Temporal Trends in Parkinson’s Disease Related Mortality from 1999-2020: A National Analysis

Parkinson’s Disease; Mortality; Outcomes; Epidemiology. ALL Metrics - Views Downloads How to cite this article Sokhal BS, Prasanna Kumar Menon S, Shepherd T et al. Temporal Trends in Parkinson’s Disease Related Mortality from 1999-2020: A National Analysis [version 1; peer review: 1 approved, 2 approved with reservations]. NIHR Open Res 2024, 4:50 (https://doi.org/10.3310/nihropenres.13623.1) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente Select a format first ▬ ✚ Research Article [version 1; peer review: 1 approved, 2 approved with reservations] Balamrit Singh Sokhal https://orcid.org/0000-0002-2315-0744 1, Sowmya Prasanna Kumar Menon1, Thomas Shepherd1, Sara Muller https://orcid.org/0000-0001-6645-5751 1, Amit Arora1,2, Christian Mallen https://orcid.org/0000-0002-2677-1028 1Balamrit Singh Sokhal https://orcid.org/0000-0002-2315-0744 1, Sowmya Prasanna Kumar Menon1, [...] Thomas Shepherd1, Sara Muller https://orcid.org/0000-0001-6645-5751 1, Amit Arora1,2, Christian Mallen https://orcid.org/0000-0002-2677-1028 1 PUBLISHED 13 Sep 2024 Author details Author details 1 School of Medicine, Keele University, Keele, England, UK 2 Department of Geriatrics, University Hospital North Midlands, Stoke-On-Trent, UK 2 Department of Geriatrics, University Hospital North Midlands, Stoke-On-Trent, UK Balamrit Singh Sokhal Roles: Conceptualization, Formal Analysis, Methodology, Project Administration, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Formal Analysis, Methodology, Project Administration, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Sowmya Prasanna Kumar Menon Roles: Methodology, Validation, Writing – Review & Editing Roles: Methodology, Validation, Writing – Review & Editing Thomas Shepherd Roles: Writing – Review & Editing Roles: Writing – Review & Editing Sara Muller Roles: Writing – Review & Editing Roles: Writing – Review & Editing Amit Arora Roles: Writing – Review & Editing Roles: Writing – Review & Editing Christian Mallen Roles: Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Supervision, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW REVIEWER STATUS Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and is associated with significant disability. The prevalence is rising, and studies have reported potential sex and race disparities in patient outcomes. Data about the demographic trends in PD-related mortality in the United States (US) is limited. This descriptive study aimed to report the national demographic trends in PD-related mortality over a 20-year period. The US Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiological Research (CDC-WONDER) Underlying Cause of Death database from January 1999 to December 2020 was used to determine the PD-related age adjusted mortality rate (AAMR) stratified by age, sex, ethnicity and geographic area, with the 1999 deaths as the reference group. Annual percentage change (APC) for AAMR was then calculated using Joinpoint regression. There were 515,884 PD-related deaths in the study period. The AAMR increased from 5.3 per 100,000 population in 1999 to 9.8 per 100,000 in 2020. Males had consistently higher AAMR than females and white race had consistently higher overall AAMR (7.6 per 100,000), followed by American Indians/Alaska Natives (4.4 per 100,000), Asians/Pacific Islanders (4.1 per 100,000) and Black/African Americans (3.4 per 100,000). The Midwest had the highest AAMR followed by West, South and Northeast. Utah, Idaho and Minnesota had the highest state-level AAMR. This study identified significant age, sex, race and geographic disparities in PD-related mortality in the US. Older age, male sex, white race and Midwest locality were associated with the highest AAMR. Parkinson's disease (PD) is a common disease that impacts the brain and as a result, movement. One in 37 people will be diagnosed with PD in their lifetime, and the risk of developing PD increases with age. PD can lead to variety of complications such as falls, depression, and death. This research aimed to summarise the demographic trends in PD-related death in the United States from 1999–2020 using death certificate data. There were 515,884 PD-related deaths in the study period. Death rates increased from 5.3 per 100,000 population in 1999 to 9.8 per 100,000 in 2020. In terms of demographics, firstly, male sex had a higher rate than female sex. Secondly, white race had death rate than American Indians/Alaska Natives, Asians/Pacific Islanders and Black/African Americans, Finally, the Midwest had a higher death rate than the West, South and Northeast. These results could be because PD is more common in these groups. Future research could investigate underlying reasons behind disparities