifest similarities with DRG neurons" This aim was successfully carried out.
The justification was to: "to verify whether differentiated F-11 cells are an adequate model of sensory neurons to be employed in the study of peripheral neuropathy and in the design of strategies of peripheral nerve reconstruction. I think the differentiated F-11 cells have more DRG-like properties than undifferentiated F-11 cells. I can not see how they would be helpful to study periperal neuropathy and nerve reconstruction design. If true, this should be explained in the discussion.

The paper describes a simple method to make the characteristics of F-11 cells more “DRG-like”. Like previously described differentiation techniques, they could be of use if a researcher is investigating some types of voltage sensitive channels or acid sensing channels and potentially better than 10% FBS cells for recording nAChR currents. The other channels found to be expressed in 1% FBS are also found in sensory neurons but are probably not expressed at high enough density to be experimentally useful.
Additional comments: The authors have made extensive improvements to the text and figures and have address most of the reviewer comments sufficiently.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: SYMPTOMATIC MENOPAUSAL TRANSITION AND RISK OF SUBSEQUENT STROKE
Review round: 1
Reviewer: 1

Output:
Basic reporting: In this study, Yu and colleagues analyzed a large-scale cohort to uncover the impact of symptomatic menopausal transition on the risk of stroke. They concluded symptomatic menopausal transition could significantly increase the risk of stroke. In general, the experiment was designed properly and this manuscript was well written with sufficient introduction and discussion. I have some suggestions to the authors:

1. Line 87-88: Could the authors specify the reason that they used a 4-year look-back period (1996–1999) in this study and excluded 11567 cases (Figure 1)?

2. Previous studies showed that age at menopause could influence the risk of ischemic stroke. Did this factor play a role in the current study? Could the authors also cite and discuss the work done by Lisabeth et. al., 2009 (Stroke)? Is that possible some cases in “control group” had early menopause?
Experimental design: no comments
Validity of the findings: no comments
Additional comments: no comments


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: SYMPTOMATIC MENOPAUSAL TRANSITION AND RISK OF SUBSEQUENT STROKE
Review round: 1
Reviewer: 2

Output:
Basic reporting: Present study by YU et al examined the symptomatic menopausal occurrence, transition, and following stroke incidence. Fourteen years follow-up large retrospective cohort study compared the development of stroke between symptomatic and non-symptomatic menopausal women. Author found that this symptomatic menopausal transition strongly associated with increased risk of stroke.

1.	Largest cohort is plus of this study. Appreciated.
2.	On other hand, it is retrospective study.
Experimental design: 1.	Data collected for 14 years
2.	Data acquired from national health insurance research database in Taiwan
3.	Study approved by IRB and does not require ethical review.
4.	Study examined 22058 control and 22058 symptomatic menopause women.
Validity of the findings: Women with symptomatic menopause had 30% increase in risk of stroke.
Overall, study has given reasonable explanation on statistical basis.
Additional comments: 1.	How did author adjust demographics with stroke incidence?
2.	 There would discrepancies menopause women undergoing HRT. Besides, the time of initiation of HRT do matters in terms of vascular reactivity. Why would not author consider excluding HRT from the cohort?
3.	Please include figure legends
4.	 Hypertension is one of the main causes of stroke and it is positively correlated with symptomatic menopause. But author wrote “The risk of stroke was further increased in symptomatic menopausal women without hypertension or without the use of hypertensives” It is not clear what author trying to convey.
5.	Line 172 & 208: is it use of hypertensives or anti-hypertensives?
6.	Is there any relation in leptin concentration on menopause or stroke?
7.	 How did author analyzed hypertension if the BP value is not given?
8.	 Are the current cohort used same individuals as  “Effects of early age at natural menopause on coronary heart disease and stroke in Chinese women.”?


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: SYMPTOMATIC MENOPAUSAL TRANSITION AND RISK OF SUBSEQUENT STROKE
Review round: 1
Reviewer: 3

Output:
Basic reporting: The article in general has very high quality. The figures and tables are well made with clear information.

