Rates, causes, place and predictors of mortality in adults with intellectual disabilities with and without Down syndrome: cohort study with record linkage

Sally-Ann Cooper; Linda Allan; Nicola Greenlaw; Paula McSkimming; Adam Jasilek; Angela Henderson; Colin McCowan; Deborah Kinnear; Craig Melville

doi:10.1136/bmjopen-2019-036465

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Rates, causes, place and predictors of mortality in adults with intellectual disabilities with and without Down syndrome: cohort study with record linkage

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Rates, causes, place and predictors of mortality in adults with intellectual disabilities with and without Down syndrome: cohort study with record linkage
Sally-Ann Cooper, Linda Allan, Nicola Greenlaw, Paula McSkimming, Adam Jasilek, Angela Henderson, Colin McCowan, Deborah Kinnear and Craig Melville
Published on: 3 June 2020
RE: Rates, causes, place and predictors of mortality in adults with intellectual disabilities with and without Down syndrome
Tomoyuki Kawada
Published on: 21 May 2020

Published on: 3 June 2020
Rates, causes, place and predictors of mortality in adults with intellectual disabilities with and without Down syndrome: cohort study with record linkage
- Sally-Ann Cooper, Professor of Learning Disabilities Institute of Health and Wellbeing, University of Glagow
- Other Contributors:
  Linda Allan, Clinical Associate Professor - Learning Disabilities
  
  Nicola Greenlaw, Consultant Biostatistician
  
  Paula McSkimming, Trainee Biostatistician
  
  Adam Jasilek, Trainee Biostatistician
  
  Angela Henderson, Deputy Director - Scottish Learning Disabilities Observatory
  
  Colin McCowan, Professor in Health Data Science
  
  Deborah Kinnear, Senior Lecturer of Intellectual Disabilities
  
  Craig Melville, Professor of Intellectual Disabilities Psychiatry
We thank Professor Kawada for his interest in our study.(1) We agree that the three recent papers he quotes are interesting studies that make important contributions. We do not agree with his expression of concerns about our study as they seem to reflect an assumption that different reporting to the papers he quoted were the concerns; these studies are not comparable to ours.

Oppewal et al. studied only elderly people,(2) whilst our study was of adults aged 16 years and over; their study included people using three care providers, whilst ours was population based. Oppewal et al. gathered cause of death information from medical case-files, and acknowledged, amongst other limitations, that information on cause of death in these files was sometimes limited which was beyond their control. Indeed they reported immediate and primary (underlying) cause of death, but not contributing causes of death, raising the question of whether it was possible for them to distinguish underlying and contributing causes of death from the case-files. We found the most common underlying causes of death for the adults with Down syndrome were dementia (35.1%), then other infection (12.3%); but when considering all contributing causes of death (not just the underlying cause), we found the most common after Down syndrome to be dementia (42.1%), and respiratory infection (38.6%) (reported in our table 5).

In a study published in the same month as ours, De Campos Gomes et al. reported hig...
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We thank Professor Kawada for his interest in our study.(1) We agree that the three recent papers he quotes are interesting studies that make important contributions. We do not agree with his expression of concerns about our study as they seem to reflect an assumption that different reporting to the papers he quoted were the concerns; these studies are not comparable to ours.

Oppewal et al. studied only elderly people,(2) whilst our study was of adults aged 16 years and over; their study included people using three care providers, whilst ours was population based. Oppewal et al. gathered cause of death information from medical case-files, and acknowledged, amongst other limitations, that information on cause of death in these files was sometimes limited which was beyond their control. Indeed they reported immediate and primary (underlying) cause of death, but not contributing causes of death, raising the question of whether it was possible for them to distinguish underlying and contributing causes of death from the case-files. We found the most common underlying causes of death for the adults with Down syndrome were dementia (35.1%), then other infection (12.3%); but when considering all contributing causes of death (not just the underlying cause), we found the most common after Down syndrome to be dementia (42.1%), and respiratory infection (38.6%) (reported in our table 5).

In a study published in the same month as ours, De Campos Gomes et al. reported higher mortality in some regions of Brazil than others, in indigenous women, in people with no years of schooling, and that in some regions mortality was related to years of schooling.(3) They attributed these findings to regional differences in access to and quality of health services. We did not study these factors as our study was located in Scotland, and schooling is universal for all in Scotland to age 16 years. These are between-country differences.

For ethical reasons, statistical disclosure controls precluded us reporting types of congenital heart malformations, as <5 of the adults with Down syndrome had congenital heart malformations identified amongst the all contributory causes of death (reported in our table 5). Results of course are different for children; in a Scotland-wide study our group published earlier this year, we reported that between 1990-2015 there were 1,235 live births with Down syndrome, of whom 92 (7.4%) had died (18.5 times more than age-sex-neighbourhood deprivation matched controls), and for 33 (34.4%) this was from congenital heart malformations.(4) This was particularly so in the first month and first year of life.

The study by Hithersay et al. is important, as the high rate of dementia in people with Down syndrome has been known for several decades. They focused on how dementia status influences mortality in older adults with Down syndrome, rather than causes of death in all adults with intellectual disabilities with, and without, Down syndrome.(5) They did not report underlying and contributory causes of death as that was not their aim. Our study is not therefore comparable with theirs. Their secondary aim was to investigate factors that influenced age at death separately for those with, and those without, dementia (unlike our methods). In their multivariable models, they reported that only late-onset epilepsy was associated with mortality in the older adults without dementia, and only APOE genotype was associated in the older adults with dementia (Professor Kawada quoted from the univariate analyses).

These studies are on different populations, and have different aims, and so different results. None of these studies investigated standardised mortality rates, nor causes of death in adults of all ages with intellectual disabilities, with and without Down syndrome, nor avoidable deaths. We hope our reply has allayed the correspondent’s concerns.

References
1. Cooper S-A, Allan L, Greenlaw N, et al. Rates, causes, place and predictors of mortality in adults with intellectual disabilities with and without Down syndrome: cohort study with record linkage. BMJ Open 2020;10(5):e036465 doi:10.1136/bmjopen-2019-036465
2. Oppewal A, Schoufour JD, van der Maarl HJK, et al. Causes of mortality in older people with intellectual disability: results fromt eh HA-ID study. Am J Intellect Dev Disabil 2018;123(1):61-71. doi:10.1352/1944-7558-123.1.61
3. De Campos Gomes F, de Melo-Neto JS, Goloni-Bertollo EM, et al. Trends and predictions for survival and mortality in individuals with Down syndrome in Brazil: a 21-year analysis. J Intellectl Disabil Res 2020 May 7. doi:10.1111/jir.12735
4. Hughes-McCormack LA, McGowan R, Pell JP, et al. Birth incidence, deaths and hospitalisations of children and young people with Down syndrome, 1990–2015: birth cohort study. BMJ Open 2020;10:e033770. doi:10.1136/ bmjopen-2019-033770
5. Hithersay R, Startin CM, Hamburg S, Association of dementia with mortality among adults with Down syndrome older than 25 years. JAMA Neurol. 2019;76(2):152-160. doi:10.1001/jamaneurol.2018.3616
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Conflict of Interest:
None declared.
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Published on: 21 May 2020
RE: Rates, causes, place and predictors of mortality in adults with intellectual disabilities with and without Down syndrome
- Tomoyuki Kawada, Professor Nippon Medical School
Cooper et al. investigated clinical predictors of mortality in adults with intellectual disabilities (1). Standardized mortality ratios (SMRs) (95% confidence interval [CI]) in Down syndrome adults and adults without Down syndrome were 5.28 (3.98, 6.57) and 1.93 (1.68, 2.18), respectively. In addition, SMRs in males and females were 1.69 (1.42, 1.95) and 3.48 (2.90, 4.06), respectively. Aspiration/reflux/choking and respiratory infection were the most common causes of mortality in adults without Down syndrome, and dementia was the most common causes of mortality in Down syndrome adults. Mortality risk related to percutaneous endoscopic gastrostomy/tube fed, Down syndrome, diabetes, lower respiratory tract infection at cohort-entry, smoking, epilepsy, hearing impairment, increasing number of prescribed drugs, increasing age were related to mortality in adults with intellectual disabilities. I have some concerns about their study.

