### CHANCE OF REMISSION FOLLOWING A BREAKTHROUGH SEIZURE ###

library(cmprsk)
library(MASS)

# load dataset #
sdat2 <- read.csv("Outcomes following Breakthrough.csv")

# Kaplan-Meier curve #
library(prodlim)
tiff(file="Fig 4.tiff",width=2250,heigh=2625,units="px",res=300)
ttime <- sdat2$rembreak.remtime/365
fit <- prodlim(Surv(ttime,rembreak.rcens)~1,data=sdat2)
plot(fit,type="cuminc",percent=FALSE,background=FALSE,lwd=0.7,atRisk.dist=1,xlab="Time from 1st Breakthrough Seizure (years)",ylab="Probability of 12 month remission",confint=FALSE,legend.x=0,legend.y=1,atrisk.labels="No. at risk:",atRisk.times=c(0,1,2,3,4,5),atRisk.adjust.labels=FALSE)
dev.off()

# Risk of a seizure 2 years following breakthrough #
summary(fit,times=2)

# Number of people with seizure recurrences #
sum(sdat2$rembreak.rcens)

# Time to seizure recurrence #
rempeeps <- subset(sdat2,rembreak.rcens==1)
summary(rempeeps$rembreak.remtime/365)

# Duration of follow-up after acheiving 12 month remission #
summary((sdat2$lastfup.dlfu-sdat2$ttss.mdfsez)/365)


## Univariable analysis ##
# Gender #
sind <- function(data)
	{
	sind <- rep(1/2,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.sex[i]=="F")
	sind[i] <- -1/2
	}
	return(sind)
	}
coxfita=coxph(Surv(rembreak.remtime,rembreak.rcens)~sind(sdat2)+strata(with.Arm),data=sdat2)
coxfita
exp(coxfita$coefficients)
exp(confint(coxfita))

# Febrile Seizure History # 
fsh <- function(data)
	{
	fsh <- rep(-1/2,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.feb[i]=="Y")
	fsh[i] <- 1/2
	}
	return(fsh)
	}
coxfita=coxph(Surv(rembreak.remtime,rembreak.rcens)~fsh(sdat2)+strata(with.Arm),data=sdat2)
coxfita
exp(coxfita$coefficients)
exp(confint(coxfita))

# First degree relative with epilepsy # 
fdr <- function(data)
	{
	fdr <- rep(-1/2,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.rels[i]=="Y")
	fdr[i] <- 1/2
	}
	return(fdr)
	}
coxfita=coxph(Surv(rembreak.remtime,rembreak.rcens)~fdr(sdat2)+strata(with.Arm),data=sdat2)
coxfita
exp(coxfita$coefficients)
exp(confint(coxfita))

# Neurological Signs #
neuro <- function(data)
	{
	neuro <- rep(0,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.neur[i]=="Y")
	neuro[i] <- 1
	}
	return(neuro)
	}
neuroa <- neuro(sdat2)
learn <- function(data)
	{
	learn <- rep(0,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.learn[i]=="Y")
	learn[i] <- 1
	}
	return(learn)
	}
learna <- learn(sdat2)
nsigna <- neuroa + learna
nsign <- function(data)
	{
	nsign <- rep(-1/2,length(data))
	for(i in 1:length(data)){
	if(data[i]>0)
	nsign[i] <- 1/2
	}
	return(nsign)
	}
coxfita=coxph(Surv(rembreak.remtime,rembreak.rcens)~nsign(nsigna)+strata(with.Arm),data=sdat2)
coxfita
exp(coxfita$coefficients)
exp(confint(coxfita))

