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Global sensitivity analysis.R
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Global sensitivity analysis.R
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#author: Joris Jean van der Lugt
#date: 20-05-2021
#Global sensitivity analysis
library(RxODE)
library(tidyverse)
library(readxl)
library(readr)
library(truncnorm)
library(reshape2)
library(sensitivity)
library(PKNCA)
#Simulations
set.seed(15204) #to ensure a reproducible output if random input is used
MW <-132.16 #The molecular weight of Cinnamaldehyde
BW <-70 #Body weight in Kg
Volume_exposure_chamber <-10 #volume exposure chamber in L
#--Physio-chemical parameters--#
#Values calculated in QSAR calculations file
#-Cinnamaldehyde-#
P_F <- 47.75 #Fat/Blood partition coefficient
P_L <- 1.83 #liver/Blood partition coefficient
P_SI <- 1.81 #Small intestine/Blood partition coefficients
P_RP <- 1.81 #Richly perfused tissues/Blood partition coefficients
P_SP <- 1.50 #Slowly perfused tissues/Blood partition coefficients
P_B <- 0.29 #Blood/Air Partition Coefficient
P_Pu <- 1.81 #lung/Blood partition coefficient
#-Cinnamyl Alcohol-#
P_OH_F <- 49.26 #Fat/Blood partition coefficient
P_OH_L <- 1.18 #liver/Blood partition coefficient
P_OH_SI <- 1.18 #Small intestine/Blood partition coefficients
P_OH_RP <- 1.18 #Richly perfused tissues/Blood partition coefficients
P_OH_SP <- 1.53 #Slowly perfused tissues/Blood partition coefficients
P_OH_Pu <- 1.18 #Lung/Blood partition coefficients
#-Tissues volumes in L #
V_F <- 14.03 #Fat
V_L <- 1.68 #Liver
V_SI <- 0.6 #Small intestine
V_A <- 1.31 #Arterial Blood
V_V <- 3.87 #Venous Blood
V_RP <- 3.14 #Richly perfused (RP)
V_SP <- 40.39 #Slowly perfused (SP)
V_Pu <- 4.98 #Lung
#-Cardiac parameters-#
Q_C <- 390 #Cardiac output in L/h
#-Blood flow to tissues in L #
Q_F <- 20.28 #Fat
Q_L <- 54.99 #Liver
Q_SI <- 33.54 #Small intestine
Q_RP <- 184.47 #Richly perfused (RP)
Q_SP <- 96.72 #Slowly perfused (SP)
Q_Pu <- Q_C #Lung
#inhalation parameters
P_V <- 540 #Alveolar ventilation L/h
#----GSH parameters----#
#--GSH synthesis in μmol/kg tissue/h--#
G_SYN_L <- 1122 * V_L #Liver
G_SYN_SI <- 27 * V_SI #Small intestine
#-Apparent first order rate constant GSH turn over(RAT?) per h-#
k_L_GLOS <- 0.142 #Liver
k_SI_GLOS <- 0.044 #Small intestine
#--Initial GSH concentration--#
init_GSH_L <- 7111 * V_L #initial amount of GSH in the liver in μmol
init_GSH_SI <- 1555 * V_SI #initial amount of GSH in the small intestine in μmol
k_GSH <- 6.6 * 10^(-4) #The second-order rate constant of the chemical reaction of cinnamaldehyde with GSH in μmol/h
#----Protein reactive sites in μmol/kg tissue----#
C_PRO_L <- 5319 * V_L #Liver
C_PRO_SI <- 245 * V_SI #Small intestine
#--Chemical parameters--#
Ka <- 0.62 #Absorption rate constant for uptake in the Small intestine in per H
