Much more complete version that was just submitted to CRAN.

git-svn-id: svn+ssh://svn.r-forge.r-project.org/svnroot/kinfit/pkg/mkin@9 edb9625f-4e0d-4859-8d74-9fd3b1da38cb

6 files changed, 356 insertions, 35 deletions

diff --git a/R/mkin_long_to_wide.R b/R/mkin_long_to_wide.R
new file mode 100644
index 0000000..45ee0a1
--- /dev/null
+++ b/R/mkin_long_to_wide.R
@@ -0,0 +1,9 @@
+mkin_long_to_wide <- function(long_data, time = "time")

+{

+  colnames <- unique(long_data$name)

+  wide_data <- data.frame(time = subset(long_data, name == colnames[1], time))

+  for (var in colnames) {

+    wide_data[var] <- subset(long_data, name == var, value)

+  }

+  return(wide_data)

+}

diff --git a/R/mkin_wide_to_long.R b/R/mkin_wide_to_long.R
new file mode 100644
index 0000000..6db2f33
--- /dev/null
+++ b/R/mkin_wide_to_long.R
@@ -0,0 +1,13 @@
+mkin_wide_to_long <- function(wide_data, time = "t")

+{

+  colnames <- names(wide_data)

+  vars <- subset(colnames, colnames != time)

+  n <- length(colnames) - 1

+  if (!(time %in% colnames)) stop("The data in wide format have to contain a variable named ", time, ".")

+  long_data <- data.frame(

+    name = rep(vars, each = length(wide_data[[time]])),

+    time = rep(wide_data[[time]], n),

+    value = unlist(wide_data[vars]),

+    row.names = NULL)

+  return(long_data)

+}

diff --git a/R/mkinerrmin.R b/R/mkinerrmin.R
new file mode 100644
index 0000000..7a922eb
--- /dev/null
+++ b/R/mkinerrmin.R
@@ -0,0 +1,14 @@
+mkinerrmin <- function(errdata, n.parms, alpha = 0.05)

+{

+  means.mean <- mean(errdata$value_mean, na.rm=TRUE)

+

+	df = length(errdata$value_mean) - n.parms

+  

+	f <- function(err)

+	{

+		(sum((errdata$value_mean - errdata$value_pred)^2/((err * means.mean)^2)) - 

+		 qchisq(1 - alpha,df))^2

+	}

+	err.min <- optimize(f, c(0.01,0.9))$minimum

+	return(list(err.min = err.min, n.optim = n.parms, df = df))

+}

diff --git a/R/mkinfit.R b/R/mkinfit.R
index 9651fd6..c149027 100644
--- a/R/mkinfit.R
+++ b/R/mkinfit.R
@@ -1,55 +1,78 @@
-mkinfit <- function(mkinmod, observed, 

+mkinfit <- function(mkinmod, observed,

   parms.ini = rep(0.1, length(mkinmod$parms)),

   state.ini = c(100, rep(0, length(mkinmod$diffs) - 1)), 

-  fixed_parms = rep(FALSE, length(mkinmod$parms)),

-  fixed_initials = c(FALSE, rep(TRUE, length(mkinmod$diffs) - 1)), 

-  plot = NULL, 

+  fixed_parms = NULL,

+  fixed_initials = names(mkinmod$diffs)[-1],

+  plot = FALSE, quiet = FALSE,

   err = NULL, weight = "none", scaleVar = FALSE,

   ...)

 {

+  mod_vars <- names(mkinmod$diffs)

+  # Subset dataframe with mapped (modelled) variables

+  observed <- subset(observed, name %in% names(mkinmod$map))

+  # Get names of observed variables

+  obs_vars = unique(as.character(observed$name))

+

   # Name the parameters if they are not named yet

   if(is.null(names(parms.ini))) names(parms.ini) <- mkinmod$parms

   # Create a function calculating the differentials specified by the model

   mkindiff <- function(t, state, parms) {

+    time <- t

     diffs <- vector()

-    for (box in names(mkinmod$diffs))

+    for (box in mod_vars)

     {

       diffname <- paste("d", box, sep="_")      

