Cadmium and volumetric mammographic density: A cross-sectional study in Polish women

Beata Pepłońska; Beata Janasik; Valerie McCormack; Agnieszka Bukowska-Damska; Paweł Kałużny

doi:10.1371/journal.pone.0233369

Peer Review History

Original SubmissionFebruary 11, 2020
19 Mar 2020 Decision Letter - Jaymie Meliker, Editor PONE-D-20-03975 Cadmium and volumetric mammographic density: a cross-sectional study in Polish women PLOS ONE Dear Dr. Peplonska, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please address all reviewers' comments in a point by point response. In particular, we will be looking for a statistical response to issues of age and smoking confounding. We would appreciate receiving your revised manuscript by May 03 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data. 6. Your ethics statement must appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please also ensure that your ethics statement is included in your manuscript, as the ethics section of your online submission will not be published alongside your manuscript. 7. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: I Don't Know ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This is a nice manuscript describing the cross-sectional association between urine cadmium and breast density in mammography screenings. Here are a few comments to help the authors improve the manuscript. 1. The manuscript needs to be looked at closely for its writing. Overall, the writing is good but there are several places where the writing needs work (e.g., lines 92-97). 2. The introduction could use a little more review of previous epi studies on Cd and breast cancer incidence. Especially the prospective cohort studies which likely are closely to the true answer on the association. 3. Because creatinine is also associated with other things, some suggest running a sensitivity analysis in which creatinine is included as a covariate in the statistical model, and not dividing by it within the U-Cd measure. I would recommend doing this and reporting the results in supplemental results. 4. The nulliparous group is too small to infer anything. Those stratified results should be moved to supplemental results. 5. Figure 1 is not necessary since results are the same as table 2. 6. Most critical is the treatment of age. The authors have clearly thought a lot about age, because it is such a strong negative confounder here (positively associated with U-Cd and negatively associated with breast density). But I think this work would be markedly improved if they could identify subsets of the population in which age is not associated with breast density. Perhaps age stratifying 50-55, 56-60, etc, would still give samples of at least one hundred and would no longer see associations between age and breast density. I still would adjust for age within these groups, but the tighter strata should mitigate the age effect. They need to work to eliminate the age confounder and this is a strategy that I would likely attempt. Reviewer #2: This manuscript, “Cadmium and volumetric mammographic density: a cross-sectional study in Polish Women” evaluates urinary cadmium levels associated with breast density. Overall this is a well written manuscript. The information about cadmium and breast density was well described. The one area that needs to be addressed is the pathophysiology between cadmium and breast density. Strong factors associated with breast density are inversely associated with cadmium exposure such as age and smoking. These analyses do not adequately address this issue of competing variables. Additional statistical feedback is needed for this paper. The only thing I could think that could address this would be stratification but I don’t know if you have sufficient numbers. Although parity has not been associated with cadmium levels, it is associated with parity. And the stratification (table 3) of parity, nulliparous took this into consideration. If the cd was evaluated using some other way to categorize such as 10th, 50th, and 90th percentiles of the creatinine-corrected urinary cadmium distribution in the overall study sample as used by Menke, would that alter the findings? See Menke A, Muntner P, Silbergeld EK, Platz EA, Guallar E. Cadmium levels in urine and mortality among U.S. adults. Environ Health Perspect. 2009;117(2):190–196. doi:10.1289/ehp.11236 for another way to categorize the data. There should be a result with cadmium as a continuous variable since categorization is an artificial way to characterize the exposure. The other issue that is puzzling, a seems to be a proxy for something else was the seasonality of the mammography. It makes no sense that this would be significantly different based on the 2 main variation—urinary cadmium should not vary significantly over time, as this captures historical exposure; similarly breast density, as far as I know, does not vary by season. Hopefully not, but could this reflect a bias in the reading of the images? ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. 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Revision 1
