Introduction to Multivariable Functional Mendelian Randomization

Nicole Fontana

2026-07-14

Overview

This vignette introduces Multivariable Functional Mendelian Randomization (MV-FMR), a method to estimate time-varying causal effects of multiple correlated longitudinal exposures on health outcomes.

Key Features

When to Use MV-FMR

Use joint multivariable estimation (mvfmr()) when:

Installation

# Install from CRAN
install.packages("mvfmr")
library(mvfmr)
library(fdapace)
library(ggplot2)
#> Warning: package 'ggplot2' was built under R version 4.3.3

Example: Joint Estimation of Two Exposures

Step 1: Simulate Data

We generate genetic instruments and two longitudinal exposures:

set.seed(473920)

# Generate exposure data
sim_data <- getX_multi_exposure(
  N = 300,              # Sample size
  J = 25,               # Number of genetic instruments
  nSparse = 10,          # Observations per subject
  n_exposures = 2        # Number of exposures (m)
)

# Check dimensions
cat("Sample size:", nrow(sim_data$details$G), "\n")
#> Sample size: 300
cat("Number of instruments:", ncol(sim_data$details$G), "\n")
#> Number of instruments: 25

Step 2: Generate Outcome

We create an outcome with linear effect from exposure 1 and exposure 2:

outcome_data <- getY_multi_exposure(
  sim_data,
  XYmodels = c("2", "2"),     # Exposure 1/2: linear beta(t) = 0.02*t
  X_effects = c(TRUE, TRUE),
  outcome_type = "continuous"
)

cat("Outcome summary:\n")
#> Outcome summary:
summary(outcome_data$Y)
#>    Min. 1st Qu.  Median    Mean 3rd Qu.    Max. 
#> -236.50  -71.40  -26.03  -23.83   28.53  182.65

Step 3: Functional Principal Component Analysis

We apply FPCA to each exposure to extract principal components:

fpca_results <- lapply(sim_data$exposures, function(exp_k) {
  FPCA(
    exp_k$Ly_sim,
    exp_k$Lt_sim,
    list(dataType = 'Sparse', error = TRUE, verbose = FALSE)
  )
})

cat("FPCA completed:\n")
#> FPCA completed:
for (k in seq_along(fpca_results)) {
  cat("  Exposure", k, ":", fpca_results[[k]]$selectK, "components selected\n")
}
#>   Exposure 1 : 3 components selected
#>   Exposure 2 : 3 components selected

Step 4: Joint Multivariable Estimation

Now we perform joint estimation using mvfmr(). All exposure-related arguments (fpca_results, max_nPC, true_effects, X_true, …) are lists or vectors of length m, one entry per exposure:

result_joint <- mvfmr(
  G = sim_data$details$G,
  fpca_results = fpca_results,
  Y = outcome_data$Y,
  outcome_type = "continuous",
  method = "gmm",
  max_nPC = c(4, 4),
  improvement_threshold = 0.001,
  bootstrap = FALSE,
  n_cores = 1,
  true_effects = c("2", "2"),
  X_true = sim_data$details$X_list,
  verbose = FALSE
)

# View results
print(result_joint)
#> 
#> Functional Multivariable MR Result
#> ==================================
#> Exposures: 2 
#> Sample size: 300 
#> Outcome: continuous 
#> Method: gmm 
#> Components selected: nPC1 = 2, nPC2 = 2 
#> 
#> Performance Metrics:
#>   Exposure 1 - MISE: 0.002458 , Coverage: 1 
#>   Exposure 2 - MISE: 0.003881 , Coverage: 0.745

Step 5: Visualize Time-Varying Effects

The estimated time-varying causal effects can be visualized using the built-in plot method:

# Plot every exposure's effect
plot(result_joint)

The solid colored lines show the estimated time-varying causal effects, with shaded bands representing 95% confidence intervals. The dashed red lines (when present) indicate the true time-varying effects used in the simulation.

Step 6: Extract Coefficients

# Estimated beta coefficients for basis functions
coef(result_joint)
#> [1] -4.035692 -1.647212 -3.634343 -1.451868

# Time-varying effects at each time point (one entry per exposure)
head(result_joint$effects[[1]])
#> [1] 0.06182589 0.07321675 0.08677954 0.10220947 0.11906258 0.13675702
head(result_joint$effects[[2]])
#> [1] 0.02302308 0.02248962 0.02740122 0.03681268 0.04977623 0.06537926

Step 7: Performance Metrics

Since we simulated data with known truth, we can evaluate performance:

cat("Performance Metrics:\n")
#> Performance Metrics:
for (k in seq_along(result_joint$effects)) {
  cat("\nExposure", k, ":\n")
  cat("  MISE:", round(result_joint$performance$MISE[[k]], 6), "\n")
  cat("  Coverage:", round(result_joint$performance$Coverage[[k]], 3), "\n")
}
#> 
#> Exposure 1 :
#>   MISE: 0.002458 
#>   Coverage: 1 
#> 
#> Exposure 2 :
#>   MISE: 0.003881 
#>   Coverage: 0.745