in mortality. In summary, PD is a significant cause of death in the US and there are differences in demographic trends in PD-related deaths. The number of deaths from PD per population count is higher with older ages, in males, people of white race and in the Midwest. Knowledge of these trends is important to build healthcare services around this growing population. Parkinson’s Disease; Mortality; Outcomes; Epidemiology. Corresponding Author(s) Balamrit Singh Sokhal ([email protected]) Grant information: This project received no specific funding. CM is funded by the National Institute for Health Research (NIHR) Applied Research Collaboration West Midlands and the NIHR School for Primary Care Research [grant number NIHR203712 ] . SM is funded by the NIHR Applied Research Collaboration which is not associated with a number. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2024 Sokhal BS et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Sokhal BS, Prasanna Kumar Menon S, Shepherd T et al. Temporal Trends in Parkinson’s Disease Related Mortality from 1999-2020: A National Analysis [version 1; peer review: 1 approved, 2 approved with reservations]. NIHR Open Res 2024, 4:50 (https://doi.org/10.3310/nihropenres.13623.1) First published: 13 Sep 2024, 4:50 (https://doi.org/10.3310/nihropenres.13623.1) Latest published: 13 Sep 2024, 4:50 (https://doi.org/10.3310/nihropenres.13623.1) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Parkinson’s Disease (PD) is the most common neurodegenerative disorder and is characterised by resting tremor, rigidity and bradykinesia. It is a leading cause of disability worldwide1–3. The prevalence of PD is rising with the increasing average age of the population, with a prevalence of 1903 per 100,000 in over 80 year olds compared to 41 per 100,000 in 40 to 49 year olds4. Studies suggest geographic variation, North America having the highest non-age adjusted prevalence (1,601 per 100,000) and Asia having the lowest prevalence (646 per 100,000), possibly due to genetic susceptibility4,5, as well as the differing age profiles of the populations. The prevalence of PD is almost double in males compared to females, possibly due to a protective effect of female gonadal factors and the lack of a protective effect of male gonadal factors6,7. Despite this, existing studies report increased mortality in females6,7. Worldwide non-age adjusted mortality rate from PD has increased between 1994 and 2019 (1.76 per 100,000 in 1994 and 5.67 per 100,000 in 2019), which could be due to a variety of factors such as an ageing population and improved reporting3. In addition to PD being associated with a significant individual burden, PD is also associated with large economic burden3. In the United States (US) in 2017, there were 1 million people living with PD, incurring a total economic cost of $51.9 billion of direct and indirect healthcare costs, which is projected to increase substantially8. There is a paucity of published data about the annual demographic trends in PD-related mortality in the US3. Therefore, the aim of this study was to examine the demographic trends in PD-related mortality using national data. Knowledge of these trends is important to monitor the growing population living with PD and improve end of life care services. There was no public or patient involvement in this study. The Centers for Disease Control and Prevention Wide-Ranging OnLine Data for Epidemiologic Research (CDC-WONDER) underlying cause of death database was utilised from 1999 to 2020. CDC-WONDER is a dataset containing details on the cause of death from the 50 US states and the District of Columbia, as obtained from death certificates9. More than 99% of US deaths are recorded on CDC WONDER9. Several studies have previously used this dataset to determine the trends in mortality for chronic conditions as well as the incidence and mortality of different cancers10–13. Using the International Classification of Diseases- Tenth Revision (ICD-10) code for PD (G20), data were collected on records with PD stated as the underlying cause of mortality14. Data for year, population size, demographics (age at death, sex and race), location of death (outpatient, emergency room, inpatient, death on arrival or unknown), region and state were extracted from CDC-WONDER using death certificate information. Annual PD-related crude mortality rates (CMR) and age-adjusted mortality rates (AAMR) per 100,000 persons were determined. To calculate crude mortality rate, the number of PD-related deaths was divided by the population of the given year and presented with 95% confidence intervals (CI). AAMR was calculated by standardizing the PD-related deaths to 1999 US population and presented with 95% CI15. Joinpont regression was used to quantify annual