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README.md
<!-- README.md is generated from README.Rmd. Please edit that file --> # Introduction `scHiCcompare` is designed for the imputation, joint normalization, and detection of differential chromatin interactions between two groups of chromosome-specific single-cell Hi-C datasets (scHi-C). The groups can be pre-defined based on biological conditions or created by clustering cells according to their chromatin interaction patterns. Clustering can be performed using methods like [Higashi](https://github.com/ma-compbio/Higashi), [scHiCcluster](https://github.com/zhoujt1994/scHiCluster) methods, etc. `scHiCcompare` works with processed Hi-C data, specifically chromosome-specific chromatin interaction matrices, and accepts five-column tab-separated text files in a sparse matrix format. The package provides two key functionalities: - Imputation of single-cell Hi-C data by random forest model with pooling technique - Differential analysis to identify differences in chromatin interactions between groups. # Installation ``` r if (!requireNamespace("BiocManager", quietly = TRUE)) { install.packages("BiocManager") } BiocManager::install("scHiCcompare") # For the latest version install from GitHub # devtools::install_github("dozmorovlab/scHiCcompare") ``` ``` r library(scHiCcompare) library(tidyr) library(ggplot2) library(gridExtra) library(lattice) library(data.table) ``` # Usage ## Input To use scHiCcompare, you’ll need to define two groups of cells to compare and save cell-specific scHi-C data (individual files in **.txt** format) in two folders. Each cell-specific scHi-C **.txt** file should be formatted as modified sparse upper triangular matrices in R, which consist of five columns (chr1, start1, chr2, start2, IF). Since the full matrix of chromatin interactions is symmetric, only the upper triangular portion, including the diagonal and excluding any 0, is stored in a sparse matrix format. The required sparse matrix format of each single-cell Hi-C is: - “chr1” - Chromosome of the first region. - “start1” - a start coordinate (in bp) of the first region. - “chr2” - Chromosome of the second region. - “start2” - a start coordinate (in bp) of the second region. - “IF” - the interaction frequency between 2 two regions (IFs). The ‘.txt’ files need to be saved in tab-separated columns and no row names, column names, or quotes around character strings with the example format below. #> chr1 start1 chr2 start2 IF #> 17669 chr20 0 chr20 0 128 #> 17670 chr20 0 chr20 1000000 1 #> 17671 chr20 1000000 chr20 1000000 179 #> 17672 chr20 0 chr20 2000000 1 #> 17673 chr20 1000000 chr20 2000000 1 #> 17674 chr20 2000000 chr20 2000000 174 To run `scHiCcompare()`, you need two folders with condition-specific scHiC ‘.txt’ files. The condition-specific groups of cells should be pre-defined based on criteria such as experimental conditions, clustering results, or biological characteristics. ### Prepare input folders Here is an example workflow using scHiC human brain datasets (Lee et al., 2019) with ODC and MG cell types at chromosome 20 with a 1MB resolution. For the following example sections, we will load samples of 10 single-cell Hi-C data (in ‘.txt’) for each cell type group in two example folders (`ODCs_example` and `MGs_axample`). The files follow the same format as those downloaded via `download_schic()` of `Bandnorm`. You can extract the folder path by the code below, which could be used as input for `scHiCcompare()` function. ``` r ## Load folder of ODC file path ODCs_example_path <- system.file("extdata/ODCs_example", package = "scHiCcompare" ) ## Load folder of MG file path MGs_example_path <- system.file("extdata/MGs_example", package = "scHiCcompare" ) ``` Since the data downloaded by `Bandnorm` has the required input format (5 columns of \[chr1, start1, chr2, start2, IF\]), we don’t need an extra step for data modification. If, after importing your data into R, its format does not follow the sparse upper triangular [input](#input) format requirement, you need to modify the data. ## scHiCcompare function The function requires two *Input Parameter*: - `file.path.1, file.path.2` - Character strings specifying paths to folders containing scHi-C data for the first and second cell type or condition groups. - `select.chromosome` - Integer or character indicating the chromosome to be analyzed (e.g., ‘chr1’ or ‘chr10’.) ``` r scHiCcompare(file.path.1, file.path.2, select.chromosome, main.Distances = 1:10000000, imputation = "RF", normalization = "LOESS", differential.detect = "MD.cluster", pool.style = "progressive", n.imputation = 5, maxit = 1, outlier.rm = TRUE, missPerc.threshold = 95, A.min = NULL, fprControl.logfc = 0.8, alpha = 0.05, Plot = T, Plot.normalize = F, save.output.path = NULL ) ``` *Optional Workflow Parameter* include: - `main.Distances` - A numeric vector indicating the range of interacting genomic distances (in base pairs) between two regions (e.g., loci or bins) to focus on (e.g., `1:100000`, `Inf`). All genomic range selections can be specified using `Inf`. The `main.Distances` vector should be proportional to the data’s resolution (e.g., for 10kb resolution: `1:10000`, `1:50000`, `1:100000`, `Inf`). As the distance range and resolution increase, the percentage of ‘0’ or missing values also increases. Selecting a large distance range at high resolution (e.g., below 200kb) may increase runtime due to extreme sparsity. By default, `main.Distances` = `1:10000000`. - `imputation` - A character string, either `'RF'` or `NULL`, indicating the imputation method. If `NULL` is selected, the workflow will skip the `imputation` step. The default is `'RF'` for Random Forest imputation. - `normalization` - A character string, either `'LOESS'` or `NULL`, indicating the normalization method. If `NULL` is selected, the workflow will skip the `normalization` step. The default is `'LOESS'`. *Optional Imputation Parameter* include: - `pool.style` - A character string specifying the pooling style for `imputation`. Options are `'none'`, `'progressive'`, or `'Fibonacci'`. The default is `'progressive'`. - `n.imputation` - An integer specifying the number of multiple imputations for the imputation step. Because the final imputed values are calculated as the average of multiple imputations, increasing the number of imputations improves the accuracy of imputed values; however, it may also extend the imputation runtime. The default is `5`. - `maxit` - An integer specifying the maximum number of iterations for the internal refinement process within a single `imputation` cycle. Increasing `maxit` can help stabilize imputed values, although it may increase the imputation runtime. The default is `1`. - `outlier.rm` - Logical. If `TRUE`, outliers are removed during `imputation`. The default is `TRUE`. - `missPerc.threshold` - A numeric value specifying the maximum allowable percentage of missing data in pool bands outside the `main.Distances` to be imputed by the `imputation` method. A higher threshold includes more extreme sparse distances for imputation (e.g., above 95 percent), which increases memory and runtime, while a lower threshold (e.g., below 50 percent) might reduce the number of distances imputed. The default is `95`. *Optional Normalization Parameter* include: - `A.min` - Numeric value or NULL that sets the A-value quantile cutoff (eg,. 