# Seizure Type #
stype <- function(data) 
	{
	for(i in 1:nrow(data)){
	if(is.na(data$all.sp)[i])
	data$all.sp[i]<-0
	if(is.na(data$all.cp)[i])
	data$all.cp[i]<-0
	if(is.na(data$all.scgtc)[i])
	data$all.scgtc[i]<-0
	if(is.na(data$all.tc)[i])
	data$all.tc[i] <- 0
	if(is.na(data$all.ta)[i])
	data$all.ta[i] <- 0
	if(is.na(data$all.aa)[i])
	data$all.aa[i] <- 0
	if(is.na(data$all.m)[i])
	data$all.m[i] <- 0
	if(is.na(data$all.otc)[i])
	data$all.otc[i] <- 0
	if(is.na(data$all.o)[i])
	data$all.o[i] <- 0
	}
	stype <- rep(7,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.sp[i]>=1 && data$all.scgtc[i]==0)
	stype[i] <- 2
	if(data$all.cp[i]>=1  && data$all.scgtc[i]==0)
	stype[i] <- 2
	if(data$all.sp[i]>=1 && data$all.scgtc[i]>=1)
	stype[i] <- 1
	if(data$all.cp[i]>=1  && data$all.scgtc[i]>=1)
	stype[i] <- 1
	if(data$all.scgtc[i]>=1)
	stype[i] <- 1	
	if(data$all.tc[i]>=1 && data$all.aa[i]==0 && data$all.ta[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- 3
	if(data$all.aa[i]>=1 && data$all.tc[i]==0 && data$all.ta[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- 4
	if(data$all.ta[i]>=1 && data$all.tc[i]==0 && data$all.aa[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- 4
	if(data$all.ta[i]>=1 && data$all.tc[i]==0 && data$all.aa[i]>=1 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- 4 
	if(data$all.m[i]>=1 && data$all.ta[i]>=1)
	stype[i] <- 4
	if(data$all.m[i]>=1 && data$all.aa[i]>=1)
	stype[i] <- 4
	if(data$all.aa[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- 5
	if(data$all.m[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- 5
	if(data$all.ta[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- 5
	if(data$all.otc[i]>=1)
	stype[i] <- 6
	if(data$all.o[i]>=1)
	stype[i] <- 7
	}
	return(stype)
	}	
stype1 <- function(data) 
	{
	for(i in 1:nrow(data)){
	if(is.na(data$all.sp)[i])
	data$all.sp[i]<-0
	if(is.na(data$all.cp)[i])
	data$all.cp[i]<-0
	if(is.na(data$all.scgtc)[i])
	data$all.scgtc[i]<-0
	if(is.na(data$all.tc)[i])
	data$all.tc[i] <- 0
	if(is.na(data$all.ta)[i])
	data$all.ta[i] <- 0
	if(is.na(data$all.aa)[i])
	data$all.aa[i] <- 0
	if(is.na(data$all.m)[i])
	data$all.m[i] <- 0
	if(is.na(data$all.otc)[i])
	data$all.otc[i] <- 0
	if(is.na(data$all.o)[i])
	data$all.o[i] <- 0
	}
	stype <- rep(-1/7,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.sp[i]>=1 && data$all.scgtc[i]==0)
	stype[i] <- 6/7
	if(data$all.cp[i]>=1  && data$all.scgtc[i]==0)
	stype[i] <- 6/7
	if(data$all.sp[i]>=1 && data$all.scgtc[i]>=1)
	stype[i] <- -1/7
	if(data$all.cp[i]>=1  && data$all.scgtc[i]>=1)
	stype[i] <- -1/7
	if(data$all.scgtc[i]>=1)
	stype[i] <- -1/7	
	if(data$all.tc[i]>=1 && data$all.aa[i]==0 && data$all.ta[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- -1/7
	if(data$all.aa[i]>=1 && data$all.tc[i]==0 && data$all.ta[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- -1/7
	if(data$all.ta[i]>=1 && data$all.tc[i]==0 && data$all.aa[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- -1/7
	if(data$all.ta[i]>=1 && data$all.tc[i]==0 && data$all.aa[i]>=1 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- -1/7 
	if(data$all.m[i]>=1 && data$all.ta[i]>=1)
	stype[i] <- -1/7
	if(data$all.m[i]>=1 && data$all.aa[i]>=1)
	stype[i] <- -1/7
	if(data$all.aa[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- -1/7
	if(data$all.m[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- -1/7
	if(data$all.ta[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- -1/7
	if(data$all.otc[i]>=1)
	stype[i] <- -1/7
	if(data$all.o[i]>=1)
	stype[i] <- -1/7
	}
	return(stype)
	}	
stype2 <- function(data) 
	{
	for(i in 1:nrow(data)){
	if(is.na(data$all.sp)[i])
	data$all.sp[i]<-0
	if(is.na(data$all.cp)[i])
	data$all.cp[i]<-0
	if(is.na(data$all.scgtc)[i])
	data$all.scgtc[i]<-0
	if(is.na(data$all.tc)[i])
	data$all.tc[i] <- 0
	if(is.na(data$all.ta)[i])
	data$all.ta[i] <- 0
	if(is.na(data$all.aa)[i])
	data$all.aa[i] <- 0
	if(is.na(data$all.m)[i])
	data$all.m[i] <- 0
	if(is.na(data$all.otc)[i])
	data$all.otc[i] <- 0
	if(is.na(data$all.o)[i])
	data$all.o[i] <- 0
	}
	stype <- rep(-1/7,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.sp[i]>=1 && data$all.scgtc[i]==0)
	stype[i] <- -1/7
	if(data$all.cp[i]>=1  && data$all.scgtc[i]==0)
	stype[i] <- -1/7