national trends in PD-related mortality by calculating the annual percentage change (APC) using the Joinpoint software16. Joinpoint regression identifies significant differences in AAMR over time using log-linear regression models for temporal variations. Microsoft Excel was used to visually present data17. This study did not require ethical approval from an institutional review board. CDC-WONDER is an publicly available, anonymised dataset9. Therefore, this study was performed in accordance with the ethical standards laid down in an appropriate version of the 1965 Declaration of Helsinki. This study was reported in accordance with the STrengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines18. Between 1999 to 2020, there were a total 515,884 PD-related deaths. Overall CMR was 7.6 per 100,000 persons (95% CI 7.6-7.7) and AAMR was 7.1 per 100,000 persons (95% CI 7.1-7.2). CMR was 5.2 per 100,000 in 1999 (95% CI 5.1-5.3) and 12.1 per 100,000 in 2020 (95% CI 12.0-12.3). AAMR was 5.3 per 100,000 in 1999 (95% CI 5.2-5.4) and 9.8 per 100,000 in 2020 (95% CI 9.7-9.9). Using Joinpoint regression analysis, the APC in AAMR was 5.71 (95% CI 2.00-8.67) from 1999–2001, 1.44 (95% CI -0.07-1.85) from 2001–2013 and 4.25 (95% CI 3.34-5.62) from 2013–2020 (shown in Table 1 and Figure 1). Older age categories had a consistently higher CMR throughout the 20 year period (Table 2 and Figure 2). CMR for patients aged over 85 was 7.6 (95% CI 172.8-174.3), compared to a CMR of 1.4 (95% CI 1.4-1.4) for patients aged 55–64 (shown in Figure 3). Male sex had a consistently higher AAMR (10.9 per 100,000 95% CI 10.8-0.9) than female sex (4.8 per 100,000 95% CI 4.7-4.8) across the study period (shown in Table 1). Using Joinpoint regression analysis, the APC in AAMR for males was 2.63 (95% CI 0.92-4.33) from 1999–2005, which then decreased to -0.17 (95% CI -1.61-3.91) from 2005–2009, increased to 2.71 (95% CI -0.36-3.48) from 2009–2018 and increased further to 6.14 (95% CI 2.93-7.90) from 2018–2020. The APC in AAMR for females was 4.61 (95% CI 2.01-9.44) from 1999–2002, 1.11 (95% CI -1.27-1.54) from 2002–2014, then 4.74 (95% CI 3.41-7.56) from 2014–2020 (shown in Figure 4 and Figure 5). White patients had consistently higher AAMR (7.6 per 100,000 95% CI 7.6-7.6) than American Indians/Alaska Natives (4.4 per 100,000 95% CI 4.3-4.4), Asians/Pacific Islanders (4.1 per 100,000 95% CI 3.9-4.3) and Black/African Americans (3.4 per 100,000 95% CI 3.5-3.6) (shown in Table 1). Using Joinpoint regression analysis, the APC in AAMR for white patients was 5.58 (95% CI 2.16-8.28) from 1999–2001, 1.66 (95% CI 0.33-1.98) from 2001–2014 and 4.63 (95% CI 3.64-6.23) from 2014 to 2020. The APC in AAMR for American Indians/Alaska Natives was 0.75 (95% CI -0.58-2.11) from 1999–2020. The APC in AAMR for Asians/Pacific Islanders was 1.50 (95% CI -1.05-2.37) from 1999–2012 and 5.10 (95% CI 3.29-11.18) from 2012–2020. The APC in AAMR for Black/African Americans was 3.22 (95% CI 1.84-7.93) from 1999–2007, reducing to -1.56 (95% CI -3.84-8.46) from 2007–2010, then increasing to 6.07 (95% CI 2.72-8.47) from 2010–2020 (shown in Figure 6 and Figure 7). The Midwest census region had the highest AAMR (7.7 per 100,000 95% CI 7.6-7.7), followed by the West (7.4 per 100,000 95% CI 7.4-7.5), South (7.2 per 100,000 95% CI 7.1-7.2) and Northeast (6.2 per 100,000 95% CI 6.1-6.2). The census division with the highest AAMR was Mountain (8.1 per 100,000 95%CI 8.0-8.2), followed by West North Central (8.0 per 100,000 95% CI 7.9-8.1), East North Central (7.5 per 100,000 95% CI 7.5-7.6), West South Central (7.5 per 100,000 95% CI 7.5-7.6), East South Central (7.2 per 100,000 95% CI 7.1-7.3), Pacific (7.2 per 100,000 95% CI 7.1-7.2), South Atlantic (7.0 per 100,000 95% CI 6.9-7.0), New England (6.8 per 100,000 95% CI 6.7-6.9) and Middle Atlantic (6.0 per 100,000 95% CI 5.9-6.0) (shown in Table 2). The top 3 health and human services (HHS) regions with the highest AAMR was region 10 (Alaska, Idaho, Oregon, Washington) (8.4 per 100,000 95% CI 8.3-8.5), followed by region 8 (Colorado, Montana, North Dakota, South Dakota, Utah and Wyoming) (9.1 per 100,000 95% CI 8.0-8.2) and region 7 (Iowa, Kansas, Missouri, Nebraska) (7.8 per 100,000 95% CI 7.7-7.9) (shown in Table 2). The 3 states with the highest AAMR were Utah (10.1 per 100,000 95% CI 9.7-10.4), followed by Idaho (9.0 per 100,000 95% CI 8.7-9.3) and Minnesota (8.9 per 100,000 95% CI 8.8-9.1). The 3 states with the lowest AAMR over the study period were New York (4.7 per 100,000 95% CI 4.7-4.8), followed by the District of Columbia (4.9 per 100,000 95% CI 4.5-5.3) and Connecticut (6.2 per 100,000 95% CI 6.0-6.4) (shown in Table 3 and Figure 3). Of all patient deaths (515,884), the most common place of death was a nursing home/long term care (45.7%), followed by the decedent’s home (28.3%), medical facility – inpatient (12.7%), other place of death (6.0%), hospice facility (5.4%), medical facility – outpatient/emergency room (1.5%), unknown place (0.2%) and medical facility – death on arrival (0.2%) (shown in Table 4). To the best of our knowledge, this is the first study to investigate the trends in PD-related mortality in the US. There are several important findings. Firstly, PD-related mortality in the US has steadily increased over a 20 year period, with an AAMR of 5.3 per 100,000 in 1999 compared to 9.8 per 100,000 in 2020. Secondly, there are significant geographical differences in PD-related mortality, with Midwest regions associated with the highest mortality rate and top 3 states with highest AAMR being Utah, Idaho and Minnesota. Finally, there are significant differences in demographic trends in mortality, where older age, male sex and white race associated with higher AAMRs over the 20 year study period. The average age of the population is increasing, and along with improved management of acute and chronic conditions, patients are living longer placing them at risk of chronic diseases19. Age is strongly associated with the development of PD, with a later age of diagnosis of PD linked to more severe motor deficit, postural instability and rapid disease progression20. Ageing alters body homeostasis through its effect on cellular processes causing mitochondrial dysfunction, free radical production and oxidative stress, predisposing to neurodegeneration of the substantia nigra21. Furthermore, the iron content of the substantia nigra increases with age and is linked to their decrease in function22. The present analysis demonstrated that increasing age was associated with an increased AAMR. Previous studies have elicited this finding, with some displaying better overall prognosis and response to pharmacological treatment such as Levodopa therapy in younger patients23,24. This study reports sex differences in PD-related mortality. There are no studies that have analysed temporal trends in sex-related disparities in PD patients. Previous studies have reported an increased prevalence of PD in males, and increased likelihood of PD mortality in females6,7. Increased prevalence in males may be due to findings of lack of protective effects of male gonadal factors, in contrast to female gonadal factors which are suspected to be protective for PD6,7. Females have a higher likelihood of overall and earlier disease course-related mortality from PD compared to males25. This could be due to a later age of diagnosis given the aforementioned protective factors, which is associated with more severe symptoms, lower responsiveness to guideline indicated treatment. The present study reports important racial differences in PD-related mortality, with white race associated with the highest AAMR. This could be because PD is most prevalent in white populations, possibly due to genetic susceptibility5. Several studies state black patients have a higher risk of mortality than white patients26–28. Common reasons for poor outcomes in black patients could be multifactorial. There are several social determinants of health that could mediate outcomes in black populations which have been demonstrated across many different studies involving the US, including geographic location, socioeconomic status and access to healthcare29–31. State-level disparities in the context of US healthcare in particular could be due to varying levels of accessibility to services and affordability32. Furthermore, certain regions of the US such as the Midwest have a higher proportion of individuals who are holder and white race33. This could explain increased AAMR in the Midwest region and associated states. Admissions to hospital in patients with PD in the US have been steadily increasing. An analysis using the National Inpatient Sample demonstrated that from 2002–2016, admissions in patients with PD rose from 212,070 to 312,98034. Mortality as an inpatient during this time decreased from 4.8% in 2002–2004 to 3.6% in 2014–201634. In the present study, PD-related AAMR increased over the study period, suggesting patients with PD are likely die outside of hospital, as this analysis also demonstrates. Previous studies have demonstrated a similar trend. An analysis of the World Health Organisation Mortality Database from 1994–2019 showed that mortality rate in 1994 was 1.76 per 100,000, rising to 5.67 per 100,000 in 2019. Mortality rate was higher in males and in European countries and the United States3. Another study similar to the present study where AAMR from PD increased from 5.4 per 100,000 to 8.8 per 100,000 in a 20 year period35. The present study observed a similar trend, with AAMR 5.3 per 100,000 in 1999 