knitr::opts_chunk$set( dev = "png", collapse = TRUE, message =FALSE, warning =FALSE, fig.width = 7, comment = "#>" ) if (capabilities(("cairo"))) { knitr::opts_chunk$set(dev.args = list(png = list(type = "cairo"))) } options(rmarkdown.html_vignette.check_title = FALSE) library(coveffectsplot) library(mrgsolve) library(ggplot2) library(ggstance) library(ggridges) library(tidyr) library(dplyr) library(table1) library(egg) library(data.table) library(ggh4x) library(patchwork) theme_set(theme_bw()) #utility function to simulate varying one covariate at a time keeping the rest at the reference expand.modelframe <- function(..., rv, covcol="covname") { args <- list(...) df <- lapply(args, function(x) x[[1]]) df[names(rv)] <- rv res <- lapply(seq_along(rv), function(i) { df[[covcol]] <- names(rv)[i] df[[names(rv)[i]]] <- args[[names(rv)[i]]] as.data.frame(df) }) do.call(rbind, res) } round_pad <- function(x, digits = 2, round5up = TRUE) { eps <- if (round5up) x * (10^(-(digits + 3))) else 0 formatC(round(x + eps, digits), digits = digits, format = "f", flag = "0") } derive.exposure <- function(time, CP) { n <- length(time) x <- c( Cmax = max(CP), Clast = CP[n], AUC = sum(diff(time) * (CP[-1] + CP[-n])) / 2 ) data.table(paramname=names(x), paramvalue=x) } cor2cov <- function (cor, sd) { if (missing(sd)) { sd <- diag(cor) } diag(cor) <- 1 n <- nrow(cor) diag(sd, n) %*% cor %*% diag(sd, n) } stat_sum_df <- function(fun, geom="point", ...) { stat_summary(fun.data = fun, geom=geom, ...) } summary_conc <- function(CP) { x <- c( Cmed = median(CP), Clow = quantile(CP, probs = 0.05), Cup = quantile(CP, probs = 0.95) ) data.table(paramname=names(x), paramvalue=x) } nbsvsubjects <- 1000 nsim <- 100 # uncertainty replicates for vignette you might want a higher number
Here we illustrate the varying one covariate at a time approach, keeping all the others at the reference value or category. A two-compartment pharmacokinetic (PK) model defined with ordinary differential equations (ODEs) is used. Covariates Weight, Albumin and Sex had effects on the Clearance (CL) model parameter while Weight and Sex had effects on the Volume of distribution (V) model parameter. For simplicity, there were no included covariates effects on other PK parameters such as peripheral clearance or volume. The approach is general and can be easily extended to any other ODEs model with multiple covariate effects on multiple model parameters.
mrgsolve
codepkmodelcov <- ' $PARAM @annotated KA : 0.5 : Absorption rate constant Ka (1/h) CL : 4 : Clearance CL (L/h) V : 10 : Central volume Vc (L) Vp : 50 : Peripheral volume Vp (L) Qp : 10 : Intercompartmental clearance Q (L/h) CLALB : -0.8 : Ablumin on CL (ref. 45 g/L) CLSEX : 0.2 : Sex on CL (ref. Female) CLWT : 1 : Weight on CL (ref. 85 kg) VSEX : 0.07 : Sex on Vc (ref. Female) VWT : 1 : Weight on Vc (ref. 85 kg) $PARAM @annotated // reference values for covariate WT : 85 : Weight (kg) SEX : 0 : Sex (0=Female, 1=Male) ALB : 45 : Albumin (g/L) $PKMODEL cmt="GUT CENT PER", depot=TRUE, trans=11 $MAIN double CLi = CL * pow((ALB/45.0), CLALB)* (SEX == 1.0 ? (1.0+CLSEX) : 1.0)* pow((WT/85.0), CLWT)*exp(nCL); double V2i = V * (SEX == 1.0 ? (1.0+VSEX) : 1.0)* pow((WT/85.0), VWT)*exp(nVC); double KAi = KA; double V3i = Vp *pow((WT/85.0), 1); double Qi = Qp *pow((WT/85.0), 0.75); $OMEGA @annotated @block nCL : 0.09 : ETA on CL nVC : 0.01 0.09 : ETA on Vc $TABLE double CP = CENT/V2i; $CAPTURE CP KAi CLi V2i V3i Qi WT SEX ALB ' modcovsim <- mcode("codepkmodelcov", codepkmodelcov) partab <- setDT(modcovsim@annot$data)[block=="PARAM", .(name, descr, unit)] partab <- merge(partab, melt(setDT(modcovsim@param@data), meas=patterns("*"), var="name")) knitr::kable(partab)
We simulate the reference subject having the reference covariate values defined in the model which are:
Weight = 85 kg, Sex = Female and Albumin = 45 g/L.
