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Load Packages

suppressPackageStartupMessages({

  # Data handling
  library(tidyverse)
  library(data.table)
  library(magrittr)
  library(janitor)
  library(here)
  library(scales)
  library(table1)
  library(tableone)
  library(flextable)
  library(gtsummary)
  library(openxlsx)
  library(writexl)
  library(readxl)
  # Visualization
  library(ggplot2)    
  library(ggpubr)
  library(ggrepel)
  library(ggbeeswarm)
  library(ggcorrplot)
  library(corrplot)
  library(pheatmap)
  library(ComplexHeatmap)
  library(circlize)
  library(RColorBrewer)
  library(EnhancedVolcano)
  library(plotly)
  library(patchwork)
  library(cowplot)
  library(gridExtra)
  library(grid)
  library(ggpattern)
  # Statistics
  library(rstatix)
  library(multcomp)
  library(car)
  library(Hmisc)
  library(MASS)       
  library(MuMIn)
  library(broom)
  library(glmnet)
  library(logistf)
  library(drc)
  library(caret)
  library(mice)
  library(pROC)
  # Clustering
  library(randomForest)
  library(factoextra)
  library(cluster)
  library(Rtsne)
  library(umap)
  library(dbscan)
  library(kernlab)
  library(Seurat)
  # Others
  library(ImmunoLogic)
  
})

Define Filepath

  basedir <- here()

Read Data (Healthy, Cohort 1, Cohort 2)

# Import BMP4 Data
  table_bmp4_healthy <- openxlsx::read.xlsx(file.path(basedir, "data", "Table_BMP4_Healthy.xlsx"))

  table_bmp4_cohort1 <- openxlsx::read.xlsx(file.path(basedir, "data", "Table_BMP4_Cohort1.xlsx")) 
  
  table_bmp4_cohort2 <- openxlsx::read.xlsx(file.path(basedir, "data", "Table_BMP4_Cohort2.xlsx"))
  
# Combine Tables
  table_bmp4_myo <- rbind(table_bmp4_cohort1, table_bmp4_cohort2)

# Import Serology Data
  table_clindat_healthy <- openxlsx::read.xlsx(file.path(basedir, "data", "Table_Serology_Healthy.xlsx")) %>%
                           dplyr::select(Study_ID, NTproBNP)
   
  table_clindat_cohort1 <- openxlsx::read.xlsx(file.path(basedir, "data", "Table_ClinicalData_Cohort1.xlsx")) %>%
                           dplyr::select(Study_ID, NTproBNP, LV_EF)

  table_clindat_cohort2 <- openxlsx::read.xlsx(file.path(basedir, "data", "Table_ClinicalData_Cohort2.xlsx")) %>%
                           dplyr::select(Study_ID, NTproBNP, LV_EF)
  
# Combine tables
  table_clindat_myo <- rbind(table_clindat_cohort1, table_clindat_cohort2)

# Import Luminex Data
  table_lum_healthy <- openxlsx::read.xlsx(file.path(basedir, "data", "Table_Lum_Healthy_DL_corr.xlsx")) %>%
                       dplyr::select(-Cohort)
   
  table_lum_cohort1 <- openxlsx::read.xlsx(file.path(basedir, "data", "Table_Lum_Cohort1_DL_corr.xlsx")) %>%
                       dplyr::select(-Cohort)
  
  table_lum_cohort2 <- openxlsx::read.xlsx(file.path(basedir, "data", "Table_Lum_Cohort2_DL_corr.xlsx")) %>%
                       dplyr::select(-Cohort)

# Combine tables
  table_lum_myo <- rbind(table_lum_cohort1, table_lum_cohort2)

# Combine tables
  table_all_myo <-    table_bmp4_myo %>%
                       left_join(table_lum_myo, by = "Study_ID") %>%
                       left_join(table_clindat_myo, by = "Study_ID")
  
  table_all_healthy <- table_bmp4_healthy %>%
                       left_join(table_lum_healthy, by = "Study_ID") %>%
                       left_join(table_clindat_healthy, by = "Study_ID")