and 9.8 per 100,000 in 2020. There are several important clinical implications of this study. This study demonstrates that PD is present as an underlying cause in a significant number of deaths in the US. Knowledge of trends in PD-related mortality is fundamental to building healthcare infrastructure around the growing needs of the increasing population living with PD. This study reports significant differences in demographic trends in PD-related mortality. Increasing age, male sex and white race were associated with the highest AAMR. This supports increased focus into the underlying reasons for these disparities and research into how these disparities can be addressed and managed. There are several limitations to this study inherent to the dataset used. Firstly, routinely collected data from death certificates may be subject to coding inaccuracies, although there is no reason to believe this would bias findings in one direction or another, it may decrease precision. Secondly, data on overall prevalence, pharmacotherapy, co-morbidities and procedures that could have mediated outcomes are not available on the dataset, and therefore, we were not able to consider the rate of deaths allowing for the underlying rate of disease or the pathway from diagnosis to death. Finally, with this dataset we cannot ascertain the exact primary cause of death (e.g. cardiovascular disease, respiratory disorders, trauma), although arguably this is not the question at hand if PD is underlying this primary cause of death. This study records PD as an underlying cause of death where it is recorded on the death certificate of the deceased patient. Future research could investigate underlying reasons behind disparities in mortality. Given the present study confirms populations with the highest prevalence of PD (older, male and white), also have the highest AAMR, further work must be completed to determine underlying reasons behind poor outcomes in female sex and non-white groups discovered in other studies. Knowledge of the factors contributing to poor outcomes could be fundamental to identify at-risk individuals. These individuals can be targeted for risk factor optimisation with the aim to reduce downstream adverse outcomes. Further research could also investigate the interplay between the aforementioned social determinants, age of diagnosis, onset of symptoms, comorbidities and how these impact demographic differences in PD-related mortality. In conclusion, there are significant differences in demographic trends in PD-related mortality in the US. PD accounts for a greater number of deaths per head of population at older ages, in males, people of white race and in the Midwest. Knowledge of these trends is important to build healthcare services around this growing population. Further research must focus on addressing these differences to optimise management and development of appropriate healthcare infrastructure around this growing, at-risk population. This study did not require ethical approval from an institutional review board. CDC-WONDER is an publicly available, anonymised dataset. made from routinely collected death certificate data. All data are covered by the provisions of the Public Health Service Act (42 U.S.C. 242m(d)). All data available in this article is publicly accessible from the database website https://wonder.cdc.gov. CRediT author statement: Conceptualisation: Balamrit Singh Sokhal; Methodology: Balamrit Singh Sokhal, Sowmya Prasanna Kumar Menon; Validation: Balamrit Singh Sokhal, Sowmya Prasanna Kumar Menon; Formal analysis: Balamrit Singh Sokhal; Writing – original draft: Balamrit Singh Sokhal, Christian D Mallen, Writing – review and editing: Balamrit Singh Sokhal, Sowmya Prasanna Kumar Menon, Thomas Shepherd, Sara Muller, Amit Arora, Christian D Mallen; Visualisation: Balamrit Singh Sokhal; Supervision: Christian D Mallen; Project administration: Balamrit Singh Sokhal. Faculty Opinions recommendedReferences - 1. Balestrino R, Schapira AHV: Parkinson disease. Eur J Neurol. 2020; 27(1): 27–42. PubMed Abstract | Publisher Full Text - 2. Jankovic J, Tan EK: Parkinson's disease: etiopathogenesis and treatment. J Neurol Neurosurg Psychiatry. 2020; 91(8): 795–808. PubMed Abstract | Publisher Full Text - 3. 