-      diffs[diffname] <- with(as.list(c(state, parms)),

+      diffs[diffname] <- with(as.list(c(time,state, parms)),

         eval(parse(text=mkinmod$diffs[[box]])))

     }

     return(list(c(diffs)))

   } 

 

   # Name the inital parameter values if they are not named yet

-  if(is.null(names(state.ini))) names(state.ini) <- names(mkinmod$diffs)

+  if(is.null(names(state.ini))) names(state.ini) <- mod_vars

 

-  # TODO: Collect parameters to be optimised

-  parms.optim <- parms.ini[!fixed_parms]

+  # Parameters to be optimised

   parms.fixed <- parms.ini[fixed_parms]

+  optim_parms <- setdiff(names(parms.ini), fixed_parms)

+  parms.optim <- parms.ini[optim_parms]

 

-  state.ini.optim <- state.ini[!fixed_initials]

-  state.ini.optim.boxnames <- names(state.ini.optim)

-  names(state.ini.optim) <- paste(names(state.ini.optim), "0", sep="_")

   state.ini.fixed <- state.ini[fixed_initials]

+  optim_initials <- setdiff(names(state.ini), fixed_initials)

+  state.ini.optim <- state.ini[optim_initials]

+  state.ini.optim.boxnames <- names(state.ini.optim)

+  if(length(state.ini.optim) > 0) {

+      names(state.ini.optim) <- paste(names(state.ini.optim), "0", sep="_")

+  }

 

+  cost.old <- 1e100

+  calls <- 0

+  out_predicted <- NA

   # Define the model cost function

   cost <- function(P)

   {

+    assign("calls", calls+1, inherits=TRUE)

     if(length(state.ini.optim) > 0) {

       odeini <- c(P[1:length(state.ini.optim)], state.ini.fixed)

       names(odeini) <- c(state.ini.optim.boxnames, names(state.ini.fixed))

     } else odeini <- state.ini.fixed

 

     odeparms <- c(P[(length(state.ini.optim) + 1):length(P)], parms.fixed)

-    # Solve the ODE

+

+    # Get more timepoints if plotting is desired

+    if(plot) {

+      outtimes = unique(sort(c(observed$time, 

+        seq(min(observed$time), max(observed$time), length.out=100))))

+    } else outtimes = unique(observed$time)

+

+    # Solve the ode

     out <- ode(

       y = odeini,

-      times = unique(observed$time),

+      times = outtimes,

       func = mkindiff, 

       parms = odeparms)

      

-    # Output transformation for models with ghost compartments like SFORB

+  

+    # Output transformation for models with unobserved compartments like SFORB

     out_transformed <- data.frame(time = out[,"time"])

     for (var in names(mkinmod$map)) {

       if(length(mkinmod$map[[var]]) == 1) {

@@ -58,9 +81,190 @@ mkinfit <- function(mkinmod, observed,
         out_transformed[var] <- rowSums(out[, mkinmod$map[[var]]])

       }

     }    

+    assign("out_predicted", subset(out_transformed, time %in% observed$time), inherits=TRUE)

+

+    mC <- modCost(out_transformed, observed, y = "value",

+      err = err, weight = weight, scaleVar = scaleVar)

+

+    # Report and/or plot if the model is improved

+    if (mC$model < cost.old) {

+      if(!quiet) cat("Model cost at call ", calls, ": ", mC$model, "\n")

+

+      # Plot the data and the current model output if requested

+      if(plot) {

+        plot(0, type="n", 

+          xlim = range(observed$time), ylim = range(observed$value, na.rm=TRUE),

+          xlab = "Time", ylab = "Observed")

+        col_obs <- pch_obs <- 1:length(obs_vars)

+        names(col_obs) <- names(pch_obs) <- obs_vars

+        for (obs_var in obs_vars) {

+          points(subset(observed, name == obs_var, c(time, value)), 

+            pch = pch_obs[obs_var], col = col_obs[obs_var])

+        }

+        matlines(out_transformed$time, out_transformed[-1])

+        legend("topright", inset=c(0.05, 0.05), legend=obs_vars, 

+          col=col_obs, pch=pch_obs, lty=1:length(pch_obs))

+      }

     

-    return(modCost(out_transformed, observed, y = "value",

-      err = err, weight = weight, scaleVar = scaleVar))

+      assign("cost.old", mC$model, inherits=TRUE)

+    }

+    return(mC)

   }

-  modFit(cost, c(state.ini.optim, parms.optim), ...)

