Demographic trends of motor neurone disease-associated mortality from 1999-2020 in the United States

Keywords Motor Neurone Disease; Mortality; Outcomes; Epidemiology. ALL Metrics - Views Downloads How to cite this article Imantalab D, Sokhal BS, Prasanna Kumar Menon S et al. Demographic trends of motor neurone disease-associated mortality from 1999-2020 in the United States [version 1; peer review: 2 approved with reservations]. NIHR Open Res 2024, 4:79 (https://doi.org/10.3310/nihropenres.13786.1) 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: 2 approved with reservations] Delaram Imantalab https://orcid.org/0009-0002-3306-5727 1*, Balamrit Singh Sokhal https://orcid.org/0000-0002-2315-0744 1*, Sowmya Prasanna Kumar Menon1, Seema Kalra1,2, Sara Muller https://orcid.org/0000-0001-6645-5751 1, Christian Mallen https://orcid.org/0000-0002-2677-1028 1Delaram Imantalab https://orcid.org/0009-0002-3306-5727 1*, Balamrit Singh Sokhal https://orcid.org/0000-0002-2315-0744 1*, [...] Sowmya Prasanna Kumar Menon1, Seema Kalra1,2, Sara Muller https://orcid.org/0000-0001-6645-5751 1, Christian Mallen https://orcid.org/0000-0002-2677-1028 1 * Equal contributors PUBLISHED 19 Dec 2024 Author details Author details 1 Keele University School of Medicine, Keele, England, UK 2 University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, England, UK 2 University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, England, UK Delaram Imantalab Roles: Writing – Original Draft Preparation, Writing – Review & Editing Roles: Writing – Original Draft Preparation, Writing – Review & Editing Balamrit Singh Sokhal Roles: Conceptualization, Formal Analysis, Methodology, Project Administration, Supervision, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Formal Analysis, Methodology, Project Administration, Supervision, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Sowmya Prasanna Kumar Menon Roles: Writing – Original Draft Preparation, Writing – Review & Editing Roles: Writing – Original Draft Preparation, Writing – Review & Editing Seema Kalra Roles: Writing – Review & Editing Roles: Writing – Review & Editing Sara Muller Roles: Writing – Review & Editing Roles: Writing – Review & Editing Christian Mallen Roles: Project Administration, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Project Administration, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW REVIEWER STATUS Motor Neurone Disease (MND) is a neurodegenerative condition affecting motor neurons in spinal cord and brainstem, leading to a reduced life expectancy. This study describes demographic trends in MND-associated mortality in the United States over a 20-year period. Data was extracted from the Centers for Disease Control and Prevention Wide-Ranging OnLine Data for Epidemiologic Research underlying cause of death database. All death certificates from 1999-2020 with MND (G12.2) recorded as the cause of mortality were extracted. Annual MND-associated crude mortality rates (CMR) and age-adjusted mortality rates (AAMR) per 100,000 persons with 95% confidence intervals (CI) were calculated. Joinpont regression was used to calculate the annual trends in MND-associated mortality by calculating the annual percentage change. Between 1999 to 2020, there were a total 140,945 MND-associated deaths. Overall AAMR was 1.9 per 100,000 persons (95% CI 1.9-1.9). Male sex had a consistently higher AAMR (2.3 per 100,000 95% CI 2.3-2.3) than female sex (1.6 per 100,000 95% CI 1.5-1.6) across the study period. White patients had higher AAMR (2.1 per 100,000 95% CI 2.0-2.1) than Black/African Americans (1.1 per 100,000 95% CI 1.0-1.1), American Indians/Alaska Natives (0.8 per 100,000 95% CI 0.7-0.9), Asians/Pacific Islanders (0.8 per 100,000 95% CI 0.7-0.9). The 3 US States with the highest AAMR were Vermont, followed by Minnesota and Maine. There are a significant number of MND-associated deaths annually in the United States. The knowledge of these trends facilitates the design of appropriate services in areas of higher need, allowing for the introduction of pathways that support more suitable care and enhanced quality of life. Motor Neurone Disease (MND) is a neurological condition affecting motor neurons in spinal cord and brainstem. MND has a poor life expectancy. We aimed to describe the demographic trends in deaths from MND over a 20 year period. Deaths associated with MND were extracted from a national database from 1999–2020. From 140,595 deaths we found that male sex and white race were characteristics associated with the highest mortality rates when age was taken into account. Knowledge of these trends facilitates the design of appropriate services in areas of higher need, allowing for the introduction of pathways that support more suitable care and enhanced quality of life. Motor Neurone Disease; Mortality; Outcomes; Epidemiology. Corresponding Author(s) Balamrit Singh Sokhal ([email protected]) Grant information: This project is funded by the National Institute for Health and Care Research (NIHR) under the ‘NIHR School for Primary Care Research’ (Grant Reference Number NIHR203712) and Applied Research Collaboration West Midlands to CDM. SM is partly funded by the NIHR Applied Research Collaboration West Midlands. 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 Imantalab D 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: Imantalab D, Sokhal BS, Prasanna Kumar Menon S et al. Demographic trends of motor neurone disease-associated mortality from 1999-2020 in the United States [version 1; peer review: 2 approved with reservations]. NIHR Open Res 2024, 4:79 (https://doi.org/10.3310/nihropenres.13786.1) First published: 19 Dec 2024, 4:79 (https://doi.org/10.3310/nihropenres.13786.1) Latest published: 26 Aug 2025, 4:79 (https://doi.org/10.3310/nihropenres.13786.2) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There is a newer version of this article available. of this article available. Motor Neurone Disease (MND) is a rapidly progressing neurological disease characterised by the degeneration of upper and lower motor neurones and thereby deterioration of motor function1. MND has several subtypes including Amyotrophic Lateral Sclerosis (ALS), progressive bulbar palsy, progressive muscular atrophy, primary lateral sclerosis, spinal muscular atrophy and post-polio syndrome1,2. The incidence of MND in the United States (US) is approximately 2 in every 100,000 of the population annually. Mortality, as well as incidence, is most common in patients aged between 55 and 753–5. Recent epidemiological trends suggest an increased prevalence and incidence of cases of MND over the time period of 2015 to 2019 which is similar to trends reported in Europe. In the US, the average length of time from the point of diagnosis to death is three years3. The most common cause of death secondary to MND is neuromuscular respiratory failure, which typically occurs between two and five years following the onset of the disease6. Factors associated with improved survival included a younger age of onset and attending a regional MND clinic7. MND is most common in white patients, therefore the majority of deaths occur in white patients8. A population-based study in England, including mortality data from 1993–2010, concluded that home deaths were more frequent than deaths occurring at a hospice for patients with MND (27.1% versus 11.2%)1. Data are limited about the demographic trends in mortality from MND in the US. Knowledge of these trends is fundamental to allow healthcare providers to ascertain the factors associated with improved survival for MND patients and identify populations facing a disparity of healthcare provision. Therefore, the aim of this study was to use national death certificate data to explore demographic trends in MND-associated mortality. This study did not have patient or public involvement. Data were extracted from the Centers for Disease Control and Prevention Wide-Ranging OnLine Data for Epidemiologic Research (CDC-WONDER) underlying cause of death database. CDC-WONDER contains details on the cause of death from death certificates from the 50 US states and the District of Columbia9. More than 99% of US deaths are recorded on CDC-WONDER9. Several studies have used this database to study a variety of conditions10–14. Using the International Classification of Diseases-Tenth Revision (ICD-10), all death certificates from 1999–2020 with MND (G12.2) recorded as a cause of mortality were extracted. Data such as year, death count, population size, demographic data such as age, sex, race, Hispanic status, geographic data such as census region and state, and other death certificate data such as place of death were also extracted. Geographical data included urbanisation levels including metropolitan (large central metropolitan (1 million or more population with a high-population density), large fringe metropolitan (1 million or more population with a high population density in counties that do not qualify as large central metropolitan), medium metropolitan (counties with populations of between 250,000–999,999 with a high population density), small metropolitan (counties with populations less than 250,000 with a high population density)), and non-metropolitan (micropolitan (counties with populations around 10,000–50,000 population) and noncore (counties that do not qualify as micropolitan))15. Annual MND-associated crude mortality rates (CMR) and age-adjusted mortality rates (AAMR) per 100,000 live persons in the population were calculated. To calculate CMR, the number of MND-associated deaths was divided by the population in the given year. Results were calculated with 95% confidence intervals (CI). AAMR was calculated by standardizing the MND-associated deaths to 1999 US population with 95% CI16. Joinpont regression was used to calculate the annual trends in MND-associated mortality by calculating the annual percentage change (APC). Joinpoint regression identifies significant differences in AAMR over time using log-linear regression models for temporal variations. Joinpoint regression software was used for APC and trend calculations17. CDC-WONDER is an publicly available, anonymised dataset, and therefore did not require ethical approval from an institutional review board9. The STrengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines were used to report this study18. Between 1999 to 2020, there were a total 140,945 MND-associated deaths. Overall, CMR was 2.1 per 100,000 persons (95% CI 2.1-2.1) and AAMR was 1.9 per 100,000 persons (95% CI 1.9-1.9). CMR was 1.8 per 100,000 in 1999 (95% CI 1.8-1.9) and 2.2 per 100,000 in 2020 (95% CI 2.2-2.2). AAMR was 1.9 per 100,000 in 1999 (95% CI 1.8-1.9) and 1.7 per 100,000 in 2020 (95% CI 1.7-1.8). Using Joinpoint regression analysis, the APC in AAMR was 0.30 (95% CI -2.81-5.94) from 1999–2014, -5.72 (95% CI -8.70-3.62) from 2014–2017 and 0.43 (95% CI -4.20-7.23) from 2017-2020 (Table 1 and Figure 1). Over the 20-year period, older age categories were associated with a consistently higher CMR. CMR for patients aged over 85 was 7.9 (95% CI 7.7-8.0), compared to a CMR of 1.5 (95% CI 1.4-1.5) for patients aged 45-54 (Table 1 and Figure 2). Male sex had a consistently higher AAMR (2.3 per 100,000 95% CI 2.3-2.3) than female sex (1.6 per 100,000 95% CI 1.5-1.6) across the study period. Using Joinpoint regression analysis, the APC in AAMR for males was 0.17 (95% CI 0.17-0.21) from 1999–2014, which then decreased to -4.75 (95% CI -4.75-0.24) from 2014–2018, and then increased to 2.54 (95% CI -2.64-5.84) from 2018–2020. The APC in AAMR for females was 0.39 (95% CI -0.19-1.48) from 1999–2012 which reduced to -2.57 (95% CI -4.98- -1.40) from 2012–2020 (Table 1 and Figure 3). White patients had consistently higher AAMR (2.1 per 100,000 95% CI 2.0-2.1) than Black/African Americans (1.1 per 100,000 95% CI 1.0-1.1), American Indians/Alaska Natives (0.8 per 100,000 95% CI 0.7-0.9) and Asians/Pacific Islanders (0.8 per 100,000 95% CI 0.7-0.9). Using Joinpoint regression analysis, the APC in AAMR for white patients was 0.40 (95% CI -0.01-0.80) from 1999–2014, reducing to -4.73 (95% CI -7.48-0.48) from 2014–2018 and increasing to 3.39 (95% CI -2.42-7.16) from 2018 to 2020. Joinpoint regression for the Black/African American, Asians/Pacific Islander and American Indians/Alaska Native groups could not be calculated due to relatively small numbers across multiple years which CDC-WONDER assigns as unreliable. Overall AAMR across the study period was higher for non-Hispanic/Latino groups (AAMR 2.0 95% CI 2.0-2.0) than Hispanic/Latino groups (AAMR 1.1 95% CI 1.0-1.1) in the population. AAMR for Hispanic/Latino deaths was 0.09 per 100,000 (95% CI -0.36-0.55). On Joinpoint regression analysis, there were no discernible difference in trend for Hispanic/Latino groups than for the whole population. APC for AAMR for non-Hispanic/Latino deaths was 0.35 (95% CI -1.45-2.18) from 1999–2014, decreasing to -5.06 (95%CI -6.88-2.18) from 2014–2017, then increasing to 0.31 (95% CI -3.13-5.03) from 2017–2020 (Table 1 and Figure 4). The Midwest census region had the highest AAMR (2.1 per 100,000 95% CI 2.1-2.1), followed by the West (1.9 per 100,000 95% CI 1.9-2.0), Northeast (1.9 per 100,000 95% CI 1.8-1.9) and South (1.8 per 100,000 95% CI 1.8-1.9). The census division with the highest AAMR was West North Central (2.2 per 100,000 95%CI 2.2-2.3), followed by New England (2.2 per 100,000 95% CI 2.2-2.3), East North Central (2.1 per 100,000 95% CI 2.0-2.1), Mountain (2.0 per 100,000 95% CI 2.0-2.0), Pacific (1.9 per 100,000 95% CI 1.8-1.9), South Atlantic (1.8 per 100,000 95% CI 1.8-1.8), East South Central (1.8 per 100,000 95% CI 1.8-1.8), Middle Atlantic (1.7 per 100,000 95% CI 1.7-1.7) and West South Central (1.7 per 100,000 95% CI 1.7-1.7) (Table 2). The top 3 health and human services (HHS) regions with the highest AAMR was region 10 (Alaska, Idaho, Oregon, Washington) (2.5 per 100,000 95% CI 2.4-2.5), followed by region 8 (Colorado, Montana, North Dakota, South Dakota, Utah and Wyoming) (2.3 per 100,000 95% CI 2.2-2.4) and region 1 (Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, and Vermont) (2.2 per 100,000 95% CI 2.2-2.3) (Table 2). The 3 states with the highest AAMR was Vermont (2.8 per 100,000 95% CI 2.5-3.0), followed by Minnesota (2.7 per 100,000 95% CI 2.6-2.8) and Maine (2.5 per 100,000 95% CI 2.4-2.7). The 3 states with the lowest AAMR over the study period was Nevada (1.4 per 100,000 95% CI 1.3-1.5), followed by the Hawaii (1.4 per 100,000 95% CI 1.3-1.5) and the District of Columbia (1.4 per 100,000 95% CI 1.2-1.6) (Table 2). Small metro urbanisation had the highest overall AAMR (2.1 95% CI 2.0-2.1), followed by large fringe metro (AAMR 2.0 95% CI 2.0-2.0), medium metro (AAMR 2.0 95% CI 2.0-2.0), nonmetro micropolitan (AAMR 2.0 95% CI 2.0-2.0), nonmetro noncore (AAMR 1.9 95% CI 1.8-1.9) and large central metro (AAMR 1.6 95% CI 1.6-1.7) (Table 2). Of all patient deaths (140,945), the most common place of death was the decedent’s home (49.2%), followed by medical facility – inpatient (20.5%), nursing home/long term care (17.0%), hospice facility (5.7%), other place of death (4.5%), medical facility – outpatient/emergency room (2.5%), unknown place (0.3%) and medical facility – death on arrival (0.3%) (Table 3). This study investigated the demographic trends in MND-associated mortality using death certificate data from the US. There are several findings of note. First, age-adjusted MND-associated mortality decreased over a 20-year period, with 140,945 total deaths and AAMR was 1.9 per 100,000 in 1999 and 1.7 per 100,000 in 2020. Second, there were race and sex trends in MND-associated mortality, with male sex and white race associated with the highest AAMR consistently over the study period. Finally, there were notable geographical differences in MND-associated mortality. The region with the highest AAMR was the Midwest and the states with the highest AAMR were Vermont, Minnesota and Maine. Over a 20-year period, we observed a rise in the deaths associated with MND. A US-based study from 2011–2014 found the overall age-adjusted mortality rate from MND was 1.70 per 100,000 (95% CI 1.68-1.72)19. Additionally, a systematic analysis for the Global Burden of Disease found there was a 1.1% increase in the age standardised rates of years lived with disability (YLDs) amongst individuals with MND between 2006 and 201620. This could be indicative of overall increase in life expectancy amongst affected patients from 1990 to 2016. Notably, Riluzole was approved by the FDA for the first pharmacological treatment of ALS in 1995 [PMID: 32847483]. The use of Riluzole for patients with motor neurone disease has been found to increase life expectancy, albeit by a modest 2–3 months of tracheostomy-free survival [PMID: 32847483]. A 2012 systematic review and meta- analysis of four randomised control trials concluded that use of Riluzole increased median survival from 11.8 to 14.8 months [PMID: 22419278]. This analysis included 195 countries from 2006 to 2016, so may not be translatable solely to the pattern observed in the USA20. Furthermore, increase in overall YLD across this timespan could be associated with improved access to healthcare for affected patients, and possibly earlier diagnosis. We found there to be higher rates of MND associated mortality in males. Overall, male sex was associated with an AAMR of 2.3 per 100,000 (95% CI 2.3-2.3) whereas this figure for women in the same study period was 1.6 per 100,0000 (95% CI 1.5-1.6). This was concordant with findings from other studies3. A UK study from 1990 to 2005, where age-standardised incidence was found to be 3.9 per 100,000 in men, in contrast to 2.6 per 100,000 in women21. In this particular study, it was found that the incidence of MND was 54% higher in men than in women (95% CI: 33%-77%)21. However, the trends in MND incidence have also been documented to vary over time in males and females. Whilst males were again found to experience a higher death rate than females22, men over 65 also experienced a significant annual reduction in overall mortality from 1999 to 2009 (p<0.001). However, men aged 20–49 experienced an increasing death rate over the study period (p=0.01). The death rate for females showed no significant change over the period of the study, however, there was a general reduction in MND-associated mortality rates in persons over 65 years of age22. The overall AAMR per 100,000 population was found to be higher in males (2.68) than in females (1.77)22. In this study, we consistently found higher rates of death in white patients, with an AAMR of 2.1 per 100,000 (95% CI 2.0-2.1). Black/African American patients experienced a lower MND-associated mortality rate of 1.1 per 100, 000 (CI 1.0-1.1), and both American Indians/ Alaska Natives and Asians/ Pacific Islanders had an AAMR of 0.8 per 100,000 (95% CI 0.7-0.9). This finding is reflected in the literature. In a study investigating racial disparities in MND associated mortality from 1999 to 2006 in the University of Arkansas for Medical Sciences clinic for MND, 466 deaths were associated with MND. 95.5% of these patients were white, 3.6% were black, and 0.9% were from an ‘other’ category. At this time, the proportion of the Arkansas population who were black was 17%8. However, the average age of onset for the black cohort was 52.8 ± 13.0 (p = 0.038), whilst it was 58.1 ± 12.4 years for the white patients in this study. It is possible that genetic differences modify risk of the development of MND and maintenance of neurological function throughout the course of disease progression8. However, it must also be considered that this disparity may, in part, be due to under-ascertainment of some cases due to poor access to healthcare as a result of socioeconomic deprivation8. There was also a difference in physiological factors, such as average pre-morbid body mass index (BMI) between the group of black patients and white patients respectively. Black patients had a pre-morbid BMI of 31.2kg/m2 (± 6.4 ) whilst white patients from this clinic had a premorbid BMI of 28.4 kg/m2 (± 5.3, p = 0.01). However, BMI also significantly reduced by the time of disease diagnosis in black patients compared to white patients8. Another study found no difference in the survival rates between affected black and white patients23. This may be due to a multitude of factors, such as different sample sizes, study designs and variations in some health determinants such as socioeconomic status and availability of healthcare for more varied populations and racial groups across different states. A previous study has reported a strong correlation between MND-associated mortality rates and the proportion of the population that uses well water. It was hypothesised that this is due to well water serving as a reservoir for Legionella, which may be result in a pathophysiological process ending with central nervous system disease, and some cases of MND4. This study was consistent in reporting Vermont as the state with the highest level of MND mortality, and cited Hawaii as the lowest4. A significant association was observed between MND associated mortality and the proportion of the population within that region that uses water wells. The statistical model derived found that MND mortality increases by 0.00783 deaths per 100,000 people for every 1% rise in the population using well water4. It has consistently been documented that rates of MND associated mortality tend to be higher in US states that are situated at higher latitudes19. It has also been found that countries at more northern latitudes in Europe experience a higher rate of ALS incidence. This could be due to multiple factors, including patterns of European settlement, genetic predisposition and environmental factors, and is in keeping with the highest recorded mortality rate being in Vermont, both in our findings and other literature, such as a study reporting all the causes of death in 2011–2014 coded under G12.2, which includes all motor neurone diseases including MND in the United States19. Beyond potentially causative environmental factors, multiple health determinants such as access to healthcare, genetic makeup of the district population and a multitude of environmental toxins as well as the genetic and epigenetic modulation of these may contribute to varying levels of both incidence of MND, rate of disease progression of MND, MND presentation and MND mortality. It is possible that the causative factor is associated with living in a northerly latitude19 rather than solely ethnicity. However, ethnicity and latitude of habitation may be confounding factors in terms of MND incidence. Regardless, findings of differences in incidence between different ethnicities in less northerly latitudes can help to reflect that ethnicity may also play a role MND incidence, such as the findings in a study in Arkansas8. There are several clinical implications of this study. MND is an underlying cause of a significant number of deaths in the US. The knowledge of these trends, and the impact of specific demographics on mortality allows healthcare services to adapt to the needs of MND patients and identify individuals at greater risk of adverse outcomes early, allowing optimisation of their risk factors. Patients who are at greatest risk of adverse outcomes can be counselled on their risk and explore methods to mitigate modifiable risk factors. Furthermore, identifying disparities in care provides health services with the information they need to improve services and supports research into the underlying causes of such disparities. Furthermore, this study aids hypothesis building and the informing of other epidemiological and pathogenic studies regarding risk factors and causative factors. These may include genetic factors, ethnicity, and gender related predispositions as well as modifiable and environmental factors. This can be very useful in informing future clinical trials, and function as a crude pointer towards healthcare service utilisation. There are several limitations to this study inherent to the dataset used. First, more granular analysis could not be conducted due to lack of data on pharmacotherapy, co-morbidities and procedures that could have mediated outcomes. This data could be used to provide adjusted analysis and comparisons between patient sub-groups to identify whether certain disparities exist after adjustment for these factors. Second, this data does not yield the exact cause of death. MND is recorded as a cause of death, but we cannot ascertain wither MND was the primary, secondary to even lower reason for death. Most MND related deaths are from respiratory complications, however the dataset does not provide the primary cause of death. Third, routinely collected electronic death certificate data is subject to information and selection bias, for instance due to differences in coding for causes of death across time, which could affect the internal validity of this study. Fourth, the dataset did not allow investigation into the subtypes of MND. MND subtypes have varying prognosis and therefore would have warranted further investigation. Finally, as CDC-WONDER provides information only on death-certificate data, analyses of quality of life and other aspects of MND care of interest to patients could not be investigated using these data. Future research could aim to reproduce the results of this research and improve it further through the use of adjusted analysis using a more detailed dataset to determine whether disparities in outcomes remain. Other research could explore why there is disparity in incidence and mortality rates across specific patient demographics. This could be across the translational pathway to determine whether there is a genetic susceptibility to the occurrence of MND and adverse events or complications from MND, or whether there are wider implications due to demographics such as social determinants of health that would be better addressed at the population level. Additionally, given the course of MND, a longitudinal study should aim to investigate the impact of these factors on survival duration. In conclusion, there are significant differences in trends in MND-related mortality in the US across demographic subgroups. Older age, male sex, white race, Midwest locality and Vermont, Minnesota and Maine state residence had the highest AAMR. The data obtained in this study is fundamental to build health services and palliative care pathways around the needs of this population group. Joinpoint Regression software is available to download for free at https://surveillance.cancer.gov/joinpoint/ Conceptualisation: Balamrit Singh Sokhal; Christian D Mallen Methodology: Balamrit Singh Sokhal, Sowmya Prasanna Kumar Menon Validation: Balamrit Singh Sokhal Formal analysis: Balamrit Singh Sokhal; Writing – original draft: Delaram Imantalab, Balamrit Singh Sokhal, Christian D Mallen; Writing – review and editing: Delaram Imantalab, Balamrit Singh Sokhal, Sowmya Prasanna Kumar Menon, Seema Kalra, Sara Muller, Christian D Mallen; Visualisation: Balamrit Singh Sokhal; Supervision: Balamrit Singh Sokhal, Christian D Mallen; Project administration: Balamrit Singh Sokhal, Christian D Mallen. Faculty Opinions recommendedReferences - 1. Sleeman KE, Ho YK, Verne J, et al.: Place of death, and its relation with underlying cause of death, in Parkinson's disease, motor neurone disease, and multiple sclerosis: a population-based study. Palliat Med. 2013; 27(9): 840–6. 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PubMed Abstract | Publisher Full Text | Free Full Text Author details Author details 1 Keele University School of Medicine, Keele, England, UK 2 University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, England, UK 2 University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, England, UK Delaram Imantalab Roles: Writing – Original Draft Preparation, Writing – Review & Editing Roles: Writing – Original Draft Preparation, Writing – Review & Editing Balamrit Singh Sokhal Roles: Conceptualization, Formal Analysis, Methodology, Project Administration, Supervision, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Formal Analysis, Methodology, Project Administration, Supervision, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Sowmya Prasanna Kumar Menon Roles: Writing – Original Draft Preparation, Writing – Review & Editing Roles: Writing – Original Draft Preparation, Writing – Review & Editing Seema Kalra Roles: Writing – Review & Editing Roles: Writing – Review & Editing Sara Muller Roles: Writing – Review & Editing Roles: Writing – Review & Editing Christian Mallen Roles: Project Administration, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Project Administration, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information This project is funded by the National Institute for Health and Care Research (NIHR) under the ‘NIHR School for Primary Care Research’ (Grant Reference Number NIHR203712) and Applied Research Collaboration West Midlands to CDM. SM is partly funded by the NIHR Applied Research Collaboration West Midlands. 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. Article Versions (2) Copyright © 2024 Imantalab D 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 Imantalab D, Sokhal BS, Prasanna Kumar Menon S et al. Demographic trends of motor neurone disease-associated mortality from 1999-2020 in the United States [version 1; peer review: 2 approved with reservations]. NIHR Open Res 2024, 4:79 (https://doi.org/10.3310/nihropenres.13786.1) 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 19 Dec 2024 Views 0 How to cite this report: Lischewski S. Reviewer Report For: Demographic trends of motor neurone disease-associated mortality from 1999-2020 in the United States [version 1; peer review: 2 approved with reservations]. NIHR Open Res 2024, 4:79 (https://doi.org/10.3310/nihropenres.14974.r34231) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-79/v1#referee-response-34231 https://openresearch.nihr.ac.uk/articles/4-79/v1#referee-response-34231 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 10 Jan 2025 Stella Lischewski, Universitätsklinikum Aachen, RWTH Aachen, Aachen, Deutschland, Germany Approved with Reservations VIEWS 0 In this manuscript, Imantalab and colleagues investigated trends in MND-associated mortality using death certificate data from the public US-based CDC-Wonder registry. The authors conclude that older age, male sex, white ethnicity, and Midwest locality were associated with the highest AAMR. ... 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 In this manuscript, Imantalab and colleagues investigated trends in MND-associated mortality using death certificate data from the public US-based CDC-Wonder registry. The authors conclude that older age, male sex, white ethnicity, and Midwest locality were associated with the highest AAMR. Overall, this work represents a valuable addition to the literature, particularly given the large size of the registry. However, I have several reservations and suggestions for revisions: - Inclusive Language: - The term "race" should be reconsidered to align with inclusive language practices (see Naini et al., The Lancet, 2024) [ref-1]. Additionally, "Hispanic status" or "Latino status" may not be sufficiently inclusive and could be rephrased to reflect modern terminology regarding ethnicity and cultural identity. - Cohort Description: - A more thorough description of the study cohort would enhance the manuscript. Providing data on the means and proportions of baseline characteristics (e.g., mean age, sex, ethnicity, and geographic location) for individuals who died of MND would offer readers a clearer understanding beyond AAMR and CMR values. - AAMR Calculation: - Clarify how AAMRs stratified by sex, ethnicity, and geographic region were calculated. For instance, if AAMRs are derived from dividing the number of deaths by the respective total population subgroup, it would be important to report the population sizes used in these calculations as per previous point. - Contextual Comparison: - The findings regarding increased mortality rates in males, specific locations, etc., would greatly benefit from a comparison with all-cause mortality rates in the US e.g. using previous literature. - Table Formatting: - The population data in Table 1 is difficult to read due to the absence of separators in large numbers. I recommend using commas (e.g., 279,040,168) to enhance readability. - Annual Trends: - In the section "Annual Trends for MND-associated Mortality," the reported APC for AAMR (0.30, 95% CI -2.81 to 5.94) appears inconsistent with its confidence intervals. Please clarify or address this discrepancy, as it may indicate a reporting or calculation error. - 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? Partly - Are sufficient details of methods and analysis provided to allow replication by others? Partly - If applicable, is the statistical analysis and its interpretation appropriate? Partly - Are all the source data underlying the results available to ensure full reproducibility? No source data required - Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Neurodegeneration, Ataxia, previously NMD CITE HOW TO CITE THIS REPORT Lischewski S. Reviewer Report For: Demographic trends of motor neurone disease-associated mortality from 1999-2020 in the United States [version 1; peer review: 2 approved with reservations]. NIHR Open Res 2024, 4:79 (https://doi.org/10.3310/nihropenres.14974.r34231) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-79/v1#referee-response-34231 https://openresearch.nihr.ac.uk/articles/4-79/v1#referee-response-34231 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. - Author Response 26 Aug 2025Balamrit Singh Sokhal, Keele University School of Medicine, Keele, UK26 Aug 2025Author ResponseReviewer's Comments (2) Comment 1: In this manuscript, Imantalab and colleagues investigated trends in MND-associated mortality using death certificate data from the public US-based CDC-Wonder registry. The authors conclude ... Continue reading Reviewer's Comments (2) Comment 1: In this manuscript, Imantalab and colleagues investigated trends in MND-associated mortality using death certificate data from the public US-based CDC-Wonder registry. The authors conclude that older age, male sex, white ethnicity, and Midwest locality were associated with the highest AAMR. Overall, this work represents a valuable addition to the literature, particularly given the large size of the registry. However, I have several reservations and suggestions for revisions. Response: We thank the reviewer for their favourable account of this manuscript and the opportunity to improve it further. We provide a point-by-point to reviewer comments below. Comment 2: The term "race" should be reconsidered to align with inclusive language practices (see Naini et al., The Lancet, 2024) [ref-1]. Additionally, "Hispanic status" or "Latino status" may not be sufficiently inclusive and could be rephrased to reflect modern terminology regarding ethnicity and cultural identity. Reponse: Thank you for your comment. Whilst, the reference noted is important to guide nomenclature for future academic practice, the terms used in the paper we have provided retains the terms used in the primary data source (CDC WONDER). We have sought not to change this as data were coded on the original, publicly available dataset using these terms. We hope this apporpirately addresses this comment. Comment 3: A more thorough description of the study cohort would enhance the manuscript. Providing data on the means and proportions of baseline characteristics (e.g., mean age, sex, ethnicity, and geographic location) for individuals who died of MND would offer readers a clearer understanding beyond AAMR and CMR values. Response: Thank you for your comment. We agree that a more granular analysis of individual level data could provide more rich data and a clearer understanding behind the analysis. Unfortunately, CDC WONDER provides data at the state, region and population level. This database does not provide data at the individual level. We have specified this in the limitations section of the manuscript. Under ‘Limitations’ section: “First, more granular analysis could not be conducted due to lack of data on pharmacotherapy, co-morbidities and procedures that could have mediated outcomes. This data could be used to provide adjusted analysis and comparisons between patient sub-groups to identify whether certain disparities exist after adjustment for these factors.” Comment 4: Clarify how AAMRs stratified by sex, ethnicity, and geographic region were calculated. For instance, if AAMRs are derived from dividing the number of deaths by the respective total population subgroup, it would be important to report the population sizes used in these calculations as per previous point. Response: We thank the reviewer for their comment. AAMR are calculated by dividing the number of deaths by the population, including by subgroup. Crude number of deaths have been reported in the tables of the manuscript. Under ‘Tables’ section. Comment 5: The findings regarding increased mortality rates in males, specific locations, etc., would greatly benefit from a comparison with all-cause mortality rates in the US e.g. using previous literature. Response: We thank the reviewer for their comment. This study sought to investigate the trends in mortality from MND stratified by various demographics over the 20 year inclusion period. We agree that an investigation of all-cause mortality stratified by patient demography would be interesting. However, causes of mortality are heterogenous and may be difficult to correlate to the findings of our study of specifically MND, therefore comparisons to all-cause mortality are beyond the scope of our study and have not been included. We hope the reviewer understands the reasons why comparisons with on all-cause mortality were not elaborated on further in the manuscript. Comment 6: The population data in Table 1 is difficult to read due to the absence of separators in large numbers. I recommend using commas (e.g., 279,040,168) to enhance readability. Response: We thank the reviewer for their comment. We have amended the tables anf gures to make them easier to read as suggested. Comment 7: In the section "Annual Trends for MND-associated Mortality," the reported APC for AAMR (0.30, 95% CI -2.81 to 5.94) appears inconsistent with its confidence intervals. Please clarify or address this discrepancy, as it may indicate a reporting or calculation error. Response: Thank you for your comment. We have verified that the APC in AAMR from 1999-2014 was 0.30% (95%CI -.2.81-5.94). Due to the confidence intervals crossing the zero value, this result was not statistically significant. Therefore we can reasonably conclude that the AAMR from 1999-2014 remained stable, and there was no significant change for this time period. We hope this adequately addresses the comment.Reviewer's Comments (2)Competing Interests: No competing interests were disclosed. Close Comment 1: In this manuscript, Imantalab and colleagues investigated trends in MND-associated mortality using death certificate data from the public US-based CDC-Wonder registry. The authors conclude that older age, male sex, white ethnicity, and Midwest locality were associated with the highest AAMR. Overall, this work represents a valuable addition to the literature, particularly given the large size of the registry. However, I have several reservations and suggestions for revisions. Response: We thank the reviewer for their favourable account of this manuscript and the opportunity to improve it further. We provide a point-by-point to reviewer comments below. Comment 2: The term "race" should be reconsidered to align with inclusive language practices (see Naini et al., The Lancet, 2024) [ref-1]. Additionally, "Hispanic status" or "Latino status" may not be sufficiently inclusive and could be rephrased to reflect modern terminology regarding ethnicity and cultural identity. Reponse: Thank you for your comment. Whilst, the reference noted is important to guide nomenclature for future academic practice, the terms used in the paper we have provided retains the terms used in the primary data source (CDC WONDER). We have sought not to change this as data were coded on the original, publicly available dataset using these terms. We hope this apporpirately addresses this comment. Comment 3: A more thorough description of the study cohort would enhance the manuscript. Providing data on the means and proportions of baseline characteristics (e.g., mean age, sex, ethnicity, and geographic location) for individuals who died of MND would offer readers a clearer understanding beyond AAMR and CMR values. Response: Thank you for your comment. We agree that a more granular analysis of individual level data could provide more rich data and a clearer understanding behind the analysis. Unfortunately, CDC WONDER provides data at the state, region and population level. This database does not provide data at the individual level. We have specified this in the limitations section of the manuscript. Under ‘Limitations’ section: “First, more granular analysis could not be conducted due to lack of data on pharmacotherapy, co-morbidities and procedures that could have mediated outcomes. This data could be used to provide adjusted analysis and comparisons between patient sub-groups to identify whether certain disparities exist after adjustment for these factors.” Comment 4: Clarify how AAMRs stratified by sex, ethnicity, and geographic region were calculated. For instance, if AAMRs are derived from dividing the number of deaths by the respective total population subgroup, it would be important to report the population sizes used in these calculations as per previous point. Response: We thank the reviewer for their comment. AAMR are calculated by dividing the number of deaths by the population, including by subgroup. Crude number of deaths have been reported in the tables of the manuscript. Under ‘Tables’ section. Comment 5: The findings regarding increased mortality rates in males, specific locations, etc., would greatly benefit from a comparison with all-cause mortality rates in the US e.g. using previous literature. Response: We thank the reviewer for their comment. This study sought to investigate the trends in mortality from MND stratified by various demographics over the 20 year inclusion period. We agree that an investigation of all-cause mortality stratified by patient demography would be interesting. However, causes of mortality are heterogenous and may be difficult to correlate to the findings of our study of specifically MND, therefore comparisons to all-cause mortality are beyond the scope of our study and have not been included. We hope the reviewer understands the reasons why comparisons with on all-cause mortality were not elaborated on further in the manuscript. Comment 6: The population data in Table 1 is difficult to read due to the absence of separators in large numbers. I recommend using commas (e.g., 279,040,168) to enhance readability. Response: We thank the reviewer for their comment. We have amended the tables anf gures to make them easier to read as suggested. Comment 7: In the section "Annual Trends for MND-associated Mortality," the reported APC for AAMR (0.30, 95% CI -2.81 to 5.94) appears inconsistent with its confidence intervals. Please clarify or address this discrepancy, as it may indicate a reporting or calculation error. Response: Thank you for your comment. We have verified that the APC in AAMR from 1999-2014 was 0.30% (95%CI -.2.81-5.94). Due to the confidence intervals crossing the zero value, this result was not statistically significant. Therefore we can reasonably conclude that the AAMR from 1999-2014 remained stable, and there was no significant change for this time period. We hope this adequately addresses the comment. COMMENTS ON THIS REPORT - Author Response 26 Aug 2025Balamrit Singh Sokhal, Keele University School of Medicine, Keele, UK26 Aug 2025Author ResponseReviewer's Comments (2) Comment 1: In this manuscript, Imantalab and colleagues investigated trends in MND-associated mortality using death certificate data from the public US-based CDC-Wonder registry. The authors conclude ... Continue reading Reviewer's Comments (2) Comment 1: In this manuscript, Imantalab and colleagues investigated trends in MND-associated mortality using death certificate data from the public US-based CDC-Wonder registry. The authors conclude that older age, male sex, white ethnicity, and Midwest locality were associated with the highest AAMR. Overall, this work represents a valuable addition to the literature, particularly given the large size of the registry. However, I have several reservations and suggestions for revisions. Response: We thank the reviewer for their favourable account of this manuscript and the opportunity to improve it further. We provide a point-by-point to reviewer comments below. Comment 2: The term "race" should be reconsidered to align with inclusive language practices (see Naini et al., The Lancet, 2024) [ref-1]. Additionally, "Hispanic status" or "Latino status" may not be sufficiently inclusive and could be rephrased to reflect modern terminology regarding ethnicity and cultural identity. Reponse: Thank you for your comment. Whilst, the reference noted is important to guide nomenclature for future academic practice, the terms used in the paper we have provided retains the terms used in the primary data source (CDC WONDER). We have sought not to change this as data were coded on the original, publicly available dataset using these terms. We hope this apporpirately addresses this comment. Comment 3: A more thorough description of the study cohort would enhance the manuscript. Providing data on the means and proportions of baseline characteristics (e.g., mean age, sex, ethnicity, and geographic location) for individuals who died of MND would offer readers a clearer understanding beyond AAMR and CMR values. Response: Thank you for your comment. We agree that a more granular analysis of individual level data could provide more rich data and a clearer understanding behind the analysis. Unfortunately, CDC WONDER provides data at the state, region and population level. This database does not provide data at the individual level. We have specified this in the limitations section of the manuscript. Under ‘Limitations’ section: “First, more granular analysis could not be conducted due to lack of data on pharmacotherapy, co-morbidities and procedures that could have mediated outcomes. This data could be used to provide adjusted analysis and comparisons between patient sub-groups to identify whether certain disparities exist after adjustment for these factors.” Comment 4: Clarify how AAMRs stratified by sex, ethnicity, and geographic region were calculated. For instance, if AAMRs are derived from dividing the number of deaths by the respective total population subgroup, it would be important to report the population sizes used in these calculations as per previous point. Response: We thank the reviewer for their comment. AAMR are calculated by dividing the number of deaths by the population, including by subgroup. Crude number of deaths have been reported in the tables of the manuscript. Under ‘Tables’ section. Comment 5: The findings regarding increased mortality rates in males, specific locations, etc., would greatly benefit from a comparison with all-cause mortality rates in the US e.g. using previous literature. Response: We thank the reviewer for their comment. This study sought to investigate the trends in mortality from MND stratified by various demographics over the 20 year inclusion period. We agree that an investigation of all-cause mortality stratified by patient demography would be interesting. However, causes of mortality are heterogenous and may be difficult to correlate to the findings of our study of specifically MND, therefore comparisons to all-cause mortality are beyond the scope of our study and have not been included. We hope the reviewer understands the reasons why comparisons with on all-cause mortality were not elaborated on further in the manuscript. Comment 6: The population data in Table 1 is difficult to read due to the absence of separators in large numbers. I recommend using commas (e.g., 279,040,168) to enhance readability. Response: We thank the reviewer for their comment. We have amended the tables anf gures to make them easier to read as suggested. Comment 7: In the section "Annual Trends for MND-associated Mortality," the reported APC for AAMR (0.30, 95% CI -2.81 to 5.94) appears inconsistent with its confidence intervals. Please clarify or address this discrepancy, as it may indicate a reporting or calculation error. Response: Thank you for your comment. We have verified that the APC in AAMR from 1999-2014 was 0.30% (95%CI -.2.81-5.94). Due to the confidence intervals crossing the zero value, this result was not statistically significant. Therefore we can reasonably conclude that the AAMR from 1999-2014 remained stable, and there was no significant change for this time period. We hope this adequately addresses the comment.Reviewer's Comments (2)Competing Interests: No competing interests were disclosed. Close Comment 1: In this manuscript, Imantalab and colleagues investigated trends in MND-associated mortality using death certificate data from the public US-based CDC-Wonder registry. The authors conclude that older age, male sex, white ethnicity, and Midwest locality were associated with the highest AAMR. Overall, this work represents a valuable addition to the literature, particularly given the large size of the registry. However, I have several reservations and suggestions for revisions. Response: We thank the reviewer for their favourable account of this manuscript and the opportunity to improve it further. We provide a point-by-point to reviewer comments below. Comment 2: The term "race" should be reconsidered to align with inclusive language practices (see Naini et al., The Lancet, 2024) [ref-1]. Additionally, "Hispanic status" or "Latino status" may not be sufficiently inclusive and could be rephrased to reflect modern terminology regarding ethnicity and cultural identity. Reponse: Thank you for your comment. Whilst, the reference noted is important to guide nomenclature for future academic practice, the terms used in the paper we have provided retains the terms used in the primary data source (CDC WONDER). We have sought not to change this as data were coded on the original, publicly available dataset using these terms. We hope this apporpirately addresses this comment. Comment 3: A more thorough description of the study cohort would enhance the manuscript. Providing data on the means and proportions of baseline characteristics (e.g., mean age, sex, ethnicity, and geographic location) for individuals who died of MND would offer readers a clearer understanding beyond AAMR and CMR values. Response: Thank you for your comment. We agree that a more granular analysis of individual level data could provide more rich data and a clearer understanding behind the analysis. Unfortunately, CDC WONDER provides data at the state, region and population level. This database does not provide data at the individual level. We have specified this in the limitations section of the manuscript. Under ‘Limitations’ section: “First, more granular analysis could not be conducted due to lack of data on pharmacotherapy, co-morbidities and procedures that could have mediated outcomes. This data could be used to provide adjusted analysis and comparisons between patient sub-groups to identify whether certain disparities exist after adjustment for these factors.” Comment 4: Clarify how AAMRs stratified by sex, ethnicity, and geographic region were calculated. For instance, if AAMRs are derived from dividing the number of deaths by the respective total population subgroup, it would be important to report the population sizes used in these calculations as per previous point. Response: We thank the reviewer for their comment. AAMR are calculated by dividing the number of deaths by the population, including by subgroup. Crude number of deaths have been reported in the tables of the manuscript. Under ‘Tables’ section. Comment 5: The findings regarding increased mortality rates in males, specific locations, etc., would greatly benefit from a comparison with all-cause mortality rates in the US e.g. using previous literature. Response: We thank the reviewer for their comment. This study sought to investigate the trends in mortality from MND stratified by various demographics over the 20 year inclusion period. We agree that an investigation of all-cause mortality stratified by patient demography would be interesting. However, causes of mortality are heterogenous and may be difficult to correlate to the findings of our study of specifically MND, therefore comparisons to all-cause mortality are beyond the scope of our study and have not been included. We hope the reviewer understands the reasons why comparisons with on all-cause mortality were not elaborated on further in the manuscript. Comment 6: The population data in Table 1 is difficult to read due to the absence of separators in large numbers. I recommend using commas (e.g., 279,040,168) to enhance readability. Response: We thank the reviewer for their comment. We have amended the tables anf gures to make them easier to read as suggested. Comment 7: In the section "Annual Trends for MND-associated Mortality," the reported APC for AAMR (0.30, 95% CI -2.81 to 5.94) appears inconsistent with its confidence intervals. Please clarify or address this discrepancy, as it may indicate a reporting or calculation error. Response: Thank you for your comment. We have verified that the APC in AAMR from 1999-2014 was 0.30% (95%CI -.2.81-5.94). Due to the confidence intervals crossing the zero value, this result was not statistically significant. Therefore we can reasonably conclude that the AAMR from 1999-2014 remained stable, and there was no significant change for this time period. We hope this adequately addresses the comment. Views 0 How to cite this report: Heckmann JM. Reviewer Report For: Demographic trends of motor neurone disease-associated mortality from 1999-2020 in the United States [version 1; peer review: 2 approved with reservations]. NIHR Open Res 2024, 4:79 (https://doi.org/10.3310/nihropenres.14974.r34285) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-79/v1#referee-response-34285 https://openresearch.nihr.ac.uk/articles/4-79/v1#referee-response-34285 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 03 Jan 2025 Approved with Reservations VIEWS 0 This audit of the CDC database for mortality stats in the US related to ALS has a main objective to determine where the gaps in health services are for patients with ALS. The report is well written. The conclusion of ... 