Multiple Imputation AM Cohort (incl. LVEF)

# Impute missing values
  imputed_data <- mice(table_all_myo, m = 5, method = 'pmm', maxit = 5, seed = 1234)

 iter imp variable
  1   1  NTproBNP  LV_EF
  1   2  NTproBNP  LV_EF
  1   3  NTproBNP  LV_EF
  1   4  NTproBNP  LV_EF
  1   5  NTproBNP  LV_EF
  2   1  NTproBNP  LV_EF
  2   2  NTproBNP  LV_EF
  2   3  NTproBNP  LV_EF
  2   4  NTproBNP  LV_EF
  2   5  NTproBNP  LV_EF
  3   1  NTproBNP  LV_EF
  3   2  NTproBNP  LV_EF
  3   3  NTproBNP  LV_EF
  3   4  NTproBNP  LV_EF
  3   5  NTproBNP  LV_EF
  4   1  NTproBNP  LV_EF
  4   2  NTproBNP  LV_EF
  4   3  NTproBNP  LV_EF
  4   4  NTproBNP  LV_EF
  4   5  NTproBNP  LV_EF
  5   1  NTproBNP  LV_EF
  5   2  NTproBNP  LV_EF
  5   3  NTproBNP  LV_EF
  5   4  NTproBNP  LV_EF
  5   5  NTproBNP  LV_EF
# Check the imputed data
  densityplot(imputed_data, col=c("grey", "blue"), pch = c(1, 20))

# Create a data set with the observed and completed data
  table_all_myo_imp <- complete(imputed_data, 1)
  
# Combine all data tables
  table_all_myo_imp <-  table_all_myo_imp %>%
                        mutate(Cohort = "Myocarditis")

  table_all_healthy <- table_all_healthy %>%
                       mutate(Cohort = "Healthy")

  table_all_myo_healthy <- bind_rows(table_all_myo_imp %>% dplyr::select(-LV_EF),
                           table_all_healthy)

BMP4/Gremlin Axis in Myocarditis vs. Healthy

# Prepare data table 
   table_para <- table_all_myo_healthy %>%
                 dplyr::select(Study_ID, Cohort, BMP4, Grem_1, Grem_2)  %>%
                 pivot_longer(cols = where(is.numeric),
                              names_to = "Parameter",
                              values_to = "Parameter_val")
# Calculate Stats
  # Wilcox Test
    stat.test <- table_para %>%
                 group_by(Parameter) %>%
                 wilcox_test(Parameter_val ~ Cohort) %>%
                 add_significance()  %>%
                 mutate(p_adj = p.adjust(p, method = "BH")) 
    
    # Get max value per parameter (for p-value position)
      max_y <- table_para %>%
               group_by(Parameter) %>%
               summarise(max_val = max(Parameter_val, na.rm = TRUE))
      
    # Get min value per parameter (for y limits)
      min_y <- table_para %>%
               group_by(Parameter) %>%
               summarise(min_val = min(Parameter_val, na.rm = TRUE))
    
    # Combine with max_y info for plotting
      stat.test <-  stat.test %>%
                    left_join(max_y, by = "Parameter") %>%
                    mutate(y.position = max_val * 1)
    
# Create the loop to create a plot
  biomarkers <- c("BMP4", "Grem_1", "Grem_2")
  y_settings <- list(BMP4 = list(limits = c(NA, 1000),  breaks = c(10, 100, 1000)),
                     Grem_1 = list(limits = c(NA, 100000), breaks = c(100, 1000, 10000,100000)),
                     Grem_2 = list(limits = c(NA, 100000), breaks = c(300, 1000, 3000, 10000, 30000, 100000)))

# Create x-axis label for loop
    biomarker_labels <- c("BMP4 (pg/ml)", "Gremlin-1 (pg/ml)", "Gremlin-2 (pg/ml)")
    names(biomarker_labels) <- biomarkers
  
