@@ -29,8 +29,9 @@

 allFitnessEffects(rT = NULL, epistasis = NULL, orderEffects = NULL,

   noIntGenes = NULL, geneToModule = NULL, drvNames = NULL,

-  genotFitness = NULL,  keepInput = TRUE, frequencyDependentFitness =

-  FALSE, frequencyType = NA)

+  genotFitness = NULL,  keepInput = TRUE, frequencyDependentBirth =

+  FALSE, frequencyDependentDeath = FALSE, frequencyDependentFitness,

+  frequencyType = NA, deathSpec = FALSE)

 allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

                    geneToModule = NULL,

@@ -75,7 +76,7 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

       three would have the same effects if a node that connects to root

       only connects to root).}

   }

-  This paramenter is not used if  \code{frequencyDependentFitness} is TRUE.

+  This paramenter is not used if  \code{frequencyDependentBirth} is TRUE.

   }

   \item{epistasis}{

     A named numeric vector. The names identify the relationship, and the

@@ -83,7 +84,7 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

     genes or modules involved is separated by a ":". A negative sign

     denotes the absence of that term.

-    This paramenter is not used if  \code{frequencyDependentFitness} is TRUE.

+    This paramenter is not used if  \code{frequencyDependentBirth} is TRUE.

   }

   \item{orderEffects}{

     A named numeric vector, as for \code{epistasis}. A ">" separates the

@@ -91,7 +92,7 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

   that the relationship is satisfied when mutation U has happened before

   mutation Z.

-  This paramenter is not used if  \code{frequencyDependentFitness} is TRUE.

+  This paramenter is not used if  \code{frequencyDependentBirth} is TRUE.

 }

 \item{noIntGenes}{

   A numeric vector (optionally named) with the fitness coefficients (or

@@ -103,7 +104,7 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

   Of course, avoid using potentially confusing characters in the

   names. In particular, "," and ">" are not allowed as gene names.

-  This paramenter is not used if  \code{frequencyDependentFitness} is TRUE.

+  This paramenter is not used if  \code{frequencyDependentBirth} is TRUE.

 }

 \item{geneToModule}{

@@ -117,7 +118,7 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

   must necessarily contain, in the first position, "Root" (since the

   restriction table contains a node named "Root"). See examples below.

-  This paramenter is not used if  \code{frequencyDependentFitness} is TRUE.

+  This paramenter is not used if  \code{frequencyDependentBirth} is TRUE.

 }

 \item{drvNames}{The names of genes that are considered drivers. This is

@@ -135,37 +136,39 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

 }

 \item{genotFitness}{A matrix or data frame that contains explicitly the

-  mapping of genotypes to fitness. For now, we only allow epistasis-like

-  relations between genes (so you cannot code order effects this way).

+  mapping of genotypes to birth and optionally death. For now, we only 

+  allow epistasis-like relations between genes (so you cannot code

+  order effects this way).

   Genotypes can be specified in two ways:

   \itemize{

-    \item As a matrix (or data frame) with g + 1 columns (where g >

-    1). Each of the first g columns contains a 1 or a 0 indicating that

+    \item As a matrix (or data frame) with g + 1 columns or g + 2 columns,

+	depending if death is specified or not(where g > 1). Each of the first 

+	g columns contains a 1 or a 0 indicating that

     the gene of that column is mutated or not. Column g+ 1 contains the

-    fitness values. This is, for instance, the output you will get from

+    birth values. This is, for instance, the output you will get from

     \code{\link{rfitness}}. If the matrix has all columns named, those

     will be used for the names of the genes. Of course, except for

     column or row names, all entries in this matrix or data frame must

-    be numeric, except when \code{frequencyDependentFitness} is TRUE.

-    In this case, last column must be character and contains fitness

+    be numeric, except when \code{frequencyDependentBirth} is TRUE.

+    In this case, last column must be character and contains birth

     equations.

-    \item As a two column data frame. The second column is fitness, and

+    \item As a two column data frame. The second column is birth, and

     the first column are genotypes, given as a character vector. For

     instance, a row "A, B" would mean the genotype with both A and B

-    mutated. If \code{frequencyDependentFitness} is TRUE both columns 

+    mutated. If \code{frequencyDependentBirth} is TRUE both columns 

     must be character vectors.

   }

-  When \code{frequencyDependentFitness = FALSE}, fitness must be

+  When \code{frequencyDependentBirth = FALSE}, fitness must be

   \code{>= 0}. If any possible genotype is missing, its fitness is

   assumed to be 0, except for WT (if WT is missing, its fitness is

   assumed to be 1 ---see examples); this also applies to

   frequency-dependent fitness.