	if(data$all.sp[i]>=1 && data$all.scgtc[i]>=1)
	stype[i] <- -1/7
	if(data$all.cp[i]>=1  && data$all.scgtc[i]>=1)
	stype[i] <- -1/7
	if(data$all.scgtc[i]>=1)
	stype[i] <- -1/7	
	if(data$all.tc[i]>=1 && data$all.aa[i]==0 && data$all.ta[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- 6/7
	if(data$all.aa[i]>=1 && data$all.tc[i]==0 && data$all.ta[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- -1/7
	if(data$all.ta[i]>=1 && data$all.tc[i]==0 && data$all.aa[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- -1/7
	if(data$all.ta[i]>=1 && data$all.tc[i]==0 && data$all.aa[i]>=1 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- -1/7 
	if(data$all.m[i]>=1 && data$all.ta[i]>=1)
	stype[i] <- -1/7
	if(data$all.m[i]>=1 && data$all.aa[i]>=1)
	stype[i] <- -1/7
	if(data$all.aa[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- -1/7
	if(data$all.m[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- -1/7
	if(data$all.ta[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- -1/7
	if(data$all.otc[i]>=1)
	stype[i] <- -1/7
	if(data$all.o[i]>=1)
	stype[i] <- -1/7
	}
	return(stype)
	}	
stype3 <- function(data) 
	{
	for(i in 1:nrow(data)){
	if(is.na(data$all.sp)[i])
	data$all.sp[i]<-0
	if(is.na(data$all.cp)[i])
	data$all.cp[i]<-0
	if(is.na(data$all.scgtc)[i])
	data$all.scgtc[i]<-0
	if(is.na(data$all.tc)[i])
	data$all.tc[i] <- 0
	if(is.na(data$all.ta)[i])
	data$all.ta[i] <- 0
	if(is.na(data$all.aa)[i])
	data$all.aa[i] <- 0
	if(is.na(data$all.m)[i])
	data$all.m[i] <- 0
	if(is.na(data$all.otc)[i])
	data$all.otc[i] <- 0
	if(is.na(data$all.o)[i])
	data$all.o[i] <- 0
	}
	stype <- rep(-1/7,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.sp[i]>=1 && data$all.scgtc[i]==0)
	stype[i] <- -1/7
	if(data$all.cp[i]>=1  && data$all.scgtc[i]==0)
	stype[i] <- -1/7
	if(data$all.sp[i]>=1 && data$all.scgtc[i]>=1)
	stype[i] <- -1/7
	if(data$all.cp[i]>=1  && data$all.scgtc[i]>=1)
	stype[i] <- -1/7
	if(data$all.scgtc[i]>=1)
	stype[i] <- -1/7	
	if(data$all.tc[i]>=1 && data$all.aa[i]==0 && data$all.ta[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- -1/7
	if(data$all.aa[i]>=1 && data$all.tc[i]==0 && data$all.ta[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- 6/7
	if(data$all.ta[i]>=1 && data$all.tc[i]==0 && data$all.aa[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- 6/7
	if(data$all.ta[i]>=1 && data$all.tc[i]==0 && data$all.aa[i]>=1 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- 6/7 
	if(data$all.m[i]>=1 && data$all.ta[i]>=1)
	stype[i] <- 6/7
	if(data$all.m[i]>=1 && data$all.aa[i]>=1)
	stype[i] <- 6/7
	if(data$all.aa[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- -1/7
	if(data$all.m[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- -1/7
	if(data$all.ta[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- -1/7
	if(data$all.otc[i]>=1)
	stype[i] <- -1/7
	if(data$all.o[i]>=1)
	stype[i] <- -1/7
	}
	return(stype)
	}
stype4 <- function(data) 
	{
	for(i in 1:nrow(data)){
	if(is.na(data$all.sp)[i])
	data$all.sp[i]<-0
	if(is.na(data$all.cp)[i])
	data$all.cp[i]<-0
	if(is.na(data$all.scgtc)[i])
	data$all.scgtc[i]<-0
	if(is.na(data$all.tc)[i])
	data$all.tc[i] <- 0
	if(is.na(data$all.ta)[i])
	data$all.ta[i] <- 0
	if(is.na(data$all.aa)[i])
	data$all.aa[i] <- 0
	if(is.na(data$all.m)[i])
	data$all.m[i] <- 0
	if(is.na(data$all.otc)[i])
	data$all.otc[i] <- 0
	if(is.na(data$all.o)[i])
	data$all.o[i] <- 0
	}
	stype <- rep(-1/7,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.sp[i]>=1 && data$all.scgtc[i]==0)
	stype[i] <- -1/7
	if(data$all.cp[i]>=1  && data$all.scgtc[i]==0)
	stype[i] <- -1/7
	if(data$all.sp[i]>=1 && data$all.scgtc[i]>=1)
	stype[i] <- -1/7
	if(data$all.cp[i]>=1  && data$all.scgtc[i]>=1)
	stype[i] <- -1/7
	if(data$all.scgtc[i]>=1)
	stype[i] <- -1/7	
	if(data$all.tc[i]>=1 && data$all.aa[i]==0 && data$all.ta[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- -1/7
	if(data$all.aa[i]>=1 && data$all.tc[i]==0 && data$all.ta[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- -1/7
	if(data$all.ta[i]>=1 && data$all.tc[i]==0 && data$all.aa[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- -1/7
	if(data$all.ta[i]>=1 && data$all.tc[i]==0 && data$all.aa[i]>=1 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- -1/7 