# Create a list for all plots created in the loop
  plots_list <- list()
  for (param in biomarkers) 
     
      {
        # Filter for the data 
          temp_data <- table_para %>% 
                       filter(Parameter == param) 
          
          temp_stat_test <- stat.test %>% 
                            filter(Parameter == param) %>% 
                            mutate(p_adj_label = ifelse(p_adj < 0.001, "<0.001", sprintf("%.3f", p_adj)))
          
        # Axis settings
          y_lim <- y_settings[[param]]$limits
          y_brk <- y_settings[[param]]$breaks 

          # Create Plot
            plot <-   ggplot(temp_data, aes(x = Cohort, y = Parameter_val)) +
                          geom_boxplot(aes(fill = Cohort), color = "black", outlier.shape = NA, 
                                       width = 0.6, alpha = 0.4) +
                          geom_point(shape = 21, size = 3, color = "black", aes(fill = Cohort),
                                   position = position_jitter(width = 0.2, height = 0)) +
                          scale_fill_manual(values = c("Myocarditis" = "darkred", 
                                                       "Healthy" = "grey")) +
                          stat_pvalue_manual(temp_stat_test, label = "p_adj_label", 
                                             y.position = log10(temp_stat_test$y.position),
                                             step.increase = 0.01, tip.length = 0) +
                          scale_y_log10(labels = function(x) format(x, scientific = FALSE, trim = TRUE),
                                      limits = y_lim, breaks = y_brk, expand = expansion(mult = c(0.05, 0))) +
                          labs(x = NULL, y = biomarker_labels[param]) +
                          theme_classic()  +
                          theme(axis.title.x = element_blank(),
                                axis.text.x  = element_blank(),
                                axis.ticks.x = element_blank(),
                                legend.position = "none")
  
          plots_list[[param]] <- plot
    }

# Combine plots to a panel
  panel <-  ggarrange(plotlist = plots_list,
                      ncol = 3, nrow = 1,
                      common.legend = TRUE)
      
  print(panel)

Roc Curves BMP4/Gremlin axis

# Data preparation
  table_roc <- table_all_myo_healthy %>%
               mutate(outcome = factor(Cohort, levels = c("Healthy", "Myocarditis")),
                      outcome_binary = ifelse(outcome == "Myocarditis", 1, 0),
                      r_Grem2_BMP4 = Grem_2 / BMP4)

# Select predictors
  param <- c("BMP4", "Grem_1", "Grem_2", "r_Grem2_BMP4")
  biomarker_labels <- c("BMP4", "Gremlin-1", "Gremlin-2", "Gremlin-2/BMP4")
  names(biomarker_labels) <- param
  
# Initialize storage
  roc_list <- list()

# Loop through each predictor
  for (p in param) 
    
  {
    roc_obj <- roc(response = table_roc$outcome_binary,
                   predictor = table_roc[[p]],
                   levels = c(0, 1),
                   direction = "auto",
                   ci = TRUE,
                   legacy.axes = TRUE)
    
    roc_list[[p]] <- roc_obj
  }
  
# AUC & CI values
  auc_vals <- sapply(roc_list[1:4], function(x) as.numeric(auc(x)))
  auc_ci   <- lapply(roc_list[1:4], function(x) ci.auc(x))
  
# Create Legend
  legend_text <- mapply(function(pred, auc, ci) 
                {
                 paste0(pred," (AUC = ", round(auc, 2),", 95% CI: ", round(ci[1], 2), "–", round(ci[3], 2), ")")
                }, 
                biomarker_labels[param], auc_vals, auc_ci)

# Combine ROC curves into ggplot
  roc_plot <- ggroc(roc_list, legacy.axes = TRUE) +
              geom_abline(intercept = 0, slope = 1, linetype = "dashed", color = "grey") +
              scale_color_manual(values = c("darkgrey", "lightgrey", "red", "darkred"),
                                 labels = legend_text) +
              theme_classic() +
              theme(panel.border = element_rect(color = "black", fill = NA, linewidth = 1),
                    legend.position = "bottom",
                    legend.direction = "vertical") +
              labs(x = "1 - Specificity", 
                   y = "Sensitivity",
                   color = "Legend") +
              coord_equal()
  
  print(roc_plot)