+  fit <- modFit(cost, c(state.ini.optim, parms.optim), ...)

+

+  # We need the function for plotting

+  fit$mkindiff <- mkindiff

+

+  # We also need various other information for summary and plotting

+  fit$map <- mkinmod$map

+  fit$diffs <- mkinmod$diffs

+  fit$observed <- mkin_long_to_wide(observed)

+  predicted_long <- mkin_wide_to_long(out_predicted, time = "time")

+  fit$predicted <- out_predicted

+

+  # Collect initial parameter values in two dataframes

+  fit$start <- data.frame(initial = c(state.ini.optim, parms.optim))

+  fit$start$type = c(rep("state", length(state.ini.optim)), rep("deparm", length(parms.optim)))

+  if (exists("lower")) fit$start$lower <- lower

+  if (exists("upper")) fit$start$upper <- upper

+

+  fit$fixed <- data.frame(

+    value = c(state.ini.fixed, parms.fixed))

+  fit$fixed$type = c(rep("state", length(state.ini.fixed)), rep("deparm", length(parms.fixed)))

+

+  # Calculate chi2 error levels according to FOCUS (2006)

+  means <- aggregate(value ~ time + name, data = observed, mean, na.rm=TRUE)

+  errdata <- merge(means, predicted_long, by = c("time", "name"), suffixes = c("_mean", "_pred"))

+  errdata <- errdata[order(errdata$time, errdata$name), ]

+  errmin.overall <- mkinerrmin(errdata, length(parms.optim) + length(state.ini.optim))

+  

+  errmin <- data.frame(err.min = errmin.overall$err.min, 

+    n.optim = errmin.overall$n.optim, df = errmin.overall$df)

+  rownames(errmin) <- "All data"

+  for (obs_var in obs_vars)

+  {

+    errdata.var <- subset(errdata, name == obs_var)

+    n.k.optim <- length(grep(paste("k", obs_var, sep="_"), names(parms.optim)))

+    n.initials.optim <- length(grep(paste(obs_var, ".*", "_0", sep=""), names(state.ini.optim)))

+    n.optim <- n.k.optim + n.initials.optim

+    if ("alpha" %in% names(parms.optim)) n.optim <- n.optim + 1

+    if ("beta" %in% names(parms.optim)) n.optim <- n.optim + 1

+    errmin.tmp <- mkinerrmin(errdata.var, n.optim)

+    errmin[obs_var, c("err.min", "n.optim", "df")] <- errmin.tmp

+  }

+  fit$errmin <- errmin

+

+  # Calculate dissipation times DT50 and DT90

+  parms.all = c(fit$par, parms.fixed)

+  fit$distimes <- data.frame(DT50 = rep(NA, length(obs_vars)), DT90 = rep(NA, length(obs_vars)), 

+    row.names = obs_vars)

+  for (obs_var in obs_vars) {

+      type = names(mkinmod$map[[obs_var]])[1]  

+      if (type == "SFO") {

+        k_names = grep(paste("k", obs_var, sep="_"), names(parms.all), value=TRUE)

+        k_tot = sum(parms.all[k_names])

+        DT50 = log(2)/k_tot

+        DT90 = log(10)/k_tot

+      }

+      if (type == "FOMC") {

+        alpha = parms.all["alpha"]

+        beta = parms.all["beta"]

+        DT50 = beta * (2^(1/alpha) - 1)

+        DT90 = beta * (10^(1/alpha) - 1)

+      }

+      if (type == "SFORB") {

+        # FOCUS kinetics (2006), p. 60 f

+        k_out_names = grep(paste("k", obs_var, "free", sep="_"), names(parms.all), value=TRUE)

+        k_out_names = setdiff(k_out_names, paste("k", obs_var, "free", "bound", sep="_"))

