library(dplyr)

1 Data retrieval

data.brain.beta <- "../DATASETS/LONDON/step5_pca_filtering/"
data.brain.pheno <- "../DATASETS/LONDON/step6_neuron_comp/"
data.blood.beta <- "../DATASETS/LONDON_blood/step5_pca_filtering/"
data.blood.pheno <- "../DATASETS/LONDON_blood/step6_neuron_comp/"
data.dmr <- "../meta_analysis_region_results/step4_dmr_vs_cpgs/"
data.cpg <- "../meta_analysis_single_cpg_results/"
data.final <- "../London_blood_brain_correlation_results/"
data.final.beta <- "../London_blood_brain_correlation_results/using_betas/"
data.final.resid <- "../London_blood_brain_correlation_results/using_residuals/"
data.BECon <- "../DATASETS/LONDON_blood/step10_blood_brain_correlation/"
brain_beta <- readRDS(
  paste0(data.brain.beta, "London_PFC_QNBMIQ_PCfiltered_withStageExclude.RDS")
)
brain_pheno <- readRDS(
  paste0(data.brain.pheno, "pheno107_PFC_withNeuronProp_withStageExclude_df.RDS")
)
blood_beta <- readRDS(
  paste0(data.blood.beta, "London_QNBMIQ_PCfiltered_withStatusExclude.RDS")
)
blood_pheno <- readRDS(
  paste0(data.blood.pheno, "pheno_BLOOD_withBloodProp_withStatusExclude_df.rds")
)

2 Limit samples in both datasets

### Renames variables
colnames(brain_pheno)[c(1, 3:ncol(brain_pheno))] <- paste0(
  "brain_", colnames(brain_pheno)[c(1, 3:ncol(brain_pheno))]
)
colnames(blood_pheno)[c(1, 3:ncol(blood_pheno))] <- paste0(
  "blood_", colnames(blood_pheno)[c(1, 3:ncol(blood_pheno))]
)

### Merge datasets
pheno_final <- merge(
  brain_pheno, blood_pheno,
  by = "subject.id"
) #dim: 69 23

### Limit beta matrices to samples in pheno_final
brain_beta_final <- brain_beta[, pheno_final$brain_sample]
blood_beta_final <- blood_beta[, pheno_final$blood_sample]

3 Calculate blood and brain correlation (without taking residuals)

### Call in datasets with sig DMRs and CpGs
main_dmrs <- read.csv(
  paste0(data.dmr, "meta_analysis_sig_no_crossHyb_smoking_ov_comb_p_with_sig_single_cpgs.csv")
)
main_cpgs <- read.csv(
  paste0(data.cpg, "meta_analysis_single_cpg_sig_no_crossHyb_smoking_df.csv")
)

3.1 for sig. regions

### Get probes from regions
probes.cluster.all <- coMethDMR::getPredefinedCluster(
  arrayType = "450k",
  clusterType = "regions"
)
## Setting options('download.file.method.GEOquery'='auto')
## Setting options('GEOquery.inmemory.gpl'=FALSE)
idx <- gsub("450k_Gene_3_200.|450k_InterGene_3_200.","",names(probes.cluster.all)) %in% main_dmrs$inputRegion
main_dmrs_cpgs <- probes.cluster.all[idx] %>% unlist %>% as.character() %>% unique

### Limit blood_beta and brain_beta to the probes above
brain_beta_regions <- brain_beta_final[
  row.names(brain_beta_final) %in% main_dmrs_cpgs,
  ]

blood_beta_regions <- blood_beta_final[
  row.names(blood_beta_final) %in% main_dmrs_cpgs,
  ]

identical(dim(brain_beta_regions), dim(blood_beta_regions))
## [1] TRUE
identical(row.names(brain_beta_regions), row.names(blood_beta_regions))
## [1] TRUE
blood_brain_cor <- plyr::adply(seq_len(nrow(brain_beta_regions)),
                               .margins = 1,
                               .fun =  function(row){
                                 