2 May 2020 Author Response Journal Requirements: When submitting your revision, we need you to address these additional requirements: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at http://www.plosone.org/attachments/PLOSOne_formatting_sample_main_body.pdf and http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pdf The files have been formatted according to PLOS ONE requirements. 2. In your Methods section, please provide additional information about the participant recruitment method and the demographic details of your participants. Please ensure you have provided sufficient details to replicate the analyses such as: a) a description of any inclusion/exclusion criteria that were applied to participant recruitment, b) a description of how participants were recruited, and c) descriptions of where participants were recruited and where the research took place. The requested information has been provided. 3. Please note that PLOS does not permit references to “data not shown.” Authors should provide the relevant data within the manuscript, the Supporting Information files, or in a public repository. If the data are not a core part of the research study being presented, we ask that authors remove any references to these data. The phrase in question has been removed accordingly. 4. Please provide a sample size and power calculation in the Methods, or discuss the reasons for not performing one before study initiation. The information about sample size and power calculation has been provided. 5. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data. The phrase has been removed. 6. Your ethics statement must appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please also ensure that your ethics statement is included in your manuscript, as the ethics section of your online submission will not be published alongside your manuscript. The ethics statement has been moved to the Methods section. 7. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. Captions for supporting files have been included according to the PLOS ONE guidelines. Reviewer #1: This is a nice manuscript describing the cross-sectional association between urine cadmium and breast density in mammography screenings. Here are a few comments to help the authors improve the manuscript. We would like to thank the Reviewer for a positive overall assessment of our manuscript. We truly appreciate the time and effort in reviewing our manuscript and the valuable comments and suggestions that will contribute to raising the scientific and editorial standard of the manuscript 1. The manuscript needs to be looked at closely for its writing. Overall, the writing is good but there are several places where the writing needs work (e.g., lines 92-97). Respective corrections have been made and the manuscript has also been language-checked as suggested. 2. The introduction could use a little more review of previous epi studies on Cd and breast cancer incidence. Especially the prospective cohort studies which likely are closely to the true answer on the association. We appreciate pointing out this issue. The information on the results of the prospective cohort studies has been included in the Introduction . 3. Because creatinine is also associated with other things, some suggest running a sensitivity analysis in which creatinine is included as a covariate in the statistical model, and not dividing by it within the U-Cd measure. I would recommend doing this and reporting the results in supplemental results. The sensitivity analysis with creatinine as a confounder has been performed. The results have not changed markedly. They have been presented in the supplemental table S1. 4. The nulliparous group is too small to infer anything. Those stratified results should be moved to supplemental results. The table with results of the stratified analysis by parity has been moved to supplemental information (table S2). 5. Figure 1 is not necessary since results are the same as table 2. Figure 1 has been removed accordingly. 6. Most critical is the treatment of age. The authors have clearly thought a lot about age, because it is such a strong negative confounder here (positively associated with U-Cd and negatively associated with breast density). But I think this work would be markedly improved if they could identify subsets of the population in which age is not associated with breast density. Perhaps age stratifying 50-55, 56-60, etc, would still give samples of at least one hundred and would no longer see associations between age and breast density. I still would adjust for age within these groups, but the tighter strata should mitigate the age effect. They need to work to eliminate the age confounder and this is a strategy that I would likely attempt. Following the Reviewer’s suggestion, a stratified analysis has been performed. Unfortunately, the group below age 45 was small, and therefore, we created three age group:s ≤50; >50-≤55, >55. However, the analysis has not revealed any significant findings. The results are presented in table S6 . Reviewer #2: This manuscript, “Cadmium and volumetric mammographic density: a cross-sectional study in Polish Women” evaluates urinary cadmium levels associated with breast density. Overall this is a well written manuscript. The information about cadmium and breast density was well described. We