It might be constructive and beneficial if in the introduction part, the authors can discuss in more details in a more compelling way on why they want to “determine whether symptomatic menopausal transition is a contributing factor to stroke” (line 69-70). The authors claim that “[n]o previous studies have assessed the direct link between symptomatic menopausal transition and the risk of stroke with a long-term follow-up,” (line 67-68) and “[t]herefore” they wanted to look at stroke. However, they have never discussed specifically about stroke in the introduction. The authors do have discussed a possible linked between menopausal transition and cerebrovascular problems (line 57-66). But cerebrovascular problems are not limited to stroke and also include transient ischemic attack, aneurysms, and vascular malformations. So why specifically looking at stroke? The way the authors put it as in line 67-70 makes it seems like it is because no one ever did such that they wanted to do so.

The writing in general is clear but does have several places that are ambiguous/misleading, two of which are discussed in the third section of my review (Validity of the findings) as they are related to the conclusions the authors made. Another place is in line 52-53, where the authors write “[d]uring menopausal transition, vasomotor symptoms, insomnia, depression, and vaginal dryness are major problems that affect 1.5 million women every year.” The message from this sentence is that 1.5 million women every year experience the major problems of menopausal transition. However, according to the reference (Santoro et al., 2015), 1.5 million women experience menopausal transition, but may not all suffer from the listed major problems. It would be inaccurate if the authors rephrase the previous study’s finding in the way that they’ve done in line 52-53.
Experimental design: The experiment design is very solid. The sample sizes of both the disease group and the control group are impressive, and the time scope of the follow-up period is remarkable, both of which make the results very credible.

However, it is unclear to me that when the authors look at the relationship between the duration of symptomatic menopausal transition and stroke, why they use the number of visits to gynecology clinics to represent duration of symptomatic menopausal transition, rather than, for example, using the length of time period since the subjects first went to gynecology clinics through the last time they did so on record. The number of visits cannot speak for the duration unless all subjects have the same frequency of visits to gynecology clinics, which is not mentioned in the article.

In addition, it would make the methods they use more transparent if they can put in more details about the propensity score matching procedure that they performed in order to select the controls. It was only mentioned briefly that they use "measured covariates" (line 119-120) for the calculation, but what exact covariates do they use?
Validity of the findings: The findings are statistically sound and controlled. And their discussion on the potential pitfalls of the study is very neat.

However, the conclusion in the article (not the one in the abstract) is not very well stated and is misleading. In line 249-250, the authors claimed that "symptomatic menopausal transition significantly increased the risk of subsequent stroke." The use of the word "increased" indicated that there is a causation relationship between symptomatic menopausal transition and the risk of subsequent stroke. Yet this study is only an association study and there is no proof that symptomatic menopausal transition would cause the risk of stroke to increase. I think the conclusion in line 249-250 should be stated the same way as they have done in the abstract (line 43-44).

A same mistake also appears in line 209-210 when the authors are referring to previous findings and write "early menopause may increase the risk of ischemic stroke." This is again misleading since the verb "increase" would imply causation, and in fact, nowhere in the reference (Rocca et al., 2012) it was directly stated that early menopause would increase ischemic stroke risk but only claimed that the two are associated.
Additional comments: Overall I enjoyed reading this article. If my comments as above are addressed, I recommend the article for publication.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: SYMPTOMATIC MENOPAUSAL TRANSITION AND RISK OF SUBSEQUENT STROKE
Review round: 1
Reviewer: 4

Output:
Basic reporting: The abstract is very short and I’ll suggest some additional information, and other edits, that it might be useful to consider here:

Line 28: This could potentially be read as the period of entry into the cohort (between 2000 and 2013) or as suggesting a cohort begun in 2000 and followed for up to 14 years. Could you make this clearer, which would be especially helpful for the reader who only reads or focuses on the abstract? Related to this, it would be useful to add the mean years of follow to the abstract’s (below) and the manuscript’s (later) results, I think.

Line 31: I wonder if you could list the variables used for the propensity score matching here. As noted, the abstract is short, so there is plenty of room for additional detail, but perhaps this would be more readable if you collapsed the individual comorbidities and long-term medications into single list items each.

Line 31: Perhaps “…as a comparison group…” (adding “a”, replacing “control” with “comparison”, and using “group” rather than “cohort” which I’d interpret as both groups combined), or simply adding “the” would also work.

Lines 31–32: The primary outcome, assuming this means the outcome variable, would just be stroke as it applies to both groups. If the “primary outcome” here is referring to a research question, the wording would be different again.

Line 33: You give an exact date (month-day-year) for the end of the cohort follow-up, so could perhaps indicate the same back on Line 28 for the start of the cohort period.