#----Liver----#
S9_scaling_L <- 143 * (V_L * 1000) #scaling factor for S9 fraction per g tissue
#----Liver----#
#-first rate order constants-#
k_L_OH <- 4.2*10^-2 * 60 / 1000 * S9_scaling_L #Scaled first rate order constant for the enzymatic oxidation of cinnamyl alcohol in the liver in umol/h
#--Michaelis menten constants--#
Km_L_CA <- 8.5 #Km for enzymatic oxidation of Cinnamaldehyde into Cinnamic acid in the liver in μM
Km_L_AO <- 330 #Km for enzymatic reduction of Cinnamaldehyde into cinnamyl alcOHol in the liver in μM
Km_L_GST <- 1.7*10^3 #Km for enzymatic conjugation of Cinnamaldehyde with GST in the liver in μM
Km_L_GST_G <- 100 #Km toward GSH for enzymatic conjugation of Cinnamaldehyde in the liver (μM)
#--Vmax values--#
Vsmax_L_CA <- 9.7 * 60 / 1000 * S9_scaling_L #Scaled Vmax for enzymatic oxidation of Cinnamaldehyde in the liver in μmol/h
Vsmax_L_AO <- 73 * 60 / 1000 * S9_scaling_L #Scaled Vmax for enzymatic reduction of Cinnamaldehyde in the liver in μmol/h
Vsmax_L_GST <- 37 * 60 / 1000 * S9_scaling_L #Scaled Vmax for enzymatic conjugation of Cinnamaldehyde with GSH in the liver in μmol/h
#----Small intestines----#
S9_scaling_SI <- 11.4 * (V_SI *1000) #scaling factor fraction S9 protein per g tissue
#--Michaelis Menten constants--#
Km_SI_CA <- 70 #Km for enzymatic oxidation of Cinnamaldehyde into Cinnamic acid in the Small Intestine in μM
Km_SI_AO <- 90 #Km for enzymatic reduction of Cinnamaldehyde into Cinnamyl alcOHol in the Small Intestine in μM
Km_SI_OH <- 290 #Km for enzymatic oxidation of Cinnamly alcOHol into Cinnamaldehyde in the Small Intestine in μM
Km_SI_GST <- 0 #Km for enzymatic conjugation of Cinnamaldehye with GST in the Small Intestine in μM (RAT value)
Km_SI_GST_G <- 100 #Km toward GSH for enzymatic conjugation of Cinnamaldehyde in the small intestine (μM)
#-Vmax values-#
Vsmax_SI_CA <- 21 * 60/1000 * S9_scaling_SI #Scaled Vmax for enzymatic oxidation of Cinnamaldehyde into Cinnamic acid in the Small Intestine in μmol/h
Vsmax_SI_AO <- 30 * 60/1000 * S9_scaling_SI #Scaled Vmax for enzymatic reduction of Cinnamaldehyde into Cinnamyl alcOHol in the Small Intestine in μmol/h
Vsmax_SI_OH <- 5.0 * 60/1000 * S9_scaling_SI #Scaled Vmax for enzymatic Oxidation of Cinnamyl alcohol into Cinnamaldehyde in the Small Intestine in μmol/h
Vsmax_SI_GST <- 0 * 60/1000 * S9_scaling_SI #Scaled Vmax for enzymatic Conjugation of Cinnamaldehyde with GSH in the in the small intestine in μmol/h (RAT value)
#Collection of all parameters so a distribution can be made with them later on in the file #Human
dist_para <- cbind(P_F,
P_L,
P_SI,
P_RP,
P_SP,
P_B,
P_Pu,
P_OH_F,
P_OH_L,
P_OH_SI,
P_OH_RP,
P_OH_SP,
P_OH_Pu,
BW,
V_F,
V_L,
V_SI,
V_A,
V_V,
V_RP,
V_SP,
V_Pu,
Q_C,
Q_Pu,
Q_F,
Q_L,
Q_SI,
Q_RP,
Q_SP,
P_V,
G_SYN_L,
G_SYN_SI,
k_L_GLOS,
k_SI_GLOS,
init_GSH_L,
init_GSH_SI,
k_GSH,
C_PRO_L,
C_PRO_SI,
Ka,