                                 spearman_cor <- cor.test(
                                   brain_beta_regions[row,],
                                   blood_beta_regions[row,],
                                   method = "spearman"
                                 )
                                 
                                 data.frame(
                                   cpg = row.names(brain_beta_regions)[row],
                                   spearman_cor = spearman_cor$estimate,
                                   pVal = spearman_cor$p.value,
                                   stringsAsFactors = FALSE
                                 )
                               },.id = NULL)

blood_brain_cor$fdr <- p.adjust(blood_brain_cor$pVal, method = "fdr")
blood_brain_cor
write.csv(
  blood_brain_cor,
  paste0(data.final.beta, "London_blood_brain_beta_correlation_dmrs.csv"),
  row.names = FALSE
)

3.2 for sig. cpgs

### Limit blood_beta and brain_beta to probes in main_cpgs
brain_beta_cpgs <- brain_beta_final[
  row.names(brain_beta_final) %in% as.character(main_cpgs$cpg),
  ]

blood_beta_cpgs <- blood_beta_final[
  row.names(blood_beta_final) %in% as.character(main_cpgs$cpg),
  ]

identical(dim(brain_beta_cpgs), dim(blood_beta_cpgs))
## [1] TRUE
identical(row.names(brain_beta_cpgs), row.names(blood_beta_cpgs))
## [1] TRUE
blood_brain_cor <-  plyr::adply(seq_len(nrow(brain_beta_cpgs)),
                                .margins = 1,
                                .fun =  function(row){
                                  spearman_cor <- cor.test(
                                    brain_beta_cpgs[row,],
                                    blood_beta_cpgs[row,],
                                    method = "spearman"
                                  )
                                  
                                  data.frame(
                                    cpg = row.names(brain_beta_cpgs)[row],
                                    spearman_cor = spearman_cor$estimate,
                                    pVal = spearman_cor$p.value,
                                    stringsAsFactors = FALSE
                                  )
                                },.id = NULL)

blood_brain_cor$fdr <- p.adjust(blood_brain_cor$pVal, method = "fdr")
blood_brain_cor
write.csv(
  blood_brain_cor,
  paste0(data.final.beta, "London_blood_brain_beta_correlation_cpgs.csv"),
  row.names = FALSE
)

4 Calculate blood and brain correlation (with taking residuals)

4.1 Take residuals

4.1.1 for brain beta matrix

### Compute M values
mvalue_mat <- log2( brain_beta_final /(1 - brain_beta_final))

### Reorder samples based on pheno_df
mvalue_mat <- mvalue_mat[, pheno_final$brain_sample]

identical(colnames(mvalue_mat), pheno_final$brain_sample)
## [1] TRUE
### Take residuals
lmF <- function(mval){
  fitE <- lm(
    as.numeric(mval) ~ brain_age.brain + brain_sex + brain_prop.neuron + as.character(brain_slide), #add batch if rosmap
    data = pheno_final,
    na.action = na.exclude
  )
  residuals (fitE)
}

library(doParallel)
## Loading required package: foreach
## Loading required package: iterators
## Loading required package: parallel
registerDoParallel(detectCores()/2)
resid <- plyr::adply(mvalue_mat,1,.fun = lmF,.progress = "time",.parallel = TRUE)
## Progress disabled when using parallel plyr
rownames(resid) <- resid[,1]
resid[,1] <- NULL
colnames(resid) <- colnames(mvalue_mat)
saveRDS(
  resid,
  paste0(data.final.resid, "London_PFC_QNBMIQ_PCfiltered_mvalResiduals.RDS")
)

