LDL-dementia simulations

Author

Gibran Hemani

Published

February 14, 2025

Background

Higher LDL increases risk of vascular dementia, has a very modest effect on Alzheimer’s disease, but its largest influence is on uncategorised dementia. This association is even larger than its association with Ischaemic heart disease.

Hypothesis that the association with uncategorised dementia is due to mortality bias. People with high LDL die earlier from IHD, so they don’t live long enough to get diagnosed with vascular dementia. People with lower LDL live longer but don’t get diagnosed with vascular dementia because the LDL level isn’t high enough

Simulation setup

  • Simulations to evaluate if mortality bias would attenuate the influence of LDL on vascular dementia
  • LDL is genetically influenced
  • LDL influences IHD
  • IHD influences death
  • LDL influences vascular dementia
  • vascular dementia happens later in life
  • People with the highest LDL get diagnosed with vascular dementia
  • Everyone else with vascular dementia gets diagnosed with unknown dementia
library(dplyr)

Attaching package: 'dplyr'
The following objects are masked from 'package:stats':

    filter, lag
The following objects are masked from 'package:base':

    intersect, setdiff, setequal, union
n <- 1000000
b_g_ldl <- 0.5
b_age_ihd <- 0.1
b_ldl_ihd <- 0.2
b_ldl_vd <- 0.3
b_age_death <- 0.2
b_ihd_death <- 1.5
b_age_vd <- 0.1

age <- rnorm(n)
g <- rbinom(n, 2, 0.4)
ldl <- g * b_g_ldl + rnorm(n, 0, 1)
ihd_liability <- age * b_age_ihd + ldl * b_ldl_ihd + rnorm(n, 0, 1)
ihd <- rbinom(n, 1, plogis(ihd_liability))
death_liability <- age * b_age_death + ihd * b_ihd_death + rnorm(n, 0, 1)
death <- rbinom(n, 1, plogis(death_liability))
vd_liability <- age * b_age_vd + ldl * b_ldl_vd + rnorm(n, 0, 1)
vd <- rbinom(n, 1, plogis(vd_liability))
mean_ldl_vd <- mean(ldl[vd == 1])
vd_diagnosed <- ldl > mean_ldl_vd & vd == 1
vd_diagnosed[vd == 1 & ldl <= mean_ldl_vd] <- NA
table(vd_diagnosed)
vd_diagnosed
 FALSE   TRUE 
474742 262284 
table(vd)
vd
     0      1 
474742 525258 
unknown_diagnosed <- vd_diagnosed
unknown_diagnosed[vd_diagnosed == 1] <- NA
unknown_diagnosed[is.na(vd_diagnosed)] <- 1

dat <- tibble(age, ldl, ihd, death, vd, g, vd_diagnosed, unknown_diagnosed)

table(dat$death)

     0      1 
357615 642385 
table(dat$vd_diagnosed)

 FALSE   TRUE 
474742 262284 
table(dat$unknown_diagnosed)

     0      1 
474742 262974 
table(dat$vd)

     0      1 
474742 525258 
library(ivreg)


summary(ivreg(ihd ~ ldl | g, data = dat))

Call:
ivreg(formula = ihd ~ ldl | g, data = dat)

Residuals:
    Min      1Q  Median      3Q     Max 
-0.7223 -0.5110  0.4048  0.4820  0.6625 

Coefficients:
             Estimate Std. Error t value Pr(>|t|)    
(Intercept) 0.5009955  0.0007576  661.29   <2e-16 ***
ldl         0.0385066  0.0014332   26.87   <2e-16 ***

Diagnostic tests:
                   df1   df2 statistic p-value    
Weak instruments 1e+00 1e+06 1.205e+05  <2e-16 ***
Wu-Hausman       1e+00 1e+06 2.083e+00   0.149    
Sargan           0e+00    NA        NA      NA    
---
Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1

Residual standard error: 0.4979 on 999998 degrees of freedom
Multiple R-Squared: 0.007339,   Adjusted R-squared: 0.007338 
Wald test: 721.8 on 1 and 999998 DF,  p-value: < 2.2e-16 
summary(ivreg(death ~ ldl | g, data = dat))

