Contents

0.1 Instalation

if (!require("BiocManager"))
  install.packages("BiocManager")
BiocManager::install("glmSparseNet")

1 Required Packages

library(dplyr)
library(ggplot2)
library(survival)
library(futile.logger)
library(curatedTCGAData)
library(TCGAutils)
#
library(glmSparseNet)
#
# Some general options for futile.logger the debugging package
.Last.value <- flog.layout(layout.format('[~l] ~m'))
.Last.value <- glmSparseNet:::show.message(FALSE)
# Setting ggplot2 default theme as minimal
theme_set(ggplot2::theme_minimal())

2 Load data

The data is loaded from an online curated dataset downloaded from TCGA using curatedTCGAData bioconductor package and processed.

To accelerate the process we use a very reduced dataset down to 107 variables only (genes), which is stored as a data object in this package. However, the procedure to obtain the data manually is described in the following chunk.

brca <- curatedTCGAData(diseaseCode = "BRCA", assays = "RNASeq2GeneNorm",
                        version = "1.1.38", dry.run = FALSE
)
brca <- curatedTCGAData(diseaseCode = "BRCA", assays = "RNASeq2GeneNorm",
                        version = "1.1.38", dry.run = FALSE)
brca <- TCGAutils::TCGAsplitAssays(brca, c('01','11'))
xdata.raw <- t(cbind(assay(brca[[1]]), assay(brca[[2]])))

# Get matches between survival and assay data
class.v        <- TCGAbiospec(rownames(xdata.raw))$sample_definition %>% factor
names(class.v) <- rownames(xdata.raw)

# keep features with standard deviation > 0
xdata.raw <- xdata.raw %>% 
  { (apply(., 2, sd) != 0) } %>% 
  { xdata.raw[, .] } %>%
  scale

set.seed(params$seed)
small.subset <- c('CD5', 'CSF2RB', 'HSF1', 'IRGC', 'LRRC37A6P', 'NEUROG2', 
                  'NLRC4', 'PDE11A', 'PIK3CB', 'QARS', 'RPGRIP1L', 'SDC1', 
                  'TMEM31', 'YME1L1', 'ZBTB11', 
                  sample(colnames(xdata.raw), 100))

xdata <- xdata.raw[, small.subset[small.subset %in% colnames(xdata.raw)]]
ydata <- class.v

3 Fit models

Fit model model penalizing by the hubs using the cross-validation function by cv.glmHub.

fitted <- cv.glmHub(xdata, ydata, 
                    family  = 'binomial',
                    network = 'correlation', 
                    nlambda = 1000,
                    network.options = networkOptions(cutoff = .6, 
                                                     min.degree = .2))

4 Results of Cross Validation

Shows the results of 1000 different parameters used to find the optimal value in 10-fold cross-validation. The two vertical dotted lines represent the best model and a model with less variables selected (genes), but within a standard error distance from the best.

plot(fitted)

4.1 Coefficients of selected model from Cross-Validation

Taking the best model described by lambda.min

coefs.v <- coef(fitted, s = 'lambda.min')[,1] %>% { .[. != 0]}
coefs.v %>% { 
  data.frame(ensembl.id  = names(.), 
             gene.name   = geneNames(names(.))$external_gene_name, 
             coefficient = .,
             stringsAsFactors = FALSE)
  } %>%
  arrange(gene.name) %>%
  knitr::kable()
ensembl.id gene.name coefficient
(Intercept) (Intercept) (Intercept) -6.8189813
CD5 CD5 AMOTL1 -1.1200445
NLRC4 NLRC4 ATR -1.4434578
PIK3CB PIK3CB B3GALT2 -0.3880002
ZBTB11 ZBTB11 BAG2 -0.3325729
ATR ATR C16orf82 1.2498304
IL2 IL2 CD5 0.6327083
GDF11 GDF11 CIITA -0.2676642
DCP1A DCP1A DCP1A 0.2994599
AMOTL1 AMOTL1 FAM86B1 0.4430643
BAG2 BAG2 FNIP2 -0.1841676
C16orf82 C16orf82 GDF11 0.0396368
FAM86B1 FAM86B1 GNG11 0.2025463
FNIP2 FNIP2 GREM2 0.6101759
MS4A4A MS4A4A GZMB 1.1614779
B3GALT2 B3GALT2 HAX1 -0.0867011
GNG11 GNG11 IL2 3.0659066
NDRG2 NDRG2 MMP28 1.1142519
HAX1 HAX1 MS4A4A -0.1516837
GREM2 GREM2 NDRG2 -0.2014884
CIITA CIITA NLRC4 0.4256103
GZMB GZMB PIK3CB -2.7663574
MMP28 MMP28 ZBTB11 -0.8438024

4.2 Hallmarks of Cancer

geneNames(names(coefs.v)) %>% { hallmarks(.$external_gene_name)$heatmap }
## Error in curl::curl_fetch_memory(url, handle = handle): error:0A000126:SSL routines::unexpected eof while reading
## Request failed [ERROR]. Retrying in 1.1 seconds...
## Error in curl::curl_fetch_memory(url, handle = handle): error:0A000126:SSL routines::unexpected eof while reading
## Request failed [ERROR]. Retrying in 1.1 seconds...
## Cannot call Hallmark API, please try again later.
## NULL