-  In contrast, if \code{frequencyDependentFitness = TRUE}, the Fitness

+  In contrast, if \code{frequencyDependentBirth = TRUE}, the Fitness

   column must contain the fitness specification equations, like

   characters, using as variables the frequencies (absolute or relative)

   of the all possible genotypes. We use "f" to denote relative

@@ -198,15 +201,26 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

   internal representation. But if you want, you can set it to FALSE and

   the object will be a little bit smaller.}

-  \item{frequencyDependentFitness}{

+  \item{frequencyDependentBirth}{

   If FALSE, the default value, all downstream work will be realised in a

   way not related to frequency depedent fitness situations. That implies

   that fitness specifications are fixed, except death rate in case of

   McFarland model (see \code{\link{oncoSimulIndiv}} for more details). If

   TRUE, you are in a frequency dependent fitness situation, where fitness

   specification ecuations must be passed as characters at 

-  \code{genotFitness}.

-}

+  \code{genotFitness}.}

+  

+  \item{frequencyDependentDeath}{

+  If FALSE, the default value, all downstream work will be realised in a

+  way not related to frequency depedent fitness situations. That implies

+  that fitness specifications are fixed, except death rate in case of

+  McFarland model (see \code{\link{oncoSimulIndiv}} for more details). If

+  TRUE, you are in a frequency dependent fitness situation, where fitness

+  specification ecuations must be passed as characters at 

+  \code{genotFitness}.}

+

+  \item{frequencyDependentFitness}{NA.}

+

   %% \item{frequencyType}{frequencyType is a character that specify wether 

   %%   we are using absolute or relatives frequecies and can take tree values

@@ -220,6 +234,12 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

   frequencies, or "rel", for relative ones. Remember that you must to

   use "f" for relative frequency and "n" for absolute in

   \code{genoFitness}. Set to NA for non-frequency-dependent fitness. }

+  

+  \item{deathSpec}{

+  If FALSE, the default value, all downstream work will be realised in a

+  way in which we assume that death is not specified by the user in \code{genotFitness}.

+  If TRUE, that means that death was specified by the user.

+  }

 }

@@ -243,27 +263,31 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

   no direct effect on fitness, but that affect mutation rate, you MUST

   specify them in the call to \code{allFitnessEffects}, for instance as

   \code{noIntGenes} with an effect of 0. When you run the simulations in

-  \code{frequencyDependentFitness} = TRUE only fitness effects are

-  allowed, and must be codified in \code{genotFitness}.

+  \code{frequencyDependentBirth} = TRUE or \code{frequencyDependentDeath} = TRUE

+  only fitness effects are allowed, and must be codified in \code{genotFitness}.

   If you use \code{genotFitness} then you cannot pass modules,

   noIntgenes, epistasis, or rT. This makes sense, because using

   \code{genotFitness} is saying

-  "this is the mapping of genotypes to fitness. Period", so we should

+  "this is the mapping of genotypes to birth and maybe death. Period", so we should

   not allow further modifications from other terms. This is always the

-  case when \code{frequencyDependentFitness} = TRUE.

+  case when \code{frequencyDependentBirth} = TRUE or

+  \code{frequencyDependentDeath} = TRUE.

   If you use \code{genotFitness} you need to be careful when you use

   Bozic's model (as you get a death rate of 0).

   If you use \code{genotFitness} note that we force the WT (wildtype) to

-  always be 1 so fitnesses are rescaled in case of 

-  \code{frequencyDependentFitness = FALSE}. In contrast, when 

-  \code{frequencyDependentFitness = TRUE} you are free to 

-  determine the fitness as a function of the frequencies of the genotypes

-  (see \code{genotFitness} and the vignette).

+  always be 1 so birth rates (death rates) are rescaled in case of 

+  \code{frequencyDependentBirth = FALSE} (\code{frequencyDependentDeath = FALSE}).

+  In contrast, when \code{frequencyDependentBirth = TRUE} (\code{frequencyDependentDeath = TRUE})

+  you are free to determine the birth rate (death rate) as a function of the frequencies of the

+  genotypes (see \code{genotFitness} and the vignette).

+

+  When using \code{genotFitness}, any genotype with a fitness <= 1e-9 is removed from the table of genotypes, thus 

+    making it a non-viable genotype during simulations. 

 }

@@ -320,18 +344,30 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

   frequency variables necessary for the C++ code. The "fvars".

 }

-  \item{frequencyDependentFitness}{TRUE or FALSE as we have explained

+  \item{frequencyDependentBirth}{TRUE or FALSE as we have explained

+  before.

+  }

+  

+  \item{frequencyDependentDeath}{TRUE or FALSE as we have explained

   before.

   }

+  \item{frequencyDependentFitness}{DEPRECATED. Use instead of \code{frequencyDependentFitness} for

+  old nomenclature.

+  }

+  

   \item{frequencyType}{A character string "abs" or "rel" (or NULL).