Correlation Matrix AM Cohort

# Subset Dataset
  table_corr <- subset(table_all_myo_imp, select = c("Grem_1", "Grem_2", 
                                                     "NTproBNP", "LV_EF", "HGF", 
                                                     "CXCL10", "CXCL9", "IL_2R",
                                                     "CCL3", "CCL4", "CXCL8", "IL_6"))
# Create Correlation Matrix
  plot_matrix <- plot_correlation_matrix(table_corr,
                 correlation_type = "spearman",
                 method = "circle",
                 legend_x_start = 1.5,
                 clean_names = T,
                 legend_width = 0.5,
                 insig = "blank")
After removing all-NA columns: 103 12 
After removing all-NA rows: 103 12 

  print(plot_matrix)
NULL

Correlation Plots

# Rename Datatables
  table_corr <- table_all_myo_healthy
                      
# Define biomarkers
  biomarkers <- c("HGF", "NTproBNP")
  x_settings <- list(HGF = list(limits = c(NA, 15000), breaks = c(150, 1500, 15000)),
                     NTproBNP  = list(limits = c(NA, 100000),  breaks = c(10, 100, 1000, 10000, 100000)))

# Define axis labels for each biomarker
  biomarker_labels <- c("HGF (pg/ml)", "NTproBNP (ng/l)")
  names(biomarker_labels) <- biomarkers

# Fixed variable
  fixed_param <- "Grem_2"

# Create list for plots
  plots_list <- list()

# Loop Correlation Plot
  for (p in biomarkers) 
    
    {
  
      # Compute Spearman correlation
        cor_test <- cor.test(table_corr[[fixed_param]], table_corr[[p]], method = "spearman")
        
      # Axis settings
        x_lim <- x_settings[[p]]$limits
        x_brk <- x_settings[[p]]$breaks 
  
      # Scatter plot with regression line
        plot <- ggplot(table_corr, aes_string(x = table_corr[[p]], y = fixed_param)) +
                  geom_point(shape = 21, size = 3, color = "black", aes(fill = Cohort),
                             position = position_jitter(width = 0.05, height = 0)) +
                  geom_smooth(method = "lm", se = TRUE, color = "black") +
                  scale_fill_manual(values = c("Myocarditis" = "darkred", "Healthy" = "grey")) +
                scale_x_log10(labels = function(x) format(x, scientific = FALSE, trim = TRUE),
                                  limits = x_lim, breaks = x_brk, expand = expansion(mult = c(0.05, 0))) +
                scale_y_log10(labels = function(x) format(x, scientific = FALSE, trim = TRUE),
                                 limits = c(NA, 100000), breaks = c(100, 300, 1000, 3000, 10000, 30000, 100000),
                                 expand = expansion(mult = c(0.05, 0), add = c(0,0))) +
                theme_classic() +
                labs(x = biomarker_labels[[p]], y = "Gremlin-2 (pg/ml)") +
                annotate("text", x = min(table_corr[[p]], na.rm = TRUE),
                                 y = max(table_corr[[fixed_param]], na.rm = TRUE),
                                label = paste0("r = ", round(cor_test$estimate, 2),
                                        "\np = ", ifelse(cor_test$p.value < 0.001, "< 0.001",signif(cor_test$p.value, 3))),
                         hjust = 0, vjust = 1, size = 6)
        
      # Store each plot
      plots_list[[p]] <- plot

  }

# Combine plots to a panel
  panel <-  ggarrange(plotlist = plots_list,
                      ncol = 2, nrow = 1,
                      common.legend = TRUE)
      
  print(panel)

session info

sessionInfo()
R version 4.4.3 (2025-02-28)
Platform: aarch64-apple-darwin20
Running under: macOS 26.3

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/Zurich
tzcode source: internal

