Train TOP logistic model

Source: vignettes/train_TOP_logistic_model.Rmd

Similar to the tutorial Training TOP quantitative occupancy model, here we show an example procedure to train TOP logistic (binary) model.

Prepare training data

Similar to the steps in the tutorial Training TOP quantitative occupancy model, we need to prepare and assemble the training data containing all training TF x cell type combinations.

Load packages

We need to have R packages R2jags and doParallel installed to train TOP models, as we use JAGS to run Gibbs sampling for the Bayesian hierarchical model.

Step 1: Prepare training data for each TF in each cell type

Firstly, we need to prepare training data for each training TF x cell type combination, and save the training data files (as .rds files in the data_file column in the table below).

For each TF in each cell type, we prepare training data for candidate binding sites: including:

  • PWM scores of the motif matches.
  • DNase (or ATAC) counts in MILLIPEDE bins.
  • binary ChIP labels (from ChIP-seq peaks).

You can follow this procedure to prepare the training data.

Step 2: Assemble training data for all TF-cell type combinations

We create a table (data frame) listing all training TF x cell type combinations. The table should have three columns: TF names, cell types, and paths to the training data files, like:

tf_name cell_type data_file
CTCF K562 CTCF.K562.data.rds
CTCF A549 CTCF.A549.data.rds
CTCF GM12878 CTCF.GM12878.data.rds
NRF1 K562 NRF1.K562.data.rds
MYC K562 MYC.K562.data.rds
… … …

Use the following assemble_training_data() function, we split the training data randomly into 10 equal partitions, so that we could run Gibbs sampling on these partitions in parallel to reduce the running time.

We can choose the training chromosomes by specifying the chromosomes in training_chrs, for example using odd chromosomes as below. The chromosome names (“chr…”) should match with those in the training data.

assembled_training_data <- assemble_training_data(tf_cell_table,
                                                  logistic_model = TRUE, # use logistic model
                                                  chip_colname = 'chip_label', # name of the column with ChIP labels in training data
                                                  training_chrs = paste0('chr', seq(1,21,2)), 
                                                  n_partitions = 10)

Fit TOP logistic models using assembled training data

Here, we fit TOP logistic models with ChIP-seq binary labels. To fit TOP quantitative occupancy models with ChIP-seq read counts, please see this tutorial.

The fit_TOP_model() function below runs Gibbs sampling for each of the 10 partitions in parallel.

We can set the following parameters for Gibbs sampling:

  • n_iter: number of total iterations per chain (including burn-in iterations).
  • n_burnin: number of burn-in iterations, i.e. number of iterations to discard at the beginning.
  • n_chains: number of Markov chains.
  • n_thin: thinning rate, must be a positive integer.

The following example runs 10000 iterations of Gibbs sampling in total, with 2000 burn-ins, 3 Markov chains, thinning rate of 2.

It could take a long time if we have many TFs and many cell types in the training data.

all_TOP_samples <- fit_TOP_M5_model(assembled_training_data, 
                                    logistic_model = TRUE,
                                    n_iter = 5000, 
                                    n_burnin = 2000,
                                    n_chains = 3,
                                    n_thin = 2,
                                    out_dir = 'TOP_logistic_fit')

This fits a TOP model on all 10 partitions in parallel on 10 CPU cores, and returns a list of posterior samples of the coefficients for each of the 10 partitions. It requires a compute node/machine with 10 cores and may require a big memory if you have training data from many TFs and cell types. Alternatively, if you have limited computing resource, you may fit model for each of the 10 the partitions on separate machines, by specifying the partition to run. For example, setting argument partitions=3 will fit TOP model for training data in the 3rd partition.

Combine TOP posterior samples from all partitions and extract the posterior mean of the regression coefficients

After we finished Gibbs sampling for all 10 partitions, we select and combine the posterior samples from all the partitions.

TOP_samples <- combine_TOP_samples(all_TOP_samples)
dim(TOP_samples)

We can extract posterior mean of the coefficients for all three levels.

TOP_mean_coef <- extract_TOP_mean_coef(TOP_samples, 
                         assembled_training_data = assembled_training_data)

Save posterior samples and posterior mean of the regression coefficients.

saveRDS(TOP_samples, 'TOP_logistic_fit/TOP_logistic_M5_combined_posterior_samples.rds')
saveRDS(TOP_mean_coef, 'TOP_logistic_fit/TOP_logistic_M5_posterior_mean_coef.rds')

We have included pre-trained model parameters using ENCODE data within this package, and also on our companion resources website. We will also train new models when new data become available, and update the model parameters on our companion site.

To make predictions for TF occupancy using new DNase- or ATAC-seq data using pretrained model coefficients, please see this tutorial.