Line 33: I think a sentence or two around the statistical methods used would be very helpful for the reader here.

Line 38: I think I know what you mean, but I’m not sure that it “remained” significant when you haven’t presented any results showing significance above. You could add the crude SHR beforehand (to show the statistical significance remaining) or reword this to note that it was significant when adjusting for these variables.

Line 38: Isn’t this a sub-hazard ratio? This applies throughout the manuscript and tables.

Line 40: Perhaps “no evidence for effect modification by…” or “no evidence for inconsistent effects for…” so that this is worded in terms of the lack of evidence rather than a claim of a lack of meaningful numerical difference (which is how I’d interpret “consistent effects”).

Line 41: I think a reader of the abstract would be interested in which age, comorbidity, etc. groups, had higher or lower risk than others.

Line 42: I’m not sure “durable” is the right word here, perhaps “There was no evidence that the effect varied by the duration of symptomatic menopausal transition.”? See also Line 186.

Line 44: I’d qualify “significantly” here as “statistically significantly”, unless you mean “statistically and clinically significantly”. I think it’s worth checking the manuscript for any instances of “significant” (or its inflected forms) where there is even the slightest ambiguity as to whether this is statistical, practical/clinical, or both.

In the background, Line 50, I wonder if it would be possible to clarify here that 12 months without a menstrual period is part of the definition of menopause, similar to how you define menopausal transition on Line 49. Also, for Line 53, you could qualify where these “1.5 million women every year” are from (e.g. “1.5 million women in [country] every year…”). Note that in the reference you provide for this figure, the figure itself appears to be referenced to an earlier article and, if I’m correct in this, I think the original source should be cited.

Lines 98–99: This might be clearer as “patients who did not survive for at least 30 days after their index date or were followed up for fewer than 30 days after this date” if I’m understanding your intention (at the moment “did not survive” is potentially unqualified). What was the reason for this exclusion and could you add this to the manuscript?

On Line 122, when you say “considered” do you mean “included”, rather than being a candidate for inclusion depending on some criterion or criteria?

Can you add a reference for Lines 123–124?

For Lines 159–162, I think I’d show the significance of the interaction first, as the first sentence could be (mis)read as reporting the age main effects until you reach the interaction p-value at the end. The same issue arises later on Lines 169–171.

For Line 160, a test for linear trend (via orthogonal polynomials) would be useful to support the description here (“decreased”) rather than a single (Wald?) p-value which would only indicate “differed”. Or you could discuss the pairwise comparisons here also alongside the interaction p-value.

Lines 165–166: I wouldn’t consider this to be a valid interpretation based on a p-value only. There is no evidence that the effect of symptomatic menopausal transition on the risk of subsequent stroke varied by HRT, but there is also no direct evidence for a consistent effect (although you could consider whether the interaction’s 95% CIs are consistent with meaningful effect modification or not). A similar point applies to Line 170 and a related one to Lines 229–230 (the final clause here is fine, it’s the use of “similarly higher” that isn’t supported by the p-value alone).

Why no interaction p-value for duration (Lines 176–178 and Table 4)? Again, a linear trend interaction would be an option (while testing for interactions with and main effects for higher-order polynomials as well).

Lines 182–183: Isn’t this “during up to 14 years of follow-up”?

It might be useful to add the variables used for the propensity scores to Figure 1 (possibly using the suggested shortening for comorbidities and medication suggested above).

I’m not sure how easy SAS makes this, but adding 95% CIs would be useful for Figure 2, and with only two groups this shouldn’t make the figure too noisy.

Table 1 might work better with the columns: total, control, symptomatic menopausal transition, and then StD so that the difference column is directly alongside the two columns that it refers to.

Also in Table 1, note that Charlson’s scores and clinic visits are both positively skewed and I don’t think means and SDs are likely to be appropriate here; perhaps you could show medians and IQRs?

In Tables 2, 3, and 4, as far as I can tell, all of the HRs and in fact SHRs. Is there a reason for not labelling them as this?

A data dictionary and, if possible, the SAS code used for the analyses would be very useful complements to the actual data for the reader trying to replicate the results in the manuscript. For example, I assume that com_stroke==2 indicates non-stroke mortality, but it would be good to have such things made clear.
Experimental design: What was the reason for selecting patients in 2005 (Line 76)? Presumably, patients who died (including following stroke) between 2000 and 2005 were thus rendered ineligible for inclusion in the study cohort, whereas a women who did not die during this period could be included in either group starting as early as 2000. This would seem to bias any excess hazard from symptomatic menopausal transition downwards (survivor bias), or am I missing something here that would prevent this?