Comparison: Joint vs. Separate Estimation

We can compare joint (multivariable) with separate (univariable) estimation. For mvfmr_separate(), instruments are passed as G_list, a list of length m (here the same shared instrument matrix is reused for both exposures):

result_separate <- mvfmr_separate(
  G_list = list(sim_data$details$G, sim_data$details$G),
  fpca_results = fpca_results,
  Y = outcome_data$Y,
  outcome_type = "continuous",
  method = "gmm",
  max_nPC = c(4, 4),
  n_cores = 1,
  true_effects = c("2", "2"),
  verbose = FALSE
)
#> [1] "Processing X1"
#> [1] "Processing X2"

print(result_separate)
#> 
#> Separate Univariable MR Results
#> ================================
#> Exposures: 2 
#> Separate instruments: TRUE 
#> Outcome: continuous 
#> Method: gmm 
#> 
#> Exposure 1 :
#>   Components: 2 
#>   MSE: 0.178885 
#>   Coverage: 0 
#> 
#> Exposure 2 :
#>   Components: 2 
#>   MSE: 0.252422 
#>   Coverage: 0.157

Performance Comparison

comparison <- data.frame(
  Method = rep(c("Joint (MV-FMR)", "Separate (U-FMR)"), each = 2),
  Exposure = rep(c("X1", "X2"), times = 2),
  MISE = c(
    result_joint$performance$MISE[[1]],
    result_joint$performance$MISE[[2]],
    result_separate$exposures[[1]]$performance$MISE,
    result_separate$exposures[[2]]$performance$MISE
  ),
  Coverage = c(
    result_joint$performance$Coverage[[1]],
    result_joint$performance$Coverage[[2]],
    result_separate$exposures[[1]]$performance$Coverage,
    result_separate$exposures[[2]]$performance$Coverage
  )
)

print(comparison)
#>             Method Exposure        MISE  Coverage
#> 1   Joint (MV-FMR)       X1 0.002458118 1.0000000
#> 2   Joint (MV-FMR)       X2 0.003881328 0.7450980
#> 3 Separate (U-FMR)       X1 0.178885369 0.0000000
#> 4 Separate (U-FMR)       X2 0.252422123 0.1568627

Instrument Strength Diagnostics

Check instrument strength using F-statistics. IS() is already generic in the number of exposures/components K:

# Calculate F-statistics
K_total <- sum(result_joint$nPC_used)

PC_stacked <- do.call(cbind, lapply(seq_along(fpca_results), function(k) {
  fpca_results[[k]]$xiEst[, 1:result_joint$nPC_used[k]]
}))

fstats <- IS(
  J = ncol(sim_data$details$G),
  K = K_total,
  PC = 1:K_total,
  datafull = cbind(sim_data$details$G, PC_stacked),
  Y = outcome_data$Y
)

fstats_df <- cbind(
  "Exposure" = unlist(lapply(seq_along(result_joint$nPC_used), function(k) {
    rep(paste0("X", k), result_joint$nPC_used[k])
  })),
  as.data.frame(fstats)
)

print(fstats_df[, c("Exposure", "PC", "cFF")])
#>   Exposure PC       cFF
#> 1       X1  1 0.3913644
#> 2       X1  2 1.1379411
#> 3       X2  3 0.3986037
#> 4       X2  4 0.9953631

Rule of thumb: cFF > 10 indicates strong instruments.

Binary Outcomes

MV-FMR also supports binary outcomes using the control function approach:

# Generate binary outcome
outcome_binary <- getY_multi_exposure(
  sim_data,
  XYmodels = c("2", "2"),
  outcome_type = "binary"
)

# Estimate with control function
result_binary <- mvfmr(
  G = sim_data$details$G,
  fpca_results = fpca_results,
  Y = outcome_binary$Y,
  outcome_type = "binary",
  method = "cf",  # Control function for binary
  max_nPC = c(3, 3),
  n_cores = 1,
  verbose = FALSE
)

print(result_binary)

Extending to More Than Two Exposures

Nothing changes in the API when moving from 2 to m exposures: fpca_results, max_nPC, true_effects and X_true simply grow to length m.