4.1.2 for blood beta matrix

### Compute M values
mvalue_mat <- log2(blood_beta_final / (1 - blood_beta_final))

### Reorder samples based on pheno_df
mvalue_mat <- mvalue_mat[, pheno_final$blood_sample]

identical(colnames(mvalue_mat),  pheno_final$blood_sample)
## [1] TRUE
lmF <- function(mval){
  fitE <- lm(
    as.numeric(mval) ~ blood_age.blood + blood_sex + blood_slide +
      blood_B + blood_NK + blood_CD4T + blood_CD8T + blood_Mono + blood_Neutro + blood_Eosino,
    data = pheno_final,
    na.action = na.exclude
  )
  residuals (fitE)
}

resid <- plyr::adply(mvalue_mat,1,.fun = lmF,.progress = "time",.parallel = TRUE)
## Progress disabled when using parallel plyr
rownames(resid) <- resid[,1]
resid[,1] <- NULL
colnames(resid) <- colnames(mvalue_mat)
saveRDS(
  resid,
  paste0(data.final.resid, "LONDON_blood_QNBMIQ_PCfiltered_mvalResiduals.RDS")
)

4.2 Call in datasets

### Call in brain and blood residual matrices
brain_beta_final <- as.matrix(
  readRDS(
    paste0(data.final.resid, "London_PFC_QNBMIQ_PCfiltered_mvalResiduals.RDS")
  )
)
blood_beta_final <- as.matrix(
  readRDS(
    paste0(data.final.resid, "LONDON_blood_QNBMIQ_PCfiltered_mvalResiduals.RDS")
  )
)

### Call in datasets with sig DMRs and CpGs
main_dmrs <- read.csv(
  paste0(data.dmr, "meta_analysis_sig_no_crossHyb_smoking_ov_comb_p_with_sig_single_cpgs.csv")
)
main_cpgs <- read.csv(
  paste0(data.cpg, "meta_analysis_single_cpg_sig_no_crossHyb_smoking_df.csv")
)

4.3 for sig. regions

### Get probes from regions
probes.cluster.all <- coMethDMR::getPredefinedCluster(
  arrayType = "450k",
  clusterType = "regions"
)

idx <- gsub("450k_Gene_3_200.|450k_InterGene_3_200.","",names(probes.cluster.all)) %in% main_dmrs$inputRegion
main_dmrs_cpgs <- probes.cluster.all[idx] %>% unlist %>% as.character() %>% unique

### Limit blood_beta and brain_beta to the probes above
brain_beta_regions <- brain_beta_final[
  row.names(brain_beta_final) %in% main_dmrs_cpgs,
  ]

blood_beta_regions <- blood_beta_final[
  row.names(blood_beta_final) %in% main_dmrs_cpgs,
  ]

identical(dim(brain_beta_regions), dim(blood_beta_regions))
## [1] TRUE
identical(row.names(brain_beta_regions), row.names(blood_beta_regions))
## [1] TRUE
blood_brain_cor <- lapply(seq_len(nrow(brain_beta_regions)), function(row){
  spearman_cor <- cor.test(
    brain_beta_regions[row,],
    blood_beta_regions[row,],
    method = "spearman"
  )
  
  data.frame(
    cpg = row.names(brain_beta_regions)[row],
    spearman_cor = spearman_cor$estimate,
    pVal = spearman_cor$p.value,
    stringsAsFactors = FALSE
  )
})

blood_brain_cor <- do.call(rbind, blood_brain_cor)

blood_brain_cor$fdr <- p.adjust(blood_brain_cor$pVal, method = "fdr")
write.csv(
  blood_brain_cor,
  paste0(data.final.resid, "London_blood_brain_residuals_correlation_dmrs.csv"),
  row.names = FALSE
)

4.4 for sig. cpgs

### Call in datasets


### Limit blood_beta and brain_beta to probes in main_cpgs
brain_beta_cpgs <- brain_beta_final[
  row.names(brain_beta_final) %in% as.character(main_cpgs$cpg),
  ]

blood_beta_cpgs <- blood_beta_final[
  row.names(blood_beta_final) %in% as.character(main_cpgs$cpg),
  ]

identical(dim(brain_beta_cpgs), dim(blood_beta_cpgs))
## [1] TRUE
identical(row.names(brain_beta_cpgs), row.names(blood_beta_cpgs))
## [1] TRUE
blood_brain_cor <- lapply(seq_len(nrow(brain_beta_cpgs)), function(row){
  spearman_cor <- cor.test(
    brain_beta_cpgs[row,],
    blood_beta_cpgs[row,],
    method = "spearman"
  )
  