When you say (Lines 95–96): “this date was also assigned to the matched control”, I’m assuming you mean for entry into the cohort? If so, could you make this explicit here?

Line 97: I’m not entirely sure why you’d need an age>100 criterion here.

Line 97: Could you explain, also in the manuscript, why you excluded those with a history of breast cancer prior to the index date? This might also lead to edits on Lines 29 and 101 (and perhaps elsewhere) to add history of breast cancer to these sentences.

I think some additional information is needed in the statistical methods. It’s not clear to me why you have used both Cox’s proportional hazards (Lines 125–128) and Fine and Gray’s model (Lines 129–130). I’m assuming participants were censored at death for the former model (which could be made clearer if this is the case) but I can’t see any reported results for the Cox’s models. The three sets of models described on Lines 150–152 (not the results, just the sets of variables in each model) seem like they should have been included here in the methods along with details of the interactions investigated (are the associated p-values for interactions from Wald tests?) Also, did you test for time-varying effects for the group, propensity score, or other variables included? And if so, how? Did you look at any other residual diagnostics for the models?

What was the basis for the sample size chosen? In the discussion, you describe a priori power for some undescribed effect size (Line 233). This should be included in the statistical methods with sufficient information to enable a reader to replicate the calculation. This might include some consideration of maximal model complexity (e.g. based on Peduzzi, et al.’s guideline).

I also suggest listing the variables used on Line 121 as well as referring to Table 1 to save the reader needing to navigate to the table for this; and combining the two method references to the details of the propensity scores (Lines 102–103 and Lines 119–124) into one place so that all of this information is together. For the latter point, I’d move the algorithm and caliper to the second reference, but this is up to you.

I’m not able to follow your reasoning for adjusting for the propensity score and then in another model adjusting for the variables used to create the propensity score (Models 2 and 3 in Table 2, and Lines 151–152, which I’ve suggested moving to the methods). Can you explain?
Validity of the findings: How confident are you that none of the “confounders” listed on Lines 111–114 are on the causal pathway between symptomatic menopausal transition and stroke? If you have drawn a DAG for this, it would be worth considering including this as a supplement. The underlying causal model here seems quite complex!

The statistical methods talk about using both Cox’s proportional hazards regression, which might be valid from an aetiological perspective but not from a prognostic one, and competing risks analysis. However, all effect sizes are labelled as “HR” and it is unclear in the text which results are from which models except that the table notes suggest all HRs are in fact SHRs. Are you, in fact, interested in a prognostic model, though, and not an aetiological one? This might be worth mentioning in the discussion.

I’m not sure that the interpretation on Lines 211–214 for the interaction with comorbidities is making it clear that those women with comorbidities would also have higher rates, I assume, of death from other causes, which for the analyses here would remove them from the risk set at the time of death (rather than censoring them with Cox’s PH model). This comes back to the aetiological versus prognostic modelling goal.

In terms of strengths, a large sample size (Line 232) isn’t a strength per se, but all other things being equal, it is more likely to produce sufficiently tight confidence intervals and (as you note, but without specifying the effect size of interest) provide more power to detect effects. Could you perhaps comment on the widths of the CIs here? Similarly, the length of follow-up (Lines 234–235) also isn’t a strength per se, but the number of events observed might be important when you consider model heuristics, such as those from Peduzzi, et al.

I appreciate you providing your list of potential confounders (Lines 235–237), which I hope will help other researchers when planning their studies. Your study limitations are very well described.
Additional comments: This is a well-performed and interesting study.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: SYMPTOMATIC MENOPAUSAL TRANSITION AND RISK OF SUBSEQUENT STROKE
Review round: 2
Reviewer: 1

Output:
Basic reporting: I appreciate the efforts made by the authors. This new version is much better. Therefore, I have no further questions.
Experimental design: no comments
Validity of the findings: no comments
Additional comments: no comments


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: SYMPTOMATIC MENOPAUSAL TRANSITION AND RISK OF SUBSEQUENT STROKE
Review round: 2
Reviewer: 2