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

other attached packages:
 [1] viridis_0.6.5          viridisLite_0.4.2      biostatUZH_2.2.7      
 [4] ImmunoLogic_0.0.0.9000 Seurat_5.3.1           SeuratObject_5.2.0    
 [7] sp_2.2-0               kernlab_0.9-33         dbscan_1.2-0          
[10] umap_0.2.10.0          Rtsne_0.17             cluster_2.1.8         
[13] factoextra_1.0.7       randomForest_4.7-1.2   pROC_1.19.0.1         
[16] mice_3.18.0            caret_7.0-1            lattice_0.22-6        
[19] drc_3.0-1              logistf_1.26.1         glmnet_4.1-10         
[22] Matrix_1.7-2           broom_1.0.11           MuMIn_1.48.11         
[25] Hmisc_5.2-3            car_3.1-3              carData_3.0-5         
[28] multcomp_1.4-28        TH.data_1.1-4          MASS_7.3-65           
[31] survival_3.8-3         mvtnorm_1.3-3          rstatix_0.7.3         
[34] ggpattern_1.2.1        gridExtra_2.3          cowplot_1.2.0         
[37] patchwork_1.3.2        plotly_4.11.0          EnhancedVolcano_1.24.0
[40] RColorBrewer_1.1-3     circlize_0.4.16        ComplexHeatmap_2.22.0 
[43] pheatmap_1.0.12        corrplot_0.95          ggcorrplot_0.1.4.1    
[46] ggbeeswarm_0.7.2       ggrepel_0.9.6          ggpubr_0.6.2          
[49] readxl_1.4.5           writexl_1.5.0          openxlsx_4.2.5.2      
[52] gtsummary_2.4.0        flextable_0.9.6        tableone_0.13.2       
[55] table1_1.4.3           scales_1.4.0           here_1.0.2            
[58] janitor_2.2.0          magrittr_2.0.4         data.table_1.17.8     
[61] lubridate_1.9.4        forcats_1.0.1          stringr_1.6.0         
[64] dplyr_1.1.4            purrr_1.2.0            readr_2.1.6           
[67] tidyr_1.3.1            tibble_3.3.0           ggplot2_4.0.1         
[70] tidyverse_2.0.0       