k_L_OH,
Km_L_CA,
Km_L_AO,
Km_L_GST,
Km_L_GST_G,
Vsmax_L_CA,
Vsmax_L_AO,
Vsmax_L_GST,
Km_SI_CA,
Km_SI_AO,
Km_SI_OH,
Km_SI_GST,
Km_SI_GST_G,
Vsmax_SI_CA,
Vsmax_SI_AO,
Vsmax_SI_OH,
Vsmax_SI_GST,
Volume_exposure_chamber,
S9_scaling_SI,
S9_scaling_L)
#Creating empty vectors for use later
colnames <- c(colnames(dist_para))
par_var <- length(colnames)
#Generating a upper and lower bound for use in the analysis
Mean <- dist_para
Lower <- Mean - 0.1 * Mean
Upper <- Mean + 0.1 * Mean
#create data frames for population
n_sim <- 2000 #number of iterations
X1 <- matrix(NA, nrow = n_sim, ncol = par_var)
colnames(X1) <- colnames
X1 <- as.data.frame(X1)
var <- X1
X2 <- matrix(NA, nrow = n_sim, ncol = par_var)
colnames(X2) <- colnames
X2 <- as.data.frame(X2)
var <- X2
#create a uniform distribution of variables between the upper and lower limit
for(i in 1:par_var){
X1[,i] <- runif(n_sim, min = Lower[,i], max = Upper[,i])
X2[,i] <- runif(n_sim, min = Lower[,i], max = Upper[,i])
}
#Removing variation in volume exposure chamber as this is supposed to be fixed
X1[,58]<- 10
X2[,58]<- 10
#the number of bootstrap replicates
n_boot <- 1000
#Sobol design
sa <- soboljansen(model=NULL, X1, X2, nboot = n_boot, conf = 0.95, events = ex)
phys <- sa$X
#Writing the result into a file so that the environment can be cleaned to conserve memory
write.csv(phys,"D:/PBK/Cinnamaldehyde-pbk\\GSA_phys_human_250mg_10%", row.names = TRUE)
#Loading extracted simulation data.
solve.pbk.sa <- read.csv("D:/PBK/Cinnamaldehyde-pbk\\SA_human_250mg_oral_CV", row.names=1)
#Analysing the generated data set
solve.pbk.sa=solve.pbk.sa[which(solve.pbk.sa[,"time"]==0.2|solve.pbk.sa[,"time"]==0.5|solve.pbk.sa[,"time"]==1|solve.pbk.sa[,"time"]==1.5|
solve.pbk.sa[,"time"]==2|solve.pbk.sa[,"time"]==3|solve.pbk.sa[,"time"]==4|
solve.pbk.sa[,"time"]==8),]
tab1=solve.pbk.sa[which(solve.pbk.sa[,"time"]==0.2),]
tab2=solve.pbk.sa[which(solve.pbk.sa[,"time"]==0.5),]
tab3=solve.pbk.sa[which(solve.pbk.sa[,"time"]==1),]
tab4=solve.pbk.sa[which(solve.pbk.sa[,"time"]==1.5),]
tab5=solve.pbk.sa[which(solve.pbk.sa[,"time"]==2),]
tab6=solve.pbk.sa[which(solve.pbk.sa[,"time"]==3),]
tab7=solve.pbk.sa[which(solve.pbk.sa[,"time"]==4),]
tab8=solve.pbk.sa[which(solve.pbk.sa[,"time"]==8),]
SimRes = as.data.frame(matrix(NA,124000,8))
SimRes[,1]=tab1[,2]
SimRes[,2]=tab2[,2]
SimRes[,3]=tab3[,2]
SimRes[,4]=tab4[,2]
SimRes[,5]=tab5[,2]
SimRes[,6]=tab6[,2]
SimRes[,7]=tab7[,2]
SimRes[,8]=tab8[,2]
write.csv(SimRes,"D:/PBK/Cinnamaldehyde-pbk\\SimRes_oral_Human2_250g.csv", row.names = TRUE)
SimRes <- read.csv("D:/PBK/Cinnamaldehyde-pbk\\SimRes.inhalation_C_Pu_popgen-100mg_4000.csv", row.names=1)
#Redefining these two variables as these are also used with dist_parm creation but not all of thet variables in dist_parm are used in the SA calculation
#so using them here would create an error.