  data.frame(
    cpg = row.names(brain_beta_cpgs)[row],
    spearman_cor = spearman_cor$estimate,
    pVal = spearman_cor$p.value,
    stringsAsFactors = FALSE
  )
})

blood_brain_cor <- do.call(rbind, blood_brain_cor)
blood_brain_cor$fdr <- p.adjust(blood_brain_cor$pVal, method = "fdr")
write.csv(
  blood_brain_cor,
  paste0(data.final.resid, "London_blood_brain_residuals_correlation_cpgs.csv"),
  row.names = FALSE
)

5 Merge final results

### Call in datasets
dmr_beta <- read.csv(
  paste0(data.final.beta, "London_blood_brain_beta_correlation_dmrs.csv")
)
dmr_resid <- read.csv(
  paste0(data.final.resid, "London_blood_brain_residuals_correlation_dmrs.csv")
)
cpg_beta <- read.csv(
  paste0(data.final.beta, "London_blood_brain_beta_correlation_cpgs.csv")
)
cpg_resid <- read.csv(
  paste0(data.final.resid, "London_blood_brain_residuals_correlation_cpgs.csv")
)

### Rename variables
colnames(dmr_beta)[2:4] <- paste0("beta_", colnames(dmr_beta)[2:4])
colnames(dmr_resid)[2:4] <- paste0("residual_", colnames(dmr_resid)[2:4])
colnames(cpg_beta)[2:4] <- paste0("beta_", colnames(cpg_beta)[2:4])
colnames(cpg_resid)[2:4] <- paste0("residual_", colnames(cpg_resid)[2:4])

### Merge datasets
dmr_cor <- merge(
  dmr_beta, 
  dmr_resid,
  by = "cpg"
)

cpg_cor <- merge(
  cpg_beta, cpg_resid,
  by = "cpg"
)

6 Merge results with results from BECon

### Call in BECon results
becon_dmrs <- read.csv(
  paste0(data.BECon, "BECon_main_dmrs_blood_brain_correlation.csv")
)

becon_cpgs <- read.csv(
  paste0(data.BECon, "BECon_main_cpgs_blood_brain_correlation.csv")
)

### Select and rename variables
becon_dmrs <- becon_dmrs[
  ,c("CpG.ID", "Cor.Blood.BA7", "Cor.Blood..BA10", "Cor.Blood..BA20", "Mean.Cor.All.Brain")
  ]
colnames(becon_dmrs) <- c(
  "cpg", "BECon_cor_BA7", "BECon_cor_BA10", "BECon_cor_BA20", "BECon_cor_mean"
)

becon_cpgs <- becon_cpgs[
  ,c("CpG.ID", "Cor.Blood.BA7", "Cor.Blood..BA10", "Cor.Blood..BA20", "Mean.Cor.All.Brain")
  ]
colnames(becon_cpgs) <- c(
  "cpg", "BECon_cor_BA7", "BECon_cor_BA10", "BECon_cor_BA20", "BECon_cor_mean"
)

### Merge BECon results with our results
dmr_final <- merge(
  dmr_cor, 
  becon_dmrs,
  by = "cpg",
  all.x = TRUE
)

cpg_final <- merge(
  cpg_cor, 
  becon_cpgs,
  by = "cpg",
  all.x = TRUE
)
### Save datasets
write.csv(
  dmr_final,
  paste0(data.final, "London_blood_brain_correlation_dmrs.csv"),
  row.names = FALSE
)

write.csv(
  cpg_final,
  paste0(data.final, "London_blood_brain_correlation_cpgs.csv"),
  row.names = FALSE
)