loaded via a namespace (and not attached):
  [1] IRanges_2.40.1           nnet_7.3-20              goftest_1.2-3           
  [4] vctrs_0.6.5              spatstat.random_3.4-3    digest_0.6.39           
  [7] png_0.1-8                shape_1.4.6.1            git2r_0.36.2            
 [10] alabama_2023.1.0         deldir_2.0-4             httpcode_0.3.0          
 [13] parallelly_1.45.1        fontLiberation_0.1.0     reshape2_1.4.5          
 [16] httpuv_1.6.16            foreach_1.5.2            BiocGenerics_0.52.0     
 [19] withr_3.0.2              xfun_0.54                crul_1.4.2              
 [22] emmeans_1.10.4           systemfonts_1.3.1        ragg_1.5.0              
 [25] zoo_1.8-14               GlobalOptions_0.1.3      gtools_3.9.5            
 [28] pbapply_1.7-4            Formula_1.2-5            promises_1.5.0          
 [31] otel_0.2.0               httr_1.4.7               globals_0.18.0          
 [34] fitdistrplus_1.2-4       rstudioapi_0.17.1        pan_1.9                 
 [37] miniUI_0.1.2             generics_0.1.4           base64enc_0.1-3         
 [40] curl_7.0.0               S4Vectors_0.44.0         mitools_2.4             
 [43] polyclip_1.10-7          quadprog_1.5-8           xtable_1.8-4            
 [46] doParallel_1.0.17        evaluate_1.0.5           hms_1.1.4               
 [49] irlba_2.3.5.1            colorspace_2.1-2         polynom_1.4-1           
 [52] ROCR_1.0-11              cmprsk_2.2-11            reticulate_1.44.1       
 [55] spatstat.data_3.1-9      lmtest_0.9-40            snakecase_0.11.1        
 [58] later_1.4.4              spatstat.geom_3.6-1      future.apply_1.20.0     
 [61] scattermore_1.2          survey_4.4-2             matrixStats_1.5.0       
 [64] RcppAnnoy_0.0.22         class_7.3-23             pillar_1.11.1           
 [67] nlme_3.1-167             iterators_1.0.14         compiler_4.4.3          
 [70] RSpectra_0.16-2          stringi_1.8.7            gower_1.0.2             
 [73] jomo_2.7-6               tensor_1.5.1             minqa_1.2.8             
 [76] plyr_1.8.9               crayon_1.5.3             abind_1.4-8             
 [79] orthopolynom_1.0-6.1     sandwich_3.1-1           whisker_0.4.1           
 [82] codetools_0.2-20         textshaping_1.0.4        basefun_1.2-4           
 [85] recipes_1.3.1            openssl_2.3.4            bslib_0.9.0             
 [88] GetoptLong_1.0.5         mime_0.13                splines_4.4.3           
 [91] Rcpp_1.1.0               fastDummies_1.7.5        psy_1.2                 
 [94] coneproj_1.20            variables_1.1-2          cellranger_1.1.0        
 [97] knitr_1.50               clue_0.3-66              lme4_1.1-38             
[100] fs_1.6.6                 listenv_0.10.0           checkmate_2.3.3         
[103] Rdpack_2.6.4             ggsignif_0.6.4           estimability_1.5.1      
[106] tzdb_0.5.0               pkgconfig_2.0.3          tools_4.4.3             
[109] cachem_1.1.0             rbibutils_2.4            numDeriv_2016.8-1.1     
[112] DBI_1.2.3                fastmap_1.2.0            rmarkdown_2.30          
[115] ica_1.0-3                tram_1.2-4               sass_0.4.10             
[118] officer_0.6.6            coda_0.19-4.1            dotCall64_1.2           
[121] RANN_2.6.2               rpart_4.1.24             farver_2.1.2            
[124] reformulas_0.4.2         mgcv_1.9-1               yaml_2.3.11             
[127] workflowr_1.7.2          foreign_0.8-88           cli_3.6.5               
[130] stats4_4.4.3             lifecycle_1.0.4          uwot_0.2.4              
[133] askpass_1.2.1            lava_1.8.0               backports_1.5.0         
[136] mlt_1.6-6                timechange_0.3.0         gtable_0.3.6            
[139] rjson_0.2.23             ggridges_0.5.7           progressr_0.18.0        
[142] parallel_4.4.3           jsonlite_2.0.0           RcppHNSW_0.6.0          
[145] mitml_0.4-5              qrng_0.0-10              spatstat.utils_3.2-0    
[148] zip_2.3.1                jquerylib_0.1.4          spatstat.univar_3.1-5   
[151] ReplicationSuccess_1.3.3 timeDate_4051.111        lazyeval_0.2.2          
[154] shiny_1.12.0             htmltools_0.5.9          sctransform_0.4.2       
[157] glue_1.8.0               gfonts_0.2.0             BB_2019.10-1            
[160] spam_2.11-1              gdtools_0.3.7            rprojroot_2.1.1         
[163] boot_1.3-31              igraph_2.2.1             R6_2.6.1                
[166] labeling_0.4.3           ipred_0.9-15             nloptr_2.2.1            
[169] tidyselect_1.2.1         vipor_0.4.7              plotrix_3.8-4           
[172] htmlTable_2.4.3          operator.tools_1.6.3     xml2_1.5.1              
[175] fontBitstreamVera_0.1.1  future_1.68.0            ModelMetrics_1.2.2.2    
[178] KernSmooth_2.23-26       S7_0.2.1                 fontquiver_0.2.1        
[181] htmlwidgets_1.6.4        rlang_1.1.6              spatstat.sparse_3.1-0   
[184] spatstat.explore_3.6-0   uuid_1.2-1               formula.tools_1.7.1     
[187] hardhat_1.4.1            beeswarm_0.4.0           prodlim_2023.08.28      
date()
[1] "Fri Mar  6 16:35:14 2026"

sessionInfo()
R version 4.4.3 (2025-02-28)
Platform: aarch64-apple-darwin20
Running under: macOS 26.3

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/Zurich
tzcode source: internal

