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#  File Name:determine_allCNbreaks.r

#  Author: jillianwise

#  Mail: jwise7@mgh.harvard.edu

#  Created Time: Mon 22 August 2022 9:25 AM EST

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#' Given multiple samples determine the CN state at all site breaks present in the dataset

#'

#' Given a data frame of CNV segments of DNA with rows representing each unique segment and columns representing the CN states and sample information break each sample into all available segments

#' @chr column of a dataframe that lists the numeric (please reformat X and Y to 23 and 24) chromosome number of the alignment

#' @start column of a dataframe representing the start site of a segment

#' @end column of a dataframe representing the end site of a segment

#' @SegCN The CN state in Numeric CN, either integer or summed raw copy states of both alleles

#' @sample the sample name used in segmentation and expression files

#' @case the case name used for identifying multiple related samples

#' @ploidy the estimated ploidy from any number of CN tools (ASCAT, facets, etc)

#' Given an a directory to write the dataframe to

determine_allCNbreaks <- function(df,outdir) {

  print("converting CN to log2-1 ploidy adjusted states")

  ###check numeric SegCN

df$SegCN <- as.numeric(df$SegCN)

  ###Now create SegCNploidyadjusted

df$tumor_ploidyc <- round(df$ploidy-2)

df$SegCNa <- (log2(df$SegCN-df$tumor_ploidyc)-1)

  ###Lets replace -inf or other negative errors with -10 a

df$SegCNa <- ifelse(df$SegCNa=="NaN", "-10", paste(df$SegCNa)) 

df$SegCNa <- ifelse(df$SegCNa=="-Inf", "-10", paste(df$SegCNa))

df$SegCNa <- as.numeric(df$SegCNa)

#Make list of every unique start and end for every chr, regardless of case, so one set of segments for all cases to be compared across#

df2 <- NULL

print("Finding All Break Points")

for (chr in unique(df$chr)) {

  print(chr)

  x=unique(df$start[df$chr == chr])

  y=unique(df$end[df$chr == chr])

  pos=sort(c(x,y))

  df2 = rbind(df2, data.frame(chr=rep(chr,length(pos)), pos=pos))

}

df2$end <- dplyr::lead(df2$pos)

for(i in 1:nrow(df2)){

  df2$end[i] <- ifelse(df2$chr[i] != df2$chr[i+1], 0, df2$end[i])}

df2 <- filter(df2, df2$end !=0)

###For each patient make a column of their CN state in that segment

require(GenomicRanges)

all <- makeGRangesFromDataFrame(df2,

                                keep.extra.columns = TRUE,

                                ignore.strand = FALSE,

                                start.field="pos",

                                end.field="end", 

                                seqnames = "chr")

###################

df3 <- list()

print("Making GRanges Object")

for (i in unique(df$sample)){

  print(i)

  tmp <- makeGRangesFromDataFrame(df[df$sample == i,],

                                  keep.extra.columns=TRUE,

                                  ignore.strand=FALSE,

                                  start.field="start",

                                  end.field="end", 

                                  seqnames = "chr") 

  df3[[i]]=tmp

}

colnames <- names(df3)

df2$idx <- rownames(df2)

df2$idx <- as.numeric(df2$idx)

#####Run granges overlap between the total segment site list and each patient segmentation granges object

tmp2 <- NULL

tmp <- NULL

print("Finding Copy State For Each Break")

for (i in (1:length(df3))){

  print(i)

  over <- findOverlaps(all, df3[[i]], minoverlap=2)

  tmp <- all[queryHits(over)]

  tmp$SegCNa <- df3[[i]]$SegCNa[subjectHits(over)]

  tmp$sample <- df3[[i]]$sample[subjectHits(over)]

  tmp <- as.data.frame(tmp, row.names = NULL)

  #####Next is to index which results segments match the total segmentation list

  for (j in (1:length(tmp$seqnames))){

    tmp2[j] <- which(tmp$seqnames[j]==df2$chr & tmp$start[j]==df2$pos & tmp$end[j]==df2$end)

  }

  tmp2 <- as.data.frame(tmp2)

  tmp2$SegCNa <- as.numeric(tmp$SegCNa)

  tmp2 <- tmp2 %>% arrange(tmp2)

  #####For each sample make a column and for the index matches add in the correct CNstate

  for (z in (1:length(tmp2$tmp2))){

    df2[tmp2$tmp2[z],paste(colnames[i],sep="")] <- tmp2$SegCNa[z]}

  tmp <- NULL

  tmp2 <- NULL

}

write.table(df2, file = paste(outdir,"allCNbreaks.txt",sep=""), append = FALSE, quote = FALSE, sep = "\t", eol = "\n", na = "NA", dec = ".", col.names = TRUE, row.names = FALSE)

return(df2)

}