We also keep the between subject variability (BSV) to illustrate its effects on the concentration-time profiles on linear and log linear scales.
idata <- data.table(ID=1:nbsvsubjects, WT=85, SEX=0, ALB=45) ev1 <- ev(time = 0, amt = 100, cmt = 1) data.dose <- ev(ev1) data.dose <- setDT(as.data.frame(data.dose)) data.all <- data.table(idata, data.dose) outputsim <- modcovsim %>% data_set(data.all) %>% mrgsim(end = 24, delta = 0.25) %>% as.data.frame %>% as.data.table outputsim$SEX <- factor(outputsim$SEX, labels="Female") # Only plot a random sample of N=500 set.seed(678549) plotdata <- outputsim[ID %in% sample(unique(ID), 500)] # New facet label names for dose variable albumin.labs <- c("albumin: 45 ng/mL") names(albumin.labs) <- c("45") wt.labs <- c("weight: 85 kg") names(wt.labs) <- c("85") p1 <- ggplot(plotdata, aes(time, CP, group = ID)) + geom_line(alpha = 0.2, size = 0.1) + facet_grid(~ WT + ALB + SEX, labeller = labeller(ALB = albumin.labs, WT = wt.labs)) + labs(y = "Plasma Concentrations", x = "Time (h)") p2 <- ggplot(plotdata, aes(time, CP, group = ID)) + geom_line(alpha = 0.2, size = 0.1) + facet_grid(~ WT + ALB + SEX, labeller = labeller(ALB = albumin.labs, WT = wt.labs)) + scale_y_log10() + labs(y = "Plasma~Concentrations\n(logarithmic scale)", x = "Time (h)") #labs(y = expression(Log[10]~Plasma~Concentrations), x = "Time (h)")+ egg::ggarrange(p1, p2, ncol = 2)
In this section we compute the PK parameters of interest, provide a plot of the parameters as well as of the standardized ones. We also summarize and report the BSV as ranges of 50 and 90% of patients for each PK parameter. Later on we might choose to include these ranges in the coveffectsplot
or not.
derive.exposure <- function(time, CP) { n <- length(time) x <- c( Cmax = max(CP), Clast = CP[n], AUC = sum(diff(time) * (CP[-1] + CP[-n])) / 2 ) data.table(paramname=names(x), paramvalue=x) } refbsv <- outputsim[, derive.exposure(time, CP), by=.(ID, WT, SEX, ALB)] p3 <- ggplot(refbsv, aes( x = paramvalue, y = paramname, fill = factor(..quantile..), height = ..ndensity..)) + facet_wrap(~ paramname, scales="free", ncol=1) + stat_density_ridges( geom="density_ridges_gradient", calc_ecdf=TRUE, quantile_lines=TRUE, rel_min_height=0.001, scale=0.9, quantiles=c(0.05, 0.25, 0.5, 0.75, 0.95)) + scale_fill_manual( name = "Probability", values = c("white", "#FF000050", "#FF0000A0", "#FF0000A0", "#FF000050", "white"), labels = c("(0, 0.05]", "(0.05, 0.25]", "(0.25, 0.5]", "(0.5, 0.75]", "(0.75, 0.95]", "(0.95, 1]")) + theme_bw() + theme( legend.position = "none", axis.text.y = element_blank(), axis.ticks.y = element_blank(), axis.title.y = element_blank()) + labs(x="PK Parameters", y="") + scale_x_log10() + coord_cartesian(expand=FALSE) # Obtain the standardized parameter value by dividing by the median. refbsv[, stdparamvalue := paramvalue/median(paramvalue), by=paramname] p4 <- ggplot(refbsv, aes( x = stdparamvalue, y = paramname, fill = factor(..quantile..), height = ..ndensity..)) + facet_wrap(~ paramname, scales="free", ncol=1) + stat_density_ridges( geom="density_ridges_gradient", calc_ecdf=TRUE, quantile_lines=TRUE, rel_min_height=0.001, scale=0.9, quantiles=c(0.05, 0.25, 0.5, 0.75, 0.95)) + scale_fill_manual( name="Probability", values=c("white", "#FF000050", "#FF0000A0", "#FF0000A0", "#FF000050", "white"), labels = c("(0, 0.05]", "(0.05, 0.25]", "(0.25, 0.5]", "(0.5, 0.75]", "(0.75, 0.95]", "(0.95, 1]")) + theme_bw() + theme( legend.position = "none", axis.text.y = element_blank(), axis.ticks.y = element_blank(), axis.title.y = element_blank()) + labs(x="Standardized PK Parameters", y="") + scale_x_log10() + coord_cartesian(expand=FALSE, xlim = c(0.3,3)) p3+p4