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PubMed Abstract | Publisher Full Text Author details Author details 1 School of Medicine, Keele University, Keele, England, UK 2 Department of Geriatrics, University Hospital North Midlands, Stoke-On-Trent, UK 2 Department of Geriatrics, University Hospital North Midlands, Stoke-On-Trent, UK Balamrit Singh Sokhal Roles: Conceptualization, Formal Analysis, Methodology, Project Administration, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Formal Analysis, Methodology, Project Administration, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Sowmya Prasanna Kumar Menon Roles: Methodology, Validation, Writing – Review & Editing Roles: Methodology, Validation, Writing – Review & Editing Thomas Shepherd Roles: Writing – Review & Editing Roles: Writing – Review & Editing Sara Muller Roles: Writing – Review & Editing Roles: Writing – Review & Editing Amit Arora Roles: Writing – Review & Editing Roles: Writing – Review & Editing Christian Mallen Roles: Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information This project received no specific funding. CM is funded by the National Institute for Health Research (NIHR) Applied Research Collaboration West Midlands and the NIHR School for Primary Care Research [grant number NIHR203712 ] . SM is funded by the NIHR Applied Research Collaboration which is not associated with a number. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright © 2024 Sokhal BS et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. metrics VIEWS $counts.viewCount downloads Citations CITE how to cite this article Sokhal BS, Prasanna Kumar Menon S, Shepherd T et al. Temporal Trends in Parkinson’s Disease Related Mortality from 1999-2020: A National Analysis [version 1; peer review: 1 approved, 2 approved with reservations]. NIHR Open Res 2024, 4:50 (https://doi.org/10.3310/nihropenres.13623.1) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. track receive updates on this article Track an article to receive email alerts on any updates to this article. Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 13 Sep 2024 Views 0 How to cite this report: Lee J. Reviewer Report For: Temporal Trends in Parkinson’s Disease Related Mortality from 1999-2020: A National Analysis [version 1; peer review: 1 approved, 2 approved with reservations]. NIHR Open Res 2024, 4:50 (https://doi.org/10.3310/nihropenres.14792.r33590) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-50/v1#referee-response-33590 https://openresearch.nihr.ac.uk/articles/4-50/v1#referee-response-33590 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 16 Jan 2025 Approved with Reservations VIEWS 0 - Rong et al. (2021) conducted similar analyses to examine temporal trends in Parkinson’s disease mortality in the USA from 1999 to 2019 using data from the National Vital Statistics System (NVSS) of the National Center for Health - Rong et al. (2021) conducted similar analyses to examine temporal trends in Parkinson’s disease mortality in the USA from 1999 to 2019 using data from the National Vital Statistics System (NVSS) of the National Center for Health Statistics (NCHS) and the Centers for Disease Control and Prevention (CDC). They also calculated the age-adjusted mortality rate each year from 1999 to 2019, stratified by age, sex, ethnicity, and region. I wonder what new insights this manuscript provides. Rong, S., Xu, G., Liu, B., Sun, Y., Snetselaar, L. G., Wallace, R. B., ... & Bao, W. (2021). Trends in mortality from Parkinson disease in the United States, 1999–2019. Neurology, 97(20), e1986-e1993. 2. Can you provide more details about the joinpoint regression models? How was the statistical significance of a change in trend assessed? Have you specified the minimum and maximum number of joinpoints? 3. In the Discussion section, the authors noted that the higher mortality rate among White patients compared to Black patients was due to the higher prevalence of Parkinson’s disease (PD) in White individuals. You may consider presenting prevalence values of PD by race/ethnicity from other literature to support this point. - Is the work clearly and accurately presented and does it cite the current literature? Yes - Is the study design appropriate and is the work technically sound? Yes - Are sufficient details of methods and analysis provided to allow replication by others? Partly - If applicable, is the statistical analysis and its interpretation appropriate? Yes - Are all the source data underlying the results available to ensure full reproducibility? Yes - Are the conclusions drawn adequately supported by the results? Yes

