Emily Chenette, PhD

Editor

PLOS ONE

Manuscript Number: PONE-D-25-31233

Dear Editor,

I am attaching the revised version of our paper titled "The prognostic value of gait speed in hemodialysis patients: A prospective observational study” for consideration as an article in PLOS ONE. The revised sections are highlighted in yellow to emphasize the changes made.

We want to express our gratitude for the opportunity to review our document and make improvements to key points, thereby meeting the journal's requirements and addressing the reviewers’ suggestions. Formatting and quality have been adjusted in accordance with the guidelines provided in the author's guide. We have implemented all the suggested changes, and the following pages contain our point-by-point responses to the queries raised by the reviewers. We have addressed the proposed notes and provided clarification for any remaining questions.

With these revisions and responses, we believe that our work is now ready for acceptance by this esteemed journal.

Yours sincerely,

Vanessa Amaral Mendonça

The corresponding author*

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Answer: This work didn’t receive any specific funding, but we must acknowledge some Brazilian agency research support. This is crucial for maintaining our line of research in Brazil. It’s essential to receive grants in our country.

“The authors thank the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil; Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil; Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) (APQ-00709-24; APQ-01522-23), Brazil; and Hemodialysis Center of Santa Casa de Caridade de Diamantina, Minas Gerais, Brazil.”

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“The authors thank the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil; Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil; Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) (APQ-00709-24; APQ-01522-23), Brazil; and Hemodialysis Center of Santa Casa de Caridade de Diamantina, Minas Gerais, Brazil.”

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Answer: Thank you. The recommendation to cite specific previously published works was reviewed and evaluated.

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Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

________________________________________

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: No

________________________________________

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

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Reviewer #1: Thank you for the invitation to review this paper, Dr. Bataglia, below are my comments

- Could the authors clarify whether the gait speed cutoff of 1.13 m/s was derived exclusively from their ROC analysis, or if it was also compared to previously established thresholds in similar populations?

Answer: Thank you for this comment. The gait speed cutoff of 1.13 m/s was derived from the ROC curve analysis performed in our sample, aiming to identify the threshold with the best balance between sensitivity and specificity for the studied outcome. Subsequently, we conducted a comparative analysis with gait speed cutoffs reported in previous studies involving populations with chronic diseases to assess the external validity of our findings. This comparison showed that the identified cutoff is slightly higher, which can be attributed to the younger age range of the population included in this study. This question is explored in the Discussion section (page 12, lines 247-253).

- In the sample size calculation, the authors mention an expected event rate of 34%. Could they explain how this percentage was determined (e.g., from prior literature or preliminary data)?

Answer: Thank you for this comment. An initial literature review was conducted to identify mortality rates reported in similar populations. Subsequently, a pilot study was performed, and the observed mortality rate of 34% was found to be consistent with values previously described in the literature.

References:

1. de Jager DJ, Grootendorst DC, Jager KJ, et al. Cardiovascular and Noncardiovascular Mortality Among Patients Starting Dialysis. JAMA. 2009;302(16):1782–1789. doi:10.1001/jama.2009.1488

2. Barra, A.B.L., Roque-da-Silva, A.P., Canziani, M.E.F. et al. Characteristics and predictors of mortality on haemodialysis in Brazil: a cohort of 5,081 incident patients. BMC Nephrol 23, 77 (2022). https://doi.org/10.1186/s12882-022-02705-x

- The results indicate that phosphorus was associated with mortality in univariate analysis but not in the adjusted model. Could the authors elaborate on possible reasons for this attenuation?

Answer: Thank you for this comment. Cox proportional hazards regression is a time-to-event analysis that estimates the association between covariates and the risk of the studied outcome, allowing the identification of independent predictors when multiple variables are included in the model. In the univariate analysis, serum phosphorus was significantly associated with mortality when evaluated in isolation. However, this association was attenuated in the multivariate model after adjustment for functional performance. This is a mathematical attenuation, and it likely occurred because, when analyzed together, functional performance captures a broader and more integrated representation of the patients' clinical and physiological status, thereby overlapping the prognostic information provided by serum phosphorus alone.

- Also, the paper didn't the criteria for an acceptable ROC-AUC value, consider this literature to help clarify an acceptable threshold https://doi.org/10.1080/23249935.2025.2516817 (typically 0.8 and above).

Answer: Thank you for this comment. In this study, an AUC greater than 0.7 was considered acceptable, while an AUC greater than 0.8 was considered excellent for the proposed cutoffs, based on the literature (Hajian-Tilaki, 2013). The AUC to identify mortality hazards in hemodialysis patients using gait speed was 0.85 (0.77-0.90), p < 0.0001, indicating an excellent result. We thank the reviewer for the suggestion. The recommended reference has been incorporated into the Methods and References sections (Reference 30).

Reference: Hajian-Tilaki K. Receiver Operating Characteristic (ROC) Curve Analysis for Medical Diagnostic Test Evaluation. Caspian J Intern Med. 2013;4(2):627–35.

- In the causes of death reported, some were listed as “undetermined origin.” Could the authors clarify how these cases were classified and whether they might influence the robustness of the survival analysis?

Answer: Thank you for this comment. Deaths classified as “undetermined origin” occurred in cases in which the patient died within their municipality and detailed information on the cause of death was not available in the medical records or official registries at the time of data collection. Importantly, these cases were classified as death events in the survival analysis regardless of the specific cause. As the primary outcome of this study was all-cause mortality, the absence of cause-specific information does not compromise the robustness of the Cox regression models. In addition, deaths due to external causes, such as accidents, trauma, or other non-disease-related events, were neither reported nor observed in this cohort.

- The manuscript highlights gait speed as a “free-of-charge measure.” Could the authors expand briefly on the feasibility of implementing this in dialysis centers with limited staffing or high patient loads?

Answer: Integrating the gait speed test into routine dialysis assessments is a practical and cost-effective strategy to enhance patient monitoring, making it particularly suitable for dialysis centers with limited staffing or high patient volumes. The test requires minimal and straightforward training, as the procedure involves only a standardized environment (an 8-meter corridor) and simple instructions (Cruz-Jentoft et al., 2019). It is quick to administer and can be scheduled at regular intervals, such as monthly or quarterly, without interfering with the dialysis routine. This integration enables longitudinal follow-up of functional capacity, providing prognostic and clinically relevant information with minimal burden on healthcare resources.

Reference: Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019 Jan 1;48(1):16–31.

- The generalizability of findings is noted as a limitation, given the single-center design. Could the authors provide more detail on the characteristics of this center (e.g., patient demographics, resources) to help readers assess comparability with other settings?

Answer: Thank you for highlighting this important point regarding generalizability. The study was conducted in a single outpatient hemodialysis center located in a region with a low Human Development Index (HDI), which influences both patient characteristics and healthcare delivery. The center provides chronic hemodialysis predominantly within a public healthcare system, and the patient population is characterized by a wide age range, with a predominance of younger adults compared to cohorts commonly reported in high-income settings. This demograp

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