Package ‘fishhook’ April 18, 2017 Title R Package for performing Gamma-Poisson regression on somatic mutation count data Version 0.1 Description Package for performing Gamma-Poisson regression on somatic mutation count data with covariates to identify mutational enrichment or depletion in a statistically calibrated fashion. Depends R (>= 3.1.0), GenomicRanges (>= 1.18), gUtils Imports MASS, rtracklayer (>= 1.26), zoo, ffTrack, data.table (>= 1.9), gUtils, GenomeInfoDb, S4Vectors, BiocGenerics, R6 Suggests parallel License GPL-2 LazyData true RoxygenNote 6.0.1

R topics documented: aggregate.targets annotate.targets . Annotated . . . . c.Cov . . . . . . Cov . . . . . . . Cov_Arr . . . . . FishHook . . . .

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aggregate.targets qq_pval . . Score . . . score.targets [.Annotate . [.Cov_Arr .

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Index

aggregate.targets

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. 8 . 9 . 10 . 10 . 11 12

aggregate.targets

Description Gathers annotated targets across a vector "by" into meta-intervals returned as a GRangesList, and returns the aggregated statistics for these meta intervals by summing coverage and counts, and performing a weighted average of all other meta data fields (except query.id) Usage aggregate.targets(targets, by = NULL, fields = NULL, rolling = NULL, disjoint = TRUE, na.rm = FALSE, FUN = list(), verbose = TRUE) Arguments targets

annotated GRanges of targets with fields $coverage, optional field, $count and additional numeric covariates, or path to .rds file of the same

by

character vector with which to split into meta-territories

fields

by default all meta data fields of targets EXCEPT reserved field names $coverage, $counts, $query.id

rolling

if specified, positive integer specifying how many (genome coordinate) adjacent to aggregate in a rolling fashion

Details If rolling = TRUE, will return a rolling collapse of the sorted input where "rolling" specifies the number of adjacent intervals that are aggregated in a rolling manner. (only makes sense for tiled target sets) If by = NULL and targets is a vector of path names, then aggregation will be done "sample wise" on the files, ie each .rds input will be assumed to comprise the same intervals in teh same order and aggregation will be computed coverage-weighted mean of covariates, a sum of coverage and counts, and (if present) a Fisher combined of $p values. Covariates are inferred from the first file in the list. Value GRangesList of input targets annotated with new aggregate covariate statistics OR GRanges if rolling is specified

annotate.targets

3

Author(s) Marcin Imielinski

annotate.targets

annotate.targets

Description Takes input of GRanges targets, an optional set of "covered" intervals, and an indefinite list of covariates which can be R objects (GRanges, ffTrack, Rle) or file paths to .rds, .bw, .bed files, and an annotated target intervals GRanges with covariates computed for each interval. These target intervals can be further annotated with mutation counts and plugged into a generalized linear regression (or other) model downstream. Usage annotate.targets(targets, covered = NULL, events = NULL, ..., mc.cores = 1, na.rm = TRUE, pad = 0, verbose = TRUE, max.slice = 1000, ff.chunk = 1e+06, max.chunk = 1e+11, out.path = NULL, covariates = list(), maxPtGene = Inf, weightEvents = FALSE) Arguments targets

path to bed or rds containing genomic target regions with optional target name

covered

optional path to bed or rds containing granges object containing "covered" genomic regions

events

optional path to bed or rds containing ranges corresponding to events (ie mutations etc)

...

paths to sequence covariates whose output names will be their argument names, and each consists of a list with $track field corresponding to a GRanges, RleList, ffTrack object (or path to rds containing that object), $type which can have one of three values "numeric", "sequence", "interval". Numeric tracks must have $score field if they are GRanges), and can have a $na.rm logical field describing how to treat NA values (set to na.rm argument by default) Sequence covariates must be ffTrack objects (or paths to ffTrack rds) and require an additional variables $signatures, which will be used as input to fftab, and can have optional logical argument $grep to specify inexact matches (see fftab) Interval covariates must be Granges (or paths to GRanges rds) or paths to bed files

out.path

out.path to save variable to

maxPtGene

Sets the maximum number of events a patient can contribute per target

out.path

out.path to save variable to

weightEvetns

If true, will weight events by thier overlap with targets. e.g. if 10 region, that target region will get assigned a score of 0.1 for that event. If false, any overlap will be given a weight of 1.