Ranges of BSV for each PK Parameter:
bsvranges <- refbsv[,list( P05 = quantile(stdparamvalue, 0.05), P25 = quantile(stdparamvalue, 0.25), P50 = quantile(stdparamvalue, 0.5), P75 = quantile(stdparamvalue, 0.75), P95 = quantile(stdparamvalue, 0.95)), by = paramname] bsvranges
Based on our observed covariate data, we compute percentiles of interest that we will use to simulate data at. Common practice is to compute the 5,25,75,95 percentiles (the median being the reference). In some cases, we might want to explore the min, max or other extreme case scenarios. Care should be taken as this approach might generate unrealistic combination of covariates that can never appear in a real patient. The utility function expand.modelframe (written by Benjamin Rich) is defined in the setup section of the vignette and can be found in the source code. It facilitates the creation of a set of covariate values varying one at a time.
reference.values <- data.frame(WT = 85, ALB = 45, SEX = 0) covcomb <- expand.modelframe( #defined at the top and now expand_modelframe was added WT = c(56, 72, 98, 128), # P05, P25, P50, P75, P95 ALB = c(40, 50), # P05, P50, P95 SEX = c(1), # Reference is for SEX=0 (female) rv = reference.values) # Add the reference covcomb <- rbind(covcomb, data.table(reference.values, covname="REF")) covcomb$ID <- 1:nrow(covcomb) covcomb
As a first step, we simulate without uncertainty and without BSV using zero_re()
at unique combination of covariates and provide a plot to visualize the effects.
idata <- data.table::copy(covcomb) idata$covname <- NULL ev1 <- ev(time=0, amt=100, cmt=1) data.dose <- as.data.frame(ev1) data.all <- data.table(idata, data.dose) outcovcomb<- modcovsim %>% data_set(data.all) %>% zero_re() %>% mrgsim(end=24, delta=0.25) %>% as.data.frame %>% as.data.table outcovcomb$SEX <- factor(outcovcomb$SEX, labels=c("Female", "Male")) albumin.labs <- c("albumin: 40 ng/mL","albumin: 45 ng/mL","albumin: 50 ng/mL") names(albumin.labs) <- c("40","45","50") wt.labs <- c("weight: 56 kg","weight: 72 kg","weight: 85 kg","weight: 98 kg","weight: 128 kg") names(wt.labs) <- c("56","72","85","98","128") pkprofiletypical <- ggplot(outcovcomb, aes(x=time, y=CP, col=factor(WT), linetype=SEX)) + geom_line(aes(group=ID), alpha = 1, linewidth = 1) + facet_nested(ALB + SEX ~ WT, labeller= labeller(ALB = albumin.labs, WT = wt.labs, SEX = label_value), switch = "y") + labs( x = "Time (h)", y = "Plasma Concentrations", linetype = "Sex", colour = "Weight", caption = "Simulation without Uncertainty and without BSV") + coord_cartesian(ylim=c(0,4)) pkprofiletypical <- pkprofiletypical +theme_bw(base_size = 13)+ theme(axis.title.y = element_text(size=15))+ guides(colour = guide_legend(override.aes = list(alpha = 1, linewidth = 1)), linetype = guide_legend(override.aes = list(linewidth = 1), order = 1))+ coord_cartesian(ylim=c(0,4)) pkprofiletypical
First, we will invent a varcov matrix by assuming 25% relative standard errors and correlations of 0.2 across the board. We then simulate a 100 set of parameters using a multivariate normal (kept at 100 for the vignette, use more replicates for a real project). Also, unless the model was written in a way to allow unconstrained parameter values, care should be taken to make sure the simulated parameters are valid and make sense. In a real modeling applications, the software used to fit the model will provide a variance covariance matrix, if possible. Otherwise, the user can rely on set of parameters generated from bootstrap replicates or SIR run.
