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. 2025 Jan 10;20(1):e0317237. doi: 10.1371/journal.pone.0317237

Shifting temporal trends and disparities in sarcoidosis mortality in the United States: A retrospective analysis from 1999 to 2020

Fatima Ali Raza 1, Sumeet Kumar 2, Ayesha Mohammad 3, Areej Amin 4, Farooq Ahmad 5, Sohaib Tousif 6, Urwah Kamran 5, Lamea Bint Sahab 7, Sajjad Ali 6, Mah I Kan Changez 8,*, Aman Goyal 9,*
Editor: Amr Ehab El-Qushayri10
PMCID: PMC11723600  PMID: 39792876

Abstract

Introduction

Sarcoidosis is an inflammatory disease characterized by granulomas, the etiology of which remains unclear. This study examines sarcoidosis-related mortality trends in the United States from 1999 to 2020, with a focus on disparities pertaining to patient sex, geographical location, and urbanization status.

Methods

We analyzed death certificate data from the CDC WONDER database, using ICD-10 code D86. Age-adjusted mortality rates (AAMR) per 1,000,000 people were calculated. Trends were analyzed using Joinpoint regression models to determine annual percentage changes (APC).

Results

A total of 37,956 Sarcoidosis-related deaths were documented from 1999 to 2020 in the United States. The AAMR increased from 3.9 in 1999 to 6.4 in 2020. Significant mortality increases were observed from 1999–2001 and again from 2018–2020. Mortality rates were consistently higher among women compared to men. A significant difference in AAMR was observed across states, with highest mortality in the South region and lowest in the West region. Urbanization trends shifted from higher AAMR rates in metropolitan to non-metropolitan areas post-2018. Non-Hispanic Black individuals experienced the highest mortality rates throughout the study period.

Conclusions

This study highlights significant racial and geographic disparities in sarcoidosis-related mortality. Women, Black patients, and those residing in non-metropolitan areas are at the highest risk for Sarcoidosis associated mortality. Targeted public health interventions are required to address these prevalent disparities.

Introduction

Sarcoidosis is a systemic inflammatory disease characterized by the formation of granulomas—microscopic clusters of immune cells—most commonly affecting the lungs and lymphatic system [1]. Although the precise etiology remains unknown, it is hypothesized that sarcoidosis results from an exaggerated immune response to an unidentified antigen, with a disproportionately higher incidence observed among Black populations [2, 3].

Previous studies have documented sarcoidosis-related mortality trends in the United States from 1999 to 2016, highlighting notable demographic and geographic disparities [4]. However, an updated analysis incorporating more recent developments is warranted and remains unexplored. We hypothesize that the plateaued mortality rate of sarcoidosis observed in their study might have experienced an inflection point since then, with a potential change in mortality based on urbanization status.

This study extends the evaluation of sarcoidosis mortality trends through 2020, with a specific focus on recent changes and disparities based on urbanization status. This study aims to provide new insights into the impact of living environments on sarcoidosis outcomes and inform targeted public health interventions to mitigate the disease burden among vulnerable populations.

Methods

Study setting and population

We conducted a descriptive analysis of death certificate data from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (WONDER) database, spanning the years 1999 to 2020.

This analysis concentrated on death certificates within the Multiple Cause of Death Public Use dataset. We identified cases where sarcoidosis was listed as a primary or contributing cause of death, using the International Classification of Diseases, 10th Revision (ICD-10) code D86.

Institutional Review Board approval was not required, as we utilized a de-identified public dataset. This study adheres to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.

Data abstraction

Data were categorized by demographics, including, sex, and location of death (medical facilities, nursing or long-term care facilities, hospices, homes or other unclassified sites). Geographic categorization was based on census regions and states as defined by the United States Census Bureau. Urbanization levels were classified using the National Center for Health Statistics Urban Rural Classification Scheme, distinguishing metropolitan areas from non-metropolitan areas.

Data synthesis

Sarcoidosis mortality trends in the United States from 1999 to 2020 were analyzed, considering sex, state, urbanization, and census regions. Crude and age-adjusted mortality rates (AAMR) per 1000,000 people were calculated, using the 2000 census for AAMR standardization.

Piecewise log-linear regression models were employed to detect trend changes using the Joinpoint Regression Program (Version 5.2.0, National Cancer Institute) [5]. Age-adjusted mortality variations were reported as annual percent change (APC) with 95% confidence intervals. Statistical significance was assessed with a two-tailed t-test with a threshold of P<0.05.