Output:
Basic reporting: no comments
Experimental design: no comments
Validity of the findings: no comments
Additional comments: The authors has addressed all the queries I have raised on this manuscript.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: SYMPTOMATIC MENOPAUSAL TRANSITION AND RISK OF SUBSEQUENT STROKE
Review round: 2
Reviewer: 3

Output:
Basic reporting: In the revised introduction where the authors nicely added the stroke part, it was neat to add a comparison between Chinese and Caucasian (line 74-75) by saying that "[t]he Chinese were reported to have higher stroke incidence than Caucasians." However, this sentence itself does not make a lot of sense without giving the incidence rate of stroke in Chinese or in Caucasians. Why use Caucasians as a reference point? Why not compare to other races or other countries? What's the exact number for the incidence rate? Say if the incidence rate in Caucasian is 1*E-100 % and that in Chinese is 1.1*E-100 %, I don't see why "there is an emerging need of stroke prevention for populations at high risk for stroke in Taiwan."
Experimental design: no comment
Validity of the findings: no comment
Additional comments: The authors did a very nice job addressing all the issues that were previously pointed out. It's just the added part in the introduction about stroke needs a bit polish to make a better sense.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: SYMPTOMATIC MENOPAUSAL TRANSITION AND RISK OF SUBSEQUENT STROKE
Review round: 2
Reviewer: 4

Output:
Basic reporting: The manuscript is much improved and I have only a few relatively minor comments to make.

Rather than referring to “Cox proportional-hazard regression models with competing risks adjustment” (Lines 39–40), I think “Fine and Gray’s proportional subhazards model” or “competing risks survival analysis using the Fine and Gray model” or similar (this point is also clearer on Lines 158–159) would be more informative. There are several alternative competing risk models and Cox’s proportional hazards models can deal with competing risks through censoring, which could still be described as “Cox proportional-hazard regression models with competing risks adjustment” (and would be preferred over Fine and Gray if your questions were around aetiology rather than prognosis).

I appreciate your comments that you were focused on associations rather than causality (“However, our study primarily focused on the association of symptomatic menopausal transition with the development of subsequent stroke rather than a direct causal relationship between them.”), but I feel that this is inconsistent with the current version of your aim: “to determine whether symptomatic menopausal transition is a contributing factor to stroke.” (Lines 90–91), which I think is definite causal language. I think you need to revisit the wording for this aim.

I’m slightly confused by the sample size section (Lines 161–164), which doesn’t provide any information about the calculations, or make it clear that this was retrospective, and which is revisited in the discussion on Lines 272–275 without sufficient information to enable replication (what is the detectable effect size, what was the assumed proportion—to determine the standard error, or was the worst case of 0.5 used—and what was the level of significance used—presumably two-sided p<0.05, but this should still be made explicit?) I appreciate that this was retrospectively calculated (as I understand your response, data collection was completed at the time it was performed and so presumably no more data would have been collected irrespective of the calculation’s result), and in this case, it is the widths of the CIs that could be best used to evaluate whether or not the study was sufficiently powered. Related to this, while you state that “Additionally, the number of events observed may be important when modelling survival data (Austin et al., 2017; Peduzzi et al., 1995).” you do not explain how there is a strength to your study in this respect. I appreciate that the connection could be seen as simple enough for the reader to fill in the blanks here, but I think that you need to make your point here explicit (and I could be guessing incorrectly about what that exact point actually is).

You still refer to “control” on Lines 45, 47, 128, 150, etc. although you changed “control” to “comparison” on Line 32 and use “comparison” in Figure 2. Personally, I prefer “comparison group” to “control group”, but this should be consistent in any case.

Looking at Table 3, can you make it clear that the p-values for interactions refer to the second adjusted models and not the first (at least this is how I am reading the table).
Experimental design: No comment.
Validity of the findings: No comment.
Additional comments: No additional comments


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: SYMPTOMATIC MENOPAUSAL TRANSITION AND RISK OF SUBSEQUENT STROKE
Review round: 3
Reviewer: 1

Output:
Basic reporting: no comment.
Experimental design: no comment.
Validity of the findings: no comment.
Additional comments: The authors nicely addressed the issue I pointed out.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: SYMPTOMATIC MENOPAUSAL TRANSITION AND RISK OF SUBSEQUENT STROKE
Review round: 3
Reviewer: 2

Output:
Basic reporting: For the control/comparison group matter, the authors might have missed a few instances (which would be entirely understandable). See Line 291 (proof version) when you refer to misclassification as “controls” and the legend for Figure 1, column headings for Table 1, row label for Table 2 and the table notes also, column headings for Table 3, and the legend for Table 4.