set.seed(163918)#281046
sim_data3 <- getX_multi_exposure(N = 500, J = 50, nSparse = 10, n_exposures = 3)

outcome_data3 <- getY_multi_exposure(
  sim_data3,
  XYmodels = c("2", "2", "2"),
  outcome_type = "continuous"
)

fpca_results3 <- lapply(sim_data3$exposures, function(exp_k) {
  FPCA(exp_k$Ly_sim, exp_k$Lt_sim, list(dataType = 'Sparse', error = TRUE, verbose = FALSE))
})

result_joint3 <- mvfmr(
  G = sim_data3$details$G,
  fpca_results = fpca_results3,
  Y = outcome_data3$Y,
  outcome_type = "continuous",
  method = "gmm",
  max_nPC = c(4, 4, 4),
  n_cores = 1,
  true_effects = c("2", "2", "2"),
  X_true = sim_data3$details$X_list,
  verbose = FALSE
)

print(result_joint3)
#> 
#> Functional Multivariable MR Result
#> ==================================
#> Exposures: 3 
#> Sample size: 500 
#> Outcome: continuous 
#> Method: gmm 
#> Components selected: nPC1 = 2, nPC2 = 2, nPC3 = 2 
#> 
#> Performance Metrics:
#>   Exposure 1 - MISE: 0.001228 , Coverage: 1 
#>   Exposure 2 - MISE: 0.004026 , Coverage: 0.706 
#>   Exposure 3 - MISE: 0.006513 , Coverage: 0.588
plot(result_joint3)

Next Steps

Learn More

Citation

If you use this package, please cite:

Fontana, N., Ieva, F., Zuccolo, L., Di Angelantonio, E., & Secchi, P. (2025). Unraveling time-varying causal effects of multiple exposures: integrating Functional Data Analysis with Multivariable Mendelian Randomization. arXiv preprint arXiv:2512.19064.

Session Info

sessionInfo()
#> R version 4.3.0 (2023-04-21)
#> Platform: aarch64-apple-darwin20 (64-bit)
#> Running under: macOS Ventura 13.6
#> 
#> Matrix products: default
#> BLAS:   /Library/Frameworks/R.framework/Versions/4.3-arm64/Resources/lib/libRblas.0.dylib 
#> LAPACK: /Library/Frameworks/R.framework/Versions/4.3-arm64/Resources/lib/libRlapack.dylib;  LAPACK version 3.11.0
#> 
#> locale:
#> [1] C/en_US.UTF-8/en_US.UTF-8/C/en_US.UTF-8/en_US.UTF-8
#> 
#> time zone: Europe/Rome
#> tzcode source: internal
#> 
#> attached base packages:
#> [1] stats     graphics  grDevices utils     datasets  methods   base     
#> 
#> other attached packages:
#> [1] ggplot2_3.5.2 fdapace_0.5.9 mvfmr_0.2.0  
#> 
#> loaded via a namespace (and not attached):
#>  [1] gtable_0.3.6        shape_1.4.6         xfun_0.41          
#>  [4] bslib_0.6.1         htmlwidgets_1.6.4   lattice_0.21-8     
#>  [7] numDeriv_2016.8-1.1 vctrs_0.6.5         tools_4.3.0        
#> [10] generics_0.1.3      parallel_4.3.0      tibble_3.2.1       
#> [13] fansi_1.0.6         highr_0.10          cluster_2.1.4      
#> [16] pkgconfig_2.0.3     Matrix_1.6-4        data.table_1.14.10 
#> [19] checkmate_2.3.1     lifecycle_1.0.4     farver_2.1.1       
#> [22] compiler_4.3.0      stringr_1.5.1       progress_1.2.3     
#> [25] munsell_0.5.0       codetools_0.2-19    htmltools_0.5.7    
#> [28] sass_0.4.8          yaml_2.3.8          glmnet_4.1-8       
#> [31] htmlTable_2.4.2     Formula_1.2-5       pracma_2.4.4       
#> [34] pillar_1.9.0        crayon_1.5.3        jquerylib_0.1.4    
#> [37] MASS_7.3-58.4       cachem_1.0.8        Hmisc_5.1-1        
#> [40] iterators_1.0.14    rpart_4.1.19        foreach_1.5.2      
#> [43] tidyselect_1.2.0    digest_0.6.33       stringi_1.8.3      
#> [46] dplyr_1.1.4         labeling_0.4.3      splines_4.3.0      
#> [49] fastmap_1.1.1       grid_4.3.0          colorspace_2.1-0   
#> [52] cli_3.6.2           magrittr_2.0.3      base64enc_0.1-3    
#> [55] survival_3.5-7      utf8_1.2.4          withr_2.5.2        
#> [58] foreign_0.8-84      prettyunits_1.2.0   scales_1.3.0       
#> [61] backports_1.5.0     rmarkdown_2.25      nnet_7.3-18        
#> [64] gridExtra_2.3       hms_1.1.3           evaluate_0.23      
#> [67] knitr_1.45          doParallel_1.0.17   rlang_1.1.6        
#> [70] Rcpp_1.1.0          glue_1.6.2          pROC_1.18.5        
#> [73] rstudioapi_0.15.0   jsonlite_1.8.8      R6_2.5.1           
#> [76] plyr_1.8.9