Variance Covariance Matrix of fixed effects:
theta <- unclass(as.list(param(modcovsim))) theta[c("WT", "SEX", "ALB")] <- NULL theta <- unlist(theta) as.data.frame(t(theta)) #note that from RsNLME or NONMEM or Monolix the software will give you the varcov just read it it in. # example NONMEM read in your run .cov # varcov <- read.csv(paste("runxyz",".cov",sep=""), header=TRUE, skip=1, sep="") varcov <- cor2cov( matrix(0.2, nrow=length(theta), ncol=length(theta)), sd=theta*0.25) rownames(varcov) <- colnames(varcov) <- names(theta) as.data.frame(varcov)
Second, we generate the sim_parameters dataset using mvrnorm
and then incorporate the uncertainty by simulating using a different set of parameters (row) for each replicate.
First Few Rows of a Dataset Containing Simulated Fixed Effects with Uncertainty:
set.seed(678549) # mvtnorm::rmvnorm is another option that can be explored # if you have run a bootstrap just use the parameters data generated using all replicates sim_parameters <- MASS::mvrnorm(nsim, theta, varcov, empirical=T) %>% as.data.table head(sim_parameters)
Third, we illustrate how you can iterate over a set of parameters value using a for
loop. We then overlay the previous simulation results without uncertainty on the one with uncertainty to visualize the effect of adding it.
idata <- data.table::copy(covcomb) idata$covname <- NULL ev1 <- ev(time=0, amt=100, cmt=1) data.dose <- as.data.frame(ev1) iter_sims <- NULL for(i in 1:nsim) { data.all <- data.table(idata, data.dose, sim_parameters[i]) out <- modcovsim %>% data_set(data.all) %>% zero_re() %>% mrgsim(start=0, end=24, delta=0.25) %>% as.data.frame %>% as.data.table out[, rep := i] iter_sims <- rbind(iter_sims, out) } iter_sims$SEX <- factor(iter_sims$SEX, labels = c("Female", "Male")) summary_conc <- function(CP) { x <- c( Cmed = median(CP), Clow = quantile(CP, probs = 0.05), Cup = quantile(CP, probs = 0.95) ) data.table(paramname=names(x), paramvalue=x) } iter_sims_sum <- iter_sims[, summary_conc(CP), by=.( time, WT, SEX, ALB)] iter_sims_sum <- spread(iter_sims_sum,paramname,paramvalue) iter_sims_sum <- as.data.frame(iter_sims_sum) albumin.labs <- c("albumin: 40 ng/mL","albumin: 45 ng/mL","albumin: 50 ng/mL") names(albumin.labs) <- c("40","45","50") wt.labs <- c("weight: 56 kg","weight: 72 kg","weight: 85 kg","weight: 98 kg","weight: 128 kg") names(wt.labs) <- c("56","72","85","98","128") pkprofileuncertainty_sum <- ggplot(iter_sims_sum, aes(x=time, col=factor(WT), fill=factor(WT), linetype=SEX)) + geom_ribbon((aes(ymin= `Clow.5%` ,ymax=`Cup.95%`)), alpha = 0.4, linetype = 0)+ geom_line(aes(y=Cmed),alpha=1 , color ="black" , linewidth = 1)+ facet_nested(ALB +SEX ~ WT, labeller= labeller(ALB = albumin.labs, WT = wt.labs, SEX = label_value),switch = "y") + labs( x = "Time (h)", y = "Plasma Concentrations", linetype = "Sex", colour = "Uncertainty\n5-95%\nWeight", fill = "Uncertainty\n5-95%\nWeight", caption = "Simulation with Uncertainty, without BSV") + theme_bw(base_size = 13)+ theme(axis.title.y = element_text(size=15))+ guides(fill = guide_legend(override.aes = list(alpha = 0.4, size = 0.4)), linetype = guide_legend(override.aes = list(linewidth = 1), order = 1))+ coord_cartesian(ylim=c(0,4)) pkprofileuncertainty_sum
Similar to an earlier section, we compute the PK parameters by patient and by replicate standardize by the computed median for reference subject and provide a plot. We add some data manipulation to construct more informative labels that will help in the plotting.