On Line 44, I’d say “matched comparison participants” or “matched comparison women”, or “matched women without symptomatic menopausal transition” rather than “matched comparisons”. Also Lines 118, 173, and 225.

Line 73: I don’t think you need either of these commas (after “range” in each case).

Line 128: Perhaps “comparison participants”,  “comparison women”, or “women without symptomatic menopausal transition” here rather than “comparisons”. Also Lines 153, 195, and 205.

Line 241: You can delete “an” here in “resulting in an weight gain”.
Experimental design: Retrospective power analyses using the observed effect size (as is the case here) turn out not to make any sense. If an effect of the observed size was statistically significant, then the actual study (or any other study with the same n) was powered at more than 50%; if an effect of the observed size was not statistically significant, then the study was powered at less than 50%. Looking at the sample size required still preserves this association for 50% power (if the actual sample size was larger than required for 50% power, the result was statistically significant and if the actual sample size was less than required for 50% power, the result was not statistically significant). This is slightly less obvious for 80% power, but there if the actual sample size was less than (approximately) half the calculated required sample size, the result was not statistically significant and if the actual sample size was more than (approximately) half the calculated required sample size, the result was statistically significant. In other words, no matter how we look at it, the retrospective power of a study using the observed effect size is determined simply by the p-value that was observed and so retrospective power using the observed effect size contributes absolutely no new information beyond that. If no other sample size calculation was performed, this fact should be stated instead of a retrospective calculation based on the observed effect and the point that the effect power of the study is communicated through the widths of confidence intervals made. This will also have implications for Line 277 (proof version).
Validity of the findings: No comment.
Additional comments: The authors have revised their manuscript well in response to my comments, and those of the other reviewers, with one important exception (under design) and a few minor details (under reporting). Well done!


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: SYMPTOMATIC MENOPAUSAL TRANSITION AND RISK OF SUBSEQUENT STROKE
Review round: 4
Reviewer: 1

Output:
Basic reporting: No comment.
Experimental design: For the power calculation, as I noted previously "...retrospective power using the observed effect size contributes absolutely no new information beyond that. If no other sample size calculation was performed, this fact should be stated instead of a retrospective calculation based on the observed effect and the point that the effect[ive] power of the study is communicated through the widths of confidence intervals made." so I have to disagree that the retrospective power calculation (Lines 164-167) provides any information whatsoever. The sentence on Lines 278-280: "However, the retrospective power of this study calculated using an observed effect size was determined mainly by the P value which was already observed." would be correct for the analysis referred to in the power calculation if "mainly" was replaced with "entirely"!

As I suggested, if no sample size calculation was performed, this fact should simply be stated in the methods along with a comment in the discussion about whether the eventual precision (as measured via the 95% CI widths) was adequate or not.

Some references which explain why retrospective power should not be reported:

https://doi.org/10.1111/1467-9884.00139  "We suggest that it is nonsensical to make power calculations after a study has been conducted and a statistical decision has been made."

https://doi.org/10.1007/s10211-004-0095-z  "As we have shown, retrospective power analyses have logical flaws and shortcomings when used for the interpretation of non-significant results." (It is rare to see retrospective power used when results are statistically significant and so adequate power is not in doubt.)

http://doi.org/10.2307/3802357  "Calculation of power after a completed study is appropriate for a future, related study, but because power is a probability, power cannot be applied to a completed study."

https://doi.org/10.1109/ICIC.2009.392  "We conclude that retrospective power calculation yield no additional insights if P value is available, and cannot be used to estimate the statistical power."

https://doi.org/10.1111/jch.13173  "Why it is nonsensical to use retrospective power analyses to conduct a postmortem on your study" (title)

https://doi.org/10.1016/j.ecns.2016.03.001 "There is a 1:1 correspondence of observed power and the p value calculated by hypothesis testing (Hoenig & Heisey,2001). This allows the researcher who does not find statistically significant results to conclude it was because her or his study was underpowered! Conversely, if an investigation results in significant findings, one can conclude the study was appropriately powered."
Validity of the findings: No comment.
Additional comments: Aside from the power calculation being retrospective, this is an excellent manuscript. Well done to the authors!