7, 10, etc) for filtering low average interaction frequencies in the outlier detection in the differential step of the `hic_compare()` function from `HiCcompare`. If not provided (NULL), A is auto-detected. *Optional Differential Test Parameter* include: - `fprControl.logfc` - Numeric value to control the false positive rate for GMM difference clusters (`differential.detect`) (e.g., 0.5, 0.8, 1, 1.5, etc.). Increasing `fprControl.logfc` may lower the false positive rate but may also reduce the number of detected chromatin interaction differences. The default is 0.8, equivalent to a 2-fold change. - `alpha` - Numeric value specifying the significance level for outlier detection during the `differential.detect` step with the `hic_compare()` function from HiCcompare. Default is 0.05. *Optional Output Parameter* : - `save.output.path` - Character string specifying the directory to save outputs, including the imputed cells in the form of a sparse upper triangular format, normalization result table, and differential analysis result table. If `save.output.path` = NULL (the default), no files are saved. - `Plot` - A logical value indicating whether to plot the `differential.detect` results in an MD plot. Default is TRUE. - `Plot.normalize` - A logical value indicating whether to plot the output of MD plot showing before/after LOESS `normalization`. Default is FALSE. ### Example of real analysis In the following example, we will work with scHi-C data from 10 single cells in both ODC and MG cell types at a 1 MG resolution. We will focus on chromosome 20, applying the full workflow of scHiCcompare, which includes imputation, pseudo-bulk normalization, and differential analysis. Our goal is to detect differences for loci with genomic distances ranging from 1 to 10,000,000 bp. The progressive pooling style will be selected to create pool bands for the random forest imputation. For the differential analysis step, we will set the log fold change - false positive control threshold to 0.8. The input file path was included in the package and conducted in the [Prepare input folders](#prepare-input-folders) section. ``` r ## Imputation with 'progressive' pooling result <- scHiCcompare( file.path.1 = ODCs_example_path, file.path.2 = MGs_example_path, select.chromosome = "chr20", main.Distances = 1:10000000, imputation = "RF", normalization = "LOESS", differential.detect = "MD.cluster", pool.style = "progressive", fprControl.logfc = 0.8, Plot = TRUE, Plot.normalize = TRUE ) ``` <img src="man/figures/README-unnamed-chunk-9-1.png" width="100%" /><img src="man/figures/README-unnamed-chunk-9-2.png" width="100%" /><img src="man/figures/README-unnamed-chunk-9-3.png" width="100%" /> From the visualizations above, normalization effectively reduces the irregular trend in the M values between the imputed pseudo-bulk matrices of the two cell types. At a 1MB resolution, the differential analysis reveals that most of the detected differences occur at closer genomic distances, particularly below 5MB. ## Output #### Output objects from the R function The `scHiCcompare()` function will return an object that contains plots, differential results, pseudo-bulk matrices, normalized results, and imputation tables. The full differential results are available in `$Differential_Analysis`. Intermediate results can be accessed with `$Intermediate`, including the imputation result table (`$Intermediate$Imputation`), the pseudo-bulk matrix in sparse