4

Annotated

Details There are three types of covariates: numeric, sequence, interval. The covariates are computed as follows: numeric covariates: the mean value sequence covarites: fraction of bases satisfying $signature interval covariates: fraction of bases overlapping feature Value GRanges of input targets annotated with covariate statistics (+/- constrained to the subranges in optional argument covered) Author(s) Marcin Imielinski

Annotated

Annotated

Description Stores the annotated data from a FishHook object. and allows users to aggregate,manipulate and score that data. This object should be generated by calling FishHook$annotateTargets(). Note that this is where the meat of the computational burden lies. For example, in our test cases, running 8k pts worth of exome seq on 20k genes took 20seconds without covariates and 20sec + ~5min per covariate added. Usage Annotated Arguments targets

Examples of targets are genes, enhancers, 1kb tiles of the genome that we can then convert into a rolling window. This param must be of class "GRanges".

events

Events are the given mutational regions and must be of class "GRanges". Examples of events are mutational data (e.g. C->G) copy number variations and fusion events. Targets are the given regions of the genome to annotate and must be of class "GRanges".

covered

This is equivalent to Eligible in the FishHook class. Eligible are the regions of the genome that we feel are fit to score. For example in the case of exome sequencing where not all regions are equally represented, eligible can be a set of regions that meet an arbitrary coverage threshold. Another example of when to use eligibility is in the case of whole genomes, where your targets are 1kb tiles. Regions of the genome you would want to exclude in this case are highly repetative regions such as centromeres, telomeres, and satelite repeates. This param must be of class "GRanges".

c.Cov covariates

5 Covariates are genomic covariates that you belive will cause your given type of event (mutations, CNVs, fusions) that are not linked to the process you are investigating (e.g. cancer biology). In the case of cancer biology we are looking for regions that are mutated as part of cancer progression, and regions that are more suceptable to random mutagenesis such as late replicating or non-expressed region (transcription coupled repair) are potential false positives. Includinig covariates for these will reduce thier prominence in the final data. This param must be of type "Cov_Arr" which can be created by wrapping Cov objects in c(). e.g. c(Cov1,Cov2,Cov3).

Format An object of class R6ClassGenerator of length 24. Value Annotate Obeject that can be scored & manipulated and aggregated. Author(s) Zoran Z. Gajic

c.Cov

c.Cov

Description Override the c operator for covariates so that when you type: c(Cov1,Cov2,Cov3) it returns a Cov_Arr object that support vector like operation. Usage ## S3 method for class 'Cov' c(...) Arguments ...

A series of Covariates, note all objects must be of type Cov

Value Cov_Arr object that can be passed directly into the FishHook object constructor Author(s) Zoran Z. Gajic

6

Cov_Arr

Cov

Cov

Description Stores Covariate for passing to FishHook object. To be packaged in the Cov_Array Class by calling c(Cov1,Cov2,Cov3) Usage Cov Arguments Covariate

object of type, GRanges, ffTrack, RleList or character. Note that character objects must be paths to files containing one of the other types as a .rds file

type

a string indicating the type of Covariate, valid options are: numeric, sequence, interval. See Annotate Targets for more information on Covariate types

signature

In the case where a ffTrack object is of type sequence, a signature field is required, see fftab in ffTrack for more information.

Format An object of class R6ClassGenerator of length 24. Value Cov object that can be passed to FishHook object constructor Author(s) Zoran Z. Gajic

Cov_Arr

Cov_Arr

Description Stores Covariates for passing to FishHook object constructor.Standard initialization involves calling c(Cov1,Cov2,Cov3). Cov_Arr serves to mask the underlieing list implemenations of Covariates in the FishHook Object. This class attempts to mimic a vector in terms of subsetting and in the future will add more vector like operations. Usage Cov_Arr

FishHook

7

Arguments ...

several Cov objects for packaging.

Format An object of class R6ClassGenerator of length 24. Value Cov_Arr object that can be passed directly to the FishHook object constructor Author(s) Zoran Z. Gajic

FishHook

FishHook

Description Stores Events, Targets, Eligible, Covariates. Usage FishHook Arguments targets

Examples of targets are genes, enhancers, 1kb tiles of the genome that we can then convert into a rolling window. This param must be of class "GRanges".

events

Events are the given mutational regions and must be of class "GRanges". Examples of events are mutational data (e.g. C->G) copy number variations and fusion events. Targets are the given regions of the genome to annotate and must be of class "GRanges".

eligible

Eligible are the regions of the genome that we feel are fit to score. For example in the case of exome sequencing where not all regions are equally represented, eligible can be a set of regions that meet an arbitrary coverage threshold. Another example of when to use eligibility is in the case of whole genomes, where your targets are 1kb tiles. Regions of the genome you would want to exclude in this case are highly repetative regions such as centromeres, telomeres, and satelite repeates. This param must be of class "GRanges".

covariates

Covariates are genomic covariates that you belive will cause your given type of event (mutations, CNVs, fusions) that are not linked to the process you are investigating (e.g. cancer biology). In the case of cancer biology we are looking for regions that are mutated as part of cancer progression, and regions that are more

8

qq_pval suceptable to random mutagenesis such as late replicating or non-expressed region (transcription coupled repair) are potential false positives. Includinig covariates for these will reduce thier prominence in the final data. This param must be of type "Cov_Arr" which can be created by wrapping Cov objects in c(). e.g. c(Cov1,Cov2,Cov3).

