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SCITE is a software package to compute mutation histories of somatic cells. Given noisy mutation profiles of single cells, SCITE performs a stochastic search to find the Maximum Likelihood (ML) or Maximum aposterori (MAP) tree and/or to sample from the posterior probability distribution. Tree reconstruction can be combined with an estimation of the error rates in the mutation profiles.

SCITE is particularly designed for reconstructing mutation histories of tumours based on mutation profiles obtained from single-cell exome sequencing experiments, but is in principle applicable to any type of (noisy) mutation profiles for which the infinite sites assumption can be made.

SCITE is freely available under a GPL3 license at https://gitlab.com/jahnka/SCITE

Start by opening a terminal and cloning the repository:

git clone https://gitlab.com/jahnka/SCITE

Easiest way to stat is using the supplied scite.sh wrapper, e.g.:

cd SCITE
export CXX=g++ # or clang++
./scite.sh -i samples/dataHou18.csv -n 18 -m 58 -r 1 -l 900000 -fd 6.04e-5 -ad 0.21545 0.21545 -cc 1.299164e-05

This call computes the ML tree(s) for the given dataset and parameter settings. See below for other program options.

Note: For subsequent runs not chaning the parameter n, m, s, transpose, and wether a truee tree is specified, you can run the same command, but replace ./scite.sh by ./scite to avoid re-compilation.

Each column specifies the mutation profile of a single cell, and each row represents one mutation. Columns are separated by a white space character.

The entry at position [i,j] should be

• 0 if mutation i is not observed in cell j,
• 1 if mutation i is observed in cell j, or
• 3 if the data point is missing

The sample datasets dataNavin.csv and dataXu.csv have this format.

The entry at position [i,j] should be

• 0 if mutation i is not observed in cell j,
• 1 if heterozygous mutation i is observed in cell j
• 2 if homozygous mutation i is observed in cell j
• 3 if the data point is missing

The sample datasets dataHou18.csv and dataHou78.csv have this format

A list specifying the names of the mutations, e.g. the name of the gene in which the mutation occurs. For the sample datasets provided here, these files have the extension .geneNames. If no such file is specified, the mutations are numbered from 1 to n.

If the true mutation tree is known (as in simulation experiments), the file with the true tree (in GraphViz format) can be specified to compare the predicted trees internally with the true tree.

ML/MAP trees are written to files in GraphViz and Newick format. Files are numbered consecutively (e.g. dataHou18_ml1.gv, dataHou18_ml1.newick, dataHou18_ml2.gv, dataHou18_ml2.newick, ...). The base name of the output file is derived from the name of the input file (unless a different name is specified via -o <filename>).

When the -p <INT> option is set, SCITE samples from the posterior distribution, and writes the sampled trees (in parent vector format) together with their scores and learned error rates to a single file (one sample per line). The name of the output file is derived from the input file name using the ending .sample.

• -i <filename> Replace <filename> with the file containing the mutation matrix

• -n <INT> Replace <INT> with the number of mutations (rows) in the dataset.

• -m <INT> Replace <INT> with the number of cells (columns) in the dataset.

• -r <INT> Set <INT> to the desired number of repetitions of the MCMC.

• -l <INT> Set <INT> to the desired chain length of each MCMC repetition

• -fd <DOUBLE> Set <DOUBLE> to the estimated false positive rate (false discoveries) of the sequencing experiment.

• -ad <DOUBLE> Set <DOUBLE> to the estimated false negative rate (allelic dropout) of the sequencing experiment.

• -fd <DOUBLE> Set <DOUBLE> to the estimated false positive rate (false calling of heterozygous mutation) of the sequencing. experiment

• -ad <DOUBLE> <DOUBLE> Set the first <DOUBLE> to the estimated rate of missed heterozygous mutations in the sequencing experiment and set the second <DOUBLE> to the estimated rate of heterozygous mutations called as homozygous mutations (dropout of the wildtype allele).

• -cc <DOUBLE> Set <DOUBLE> to the estimated rate of non-mutated sites called as homozygous mutations.

• -s Setting this option causes the sample attachment points (i. e. where the cells would attach to the tree) to be marginalized out.

• -p <INT> When setting this option, SCITE samples from the posterior distribution, and writes the trees to a file using the parent vector format. The value of <INT> specifies how dense the sampling is. The name of the output file is derived from the input file name using the ending .sample. To make sure that SCITE samples from the posterior distribution -p <INT> needs to be combined with -s (single cell attachment to the tree is marginalized out) and -g 1 (gamma is set to 1).

• -transpose This changes the tree representation from mutation tree to rooted binary leaf-labelled tree, where the samples are the leaf labels and mutations are placed on the edges. Using this option can decrease the search space size when there are more mutations than samples. This only works for ML trees.

• -e <double> Invokes the learning of error rate beta. Set <double> to a value between zero and one to specify the probability to chose the move for changing the error rate in the MCMC.

• -x <double> Scaling of the known error rate for the MH jump (default is 10).

• -sd <double> Prior standard deviation for AD error rate (default is 0.1). For the mean, the error rate specified after -ad is used.

• -o <filename> Replace <filename> with the desired base of the output file to overwrite the default output file names.

• -names <filename> Replace <filename> with a file listing the mutation names. By default the mutations are numbered from 1 to n by order of appearance in the inputfile.

• -a When setting this option, SCITE adds the individual cells as additional nodes (leafs) to the reported trees. Cells are attached where they fit best in the given tree (with respect to the error rates). By default, only the mutation tree is reported.

• -max_treelist_size <INT> This limits the number of co-optimal trees written to output files to the specified value.

• -g <DOUBLE> For ML/MAP computation only: Set <DOUBLE> to the desired value of gamma (gamma > 1: more local exploration, possibly local optimum; gamma < 1: easier to explore the space, but less deeply). The default value of gamma is 1 which is necessary for the MCMC chain to converge to the posterior distribution.

• -seed <INT> Replace <INT> with a positive integer to be used as a fixed seed for the random number generator.

• -t <filename> Replace <filename> with a file containing the true tree in GraphViz format.

• -move_probs <double> <double> <double> Changes the default probabilities for the three MCMC moves to the spedified values. The first move is prune and re-attach, the second is swap node labels, the third is swap subtrees. The default values are (0.55, 0.4, 0.05).

When combined with -transpose there are only two move types, prune and re-attach and swap leaf labels with default probabilities (0.4, 0.6). Therefore the parameter format for changing these move probabilities is -move_probs <double> <double>.