For data indicating zero to nine (0–9) deaths, the rates were suppressed. When there are less than ten people in the population, the corresponding denominator population estimates are likewise suppressed. When there were fewer than 20 deaths, rates were labeled as "unreliable." Rates with "not stated" or unknown age or ethnicity were denoted as "not applicable" when the denominator population number was not available. AAMRs were not computed for deaths of individuals whose ages were "not stated" or unknown.

Ethics statement

Institutional Review Board approval and patient consent were not required for our study, as all data were retrospectively analyzed from a publicly accessible, de-identified, and anonymized database. The data were accessed from the CDC Wonder Database on 10/15/2024.

Results

A total of 37956 Sarcoidosis-related deaths were documented in the United States between 1999 and 2020 (S1 Table). Of these, 63.8% occurred within medical facilities, 24.9% occurred in home, 7.62% occurred in nursing home/long-term care facilities, and 3.5% occurred at hospice (S2 Table).

Annual trends for sarcoidosis-related mortality

The AAMR for Sarcoidosis-related deaths in the United States was 3.9 in 1999, rising roughly to double 6.4 in 2020 (S3 Table). The AAMR showed a significant increase from 1999 to 2001, with an APC of 9.66 (95% CI, 2.26 to 15.92). From 2001 to 2018, the trend plateaued with a minimal increase in AAMR, reflected by an APC of 0.52 (95% CI, -0.65 to 0.77). However, an increase in mortality was observed from 2018 to 2020, with an APC of 8.54 (95% CI, 2.66 to 11.52) (S4 Table).

Sarcoidosis-related AAMR stratified by sex

Women consistently had higher age-adjusted sarcoidosis mortality rates than men, with rates increasing from 4.4 per 100,000 in 1999 to 6.6 per 100,000 in 2020 (S3 Table).

Initially, from 1999 to 2001, there was a significant rise with an APC of 13.43%, followed by a slight decline between 2001 and 2018 (APC: -0.45%). However, from 2018 to 2020, mortality rates for women surged again with an APC of 9.20% (S4 Table).

In contrast, men started with a lower mortality rate of 3.2 per 100,000 in 1999, which increased to 6.1 per 100,000 by 2020 (S3 Table). From 1999 to 2018, the increase in men’s mortality was moderate (APC: 2.01%) but became more pronounced from 2018 to 2020, with an APC of 7.43% (S4 Table, Fig 1).

Fig 1. Sex-based disparities in sarcoidosis-related AAMRs in the U.S. from 1999 to 2020, with women experiencing higher rates than men.

Fig 1

Sarcoidosis-related AAMR stratified by state and census region

A significant difference in AAMR was observed across states, with the 2020 AAMRs ranging from the lowest AAMR of 0.7 per 100,000 [95% CI: 0.4–1.0] in Hawaii to the highest AAMR of 21.9 per 100,000 [95% CI: 19.3–24.4] in the District of Columbia (Fig 2).

Fig 2. Bar chart comparing sarcoidosis-related AAMRs across U.S. states, highlighting geographic disparities in mortality.

Fig 2

States that fell into the top 90th percentile, including the District of Columbia, South Carolina, and Maryland, were compared with states in the lower 10th percentile, namely Hawaii, Arizona, and New Mexico (S5 Table).

States with the highest overall AAMR change from 2003 to 2020 were observed in the District of Columbia, South Carolina, and North Carolina, reflecting significant increases over the study period.

On average, over the course of the study period, the highest mortality was observed in the South region (AAMR: 6.1 per 1,000,000, 95% CI: 5.6–6.5), followed by the Northeast region (AAMR: 5.3 per 1,000,000, 95% CI: 4.8–5.8), the Midwest region (AAMR: 4.8 per 1,000,000, 95% CI: 4.3–5.3), and the West region (AAMR: 3.3 per 1,000,000, 95% CI: 2.9–3.7) (S6 Table, Fig 3).

Fig 3. Regional differences in sarcoidosis-related AAMRs across U.S. Census regions, with notable disparities seen among different census regions.

Fig 3

Sarcoidosis-related AAMR stratified by urbanization status

From 1999 to 2018, metropolitan areas consistently had higher Sarcoidosis-related AAMRs compared to non-metropolitan areas. Following 2018, this trend began to shift, with non-metropolitan areas showing increasingly higher AAMRs than metropolitan areas (S7 Table, Fig 4).