out.df.univariatecov.nca <- iter_sims[, derive.exposure(time, CP), by=.(rep, ID, WT, SEX, ALB)] refvalues <- out.df.univariatecov.nca[ ALB==45 & WT==85 & SEX=="Female", .(medparam = median(paramvalue)), by= .(rep,paramname) ] head(data.frame(refvalues))
Median Parameter Values for the Reference:
covcomb$covvalue[covcomb$covname=="WT"] <- paste(covcomb$WT[covcomb$covname=="WT"],"kg") covcomb$covvalue[covcomb$covname=="ALB"] <- paste(covcomb$ALB[covcomb$covname=="ALB"],"g/L") covcomb$covvalue[covcomb$covname=="SEX"] <- "Male" covcomb$covvalue[covcomb$covname=="REF"] <- "85 kg\nFemale\n45 g/L" #covcomb[covname=="REF", covvalue := "85 kg Female 45 g/L"] covcomb <- as.data.table(covcomb) out.df.univariatecov.nca <- merge( out.df.univariatecov.nca, covcomb[, list(ID, covname, covvalue)] ) setkey(out.df.univariatecov.nca, paramname,rep) out.df.univariatecov.nca <- merge( out.df.univariatecov.nca, refvalues) out.df.univariatecov.nca[, paramvaluestd := paramvalue/medparam] boxplotdat <- out.df.univariatecov.nca[covname!="REF"] boxplotdat[covname=="WT", covname2 := "Weight"] boxplotdat[covname=="ALB", covname2 := "Albumin"] boxplotdat[covname=="SEX", covname2 := "Sex"] boxplotdatREFWT <- out.df.univariatecov.nca[covname=="REF"] boxplotdatREFWT[, covname2 := "Weight"] boxplotdatREFWT[, covvalue := covcomb[covname=="REF", covvalue]] boxplotdatREFSEX <- out.df.univariatecov.nca[covname=="REF"] boxplotdatREFSEX[, covname2 := "Sex"] boxplotdatREFSEX[, covvalue := covcomb[covname=="REF", covvalue]] boxplotdatREFALB <- out.df.univariatecov.nca[covname=="REF"] boxplotdatREFALB[, covname2 := "Albumin"] boxplotdatREFALB[, covvalue := covcomb[covname=="REF", covvalue]] boxplotdat <- rbind( boxplotdat, boxplotdatREFWT, boxplotdatREFSEX, boxplotdatREFALB) boxplotdat[paramname=="AUC", paramname2 := "AUC"] boxplotdat[paramname=="Clast", paramname2 := "C[last]"] boxplotdat[paramname=="Cmax", paramname2 := "C[max]"] boxplotdat[, covname2 := factor(covname2, levels=unique(covname2))] #boxplotdat[, covvalue := factor(covvalue, levels=unique(covvalue))] boxplotdat[, covvalue := factor(covvalue, levels=c("56 kg", "72 kg", "40 g/L", "Male", "85 kg\nFemale\n45 g/L", "98 kg", "128 kg", "50 g/L"))] pkparametersboxplot<- ggplot(boxplotdat, aes(x=covvalue, y=paramvalue))+ facet_grid(paramname2 ~ covname2, scales="free", labeller=label_parsed, switch="both") + geom_boxplot() + labs(y="Parameter Values") + theme(axis.title=element_blank(), strip.placement = "outside") pkparametersboxplot
Here we provide an alternative visual summary of the standardized PK parameters. It shows the distribution, quantiles of interest. It isolates each covariate effects in one panel keeping the reference on its own. It is exactly the same data as the boxplots. Which visual presentation do you prefer? Which one enables you to clearly see and compare the covariate effects?