1. Rong S, Xu G, Liu B, Sun Y, et al.: Trends in Mortality From Parkinson Disease in the United States, 1999-2019.Neurology. 2021; 97 (20): e1986-e1993 PubMed Abstract | Publisher Full TextCompeting Interests: No competing interests were disclosed. Reviewer Expertise: Biostatistics, Epidemiology CITE HOW TO CITE THIS REPORT Lee J. Reviewer Report For: Temporal Trends in Parkinson’s Disease Related Mortality from 1999-2020: A National Analysis [version 1; peer review: 1 approved, 2 approved with reservations]. NIHR Open Res 2024, 4:50 (https://doi.org/10.3310/nihropenres.14792.r33590) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-50/v1#referee-response-33590 https://openresearch.nihr.ac.uk/articles/4-50/v1#referee-response-33590 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. Views 0 How to cite this report: Dauer LT. Reviewer Report For: Temporal Trends in Parkinson’s Disease Related Mortality from 1999-2020: A National Analysis [version 1; peer review: 1 approved, 2 approved with reservations]. NIHR Open Res 2024, 4:50 (https://doi.org/10.3310/nihropenres.14792.r34189) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-50/v1#referee-response-34189 https://openresearch.nihr.ac.uk/articles/4-50/v1#referee-response-34189 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 06 Jan 2025 Lawrence T Dauer, Memorial Sloan Kettering Cancer Center, New York, USA Approved with Reservations VIEWS 0 Article reports on age-adjusted mortality rates of Parkinson's Disease using the CDC-WONDER underlying COD database from 1999-2020 and reports a near doubling of the AAMR over that period and that older age, males, white race, and Midwest regions had highest ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close Article reports on age-adjusted mortality rates of Parkinson's Disease using the CDC-WONDER underlying COD database from 1999-2020 and reports a near doubling of the AAMR over that period and that older age, males, white race, and Midwest regions had highest AAMRs. Note that this is not the first study over this time period that has utilized the same database. In the present form, it is not clear what this evaluation provides that is new or original. Several comments/suggestions for Improvement: 1. Census region, HHS region, and State level mortality results could be improved if there were adjustments based on race and age demographics for those regions (as pointed out by the authors Midwest has older and more generally white). Census data over time could be utilized for those adjustments. An adjusted evaluation would be more informative when evaluating regional differences. If such an evaluation were performed, it would be a unique addition to the literature that already exists over this time period. In addition a rural vs urban breakdown would be helpful to compare with other previously reported results. 2. Page 7 of 15 - as this is not the first study to investigate trends in PD-related mortality in the US (example Ref 35 - and others noted below), should remove this sentence. 3. Page 7 of 15 - other studies have evaluated sex-related differences ( example Ref 35 and others) and they should be compared with. 4. Page 7 of 15 - spelling error for "holder" meaning "older". 5. Figures 2 and 6 should be enlarged, difficult to read. 6. Several other studies should be referenced and discussed and a clear distinction made between this study and those earlier reported results. In fact, Ref 35, Rong et al should be compared with as it is not clear what is different in this study vs that study. In addition, see other examples: Tharwani et al 2024 - https://www.prd-journal.com/article/S1353-8020(24)01122-2/abstract and a systematic review of global trends from Lancet Zhu et al 2024 (Ref-1) - https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(24)00094-1/fulltext Several comments/suggestions for Improvement: 1. Census region, HHS region, and State level mortality results could be improved if there were adjustments based on race and age demographics for those regions (as pointed out by the authors Midwest has older and more generally white). Census data over time could be utilized for those adjustments. An adjusted evaluation would be more informative when evaluating regional differences. If such an evaluation were performed, it would be a unique addition to the literature that already exists over this time period. In addition a rural vs urban breakdown would be helpful to compare with other previously reported results. 2. Page 7 of 15 - as this is not the first study to investigate trends in PD-related mortality in the US (example Ref 35 - and others noted below), should remove this sentence. 3. Page 7 of 15 - other studies have evaluated sex-related differences ( example Ref 35 and others) and they should be compared with. 4. Page 7 of 15 - spelling error for "holder" meaning "older". 5. Figures 2 and 6 should be enlarged, difficult to read. 6. Several other studies should be referenced and discussed and a clear distinction made between this study and those earlier reported results. In fact, Ref 35, Rong et al should be compared with as it is not clear what is different in this study vs that study. In addition, see other examples: Tharwani et al 2024 - https://www.prd-journal.com/article/S1353-8020(24)01122-2/abstract and a systematic review of global trends from Lancet Zhu et al 2024 (Ref-1) - https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(24)00094-1/fulltext - Is the work clearly and accurately presented and does it cite the current literature? No - Is the study design appropriate and is the work technically sound? Yes - Are sufficient details of methods and analysis provided to allow replication by others? Yes - If applicable, is the statistical analysis and its interpretation appropriate? Yes - Are all the source data underlying the results available to ensure full reproducibility? Yes - Are the conclusions drawn adequately supported by the results? Partly

