PONE-D-20-19873

Birth weight, growth, nutritional status and mortality of infants from Lambaréné and Fougamou in Gabon in their first year of life

PLOS ONE

Dear Dr. Mombo-Ngoma,

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.

During the review please address the following major issues.

1. Please explore the the issue of loss to follow up bias by statistically comparing individuals retained and dropped out of the study at different stages of the study. 

2. Please provide a clear and objective criteria how the potential confounders were selected for statistical adjustment. 

Please submit your revised manuscript by Nov 01 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're 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.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Samson Gebremedhin, PhD

Academic Editor

PLOS ONE

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

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

3. Thank you for stating the following in the Competing Interests section:

'I have read the journal's policy and the authors of this manuscript have the following competing interests: CM is a member of the Editorial Board of PLOS Medicine. The authors have declared that no other competing interests exist'

a. Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests).  If there are restrictions on sharing of data and/or materials, please state these.

Please note that we cannot proceed with consideration of your article until this information has been declared.

b. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests

[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: No

Reviewer #2: Yes

**********

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: No

Reviewer #2: No

**********

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: No

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 manuscript is on an important topic, but the writing is somewhat confusing and needs a close grammar proofread; not all of the numbers in the text match the tables; and I have certain concerns about the data and analyses as presented.

Major concerns:

My 2 major concerns are about the amount of missing data and the selected confounders. The most concerning issue for me is that loss to follow up is a huge limitation. The study lost either 25 or about 45% of the sample, depending on how you choose the denominator (one month vs. baseline). This issue is not addressed anywhere in the limitations or in the manuscript. I think the authors need to present some sensitivity analyses and say something about how they differed than the study participants who were retained, and how those differences might influence the study's findings. It's also not clear which children are in the KM and hazard analyses--have the authors censored the LTFs at last seen date, or just ignored them in that analysis?

My other major concern is that the authors have some specific confounders they controlled for, but why these specific ones were chosen are mysterious. There are other factors also possibly relevant--breast feeding history, complementary feeding history, family wealth, number of other kids in household, availability of & use of antenatal care--so what was the rationale for including these specific confounders and nothing else?

Minor concerns

Line 68-71: this sentence is hard to understand. I'd break it into 2 because you seem to have 2 concepts here.

Line 80: "Once established, stunting and its effects typically become permanent. Stunting is an appropriate indicator for chronic malnutrition"...There's some controversy about this. Some studies have shown trajectories in which children recover and others in which they don't. Early intervention is believed to help with this. You need some citations for your contention here.

Line 82:"Underweight is most commonly used as nutritional indicator due to difficulties..." This statement again needs some citation. DHS,. MICS, and a lot of other national programs use stunting and wasting. Saying that underweight is most commonly used needs to be backed up with some evidence.

Line 133: "For those with no weight available at birth but in the first week of life in case of home deliveries weight was estimated using a regression model". This needs some explanation. How do you estimate weight with regression?

Table 1: Preterm birth totals don't add to 907 or 115. I suggest that the authors present "n"s when they don't match the stated denominator.

Line 189: Authors haven't defined a weight gain ratio.

Line 200: if the authors are presenting decimal places in the table, it makes sense to match that in the text.

Line 208: "There were more significantly observed underweight LBW infants compared to their normal weight counterpart". I did not understand the sentence. what does it mean to be significantly observed underweight?

Lines 200-212: I found it challenging to read and follow this paragraph. Maybe the authors could restructure this so that they talk about each endpoint separately? So, first stunting, and what's associated. Then wasting, and what's associated with that, etc.

Lines 221-222: These numbers should all match what is in table 4. I found this paragraph also very confusing. LBW was associated with higher stunting at months 1 AND month 12, but not in between . These are all one model, correct? So preterm birth is associated with stunting independent of LBW ?

Discussion: the English here needs some boosting also.

Lines 263-265: I didn't understand what it means to have a nutritional gain if the prevalence of stunting and underweight increased and prevalence of wasting stayed the same. Perhaps reword this? Do you mean that mean weight increased for all children?

Lines 272-274: "We hypothesize that this catching up in weight gain is at least in part due to the particular attention caused by mothers and the health care system allowing children born with LBW to acquire a normal weight" What is this extra attention? Can you be more specific about Gabon's practices in the health care system to address these nutritional challenges in LBW children?

Lines 293-296: I don;t understand this paragraph. LBW is an independently associated with stunting at 12 months in this setting--but what does that have to do with weight deficit since birth? These 2 things are probably true, but the authors haven't really connected them coherently here.

Lines 303-304: "This indicates that 302 health interventions need to focus primarily on the two first months of life, particularly for newborns with LBW." I'm not sure this is a reasonable suggestion. What do the authors mean by "primarily"? Even among those who survive, a high proportion have poor nutrition outcomes. So I'm not sure it makes sense to say that that health care programs should put most focus on the first 2 months. Obviously something needs to be done but the children who survive also need health care support. Also, the authors don;t mention what proportion of deaths occur as neonates. Health interventions often don't help to move the needle on neonatal death. What might help with these early deaths is antenatal care, facility delivery in a well-stocked facility, etc. Other health service interventions may be of more benefit in children after the first few weeks of life.