Fig 4. The impact of urbanization on sarcoidosis-related AAMRs, showing variation between rural and urban settings.

Fig 4

The overall APC for metropolitan areas was [APC: 0.39% (95% CI: -3.93–0.66)], indicating a generally stable trend with minor fluctuations. In contrast, the APC for non-metropolitan areas was [APC: 1.34% (95% CI: -0.65–2.21)], suggesting a modest upward trend over the entire study period (S4 Table). indicating the significant rise in non-metropolitan areas in recent years.

Sarcoidosis-related AAMR stratified by race

Throughout the study period, Non-Hispanic Black individuals consistently experienced the highest AAMRs for Sarcoidosis, peaking at 27.4 per 100,000 in 2002 and 28.4 per 100,000 in 2020. Despite some fluctuations, their AAMRs remained significantly higher than those of other racial and ethnic groups. In contrast, Non-Hispanic White individuals had much lower AAMRs but showed a steady increase from 1.9 per 100,000 in 1999 to 4.1 per 100,000 in 2020 (Fig 5).

Fig 5. Racial disparities in sarcoidosis-related AAMRs, with Black individuals experiencing the highest rates.

Fig 5

For Hispanic individuals, AAMRs were generally low, fluctuating between 1.2 and 2.1 per 100,000 over the years, with a gradual rise from 1.2 in 1999 to 2.1 in 2020. The data for Non-Hispanic American Indian or Alaska Native and Non-Hispanic Asian or Pacific Islander populations were often unreliable due to small sample sizes, but when available, the AAMRs were relatively low and variable, indicating less consistent trends (S8 Table).

Discussion

This study highlights significant racial and geographic disparities in sarcoidosis AAMRs in the United States from 1999 to 2020. Black patients consistently experienced the highest AAMRs, aligning with previous studies [6, 7]. This disparity may be influenced by factors such as socioeconomic status, genetics, and systemic racial discrimination [8]. Geographic trends also reflect earlier findings, with substantial increases in AAMRs from 2003 to 2020, particularly in the District of Columbia, South Carolina, and North Carolina [6, 7]. Nam et al. similarly identified high prevalence in the East Coast, attributed to urbanization, racial composition, and socioeconomic inequalities [9].

An unexpected finding was the shift in higher AAMRs from metropolitan to non-metropolitan areas after 2018. Initially, metropolitan areas had higher mortality rates, consistent with previous studies [9]. However, the rise in non-metropolitan areas may be explained by migration patterns leading to an aging population and higher mortality rates among adults aged 55–64 [10]. Non-metropolitan areas also showed increased poverty rates and prevalence of chronic diseases in 2018 [8, 11], which are linked to higher mortality. Additionally, these regions have seen a rise in racial diversity and limited healthcare access, highlighted by the closure of 138 non-metropolitan hospitals from 2010 to 2021 [11, 12].

The South consistently exhibited the highest AAMRs, from 4.5 per million in 1999 to 7.4 per million in 2020, potentially due to the higher prevalence of sarcoidosis among Black patients in this region [13, 14]. The Northeast also had elevated mortality rates, likely influenced by socioeconomic disparities and environmental exposures [7, 14]. Conversely, the Midwest’s modest increase and the West’s lower rates may be related to regional agricultural exposures and better healthcare access, respectively [15].

Mortality trends were marked by three phases: an initial sharp increase from 1999 to 2001 (APC 9.66%), likely due to advancements in diagnostic techniques [16]; a stabilization period from 2001 to 2018 (APC 0.52%) reflecting treatment improvements [17, 18]; and a resurgence from 2018 to 2020 (APC 8.54%). One possible reason for this recent inflection point could be variations in the coding practices for sarcoidosis-related mortality by physicians, as well as an increased rate of diagnosis and documentation of mortality facilitated by advanced imaging modalities such as high-resolution computed tomography and positron emission tomography scans [19]. Furthermore, despite advancements in therapeutics, adequate management for advanced fibrocystic cases remains unavailable [20], which may further contribute to our findings. Further prospective studies with standard guidelines need to be developed to manage more complex cases of sarcoidosis. Sex disparities were notable, with women generally experiencing higher mortality rates than men, except during the stabilization period, possibly due to hormonal factors [21]. We hypothesize that the sharp increase in mortality among men during 2018–2020 may relate to delayed diagnosis and higher baseline comorbidity rates, and increased vulnerability during the pandemic [22].