colnames <- colnames(X1)
par_var <- length(X1)
#Sobol analysis plot blood Nrow is the number of paramters in the model
t_A<-(c(0.2,0.5,1,1.5,2,3,4,8))
FOI = TI = TI.borninf = TI.bornsup = matrix(NA, nrow = par_var, ncol = length(t_A))
rownames(FOI)= rownames(TI)= rownames(TI.borninf) = rownames(TI.bornsup)= colnames
t_SA <-0.2
for(i in 1:length(t_A)){
print(i)
if (t_A[i] %in% t_SA) {
sa=tell(sa, y = SimRes[,i], nboot = n_boot, conf = 0.95)
FOI[,i] <- sa$S[,1] #First order indices
TI[,i] <- sa$T[,1] #Total indices
TI.borninf[,i] <- sa$T[,4] #Lower CL total indices
TI.bornsup[,i] <- sa$T[,5] #Upper CL total indices
plot(sa, main=colnames(SimRes)[i],las=3, cex=0.7)
}
}
FOI.L = as.matrix(FOI[,1:length(t_A)]) # as.matrix
TI.L = as.matrix(TI[,1:length(t_A)])
FOI.L.t <- apply(FOI.L, 1, mean, na.rm=TRUE)
TI.L.t <- apply(TI.L, 1, mean, na.rm=TRUE)
sorting = order(TI.L.t, decreasing = F)
TI.L.t = TI.L.t[sorting]
FOI.L.t = FOI.L.t[sorting]
FOI.L.t = ifelse(FOI.L.t <= 0, 0, FOI.L.t)
tempC = t(cbind(FOI.L.t, TI.L.t))
tempC2 <- as.data.frame(tempC[,c(50:60)])
#t_SA = 0.2
sa.plot_0.2 <-as.data.frame(tempC[,c(50:60)])
rownames(sa.plot_0.2 <- c("0.2h main","0.2h total"))
par(mfrow=c(1,1), las=1, mai=c(0.35,1,0.35,0.1), mgp = c(3.5,0.5,0))
plot_Pu_0.2 <- barplot(as.matrix(tempC2), col=c("firebrick1","firebrick4"), horiz = T, beside =T , main="", cex.lab=1.5 , xlim=c(0,1.1) )
t_SA <-0.5
for(i in 1:length(t_A)){
print(i)
if (t_A[i] %in% t_SA) {
sa=tell(sa, y = SimRes[,i], nboot = n_boot, conf = 0.95)
FOI[,i] <- sa$S[,1] #First order indices
TI[,i] <- sa$T[,1] #Total indices
TI.borninf[,i] <- sa$T[,4] #Lower CL total indices
TI.bornsup[,i] <- sa$T[,5] #Upper CL total indices
plot(sa, main=colnames(SimRes)[i],las=3, cex=0.7)
}
}
FOI.L = as.matrix(FOI[,1:length(t_A)]) # as.matrix
TI.L = as.matrix(TI[,1:length(t_A)])
FOI.L.t <- apply(FOI.L, 1, mean, na.rm=TRUE)
TI.L.t <- apply(TI.L, 1, mean, na.rm=TRUE)
sorting = order(TI.L.t, decreasing = F)
TI.L.t = TI.L.t[sorting]
FOI.L.t = FOI.L.t[sorting]
FOI.L.t = ifelse(FOI.L.t <= 0, 0, FOI.L.t)
tempC = t(cbind(FOI.L.t, TI.L.t))
tempC2 <- as.data.frame(tempC[,c(50:60)])
#t_SA = 0.5
sa.plot_0.5 <-as.data.frame(tempC[,c(50:60)])
rownames(sa.plot_0.5) <- c("0.5h main","0.5h total")