Reviewer #2: The manuscript presented an interesting data on the significance of LWB for survival and nutritional status of infants in Gabon. While the findings of the analysis are not new, they may help to consolidate the existing knowledge on the topic. In general, the manuscript is also well written.

I recommend the authors accommodate the following comments.

Exhaustive list of potential confounders along with approach used for selecting the variables for multivariable adjustment should be provided. For example, it is not clear how the authors decided to adjust the multivariable models for infant sex, maternal age and maternal literacy.

The adequacy of the sample size for comparing mortality between LBW and normal birthweight infants should be evaluated through post-hoc power calculation.

The possibility of loss to follow up bias should be explored by comparing the characteristics of the study participants retained and dropped out of the study.

The basic characteristics of exposed and non-exposed subjects should be described and statistically compared at the beginning of the Results section.

**********

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.]

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. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-20-19873R1

Birth weight, growth, nutritional status and mortality of infants from Lambaréné and Fougamou in Gabon in their first year of life

PLOS ONE

Dear Dr. Mombo-Ngoma,

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. Specially I recommend you to address issues raised on the sensitivity analysis and the approach used for selecting variables for the statistical adjustment. 

Please submit your revised manuscript by Jan 21 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're 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.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Samson Gebremedhin, PhD

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: (No Response)

**********

2. 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

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

**********

4. 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: (No Response)

**********

5. 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

**********

6. 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: I thank the authors for their efforts to address the comments that the other reviewer and I made. I appreciate their time. However, I still have one large concern and a few minor changes and suggestions.

MAIN large reservation:

I don’t think that the authors entirely understood my request to do a sensitivity analysis of those who were lost to follow up, or if they did, it’s not reflected in the supplemental table. In lines 317-323 “sensitivity analyses that demonstrated that the baseline characteristics of the retained children were not different from the entire population at baseline [**assuming that those dropped out were similar to those retained with regard to these characteristics**].” I have bracketed the concerning portion because in my view, that assumption renders the authors’ sensitivity analysis invalid.

What I am thinking of here is a sensitivity analysis in its simplest form as follows: those who were LTFU are one category and those who were never LTFU or missing are another. Then compare those 2 categories on things like LBW, malnutrition, preterm birth, infant sex, etc., What I see in the Supplementary table are descriptions of those who were retained at different time points, with no p values or comparisons. Just based on the numbers I see in the table, at 9 mo, the authors have 60/115 LBW kids (~52%) vs 515/792 normal birthweight kids (~65%). Which could very well be a statistically significant difference, but we don't know. The mean birthweight in your LBW children at 12 months was somewhat higher than in the LBW children at baseline. My point is that the children that were lost may be different in meaningful ways than the ones who were retained. My suggestion is to figure out whether there were differences, present p values in the supplement table to reassure the readers, and if there are differences, mention in the discussion whether you think they’d impact the results and how. It may be that you suspect that if everyone were there, you’d get even stronger associations.

Minor comments and proofreading:

Line 35, don’t need comma after “both”

Line 40 : included between 2009 and 2012 makes it sound like these are “n”s . Suggest you move the word “included” to after 2012.

Line 48: It could be the same number of infants that were LBW, it’s just that you’ve lost more during follow up. What are the actual ns? Is it same kids?

Line 55: ratio, not ration.

Body:

line 77 “”stunting is reported to be a strong marker of healthy growth”. It’s more like unhealthy growth, no?

line 86” While stunting wasting and underweight…low birth weight…” maybe make that the first sentence of the LBW paragraph

line 139: “like describe elsewhere”. This is not great grammar and not especially useful. I’d suggest you say something like “calculated using standard formula” and cite maybe DHS statistics or WHO web page that talks about how to calculate,

line 139

Height-for-age Z-score (HAZ), weight-for-age Z-score (WAZ) and weight-for-height Z-score (WHZ) were used to define respectively stunting, underweight and wasting. HAZ <-2 standard deviations (SD), WAZ <-2 141SD and WHZ <-2 SD.

Suggest you reword to make complete sentences:

Ex: Height-for-age Z-score (HAZ, <-2 standard deviations below an international reference mean), weight-for-age Z-score (WAZ <-2 SD), and weight-for-height Z-score (WHZ <-2 SD) were used to define respectively stunting, underweight and wasting.

144: data”were” . Data is a plural

Line 148: on comparing baseline characteristics of infants attending each visit to explore whether there was any alteration that could be imputed to the lost to follow-up.

Sentence is confusing. try instead “to explore whether any differences existed that could be associated with loss to follow up”

Table 4: I’ve forgotten why Wasting is only assessed at month 1. I’d suggest the authors add a footnote to the table about that, because the authors obviously calculated prevalence of wasting at all times.

Reviewer #2: Most of my concerns have been addressed. However, it remains vague how the variables infant sex, maternal age and maternal literacy were selected for adjustments. What possible control variables did the authors considered at the beginning of the analysis? How did the end up in the three variables? This must be clearly described in the manuscript.

**********

7. 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.]

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. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Birth weight, growth, nutritional status and mortality of infants from Lambaréné and Fougamou in Gabon in their first year of life

PONE-D-20-19873R2

Dear Dr. Mombo-Ngoma,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. 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 help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- 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.

Kind regards,

Samson Gebremedhin, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: