Crystal Shaw1,2, Eleanor Hayes-Larson1, M Maria Glymour3, Carole Dufouil4,5, Timothy J Hohman6,7, Rachel A Whitmer8,9, Lindsay C Kobayashi10, Ron Brookmeyer2, Elizabeth Rose Mayeda1. 1. Fielding School of Public Health, Department of Epidemiology, University of California, Los Angeles. 2. Fielding School of Public Health, Department of Biostatistics, University of California, Los Angeles. 3. Department of Epidemiology and Biostatistics, University of California, San Francisco. 4. Centre Inserm U1219, d'Epidémiologie et de Développement, Bordeaux School of Public Health, Institut de Santé Publique Université de Bordeaux, Bordeaux, France. 5. Pole de sante publique, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France. 6. Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, Tennessee. 7. Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee. 8. Alzheimer's Disease Research Center, University of California, Davis. 9. Department of Public Health Sciences, University of California, Davis. 10. Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor.
Abstract
Importance: Dementia research is susceptible to bias arising from selective survival, a process that results in individuals with certain characteristics disproportionately surviving to old age. Spurious associations between risk factors and dementia may be induced when factors associated with longer survival also influence dementia incidence. Objective: To assess the role of selective survival in explaining reported sex/gender differences in dementia incidence. Design, Setting, and Participants: This decision analytical model used a simulated cohort of US participants aged 50 years and without dementia at baseline followed up for incident dementia through age 95 years. Selective survival was induced by a selection characteristic (eg, childhood social disadvantage or Alzheimer genetic risk) that influenced both mortality and dementia incidence at varying magnitudes. Data analysis was performed from April 2018 to May 2020. Exposure: Sex/gender, conceptualized as the combination of biological sex and social consequences of gender. Main Outcomes and Measures: Dementia incidence rate ratios (IRRs) for women compared with men. In all simulations, it was assumed that there would be no true effect of sex/gender on dementia incidence; all observed sex/gender differences were due to selective survival. Results: At baseline, the simulation included 100 000 participants aged 50 years (51 000 [51%] women, mirroring the 1919-1921 US birth cohort of non-Latino White individuals at age 50 years); distributions of the selection characteristic were standard normal (mean [SD], 0.0 [1.0]). Observed sex/gender differences in dementia incidence in individuals aged 85 years or older ranged from insignificant (IRR, 1.00; 95% CI, 0.91-1.11) to consistent with sex/gender differences (20% higher risk for women [IRR, 1.20; 95% CI, 1.08-1.32]) reported in an extant study. Simulations in which bias was large enough to explain prior findings required moderate to large differential effects of selective survival (eg, hazard ratio for selection characteristic on mortality at least 2.0 among men, no effect among women). Conclusions and Relevance: These results suggest that selective survival may contribute to observed sex/gender differences in dementia incidence but do not preclude potential contributions of sex/gender-specific mechanisms. Further research on plausibility of selection characteristics with outcomes of the magnitude required for selective survival to explain sex/gender differences in dementia incidence and sex/gender-specific mechanisms represent an opportunity to understand prevention and treatment of dementia.
Importance: Dementia research is susceptible to bias arising from selective survival, a process that results in individuals with certain characteristics disproportionately surviving to old age. Spurious associations between risk factors and dementia may be induced when factors associated with longer survival also influence dementia incidence. Objective: To assess the role of selective survival in explaining reported sex/gender differences in dementia incidence. Design, Setting, and Participants: This decision analytical model used a simulated cohort of US participants aged 50 years and without dementia at baseline followed up for incident dementia through age 95 years. Selective survival was induced by a selection characteristic (eg, childhood social disadvantage or Alzheimer genetic risk) that influenced both mortality and dementia incidence at varying magnitudes. Data analysis was performed from April 2018 to May 2020. Exposure: Sex/gender, conceptualized as the combination of biological sex and social consequences of gender. Main Outcomes and Measures: Dementia incidence rate ratios (IRRs) for women compared with men. In all simulations, it was assumed that there would be no true effect of sex/gender on dementia incidence; all observed sex/gender differences were due to selective survival. Results: At baseline, the simulation included 100 000 participants aged 50 years (51 000 [51%] women, mirroring the 1919-1921 US birth cohort of non-Latino White individuals at age 50 years); distributions of the selection characteristic were standard normal (mean [SD], 0.0 [1.0]). Observed sex/gender differences in dementia incidence in individuals aged 85 years or older ranged from insignificant (IRR, 1.00; 95% CI, 0.91-1.11) to consistent with sex/gender differences (20% higher risk for women [IRR, 1.20; 95% CI, 1.08-1.32]) reported in an extant study. Simulations in which bias was large enough to explain prior findings required moderate to large differential effects of selective survival (eg, hazard ratio for selection characteristic on mortality at least 2.0 among men, no effect among women). Conclusions and Relevance: These results suggest that selective survival may contribute to observed sex/gender differences in dementia incidence but do not preclude potential contributions of sex/gender-specific mechanisms. Further research on plausibility of selection characteristics with outcomes of the magnitude required for selective survival to explain sex/gender differences in dementia incidence and sex/gender-specific mechanisms represent an opportunity to understand prevention and treatment of dementia.
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