---
title: "Plotting Howgate/Johnson data"
author: "Caroline Ring"
date: "`r Sys.Date()`"
output: rmarkdown::html_vignette
vignette: >
  %\VignetteIndexEntry{Plotting Howgate/Johnson data}
  %\VignetteEngine{knitr::rmarkdown}
  %\VignetteEncoding{UTF-8}
---

```{r, include=FALSE}
knitr::opts_chunk$set(collapse = TRUE, comment = '#>')
```

This vignette plots HTTK-Pop-predicted Css against *in vivo* Css from Howgate 2006 and Johnson 2006.

First load some packages.
```{r load_packages}
library('data.table')
library('httk')
library('ggplot2')
library('RColorBrewer')
```
Then, we need to read in the study data.
```{r read_study_data, eval=FALSE}
jhchem <- readRDS(file="data/jhchem.Rdata")
#Get Funbound.plasma measured values from HTTK
chem.dt <- as.data.table(httk::get_cheminfo(model='3compartmentss',
                                            species='Human',
                                            info=c('CAS', "MW", "Funbound.plasma"),
                                            exclude.fub.zero=FALSE))
#Get CLint measured values from HTTK
chem.dt[, Clint:=sapply(CAS, 
                        function(x) parameterize_steadystate(chem.cas=x,
                                                             species='Human')$Clint)]
setnames(chem.dt, 'Human.Funbound.plasma', 'Funbound.plasma')
chem.dt[, fup.zero:=Funbound.plasma==0.005]
chem.dt[, Clint.zero:=Clint==0]

jhchem <- merge(jhchem,chem.dt,by='CAS')
```
Define a function to plot the confidence intervals as ellipses. This function takes the confidence interval bounds in two dimensions and returns points along the circumference of an ellipse with major and minor axes defined by the confidence intervals in each dimension. By default it returns 100 points; this seems to be plenty to draw a smooth-looking ellipse.
```{r, eval=FALSE}
ellipse_fun <- function(x.CI.max,
                        x.CI.min,
                        y.CI.max,
                        y.CI.min,
                        npts=100){
  #Compute length of axes
  a <- (x.CI.max - x.CI.min)/2
  b <- (y.CI.max - y.CI.min)/2
  #Compute center point
  x0 <- mean(c(x.CI.min,x.CI.max))
  y0 <- mean(c(y.CI.min,y.CI.max))
  #get x and y coordinates of ellipse circumference
  ellipse.x <- a*cos(seq(from=0, 
                         to=2*pi, 
                         length.out=npts)) + x0
  ellipse.y <- b*sin(seq(from=0, 
                         to=2*pi, 
                         length.out=npts)) + y0
  return(data.table(ellipse.x=ellipse.x,
                    ellipse.y=ellipse.y))
  
  }
```
Next, define a function to actually do the plotting -- one that can be called with arguments for poormetab and fup.censor.
```{r, eval=FALSE}
plot_virtstudy_innerfunction <- function(model,
                                              fup.censor,
                                              poormetab,
                                         fuptofub,
                                              jhchem){
  
  if (fuptofub){
  overall.dt <- readRDS(paste0('data/',
                               paste('virtstudypop', 'overallstats', model,
                                     'poormetab', poormetab,
                                     'fup.censor', fup.censor, 
                                     "FuptoFub", sep='_'),
                               '.Rdata'))
  }else{
    overall.dt <- readRDS(paste0('data/',
                               paste('virtstudypop', 'overallstats', model,
                                     'poormetab', poormetab,
                                     'fup.censor', fup.censor, sep='_'),
                               '.Rdata'))
  }
  overall.dt <- merge(overall.dt,
                      jhchem[, .(Study.id,
                                 Compound,
                                 Total.subjects,
                                 Clearance.median,
                                 Clearance.95CI.min,
                                 Clearance.95CI.max,
                                 Clearance.units,
                                 src,
                                 MW,
                                 fup.zero,
                                 Clint.zero)],
                      by='Study.id')
  overall.dt[Clearance.units=='1/h',
