#' Non-Invasive Multilinear Logan Plot
#'
#' Function to fit the non-invasive modification of the multilinear Logan plot model of Turkheimer et al. (2003) to data.
#'
#' @param t_tac Numeric vector of times for each frame in minutes. We use the time halfway through the frame as well as a
#' zero. If a time zero frame is not included, it will be added.
#' @param reftac Numeric vector of radioactivity concentrations in the reference tissue for each frame. We include zero at
#' time zero: if not included, it is added.
#' @param roitac Numeric vector of radioactivity concentrations in the target tissue for each frame. We include zero at time
#' zero: if not included, it is added.
#' @param k2prime Value of k2prime to be used for the fitting, i.e. the average tissue-to-plasma clearance rate. This can be
#' obtained from another model, or set at a specified value. If using SRTM to estimate this value, it is equal to k2 / R1.
#' @param tstarIncludedFrames The number of frames to be used in the regression model, i.e. the number of frames for which
#' the function is linear after pseudo-equilibrium is reached. This is a count from the end of the measurement, so a value of
#' 10 means that last 10 frames will be used. This value can be estimated using \code{refmlLogan_tstar}.
#' @param weights Optional. Numeric vector of the weights assigned to each frame in the fitting. We include zero at time zero:
#' if not included, it is added. If not specified, uniform weights will be used.
#' @param dur Optional. Numeric vector of the time durations of the frames. If
#' not included, the integrals will be calculated using trapezoidal integration.
#' @param frameStartEnd Optional: This allows one to specify the beginning and final frame to use for modelling, e.g. c(1,20).
#' This is to assess time stability.
#'
#' @return A list with a data frame of the fitted parameters \code{out$par}, the model fit object \code{out$fit}, a dataframe
#' containing the TACs of the data \code{out$tacs}, a dataframe containing the TACs of the fitted values \code{out$fitvals},
#' a vector of the weights \code{out$weights}, the specified k2prime value \code{out$k2prime}, and the specified
#' tstarIncludedFrames value \code{out$tstarIncludedFrames}
#'
#' @examples
#' data(simref)
#'
#' t_tac <- simref$tacs[[2]]$Times
#' reftac <- simref$tacs[[2]]$Reference
#' roitac <- simref$tacs[[2]]$ROI1
#' weights <- simref$tacs[[2]]$Weights
#'
#' fit <- refmlLogan(t_tac, reftac, roitac, k2prime = 0.1, tstarIncludedFrames = 10, weights = weights)
#' @author Granville J Matheson, \email{mathesong@@gmail.com}
#'
#' @references Turkheimer FE, Aston JA, Banati RB, Riddell C, Cunningham VJ. A linear wavelet filter for parametric imaging with dynamic PET. IEEE transactions on medical imaging. 2003 Mar;22(3):289-301.
#'
#' @export
refmlLogan <- function(t_tac, reftac, roitac, k2prime, tstarIncludedFrames,
weights = NULL, dur = NULL, frameStartEnd = NULL) {
# Tidying
tidyinput <- tidyinput_ref(t_tac, reftac, roitac, weights, frameStartEnd)
if (!is.null(dur)) {
tidyinput_dur <- tidyinput_ref(dur, reftac, roitac, weights, frameStartEnd)
dur <- tidyinput_dur$t_tac
}
t_tac <- tidyinput$t_tac
reftac <- tidyinput$reftac
roitac <- tidyinput$roitac
weights <- tidyinput$weights
# Parameters
if (!is.null(dur)) {
term1_dv <- frame_cumsum(dur, roitac)
term2 <- frame_cumsum(dur, reftac) + reftac / k2prime
term3 <- -roitac
} else {
term1_dv <- pracma::cumtrapz(t_tac, roitac)
term2 <- pracma::cumtrapz(t_tac, reftac) + reftac / k2prime
term3 <- -roitac
}
fitvals <- data.frame(
Time = t_tac, Reference = reftac, Weights = weights,
Term1_DV = term1_dv, Term2 = term2, Term3 = term3 )
if (is.null(tstarIncludedFrames) != T) {
equil <- rep("Before", length(roitac))
equil[(length(equil) - tstarIncludedFrames + 1):length(equil)] <- "After"
} else {
equil <- rep("After", length(roitac))
}
fitvals$Equilibrium <- equil
fitvals_equil <- subset(fitvals, fitvals$Equilibrium == "After")
# Solution
mllogan_model <- lm(Term1_DV ~ Term2 + Term3 - 1, weights = Weights, data = fitvals_equil)
# Output
bp <- as.numeric(mllogan_model$coefficients[1]) - 1
k2 <- as.numeric(1 / mllogan_model$coefficients[2])
par <- as.data.frame(list(bp = bp, k2 = k2))
fit <- mllogan_model
tacs <- data.frame(Time = t_tac, Reference = reftac, Target = roitac)
if(!is.null(dur)) { tacs$Duration = dur }
fittedvals <- (as.numeric(mllogan_model$coefficients[1]) * term2) + (as.numeric(mllogan_model$coefficients[2] * term3))
fitvals <- data.frame(Term1_DV = term1_dv, Term2 = term2, Term3 = term3, Fitted = fittedvals)
out <- list(
par = par, fit = fit, tacs = tacs, fitvals = fitvals, weights = weights, k2prime = k2prime,
tstarIncludedFrames = tstarIncludedFrames, model = "refmlLogan"
)
class(out) <- c("refmlLogan", "kinfit")
return(out)
}
#' Plot: Non-Invasive Multilinear Logan Plot
#'
#' Function to visualise the fit of the refmlLogan model to data.