format (`$Intermediate$PseudoBulk`), and the normalization table (`$Intermediate$Bulk.Normalization`). These output table objects have the following structure: - `$Intermediate$PseudoBulk` for each condition group (`$condition1` and `$condition2`) has a standard sparse upper triangular format with 3 columns of \[region1, region2, IF\]. - `$Intermediate$Imputation` for each condition group (`$condition1` and `$condition2`) has modified sparse upper triangular format: - Interacting bins coordination \[region1, region2, cell (condition 1 or condition2), chr\] - Imputed interaction frequency of each single-cell \[imp.IF\_{cell name 1}, imp.IF\_{cell name 2}, imp.IF\_{cell name 3}, …,etc\] - `$Intermediate$Bulk.Normalization` has 15 columns - Interacting bins coordination \[chr1, start1, end1, chr2, start2, end2, D (scaled genomic distance)\] - Bulk IF values \[bulk.IF1, bulk.IF2, M (their log fold change, $log(IF_2/IF_1)$)\] - Normalized bulk IF values \[adj.bulk.IF1, adj.bulk.IF2, adj.M (their log fold change, $log(adj.IF_2/adj.IF_1)$)\] - LOESS correction factor \[mc\]; - Average expression value of bulk IF \[A\]. - `$Differential_Analysis` has same structure as `$Intermediate$Bulk.Normalization` with addition of 2 differential detection results columns - Z score of interaction frequencies’s log fold change \[Z\] - Differential result cluster \[Difference.cluster\] #### Externally saved output files You also can have the option to save the results into the chosen directory by a parameter in `scHiCcompare()` [function](#schiccompare-function). This will save the normalization result table, differential result table, and imputed cell scHi-C data (each group is a sub-folder). The sample of the saved output folder structure is: \|– Bulk_normalization_table.txt \|– Differential_analysis_table.txt \|– Imputed\_{group 1’s name}/ - \|– imp\_{cell name}.txt \|– Imputed\_{group 2’s name}/ - \|– imp\_{cell name}.txt The normalization result `Bulk_normalization_table.txt` has the same format as the output object from the `scHiCcompare()` function, `$Intermediate$Bulk.Normalization`, which is shown in the structure example below. The differential result table `Differential_analysis_table.txt` also has the same format as the output object `$Differential_Analysis` from the function. The imputed cell’s scHiC data is saved in a folder for each group, which has a modified sparse upper triangular format of five columns \[chr1, start1, chr2, start2, IF\]. ### Example of output Below is a continuous example from [Example of real anlysis](#example-of-real-anlysis) above, showing how you can extract different result options from the `scHiCcompare()` function. ``` r ### Extract imputed differential result diff_result <- result$Differential_Analysis head(diff_result) #> chr1 start1 end1 chr2 start2 end2 bulk.IF1 bulk.IF2 D M #> <char> <num> <num> <char> <num> <num> <num> <num> <num> <num> #> 1: chr20 0e+00 1e+06 chr20 1e+06 2e+06 43 35 1 -0.29698174 #> 2: chr20 1e+06 2e+06 chr20 2e+06 3e+06 38 45 1 0.24392558 #> 3: chr20 2e+06 3e+06 chr20 3e+06 4e+06 33 32 1 -0.04439412 #> 4: chr20 3e+06 4e+06 chr20 4e+06 5e+06 26 28 1 0.10691520 #> 5: chr20 4e+06 5e+06 chr20 5e+06 6e+06 41 33 1 -0.31315789 #> 6: chr20 5e+06 6e+06 chr20 6e+06 7e+06 35 20 1 -0.80735492 #> adj.bulk.IF1 bulk.adj.IF2 adj.M mc A Z #> <num> <num> <num> <num> <num> <num> #> 1: 40.49493 37.16514 -0.1237912 -0.1731905 38.83004 -0.3167693 #> 2: 35.78622 47.78376 0.4171161 -0.1731905 41.78499 1.0969765 #> 3: 31.07751 33.97956 0.1287964 -0.1731905 32.52853 0.3434079 #> 4: 24.48531 29.73211 0.2801057 -0.1731905 27.10871 0.7388785 #> 