1. Zhu J, Cui Y, Zhang J, Yan R, et al.: Temporal trends in the prevalence of Parkinson's disease from 1980 to 2023: a systematic review and meta-analysis.Lancet Healthy Longev. 2024; 5 (7): e464-e479 PubMed Abstract | Publisher Full TextCompeting Interests: No competing interests were disclosed. Reviewer Expertise: Cognitive related outcome epidemiology. CITE HOW TO CITE THIS REPORT Dauer LT. Reviewer Report For: Temporal Trends in Parkinson’s Disease Related Mortality from 1999-2020: A National Analysis [version 1; peer review: 1 approved, 2 approved with reservations]. NIHR Open Res 2024, 4:50 (https://doi.org/10.3310/nihropenres.14792.r34189) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-50/v1#referee-response-34189 https://openresearch.nihr.ac.uk/articles/4-50/v1#referee-response-34189 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. Views 0 How to cite this report: Sassone J. Reviewer Report For: Temporal Trends in Parkinson’s Disease Related Mortality from 1999-2020: A National Analysis [version 1; peer review: 1 approved, 2 approved with reservations]. NIHR Open Res 2024, 4:50 (https://doi.org/10.3310/nihropenres.14792.r34191) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-50/v1#referee-response-34191 https://openresearch.nihr.ac.uk/articles/4-50/v1#referee-response-34191 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 31 Dec 2024 Approved VIEWS 0 This study analyzes the demographic trends in PD-related mortality in the United States. The data are from CDC-WONDER and refer to the time interval January 1999 - December 2020. The work clearly and accurately presents and cites the ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close PD-related mortality in the United States. The data are from CDC-WONDER and refer to the time interval January 1999 - December 2020. The work clearly and accurately presents and cites the ... Continue reading This study analyzes the demographic trends in PD-related mortality in the United States. The data are from CDC-WONDER and refer to the time interval January 1999 - December 2020. The work clearly and accurately presents and cites the literature. The statistical analysis and its interpretation are appropriate If possible, it would be useful and interesting to add a section about the cause of death (cancer, depression, ischemic heart disease, stroke…….). This section would give a more complete view of the results. PD-related mortality in the United States. The data are from CDC-WONDER and refer to the time interval January 1999 - December 2020. The work clearly and accurately presents and cites the literature. The statistical analysis and its interpretation are appropriate If possible, it would be useful and interesting to add a section about the cause of death (cancer, depression, ischemic heart disease, stroke…….). This section would give a more complete view of the results. - Is the work clearly and accurately presented and does it cite the current literature? Yes - Is the study design appropriate and is the work technically sound? Yes - Are sufficient details of methods and analysis provided to allow replication by others? Yes - If applicable, is the statistical analysis and its interpretation appropriate? Yes - Are all the source data underlying the results available to ensure full reproducibility? Yes - Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: parkinson's disease CITE HOW TO CITE THIS REPORT Sassone J. Reviewer Report For: Temporal Trends in Parkinson’s Disease Related Mortality from 1999-2020: A National Analysis [version 1; peer review: 1 approved, 2 approved with reservations]. NIHR Open Res 2024, 4:50 (https://doi.org/10.3310/nihropenres.14792.r34191) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-50/v1#referee-response-34191 https://openresearch.nihr.ac.uk/articles/4-50/v1#referee-response-34191 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. Alongside their report, reviewers assign a status to the article: - Approved - Approved with reservations - Not approved | Invited Reviewers | ||| |---|---|---|---| | 1 | 2 | 3 | | | Version 1 13 Sep 24 | read | read | read | Sign up for content alerts You are now signed up to receive this alert Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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