	if(data$all.m[i]>=1 && data$all.ta[i]>=1)
	stype[i] <- -1/7
	if(data$all.m[i]>=1 && data$all.aa[i]>=1)
	stype[i] <- -1/7
	if(data$all.aa[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- 6/7
	if(data$all.m[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- 6/7
	if(data$all.ta[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- 6/7
	if(data$all.otc[i]>=1)
	stype[i] <- -1/7
	if(data$all.o[i]>=1)
	stype[i] <- -1/7
	}
	return(stype)
	}	
stype5 <- function(data) 
	{
	for(i in 1:nrow(data)){
	if(is.na(data$all.sp)[i])
	data$all.sp[i]<-0
	if(is.na(data$all.cp)[i])
	data$all.cp[i]<-0
	if(is.na(data$all.scgtc)[i])
	data$all.scgtc[i]<-0
	if(is.na(data$all.tc)[i])
	data$all.tc[i] <- 0
	if(is.na(data$all.ta)[i])
	data$all.ta[i] <- 0
	if(is.na(data$all.aa)[i])
	data$all.aa[i] <- 0
	if(is.na(data$all.m)[i])
	data$all.m[i] <- 0
	if(is.na(data$all.otc)[i])
	data$all.otc[i] <- 0
	if(is.na(data$all.o)[i])
	data$all.o[i] <- 0
	}
	stype <- rep(-1/7,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.sp[i]>=1 && data$all.scgtc[i]==0)
	stype[i] <- -1/7
	if(data$all.cp[i]>=1  && data$all.scgtc[i]==0)
	stype[i] <- -1/7
	if(data$all.sp[i]>=1 && data$all.scgtc[i]>=1)
	stype[i] <- -1/7
	if(data$all.cp[i]>=1  && data$all.scgtc[i]>=1)
	stype[i] <- -1/7
	if(data$all.scgtc[i]>=1)
	stype[i] <- -1/7	
	if(data$all.tc[i]>=1 && data$all.aa[i]==0 && data$all.ta[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- -1/7
	if(data$all.aa[i]>=1 && data$all.tc[i]==0 && data$all.ta[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- -1/7
	if(data$all.ta[i]>=1 && data$all.tc[i]==0 && data$all.aa[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- -1/7
	if(data$all.ta[i]>=1 && data$all.tc[i]==0 && data$all.aa[i]>=1 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- -1/7 
	if(data$all.m[i]>=1 && data$all.ta[i]>=1)
	stype[i] <- -1/7
	if(data$all.m[i]>=1 && data$all.aa[i]>=1)
	stype[i] <- -1/7
	if(data$all.aa[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- -1/7
	if(data$all.m[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- -1/7
	if(data$all.ta[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- -1/7
	if(data$all.otc[i]>=1)
	stype[i] <- 6/7
	if(data$all.o[i]>=1)
	stype[i] <- -1/7
	}
	return(stype)
	}	
stype6 <- function(data) 
	{
	for(i in 1:nrow(data)){
	if(is.na(data$all.sp)[i])
	data$all.sp[i]<-0
	if(is.na(data$all.cp)[i])
	data$all.cp[i]<-0
	if(is.na(data$all.scgtc)[i])
	data$all.scgtc[i]<-0
	if(is.na(data$all.tc)[i])
	data$all.tc[i] <- 0
	if(is.na(data$all.ta)[i])
	data$all.ta[i] <- 0
	if(is.na(data$all.aa)[i])
	data$all.aa[i] <- 0
	if(is.na(data$all.m)[i])
	data$all.m[i] <- 0
	if(is.na(data$all.otc)[i])
	data$all.otc[i] <- 0
	if(is.na(data$all.o)[i])
	data$all.o[i] <- 0
	}
	stype <- rep(6/7,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.sp[i]>=1 && data$all.scgtc[i]==0)
	stype[i] <- -1/7
	if(data$all.cp[i]>=1  && data$all.scgtc[i]==0)
	stype[i] <- -1/7
	if(data$all.sp[i]>=1 && data$all.scgtc[i]>=1)
	stype[i] <- -1/7
	if(data$all.cp[i]>=1  && data$all.scgtc[i]>=1)
	stype[i] <- -1/7
	if(data$all.scgtc[i]>=1)
	stype[i] <- -1/7	
	if(data$all.tc[i]>=1 && data$all.aa[i]==0 && data$all.ta[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- -1/7
	if(data$all.aa[i]>=1 && data$all.tc[i]==0 && data$all.ta[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- -1/7
	if(data$all.ta[i]>=1 && data$all.tc[i]==0 && data$all.aa[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- -1/7
	if(data$all.ta[i]>=1 && data$all.tc[i]==0 && data$all.aa[i]>=1 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- -1/7 
	if(data$all.m[i]>=1 && data$all.ta[i]>=1)
	stype[i] <- -1/7
	if(data$all.m[i]>=1 && data$all.aa[i]>=1)
	stype[i] <- -1/7
	if(data$all.aa[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- -1/7
	if(data$all.m[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- -1/7
	if(data$all.ta[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- -1/7
	if(data$all.otc[i]>=1)
	stype[i] <- -1/7
	if(data$all.o[i]>=1)
	stype[i] <- 6/7
	}
	return(stype)
	}		
coxfita=coxph(Surv(rembreak.remtime,rembreak.rcens)~stype1(sdat2)+stype2(sdat2)+stype3(sdat2)+stype4(sdat2)+stype5(sdat2)+stype6(sdat2)+strata(with.Arm),data=sdat2)
coxfita
exp(coxfita$coefficients)
exp(confint(coxfita))