Call:
ivreg(formula = death ~ ldl | g, data = dat)

Residuals:
    Min      1Q  Median      3Q     Max 
-0.7011 -0.6359  0.3485  0.3607  0.4160 

Coefficients:
             Estimate Std. Error t value Pr(>|t|)    
(Intercept) 0.6380094  0.0007291 875.104  < 2e-16 ***
ldl         0.0109827  0.0013792   7.963 1.68e-15 ***

Diagnostic tests:
                   df1   df2 statistic p-value    
Weak instruments 1e+00 1e+06 1.205e+05  <2e-16 ***
Wu-Hausman       1e+00 1e+06 1.270e-01   0.721    
Sargan           0e+00    NA        NA      NA    
---
Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1

Residual standard error: 0.4791 on 999998 degrees of freedom
Multiple R-Squared: 0.0006391,  Adjusted R-squared: 0.0006381 
Wald test: 63.41 on 1 and 999998 DF,  p-value: 1.683e-15 
summary(ivreg(vd ~ ldl | g, data = dat))

Call:
ivreg(formula = vd ~ ldl | g, data = dat)

Residuals:
    Min      1Q  Median      3Q     Max 
-0.8361 -0.5120  0.3585  0.4708  0.7639 

Coefficients:
             Estimate Std. Error t value Pr(>|t|)    
(Intercept) 0.5006012  0.0007536  664.31   <2e-16 ***
ldl         0.0618878  0.0014256   43.41   <2e-16 ***

Diagnostic tests:
                   df1   df2 statistic p-value    
Weak instruments 1e+00 1e+06 1.205e+05  <2e-16 ***
Wu-Hausman       1e+00 1e+06 1.186e+00   0.276    
Sargan           0e+00    NA        NA      NA    
---
Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1

Residual standard error: 0.4952 on 999998 degrees of freedom
Multiple R-Squared: 0.01642,    Adjusted R-squared: 0.01642 
Wald test:  1885 on 1 and 999998 DF,  p-value: < 2.2e-16 
summary(ivreg(vd_diagnosed ~ ldl | g, data = dat))

Call:
ivreg(formula = vd_diagnosed ~ ldl | g, data = dat)

Residuals:
     Min       1Q   Median       3Q      Max 
-1.44993 -0.33306 -0.08287  0.42341  0.92120 

Coefficients:
            Estimate Std. Error t value Pr(>|t|)    
(Intercept) 0.206503   0.001020   202.4   <2e-16 ***
ldl         0.229349   0.001379   166.3   <2e-16 ***

Diagnostic tests:
                    df1    df2 statistic p-value    
Weak instruments      1 737024  89237.91 < 2e-16 ***
Wu-Hausman            1 737023     15.16 9.9e-05 ***
Sargan                0     NA        NA      NA    
---
Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1

Residual standard error: 0.4148 on 737024 degrees of freedom
Multiple R-Squared: 0.2492, Adjusted R-squared: 0.2492 
Wald test: 2.765e+04 on 1 and 737024 DF,  p-value: < 2.2e-16 
summary(ivreg(unknown_diagnosed ~ ldl | g, data = dat))

Call:
ivreg(formula = unknown_diagnosed ~ ldl | g, data = dat)

Residuals:
    Min      1Q  Median      3Q     Max 
-1.0940 -0.3711 -0.2081  0.5517  0.7138 

Coefficients:
              Estimate Std. Error t value Pr(>|t|)    
(Intercept)  0.3644671  0.0005445  669.32   <2e-16 ***
ldl         -0.1483687  0.0018707  -79.31   <2e-16 ***

Diagnostic tests:
                    df1    df2 statistic  p-value    
Weak instruments      1 737714  71584.97  < 2e-16 ***
Wu-Hausman            1 737713     20.41 6.24e-06 ***
Sargan                0     NA        NA       NA    
---
Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1

Residual standard error: 0.4596 on 737714 degrees of freedom
Multiple R-Squared: 0.07912,    Adjusted R-squared: 0.07912 
Wald test:  6291 on 1 and 737714 DF,  p-value: < 2.2e-16 
summary(ivreg(vd_diagnosed ~ ldl | g, data = dat %>% subset(death != 1)))