par(mfrow=c(1,1), las=1, mai=c(0.35,1,0.35,0.1), mgp = c(3.5,0.5,0))
#colnames(tempC2) <- c("Q_SI", "Ka", "V_SP", "Q_RP", "P_SP", "Q_SP", "k_GSH", "C_PRO_L", "VL", "QC")
plot_Pu_0.5 <- barplot(as.matrix(tempC2), col=c("firebrick1","firebrick4"), horiz = T, beside =T , main="", cex.lab=1.5 , xlim=c(0,1.1) )
t_SA <-1
for(i in 1:length(t_A)){
print(i)
if (t_A[i] %in% t_SA) {
sa=tell(sa, y = SimRes[,i], nboot = n_boot, conf = 0.95)
FOI[,i] <- sa$S[,1] #First order indices
TI[,i] <- sa$T[,1] #Total indices
TI.borninf[,i] <- sa$T[,4] #Lower CL total indices
TI.bornsup[,i] <- sa$T[,5] #Upper CL total indices
plot(sa, main=colnames(SimRes)[i],las=3, cex=0.7)
}
}
FOI.L = as.matrix(FOI[,1:length(t_A)]) # as.matrix
TI.L = as.matrix(TI[,1:length(t_A)])
FOI.L.t <- apply(FOI.L, 1, mean, na.rm=TRUE)
TI.L.t <- apply(TI.L, 1, mean, na.rm=TRUE)
sorting = order(TI.L.t, decreasing = F)
TI.L.t = TI.L.t[sorting]
FOI.L.t = FOI.L.t[sorting]
FOI.L.t = ifelse(FOI.L.t <= 0, 0, FOI.L.t)
tempC = t(cbind(FOI.L.t, TI.L.t))
tempC2 <- as.data.frame(tempC[,c(50:60)])
#t_SA = 1
sa.plot_1 <-as.data.frame(tempC[,c(50:60)])
rownames(sa.plot_1) <- c("1h main","1h total")
par(mfrow=c(1,1), las=1, mai=c(0.35,1,0.35,0.1), mgp = c(3.5,0.5,0))
#colnames(tempC2) <- c("Q_SI", "Ka", "V_SP", "Q_RP", "P_SP", "Q_SP", "k_GSH", "C_PRO_L", "VL", "QC")
plot_Pu_1 <- barplot(as.matrix(tempC2), col=c("firebrick1","firebrick4"), horiz = T, beside =T , main="", cex.lab=1.5 , xlim=c(0,1.1) )
t_SA <-1.5
for(i in 1:length(t_A)){
print(i)
if (t_A[i] %in% t_SA) {
sa=tell(sa, y = SimRes[,i], nboot = n_boot, conf = 0.95)
FOI[,i] <- sa$S[,1] #First order indices
TI[,i] <- sa$T[,1] #Total indices
TI.borninf[,i] <- sa$T[,4] #Lower CL total indices
TI.bornsup[,i] <- sa$T[,5] #Upper CL total indices
plot(sa, main=colnames(SimRes)[i],las=3, cex=0.7)
}
}
FOI.L = as.matrix(FOI[,1:length(t_A)]) # as.matrix
TI.L = as.matrix(TI[,1:length(t_A)])
FOI.L.t <- apply(FOI.L, 1, mean, na.rm=TRUE)
TI.L.t <- apply(TI.L, 1, mean, na.rm=TRUE)
sorting = order(TI.L.t, decreasing = F)
TI.L.t = TI.L.t[sorting]
FOI.L.t = FOI.L.t[sorting]
FOI.L.t = ifelse(FOI.L.t <= 0, 0, FOI.L.t)
tempC = t(cbind(FOI.L.t, TI.L.t))
tempC2 <- as.data.frame(tempC[,c(50:60)])
#t_SA = 1.5
sa.plot_1.5 <-as.data.frame(tempC[,c(50:60)])
rownames(sa.plot_1.5) <- c("1.5h main","1.5h total")
