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Tutorial with NCI60 cohort

libraries, data loading and feature selection

# We advise to instal from github to get the latest version of the tool.
# if (!requireNamespace("devtools", quietly = TRUE))
#   install.packages("devtools")
# 
# devtools::install_github("saezlab/cosmosR")

library(cosmosR)
library(reshape2)
library(readr)

data("meta_network")

meta_network <- meta_network_cleanup(meta_network)

## Warning: `summarise_each()` was deprecated in dplyr 0.7.0.
## ℹ Please use `across()` instead.
## ℹ The deprecated feature was likely used in the cosmosR package.
##   Please report the issue at <https://github.com/saezlab/COSMOSR/issues>.
## This warning is displayed once every 8 hours.
## Call `lifecycle::last_lifecycle_warnings()` to see where this warning was
## generated.

## Warning: `funs()` was deprecated in dplyr 0.8.0.
## ℹ Please use a list of either functions or lambdas:
## 
## # Simple named list: list(mean = mean, median = median)
## 
## # Auto named with `tibble::lst()`: tibble::lst(mean, median)
## 
## # Using lambdas list(~ mean(., trim = .2), ~ median(., na.rm = TRUE))
## ℹ The deprecated feature was likely used in the cosmosR package.
##   Please report the issue at <https://github.com/saezlab/COSMOSR/issues>.
## This warning is displayed once every 8 hours.
## Call `lifecycle::last_lifecycle_warnings()` to see where this warning was
## generated.

load("data/cosmos/cosmos_inputs.RData")

names(cosmos_inputs)

##  [1] "786-0"       "A498"        "A549/ATCC"   "ACHN"        "BT-549"     
##  [6] "CAKI-1"      "CCRF-CEM"    "COLO 205"    "DU-145"      "EKVX"       
## [11] "HCC-2998"    "HCT-116"     "HCT-15"      "HL-60(TB)"   "HOP-62"     
## [16] "HOP-92"      "HS 578T"     "HT29"        "IGROV1"      "K-562"      
## [21] "KM12"        "LOX IMVI"    "M14"         "MALME-3M"    "MCF7"       
## [26] "MDA-MB-435"  "MOLT-4"      "NCI-H226"    "NCI-H23"     "NCI-H322M"  
## [31] "NCI-H460"    "NCI-H522"    "NCI/ADR-RES" "OVCAR-3"     "OVCAR-4"    
## [36] "OVCAR-5"     "OVCAR-8"     "PC-3"        "RPMI-8226"   "SF-268"     
## [41] "SF-295"      "SF-539"      "SK-MEL-28"   "SK-MEL-5"    "SK-OV-3"    
## [46] "SN12C"       "SNB-19"      "SNB-75"      "SR"          "SW-620"     
## [51] "T-47D"       "TK-10"       "U251"        "UACC-257"    "UACC-62"    
## [56] "UO-31"

cell_line <- "786-0"

#see scripts/prepare_cosmos_inputs.R
sig_input <- cosmos_inputs[[cell_line]]$TF_scores
metab_input <- cosmos_inputs[[cell_line]]$metabolomic
RNA_input <- cosmos_inputs[[cell_line]]$RNA

#Choose which compartment to assign to the metabolic measurments
metab_input <- prepare_metab_inputs(metab_input, c("c","m"))

## [1] "Adding compartment codes."

##Filter significant inputs
sig_input <- sig_input[abs(sig_input) > 2]
# metab_input <- metab_input[abs(metab_input) > 2]

Filter inputs and prior knowledge network

#Remove genes that are not expressed from the meta_network
meta_network <- cosmosR:::filter_pkn_expressed_genes(names(RNA_input), meta_pkn = meta_network)

## [1] "COSMOS: removing unexpressed nodes from PKN..."
## [1] "COSMOS: 20357 interactions removed"

#Filter inputs and prune the meta_network to only keep nodes that can be found downstream of the inputs
#The number of step is quite flexible, 7 steps already covers most of the network

n_steps <- 6

# in this step we prune the network to keep only the relevant part between upstream and downstream nodes
sig_input <- cosmosR:::filter_input_nodes_not_in_pkn(sig_input, meta_network)

## [1] "COSMOS: 12 input/measured nodes are not in PKN any more: CEBPA, ESR1, FOS, FOXA1, GATA3, HNF4A and 6 more."

meta_network <- cosmosR:::keep_controllable_neighbours(meta_network, n_steps, names(sig_input))

## [1] "COSMOS: removing nodes that are not reachable from inputs within 6 steps"
## [1] "COSMOS: 26540 from  37740 interactions are removed from the PKN"

metab_input <- cosmosR:::filter_input_nodes_not_in_pkn(metab_input, meta_network)

## [1] "COSMOS: 195 input/measured nodes are not in PKN any more: Metab__HMDB0011747_c, Metab__HMDB0000755_c, Metab__HMDB0000905_c, Metab__HMDB0001191_c, Metab__HMDB0000355_c, Metab__HMDB0000479_c and 189 more."

meta_network <- cosmosR:::keep_observable_neighbours(meta_network, n_steps, names(metab_input))

## [1] "COSMOS: removing nodes that are not observable by measurements within 6 steps"
## [1] "COSMOS: 3657 from  11200 interactions are removed from the PKN"

sig_input <- cosmosR:::filter_input_nodes_not_in_pkn(sig_input, meta_network)