7 Result summary for dmr_final

sum(
  abs(dmr_final$residual_spearman_cor) >= 0.5
)
## [1] 14
# [1] 14

sum(
  dmr_final$residual_spearman_cor >= 0.5
)
## [1] 14
# [1] 14

sum(
  abs(dmr_final$residual_spearman_cor) >= 0.5 &
    dmr_final$residual_fdr < 0.05
)
## [1] 14
# [1] 14

dmr_final[
  abs(dmr_final$residual_spearman_cor) >= 0.5 &
    dmr_final$residual_fdr < 0.05, 
  ][, c("cpg", "BECon_cor_BA7", "BECon_cor_BA10", "BECon_cor_BA20", "BECon_cor_mean")]
### Conclustion: all correlation > 0.5 are positive correlated, and all significant

8 Result summary for cpg_final

sum(
  abs(cpg_final$residual_spearman_cor) >= 0.5
)
## [1] 45
# [1] 45

sum(
  cpg_final$residual_spearman_cor >= 0.5
)
## [1] 45
# [1] 45

sum(
  abs(cpg_final$residual_spearman_cor) >= 0.5 &
    cpg_final$residual_fdr < 0.05
)
## [1] 45
# [1] 45

cpg_final[
  abs(cpg_final$residual_spearman_cor) >= 0.5 &
    cpg_final$residual_fdr < 0.05, 
  ][, c("cpg", "BECon_cor_BA7", "BECon_cor_BA10", "BECon_cor_BA20")]
### Conclustion: all correlation > 0.5 are positive correlated, and all significant

8.1 Results: filtering results using BeCon

cpg_final %>% rbind(dmr_final) %>% 
  dplyr::filter(
    abs(residual_spearman_cor) > 0.5 &
      abs(beta_spearman_cor)  > 0.5 &
      residual_fdr < 0.05 &
      beta_fdr < 0.05 &
      BECon_cor_BA10 > 0.5
  )

