#' Ichise Multilinear Analysis 1
#'
#' Function to fit the MA1 of Ichise et al (2002) 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 tac 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 input Data frame containing the blood, plasma, and parent fraction concentrations over time. This can be generated
#' using the \code{blood_interp} function.
#' @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{ma1_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 inpshift Optional. The number of minutes by which to shift the timing of the input data frame forwards or backwards.
#' If not specified, this will be set to 0. This can be fitted using 1TCM or 2TCM.
#' @param vB Optional. The blood volume fraction. If not specified, this will be ignored and assumed to be 0%. If specified, it
#' will be corrected for prior to parameter estimation using the following equation:
#' \deqn{C_{T}(t) = \frac{C_{Measured}(t) - vB\times C_{B}(t)}{1-vB}}
#' @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$tacs}, a dataframe containing the fitted values \code{out$fitvals},
#' the blood input data frame after time shifting \code{input}, a vector of the weights \code{out$weights},
#' the inpshift value used \code{inpshift}, the specified vB value \code{out$vB} and the specified tstarIncludedFrames
#' value \code{out$tstarIncludedFrames}.
#'
#' @examples
#' data(pbr28)
#'
#' t_tac <- pbr28$tacs[[2]]$Times / 60
#' tac <- pbr28$tacs[[2]]$FC
#' weights <- pbr28$tacs[[2]]$Weights
#' dur <- pbr28$tacs[[2]]$Duration/60
#'
#' input <- blood_interp(
#' pbr28$procblood[[2]]$Time / 60, pbr28$procblood[[2]]$Cbl_dispcorr,
#' pbr28$procblood[[2]]$Time / 60, pbr28$procblood[[2]]$Cpl_metabcorr,
#' t_parentfrac = 1, parentfrac = 1
#' )
#'
#' fit1 <- ma1(t_tac, tac, input, 10, weights)
#' fit2 <- ma1(t_tac, tac, input, 10, weights, inpshift = 0.1, vB = 0.05)
#' fit3 <- ma1(t_tac, tac, input, 10, weights, inpshift = 0.1, vB = 0.05, dur = dur)
#' @author Granville J Matheson, \email{mathesong@@gmail.com}
#'
#' @references Ichise M, Toyama H, Innis RB, Carson RE. Strategies to improve neuroreceptor parameter estimation by linear regression analysis. Journal of Cerebral Blood Flow & Metabolism. 2002 Oct 1;22(10):1271-81.
#'
#' @export
ma1 <- function(t_tac, tac, input, tstarIncludedFrames, weights = NULL,
inpshift = 0, vB = 0, dur = NULL, frameStartEnd = NULL) {
# Tidying
tidyinput <- tidyinput_art(t_tac, tac, weights, frameStartEnd)
if (!is.null(dur)) {
tidyinput_dur <- tidyinput_art(dur, tac, weights, frameStartEnd)
dur <- tidyinput_dur$t_tac
}
t_tac <- tidyinput$t_tac
tac <- tidyinput$tac
weights <- tidyinput$weights
newvals <- shift_timings(
t_tac = t_tac,
tac = tac,
input = input,
inpshift = inpshift
)
t_tac <- newvals$t_tac
tac <- newvals$tac
t_inp <- newvals$input$Time
blood <- newvals$input$Blood
aif <- newvals$input$AIF
# Parameters
interptime <- newvals$input$Time
i_tac <- pracma::interp1(t_tac, tac, interptime, method = "linear")
# Blood Volume Correction (nothing happens if vB = 0)
i_tac <- (i_tac - vB * blood) / (1 - vB)
tac_uncor <- tac
tac <- pracma::interp1(interptime, i_tac, t_tac, method = "linear")
if (!is.null(dur)) {
term1 <- as.numeric(pracma::cumtrapz(interptime, aif))
term1 <- pracma::interp1(interptime, term1, t_tac, method = "linear")
term2 <- frame_cumsum(dur, tac)
} else {
term1 <- as.numeric(pracma::cumtrapz(interptime, aif))
term2 <- as.numeric(pracma::cumtrapz(interptime, i_tac))
term1 <- pracma::interp1(interptime, term1, t_tac, method = "linear")
term2 <- pracma::interp1(interptime, term2, t_tac, method = "linear")
}
tac_equil <- tail(tac, tstarIncludedFrames)
t_tac_equil <- tail(t_tac, tstarIncludedFrames)
term1_equil <- tail(term1, tstarIncludedFrames)
term2_equil <- tail(term2, tstarIncludedFrames)
weights_equil <- tail(weights, tstarIncludedFrames)
# Solution
ma1_model <- lm(tac_equil ~ term1_equil + term2_equil - 1, weights = weights_equil)
# Output
Vt <- as.numeric(-ma1_model$coefficients[1] / ma1_model$coefficients[2])
par <- as.data.frame(list(Vt = Vt))
fit <- ma1_model
tacs <- data.frame(Time = t_tac, Target = tac, Target_uncor = tac_uncor) # uncorrected for blood volume
if(!is.null(dur)) { tacs$Duration = dur }
fitvals <- data.frame(
Time = t_tac_equil, Target = tac_equil, Term1 = term1_equil, Term2 = term2_equil,
Target_fitted = as.numeric(predict(ma1_model)), Weights = weights_equil
)
input <- newvals$input
par.se <- par
names(par.se) <- paste0(names(par.se), ".se")
par.se$Vt.se <- get_se(ma1_model, "-term1_equil / term2_equil")
out <- list(
par = par, par.se = par.se, fit = ma1_model, tacs = tacs, fitvals = fitvals,
input = input, weights = weights, inpshift = inpshift, vB = vB,
tstarIncludedFrames = tstarIncludedFrames, model = "ma1"
)
class(out) <- c("ma1", "kinfit")
return(out)
}
#' Plot: Ichise Multilinear Analysis 1
#'
#' Function to visualise the fit of the MA1 model to data.