   }

-

-   \item{full_FDF_spec}{For frequency-dependent fitness, a complete

+	

+  \item{deathSpec}{TRUE or FALSE as we have explained

+  before.

+  }

+  

+   \item{full_FDF_spec}{For frequency-dependent birth (death), a complete

   data frame showing the genotypes (as matrix, letters, and "fvars") and the

-  fitness specification, in terms of the original specification

-  (Fitness_as_letters) and with genotypes mapped to numbers according to

-  the "fvars" (Fitness_as_fvars). If fitness was originally specified in

+  birth (death) specification, in terms of the original specification

+  (Birth_as_letters (Death_as_letters) and with genotypes mapped to numbers according to

+  the "fvars" (Birth_as_fvars (Death_as_fvars)). If birth (death) was originally specified in

   terms of numbers, these two columns will be identical. All the

   information in this data frame is implicitly above, but this

   simplifies checking that you are doing what you think you are doing.

@@ -545,17 +581,17 @@ evalAllGenotypes(allFitnessEffects(genotFitness = m9),

                  addwt = TRUE)

-#########  Frequency Dependent Fitness

+#########  Frequency Dependent Birth

 genofit <- data.frame(A = c(0, 1, 0, 1),

                       B = c(0, 0, 1, 1),

-                      Fitness = c("max(3, 2*f_)",

+                      Birth = c("max(3, 2*f_)",

                                   "max(1.5, 3*(f_ + f_1))",

                                   "max(2, 3*(f_ + f_2))",

                                   "max(2, 5*f_ - 0.5*( f_1 + f_2) + 15*f_1_2)"),

                       stringsAsFactors = FALSE)

 afe <- allFitnessEffects(genotFitness = genofit,

-                         frequencyDependentFitness = TRUE,

+                         frequencyDependentBirth = TRUE,

                          frequencyType = "rel")

 ##Ploting fitness landscape in case of spPopSizes = c(5000, 2500, 3000, 7500)

@@ -16,6 +16,11 @@

   mapping of genes to modules, return the complete specification of how

   mutations affect the mutation rate.

+  This function can be used also to produce the fitness specification

+  needed to run simulations in a frequency dependent fitness way. In that

+  situation we presume that the effects must be considered as fitness effects

+  and never as mutator effects (see \code{details} for more info).

+

   The output of these functions is not intended for user consumption,

   but as a way of preparing data to be sent to the C++ code.  }

@@ -24,7 +29,8 @@

 allFitnessEffects(rT = NULL, epistasis = NULL, orderEffects = NULL,

   noIntGenes = NULL, geneToModule = NULL, drvNames = NULL,

-  genotFitness = NULL,  keepInput = TRUE)

+  genotFitness = NULL,  keepInput = TRUE, frequencyDependentFitness =

+  FALSE, frequencyType = NA)

 allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

                    geneToModule = NULL,

@@ -69,18 +75,23 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

       three would have the same effects if a node that connects to root

       only connects to root).}

   }

+  This paramenter is not used if  \code{frequencyDependentFitness} is TRUE.

   }

   \item{epistasis}{

     A named numeric vector. The names identify the relationship, and the

     numeric value is the fitness (or mutator) effect. For the names, each of the

     genes or modules involved is separated by a ":". A negative sign

     denotes the absence of that term.

+

+    This paramenter is not used if  \code{frequencyDependentFitness} is TRUE.

   }

   \item{orderEffects}{

     A named numeric vector, as for \code{epistasis}. A ">" separates the

   names of the genes of modules of a relationship, so that "U > Z" means

   that the relationship is satisfied when mutation U has happened before

   mutation Z.

+

+  This paramenter is not used if  \code{frequencyDependentFitness} is TRUE.

 }

 \item{noIntGenes}{

   A numeric vector (optionally named) with the fitness coefficients (or

@@ -91,6 +102,8 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

   Of course, avoid using potentially confusing characters in the

   names. In particular, "," and ">" are not allowed as gene names.

+

+  This paramenter is not used if  \code{frequencyDependentFitness} is TRUE.

 }

 \item{geneToModule}{

@@ -103,8 +116,9 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

   argument, and you used a restriction table, the \code{geneToModule} 

   must necessarily contain, in the first position, "Root" (since the

   restriction table contains a node named "Root"). See examples below.

-}

+  This paramenter is not used if  \code{frequencyDependentFitness} is TRUE.

+}

 \item{drvNames}{The names of genes that are considered drivers. This is

   only used for: a) deciding when to stop the simulations, in case you

@@ -134,16 +148,47 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

     \code{\link{rfitness}}. If the matrix has all columns named, those

     will be used for the names of the genes. Of course, except for

     column or row names, all entries in this matrix or data frame must

-    be numeric.

+    be numeric, except when \code{frequencyDependentFitness} is TRUE.

+    In this case, last column must be character and contains fitness

+    equations.

     \item As a two column data frame. The second column is fitness, and

     the first column are genotypes, given as a character vector. For

-    instance, a row "A, B" would mean the genotype with both A and B mutated.

+    instance, a row "A, B" would mean the genotype with both A and B

+    mutated. If \code{frequencyDependentFitness} is TRUE both columns 

+    must be character vectors.

+  }

+  

+  When \code{frequencyDependentFitness = FALSE}, fitness must be

+  \code{>= 0}. If any possible genotype is missing, its fitness is

+  assumed to be 0, except for WT (if WT is missing, its fitness is

+  assumed to be 1 ---see examples); this also applies to

+  frequency-dependent fitness.

+

+  In contrast, if \code{frequencyDependentFitness = TRUE}, the Fitness

+  column must contain the fitness specification equations, like

+  characters, using as variables the frequencies (absolute or relative)

+  of the all possible genotypes. We use "f" to denote relative

+  frecuencies and "n" for absolute. Letter "N" (UPPER CASE) is reserved

+  to denote total population size, thus f=n/N for each possible

+  genotype.  Relative frequency variables must be f_ for wild type, f_1

+  or f_A if first gene is mutated, f_2 or f_B if is the case for the

+  second one, f_1_2 or f_A_B, if both the first and second genes are

+  mutated, and so on. For anything beyond the trivially simple, using

+  letters (not numbers) is strongly recommended. Note also that you need

+  not specify the fitness of every genotype (those missing are assumed

+  to have a fitness of 0), nor do you need to pass the WT genotype. See

+  the vignette for many examples.

+

+  If we want to use absolute numbers (absolute frequencies), just

+  subtitute "f" for "n". The choice between relative or absolute

+  frequencies may be specified also in \code{frequencyType} or, if using

+  the default (auto) it can be automatically inferred.

+

+  Mathematical operations and symbols allowed are described in the

+  documentation of C++'s library ExprTk that is used to parse and

+  evaluate the fitness equations (see references for more information).

   }

-  In all cases, fitness must be \code{>= 0}. If any possible genotype is

-  missing, its fitness is assumed to be 0, except for WT (if WT is

-    missing, its fitness is assumed to be 1 ---see examples).

-}

 \item{keepInput}{

@@ -152,14 +197,39 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

   decode, say, the restriction table from the data frame than from the

   internal representation. But if you want, you can set it to FALSE and

   the object will be a little bit smaller.}

+

+  \item{frequencyDependentFitness}{

+  If FALSE, the default value, all downstream work will be realised in a

+  way not related to frequency depedent fitness situations. That implies

+  that fitness specifications are fixed, except death rate in case of

+  McFarland model (see \code{\link{oncoSimulIndiv}} for more details). If

+  TRUE, you are in a frequency dependent fitness situation, where fitness

+  specification ecuations must be passed as characters at 

+  \code{genotFitness}.

+}

+

+  %% \item{frequencyType}{frequencyType is a character that specify wether 

+  %%   we are using absolute or relatives frequecies and can take tree values

+  %%   depending on \code{frequencyDependentFitness}. When FALSE is 

+  %%   "unemployed" and for TRUE we can use "abs", for absolute frequencies,

+  %%   or "rel", for relative ones. Remember that you must to use "f" for

+  %% relative frequency and "n" for absolute in \code{genoFitness}.

+  \item{frequencyType}{frequencyType is a character that specify whether

+  we are using absolute or relatives frequecies and can take tree values

+  depending on \code{frequencyDependentFitness}. Use "abs", for absolute

+  frequencies, or "rel", for relative ones. Remember that you must to

+  use "f" for relative frequency and "n" for absolute in

+  \code{genoFitness}. Set to NA for non-frequency-dependent fitness. }

+

 }

 \details{

   \code{allFitnessEffects} is used for extremely flexible specification of fitness

   and mutator effects, including posets, XOR relationships, synthetic mortality and

   synthetic viability, arbitrary forms of epistatis, arbitrary forms of

-  order effects, etc. Please, see the vignette for detailed and

-  commented examples.

+  order effects, etc. \code{allFitnessEffects} produce the output necessary

+  to pass to the C++ code the fitness/mutator specifications to run simulations.

+  Please, see the vignette for detailed and commented examples.

   \code{allMutatorEffects} provide the same flexibility, but without

   order and posets (this might be included in the future, but I have

@@ -172,22 +242,27 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

   \code{allFitnessEffects} object. If you want to have genes that have

   no direct effect on fitness, but that affect mutation rate, you MUST

   specify them in the call to \code{allFitnessEffects}, for instance as

-  \code{noIntGenes} with an effect of 0.

-

+  \code{noIntGenes} with an effect of 0. When you run the simulations in

+  \code{frequencyDependentFitness} = TRUE only fitness effects are

+  allowed, and must be codified in \code{genotFitness}.