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 This audit of the CDC database for mortality stats in the US related to ALS has a main objective to determine where the gaps in health services are for patients with ALS. The report is well written. The conclusion of the work that ALS mortality is higher in older white males is somewhat circular since the authors acknowledge that there are many limitations to access of other races to healthcare. The main limitation being that a patient with poor access to health services may not receive a diagnosis of ALS and therefore will never be recorded as dying from ALS. This would be the very group which would need better services. To this end I feel the obvious gap in the work is that the granularity of the place where patients die, may offer a glimpse to this socioeconomic problem. For example, those patients who are offered a timeous diagnosis and are prepared for palliative care will likely die at home or in hospice. What is the racial makeup of these patients and the ones that die in ERs and in hospital and other? I suggest less emphasis on riluzole and other "therapies" (3 month survival increase) and the possibility that the reduced mortality >2015 could be due to better clinics? (since none of the treatment trials have been positive excl SOD1 cases). Also, why did the deaths in Blacks and other races double after 2010 compared to 2015 could be due to better clinics? (since none of the treatment trials have been positive excl SOD1 cases). Also, why did the deaths in Blacks and other races double after 2010 compared to <2010? increased awareness of ALS? - 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? I cannot comment. A qualified statistician is required. - Are all the source data underlying the results available to ensure full reproducibility? Yes - Are the conclusions drawn adequately supported by the results? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Neuromuscular disease, including ALS, in Africa CITE HOW TO CITE THIS REPORT Heckmann JM. Reviewer Report For: Demographic trends of motor neurone disease-associated mortality from 1999-2020 in the United States [version 1; peer review: 2 approved with reservations]. NIHR Open Res 2024, 4:79 (https://doi.org/10.3310/nihropenres.14974.r34285) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/4-79/v1#referee-response-34285 https://openresearch.nihr.ac.uk/articles/4-79/v1#referee-response-34285 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. - Author Response 26 Aug 2025Balamrit Singh Sokhal, Keele University School of Medicine, Keele, UK26 Aug 2025Author ResponseReviewer's Comments (1) Comment 1: This audit of the CDC database for mortality stats in the US related to ALS has a main objective to determine where the ... Continue reading Reviewer's Comments (1) Comment 1: This audit of the CDC database for mortality stats in the US related to ALS has a main objective to determine where the gaps in health services are for patients with ALS. The report is well written. The conclusion of the work that ALS mortality is higher in older white males is somewhat circular since the authors acknowledge that there are many limitations to access of other races to healthcare. The main limitation being that a patient with poor access to health services may not receive a diagnosis of ALS and therefore will never be recorded as dying from ALS. This would be the very group which would need better services. To this end I feel the obvious gap in the work is that the granularity of the place where patients die, may offer a glimpse to this socioeconomic problem. For example, those patients who are offered a timeous diagnosis and are prepared for palliative care will likely die at home or in hospice. What is the racial makeup of these patients and the ones that die in ERs and in hospital and other? Response: We thank the reviewer for their comment and positive appraisal of the manuscript. Access to healthcare is an important issue and can mediate outcomes. As requested, we have provided a supplementary table to compliment the main analyses by stratifying location of death by sex and race. Many of these numbers were small, especially for non-white and non-black populations, therefore, analysis by year could not be performed. Furthermore, due to availability of data and low numbers in the CDC WONDER database, analysis of percentage of deaths as a proportion of total number of deaths in the demographic were not able to be performed. We hope this adequately addresses the comment. Comment 2: I suggest less emphasis on riluzole and other "therapies" (3 month survival increase) and the possibility that the reduced mortality >2015 could be due to better clinics? (since none of the treatment trials have been positive excl SOD1 cases). Response: Thank you for your comment. The observed trends could be due several reasons. One of which could be due to better patient follow up in clinics via a multidisciplinary approach. In particular this improves better patient care in clinics. Therefore, this has been noted in our study. Additionally, we believe it is also important to highlight the potential impact newly approved medical treatments that could aid with the quality of life of patients with MND. Comment 3: Also, why did the deaths in Blacks and other races double after 2010 compared to <2010? increased awareness of ALS? Response: Thank you for your comment. It is clear that there are disparities in the race of the patient and the clinical outcomes. The overall deaths of patients of non-white ethnicities increase after 2010. This could be due to better awareness of ALS presentation differing between the various races. Therefore the onset of diagnosis itself may be delayed, leading to worse outcomes. We have included this in the manuscript. Under 'Discussion' section: “Furthermore, the overall deaths of patients of non-white patients increase after 2010. This could be due to inadequate awareness of MND and its presentation in non-white groups. Therefore the time to diagnosis may be delayed, leading to worse outcomes if the disease is in a more advanced state.” Under 'Discussion' section: “Additionally, it is important to note that a multidisciplinary clinic approach also improves survival rate in ALS. One particular study in Ireland and northern Ireland showed that there was a survival benefit for patients who attended ALS clinics due to better community based care.”Reviewer's Comments (1)Competing Interests: No competing interests were disclosed. Close Comment 1: This audit of the CDC database for mortality stats in the US related to ALS has a main objective to determine where the gaps in health services are for patients with ALS. The report is well written. The conclusion of the work that ALS mortality is higher in older white males is somewhat circular since the authors acknowledge that there are many limitations to access of other races to healthcare. The main limitation being that a patient with poor access to health services may not receive a diagnosis of ALS and therefore will never be recorded as dying from ALS. This would be the very group which would need better services. To this end I feel the obvious gap in the work is that the granularity of the place where patients die, may offer a glimpse to this socioeconomic problem. For example, those patients who are offered a timeous diagnosis and are prepared for palliative care will likely die at home or in hospice. What is the racial makeup of these patients and the ones that die in ERs and in hospital and other? Response: We thank the reviewer for their comment and positive appraisal of the manuscript. Access to healthcare is an important issue and can mediate outcomes. As requested, we have provided a supplementary table to compliment the main analyses by stratifying location of death by sex and race. Many of these numbers were small, especially for non-white and non-black populations, therefore, analysis by year could not be performed. Furthermore, due to availability of data and low numbers in the CDC WONDER database, analysis of percentage of deaths as a proportion of total number of deaths in the demographic were not able to be performed. We hope this adequately addresses the comment. Comment 2: I suggest less emphasis on riluzole and other "therapies" (3 month survival increase) and the possibility that the reduced mortality >2015 could be due to better clinics? (since none of the treatment trials have been positive excl SOD1 cases). Response: Thank you for your comment. The observed trends could be due several reasons. One of which could be due to better patient follow up in clinics via a multidisciplinary approach. In particular this improves better patient care in clinics. Therefore, this has been noted in our study. Additionally, we believe it is also important to highlight the potential impact newly approved medical treatments that could aid with the quality of life of patients with MND. Comment 3: Also, why did the deaths in Blacks and other races double