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: SYMPTOMATIC MENOPAUSAL TRANSITION AND RISK OF SUBSEQUENT STROKE
Review round: 5
Reviewer: 1

Output:
Basic reporting: No comment
Experimental design: No comment
Validity of the findings: No comment
Additional comments: The revisions around the power of the study have addressed my comments from before and I have no new comments to make. Well done to the authors!


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: MACHINE LEARNING ANALYSIS TO IDENTIFY THE ASSOCIATION BETWEEN RISK FACTORS AND ONSET OF NOSOCOMIAL DIARRHEA: A RETROSPECTIVE COHORT STUDY
Review round: 1
Reviewer: 1

Output:
Basic reporting: Well-structured paper. But I have some comments on the discussion and table 1 that I listed under the comments below.
Experimental design: No comment.
Validity of the findings: Findings seem valid and interesting; however, I have one concern (comment no. 4) and a suggestion to add an important finding regarding Clostridioides (formerly Clostridium) difficile infection (comment no. 5). Please find the details in my comments below.
Additional comments: This is an interesting and well-designed study by Kurisu and colleagues assessing risk factors associated with nosocomial diarrhea in patients admitted with cerebral infarction. However, I have some comments and questions:

Major comments:
1. On Table 1: Regarding the variables of antibiotic use, Tube feeding use, PPI, and H2RA use, what do the P values represent? Do they represent the difference between the two groups in terms of using these variables or the number of days of using them? The P values appear to be in the middle between the use of the variable and the number of days, hence, it isn't clear to which of the two it belongs. Please clarify, and if there's another P value for the other part of the variable, please add it. For example, if the P value represents the antibiotic use, then please add the P value for the difference in the number of days of antibiotic use.
2. Also on Table 1: the P value corresponding to the male sex is 0.047 which rounds to 0.05. In the medical literature, such P value (that can be rounded to 0.05) is considered insignificant. As such, I would suggest removing the part that says "included more men" on line 141 which can indicate that male sex is significantly associated with nosocomial diarrhea.
3. I wonder why the authors only examined the number of days of the use of the variables but not their use or lack of thereof. I suggest, if possible, including the presence or absence of these variables in the random forest model and then present the data of the number of days as a subgroup analysis in each group of patients where only the variables of statistical significance were present (i.e., only the variables that were significantly associated with nosocomial diarrhea are evaluated for the association of the number of days of use). Alternatively, I suggest that the authors justify and explain the rationale behind the inclusion of only the number of days in the last part of the introduction where they list the study's objectives.
4. I found it interesting that there seem to be some sort of inconsistency between the findings of Table 1 and Figure 2 that I suggest that the authors comment on in the discussion section or perhaps double check their results and statistics. The discrepancies are in the level of importance of each variable (or how strongly each is associated) with nosocomial diarrhea. For instance, PPI use (or the number of days; please address my comment no. 1) has a P value of 0.81 on Table 1 while H2RA use has a significant P value of 0.02. On the other hand, Figure 2 shows the number of days of PPI use is more associated with nosocomial diarrhea than the number of days of H2RA use! In my opinion, if the use of PPI was actually not significantly associated with nosocomial diarrhea as presented on Table 1, then I think it might be inappropriate to include the association of the number of days of their use in the analysis since it is not a variable that's associated with the outcome in question (nosocomial diarrhea) to start with. Again, since sex is supposed to be not significantly associated with diarrhea given a P value that rounds to 0.05 per Chi-square test, I suggest removing this variable from the random forest modeling analysis and thus removing it from Figure 2.
5. I don't see anywhere in the manuscript the assessment of the presence of Clostridioides (formerly Clostridium) difficile infection in the group of patients with diarrhea since it accounts for 20-30% of cases of nosocomial diarrhea (McDonald LC, et al. Clin Infect Dis. 2018;66 (7):987-94). In fact, many published studies showed the association of the use of antibiotics, PPI, and H2RA with this infection, and these are the same variable evaluated in the present study. As such, I strongly suggest the authors to include the number of patients with C. difficile infection on Table 1 under the "Diarrhea group" column and to type "Not applicable" under the "Non-diarrhea group" column. Adding such information would aid the clinicians to consider (or not to) testing for C. difficile infection in patients with cerebral infarction who develop diarrhea. If this information is to be included, then I advise the authors to also include the type of C. difficile detection test used by the microbiology lab in their hospital (E.g., PCR or toxin immunoassay) under the methods section of the manuscript. Additionally, a comment on C. difficile infection would be highly recommended to be added to the discussion section when discussing the association of antibiotics with the infection (lines 189-198), as well as acid suppressing agents (not currently present in the discussion. See comment no. 6 below).
6. Discussion: There was no commenting on PPI and H2RA use and their association with nosocomial diarrhea, especially that H2RA use was significantly associated with diarrhea as on Table 1 and that both can be associated with C. difficile infection (a common nosocomial diarrhea as stated in comment no. 5 above) as observed in many published studies. Authors are recommended to comment on that aspect while relating their findings with data from the literature on the association of acid suppression with C. difficile infection or nosocomial diarrhea in general as they did with the other variables.
7. Discussion: The third limitation states that the causes of diarrhea were not included in the study. Although I thank the authors for disclosing this as a limitation, I would still suggest including the number of patients with C. difficile infection among the diarrhea group. Afterwards, this limitation can be either eliminated or amended to state that "the causes of diarrhea other than the presence of C. difficile infection were not included in the study" since there are other triggers for the nosocomial diarrhea other than gut infections.

