Evaluation of Selective Survival and Sex/Gender Differences in Dementia Incidence Using a Simulation Model

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.

Figure 1.. Causal Scenarios Under Investigation

In all scenarios, sex/gender affected survival while U (selection characteristic) influenced level of cognitive function at age 50 years (the age at baseline in all simulations) and subsequent dementia incidence. In the no selective survival scenario (A), U had no effect on survival. In the homogeneous selective survival scenario (B), U affected survival for both men and women. In the heterogeneous selective survival scenario (C), U affected survival for men only (interaction effect between U and sex/gender). The red arrows in B and C highlight U’s effect on survival, which induces the selective survival process. Although it is unconventional to show interaction terms in directed acyclic graphs, the pseudo–directed acyclic graph in C explicitly shows the sex/gender-U interaction term for clarity.

Figure 2.. Mean Estimated Dementia Incidence Rate Ratio (IRR) for Women vs Men for Individuals Aged 80 Years and Older Across 1000 Simulated Cohorts for All Scenarios Compared With the Adult Changes in Thought Study

Data were acquired from the Adult Changes in Thought study as reported by Tom et al. The mean estimated IRR was calculated across 1000 simulated cohorts as e^{mean(log[estimated IRR women vs men])}. Homogeneous selective survival 1 and heterogeneous selective survival 1 indicate scenarios with moderate effect sizes for U; homogeneous selective survival 2 and heterogeneous selective survival 2 indicate scenarios with large effect sizes for U. Error bars indicate 95% CIs for each estimate; black line, estimated dementia IRR of 1.0 (ie, the null value).

Figure 3.. Box Plots of Selection Characteristic, U, by Age and Sex/Gender for All Simulation Scenarios

Distributions presented are for 1 cohort of 100 000 individuals. The vertical black line at 0.0 denotes the mean value of U at baseline (age 50 years). Homogeneous selective survival 1 and heterogeneous selective survival 1 indicate scenarios with moderate effect sizes for U; homogeneous selective survival 2 and heterogeneous selective survival 2 indicate scenarios with large effect sizes for U.