To better understand these shifting trends, further research is essential. Cohort studies comparing outcomes between patients with and without COVID-19, along with investigations into healthcare access and treatment continuity during the COVID-19 pandemic, are critical. These efforts will help determine whether the observed mortality increase and the shifting disparities—such as higher mortality in non-metropolitan areas—are partly attributable to the COVID-19 pandemic or other factors. Ultimately, this research will guide targeted interventions to improve outcomes for sarcoidosis patients.

Limitations

There are several limitations to this study that should be considered. First, the reliance on ICD codes and death certificates for sarcoidosis-related mortality introduces the potential for misclassification or omission, as sarcoidosis may not always be listed as a primary cause of death, particularly in cases where complications or comorbidities were more prominent. Second, variations in clinical practices and diagnostic criteria for sarcoidosis over the study period may have affected the consistency and comparability of mortality data across different regions and time points. Third, this study did not have access to data on medical therapies or treatment regimens for sarcoidosis, which could have provided insights into the impact of evolving treatment practices on mortality outcomes. Lastly, socioeconomic factors, such as income, education, and health insurance status, which are critical determinants of healthcare access and outcomes, were not available in the dataset. This limitation makes it challenging to fully understand how disparities in access to care may have contributed to regional variations in mortality associated with sarcoidosis.

Conclusion

This study provides a detailed examination of sarcoidosis-related mortality in the U.S. from 1999 to 2020, revealing significant differences based on race, geography, and time. Black patients consistently had the highest AAMRs, likely due to a mix of socioeconomic challenges, genetic factors, and unequal access to healthcare. Geographically, the Southern states showed the highest death rates, which may be related to the larger Black population and differences in healthcare availability and environmental factors in the region.

The study identified three key phases in mortality trends: an initial sharp rise from 1999 to 2001, a period of stability from 2001 to 2018, and a resurgence from 2018 to 2020. Moreover, the trends in mortality rates began shifting from urban to rural areas after 2018, likely due to reduced access to specialized care and the closure of healthcare facilities in non-metropolitan regions. Women had higher mortality rates than men.

These findings highlight the urgent need for public health efforts to address these disparities.

Supporting information

S1 Table. Sarcoidosis related deaths, stratified by sex, in the United States, 1999 to 2020.

(DOCX)

S2 Table. Sarcoidosis related mortality, stratified by place of death in the United States, 1999 to 2020.

(DOCX)

pone.0317237.s002.docx (8.9KB, docx)
S3 Table. Overall and sex‐stratified sarcoidosis related age-adjusted mortality rates per 1,000,000 in the United States, 1999 to 2020.

(DOCX)

pone.0317237.s003.docx (8.8KB, docx)
S4 Table. Annual percent change (APC) of sarcoidosis related age-adjusted mortality rates per 1,000,000 in the United States, 1999 to 2020, 1999 to 2020.

(DOCX)

pone.0317237.s004.docx (9.6KB, docx)
S5 Table. State‐stratified sarcoidosis related age-adjusted mortality rates per 1,000,000 in the United States, 1999 to 2020.

(DOCX)

pone.0317237.s005.docx (9.2KB, docx)
S6 Table. Census region‐stratified sarcoidosis related age-adjusted mortality rates per 1,000,000 in the United States, 1999 to 2020.

(DOCX)

pone.0317237.s006.docx (10.3KB, docx)
S7 Table. Urbanization‐stratified sarcoidosis related age-adjusted mortality rates per 1,000,000 in the United States, 1999 to 2020.

(DOCX)

pone.0317237.s007.docx (8.6KB, docx)
S8 Table. State‐stratified sarcoidosis related age-adjusted mortality rates per 1,000,000 in the United States, 1999 to 2020.

(DOCX)

pone.0317237.s008.docx (9.6KB, docx)

Abbreviations

1. AAMR

Age-Adjusted Mortality Rate

2. APC

Annual Percentage Change

3.CDC

Centers for Disease Control and Prevention

4. ICD-10

International Classification of Diseases, 10th Revision

5. STROBE

Strengthening the Reporting of Observational Studies in Epidemiology

6. CI

Confidence Interval

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Amr Ehab El-Qushayri

1 Dec 2024

PONE-D-24-50326Disparities in Mortality from Sarcoidosis by Age, Gender, Ethnoracial Background, and Housing Status: A Retrospective Analysis from 1999 to 2020PLOS ONE

Dear Dr. Changez,

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.