would like to thank the Reviewer for his/her careful review of the manuscript and for the detailed comments and suggestions. They will certainly be helpful in raising the standard of the manuscript. The one area that needs to be addressed is the pathophysiology between cadmium and breast density. Strong factors associated with breast density are inversely associated with cadmium exposure such as age and smoking. These analyses do not adequately address this issue of competing variables. Additional statistical feedback is needed for this paper. The only thing I could think that could address this would be stratification but I don’t know if you have sufficient numbers. Although parity has not been associated with cadmium levels, it is associated with parity. And the stratification (table 3) of parity, nulliparous took this into consideration. To address the issue raised above, we ran additional analyses by age groups and smoking. Age and smoking were mutually adjusted besides other significant covariates. However, none of these brought forth any new findings - we did not record any significant modification of the effect. The results of these analyses are included in the supplementary tables S3 and S6. If the cd was evaluated using some other way to categorize such as 10th, 50th, and 90th percentiles of the creatinine-corrected urinary cadmium distribution in the overall study sample as used by Menke, would that alter the findings? See Menke A, Muntner P, Silbergeld EK, Platz EA, Guallar E. Cadmium levels in urine and mortality among U.S. adults. Environ Health Perspect. 2009;117(2):190–196. doi:10.1289/ehp.11236 for another way to categorize the data. There should be a result with cadmium as a continuous variable since categorization is an artificial way to characterize the exposure. We thank the Reviewer for this recommendation. We ran a similar analysisas suggested; however, the results have not changed substantially. Specifically, the generalized linear model with adaptive cubic regression spline of Cadmium/Cre (similar to the one presented by Menke at al., but with a free knot location) was fit to VMD and fibroglandular volume, and produced the following graphical summary, with the solid line representing the best fit of Cd to VMD (the shaded region represents standard error of the estimate): The above findings indicated a weak tendency towards a smaller VMD, around Cd/Cre=0.5, and little nonlinearity in cadmium effect on VMD, but it did not generally change our conclusions. The plot for FG volume was analogous. In the manuscript, we present data for cadmium and mammographic density measured as continuous variables. In addition, we present data in quartiles for the clarity of presentation. The other issue that is puzzling, a seems to be a proxy for something else was the seasonality of the mammography. It makes no sense that this would be significantly different based on the 2 main variation—urinary cadmium should not vary significantly over time, as this captures historical exposure; similarly breast density, as far as I know, does not vary by season. Hopefully not, but could this reflect a bias in the reading of the images? We considered the season of the year as a potential confounder based on other authors’ findings. Seasonal variations in mammographic density have been suggested for premenopausal women in the study by Brisson et al. (1). We also observed that the season of the year was a significant covariate in our previous study (2). While the nature of this observation remains unknown, the season of the year in the current dataset turned out to be a significant covariate as well and was retained in the multivariate model, with Akaike criterion applied for confounders selection. Reference List 1. Brisson J, Berube S, Diorio C, Sinotte M, Pollak M, Masse B. Synchronized seasonal variations of mammographic breast density and plasma 25-hydroxyvitamin d. Cancer Epidemiol Biomarkers Prev. 2007;16(5):929-33. 2. Peplonska B, Bukowska A, Sobala W, Reszka E, Gromadzinska J, Wasowicz W, et al. Rotating night shift work and mammographic density. Cancer Epidemiol Biomarkers Prev. 2012;21(7):1028-37. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0233369.r002
5 May 2020 Decision Letter - Jaymie Meliker, Editor Cadmium and volumetric mammographic density: a cross-sectional study in Polish women PONE-D-20-03975R1 Dear Dr. Peplonska, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements. Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication. Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. With kind regards, Jaymie Meliker, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0233369.r003
Formally Accepted
11 May 2020 Acceptance Letter - Jaymie Meliker, Editor PONE-D-20-03975R1 Cadmium and volumetric mammographic density: a cross-sectional study in Polish women Dear Dr. Peplonska: I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. For any other questions or concerns, please email plosone@plos.org. Thank you for submitting your work to PLOS ONE. With kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Jaymie Meliker Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0233369.r004

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