+        k_1output = sum(parms.all[[k_out_names]])

+        k_12 = parms.all[[paste("k", obs_var, "free", "bound", sep="_")]]

+        k_21 = parms.all[[paste("k", obs_var, "bound", "free", sep="_")]]

+

+        sqrt_exp = sqrt(1/4 * (k_12 + k_21 + k_1output)^2 + k_12 * k_21 - (k_12 + k_1output) * k_21)

+        b1 = 0.5 * (k_12 + k_21 + k_1output) + sqrt_exp

+        b2 = 0.5 * (k_12 + k_21 + k_1output) - sqrt_exp

+

+        SFORB_fraction = function(t) {

+          ((k_12 + k_21 - b1)/(b2 - b1)) * exp(-b1 * t) +

+          ((k_12 + k_21 - b2)/(b1 - b2)) * exp(-b2 * t)

+        }

+        f_50 <- function(t) (SFORB_fraction(t) - 0.5)^2

+        max_DT <- 1000

+        DT50.o <- optimize(f_50, c(0.01, max_DT))$minimum

+        if (abs(DT50.o - max_DT) < 0.01) DT50 = NA else DT50 = DT50.o

+        f_90 <- function(t) (SFORB_fraction(t) - 0.1)^2

+        DT90.o <- optimize(f_90, c(0.01, 1000))$minimum

+        if (abs(DT90.o - max_DT) < 0.01) DT90 = NA else DT90 = DT90.o

+      }

+      fit$distimes[obs_var, ] = c(DT50, DT90)

+  }

+

+  # Collect observed, predicted and residuals

+  data <- merge(observed, predicted_long, by = c("time", "name"))

+  names(data) <- c("time", "variable", "observed", "predicted")

+  data$residual <- data$observed - data$predicted

+  data$variable <- ordered(data$variable, levels = obs_vars)

+  fit$data <- data[order(data$variable, data$time), ]

+

+  class(fit) <- c("mkinfit", "modFit") 

+  return(fit)

+}

+

+summary.mkinfit <- function(object, data = TRUE, distimes = TRUE, cov = FALSE,...) {

+  ans <- FME:::summary.modFit(object, cov = cov)

+  ans$diffs <- object$diffs

+  if(data) ans$data <- object$data

+  ans$start <- object$start

+  ans$fixed <- object$fixed

+  ans$errmin <- object$errmin 

+  if(distimes) ans$distimes <- object$distimes

+  class(ans) <- c("summary.mkinfit", "summary.modFit") 

+  return(ans)  

+}

+

+# Expanded from print.summary.modFit

+print.summary.mkinfit <- function(x, digits = max(3, getOption("digits") - 3), ...) {

+  cat("\nEquations:\n")

+  print(noquote(as.character(x[["diffs"]])))

+  df  <- x$df

+  rdf <- df[2]

+

+  cat("\nStarting values for optimised parameters:\n")

+  print(x$start)

+

+  cat("\nFixed parameter values:\n")

+  if(length(x$fixed$value) == 0) cat("None\n")

+  else print(x$fixed)

+  

+  cat("\nOptimised parameters:\n")

+  printCoefmat(x$par, digits = digits, ...)

+

+  cat("\nResidual standard error:",

+      format(signif(x$sigma, digits)), "on", rdf, "degrees of freedom\n")

+

+  cat("\nChi2 error levels in percent:\n")

+  x$errmin$err.min <- 100 * x$errmin$err.min

+  print(x$errmin, digits=digits,...)

+

+  printdistimes <- !is.null(x$distimes)

+  if(printdistimes){

+    cat("\nEstimated disappearance times\n")

+    print(x$distimes, digits=digits,...)

+  }    

+

+  printcor <- !is.null(x$cov.unscaled)

+  if (printcor){

+    Corr <- cov2cor(x$cov.unscaled)

+    rownames(Corr) <- colnames(Corr) <- rownames(x$par)

+    cat("\nParameter correlation:\n")

+    print(Corr, digits = digits, ...)