#'
#' @param refmlloganout The output object of the refmlLogan fitting procedure.
#' @param roiname Optional. The name of the Target Region to see it on the plot.
#'
#' @return A ggplot2 object of the plot.
#'
#' @examples
#' data(simref)
#'
#' t_tac <- simref$tacs[[2]]$Times
#' reftac <- simref$tacs[[2]]$Reference
#' roitac <- simref$tacs[[2]]$ROI1
#' weights <- simref$tacs[[2]]$Weights
#'
#' fit <- refmlLogan(t_tac, reftac, roitac, k2prime = 0.1, tstarIncludedFrames = 10, weights = weights)
#'
#' plot_refmlLoganfit(fit)
#' @author Granville J Matheson, \email{mathesong@@gmail.com}
#'
#' @import ggplot2
#'
#' @export
plot_refmlLoganfit <- function(refmlloganout, roiname = NULL) {
plotdf <- data.frame(
Weights = refmlloganout$weights,
Term1_DV = refmlloganout$fitvals$Term1_DV,
Fitted = refmlloganout$fitvals$Fitted,
Equilibrium = as.character("Before")
)
plotdf$Equilibrium <- as.character(plotdf$Equilibrium)
plotdf$Equilibrium [ (nrow(plotdf) - (refmlloganout$tstarIncludedFrames - 1)):nrow(plotdf) ] <- "After"
plotdf$Equilibrium <- forcats::fct_inorder(factor(plotdf$Equilibrium))
myColors <- RColorBrewer::brewer.pal(3, "Set1")
names(myColors) <- levels(plotdf$Equilibrium)
colScale <- scale_colour_manual(name = paste0(roiname, "\nEquilibrium"), values = myColors)
outplot <- ggplot(data = plotdf, aes(x = Fitted, y = Term1_DV, colour = Equilibrium)) +
geom_point(aes(shape = "a", size = Weights)) +
geom_abline(slope = 1, intercept = 0) +
xlab("Fitted Values") + ylab("Integ(C_Tissue)") + colScale +
guides(shape = "none", color = guide_legend(order = 1)) + scale_size(range = c(1, 3))
return(outplot)
}
#' Tstar Finder: Non-Invasive Multilinear Logan Plot
#'
#' Function to identify where t* is for the non-invasive multilinear Logan plot.
#'
#'
#' @param t_tac Numeric vector of times for each frame in minutes. We use the time halfway through the frame as well as a
#' zero. If a time zero frame is not included, it will be added.
#' @param reftac Numeric vector of radioactivity concentrations in the reference tissue for each frame.
#' @param lowroi Numeric vector of radioactivity concentrations in a target tissue for each frame. This should be from a ROI with low binding.
#' @param medroi Numeric vector of radioactivity concentrations in a target tissue for each frame. This should be from a ROI with medium binding.
#' @param highroi Numeric vector of radioactivity concentrations in a target tissue for each frame. This should be from a ROI with high binding.
#' @param k2prime Value of k2prime to be used for the fitting, i.e. the average tissue-to-plasma clearance rate. This can be
#' obtained from another model, or set at a specified value. If using SRTM to estimate this value, it is equal to k2 / R1.
#' @param filename The name of the output image: filename_refmlLogan.jpeg
#' @param frameStartEnd Optional: This allows one to specify the beginning and final frame to use for modelling, e.g. c(1,20).
#' This is to assess time stability.
#' @param gridbreaks Optional. The size of the grid in the plots. Default: 2.