out.df.univariatecov.nca[covname=="WT", covname2 := "Weight"] out.df.univariatecov.nca[covname=="ALB", covname2 := "Albumin"] out.df.univariatecov.nca[covname=="SEX", covname2 := "Sex"] out.df.univariatecov.nca[covname=="REF", covname2 := "Reference"] out.df.univariatecov.nca[paramname=="AUC", paramname2 := "AUC"] out.df.univariatecov.nca[paramname=="Clast", paramname2 := "C[last]"] out.df.univariatecov.nca[paramname=="Cmax", paramname2 := "C[max]"] out.df.univariatecov.nca[, covvalue := factor(covvalue, levels=unique(covvalue))] out.df.univariatecov.nca[, covname2 := factor(covname2, levels=unique(covname2))] out.df.univariatecov.nca[, paramname2 := factor(paramname2, levels=unique(paramname2))] ggplot(out.df.univariatecov.nca[out.df.univariatecov.nca$covname!="REF",], aes( x = paramvaluestd, y = covvalue, fill = factor(..quantile..), height = ..ndensity..)) + facet_grid(covname2 ~ paramname2, scales = "free_y", space = "free", labeller = label_parsed)+ annotate("rect", xmin = 0.8, xmax = 1.25, ymin = -Inf, ymax = Inf, fill = "gray", alpha = 0.4) + stat_density_ridges( geom = "density_ridges_gradient", calc_ecdf = TRUE, quantile_lines = TRUE, rel_min_height = 0.001, scale = 0.9, quantiles = c(0.05,0.5, 0.95)) + scale_x_continuous( breaks = c(0.25, 0.5, 0.8, 1/0.8, 1/0.5, 1/0.25), tran = "log") + scale_fill_manual( name = "Probability", values = c("white", "#0000FFA0", "#0000FFA0", "white"), labels = c("(0, 0.05]", "(0.05, 0.5]","(0.5, 0.95]", "(0.95, 1]")) + geom_vline(aes(xintercept=1), size=1) + theme_bw() + labs(x="Effects Relative to Parameter Reference Value", y="")+ scale_x_continuous(breaks=c(0.25,0.5,0.8,1,1/0.8,1/0.5,1/0.25), labels=c("1/4","1/2","0.8","1","1.25","2","4"), trans ="log" )
forest_plot
To contrast the covariate effects with random unexplained variability we add to the data the BSV intervals computed in an earlier section. We then do some data manipulation and formatting to produce a plot from the package function forest_plot
. To simplify we will only keep AUC before revisiting more than one parameter plots at the end. The user can also compute an show the BSV for all presented effects not just for the reference. Refer to the approach that incorporate BSV and full covariate distributions presented in another vignette.
fpdata <- out.df.univariatecov.nca[, setNames(as.list(quantile(paramvaluestd, probs=c(0.5, 0.05, 0.95))), c("mid", "lower", "upper")), by=.(paramname2, covname2, covvalue)] bsvranges[paramname=="AUC", paramname2 := "AUC"] bsvranges[paramname=="Clast", paramname2 := "C[last]"] bsvranges[paramname=="Cmax", paramname2 := "C[max]"] setkey(bsvranges, paramname2) fpdataBSV50 <- fpdata[covname2 == "Reference"] fpdataBSV50$covname2 <- "BSV" fpdataBSV50$covvalue <- "50% of patients" setkey(fpdataBSV50, paramname2) fpdataBSV50$lower <- bsvranges[,"P25"] fpdataBSV50$upper <- bsvranges[,"P75"] fpdataBSV90 <- fpdata[covname2 == "Reference"] fpdataBSV90$covname2 <- "BSV" fpdataBSV90$covvalue <- "90% of patients" setkey(fpdataBSV90, paramname2) fpdataBSV90$lower <- bsvranges[,"P05"] fpdataBSV90$upper <- bsvranges[,"P95"] fpdata <- rbind(fpdata, fpdataBSV90, fpdataBSV50) fpdata[, LABEL := sprintf("%s [%s, %s]", round_pad(mid, 2), round_pad(lower, 2), round_pad(upper, 2)) ] setnames(fpdata, "paramname2", "paramname") setnames(fpdata, "covname2", "covname") setnames(fpdata, "covvalue", "label") fpdata[, label := factor(label, levels=unique(label))] interval_legend_text <- "Median (points)\n90% CI (horizontal lines)" interval_bsv_text <- "BSV (points)\nPrediction Intervals (horizontal lines)" ref_legend_text <- "Reference (vertical line)\nClinically relevant limits\n(gray area)" area_legend_text <- "Reference (vertical line)\nClinically relevant limits\n(gray area)" png("./Figure4_6.png",width =9 ,height = 6,units = "in",res=72) coveffectsplot::forest_plot(fpdata[paramname=="AUC" & covname!="Reference" & covname!="BSV",], ref_area = c(0.8, 1/0.8), x_range = c(0.5, 2), strip_placement = "inside", base_size = 18, y_label_text_size = 12, y_facet_text_angle = 0, xlabel = "Fold Change Relative to Reference", ref_legend_text = ref_legend_text, area_legend_text = area_legend_text, interval_legend_text = interval_legend_text, interval_bsv_text = interval_bsv_text, plot_title = "", facet_formula = "covname ~ paramname", facet_switch = "y", facet_scales = "free_y", facet_space = "free", paramname_shape = FALSE, table_position = "right", table_text_size = 4, plot_table_ratio = 3, show_table_facet_strip = "none", logxscale = TRUE, major_x_ticks = c(0.5, 0.8,1, 1/0.8, 1/0.5), major_x_labels = c("1/2", "0.8","1", "1.25", "2"), return_list = FALSE) dev.off()
In this section, we first show a forest_plot
built-in theme, then how you return the ggplot objects as a list for further editing using regular 'ggplot2' code.
theme_benrich
along Additional OptionsThis is achieved by setting theme_benrich = TRUE
, specifying that you want no legend legend_position = "none"
.