   If you use \code{genotFitness} then you cannot pass modules,

   noIntgenes, epistasis, or rT. This makes sense, because using

   \code{genotFitness} is saying

   "this is the mapping of genotypes to fitness. Period", so we should

-  not allow further modifications from other terms.

+  not allow further modifications from other terms. This is always the

+  case when \code{frequencyDependentFitness} = TRUE.

   If you use \code{genotFitness} you need to be careful when you use

   Bozic's model (as you get a death rate of 0).

   If you use \code{genotFitness} note that we force the WT (wildtype) to

-  always be 1 so fitnesses are rescaled. 

-

+  always be 1 so fitnesses are rescaled in case of 

+  \code{frequencyDependentFitness = FALSE}. In contrast, when 

+  \code{frequencyDependentFitness = TRUE} you are free to 

+  determine the fitness as a function of the frequencies of the genotypes

+  (see \code{genotFitness} and the vignette).

 }

@@ -226,18 +301,58 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

   \item{noIntGenes}{If \code{keepInput} is TRUE, the original 

     noIntGenes.}

+

+  \item{fitnessLandscape}{A data.frame that contains number of genes + 1 columns,

+  where the first columns are the genes (1 if mutated and 0 if not) and the last

+  one contains the fitnesses.

+  }

+

+  \item{fitnessLandscape_df}{A data.frame with the same information of \code{fitnessLandscape},

+  but in this case ther are only two columns: Genotype, that has genotypes as vectors

+  codified as characters, and Fitness.

+  }

+

+  \item{fitnessLandscape_gene_id}{A data.frame with two columns (Gene and GeneNumID),

+  that map by rows genes as letters (Gene) with genes as numbers (GeneNumID).

+  }

+

+  \item{fitnessLandscapeVariables}{A character vector that contains the

+  frequency variables necessary for the C++ code. The "fvars".

 }

+

+  \item{frequencyDependentFitness}{TRUE or FALSE as we have explained

+  before.

+  }

+  

+  \item{frequencyType}{A character string "abs" or "rel" (or NULL).

+  }

+

+   \item{full_FDF_spec}{For frequency-dependent fitness, a complete

+  data frame showing the genotypes (as matrix, letters, and "fvars") and the

+  fitness specification, in terms of the original specification

+  (Fitness_as_letters) and with genotypes mapped to numbers according to

+  the "fvars" (Fitness_as_fvars). If fitness was originally specified in

+  terms of numbers, these two columns will be identical. All the

+  information in this data frame is implicitly above, but this

+  simplifies checking that you are doing what you think you are doing.

+  }

+

+}

+

 \references{

     Diaz-Uriarte, R. (2015). Identifying restrictions in the order of

   accumulation of mutations during tumor progression: effects of

   passengers, evolutionary models, and sampling

-  \url{http://www.biomedcentral.com/1471-2105/16/41/abstract}

+  \url{http://www.biomedcentral.com/1471-2105/16/41/abstract}.

     McFarland, C.~D. et al. (2013). Impact of deleterious passenger

   mutations on cancer progression.  \emph{Proceedings of the National

   Academy of Sciences of the United States of America\/}, \bold{110}(8),

   2910--5.

+    Partow, A. ExprTk: C++ Mathematical Expression Library (MIT Open

+    Souce License). \url{http://www.partow.net/programming/exprtk/}.

+

 }

@@ -255,7 +370,15 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

   characters because you know those characters have special meanings to

   separate names or indicate epistasis or order relationships.  Right

   now, using those characters as names is caught (and result in

-  stopping) if passed as names for noIntGenes.  }

+  stopping) if passed as names for noIntGenes.

+

+  At the moment, the variables you need to specify in the fitness

+  equations when you are in a frequency dependent fitness situation are

+  fixed as we have explained in \code{genotFitness}. Perhaps using

+  different and strange combinations of "f_" or "n_" followed by letters

+  and numbers you could confuse the R parser, but never the C++ one. For

+  a correct performance please be aware of this.

+  }

@@ -265,7 +388,9 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

 \seealso{

-  \code{\link{evalGenotype}}, \code{\link{oncoSimulIndiv}},

+  \code{\link{evalGenotype}},

+  \code{\link{evalAllGenotypes}},

+  \code{\link{oncoSimulIndiv}},

   \code{\link{plot.fitnessEffects}},

   \code{\link{evalGenotypeFitAndMut}},

   \code{\link{rfitness}},

@@ -394,7 +519,7 @@ evalAllGenotypes(fem6, addwt = TRUE, order = FALSE)

 ## Plotting a fitness landscape

 fe2 <- allFitnessEffects(noIntGenes =

-                         c(a1 = 0.1, 

+                         c(a1 = 0.1,

                            b1 = 0.01,

                            c1 = 0.3))