#'
#'
#' @return Saves a jpeg of the plots as filename_refmlLogan.jpeg
#'
#' @examples
#' \dontrun{
#' refmlLogan_tstar(t_tac, reftac, taclow, tacmed, tachigh,
#' k2prime = k2prime, "demonstration"
#' )
#' }
#'
#' @author Granville J Matheson, \email{mathesong@@gmail.com}
#'
#' @import ggplot2
#'
#' @export
refmlLogan_tstar <- function(t_tac, reftac, lowroi, medroi, highroi, k2prime, filename = NULL, frameStartEnd = NULL, gridbreaks = 2) {
frames <- length(reftac)
lowroi_fit <- refmlLogan(t_tac, reftac, lowroi, k2prime, length(reftac), frameStartEnd = frameStartEnd)
medroi_fit <- refmlLogan(t_tac, reftac, medroi, k2prime, length(reftac), frameStartEnd = frameStartEnd)
highroi_fit <- refmlLogan(t_tac, reftac, highroi, k2prime, length(reftac), frameStartEnd = frameStartEnd)
mllogan_xlab <- "Fitted Values"
mllogan_ylab <- "Integ(C_Tissue)"
low_linplot <- qplot(lowroi_fit$fitvals$Fitted, lowroi_fit$fitvals$Term1_DV) + ggtitle("Low") + xlab(mllogan_xlab) + ylab(mllogan_ylab)
med_linplot <- qplot(medroi_fit$fitvals$Fitted, medroi_fit$fitvals$Term1_DV) + ggtitle("Medium") + xlab(mllogan_xlab) + ylab(mllogan_ylab)
high_linplot <- qplot(highroi_fit$fitvals$Fitted, highroi_fit$fitvals$Term1_DV) + ggtitle("High") + xlab(mllogan_xlab) + ylab(mllogan_ylab)
tstarInclFrames <- 3:frames
zeros <- rep(0, length(tstarInclFrames))
r2_df <- data.frame(Frames = tstarInclFrames, Low = zeros, Medium = zeros, High = zeros)
maxperc_df <- data.frame(Frames = tstarInclFrames, Time = t_tac[ tstarInclFrames ], Low = zeros, Medium = zeros, High = zeros)
bp_df <- data.frame(Frames = tstarInclFrames, Time = t_tac[ tstarInclFrames ], Low = zeros, Medium = zeros, High = zeros)
for (i in 1:length(tstarInclFrames)) {
lowfit <- refmlLogan(t_tac, reftac, lowroi, k2prime, tstarIncludedFrames = tstarInclFrames[i], frameStartEnd = frameStartEnd)
medfit <- refmlLogan(t_tac, reftac, medroi, k2prime, tstarIncludedFrames = tstarInclFrames[i], frameStartEnd = frameStartEnd)
highfit <- refmlLogan(t_tac, reftac, highroi, k2prime, tstarIncludedFrames = tstarInclFrames[i], frameStartEnd = frameStartEnd)
r2_df$Low[i] <- summary(lowfit$fit)$r.squared
r2_df$Medium[i] <- summary(medfit$fit)$r.squared
r2_df$High[i] <- summary(highfit$fit)$r.squared
maxperc_df$Low[i] <- maxpercres(lowfit)
maxperc_df$Medium[i] <- maxpercres(medfit)
maxperc_df$High[i] <- maxpercres(highfit)
bp_df$Low[i] <- lowfit$par$bp
bp_df$Medium[i] <- medfit$par$bp
bp_df$High[i] <- highfit$par$bp
}
xlabel <- "Number of Included Frames"
ylab_r2 <- expression(R^2)
ylab_mp <- "Maximum Percentage Variance"
# R Squared plots
low_r2plot <- ggplot(r2_df, aes(x = Frames, y = Low)) + geom_point() + scale_x_continuous(breaks = seq(min(tstarInclFrames), max(tstarInclFrames), by = gridbreaks)) + coord_cartesian(ylim = c(0.99, 1)) + xlab(xlabel) + ylab(ylab_r2)
med_r2plot <- ggplot(r2_df, aes(x = Frames, y = Medium)) + geom_point() + scale_x_continuous(breaks = seq(min(tstarInclFrames), max(tstarInclFrames), by = gridbreaks)) + coord_cartesian(ylim = c(0.99, 1)) + xlab(xlabel) + ylab(ylab_r2)
high_r2plot <- ggplot(r2_df, aes(x = Frames, y = High)) + geom_point() + scale_x_continuous(breaks = seq(min(tstarInclFrames), max(tstarInclFrames), by = gridbreaks)) + coord_cartesian(ylim = c(0.99, 1)) + xlab(xlabel) + ylab(ylab_r2)
# Max Percentage Variation Plots
maxperc_df$inclmins <- rev(max(t_tac) - t_tac)[-c(1, 2)]
maxperc_df$tstar <- rev(t_tac)[-c(1, 2)]