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Additional Editor Comments:

I would like to congratulate the authors for this good paper.

I have some comments to be addressed by the authors:

1-You included 2020 in your study and reflected it on COVID-19 pandemic. What is the last date of the recruitment period in 2020? As WHO declared the pandemic in March 2020.

2-If you have the cause of death, it would be worth noting to report it to exclude if it is COVID-19 related or not, as well as, to know the trends of causes of death. If you can not access it, it is not recommended to report that it is related to COVID-19 directly or indirectly.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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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: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

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: 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: The manuscript is well-structured and well-analyzed and provides paramount results. The figures are greatly depicted and are structured and clear. The Discussion section is comprehensive and offers a detailed analysis. Furthermore, the study's limitations are effectively addressed.

General comments:

Strengths:

1:

Conclusion part is appropriately detailed and comprehensive. And provides a full overview of the whole article.

2:

Additionally, limitations of the study are provided in a separate and dedicated section, which is highly informative.

Minor revision points:

3:

Clarity of Figures 1-6, while informative, could benefit from more detailed explanations and consistent formatting to improve readability.

4:

It is advised to incorporate an additional section following the conclusion to clearly define and list all abbreviations used in the article.

Thanks to the authors for their hard work on this Study. It’s a pleasure to review such a contribution to the field.

Reviewer #2: Overall it's a well written paper and easy to understand. There is not much comment from me except to suggest to put all the figures after the description text. eg. figure 1 should be following the text for sarcoidosis related AAMR stratified by gender.

**********

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: Yes: SEYED AMIRHOSSEIN MAZHARI

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.

Attachment

Submitted filename: Review 29.pdf

pone.0317237.s009.pdf (36.2KB, pdf)
PLoS One. 2025 Jan 10;20(1):e0317237. doi: 10.1371/journal.pone.0317237.r002

Author response to Decision Letter 0


9 Dec 2024

Dear Respectful Editor and Reviewers,

Thank you for your feedback on our manuscript titled “Shifting Temporal Trends and Disparities in Sarcoidosis Mortality in the United States: A Retrospective Analysis from 1999 to 2020.” We appreciate your recognition of the study's strengths and the valuable insights you provided.

Below we are attaching our in-depth response to each query by the reviewers:

Editor’s Comments:

I would like to congratulate the authors for this good paper.

I have some comments to be addressed by the authors:

1-You included 2020 in your study and reflected it on COVID-19 pandemic. What is the last date of the recruitment period in 2020? As WHO declared the pandemic in March 2020.

2-If you have the cause of death, it would be worth noting to report it to exclude if it is COVID-19 related or not, as well as, to know the trends of causes of death. If you can not access it, it is not recommended to report that it is related to COVID-19 directly or indirectly.

-> Dear Editor,

The CDC Wonder database includes data up to the end of each calendar year, with 2020 data extending through the last day of December. However, as per your appropriate suggestion in point 2, the CDC Wonder database does not provide information on causes of death. Accordingly, we have removed any direct or indirect mentions of COVID-19 as a cause, as well as references to it in any hypothesis statements. We would be happy to make any further changes you suggest.

We have added this to our discussion, instead of the COVID-19 hypothesis:

“One possible reason for this recent inflection point could be variations in the coding practices for sarcoidosis-related mortality by physicians, as well as an increased rate of diagnosis and documentation of mortality facilitated by advanced imaging modalities such as high-resolution computed tomography and positron emission tomography scans [19]. Furthermore, despite advancements in therapeutics, adequate management for advanced fibrocystic cases remains unavailable [20], which may further contribute to our findings. Further prospective studies with standard guidelines need to be developed to manage more complex cases of sarcoidosis. Sex disparities were notable, with women generally experiencing higher mortality rates than men, except during the stabilization period, possibly due to hormonal factors [21]. We hypothesize that the sharp increase in mortality among men during 2018-2020 may relate to delayed diagnosis and higher baseline comorbidity rates, and increased vulnerability during the pandemic [22].