             Clearance.units:='L/h'] #correct typo/misreading of "1" for lowercase "L"
  #For clearances given as L/h/kg:
  #1 mg/kg/day over L/day/kg = Css in mg/L
  #Css in mg/L divided by MW in mg/umol = umol/L = uM
  overall.dt[Clearance.units=='L/h/kg',
             css.median.invivo:=1/(24*Clearance.median*(MW/1000))]
  overall.dt[Clearance.units=='L/h/kg',
             css.95CImax.invivo:=1/(24*Clearance.95CI.min*(MW/1000))]
  overall.dt[Clearance.units=='L/h/kg',
             css.95CImin.invivo:=1/(24*Clearance.95CI.max*(MW/1000))]
  #For clearances given as L/h:
  #1 mg/kg/day over L/day = mg/L/kg = Css/kg BW
  #mg/L/kg divided by MW in mg/umol = uM/kg = Css/kg BW
  overall.dt[Clearance.units=='L/h',
             css.bw.median.invivo:=1/(24*Clearance.median*(MW/1000))]
  overall.dt[Clearance.units=='L/h',
             css.bw.95CImax.invivo:=1/(24*Clearance.95CI.min*(MW/1000))]
  overall.dt[Clearance.units=='L/h',
             css.bw.95CImin.invivo:=1/(24*Clearance.95CI.max*(MW/1000))]
  #Get overall bounds on Css and clearance
  overall.dt[, mean.css.95CI.max:=mean.css.95CI.max.fold*median.css.median]
  overall.dt[, mean.css.95CI.min:=mean.css.95CI.min.fold*median.css.median]
  overall.dt[, mean.css.bw.95CI.max:=mean.css.bw.95CI.max.fold*median.css.bw.median]
  overall.dt[, mean.css.bw.95CI.min:=mean.css.bw.95CI.min.fold*median.css.bw.median]
  overall.dt[, poormetab:=poormetab]
  overall.dt[, fup.censor:=fup.censor]
  overall.dt[, fuptofub:=fuptofub]

  #Generate ellipses for Css
  overall.ellipse <- overall.dt[Clearance.units=='L/h/kg',
                                ellipse_fun(x.CI.max=log10(css.95CImax.invivo), 
                                            x.CI.min=log10(css.95CImin.invivo), 
                                            y.CI.max=log10(mean.css.95CI.max), 
                                            y.CI.min=log10(mean.css.95CI.min)), 
                                by=.(Study.id, Compound, Clearance.units, src)]
  #Define colors for plotting
  #from ColorBrewer2.org -- qualitative scale with 12 colors (the max), plus 3 greys
  colvect <- c(brewer.pal(12, 'Paired'),
               c("gray75", "gray50", "black"))
  names(colvect) <- overall.dt[, unique(Compound)]
  #swap alprazolam (light blue) and omeprazole (light purple)
  #makes it easier to tell differences
  tmp <- colvect['omeprazole']
  colvect['omeprazole'] <- colvect['alprazolam']
  colvect['alprazolam'] <- tmp
  rm(tmp)
  #colvect['theophylline']<-'gray50'
  #Set up function to rescale axis labels
  labels.rescale <- function(){
    function(x) 10^x
    }
  
  
  #Generate ellipses for Css/kg BW
  overall.ellipse2 <- overall.dt[Clearance.units=='L/h',
                                 ellipse_fun(x.CI.max=log10(css.bw.95CImax.invivo),
                                             x.CI.min=log10(css.bw.95CImin.invivo),
                                             y.CI.max=log10(mean.css.bw.95CI.max),
                                             y.CI.min=log10(mean.css.bw.95CI.min)),
                                 by=.(Study.id, Compound, Clearance.units, src)]


ellipse.dt <- rbind(overall.ellipse, overall.ellipse2)

ellipse.dt[Clearance.units=="L/h", Css.units:="Css in uM/kg"]
ellipse.dt[Clearance.units=="L/h/kg", Css.units:="Css in uM"]

ptest <- ggplot(data=ellipse.dt)

for (i in ellipse.dt[, unique(Study.id)]) {
ptest <- ptest + geom_path(data=ellipse.dt[Study.id==i,],
aes(x=ellipse.x, y=ellipse.y,
color=Compound))
}

ptest<- ptest + geom_abline(slope=1,intercept=0, linetype=2)+
scale_color_manual(limits=ellipse.dt[, unique(Compound)],
values=colvect)+
scale_x_continuous(labels=labels.rescale()) + #force axes equal range
scale_y_continuous(labels=labels.rescale()) + #force axes equal range
facet_wrap(~Css.units, scales="free") + #, space="free") +
  coord_fixed(ratio=1) + 
labs(x=expression(paste(C[ss], ' in vivo')),
y=expression(paste(C[ss], ' predicted'))) +
theme_bw() +
theme(legend.key=element_blank(),
aspect.ratio=1,
strip.background=element_blank(),
legend.position="bottom")


  return(list(ptest=list(ptest), ov.dt=list(overall.dt)))
  }
```

Finally, let's call the plotting function for the four combinations of poormetab and fup.censor.