9 Session information

devtools::session_info()
## ─ Session info ───────────────────────────────────────────────────────────────
##  setting  value                                             
##  version  R Under development (unstable) (2020-02-25 r77857)
##  os       macOS Catalina 10.15.3                            
##  system   x86_64, darwin15.6.0                              
##  ui       X11                                               
##  language (EN)                                              
##  collate  en_US.UTF-8                                       
##  ctype    en_US.UTF-8                                       
##  tz       America/New_York                                  
##  date     2020-04-26                                        
## 
## ─ Packages ───────────────────────────────────────────────────────────────────
##  package                                       * version     date       lib
##  annotate                                        1.65.1      2020-01-27 [1]
##  AnnotationDbi                                   1.49.1      2020-01-25 [1]
##  askpass                                         1.1         2019-01-13 [1]
##  assertthat                                      0.2.1       2019-03-21 [1]
##  backports                                       1.1.6       2020-04-05 [1]
##  base64                                          2.0         2016-05-10 [1]
##  beanplot                                        1.2         2014-09-19 [1]
##  Biobase                                         2.47.3      2020-03-16 [1]
##  BiocFileCache                                   1.11.6      2020-04-16 [1]
##  BiocGenerics                                    0.33.3      2020-03-23 [1]
##  BiocParallel                                    1.21.2      2019-12-21 [1]
##  biomaRt                                         2.43.5      2020-04-02 [1]
##  Biostrings                                      2.55.7      2020-03-24 [1]
##  bit                                             1.1-15.2    2020-02-10 [1]
##  bit64                                           0.9-7       2017-05-08 [1]
##  bitops                                          1.0-6       2013-08-17 [1]
##  blob                                            1.2.1       2020-01-20 [1]
##  boot                                            1.3-24      2019-12-20 [1]
##  bumphunter                                      1.29.0      2019-11-07 [1]
##  callr                                           3.4.3       2020-03-28 [1]
##  cli                                             2.0.2       2020-02-28 [1]
##  codetools                                       0.2-16      2018-12-24 [1]
##  colorspace                                      1.4-1       2019-03-18 [1]
##  coMethDMR                                       0.0.0.9001  2020-03-24 [1]
##  crayon                                          1.3.4       2017-09-16 [1]
##  curl                                            4.3         2019-12-02 [1]
##  data.table                                      1.12.9      2020-02-26 [1]
##  DBI                                             1.1.0       2019-12-15 [1]
##  dbplyr                                          1.4.3       2020-04-19 [1]
##  DelayedArray                                    0.13.12     2020-04-10 [1]
##  DelayedMatrixStats                              1.9.1       2020-03-30 [1]
##  desc                                            1.2.0       2018-05-01 [1]
##  devtools                                        2.3.0       2020-04-10 [1]
##  digest                                          0.6.25      2020-02-23 [1]
##  doParallel                                    * 1.0.15      2019-08-02 [1]
##  doRNG                                           1.8.2       2020-01-27 [1]
##  dplyr                                         * 0.8.99.9002 2020-04-02 [1]
##  ellipsis                                        0.3.0       2019-09-20 [1]
##  evaluate                                        0.14        2019-05-28 [1]
##  fansi                                           0.4.1       2020-01-08 [1]
##  foreach                                       * 1.5.0       2020-03-30 [1]
##  fs                                              1.4.1       2020-04-04 [1]
##  genefilter                                      1.69.0      2019-11-06 [1]
##  generics                                        0.0.2       2018-11-29 [1]
##  GenomeInfoDb                                    1.23.17     2020-04-13 [1]
##  GenomeInfoDbData                                1.2.3       2020-04-20 [1]
##  GenomicAlignments                               1.23.2      2020-03-24 [1]
##  GenomicFeatures                                 1.39.7      2020-03-19 [1]
##  GenomicRanges                                   1.39.3      2020-04-08 [1]
##  GEOquery                                        2.55.1      2019-11-18 [1]
##  ggplot2                                         3.3.0       2020-03-05 [1]
##  ggpubr                                          0.2.5       2020-02-13 [1]
##  ggsignif                                        0.6.0       2019-08-08 [1]
##  glue                                            1.4.0       2020-04-03 [1]
##  gtable                                          0.3.0       2019-03-25 [1]
##  HDF5Array                                       1.15.18     2020-04-10 [1]
##  hms                                             0.5.3       2020-01-08 [1]
##  htmltools                                       0.4.0       2019-10-04 [1]
##  httr                                            1.4.1       2019-08-05 [1]
##  IlluminaHumanMethylation450kanno.ilmn12.hg19    0.6.0       2020-03-24 [1]
##  IlluminaHumanMethylationEPICanno.ilm10b2.hg19   0.6.0       2020-03-24 [1]
##  illuminaio                                      0.29.0      2019-11-06 [1]
##  IRanges                                         2.21.8      2020-03-25 [1]
##  iterators                                     * 1.0.12      2019-07-26 [1]
##  jsonlite                                        1.6.1       2020-02-02 [1]
##  knitr                                           1.28        2020-02-06 [1]
##  lattice                                         0.20-41     2020-04-02 [1]
##  lifecycle                                       0.2.0       2020-03-06 [1]
##  limma                                           3.43.8      2020-04-14 [1]
##  lme4                                            1.1-23      2020-04-07 [1]
##  lmerTest                                        3.1-2       2020-04-08 [1]
##  locfit                                          1.5-9.4     2020-03-25 [1]
##  magrittr                                        1.5         2014-11-22 [1]
##  MASS                                            7.3-51.5    2019-12-20 [1]
##  Matrix                                          1.2-18      2019-11-27 [1]
##  matrixStats                                     0.56.0      2020-03-13 [1]
##  mclust                                          5.4.6       2020-04-11 [1]
##  memoise                                         1.1.0       2017-04-21 [1]
##  minfi                                           1.33.1      2020-03-05 [1]
##  minqa                                           1.2.4       2014-10-09 [1]
##  multtest                                        2.43.1      2020-03-12 [1]
##  munsell                                         0.5.0       2018-06-12 [1]
##  nlme                                            3.1-147     2020-04-13 [1]
##  nloptr                                          1.2.2.1     2020-03-11 [1]
##  nor1mix                                         1.3-0       2019-06-13 [1]
##  numDeriv                                        2016.8-1.1  2019-06-06 [1]
##  openssl                                         1.4.1       2019-07-18 [1]
##  pillar                                          1.4.3       2019-12-20 [1]
##  pkgbuild                                        1.0.6       2019-10-09 [1]
##  pkgconfig                                       2.0.3       2019-09-22 [1]
##  pkgload                                         1.0.2       2018-10-29 [1]
##  plyr                                            1.8.6       2020-03-03 [1]
##  preprocessCore                                  1.49.2      2020-02-01 [1]
##  prettyunits                                     1.1.1       2020-01-24 [1]
##  processx                                        3.4.2       2020-02-09 [1]
##  progress                                        1.2.2       2019-05-16 [1]
##  ps                                              1.3.2       2020-02-13 [1]
##  purrr                                           0.3.4       2020-04-17 [1]
##  quadprog                                        1.5-8       2019-11-20 [1]
##  R6                                              2.4.1       2019-11-12 [1]
##  rappdirs                                        0.3.1       2016-03-28 [1]
##  RColorBrewer                                    1.1-2       2014-12-07 [1]
##  Rcpp                                            1.0.4.6     2020-04-09 [1]
##  RCurl                                           1.98-1.2    2020-04-18 [1]
##  readr                                           1.3.1       2018-12-21 [1]
##  remotes                                         2.1.1       2020-02-15 [1]
##  reshape                                         0.8.8       2018-10-23 [1]
##  reshape2                                        1.4.4       2020-04-09 [1]
##  rhdf5                                           2.31.10     2020-04-02 [1]
##  Rhdf5lib                                        1.9.3       2020-04-15 [1]
##  rlang                                           0.4.5.9000  2020-03-20 [1]
##  rmarkdown                                       2.1         2020-01-20 [1]
##  rngtools                                        1.5         2020-01-23 [1]
##  rprojroot                                       1.3-2       2018-01-03 [1]
##  Rsamtools                                       2.3.7       2020-03-18 [1]
##  RSQLite                                         2.2.0       2020-01-07 [1]
##  rtracklayer                                     1.47.0      2019-11-06 [1]
##  S4Vectors                                       0.25.15     2020-04-04 [1]
##  scales                                          1.1.0       2019-11-18 [1]
##  scrime                                          1.3.5       2018-12-01 [1]
##  sessioninfo                                     1.1.1       2018-11-05 [1]
##  siggenes                                        1.61.0      2019-11-06 [1]
##  statmod                                         1.4.34      2020-02-17 [1]
##  stringi                                         1.4.6       2020-02-17 [1]
##  stringr                                         1.4.0       2019-02-10 [1]
##  SummarizedExperiment                            1.17.5      2020-03-27 [1]
##  survival                                        3.1-12      2020-04-10 [1]
##  testthat                                        2.3.2       2020-03-02 [1]
##  tibble                                          3.0.1       2020-04-20 [1]
##  tidyr                                           1.0.2       2020-01-24 [1]
##  tidyselect                                      1.0.0       2020-01-27 [1]
##  usethis                                         1.6.0       2020-04-09 [1]
##  vctrs                                           0.2.99.9010 2020-04-02 [1]
##  withr                                           2.1.2       2018-03-15 [1]
##  xfun                                            0.13        2020-04-13 [1]
##  XML                                             3.99-0.3    2020-01-20 [1]
##  xml2                                            1.3.1       2020-04-09 [1]
##  xtable                                          1.8-4       2019-04-21 [1]
##  XVector                                         0.27.2      2020-03-24 [1]
##  yaml                                            2.2.1       2020-02-01 [1]
##  zlibbioc                                        1.33.1      2020-01-24 [1]
##  source                                     
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##  Github (Bioconductor/GenomicRanges@70e6e69)
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##  Github (r-lib/rlang@a90b04b)               
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## 
## [1] /Library/Frameworks/R.framework/Versions/4.0/Resources/library