To better understand these shifting trends, further research is essential. Cohort studies comparing outcomes between patients with and without COVID-19, along with investigations into healthcare access and treatment continuity during the COVID-19 pandemic, are critical. These efforts will help determine whether the observed mortality increase and the shifting disparities—such as higher mortality in non-metropolitan areas—are partly attributable to the COVID-19 pandemic or other factors. Ultimately, this research will guide targeted interventions to improve outcomes for sarcoidosis patients.”

2. Review Comments to the Author

2.1. Reviewer #1:

The manuscript is well-structured and well-analyzed and provides paramount results. The figures are greatly depicted and are structured and clear. The Discussion section is comprehensive and offers a detailed analysis. Furthermore, the study's limitations are effectively addressed.

Strengths:

1: Conclusion part is appropriately detailed and comprehensive. And provides a full overview of the whole article.

2: Additionally, limitations of the study are provided in a separate and dedicated section, which is highly informative.

Minor revision points:

3: Clarity of Figures 1-6, while informative, could benefit from more detailed explanations and consistent formatting to improve readability.

-> Dear reviewer, as per your suggestion, we have now added more detail into the figure caption for each figure in the Figure Legend section of our manuscript after the References. 

4: It is advised to incorporate an additional section following the conclusion to clearly define and list all abbreviations used in the article.

-> Dear reviewer, a new subheader after the conclusion section for Abbreviations has been created as per your suggestion. 

Thanks to the authors for their hard work on this Study. It’s a pleasure to review such a contribution to the field.

-> Dear Reviewer, thank you for your thoughtful comments regarding the strength and novelty of our manuscript.

2.2. Reviewer #2:

Overall it's a well written paper and easy to understand. There is not much comment from me except to suggest to put all the figures after the description text. eg. figure 1 should be following the text for sarcoidosis related AAMR stratified by gender.

-> Dear reviewer, thank you for your suggestions. We have added all figures separately as TIFF file in the editorial manager as per the journal’s requirement. However, we have provided the figure caption right after the text, and an additional figure legend at end of the manuscript as per your suggestion.

Thank you,

Mah I Kan Changez, MBBS

Yale University

Mahikan.changez@yale.edu

Attachment

Submitted filename: R2R PONE R1 Sarcoidosis.docx

pone.0317237.s010.docx (9.8KB, docx)

Decision Letter 1

Amr Ehab El-Qushayri

22 Dec 2024

PONE-D-24-50326R1Shifting Temporal Trends and Disparities in Sarcoidosis Mortality in the United States: A Retrospective Analysis from 1999 to 2020PLOS ONE

Dear Dr. Changez,

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 submit your revised manuscript by Feb 05 2025 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.

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We look forward to receiving your revised manuscript.

Kind regards,

Amr Ehab El-Qushayri

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #3: (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: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #3: 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 #3: Yes

**********

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 #3: 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: Some Minor revisions points have been suggested and they all have been addressed

appropriately.

Minor revision points:

Thanks to the authors for their hard work on this Revision. It’s a pleasure to review such a

contribution to the field.

Reviewer #3: I appreciate your response to the editor’s suggestion regarding the deletion of content related to COVID-19 mortality. However, I noticed that this content is still present in the abstract and keywords. I recommend that you replace it in these sections as you did in the manuscript and remove it from the keywords, as it is not central to the core of the research. Additionally, on page 8, you used the abbreviation “AAPC.” If this was intended to be “APC,” please correct it. If not, kindly provide an explanation for “AAPC” in the abbreviation list. Thank you for your efforts.

**********

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: Yes: SEYED AMIRHOSSEIN MAZHARI

Reviewer #3: 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.

Attachment

Submitted filename: Review 29a.pdf

pone.0317237.s011.pdf (36.2KB, pdf)
PLoS One. 2025 Jan 10;20(1):e0317237. doi: 10.1371/journal.pone.0317237.r004

Author response to Decision Letter 1


23 Dec 2024

Dear Respectful Editor and Reviewers,

Thank you for your feedback on our manuscript titled “Shifting Temporal Trends and Disparities in Sarcoidosis Mortality in the United States: A Retrospective Analysis from 1999 to 2020.” We appreciate your recognition of the study's strengths and the valuable insights you provided.

Below we are attaching our in-depth response to each query by the reviewers:

Reviewer #1: Some Minor revisions points have been suggested and they all have been addressed

appropriately.

Minor revision points:

Thanks to the authors for their hard work on this Revision. It’s a pleasure to review such a

contribution to the field.