@@ -407,18 +532,34 @@ plotFitnessLandscape(evalAllGenotypes(fe2, order = FALSE))

 plotFitnessLandscape(fe2)

-###### Defaults for missing genotypes

+###### Defaults for missing genotypes

 ## As a two-column data frame

-

 (m8 <- data.frame(G = c("A, B, C", "B"), F = c(3, 2)))

-evalAllGenotypes(allFitnessEffects(genotFitness = m8), addwt = TRUE)

+evalAllGenotypes(allFitnessEffects(genotFitness = m8),

+                 addwt = TRUE)

 ## As a matrix 

-

 (m9 <- rbind(c(0, 1, 0, 1, 4), c(1, 0, 1, 0, 1.5)))

-evalAllGenotypes(allFitnessEffects(genotFitness = m9), addwt = TRUE)

-

+evalAllGenotypes(allFitnessEffects(genotFitness = m9),

+                 addwt = TRUE)

+

+

+#########  Frequency Dependent Fitness

+genofit <- data.frame(A = c(0, 1, 0, 1),

+                      B = c(0, 0, 1, 1),

+                      Fitness = c("max(3, 2*f_)",

+                                  "max(1.5, 3*(f_ + f_1))",

+                                  "max(2, 3*(f_ + f_2))",

+                                  "max(2, 5*f_ - 0.5*( f_1 + f_2) + 15*f_1_2)"),

+                      stringsAsFactors = FALSE)

+

+afe <- allFitnessEffects(genotFitness = genofit,

+                         frequencyDependentFitness = TRUE,

+                         frequencyType = "rel")

+                         

+##Ploting fitness landscape in case of spPopSizes = c(5000, 2500, 3000, 7500)

+plotFitnessLandscape(evalAllGenotypes(afe, spPopSizes = c(5000, 2500, 3000, 7500)))

 ## Reinitialize the seed

 set.seed(NULL)

@@ -141,7 +141,8 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

     instance, a row "A, B" would mean the genotype with both A and B mutated.

   }

   In all cases, fitness must be \code{>= 0}. If any possible genotype is

-  missing, its fitness is assumed to be 1.

+  missing, its fitness is assumed to be 0, except for WT (if WT is

+    missing, its fitness is assumed to be 1 ---see examples).

 }

@@ -406,6 +407,19 @@ plotFitnessLandscape(evalAllGenotypes(fe2, order = FALSE))

 plotFitnessLandscape(fe2)

+###### Defaults for missing genotypes

+

+## As a two-column data frame

+

+(m8 <- data.frame(G = c("A, B, C", "B"), F = c(3, 2)))

+evalAllGenotypes(allFitnessEffects(genotFitness = m8), addwt = TRUE)

+

+## As a matrix 

+

+(m9 <- rbind(c(0, 1, 0, 1, 4), c(1, 0, 1, 0, 1.5)))

+evalAllGenotypes(allFitnessEffects(genotFitness = m9), addwt = TRUE)

+

+

 ## Reinitialize the seed

 set.seed(NULL)

 }

@@ -127,12 +127,14 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

   Genotypes can be specified in two ways:

   \itemize{

-    \item As a matrix (or data frame) with g + 1 columns. Each of the

-    first g columns contains a 1 or a 0 indicating that the gene of that

-    column is mutated or not. Column g+ 1 contains the fitness

-    values. This is, for instance, the output you will get from

+    \item As a matrix (or data frame) with g + 1 columns (where g >

+    1). Each of the first g columns contains a 1 or a 0 indicating that

+    the gene of that column is mutated or not. Column g+ 1 contains the

+    fitness values. This is, for instance, the output you will get from

     \code{\link{rfitness}}. If the matrix has all columns named, those

-    will be used for the names of the genes.

+    will be used for the names of the genes. Of course, except for

+    column or row names, all entries in this matrix or data frame must

+    be numeric.

     \item As a two column data frame. The second column is fitness, and

     the first column are genotypes, given as a character vector. For

@@ -114,7 +114,7 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

   specifiy anything if you do not want to, and you can pass an empty

   vector (as \code{character(0)}). The default has changed with respect

   to v.2.1.3 and previous: it used to be to assume that all

-  genes that were not in the \code{noIntGenes} were drivers. The fault

+  genes that were not in the \code{noIntGenes} were drivers. The default

   now is to assume nothing: if you want \code{drvNames} you have

   to specify them.

@@ -127,10 +127,12 @@ allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

   Genotypes can be specified in two ways:

   \itemize{

-    \item As a matrix (or data frame) with g + 1 columns. Each of the first g columns contains a 1 or a 0 indicating that the

-    gene of that column is mutated or not. Column g+ 1 contains the

-    fitness values. This is, for instance, the output you will get from

-    \code{\link{rfitness}}.