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

other attached packages:
 [1] viridis_0.6.5          viridisLite_0.4.2      biostatUZH_2.2.7      
 [4] ImmunoLogic_0.0.0.9000 Seurat_5.3.1           SeuratObject_5.2.0    
 [7] sp_2.2-0               kernlab_0.9-33         dbscan_1.2-0          
[10] umap_0.2.10.0          Rtsne_0.17             cluster_2.1.8         
[13] factoextra_1.0.7       randomForest_4.7-1.2   pROC_1.19.0.1         
[16] mice_3.18.0            caret_7.0-1            lattice_0.22-6        
[19] drc_3.0-1              logistf_1.26.1         glmnet_4.1-10         
[22] Matrix_1.7-2           broom_1.0.11           MuMIn_1.48.11         
[25] Hmisc_5.2-3            car_3.1-3              carData_3.0-5         
[28] multcomp_1.4-28        TH.data_1.1-4          MASS_7.3-65           
[31] survival_3.8-3         mvtnorm_1.3-3          rstatix_0.7.3         
[34] ggpattern_1.2.1        gridExtra_2.3          cowplot_1.2.0         
[37] patchwork_1.3.2        plotly_4.11.0          EnhancedVolcano_1.24.0
[40] RColorBrewer_1.1-3     circlize_0.4.16        ComplexHeatmap_2.22.0 
[43] pheatmap_1.0.12        corrplot_0.95          ggcorrplot_0.1.4.1    
[46] ggbeeswarm_0.7.2       ggrepel_0.9.6          ggpubr_0.6.2          
[49] readxl_1.4.5           writexl_1.5.0          openxlsx_4.2.5.2      
[52] gtsummary_2.4.0        flextable_0.9.6        tableone_0.13.2       
[55] table1_1.4.3           scales_1.4.0           here_1.0.2            
[58] janitor_2.2.0          magrittr_2.0.4         data.table_1.17.8     
[61] lubridate_1.9.4        forcats_1.0.1          stringr_1.6.0         
[64] dplyr_1.1.4            purrr_1.2.0            readr_2.1.6           
[67] tidyr_1.3.1            tibble_3.3.0           ggplot2_4.0.1         
[70] tidyverse_2.0.0       