Call:
ivreg(formula = vd_diagnosed ~ ldl | g, data = dat %>% subset(death != 
    1))

Residuals:
    Min      1Q  Median      3Q     Max 
-1.3291 -0.3276 -0.0848  0.4186  0.8088 

Coefficients:
            Estimate Std. Error t value Pr(>|t|)    
(Intercept) 0.206043   0.001613   127.7   <2e-16 ***
ldl         0.228060   0.002278   100.1   <2e-16 ***

Diagnostic tests:
                    df1    df2 statistic p-value    
Weak instruments      1 261600 31766.914  <2e-16 ***
Wu-Hausman            1 261599     3.263  0.0709 .  
Sargan                0     NA        NA      NA    
---
Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1

Residual standard error: 0.4107 on 261600 degrees of freedom
Multiple R-Squared: 0.2548, Adjusted R-squared: 0.2548 
Wald test: 1.003e+04 on 1 and 261600 DF,  p-value: < 2.2e-16 
summary(ivreg(unknown_diagnosed ~ ldl | g, data = dat %>% subset(death != 1)))

Call:
ivreg(formula = unknown_diagnosed ~ ldl | g, data = dat %>% subset(death != 
    1))

Residuals:
    Min      1Q  Median      3Q     Max 
-1.0323 -0.3744 -0.2083  0.5509  0.7160 

Coefficients:
              Estimate Std. Error t value Pr(>|t|)    
(Intercept)  0.3632821  0.0008972  404.92   <2e-16 ***
ldl         -0.1503424  0.0031415  -47.86   <2e-16 ***

Diagnostic tests:
                    df1    df2 statistic  p-value    
Weak instruments      1 267055  25804.97  < 2e-16 ***
Wu-Hausman            1 267054     21.08 4.41e-06 ***
Sargan                0     NA        NA       NA    
---
Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1

Residual standard error: 0.4619 on 267055 degrees of freedom
Multiple R-Squared: 0.07365,    Adjusted R-squared: 0.07364 
Wald test:  2290 on 1 and 267055 DF,  p-value: < 2.2e-16 
sessionInfo()
R version 4.4.3 (2025-02-28)
Platform: aarch64-apple-darwin20
Running under: macOS Sonoma 14.6.1

Matrix products: default
BLAS:   /Library/Frameworks/R.framework/Versions/4.4-arm64/Resources/lib/libRblas.0.dylib 
LAPACK: /Library/Frameworks/R.framework/Versions/4.4-arm64/Resources/lib/libRlapack.dylib;  LAPACK version 3.12.0

locale:
[1] en_US.UTF-8/en_US.UTF-8/en_US.UTF-8/C/en_US.UTF-8/en_US.UTF-8

time zone: Europe/London
tzcode source: internal

attached base packages:
[1] stats     graphics  grDevices utils     datasets  methods   base     

other attached packages:
[1] ivreg_0.6-5 dplyr_1.1.4

loaded via a namespace (and not attached):
 [1] vctrs_0.6.5       cli_3.6.3         knitr_1.48        rlang_1.1.4      
 [5] xfun_0.48         Formula_1.2-5     car_3.1-3         generics_0.1.3   
 [9] jsonlite_1.8.9    zoo_1.8-12        glue_1.8.0        htmltools_0.5.8.1
[13] lmtest_0.9-40     fansi_1.0.6       rmarkdown_2.27    grid_4.4.3       
[17] abind_1.4-8       carData_3.0-5     evaluate_1.0.1    tibble_3.2.1     
[21] MASS_7.3-64       fastmap_1.2.0     yaml_2.3.10       lifecycle_1.0.4  
[25] compiler_4.4.3    htmlwidgets_1.6.4 pkgconfig_2.0.3   lattice_0.22-6   
[29] digest_0.6.37     R6_2.5.1          tidyselect_1.2.1  utf8_1.2.4       
[33] pillar_1.9.0      magrittr_2.0.3    tools_4.4.3