The Effect of Sleep Disorder Diagnosis on Mortality in End-Stage Renal Disease Patients

Round 1

Reviewer 1 Report

Overall, the manuscript is well written. However, there are a few areas that need to be addressed. 

1. Throughout the manuscript, there are several words that are run together. 

2. The tables are messy with all the lines. Remove the lines and reformat.

3. There needs to be a conclusion section at the end of the manuscript. 

Author Response

We appreciate the reviewers’ comments overall that the manuscript is “well-written” and that the conclusions “…are backed by adequate design…,” “the limitations are carefully discussed” and the results are “interesting.” We also greatly appreciate the efforts of reviewer 1 and would like to respond to their helpful comments.

Reviewer #1

1. Throughout the manuscript, there are several words that are run together. 

We have edited the manuscript to correct these issues.

2. The tables are messy with all the lines. Remove the lines and reformat.

We removed some of the lines and reformatted.

3. There needs to be a conclusion section at the end of the manuscript.

A conclusion section has been added to the end of the Discussion section.

Reviewer 2 Report

The following study submitted to Applied Sciences evaluates the relationship between sleep disorders and mortality in ESRD patients. The presented conclusions are backed by adequate design and the statistical analysis followed a conventional approach for analyzing large-scale observational data and addressing the research question. Additionally, the limitations are carefully discussed.

Please find below some minor issues:

-        Bibliography should be a little more exhaustive at least in the introduction, and include more literature on sleep apnea and ESRD. Some reviews might help on this matter (PMID: 31542452; PMID: 16969388; PMID: 33479446; PMID: 34476089).

-        In the discussion section, briefly describing the treatment strategies that are usually used after sleep disorders diagnosis could be of added value.

-        The supplementary materials are missing.

Author Response

We appreciate the reviewer comments overall that the manuscript is “well-written” and that the conclusions “…are backed by adequate design…,” “the limitations are carefully discussed” and the results are “interesting.” We also specifically appreciate the comments of reviewer #2 which we feel strengthen the manuscript. Please find our replies below. Thank you.

Reviewer #2

(1) Bibliography should be a little more exhaustive at least in the introduction, and include more literature on sleep apnea and ESRD. Some reviews might help on this matter (PMID: 31542452; PMID: 16969388; PMID: 33479446; PMID: 34476089).

We have now expanded the introduction and referenced the indicated reviews.

(2) In the discussion section, briefly describing the treatment strategies that are usually used after sleep disorders diagnosis could be of added value.

In the discussion we have now included a description of treatment strategies for sleep disorders.

(3) The supplementary materials are missing.

We apologize for the oversight and now include the supplementary materials.

Reviewer 3 Report

Nixson and colleagues investigated the association between sleep disorders and mortality among end-stage renal disease patients. In the final regression model, sleep disorder diagnoses were associated with decreased risk of mortality, with hazard  ratios (and 95% confidence intervals) for insomnia, hypersomnolence, restless leg syndrome, and obstructive/central sleep apnea of 0.76 (0.75-0.76), 0.81 (0.78-0.84), 0.79 (0.77-0.80), and 0.82 (0.81- 0.82). This results is both interesting and surprising as contraintuitive.

When I read methods of the study, for me is not fully clear if authors conducted Proportional Hazard Cox Regression or no.  I however can see that sleep disorder diagnoses were considered in the time between index date and mortality. This is not usual for this kind of models.  IN this case, authors would need to run the time-dependent Cox regression.  In other case, each sleep disorder diagnosis as further visit would increase the time to mortality.  The more events/visits you have in the follow-up time , the longer this takes until death, as patients need to have time to do these visits, and this time is positively correlated with time to death.

That’s being said, I mean, the Cox model was not performed in the optimal way, or I did not understand that correctly.  The most pragmatic solution would be to adjust for the number of visits during the follow up.  Patients with sleep disorders have to have the same number of visits as patients without sleep disorders, no matter what the reason of visits was.  IN other case, these results cannot be considered valid. This is highly possible that after adjusting for the number of visits, sleep disorders will become positively associated with mortality (I know it from own experience as I done such studies in the past).

Author Response

We appreciate the overall reviewer comments that the manuscript is “well-written” and that the conclusions “…are backed by adequate design…,” “the limitations are carefully discussed” and the results are “interesting.” We also specifically appreciate the comments of reviewer #3 which we feel strengthen the manuscript. Please find our reply below.

Reviewer #3

We agree that controlling for the number of visits may enhance the analysis. However, we do not feel that this would change the results. The frequency of dialysis visits during which the database variables are collected greatly outnumbers other types of outpatient visits. So, while this is a potential limitation, we feel that overall the diagnosis of a sleep disorder being protective is valid, as it indicates that the patients are receiving enhanced physician scrutiny and/or receiving treatment of diagnosed conditions. This is further supported by the lower prevalence of these disorders that were detected in our study versus questionnaire-based studies of CKD and ESRD. Additionally, a time to event, Cox Proportional Hazards model analysis was performed. We excluded individuals who had no follow-up from this sample, which should aid in diminishing bias due to any potential differences in number of visits. While a Kaplan-Meier analysis was performed, this was used for descriptive purposes. However, the reduced risk is also seen in these Kaplan-Meier plots, with the blue line corresponding to those with the sleep disorder showing better survival than the red line, which corresponds to those without the sleep disorder, suggesting the validity of the results.

Round 2

Reviewer 3 Report

N/A