5: 38.61145 35.04142 -0.1399674 -0.1731905 36.82643 -0.3590482 #> 6: 32.96099 21.23722 -0.6341644 -0.1731905 27.09911 -1.6507094 #> Difference.cluster #> <num> #> 1: 1 #> 2: 1 #> 3: 1 #> 4: 1 #> 5: 1 #> 6: 1 ``` ``` r ### Extract imputed pseudo bulk matrices normalization norm_result <- result$Intermediate$Bulk.Normalization head(norm_result) #> chr1 start1 end1 chr2 start2 end2 bulk.IF1 bulk.IF2 D M #> <char> <num> <num> <char> <num> <num> <num> <num> <num> <num> #> 1: chr20 1e+06 2e+06 chr20 1e+06 2e+06 1830 2246 0 0.2955143 #> 2: chr20 2e+06 3e+06 chr20 2e+06 3e+06 2009 2260 0 0.1698452 #> 3: chr20 3e+06 4e+06 chr20 3e+06 4e+06 1502 1956 0 0.3810216 #> 4: chr20 4e+06 5e+06 chr20 4e+06 5e+06 1749 2317 0 0.4057278 #> 5: chr20 5e+06 6e+06 chr20 5e+06 6e+06 2040 2400 0 0.2344653 #> 6: chr20 6e+06 7e+06 chr20 6e+06 7e+06 2020 2361 0 0.2250427 #> adj.bulk.IF1 bulk.adj.IF2 adj.M mc A #> <num> <num> <num> <num> <num> #> 1: 1992.411 2062.918 0.05017112 0.2453432 2027.664 #> 2: 2187.297 2075.777 -0.07549795 0.2453432 2131.537 #> 3: 1635.301 1796.557 0.13567840 0.2453432 1715.929 #> 4: 1904.222 2128.130 0.16038459 0.2453432 2016.176 #> 5: 2221.048 2204.365 -0.01087791 0.2453432 2212.706 #> 6: 2199.273 2168.544 -0.02030041 0.2453432 2183.908 ``` ``` r ### Extract imputed ODC cell type table imp_ODC_table <- result$Intermediate$Imputation$condition1 head(imp_ODC_table) #> region1 region2 cell chr imp.IF_ODC.bandnorm_chr20_1 #> 1 1e+06 1e+06 condition1 chr20 179 #> 2 2e+06 2e+06 condition1 chr20 189 #> 3 3e+06 3e+06 condition1 chr20 204 #> 4 4e+06 4e+06 condition1 chr20 177 #> 5 5e+06 5e+06 condition1 chr20 181 #> 6 6e+06 6e+06 condition1 chr20 199 #> imp.IF_ODC.bandnorm_chr20_2 imp.IF_ODC.bandnorm_chr20_3 #> 1 174 194 #> 2 191 217 #> 3 197 190 #> 4 187 156 #> 5 196 218 #> 6 167 184 #> imp.IF_ODC.bandnorm_chr20_4 imp.IF_ODC.bandnorm_chr20_5 #> 1 201 171 #> 2 179 180 #> 3 200 108 #> 4 178 146 #> 5 200 263 #> 6 200 214 #> imp.IF_ODC.bandnorm_chr20_6 imp.IF_ODC.bandnorm_chr20_7 #> 1 142 198 #> 2 201 215 #> 3 25 184 #> 4 144 150 #> 5 162 215 #> 6 218 232 #> imp.IF_ODC.bandnorm_chr20_8 imp.IF_ODC.bandnorm_chr20_9 #> 1 175 208 #> 2 205 214 #> 3 176 54 #> 4 199 208 #> 5 191 191 #> 6 209 173 #> imp.IF_ODC.bandnorm_chr20_10 #> 1 188 #> 2 218 #> 3 164 #> 4 204 #> 5 223 #> 6 224 ``` ``` r ## Extract Pseudo-bulk matrix from imputed scHi-C data ## Pseudo bulk matrix in standard sparse format psudobulk_result <- result$Intermediate$PseudoBulk$condition1 head(psudobulk_result) #> region1 region2 IF #> 1 1e+06 1e+06 1830 #> 2 2e+06 2e+06 2009 #> 3 3e+06 3e+06 1502 #> 4 4e+06 4e+06 1749 #> 5 5e+06 5e+06 2040 #> 6 6e+06 6e+06 2020 ``` Furthermore, you also have some parameter options in the function to indicate which plots to output and an option to save the results in a given directory. # Helper functions There are several other functions included in `scHiCcompare` package. ## Heatmap HiC matrix plot `plot_HiCmatrix_heatmap()` produces a heatmap visualization for HiC and scHiC matrices. It requires, as input, a modified sparse matrix, the same format from `scHiCcompare()` [Input](#input) with five columns of chr1, start1, chr2 start2, IF. More information can be found in its help document and the example below. ``` r data("ODC.bandnorm_chr20_1") plot_HiCmatrix_heatmap(scHiC.sparse = ODC.bandnorm_chr20_1, main = "scHiC matrix of a ODC cell", zlim = c(0, 5)) #> Matrix dimensions: 63x63 ``` <img src="man/figures/README-unnamed-chunk-14-1.png" width="100%" /> ## Imputation Diagnostic plot `plot_imputed_distance_diagnostic()` generates a diagnostic visualization of imputation across genomic