+    \item As a matrix (or data frame) with g + 1 columns. Each of the

+    first g columns contains a 1 or a 0 indicating that the gene of that

+    column is mutated or not. Column g+ 1 contains the fitness

+    values. This is, for instance, the output you will get from

+    \code{\link{rfitness}}. If the matrix has all columns named, those

+    will be used for the names of the genes.

     \item As a two column data frame. The second column is fitness, and

     the first column are genotypes, given as a character vector. For

@@ -389,9 +389,9 @@ evalAllGenotypes(fem6, addwt = TRUE, order = FALSE)

 ## Plotting a fitness landscape

 fe2 <- allFitnessEffects(noIntGenes =

-                         c(a1 = 0.1, a2 = 0.2,

-                           b1 = 0.01, b2 = 0.3, b3 = 0.2,

-                           c1 = 0.3, c2 = -0.2))

+                         c(a1 = 0.1, 

+                           b1 = 0.01,

+                           c1 = 0.3))

 plot(evalAllGenotypes(fe2, order = FALSE))

@@ -1,23 +1,38 @@

 \name{allFitnessEffects}

 \alias{allFitnessEffects}

-\title{Create fitness effects specification from restrictions,

-  epistasis, and order effects.

-}

+\alias{allMutatorEffects}

+

+\title{Create fitness and mutation effects specification from

+  restrictions, epistasis, and order effects.  }

+

 \description{

   Given one or more of a set of poset restrictions, epistatic

   interactions, order effects, and genes without interactions, as well

   as, optionally, a mapping of genes to modules, return the complete

   fitness specification.

-  The output of this function is not intended for user consumption, but

-  as a way of preparing data to be sent to the C++ code.  }

+  For mutator effects, given one or more of a set of epistatic

+  interactions and genes without interactions, as well as, optionally, a

+  mapping of genes to modules, return the complete specification of how

+  mutations affect the mutation rate.

+  

+  The output of these functions is not intended for user consumption,

+  but as a way of preparing data to be sent to the C++ code.  }

 \usage{

 allFitnessEffects(rT = NULL, epistasis = NULL, orderEffects = NULL,

-  noIntGenes = NULL, geneToModule = NULL, drvNames = NULL, keepInput =

-  TRUE) }

+  noIntGenes = NULL, geneToModule = NULL, drvNames = NULL,

+  genotFitness = NULL,  keepInput = TRUE)

+

+allMutatorEffects(epistasis = NULL, noIntGenes = NULL,

+                   geneToModule = NULL,

+                  keepInput =  TRUE)

+}

+

+

+

 \arguments{

   \item{rT}{A restriction table that is an extended version of a poset 

@@ -49,7 +64,6 @@ allFitnessEffects(rT = NULL, epistasis = NULL, orderEffects = NULL,

 	  relationship to be satisfied. Specify it as "XOR" or "xmpn" or

 	  "XMPN".}

       }

-

       In addition, for the nodes that depend only on the root node, you

       can use "--" or "-" if you want (though using any of the other

       three would have the same effects if a node that connects to root

@@ -58,7 +72,7 @@ allFitnessEffects(rT = NULL, epistasis = NULL, orderEffects = NULL,

   }

   \item{epistasis}{

     A named numeric vector. The names identify the relationship, and the

-    numeric value is the fitness effect. For the names, each of the

+    numeric value is the fitness (or mutator) effect. For the names, each of the

     genes or modules involved is separated by a ":". A negative sign

     denotes the absence of that term.

   }

@@ -69,7 +83,8 @@ allFitnessEffects(rT = NULL, epistasis = NULL, orderEffects = NULL,

   mutation Z.

 }

 \item{noIntGenes}{

-  A numeric vector (optionally named) with the fitness coefficients of genes

+  A numeric vector (optionally named) with the fitness coefficients (or

+      mutator multiplier factor) of genes

   (only genes, not modules) that show no interactions. These genes

   cannot be part of modules. But you can specify modules that have

   no epistatic interactions. See examples and vignette.

@@ -97,8 +112,34 @@ allFitnessEffects(rT = NULL, epistasis = NULL, orderEffects = NULL,

   \code{\link{oncoSimulIndiv}}); b) for summarization purposes (e.g.,

   how many drivers are mutated); c) in figures. But you need not

   specifiy anything if you do not want to, and you can pass an empty

-  vector (as \code{character(0)}). The default is to assume that all

-  genes that are not in the \code{noIntGenes} are drivers.}

+  vector (as \code{character(0)}). The default has changed with respect

+  to v.2.1.3 and previous: it used to be to assume that all

+  genes that were not in the \code{noIntGenes} were drivers. The fault

+  now is to assume nothing: if you want \code{drvNames} you have

+  to specify them.