Format An object of class R6ClassGenerator of length 24. Value FishHook object that can be annotated. Author(s) Zoran Z. Gajic

qq_pval

qq plot given input p values

Usage qq_pval(obs, highlight = c(), exp = NULL, lwd = 1, bestfit = T, col = NULL, col.bg = "black", pch = 18, cex = 1, conf.lines = T, max = NULL, max.x = NULL, max.y = NULL, qvalues = NULL, label = NULL, plotly = FALSE, annotations = list(), gradient = list(), titleText = "", subsample = NA, ...) Arguments obs

vector of pvalues to plot, names of obs can be intepreted as labels

highlight

optional arg specifying indices of data points to highlight (ie color red)

lwd

integer, optional, specifying thickness of line fit to data

pch

integer dot type for scatter plot

cex

integer dot size for scatter plot

conf.lines

logical, optional, whether to draw 95 percent confidence interval lines around x-y line

max

numeric, optional, threshold to max the input p values

label

character vector, optional specifying which data points to label (obs vector has to be named, for this to work)

plotly

toggles between creating a pdf (FALSE) or an interactive html widget (TRUE)

annotations

named list of vectors containing information to present as hover text (html widget), must be in same order as obs input

Score

9

gradient

named list that contains one vector that color codes points based on value, must bein same order as obs input

titleText

title for plotly (html) graph only

samp

integer, optional specifying how many samples to draw from input data (default NULL)

Author(s) Marcin Imielinski, Eran Hodis, Zoran Z. Gajic

Score

Score

Description Stores the scored targets. Note that this constructors should be called from Annotated$scoreTargets(). Scores can also be plotted on qqplots using included functions. For other params see score.targets() Usage Score Arguments annotated

The annotated targets as an output from Annotated$scoreTargets() or the standard score.targets().

Format An object of class R6ClassGenerator of length 24. Value Score object that can be plotted/analyzed Author(s) Zoran Z. Gajic

10

[.Annotate

score.targets

score.targets

Description Scores targets based on covariates using gamma-poisson model with coverage as constant Usage score.targets(targets, covariates = names(values(targets)), model = NULL, return.model = FALSE, nb = TRUE, verbose = TRUE, iter = 200, subsample = 1e+05, seed = NULL, p.randomized = TRUE, classReturn = FALSE) Arguments targets

annotated targets with fields $coverage, optional field, $count and additional numeric covariates

Value GRanges of scored results Author(s) Marcin Imielinski

[.Annotate

[.Annotate

Description Overrides the "[" operator for the Annotated object. This allows subsetting of the annotated data in Annotated Objects. Usage ## S3 method for class 'Annotate' obj[range] Arguments obj

This is the Annotated object to be subset

range

This is the range of targets to return, like subsetting a vector. e.g. c(1,2,3,4,5)[3:4] == c(3,4)

[.Cov_Arr

11

Value Annotated object that can manipulated and scored, but cannot be aggregated again. Author(s) Zoran Z. Gajic

[.Cov_Arr

[.Cov_Arr

Description Overrides the subset operator x[] for use with Cov_Arr to allow for vector like subsetting Usage ## S3 method for class 'Cov_Arr' obj[range] Arguments obj

This is the Cov_Arr to be subset

range

This is the range of Covariates to return, like subsetting a vector. e.g. c(1,2,3,4,5)[3:4] == c(3,4)

Value A new Cov_Arr object that contains only the Covs within the given range Author(s) Zoran Z. Gajic

Index ∗Topic datasets Annotated, 4 Cov, 6 Cov_Arr, 6 FishHook, 7 Score, 9 [.Annotate, 10 [.Cov_Arr, 11 aggregate.targets, 2 annotate.targets, 3 Annotated, 4 c.Cov, 5 Cov, 6 Cov_Arr, 6 FishHook, 7 qq_pval, 8 Score, 9 score.targets, 10

12

Package 'fishhook' - GitHub

Apr 18, 2017 - count data with covariates to identify mutational enrichment or depletion in a .... $signature interval covariates: fraction of bases overlapping feature .... toggles between creating a pdf (FALSE) or an interactive html widget ...

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