First, Oppewal et al. also reported the cause-specific mortality of older Down syndrome adults with intellectual disability (2). The common cause of mortality was respiratory disease (51.1%), followed by dementia (22.2%), and this information was not consistent with data by Cooper et al. Methodological difference of survey, including definition, might contribute to the statistical information.

Second, de Campos Gomes et al. analyzed mortality and related factors in individuals with Down syndrome in Brazil (3). They concluded that ethn...
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Cooper et al. investigated clinical predictors of mortality in adults with intellectual disabilities (1). Standardized mortality ratios (SMRs) (95% confidence interval [CI]) in Down syndrome adults and adults without Down syndrome were 5.28 (3.98, 6.57) and 1.93 (1.68, 2.18), respectively. In addition, SMRs in males and females were 1.69 (1.42, 1.95) and 3.48 (2.90, 4.06), respectively. Aspiration/reflux/choking and respiratory infection were the most common causes of mortality in adults without Down syndrome, and dementia was the most common causes of mortality in Down syndrome adults. Mortality risk related to percutaneous endoscopic gastrostomy/tube fed, Down syndrome, diabetes, lower respiratory tract infection at cohort-entry, smoking, epilepsy, hearing impairment, increasing number of prescribed drugs, increasing age were related to mortality in adults with intellectual disabilities. I have some concerns about their study.

First, Oppewal et al. also reported the cause-specific mortality of older Down syndrome adults with intellectual disability (2). The common cause of mortality was respiratory disease (51.1%), followed by dementia (22.2%), and this information was not consistent with data by Cooper et al. Methodological difference of survey, including definition, might contribute to the statistical information.

Second, de Campos Gomes et al. analyzed mortality and related factors in individuals with Down syndrome in Brazil (3). They concluded that ethnic factors and years of schooling influenced mortality across the administrative regions. Different region has ethnic difference and different races, which would contribute to educational difference and medical service. These factors would relate each other, and contribute mortality in individuals with Down syndrome.

Regarding complication in Down syndrome, congenital heart defects (CHDs) should be classified to typical and atypical CHDs for mortality risk (4). Atypical CHDs include aortic coarctation and univentricular hearts, and survival rate at 10 and 40 years in patients with typical CHDs were 99% and 98%, which were significantly higher than those in patients with atypical CHDs, presenting 91% and 84%. Complication might contribute to prognosis in individuals of Down syndrome, which had been also recognized (1, 5).

Finally, Hithersay et al. examined factors associated with dementia in Down syndrome adults (6). Hazard ratio (HR) (95% CI) of APOE ε4 carriers for mortality in Down syndrome adults with dementia was 6.91 (1.756, 27.195). In addition, HR (95% CI) of epilepsy for mortality in Down syndrome adults without dementia was 9.66 (1.59, 58.56). Furthermore, HRs (95% CIs) of APOE ε4 carriers, adults with early-onset epilepsy, multiple health comorbidities, and those living with family for earlier dementia diagnoses were 4.91 (2.53, 9.56), 3.61 (1.12, 11.60), 1.956 (1.087, 3.519), and 2.14 (1.08, 4.20), respectively. Dementia was the most common causes of mortality in Down syndrome adults (1), and factors of earlier dementia diagnoses were specified.

References
1. BMJ Open. 2020;10(5):e036465. doi:10.1136/bmjopen-2019-036465
2. Am J Intellect Dev Disabil. 2018;123(1):61-71. doi:10.1352/1944-7558-123.1.61
3. J Intellect Disabil Res. 2020 May 7. doi:10.1111/jir.12735
4. Am J Med Genet A. 2020 Apr 22. doi:10.1002/ajmg.a.61586
5. J Appl Res Intellect Disabil. 2020;33(3):420-429. doi:10.1111/jar.12684
6. JAMA Neurol. 2019;76(2):152-160. doi:10.1001/jamaneurol.2018.3616
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Conflict of Interest:
None declared.
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