after 2010 compared to <2010? increased awareness of ALS? Response: Thank you for your comment. It is clear that there are disparities in the race of the patient and the clinical outcomes. The overall deaths of patients of non-white ethnicities increase after 2010. This could be due to better awareness of ALS presentation differing between the various races. Therefore the onset of diagnosis itself may be delayed, leading to worse outcomes. We have included this in the manuscript. Under 'Discussion' section: “Furthermore, the overall deaths of patients of non-white patients increase after 2010. This could be due to inadequate awareness of MND and its presentation in non-white groups. Therefore the time to diagnosis may be delayed, leading to worse outcomes if the disease is in a more advanced state.” Under 'Discussion' section: “Additionally, it is important to note that a multidisciplinary clinic approach also improves survival rate in ALS. One particular study in Ireland and northern Ireland showed that there was a survival benefit for patients who attended ALS clinics due to better community based care.” COMMENTS ON THIS REPORT - Author Response 26 Aug 2025Balamrit Singh Sokhal, Keele University School of Medicine, Keele, UK26 Aug 2025Author ResponseReviewer's Comments (1) Comment 1: This audit of the CDC database for mortality stats in the US related to ALS has a main objective to determine where the ... Continue reading Reviewer's Comments (1) Comment 1: This audit of the CDC database for mortality stats in the US related to ALS has a main objective to determine where the gaps in health services are for patients with ALS. The report is well written. The conclusion of the work that ALS mortality is higher in older white males is somewhat circular since the authors acknowledge that there are many limitations to access of other races to healthcare. The main limitation being that a patient with poor access to health services may not receive a diagnosis of ALS and therefore will never be recorded as dying from ALS. This would be the very group which would need better services. To this end I feel the obvious gap in the work is that the granularity of the place where patients die, may offer a glimpse to this socioeconomic problem. For example, those patients who are offered a timeous diagnosis and are prepared for palliative care will likely die at home or in hospice. What is the racial makeup of these patients and the ones that die in ERs and in hospital and other? Response: We thank the reviewer for their comment and positive appraisal of the manuscript. Access to healthcare is an important issue and can mediate outcomes. As requested, we have provided a supplementary table to compliment the main analyses by stratifying location of death by sex and race. Many of these numbers were small, especially for non-white and non-black populations, therefore, analysis by year could not be performed. Furthermore, due to availability of data and low numbers in the CDC WONDER database, analysis of percentage of deaths as a proportion of total number of deaths in the demographic were not able to be performed. We hope this adequately addresses the comment. Comment 2: I suggest less emphasis on riluzole and other "therapies" (3 month survival increase) and the possibility that the reduced mortality >2015 could be due to better clinics? (since none of the treatment trials have been positive excl SOD1 cases). Response: Thank you for your comment. The observed trends could be due several reasons. One of which could be due to better patient follow up in clinics via a multidisciplinary approach. In particular this improves better patient care in clinics. Therefore, this has been noted in our study. Additionally, we believe it is also important to highlight the potential impact newly approved medical treatments that could aid with the quality of life of patients with MND. Comment 3: Also, why did the deaths in Blacks and other races double after 2010 compared to <2010? increased awareness of ALS? Response: Thank you for your comment. It is clear that there are disparities in the race of the patient and the clinical outcomes. The overall deaths of patients of non-white ethnicities increase after 2010. This could be due to better awareness of ALS presentation differing between the various races. Therefore the onset of diagnosis itself may be delayed, leading to worse outcomes. We have included this in the manuscript. Under 'Discussion' section: “Furthermore, the overall deaths of patients of non-white patients increase after 2010. This could be due to inadequate awareness of MND and its presentation in non-white groups. Therefore the time to diagnosis may be delayed, leading to worse outcomes if the disease is in a more advanced state.” Under 'Discussion' section: “Additionally, it is important to note that a multidisciplinary clinic approach also improves survival rate in ALS. One particular study in Ireland and northern Ireland showed that there was a survival benefit for patients who attended ALS clinics due to better community based care.”Reviewer's Comments (1)Competing Interests: No competing interests were disclosed. Close Comment 1: This audit of the CDC database for mortality stats in the US related to ALS has a main objective to determine where the gaps in health services are for patients with ALS. The report is well written. The conclusion of the work that ALS mortality is higher in older white males is somewhat circular since the authors acknowledge that there are many limitations to access of other races to healthcare. The main limitation being that a patient with poor access to health services may not receive a diagnosis of ALS and therefore will never be recorded as dying from ALS. This would be the very group which would need better services. To this end I feel the obvious gap in the work is that the granularity of the place where patients die, may offer a glimpse to this socioeconomic problem. For example, those patients who are offered a timeous diagnosis and are prepared for palliative care will likely die at home or in hospice. What is the racial makeup of these patients and the ones that die in ERs and in hospital and other? Response: We thank the reviewer for their comment and positive appraisal of the manuscript. Access to healthcare is an important issue and can mediate outcomes. As requested, we have provided a supplementary table to compliment the main analyses by stratifying location of death by sex and race. Many of these numbers were small, especially for non-white and non-black populations, therefore, analysis by year could not be performed. Furthermore, due to availability of data and low numbers in the CDC WONDER database, analysis of percentage of deaths as a proportion of total number of deaths in the demographic were not able to be performed. We hope this adequately addresses the comment. Comment 2: I suggest less emphasis on riluzole and other "therapies" (3 month survival increase) and the possibility that the reduced mortality >2015 could be due to better clinics? (since none of the treatment trials have been positive excl SOD1 cases). Response: Thank you for your comment. The observed trends could be due several reasons. One of which could be due to better patient follow up in clinics via a multidisciplinary approach. In particular this improves better patient care in clinics. Therefore, this has been noted in our study. Additionally, we believe it is also important to highlight the potential impact newly approved medical treatments that could aid with the quality of life of patients with MND. Comment 3: Also, why did the deaths in Blacks and other races double after 2010 compared to <2010? increased awareness of ALS? Response: Thank you for your comment. It is clear that there are disparities in the race of the patient and the clinical outcomes. The overall deaths of patients of non-white ethnicities increase after 2010. This could be due to better awareness of ALS presentation differing between the various races. Therefore the onset of diagnosis itself may be delayed, leading to worse outcomes. We have included this in the manuscript. Under 'Discussion' section: “Furthermore, the overall deaths of patients of non-white patients increase after 2010. This could be due to inadequate awareness of MND and its presentation in non-white groups. Therefore the time to diagnosis may be delayed, leading to worse outcomes if the disease is in a more advanced state.” Under 'Discussion' section: “Additionally, it is important to note that a multidisciplinary clinic approach also improves survival rate in ALS. One particular study in Ireland and northern Ireland showed that there was a survival benefit for patients who attended ALS clinics due to better community based care.” Alongside their report, reviewers assign a status to the article: - Approved - Approved with reservations - Not approved | Invited Reviewers | ||| |---|---|---|---| | 1 | 2 | 3 | | | Version 2 (revision) 26 Aug 25 | read | read | read | | Version 1 19 Dec 24 | 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. 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