4.3 Accuracy

## [INFO] Misclassified (11)
## [INFO]   * False primary solid tumour: 7
## [INFO]   * False normal              : 4

Histogram of predicted response

ROC curve

## Setting levels: control = Primary Solid Tumor, case = Solid Tissue Normal
## Setting direction: controls < cases

5 Session Info

sessionInfo()
## R Under development (unstable) (2022-10-25 r83175)
## Platform: x86_64-pc-linux-gnu (64-bit)
## Running under: Ubuntu 22.04.1 LTS
## 
## Matrix products: default
## BLAS:   /home/biocbuild/bbs-3.17-bioc/R/lib/libRblas.so
## LAPACK: /usr/lib/x86_64-linux-gnu/lapack/liblapack.so.3.10.0
## 
## locale:
##  [1] LC_CTYPE=en_US.UTF-8       LC_NUMERIC=C              
##  [3] LC_TIME=en_GB              LC_COLLATE=C              
##  [5] LC_MONETARY=en_US.UTF-8    LC_MESSAGES=en_US.UTF-8   
##  [7] LC_PAPER=en_US.UTF-8       LC_NAME=C                 
##  [9] LC_ADDRESS=C               LC_TELEPHONE=C            
## [11] LC_MEASUREMENT=en_US.UTF-8 LC_IDENTIFICATION=C       
## 
## attached base packages:
## [1] stats4    stats     graphics  grDevices utils     datasets  methods  
## [8] base     
## 
## other attached packages:
##  [1] glmSparseNet_1.17.0         glmnet_4.1-4               
##  [3] Matrix_1.5-1                TCGAutils_1.19.0           
##  [5] curatedTCGAData_1.19.2      MultiAssayExperiment_1.25.0
##  [7] SummarizedExperiment_1.29.0 Biobase_2.59.0             
##  [9] GenomicRanges_1.51.0        GenomeInfoDb_1.35.0        
## [11] IRanges_2.33.0              S4Vectors_0.37.0           
## [13] BiocGenerics_0.45.0         MatrixGenerics_1.11.0      
## [15] matrixStats_0.62.0          futile.logger_1.4.3        
## [17] survival_3.4-0              ggplot2_3.3.6              
## [19] dplyr_1.0.10                BiocStyle_2.27.0           
## 
## loaded via a namespace (and not attached):
##   [1] DBI_1.1.3                     bitops_1.0-7                 
##   [3] pROC_1.18.0                   formatR_1.12                 
##   [5] biomaRt_2.55.0                rlang_1.0.6                  
##   [7] magrittr_2.0.3                compiler_4.3.0               
##   [9] RSQLite_2.2.18                GenomicFeatures_1.51.0       
##  [11] png_0.1-7                     vctrs_0.5.0                  
##  [13] rvest_1.0.3                   stringr_1.4.1                
##  [15] shape_1.4.6                   pkgconfig_2.0.3              
##  [17] crayon_1.5.2                  fastmap_1.1.0                
##  [19] magick_2.7.3                  dbplyr_2.2.1                 
##  [21] XVector_0.39.0                ellipsis_0.3.2               
##  [23] labeling_0.4.2                utf8_1.2.2                   
##  [25] Rsamtools_2.15.0              promises_1.2.0.1             
##  [27] rmarkdown_2.17                tzdb_0.3.0                   
##  [29] purrr_0.3.5                   bit_4.0.4                    
##  [31] xfun_0.34                     zlibbioc_1.45.0              
##  [33] cachem_1.0.6                  jsonlite_1.8.3               
##  [35] progress_1.2.2                blob_1.2.3                   
##  [37] highr_0.9                     later_1.3.0                  
##  [39] DelayedArray_0.25.0           BiocParallel_1.33.0          
##  [41] interactiveDisplayBase_1.37.0 parallel_4.3.0               
##  [43] prettyunits_1.1.1             R6_2.5.1                     
##  [45] bslib_0.4.0                   stringi_1.7.8                
##  [47] rtracklayer_1.59.0            jquerylib_0.1.4              
##  [49] iterators_1.0.14              Rcpp_1.0.9                   
##  [51] bookdown_0.29                 assertthat_0.2.1             
##  [53] knitr_1.40                    readr_2.1.3                  
##  [55] httpuv_1.6.6                  splines_4.3.0                
##  [57] tidyselect_1.2.0              yaml_2.3.6                   
##  [59] codetools_0.2-18              curl_4.3.3                   
##  [61] plyr_1.8.7                    lattice_0.20-45              
##  [63] tibble_3.1.8                  shiny_1.7.3                  
##  [65] withr_2.5.0                   KEGGREST_1.39.0              
##  [67] evaluate_0.17                 lambda.r_1.2.4               
##  [69] BiocFileCache_2.7.0           xml2_1.3.3                   
##  [71] ExperimentHub_2.7.0           Biostrings_2.67.0            
##  [73] pillar_1.8.1                  BiocManager_1.30.19          
##  [75] filelock_1.0.2                foreach_1.5.2                
##  [77] generics_0.1.3                RCurl_1.98-1.9               
##  [79] BiocVersion_3.17.0            hms_1.1.2                    
##  [81] munsell_0.5.0                 scales_1.2.1                 
##  [83] xtable_1.8-4                  glue_1.6.2                   
##  [85] tools_4.3.0                   BiocIO_1.9.0                 
##  [87] AnnotationHub_3.7.0           GenomicAlignments_1.35.0     
##  [89] forcats_0.5.2                 XML_3.99-0.12                
##  [91] grid_4.3.0                    AnnotationDbi_1.61.0         
##  [93] colorspace_2.0-3              GenomeInfoDbData_1.2.9       
##  [95] restfulr_0.0.15               cli_3.4.1                    
##  [97] rappdirs_0.3.3                futile.options_1.0.1         
##  [99] fansi_1.0.3                   GenomicDataCommons_1.23.0    
## [101] gtable_0.3.1                  sass_0.4.2                   
## [103] digest_0.6.30                 farver_2.1.1                 
## [105] rjson_0.2.21                  memoise_2.0.1                
## [107] htmltools_0.5.3               lifecycle_1.0.3              
## [109] httr_1.4.4                    mime_0.12                    
## [111] bit64_4.0.5