#'
#' @param ma1out The output object of the MA1 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(pbr28)
#'
#' t_tac <- pbr28$tacs[[2]]$Times / 60
#' tac <- pbr28$tacs[[2]]$FC
#' weights <- pbr28$tacs[[2]]$Weights
#'
#' input <- blood_interp(
#' pbr28$procblood[[2]]$Time / 60, pbr28$procblood[[2]]$Cbl_dispcorr,
#' pbr28$procblood[[2]]$Time / 60, pbr28$procblood[[2]]$Cpl_metabcorr,
#' t_parentfrac = 1, parentfrac = 1
#' )
#'
#' fit <- ma1(t_tac, tac, input, 10, weights)
#' plot_ma1fit(fit)
#' @author Granville J Matheson, \email{mathesong@@gmail.com}
#'
#' @import ggplot2
#'
#' @export
plot_ma1fit <- function(ma1out, roiname = NULL) {
measured <- data.frame(
Time = ma1out$tacs$Time,
Target.measured = ma1out$tacs$Target,
Weights = ma1out$weights
)
fitted <- data.frame(
Time = ma1out$fitvals$Time,
Target.fitted = ma1out$fitvals$Target_fitted,
Weights = ma1out$fitvals$Weights
)
if (is.null(roiname)) {
roiname <- "ROI"
}
measured <- plyr::rename(measured, c("Target.measured" = paste0(roiname, ".measured")))
fitted <- plyr::rename(fitted, c("Target.fitted" = paste0(roiname, ".fitted")))
tidymeasured <- tidyr::gather(
measured,
key = Region, value = Radioactivity,
-Time, -Weights, factor_key = F
)
tidyfitted <- tidyr::gather(
fitted,
key = Region, value = Radioactivity,
-Time, -Weights, factor_key = F
)
Region <- forcats::fct_inorder(factor(c(tidymeasured$Region, tidyfitted$Region)))
myColors <- RColorBrewer::brewer.pal(3, "Set1")
names(myColors) <- levels(Region)
colScale <- scale_colour_manual(name = "Region", values = myColors)
outplot <- ggplot(tidymeasured, aes(x = Time, y = Radioactivity, colour = Region)) +
geom_point(data = tidymeasured, aes(shape = "a", size = Weights)) +
geom_line(data = tidyfitted) + colScale +
guides(shape = "none", color = guide_legend(order = 1)) + scale_size(range = c(1, 3))
return(outplot)
}
#' Tstar Finder: Ichise Multilinear Analysis 1
#'
#' Function to identify where t* is for MA1.
#'
#'
#' @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 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 input Data frame containing the blood, plasma, and parent fraction concentrations over time. This can be generated
#' using the \code{blood_interp} function.
#' @param filename The name of the output image: filename_ma1.jpeg
#' @param inpshift Optional. The number of minutes by which to shift the timing of the input data frame forwards or backwards.
#' If not specified, this will be set to 0. This can be fitted using 1TCM or 2TCM.