```{r, eval=FALSE}
args.dt <- as.data.table(expand.grid(poormetab=c(TRUE, FALSE), 
                         fup.censor=c(TRUE, FALSE), 
                         fuptofub=c(TRUE, FALSE)))
out.dt <- args.dt[, plot_virtstudy_innerfunction(model="3compartmentss",
                                       poormetab=poormetab,
                                       fup.censor=fup.censor,
                                       fuptofub=fuptofub,
                                       jhchem=jhchem),
        by=.(poormetab, fup.censor, fuptofub)]

plotfun <- function(ptmp, poormetab, fup.censor, fuptofub){
  print(ptmp[[1]] + ggtitle(paste(c("poormetab",
                               "fup.censor",
                               "Fup to Fub"),
                             c(poormetab,
                               fup.censor,
                               fuptofub),
                             sep=" = ",
                             collapse=", ")))
  ggsave(paste0(paste("pdf_figures/howgatejohnson_css_poormetab",
               poormetab,
               "fupcensor",
               fup.censor,
               "FuptoFub",
               fuptofub,
               sep="_"),
               ".pdf"),
         ptmp[[1]],
         width=8.5,
         height=5.4)
}

out.dt[, plotfun(ptmp=ptest, 
                 poormetab=poormetab, 
                 fup.censor=fup.censor, 
                 fuptofub=fuptofub), 
       by=.(poormetab, fup.censor, fuptofub)]
```


```{r, eval=FALSE}
stats.dt <- rbindlist(out.dt[, ov.dt])
#Also show a table of how many are within 2-fold, 5-fold, 10-fold
#Compare Css medians:
stats.dt[src=="Howgate et al. 2006",
           css.median.pred.over.lit:=median.css.bw.median/css.bw.median.invivo]
stats.dt[src=="Johnson et al. 2006",
           css.median.pred.over.lit:=median.css.median/css.median.invivo]
#Compare 95% CI ranges:
stats.dt[src=="Johnson et al. 2006",
           css.95CI.range.pred.over.lit:=(mean.css.95CI.max-mean.css.95CI.min)/(css.95CImax.invivo - css.95CImin.invivo)]
stats.dt[src=="Howgate et al. 2006",
           css.95CI.range.pred.over.lit:=(mean.css.bw.95CI.max-mean.css.bw.95CI.min)/(css.bw.95CImax.invivo - css.bw.95CImin.invivo)]
```



```{r, eval=FALSE}
cssmed.dt <- stats.dt[, list(sum(css.median.pred.over.lit<=2 & 
                                                    css.median.pred.over.lit>=0.5),
                                              sum(css.median.pred.over.lit<=5 & 
                                                    css.median.pred.over.lit>=0.2),
                                              sum(css.median.pred.over.lit<=10 & 
                                                    css.median.pred.over.lit>=0.1),
                                      length(unique(Study.id))),
                   by=.(poormetab, fup.censor, fuptofub, src)]
setnames(cssmed.dt, paste0("V", 1:4), c("within.2fold",
                       "within.5fold",
                       "within.10fold",
                       "Total"))
knitr::kable(cssmed.dt,
             format="html",
             col.names=c("PMs included?",
                         "Funbound.plasma censored below avg LOD?",
                         "Funbound.plasma converted to Funbound.blood?",
               "Data from",
                         "Within 2-fold",
                         "Within 5-fold",
                         "Within 10-fold",
                         "Total"),
             caption="Css median, predicted vs. literature in vivo, number of studies")
```

```{r, eval=FALSE}
css95CI.dt <- stats.dt[, list(sum(css.95CI.range.pred.over.lit<=2 & 
                                                    css.95CI.range.pred.over.lit>=0.5),
                                              sum(css.95CI.range.pred.over.lit<=5 & 
                                                    css.95CI.range.pred.over.lit>=0.2),
                                              sum(css.95CI.range.pred.over.lit<=10 & 
                                                    css.95CI.range.pred.over.lit>=0.1),
                                      length(unique(Study.id))),
                   by=.(poormetab, fup.censor, fuptofub, src)]
setnames(css95CI.dt, paste0("V", 1:4), c("within.2fold",
                       "within.5fold",
                       "within.10fold",
                       "Total"))
knitr::kable(css95CI.dt,
             format="html",
             col.names=c("PMs included?",
                         "Funbound.plasma censored below avg LOD?",
                         "Funbound.plasma converted to Funbound.blood?",
               "Data from",
                         "Within 2-fold",
                         "Within 5-fold",
                         "Within 10-fold",
                         "Total"),
             caption="Css 95% CI range, predicted vs. literature in vivo, number of studies")
```