distances for all single cells. It compares the distribution of all cells’ interaction frequency at a given distance data before and after imputation. It requires, as input, the scHiC table format of the original and imputed scHiC datasets. ScHiC table format includes columns of genomic loci coordinates and interaction frequencies (IF) of each cell (cell, chromosome, start1, end1, IF1, IF2, IF3, etc). The output of `$Intermediate$Imputation` of `scHiCcompare()` function is directly compatible with this format. For more details, see the sections on [Output](#output)) ``` r # Extract imputed table result imp_MG_table <- result$Intermediate$Imputation$condition2 imp_ODC_table <- result$Intermediate$Imputation$condition1 ``` #> region1 region2 cell chr imp.IF_ODC.bandnorm_chr20_1 #> 1 1e+06 1e+06 condition1 chr20 179 #> 2 2e+06 2e+06 condition1 chr20 189 #> 3 3e+06 3e+06 condition1 chr20 204 #> 4 4e+06 4e+06 condition1 chr20 177 #> 5 5e+06 5e+06 condition1 chr20 181 #> 6 6e+06 6e+06 condition1 chr20 199 #> imp.IF_ODC.bandnorm_chr20_2 imp.IF_ODC.bandnorm_chr20_3 #> 1 174 194 #> 2 191 217 #> 3 197 190 #> 4 187 156 #> 5 196 218 #> 6 167 184 #> imp.IF_ODC.bandnorm_chr20_4 imp.IF_ODC.bandnorm_chr20_5 #> 1 201 171 #> 2 179 180 #> 3 200 108 #> 4 178 146 #> 5 200 263 #> 6 200 214 #> imp.IF_ODC.bandnorm_chr20_6 imp.IF_ODC.bandnorm_chr20_7 #> 1 142 198 #> 2 201 215 #> 3 25 184 #> 4 144 150 #> 5 162 215 #> 6 218 232 #> imp.IF_ODC.bandnorm_chr20_8 imp.IF_ODC.bandnorm_chr20_9 #> 1 175 208 #> 2 205 214 #> 3 176 54 #> 4 199 208 #> 5 191 191 #> 6 209 173 #> imp.IF_ODC.bandnorm_chr20_10 #> 1 188 #> 2 218 #> 3 164 #> 4 204 #> 5 223 #> 6 224 We need to create the table input for original IFs values in the same format. Below is a continuous example from [Example of real anlysis](#example-of-real-anlysis) above, showing how you can construct scHiC table for original IF values and compare them with the output of imputed IF values. ``` r # Create scHiC table object for original ODC interaction frequencies (IF) scHiC.table_ODC <- imp_ODC_table[c("region1", "region2", "cell", "chr")] # List all files in the specified directory for original ODC data file.names <- list.files(path = ODCs_example_path, full.names = TRUE, recursive = TRUE) # Loop through each file to read and merge data for (i in 1:length(file.names)) { # Read the current file into a data frame data <- read.delim(file.names[[i]]) names(data) <- c("chr", "region1", "chr2", "region2", paste0("IF_", i)) data <- data[, names(data) %in% c("chr", "region1", "region2", paste0("IF_", i))] # Merge the newly read data with the existing scHiC.table_ODC scHiC.table_ODC <- merge(scHiC.table_ODC, data, by = c("region1", "region2", "chr"), all = TRUE ) } # Create scHiC table object for original MG interaction frequencies (IF) scHiC.table_MG <- imp_MG_table[c("region1", "region2", "cell", "chr")] # List all files in the specified directory for original MG data file.names <- list.files(path = MGs_example_path, full.names = TRUE, recursive = TRUE) # Loop through each file to read and merge data for (i in 1:length(file.names)) { # Read the current file into a data frame data <- read.delim(file.names[[i]]) names(data) <- c("chr", "region1", "chr2", "region2", paste0("IF_", i)) data <- data[, names(data) %in% c("chr", "region1", "region2", paste0("IF_", i))] # Merge the newly read data with the existing scHiC.table_MG scHiC.table_MG <- merge(scHiC.table_MG, data, by = c("region1", "region2", "chr"), all = TRUE ) } ``` ``` r # plot imputed Distance Diagnostic of MG plot1 <- plot_imputed_distance_diagnostic( raw_sc_data = scHiC.table_MG, imp_sc_data = imp_MG_table, D = 1 ) plot2 <- plot_imputed_distance_diagnostic( raw_sc_data = scHiC.table_MG, imp_sc_data = imp_MG_table, D = 2 ) plot3 <- plot_imputed_distance_diagnostic( raw_sc_data = scHiC.table_MG, imp_sc_data = imp_MG_table, D = 3 ) plot4 <- plot_imputed_distance_diagnostic( raw_sc_data = scHiC.table_MG, imp_sc_data = imp_MG_table, D = 4 ) grid.arrange(plot1, plot2, plot3, plot4, ncol = 2, nrow = 2) ``` <img src="man/figures/README-unnamed-chunk-18-1.png" width="100%" /> The diagnostic visualizations demonstrate that with a sample of only 10 single cells per group (note: this small sample size is for demonstration purposes only), the imputed values for MG closely match the original distribution only at shorter genomic distances (e.g., D1, D2). Increasing the number of single cells per group enhances imputation accuracy across distances. We recommend using a minimum of 80 single cells per group for optimal imputation performance. # Session Info #> R version 4.2.3 (2023-03-15) #> Platform: x86_64-apple-darwin17.0 (64-bit) #> Running under: macOS Big Sur ... 10.16 #> #> Matrix products: default #> BLAS: /Library/Frameworks/R.framework/Versions/4.2/Resources/lib/libRblas.0.dylib #> LAPACK: /Library/Frameworks/R.framework/Versions/4.2/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] data.table_1.16.4 lattice_0.22-6 gridExtra_2.3 #> [4] ggplot2_3.5.1 tidyr_1.3.1 scHiCcompare_0.99.5 #> #> loaded via a namespace (and not attached): #> [1] minqa_1.2.6 colorspace_2.1-1 #> [3] CGHcall_2.60.0 mclust_6.0.1 #> [5] DNAcopy_1.72.3 XVector_0.38.0 #> [7] GenomicRanges_1.50.2 rstudioapi_0.17.1 #> [9] mice_3.17.0 farver_2.1.2 #> [11] listenv_0.9.1 HiCcompare_1.20.0 #> [13] ranger_0.17.0 codetools_0.2-20 #> [15] splines_4.2.3 R.methodsS3_1.8.2 #> [17] impute_1.72.3 knitr_1.49 #> [19] Formula_1.2-5 nloptr_2.0.3 #> [21] Rsamtools_2.14.0 broom_1.0.7 #> [23] miceadds_3.16-18 R.oo_1.27.0 #> [25] pheatmap_1.0.12 compiler_4.2.3 #> [27] backports_1.5.0 Matrix_1.6-4 #> [29] fastmap_1.2.0 limma_3.54.2 #> [31] cli_3.6.3 htmltools_0.5.8.1 #> [33] tools_4.2.3 gtable_0.3.6 #> [35] glue_1.8.0 GenomeInfoDbData_1.2.9 #> [37] dplyr_1.1.4 Rcpp_1.0.14 #> [39] carData_3.0-5 Biobase_2.58.0 #> [41] vctrs_0.6.5 Biostrings_2.66.0 #> [43] rhdf5filters_1.10.1 nlme_3.1-164 #> [45] iterators_1.0.14 QDNAseq_1.34.0 #> [47] xfun_0.50 globals_0.16.3 #> [49] rbibutils_2.3 lme4_1.1-36 #> [51] lifecycle_1.0.4 gtools_3.9.5 #> [53] rstatix_0.7.2 InteractionSet_1.26.1 #> [55] future_1.34.0 pan_1.9 #> [57] zlibbioc_1.44.0 MASS_7.3-60.0.1 #> [59] scales_1.3.0 MatrixGenerics_1.10.0 #> [61] parallel_4.2.3 SummarizedExperiment_1.28.0 #> [63] rhdf5_2.42.1 RColorBrewer_1.1-3 #> [65] yaml_2.3.10 rpart_4.1.24 #> [67] CGHbase_1.58.0 S4Vectors_0.36.2 #> [69] foreach_1.5.2 BiocGenerics_0.44.0 #> [71] boot_1.3-31 BiocParallel_1.32.6 #> [73] shape_1.4.6.1 GenomeInfoDb_1.34.9 #> [75] Rdpack_2.6.2 rlang_1.1.5 #> [77] pkgconfig_2.0.3 matrixStats_1.5.0 #> [79] bitops_1.0-9 evaluate_1.0.3 #> [81] purrr_1.0.2 Rhdf5lib_1.20.0 #> [83] labeling_0.4.3 tidyselect_1.2.1 #> [85] parallelly_1.42.0 magrittr_2.0.3 #> [87] R6_2.5.1 IRanges_2.32.0 #> [89] reformulas_0.4.0 generics_0.1.3 #> [91] mitml_0.4-5 DelayedArray_0.24.0 #> [93] DBI_1.2.3 withr_3.0.2 #> [95] pillar_1.10.1 mgcv_1.9-1 #> [97] abind_1.4-8 survival_3.8-3 #> [99] RCurl_1.98-1.16 nnet_7.3-20 #> [101] tibble_3.2.1 future.apply_1.11.3 #> [103] car_3.1-3 crayon_1.5.3 #> [105] jomo_2.7-6 KernSmooth_2.23-22 #> [107] rmarkdown_2.29 grid_4.2.3 #> [109] marray_1.76.0 digest_0.6.37 #> [111] R.utils_2.12.3 stats4_4.2.3 #> [113] munsell_0.5.1 glmnet_4.1-8 #> [115] mitools_2.4