loaded via a namespace (and not attached):
  [1] IRanges_2.40.1           nnet_7.3-20              goftest_1.2-3           
  [4] vctrs_0.6.5              spatstat.random_3.4-3    digest_0.6.39           
  [7] png_0.1-8                shape_1.4.6.1            git2r_0.36.2            
 [10] alabama_2023.1.0         deldir_2.0-4             httpcode_0.3.0          
 [13] parallelly_1.45.1        fontLiberation_0.1.0     reshape2_1.4.5          
 [16] httpuv_1.6.16            foreach_1.5.2            BiocGenerics_0.52.0     
 [19] withr_3.0.2              xfun_0.54                crul_1.4.2              
 [22] emmeans_1.10.4           systemfonts_1.3.1        ragg_1.5.0              
 [25] zoo_1.8-14               GlobalOptions_0.1.3      gtools_3.9.5            
 [28] pbapply_1.7-4            Formula_1.2-5            promises_1.5.0          
 [31] otel_0.2.0               httr_1.4.7               globals_0.18.0          
 [34] fitdistrplus_1.2-4       rstudioapi_0.17.1        pan_1.9                 
 [37] miniUI_0.1.2             generics_0.1.4           base64enc_0.1-3         
 [40] curl_7.0.0               S4Vectors_0.44.0         mitools_2.4             
 [43] polyclip_1.10-7          quadprog_1.5-8           xtable_1.8-4            
 [46] doParallel_1.0.17        evaluate_1.0.5           hms_1.1.4               
 [49] irlba_2.3.5.1            colorspace_2.1-2         polynom_1.4-1           
 [52] ROCR_1.0-11              cmprsk_2.2-11            reticulate_1.44.1       
 [55] spatstat.data_3.1-9      lmtest_0.9-40            snakecase_0.11.1        
 [58] later_1.4.4              spatstat.geom_3.6-1      future.apply_1.20.0     
 [61] scattermore_1.2          survey_4.4-2             matrixStats_1.5.0       
 [64] RcppAnnoy_0.0.22         class_7.3-23             pillar_1.11.1           
 [67] nlme_3.1-167             iterators_1.0.14         compiler_4.4.3          
 [70] RSpectra_0.16-2          stringi_1.8.7            gower_1.0.2             
 [73] jomo_2.7-6               tensor_1.5.1             minqa_1.2.8             
 [76] plyr_1.8.9               crayon_1.5.3             abind_1.4-8             
 [79] orthopolynom_1.0-6.1     sandwich_3.1-1           whisker_0.4.1           
 [82] codetools_0.2-20         textshaping_1.0.4        basefun_1.2-4           
 [85] recipes_1.3.1            openssl_2.3.4            bslib_0.9.0             
 [88] GetoptLong_1.0.5         mime_0.13                splines_4.4.3           
 [91] Rcpp_1.1.0               fastDummies_1.7.5        psy_1.2                 
 [94] coneproj_1.20            variables_1.1-2          cellranger_1.1.0        
 [97] knitr_1.50               clue_0.3-66              lme4_1.1-38             
[100] fs_1.6.6                 listenv_0.10.0           checkmate_2.3.3         
[103] Rdpack_2.6.4             ggsignif_0.6.4           estimability_1.5.1      
[106] tzdb_0.5.0               pkgconfig_2.0.3          tools_4.4.3             
[109] cachem_1.1.0             rbibutils_2.4            numDeriv_2016.8-1.1     
[112] DBI_1.2.3                fastmap_1.2.0            rmarkdown_2.30          
[115] ica_1.0-3                tram_1.2-4               sass_0.4.10             
[118] officer_0.6.6            coda_0.19-4.1            dotCall64_1.2           
[121] RANN_2.6.2               rpart_4.1.24             farver_2.1.2            
[124] reformulas_0.4.2         mgcv_1.9-1               yaml_2.3.11             
[127] workflowr_1.7.2          foreign_0.8-88           cli_3.6.5               
[130] stats4_4.4.3             lifecycle_1.0.4          uwot_0.2.4              
[133] askpass_1.2.1            lava_1.8.0               backports_1.5.0         
[136] mlt_1.6-6                timechange_0.3.0         gtable_0.3.6            
[139] rjson_0.2.23             ggridges_0.5.7           progressr_0.18.0        
[142] parallel_4.4.3           jsonlite_2.0.0           RcppHNSW_0.6.0          
[145] mitml_0.4-5              qrng_0.0-10              spatstat.utils_3.2-0    
[148] zip_2.3.1                jquerylib_0.1.4          spatstat.univar_3.1-5   
[151] ReplicationSuccess_1.3.3 timeDate_4051.111        lazyeval_0.2.2          
[154] shiny_1.12.0             htmltools_0.5.9          sctransform_0.4.2       
[157] glue_1.8.0               gfonts_0.2.0             BB_2019.10-1            
[160] spam_2.11-1              gdtools_0.3.7            rprojroot_2.1.1         
[163] boot_1.3-31              igraph_2.2.1             R6_2.6.1                
[166] labeling_0.4.3           ipred_0.9-15             nloptr_2.2.1            
[169] tidyselect_1.2.1         vipor_0.4.7              plotrix_3.8-4           
[172] htmlTable_2.4.3          operator.tools_1.6.3     xml2_1.5.1              
[175] fontBitstreamVera_0.1.1  future_1.68.0            ModelMetrics_1.2.2.2    
[178] KernSmooth_2.23-26       S7_0.2.1                 fontquiver_0.2.1        
[181] htmlwidgets_1.6.4        rlang_1.1.6              spatstat.sparse_3.1-0   
[184] spatstat.explore_3.6-0   uuid_1.2-1               formula.tools_1.7.1     
[187] hardhat_1.4.1            beeswarm_0.4.0           prodlim_2023.08.28