PONE-D-24-33750PREDICTORS OF FREQUENCY OF CF CARE IN THE US CYSTIC FIBROSIS FOUNDATION PATIENT REGISTRYPLOS ONE

Dear Dr. Hinton,

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Abdelwahab Omri, Pharm B, Ph.D, Laurentian University

Academic Editor

PLOS ONE

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2. Thank you for stating the following in the Acknowledgments Section of your manuscript:

“The authors thank the Cystic Fibrosis Foundation for the use of United States CF Foundation Patient Registry (USCFFPR) data to conduct this study and for and StatNet grant 003847Y7122. Additionally, the authors thank the people with CF, care providers, and clinic coordinators at CF centers throughout the USA for their contributions to the USCFFPR. Data are available upon request through the USCFFPR Comparative Effectiveness Research Committee. The committee can be contacted at datarequests@cff.org. “

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“AM and JZ received funding from the Cystic Fibrosis Foundation (https://www.cff.org/) through the StatNet grant 003847Y7122.  Funders did not play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

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 3. We noted in your submission details that a portion of your manuscript may have been presented or published elsewhere. [Preliminary results were published as an abstract associated with the 2023 North American Cystic Fibrosis Conference. A. Hinton ES, S. Lopez-Pintado, J. Zuckerman. 614 Time between clinic visits of individuals with cystic fibrosis: patterns across the lifespan. Journal of Cystic Fibrosis. 2023;22:S327-S328. doi:https://doi.org/10.1016/S1569-1993(23)01536-9

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Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: Thank you for your very interesting study that I careful read with great pleasure.

Your observational cohort study, conducted using data of the USCFF patients’ registry, aimed to investigate sociodemographic and disease-related factors predictive of visit frequency in people with CF and to assess how these effects vary across the lifespan. The relationship between patient-level characteristics and between-visit interval (BVI) was modeled using multivariable longitudinal semiparametric regression.

The study, with an important data collection on more than 28,000 subjects with more than 850,000 encountered, showed that 55% of visits (in pwCF 6-60 years old) occurred within 90 days of the prior visit, adhering to national guidelines. Males, non-white individuals, uninsured, especially young adults, and subjects without CF complications had a longer BVI, while close visits in patients with complications reflect their greater needs for care.

The study also identifies categories of patients with intervals between visits greater than 6 or 12 months (59% and 25% respectively in the 18-25 age group), intervals that may increase the risk of greater lung damage.

I found the study, and your paper, complex but comprehensive, and it provides a lot of information to help clinicians undertake quality improvement programs for non-standardized BVI, thus CF patient management could be designed on characteristics and needs of patients, improving CF care delivery and somehow an increase in patients' awareness of their needs.

There are two typo, line 114, pwCF � CF and line 124 QI � quality improvement (QI)

Reviewer #2: This paper, authored by an experienced group, focuses on the frequency of patient visits to cystic fibrosis (CF) centers, drawing from a large cohort in the US Cystic Fibrosis Foundation Patient Registry (USCFFPR). The study offers valuable insights and makes a strong case for refining guidelines to promote more frequent and tailored care, particularly for those at risk of poor outcomes due to sociodemographic and insurance-related factors. Its findings are particularly relevant for CF clinicians, caregivers, health insurers, and researchers in healthcare delivery.

However, there are a few key points that the authors should address before publication:

� ETI's Impact on CF Care: The data was collected before the introduction of elexacaftor/tezacaftor/ivacaftor (ETI), which has revolutionized CF treatment. This should be discussed in more detail, as it could significantly impact patient care moving forward.

� In line with the above mentioned point: Ivacaftor and Visit Frequency: Ivacaftor was approved in 2012 for patients with at least one G551D mutation, which may have influenced visit patterns. Can you extrapolate between-visit intervals (BVI) for this specific group and compare visit frequency before and after the introduction of Ivacaftor? Addressing whether this therapy impacted BVI would enhance the relevance of your findings.

� Quality vs. Frequency of Visits: While the study emphasizes visit frequency, it lacks an assessment of the quality of care provided during those visits. Increased visit frequency does not always correlate with improved outcomes unless care is effectively tailored to the patient’s needs. It would be valuable to include data on how many patients received the standard of care regarding medications. Additionally, could patients who are unable to afford necessary drugs be skipping visits due to frustration over diagnostic results that do not lead to receiving appropriate therapy? Discussing this would add depth to the analysis.

� Patient-Reported Outcomes: The abstract does not mention patient-reported outcomes, such as satisfaction with care or perceived barriers to attending visits. Including patient perspectives would provide important context for understanding the observed disparities. Please consider addressing this in the discussion section.

� Potential Data Limitations: There is a possibility that visit frequency was underreported, and some sociodemographic variables may have been categorized too broadly. Clarifying the extent of this issue could help address concerns about data completeness and accuracy.

� Data Imputation Methods: The use of Last Observation Carried Forward (LOCF) and Next Observation Carried Backward (NOCB) for imputing missing data may introduce bias. Please discuss how these methods might have influenced your findings.

By addressing these points, the paper would offer a more comprehensive understanding of the factors influencing care frequency and the impact of recent treatment advancements on CF management.

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Reviewer #1: No

Reviewer #2: Yes: Dr. Olaf Eickmeier

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PREDICTORS OF FREQUENCY OF CF CARE IN THE US CYSTIC FIBROSIS FOUNDATION PATIENT REGISTRY

PONE-D-24-33750R1

Dear Dr. Alexandra C Hinton,

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.

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Kind regards,

Abdelwahab Omri, Pharm B, Ph.D, Laurentian University

Academic Editor

PLOS ONE