With this theme active you can also control the table_title
text and table_title_size
arguments.
png("./coveffectsplot4.png",width =9 ,height = 6,units = "in",res=72) coveffectsplot::forest_plot(fpdata[paramname=="AUC"], ref_area = c(0.8, 1/0.8), x_range = c(0.5,2), xlabel = "Fold Change Relative to Reference", x_label_text_size= 10, y_facet_text_angle = 0, facet_formula = "covname~paramname", theme_benrich = TRUE, table_title_size = 15, table_title = "Median [90% CI]", interval_legend_text = interval_legend_text, interval_bsv_text = interval_bsv_text, legend_position = "none", strip_placement = "outside", base_size = 12, facet_switch = "y", facet_scales = "free_y", facet_space = "free", paramname_shape = FALSE, table_position = "right", table_text_size=4, plot_table_ratio = 3, show_table_facet_strip = "none", logxscale = TRUE, major_x_ticks = c(0.25,0.5,0.8,1,1/0.8,1/0.5,1/0.25), major_x_labels = c("1/4","1/2","0.8","1","1.25","2","4"), return_list = FALSE) dev.off()
You can get the underlying ggplots as a list for further editing by setting return_list = TRUE
and saving it into an object. The list will contain two objects the first being the main plot and the second the table. We illustrate how you can modify the look of the plots using regular ggplot code that modify the facet text color to gray
and italic. Finally we recombine the plots using egg::ggarrange
.
png("./coveffectsplot0.png",width = 9 ,height = 6,units = "in",res=72) plotlists <- coveffectsplot::forest_plot(fpdata[paramname=="AUC"], ref_area = c(0.8, 1/0.8), xlabel = "Fold Change Relative to Reference", ref_legend_text = "Reference (vertical line)\nClinically relevant limits\n(gray area)", area_legend_text = "Reference (vertical line)\nClinically relevant limits\n(gray area)", interval_legend_text = interval_legend_text, plot_title = "", interval_bsv_text = interval_bsv_text, facet_formula = "covname~paramname", facet_switch = "y", facet_scales = "free_y", facet_space = "free", paramname_shape = FALSE, table_position = "right", table_text_size=4, plot_table_ratio = 4, show_table_facet_strip = "none", logxscale = TRUE, major_x_ticks = c(0.25,0.5,0.8,1,1/0.8,1/0.5,1/0.25), major_x_labels = c("1/4","1/2","0.8","1","1.25","2","4"), return_list = TRUE) plotlists dev.off()
main_plot <- plotlists[[1]] + theme( panel.spacing=unit(10, "pt"), panel.grid=element_blank(), panel.grid.minor=element_blank(), legend.position="bottom", strip.placement.y="outside", strip.background.y=element_blank(), strip.text.y=element_text( hjust=1, vjust=1, face="italic",color="gray", size=rel(1)), legend.text = element_text(size=rel(0.5)), plot.margin = margin(t=0,r=0,b=0,l=5,unit="pt")) + scale_y_discrete( breaks=c("90% of patients", "50% of patients", "85 kg\nFemale\n45 g/L", "40 g/L","50 g/L","Male", "56 kg","72 kg","98 kg","128 kg" ), labels=c("90% of patients", "50% of patients", "85 kg-Female-45 g/L", "40 g/L","50 g/L","Male", "56 kg","72 kg","98 kg","128 kg" ) ) table_plot <- plotlists[[2]] + theme( panel.border=element_blank(), panel.spacing=unit(10, "pt"), strip.background.y=element_blank(), legend.text = element_text(size=rel(0.5)), plot.margin = margin(t=0,r=5,b=0,l=0,unit="pt")) png("./coveffectsplot5.png",width =8.5 ,height = 6,units = "in",res=72) egg::ggarrange( main_plot, table_plot, nrow = 1, widths = c(3, 1) ) dev.off()
You can also have plots with more than one PK parameter. You may want to facet by parameter, or to use different shape by parameter.