#' @param vB Optional. The blood volume fraction. If not specified, this will
#' be ignored and assumed to be 0%. If specified, it will be corrected for
#' prior to parameter estimation using the following equation: \deqn{C_{T}(t)
#' = \frac{C_{Measured}(t) - vB\times C_{B}(t)}{1-vB}}
#' @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_ma1.jpeg
#'
#' @examples
#' \dontrun{
#' ma1_tstar(t_tac, lowroi, medroi, highroi, input,
#' filename = "demonstration",
#' inpshift = onetcmout$par$inpshift, frameStartEnd, gridbreaks = 4
#' )
#' }
#'
#' @author Granville J Matheson, \email{mathesong@@gmail.com}
#'
#' @import ggplot2
#'
#' @export
ma1_tstar <- function(t_tac, lowroi, medroi, highroi, input, filename = NULL, inpshift = 0, vB = 0, frameStartEnd = NULL, gridbreaks = 2) {
frames <- length(t_tac)
lowroi_fit <- ma1(t_tac, lowroi, input, tstarIncludedFrames = frames, inpshift = inpshift, vB = vB, frameStartEnd = frameStartEnd)
medroi_fit <- ma1(t_tac, medroi, input, tstarIncludedFrames = frames, inpshift = inpshift, vB = vB, frameStartEnd = frameStartEnd)
highroi_fit <- ma1(t_tac, highroi, input, tstarIncludedFrames = frames, inpshift = inpshift, vB = vB, frameStartEnd = frameStartEnd)
low_linplot <- plot_ma1fit(lowroi_fit) + ggtitle("Low") + ylim(0, max(lowroi_fit$tacs$Target * 1.1)) + theme(legend.position = "none")
med_linplot <- plot_ma1fit(medroi_fit) + ggtitle("Medium") + ylim(0, max(medroi_fit$tacs$Target * 1.1)) + theme(legend.position = "none")
high_linplot <- plot_ma1fit(highroi_fit) + ggtitle("High") + ylim(0, max(highroi_fit$tacs$Target * 1.1)) + theme(legend.position = "none")
tstarInclFrames <- 3:frames
zeros <- rep(0, length(tstarInclFrames))
r2_df <- data.frame(Frames = tstarInclFrames, Low = zeros, Medium = zeros, High = zeros)
maxperc_df <- data.frame(Frames = tstarInclFrames, Time = t_tac[ tstarInclFrames ], Low = zeros, Medium = zeros, High = zeros)
vt_df <- data.frame(Frames = tstarInclFrames, Time = t_tac[ tstarInclFrames ], Low = zeros, Medium = zeros, High = zeros)
for (i in 1:length(tstarInclFrames)) {
lowfit <- ma1(t_tac, lowroi, input, tstarIncludedFrames = tstarInclFrames[i], inpshift = inpshift, vB = vB, frameStartEnd = frameStartEnd)
medfit <- ma1(t_tac, medroi, input, tstarIncludedFrames = tstarInclFrames[i], inpshift = inpshift, vB = vB, frameStartEnd = frameStartEnd)
highfit <- ma1(t_tac, highroi, input, tstarIncludedFrames = tstarInclFrames[i], inpshift = inpshift, vB = vB, frameStartEnd = frameStartEnd)
r2_df$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$High[i] <- maxpercres(highfit)
vt_df$Low[i] <- lowfit$par$Vt
vt_df$Medium[i] <- medfit$par$Vt
vt_df$High[i] <- highfit$par$Vt
}
xlabel <- "Number of Included Frames"
ylab_r2 <- expression(R^2)
ylab_mp <- "Maximum Percentage Deviation"
# 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, 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$Region)
colScale <- scale_colour_manual(name = "Region", values = myColors)
tacplot <- ggplot(tacplotdf, aes(x = Time, y = Radioactivity, colour = Region)) + geom_point() + geom_line() + colScale
# Vt Plot
vtplotdf <- tidyr::gather(vt_df, key = Region, value = Vt, -Frames, -Time)
vtplotdf$Region <- forcats::fct_rev(forcats::fct_inorder(factor(vtplotdf$Region)))
ylimits <- c(min(vtplotdf$Vt), max(vtplotdf$Vt))
if (max(vtplotdf$Vt) > 20 || min(vtplotdf$Vt) < 0) {
ylimits <- c(0, 20)
}
vtplot <- ggplot(vtplotdf, aes(x = Frames, y = Vt, colour = Region)) + geom_point() + geom_line() + scale_x_continuous(breaks = seq(min(tstarInclFrames), max(tstarInclFrames), by = gridbreaks)) + ylab(expression(V[T])) + ylim(ylimits) + 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, vtplot, rel_widths = c(2, 1))
totalplot <- cowplot::plot_grid(linrow, r2row, mprow, outrow, nrow = 4)
if (!is.null(filename)) {
jpeg(filename = paste0(filename, "_ma1.jpeg"), width = 300, height = 400, units = "mm", res = 600)
totalplot
dev.off()
}
return(totalplot)
}
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