-> Dear Reviewer, Thank you for your suggestions and for your feedback that the work is ready for publication.

Reviewer #3: I appreciate your response to the editor’s suggestion regarding the deletion of content related to COVID-19 mortality. However, I noticed that this content is still present in the abstract and keywords. I recommend that you replace it in these sections as you did in the manuscript and remove it from the keywords, as it is not central to the core of the research. Additionally, on page 8, you used the abbreviation “AAPC.” If this was intended to be “APC,” please correct it. If not, kindly provide an explanation for “AAPC” in the abbreviation list. Thank you for your efforts.

-> Dear Reviewer,

We have updated the Abstract and removed the COVID-19 section to reflect the changes made during the Round 1 revisions, which we had inadvertently omitted from the submission portal. Additionally, we have revised the keywords and changed “AAPC” to “APC” in accordance with your comments. Thank you for your valuable feedback.

Please let us know if you’d like any further changes.

Thank you,

Mah I Kan Changez, MBBS

Yale University

Mahikan.changez@yale.edu

Attachment

Submitted filename: R2R PONE R2 Sarcoidosis.docx

pone.0317237.s012.docx (7.7KB, docx)

Decision Letter 2

Amr Ehab El-Qushayri

26 Dec 2024

Shifting Temporal Trends and Disparities in Sarcoidosis Mortality in the United States: A Retrospective Analysis from 1999 to 2020

PONE-D-24-50326R2

Dear Dr. Mah I Kan Changez,

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.

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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,

Amr Ehab El-Qushayri

Academic Editor

PLOS ONE

Acceptance letter

Amr Ehab El-Qushayri

31 Dec 2024

PONE-D-24-50326R2

PLOS ONE

Dear Dr. Changez,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

* All references, tables, and figures are properly cited

* All relevant supporting information is included in the manuscript submission,

* There are no issues that prevent the paper from being properly typeset

If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps.

Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, 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.

If we can help with anything else, please email us at customercare@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Amr Ehab El-Qushayri

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Sarcoidosis related deaths, stratified by sex, in the United States, 1999 to 2020.

    (DOCX)

    S2 Table. Sarcoidosis related mortality, stratified by place of death in the United States, 1999 to 2020.

    (DOCX)

    pone.0317237.s002.docx (8.9KB, docx)
    S3 Table. Overall and sex‐stratified sarcoidosis related age-adjusted mortality rates per 1,000,000 in the United States, 1999 to 2020.

    (DOCX)

    pone.0317237.s003.docx (8.8KB, docx)
    S4 Table. Annual percent change (APC) of sarcoidosis related age-adjusted mortality rates per 1,000,000 in the United States, 1999 to 2020, 1999 to 2020.

    (DOCX)

    pone.0317237.s004.docx (9.6KB, docx)
    S5 Table. State‐stratified sarcoidosis related age-adjusted mortality rates per 1,000,000 in the United States, 1999 to 2020.

    (DOCX)

    pone.0317237.s005.docx (9.2KB, docx)
    S6 Table. Census region‐stratified sarcoidosis related age-adjusted mortality rates per 1,000,000 in the United States, 1999 to 2020.

    (DOCX)

    pone.0317237.s006.docx (10.3KB, docx)
    S7 Table. Urbanization‐stratified sarcoidosis related age-adjusted mortality rates per 1,000,000 in the United States, 1999 to 2020.

    (DOCX)

    pone.0317237.s007.docx (8.6KB, docx)
    S8 Table. State‐stratified sarcoidosis related age-adjusted mortality rates per 1,000,000 in the United States, 1999 to 2020.

    (DOCX)

    pone.0317237.s008.docx (9.6KB, docx)
    Attachment

    Submitted filename: Review 29.pdf

    pone.0317237.s009.pdf (36.2KB, pdf)
    Attachment

    Submitted filename: R2R PONE R1 Sarcoidosis.docx

    pone.0317237.s010.docx (9.8KB, docx)
    Attachment

    Submitted filename: Review 29a.pdf

    pone.0317237.s011.pdf (36.2KB, pdf)
    Attachment

    Submitted filename: R2R PONE R2 Sarcoidosis.docx

    pone.0317237.s012.docx (7.7KB, docx)

    Data Availability Statement

    All relevant data are within the manuscript and its Supporting Information files.


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