low_mpplot <- ggplot(maxperc_df, aes(x = Frames, y = Low)) + geom_point() + scale_x_continuous(breaks = seq(min(tstarInclFrames), max(tstarInclFrames), by = gridbreaks)) + coord_cartesian(ylim = c(0, 20)) + xlab(xlabel) + ylab(ylab_mp) + annotate("text", x = 3, y = 20, label = "t* Minutes", colour = "red", size = 3, hjust = 0) + annotate("text", x = maxperc_df$Frames, y = maxperc_df$Low + 1.4, label = round(maxperc_df$tstar, 1), size = 3, colour = "red") + annotate("text", x = 3, y = 20 - 0.7, label = "Included Minutes", colour = "blue", size = 3, hjust = 0) + annotate("text", x = maxperc_df$Frames, y = maxperc_df$Low + 0.7, label = round(maxperc_df$inclmins, 1), size = 3, colour = "blue")
med_mpplot <- ggplot(maxperc_df, aes(x = Frames, y = Medium)) + geom_point() + scale_x_continuous(breaks = seq(min(tstarInclFrames), max(tstarInclFrames), by = gridbreaks)) + coord_cartesian(ylim = c(0, 20)) + xlab(xlabel) + ylab(ylab_mp) + annotate("text", x = 3, y = 20, label = "t* Minutes", colour = "red", size = 3, hjust = 0) + annotate("text", x = maxperc_df$Frames, y = maxperc_df$Medium + 1.4, label = round(maxperc_df$tstar, 1), size = 3, colour = "red") + annotate("text", x = 3, y = 20 - 0.7, label = "Included Minutes", colour = "blue", size = 3, hjust = 0) + annotate("text", x = maxperc_df$Frames, y = maxperc_df$Medium + 0.7, label = round(maxperc_df$inclmins, 1), size = 3, colour = "blue")
high_mpplot <- ggplot(maxperc_df, aes(x = Frames, y = High)) + geom_point() + scale_x_continuous(breaks = seq(min(tstarInclFrames), max(tstarInclFrames), by = gridbreaks)) + coord_cartesian(ylim = c(0, 20)) + xlab(xlabel) + ylab(ylab_mp) + annotate("text", x = 3, y = 20, label = "t* Minutes", colour = "red", size = 3, hjust = 0) + annotate("text", x = maxperc_df$Frames, y = maxperc_df$High + 1.4, label = round(maxperc_df$tstar, 1), size = 3, colour = "red") + annotate("text", x = 3, y = 20 - 0.7, label = "Included Minutes", colour = "blue", size = 3, hjust = 0) + annotate("text", x = maxperc_df$Frames, y = maxperc_df$High + 0.7, label = round(maxperc_df$inclmins, 1), size = 3, colour = "blue")
# TAC Plot
tacplotdf <- data.frame(cbind(Time = lowroi_fit$tacs$Time, Reference = lowroi_fit$tacs$Reference, Low = lowroi_fit$tacs$Target, Medium = medroi_fit$tacs$Target, High = highroi_fit$tacs$Target))
tacplotdf <- tidyr::gather(tacplotdf, key = Region, value = Radioactivity, -Time)
tacplotdf$Region <- forcats::fct_rev(forcats::fct_inorder(factor(tacplotdf$Region)))
myColors <- RColorBrewer::brewer.pal(4, "Set1")
names(myColors) <- levels(tacplotdf$Region)
colScale <- scale_colour_manual(name = "Region", values = myColors)
tacplot <- ggplot(tacplotdf, aes(x = Time, y = Radioactivity, colour = Region)) + geom_point() + geom_line() + colScale
# BP Plot
bpplotdf <- tidyr::gather(bp_df, key = Region, value = BP, -Frames, -Time)
bpplotdf$Region <- forcats::fct_rev(forcats::fct_inorder(factor(bpplotdf$Region)))
bpplot <- ggplot(bpplotdf, aes(x = Frames, y = BP, colour = Region)) + geom_point() + geom_line() + scale_x_continuous(breaks = seq(min(tstarInclFrames), max(tstarInclFrames), by = gridbreaks)) + ylab(expression(BP[ND])) + colScale
# Output
linrow <- cowplot::plot_grid(low_linplot, med_linplot, high_linplot, nrow = 1)
r2row <- cowplot::plot_grid(low_r2plot, med_r2plot, high_r2plot, nrow = 1)
mprow <- cowplot::plot_grid(low_mpplot, med_mpplot, high_mpplot, nrow = 1)
outrow <- cowplot::plot_grid(tacplot, bpplot, rel_widths = c(2, 1))
totalplot <- cowplot::plot_grid(linrow, r2row, mprow, outrow, nrow = 4)
if (!is.null(filename)) {
jpeg(filename = paste0(filename, "_refmlLogan.jpeg"), width = 300, height = 400, units = "mm", res = 600)
totalplot
dev.off()
}
return(totalplot)
}
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