par(mfrow=c(1,1), las=1, mai=c(0.35,1,0.35,0.1), mgp = c(3.5,0.5,0))
#colnames(tempC2) <- c("Q_SI", "Ka", "V_SP", "Q_RP", "P_SP", "Q_SP", "k_GSH", "C_PRO_L", "VL", "QC")
plot_Pu_1.5 <- barplot(as.matrix(tempC2), col=c("firebrick1","firebrick4"), horiz = T, beside =T , main="", cex.lab=1.5 , xlim=c(0,1.1) )
t_SA <-2
for(i in 1:length(t_A)){
print(i)
if (t_A[i] %in% t_SA) {
sa=tell(sa, y = SimRes[,i], nboot = n_boot, conf = 0.95)
FOI[,i] <- sa$S[,1] #First order indices
TI[,i] <- sa$T[,1] #Total indices
TI.borninf[,i] <- sa$T[,4] #Lower CL total indices
TI.bornsup[,i] <- sa$T[,5] #Upper CL total indices
plot(sa, main=colnames(SimRes)[i],las=3, cex=0.7)
}
}
FOI.L = as.matrix(FOI[,1:length(t_A)]) # as.matrix
TI.L = as.matrix(TI[,1:length(t_A)])
FOI.L.t <- apply(FOI.L, 1, mean, na.rm=TRUE)
TI.L.t <- apply(TI.L, 1, mean, na.rm=TRUE)
sorting = order(TI.L.t, decreasing = F)
TI.L.t = TI.L.t[sorting]
FOI.L.t = FOI.L.t[sorting]
FOI.L.t = ifelse(FOI.L.t <= 0, 0, FOI.L.t)
tempC = t(cbind(FOI.L.t, TI.L.t))
tempC2 <- as.data.frame(tempC[,c(50:60)])
par(mfrow=c(1,1), las=1, mai=c(0.35,1,0.35,0.1), mgp = c(3.5,0.5,0))
#colnames(tempC2) <- c("Q_SI", "Ka", "V_SP", "Q_RP", "P_SP", "Q_SP", "k_GSH", "C_PRO_L", "VL", "QC")
plot_Pu_2 <- barplot(as.matrix(tempC2), col=c("firebrick1","firebrick4"), horiz = T, beside =T , main="", cex.lab=1.5 , xlim=c(0,1.1) )
#t_SA = 2
sa.plot_2 <-as.data.frame(tempC[,c(50:60)])
rownames(sa.plot_2) <- c("2h main","2h total")
t_SA <-4
for(i in 1:length(t_A)){
print(i)
if (t_A[i] %in% t_SA) {
sa=tell(sa, y = SimRes[,i], nboot = n_boot, conf = 0.95)
FOI[,i] <- sa$S[,1] #First order indices
TI[,i] <- sa$T[,1] #Total indices
TI.borninf[,i] <- sa$T[,4] #Lower CL total indices
TI.bornsup[,i] <- sa$T[,5] #Upper CL total indices
plot(sa, main=colnames(SimRes)[i],las=3, cex=0.7)
}
}
FOI.L = as.matrix(FOI[,1:length(t_A)]) # as.matrix
TI.L = as.matrix(TI[,1:length(t_A)])
FOI.L.t <- apply(FOI.L, 1, mean, na.rm=TRUE)
TI.L.t <- apply(TI.L, 1, mean, na.rm=TRUE)
sorting = order(TI.L.t, decreasing = F)
TI.L.t = TI.L.t[sorting]
FOI.L.t = FOI.L.t[sorting]
FOI.L.t = ifelse(FOI.L.t <= 0, 0, FOI.L.t)
tempC = t(cbind(FOI.L.t, TI.L.t))
tempC2 <- as.data.frame(tempC[,c(50:60)])
par(mfrow=c(1,1), las=1, mai=c(0.35,1,0.35,0.1), mgp = c(3.5,0.5,0))