+  }

+

+  printdata <- !is.null(x$data)

+  if (printdata){

+    cat("\nData:\n")

+    print(format(x$data, digits = digits, scientific = FALSE,...), row.names = FALSE)

+  }

+

+  invisible(x)

 }

diff --git a/R/mkinmod.R b/R/mkinmod.R
index 7e64f87..643e855 100644
--- a/R/mkinmod.R
+++ b/R/mkinmod.R
@@ -1,38 +1,53 @@
-mkinmod <- function(spec = list(parent = list(type = "SFO", to = NA, sink = TRUE)))

+mkinmod <- function(...)

 {

-  if(!is.list(spec)) stop("spec must be a list of model specifications for each observed variable")

+  spec <- list(...)

+  obs_vars <- names(spec)

 

-  # The returned model will be a list of two character vectors, containing

-  # differential equations and parameter names

+  # The returned model will be a list of character vectors, containing

+  # differential equations, parameter names and a mapping from model variables

+  # to observed variables

   parms <- vector()

   diffs <- vector()

   map <- list()

 

   # Establish list of differential equations

-  for (varname in names(spec))

+  for (varname in obs_vars)

   {

-    if(!spec[[varname]]$type %in% c("SFO", "SFORB")) stop("Available types are SFO and SFORB only")

+    if(is.null(spec[[varname]]$type)) stop("Every argument to mkinmod must be a list containing a type component")

+    if(!spec[[varname]]$type %in% c("SFO", "FOMC", "SFORB")) stop("Available types are SFO, FOMC and SFORB only")

     new_parms <- vector()

 

     # New (sub)compartments (boxes) needed for the model type

     new_boxes <- switch(spec[[varname]]$type,

       SFO = varname,

+      FOMC = varname,

       SFORB = paste(varname, c("free", "bound"), sep="_")

     )

     map[[varname]] <- new_boxes

+    names(map[[varname]]) <- rep(spec[[varname]]$type, length(new_boxes))

 

     # Start a new differential equation for each new box

     new_diffs <- paste("d_", new_boxes, " =", sep="")

 

     # Construct terms for transfer to sink and add if appropriate

+    if(is.null(spec[[varname]]$sink)) spec[[varname]]$sink <- TRUE

     if(spec[[varname]]$sink) {

-      k_compound_sink <- paste("k", new_boxes[[1]], "sink", sep="_")

-      sink_term <- paste("-", k_compound_sink, "*", new_boxes[[1]])

-      # Only add sink term to first (or only) box for SFO and SFORB models

+      # Add first-order sink term to first (or only) box for SFO and SFORB models

       if(spec[[varname]]$type %in% c("SFO", "SFORB")) {

+        k_compound_sink <- paste("k", new_boxes[[1]], "sink", sep="_")

+        sink_term <- paste("-", k_compound_sink, "*", new_boxes[[1]])

         new_diffs[[1]] <- paste(new_diffs[[1]], sink_term)

+        new_parms <- k_compound_sink

+      }

+      if(spec[[varname]]$type == "FOMC") {

+        if(match(varname, obs_vars) != 1) {

+          stop("Type FOMC is only allowed for the first compartment, which is assumed to be the source compartment")

+        }

+        # From p. 53 of the FOCUS kinetics report

+        fomc_term <- paste("(alpha/beta) * ((time/beta) + 1)^-1 *", new_boxes[[1]])

+        new_diffs[[1]] <- paste(new_diffs[[1]], "-", fomc_term)

+        new_parms <- c("alpha", "beta")

       }

-      new_parms <- k_compound_sink

     }

    

     # Add reversible binding if appropriate

@@ -53,24 +68,41 @@ mkinmod <- function(spec = list(parent = list(type = "SFO", to = NA, sink = TRUE
   }

 

   # Transfer between compartments

-  for (varname in names(spec)) {

+  for (varname in obs_vars) {

     to <- spec[[varname]]$to

-    if(!is.na(to)) {

+    if(!is.null(to)) {

       origin_box <- switch(spec[[varname]]$type,

         SFO = varname,

+        FOMC = varname,

         SFORB = paste(varname, "free", sep="_"))

+      fraction_left <- NULL

       for (target in to) {

         target_box <- switch(spec[[target]]$type,

           SFO = target,

           SFORB = paste(target, "free", sep="_"))