## [1] "COSMOS: 4 input/measured nodes are not in PKN any more: CTCF, EPAS1, ETS1, USF1 and 0 more."

#compress the network
meta_network_compressed_list <- compress_same_children(meta_network, sig_input = sig_input, metab_input = metab_input)

meta_network_compressed <- meta_network_compressed_list$compressed_network

node_signatures <- meta_network_compressed_list$node_signatures

duplicated_parents <- meta_network_compressed_list$duplicated_signatures

meta_network_compressed <- meta_network_cleanup(meta_network_compressed)

run MOON ot score the and contextualise the PKN

load("support/dorothea_reg.RData")

meta_network_TF_to_metab <- meta_network_compressed

before <- 1
after <- 0
i <- 1
while (before != after & i < 10) {
  before <- length(meta_network_TF_to_metab[,1])
  moon_res <- moon(upstream_input = sig_input, 
                                                 downstream_input = metab_input, 
                                                 meta_network = meta_network_TF_to_metab, 
                                                 n_layers = n_steps, 
                                                 statistic = "ulm") 
  
  meta_network_TF_to_metab <- filter_incohrent_TF_target(moon_res, dorothea_reg, meta_network_TF_to_metab, RNA_input)
  after <- length(meta_network_TF_to_metab[,1])
  i <- i + 1
}

## [1] 2
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if(i < 10)
{
  print(paste("Converged after ",paste(i-1," iterations", sep = ""),sep = ""))
} else
{
  print(paste("Interupted after ",paste(i," iterations. Convergence uncertain.", sep = ""),sep = ""))
}

## [1] "Converged after 3 iterations"

#####
write_csv(moon_res, file = paste("results/moon/",paste(cell_line, "_ATT_decouplerino_full.csv",sep = ""), sep = ""))

source("scripts/support_decompression.R")
moon_res <- decompress_moon_result(moon_res, meta_network_compressed_list, meta_network_TF_to_metab)

plot(density(moon_res$score))
abline(v = 1)
abline(v = -1)


solution_network <- reduce_solution_network(decoupleRnival_res = moon_res, 
                                            meta_network = meta_network,
                                            cutoff = 0.5, 
                                            upstream_input = sig_input, 
                                            RNA_input = RNA_input, 
                                            n_steps = n_steps)

## [1] "COSMOS: removing nodes that are not reachable from inputs within 6 steps"
## [1] "COSMOS: 458 from  1747 interactions are removed from the PKN"

SIF <- solution_network$SIF
names(SIF)[3] <- "sign"
ATT <- solution_network$ATT

data("HMDB_mapper_vec")

translated_res <- translate_res(SIF,ATT,HMDB_mapper_vec)

SIF <- translated_res[[1]]
ATT <- translated_res[[2]]

write_csv(SIF, file = paste("results/",paste(cell_line, "_dec_compressed_SIF.csv",sep = ""), sep = ""))
write_csv(ATT, file = paste("results/",paste(cell_line, "_dec_compressed_ATT.csv",sep = ""), sep = ""))

sessionInfo()

## R version 4.2.0 (2022-04-22)
## Platform: aarch64-apple-darwin20 (64-bit)
## Running under: macOS Monterey 12.6
## 
## Matrix products: default
## BLAS:   /Library/Frameworks/R.framework/Versions/4.2-arm64/Resources/lib/libRblas.0.dylib
## LAPACK: /Library/Frameworks/R.framework/Versions/4.2-arm64/Resources/lib/libRlapack.dylib
## 
## locale:
## [1] en_US.UTF-8/en_US.UTF-8/en_US.UTF-8/C/en_US.UTF-8/en_US.UTF-8
## 
## attached base packages:
## [1] stats     graphics  grDevices utils     datasets  methods   base     
## 
## other attached packages:
## [1] readr_2.1.4    reshape2_1.4.4 cosmosR_1.5.2 
## 
## loaded via a namespace (and not attached):
##  [1] Rcpp_1.0.10       highr_0.10        plyr_1.8.8        pillar_1.9.0     
##  [5] compiler_4.2.0    prettyunits_1.1.1 tools_4.2.0       progress_1.2.2   
##  [9] bit_4.0.5         digest_0.6.31     evaluate_0.20     lifecycle_1.0.3  
## [13] tibble_3.2.1      lattice_0.20-45   pkgconfig_2.0.3   rlang_1.1.0      
## [17] igraph_1.4.2      Matrix_1.5-3      cli_3.6.1         rstudioapi_0.14  
## [21] yaml_2.3.7        parallel_4.2.0    xfun_0.42         fastmap_1.1.1    
## [25] withr_2.5.0       dplyr_1.1.3       stringr_1.5.0     knitr_1.42       
## [29] generics_0.1.3    vctrs_0.6.1       hms_1.1.3         bit64_4.0.5      
## [33] grid_4.2.0        tidyselect_1.2.0  glue_1.6.2        R6_2.5.1         
## [37] fansi_1.0.4       parallelly_1.34.0 vroom_1.6.1       rmarkdown_2.21   
## [41] tzdb_0.3.0        tidyr_1.3.0       purrr_1.0.1       decoupleR_2.9.1  
## [45] magrittr_2.0.3    htmltools_0.5.5   utf8_1.2.3        stringi_1.7.12   
## [49] crayon_1.5.2