#colnames(tempC2) <- c("Q_SI", "Ka", "V_SP", "Q_RP", "P_SP", "Q_SP", "k_GSH", "C_PRO_L", "VL", "QC")
plot_Pu_4 <- barplot(as.matrix(tempC2), col=c("firebrick1","firebrick4"), horiz = T, beside =T , main="", cex.lab=1.5 , xlim=c(0,1.1) )
#t_SA = 4
sa.plot_4 <-as.data.frame(tempC[,c(50:60)])
rownames(sa.plot_4) <- c("4h main","4h total")
t_SA <-8
for(i in 1:length(t_A)){
print(i)
if (t_A[i] %in% t_SA) {
sa=tell(sa, y = SimRes[,i], nboot = n_boot, conf = 0.95)
FOI[,i] <- sa$S[,1] #First order indices
TI[,i] <- sa$T[,1] #Total indices
TI.borninf[,i] <- sa$T[,4] #Lower CL total indices
TI.bornsup[,i] <- sa$T[,5] #Upper CL total indices
plot(sa, main=colnames(SimRes)[i],las=3, cex=0.7)
}
}
FOI.L = as.matrix(FOI[,1:length(t_A)]) # as.matrix
TI.L = as.matrix(TI[,1:length(t_A)])
FOI.L.t <- apply(FOI.L, 1, mean, na.rm=TRUE)
TI.L.t <- apply(TI.L, 1, mean, na.rm=TRUE)
sorting = order(TI.L.t, decreasing = F)
TI.L.t = TI.L.t[sorting]
FOI.L.t = FOI.L.t[sorting]
FOI.L.t = ifelse(FOI.L.t <= 0, 0, FOI.L.t)
tempC = t(cbind(FOI.L.t,TI.L.t))
tempC2 <- as.data.frame(tempC[,c(50:60)])
#t_SA = 8
sa.plot_8 <-as.data.frame(tempC[,c(50:60)])
rownames(sa.plot_8) <- c("8h total","8h main")
par(mfrow=c(2,3),las=1, mar=c(3,5,3,3.5), mgp = c(3.5,0.5,0))
mtext("Main and total sensitivity indexes", side=2, line=1)
#barplot(as.matrix(sa.plot_0.2), col=c("firebrick1","firebrick4"), horiz = T, beside =T , main="20 min", cex.lab=1.5 , xlim=c(0,1.1) )
barplot(as.matrix(sa.plot_0.5), col=c("firebrick1","firebrick4"), horiz = T, beside =T , main="30 min", cex.lab=1.5 , xlim=c(0,1.1) )
barplot(as.matrix(sa.plot_1), col=c("firebrick1","firebrick4"), horiz = T, beside =T , main="1 hour", cex.lab=1.5 , xlim=c(0,1.1) )
barplot(as.matrix(sa.plot_1,5), col=c("firebrick1","firebrick4"), horiz = T, beside =T , main="1.5 hours", cex.lab=1.5 , xlim=c(0,1.1) )
barplot(as.matrix(sa.plot_2), col=c("firebrick1","firebrick4"), horiz = T, beside =T , main="2 hours", cex.lab=1.5 , xlim=c(0,1.1) )
barplot(as.matrix(sa.plot_4), col=c("firebrick1","firebrick4"), horiz = T, beside =T , main="4 hours", cex.lab=1.5 , xlim=c(0,1.1) )
barplot(as.matrix(sa.plot_8), col=c("firebrick1","firebrick4"), horiz =T , beside =T , main="8 hours", cex.lab=1.5 , xlim=c(0,1.1))