+        if(spec[[varname]]$type %in% c("SFO", "SFORB")) {

+          k_from_to <- paste("k", origin_box, target_box, sep="_")

+          diffs[[origin_box]] <- paste(diffs[[origin_box]], "-", k_from_to, "*", origin_box)

+          diffs[[target_box]] <- paste(diffs[[target_box]], "+", k_from_to, "*", origin_box)

+          parms <- c(parms, k_from_to)

+        }

+        if(spec[[varname]]$type == "FOMC") {

+          fraction_to_target = paste("f_to", target, sep="_")

+          fraction_not_to_target = paste("(1 - ", fraction_to_target, ")", sep="")

+          if(is.null(fraction_left)) {

+            fraction_really_to_target = fraction_to_target

+            fraction_left = fraction_not_to_target

+          } else {

+            fraction_really_to_target = paste(fraction_left, " * ", fraction_to_target, sep="")

+            fraction_left = paste(fraction_left, " * ", fraction_not_to_target, sep="")

+          }

+          diffs[[target_box]] <- paste(diffs[[target_box]], "+", fraction_really_to_target, "*", fomc_term)

+          parms <- c(parms, fraction_to_target)

+        }

       }

-      k_from_to <- paste("k", origin_box, target_box, sep="_")

-      diffs[[origin_box]] <- paste(diffs[[origin_box]], "-", k_from_to, "*", origin_box)

-      diffs[[target_box]] <- paste(diffs[[target_box]], "+", k_from_to, "*", origin_box)

-      parms <- c(parms, k_from_to)

     }

   }

   model <- list(diffs = diffs, parms = parms, map = map)

   class(model) <- "mkinmod"

-  return(model)

+  invisible(model)

 }

diff --git a/R/mkinplot.R b/R/mkinplot.R
new file mode 100644
index 0000000..d2880c0
--- /dev/null
+++ b/R/mkinplot.R
@@ -0,0 +1,49 @@
+mkinplot <- function(fit, xlab = "Time", ylab = "Observed", xlim = range(fit$data$time), ylim = range(fit$data$observed, na.rm = TRUE), ...)
+{
+  fixed <- fit$fixed$value
+  names(fixed) <- rownames(fit$fixed)
+  parms.all <- c(fit$par, fixed)
+  ininames <- c(
+    rownames(subset(fit$start, type == "state")),
+    rownames(subset(fit$fixed, type == "state")))
+  odeini <- parms.all[ininames]
+  names(odeini) <- names(fit$diffs)
+
+  outtimes <- seq(xlim[1], xlim[2], length.out=100)
+
+  odenames <- c(
+    rownames(subset(fit$start, type == "deparm")),
+    rownames(subset(fit$fixed, type == "deparm")))
+  odeparms <- parms.all[odenames]
+
+  # Solve the ode
+  out <- ode(
+    y = odeini,
+    times = outtimes,
+    func = fit$mkindiff, 
+    parms = odeparms)
+    
+  # Output transformation for models with unobserved compartments like SFORB
+  out_transformed <- data.frame(time = out[,"time"])
+  for (var in names(fit$map)) {
+    if(length(fit$map[[var]]) == 1) {
+      out_transformed[var] <- out[, var]
+    } else {
+      out_transformed[var] <- rowSums(out[, fit$map[[var]]])
+    }
+  }    
+
+  # Plot the data and model output
+  plot(0, type="n", 
+    xlim = xlim, ylim = ylim,
+      xlab = xlab, ylab = ylab, ...)
+    col_obs <- pch_obs <- 1:length(fit$map)
+    names(col_obs) <- names(pch_obs) <- names(fit$map)
+    for (obs_var in names(fit$map)) {
+      points(subset(fit$data, variable == obs_var, c(time, observed)), 
+        pch = pch_obs[obs_var], col = col_obs[obs_var])
+    }
+    matlines(out_transformed$time, out_transformed[-1])
+      legend("topright", inset=c(0.05, 0.05), legend=names(fit$map),
+      col=col_obs, pch=pch_obs, lty=1:length(pch_obs))
+}