Minor comments:
8. Line 175: Please correct the first sentence to say either "which was used as an indicator of diseases severity, held the second place as a factor strongly associated with nosocomial diarrhea" or "which was used as an indicator of diseases severity, was the second strong factor associated with nosocomial diarrhea."
9. Line 178: I'm not sure if "transferring" is considered a daily activity in this context. Instead, I suggest using the word "mode of movement" as it indicates the way the patient moves (or is moved) around whether with or without assistance, especially that the authors are tailing this finding with a comment on the effect of regular exercise on diarrhea.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: MACHINE LEARNING ANALYSIS TO IDENTIFY THE ASSOCIATION BETWEEN RISK FACTORS AND ONSET OF NOSOCOMIAL DIARRHEA: A RETROSPECTIVE COHORT STUDY
Review round: 1
Reviewer: 2

Output:
Basic reporting: - There are some language mistakes or typos that should be improved in the revised version.
- Literature references are weak. They didn't support a good research objective.
- To mention Random Forest, the authors have to cite more related published works that used it in biomedical field, such as https://doi.org/10.1002/jcc.24842 and https://doi.org/10.1016/j.ab.2018.06.011.
- Hypotheses need to be mentioned clearly.
Experimental design: - The research question is not well defined, relevant and meaningful.
- Area under the curve (AUC) and n-fold cross-validation had been used successfully in a lot of biomedical works such as https://doi.org/10.1016/j.ab.2019.02.017 and https://doi.org/10.1016/j.ab.2019.03.017. Therefore, the authors should cite more related papers to attract broader readership.
- Did the authors select the optimal parameters in their Random Forest algorithm? If selected, what was the strategy?
Validity of the findings: - Since Random Forest is one kind of machine learning technique, the authors have to explain why did they choose this algorithm. Is there any reason that helps Random Forest become a suitable algorithm for this problem? If possible, the authors should compare their performance with the state-of-the-art machine learning algorithms, i.e., SVM or RBF network.
- There is a need for validating on an external set of data.
- There is a need for discussing on some tests with p-value > 0.05 (not significant).
- The authors have to perform feature selection in their model.
Additional comments: No comment.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: MACHINE LEARNING ANALYSIS TO IDENTIFY THE ASSOCIATION BETWEEN RISK FACTORS AND ONSET OF NOSOCOMIAL DIARRHEA: A RETROSPECTIVE COHORT STUDY
Review round: 2
Reviewer: 1

Output:
Basic reporting: Very good
Experimental design: Very good
Validity of the findings: Very good
Additional comments: Great work revising the manuscript and precisely addressing the reviewers comments. I think it can be accepted in the current format.


Instruction: You are one of the reviewers, your task is to write a review for the article. You will be given the title of the article, the number of the round in which the article is located, and your order among the reviewers.

Input:
Title: MACHINE LEARNING ANALYSIS TO IDENTIFY THE ASSOCIATION BETWEEN RISK FACTORS AND ONSET OF NOSOCOMIAL DIARRHEA: A RETROSPECTIVE COHORT STUDY
Review round: 2
Reviewer: 2

Output:
Basic reporting: No comment
Experimental design: No comment
Validity of the findings: No comment
Additional comments: No additional comments