+

+}

+

+\item{genotFitness}{A matrix or data frame that contains explicitly the

+  mapping of genotypes to fitness. For now, we only allow epistasis-like

+  relations between genes (so you cannot code order effects this way).

+

+  Genotypes can be specified in two ways:

+  \itemize{

+    

+    \item As a matrix (or data frame) with g + 1 columns. Each of the first g columns contains a 1 or a 0 indicating that the

+    gene of that column is mutated or not. Column g+ 1 contains the

+    fitness values. This is, for instance, the output you will get from

+    \code{\link{rfitness}}.

+    

+    \item As a two column data frame. The second column is fitness, and

+    the first column are genotypes, given as a character vector. For

+    instance, a row "A, B" would mean the genotype with both A and B mutated.

+  }

+  In all cases, fitness must be \code{>= 0}. If any possible genotype is

+  missing, its fitness is assumed to be 1.

+}

+

 \item{keepInput}{

   If TRUE, whether to keep the original input. This is only useful for

@@ -107,17 +148,50 @@ allFitnessEffects(rT = NULL, epistasis = NULL, orderEffects = NULL,

   internal representation. But if you want, you can set it to FALSE and

   the object will be a little bit smaller.}

 }

+

 \details{

-  This function is used for extremely flexible specification of fitness

-  effects, including posets, XOR relationships, synthetic mortality and

+  \code{allFitnessEffects} is used for extremely flexible specification of fitness

+  and mutator effects, including posets, XOR relationships, synthetic mortality and

   synthetic viability, arbitrary forms of epistatis, arbitrary forms of

   order effects, etc. Please, see the vignette for detailed and

   commented examples.

+

+  \code{allMutatorEffects} provide the same flexibility, but without

+  order and posets (this might be included in the future, but I have

+  seen no empirical or theoretical argument for their existence or

+  relevance as of now, so I do not add them to minimize unneeded complexity).

+

+  If you use both for simulations in the same call to, say,

+  \code{\link{oncoSimulIndiv}}, all the genes specified in

+  \code{allMutatorEffects} MUST be included in the

+  \code{allFitnessEffects} object. If you want to have genes that have

+  no direct effect on fitness, but that affect mutation rate, you MUST

+  specify them in the call to \code{allFitnessEffects}, for instance as

+  \code{noIntGenes} with an effect of 0.

+

+

+  If you use \code{genotFitness} then you cannot pass modules,

+  noIntgenes, epistasis, or rT. This makes sense, because using

+  \code{genotFitness} is saying

+  "this is the mapping of genotypes to fitness. Period", so we should

+  not allow further modifications from other terms.

+

+  If you use \code{genotFitness} you need to be careful when you use

+  Bozic's model (as you get a death rate of 0).

+

+

+  If you use \code{genotFitness} note that we force the WT (wildtype) to

+  always be 1 so fitnesses are rescaled. 

+

+

 }

+

 \value{

-  An object of class "fitnessEffects". This is just a list, but it is not

-  intended for human consumption.  The components are:

+  

+  An object of class "fitnessEffects" or "mutatorEffects". This is just

+  a list, but it is not intended for human consumption.  The components

+  are:

   \item{long.rt}{The restriction table in "long format", so as to be

     easy to parse by the C++ code.}

@@ -178,11 +252,20 @@ allFitnessEffects(rT = NULL, epistasis = NULL, orderEffects = NULL,

   now, using those characters as names is caught (and result in

   stopping) if passed as names for noIntGenes.  }

+

+

+

 \author{ Ramon Diaz-Uriarte

 }

 \seealso{

-  \code{\link{evalGenotype}}, \code{\link{oncoSimulIndiv}}, \code{\link{plot.fitnessEffects}}

+  

+  \code{\link{evalGenotype}}, \code{\link{oncoSimulIndiv}},

+  \code{\link{plot.fitnessEffects}},

+  \code{\link{evalGenotypeFitAndMut}},

+  \code{\link{rfitness}},

+  \code{\link{plotFitnessLandscape}}

+

 }

 \examples{

 ## A simple poset or CBN-like example

@@ -240,6 +323,87 @@ fnme <- allFitnessEffects(epistasis = c("A" = 0.1,

 evalAllGenotypes(fnme, order = FALSE, addwt = TRUE)

+

+## Epistasis for fitness and simple mutator effects

+

+fe <- allFitnessEffects(epistasis = c("a : b" = 0.3,

+                                          "b : c" = 0.5),

+                            noIntGenes = c("e" = 0.1))

+

+fm <- allMutatorEffects(noIntGenes = c("a" = 10,

+                                       "c" = 5))

+

+evalAllGenotypesFitAndMut(fe, fm, order = FALSE)

+

+

+## Simple fitness effects (noIntGenes) and modules

+## for mutators

+

+fe2 <- allFitnessEffects(noIntGenes =