This is achieved by setting paramname_shape = FALSE
and facet_formula = "covname~paramname"
. We also suppress the table by using table_position = "none"
and reduce the plot text sizes using base_size = 11
.
png("./coveffectsplot6.png",width =9.5 ,height = 6,units = "in",res=72) forest_plot(fpdata, ref_area = c(0.8, 1/0.8), x_range = c(0.5,2), xlabel = "Fold Change Relative to Reference", facet_formula = "covname~paramname", interval_legend_text = interval_legend_text, interval_bsv_text = interval_bsv_text, facet_switch = "y", facet_scales = "free_y", facet_space = "free", facet_labeller = "label_parsed", paramname_shape = FALSE, table_position = "none", table_text_size=4, base_size = 11, plot_table_ratio = 4, show_table_facet_strip = "none", logxscale = TRUE, major_x_ticks = c(0.5,0.8,1,1/0.8,1/0.5), major_x_labels = c("1/2","0.8","1","1.25","2"), x_label_text_size = 10, return_list = FALSE) dev.off()
This is achieved by setting paramname_shape = TRUE
we also illustrate how you can use legend_order
to choose the legend ordering and few other options.
png("./coveffectsplot7.png",width =9.5 ,height = 6,units = "in",res=72) forest_plot(fpdata[paramname!="AUC"], ref_area = c(0.8, 1/0.8), x_range = c(0.35,1/0.35), xlabel = "Fold Change Relative to Reference", ref_legend_text = "Reference\nClinically relevant limits\n(0.8-1.25)", area_legend_text = "Reference\nClinically relevant limits\n(0.8-1.25)", interval_legend_text = "Median\n90% CI", interval_bsv_text = "BSV\nPrediction Intervals", facet_formula = "covname~.", paramname_shape = TRUE, legend_order =c("shape","pointinterval","ref", "area"), legend_shape_reverse = TRUE, bsv_col = scales::muted("red"), interval_col = scales::muted("blue"), facet_switch = "y", facet_scales = "free_y", facet_space = "free", table_position = "none", table_text_size=4, base_size = 9, plot_table_ratio = 4, show_table_facet_strip = "none", logxscale = TRUE, major_x_ticks = c(0.5,0.8,1,1/0.8,1/0.5), major_x_labels = c("1/2","0.8","1","1.25","2"), legend_space_x_mult = 0.01, legend_position = "right", return_list = FALSE) dev.off()
This is achieved by setting paramname_color = TRUE
(on top of paramname_shape = TRUE
or not) and the the user can then pass a vector of colors in the interval_col
argument
png("./coveffectsplot_color.png",width =9.5 ,height = 6,units = "in",res=72) forest_plot(fpdata[paramname!="AUC" & covname!="BSV"& covname!="Reference",], ref_area = c(0.8, 1/0.8), x_range = c(0.35,1/0.35), xlabel = "Fold Change Relative to Reference", ref_legend_text = "Reference\nClinically relevant limits\n(0.8-1.25)", area_legend_text = "Reference\nClinically relevant limits\n(0.8-1.25)", facet_formula = "covname~.", paramname_shape = TRUE, paramname_color = TRUE, combine_interval_shape_legend = TRUE, legend_order =c("shape","pointinterval","ref", "area"), legend_shape_reverse = TRUE, bsv_col = scales::muted("red"), facet_switch = "y", facet_scales = "free_y", facet_space = "free", table_position = "none", base_size = 12, logxscale = TRUE, major_x_ticks = c(0.5,0.8,1,1/0.8,1/0.5), major_x_labels = c("1/2","0.8","1","1.25","2"), legend_space_x_mult = 0.01, legend_position = "right", return_list = TRUE)[[1]]+ scale_color_manual(labels = c(expression(C[last]),expression(C[max])), values = c(scales::muted("blue"),scales::muted("red")))+ scale_shape_discrete(labels = c(expression(C[last]),expression(C[max]))) dev.off()
While we covered varying one at a time covariate value (marginal effects), we can use observed or simulated distribution of correlated covariates and simulate joint covariate effects as illustrated in the Pediatric Application vignette.It can be misleading to show the BSV around the reference only as it operates at all levels of covariate as such we recommend to fully represent the intervals with BSV and Uncertainty at all levels / covariate splits (full Distribution PK example vignette.)
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