# Epilepsy type analysis #
pgu1 <- function(data)
	{
	x1 <- rep(-1/3,nrow(data))
	for(i in 1:nrow(data)){
	if(is.na(data$all.type)[i])
	data$all.type[i]<-"U"
	}
	for(i in 1:nrow(data)){
	if(data$all.type[i]=="P")
	x1[i] <- -1/3
	if(data$all.type[i]=="G")
	x1[i] <- 2/3
	if(data$all.type[i]=="U")
	x1[i] <- -1/3
	}
	return(x1)
	}
pgu2 <- function(data)
	{
	x2 <- rep(-1/3,nrow(data))
	for(i in 1:nrow(data)){
	if(is.na(data$all.type)[i])
	data$all.type[i]<-"U"
	}
	for(i in 1:nrow(data)){
	if(data$all.type[i]=="P")
	x2[i]<- -1/3
	if(data$all.type[i]=="G")
	x2[i]<- -1/3
	if(data$all.type[i]=="U")
	x2[i]<- 2/3
	}
	return(x2)
	}
coxfita=coxph(Surv(rembreak.remtime,rembreak.rcens)~pgu1(sdat2)+pgu2(sdat2)+strata(with.Arm),data=sdat2)
coxfita
exp(coxfita$coefficients)
exp(confint(coxfita))

# EEG Results #
eegfour <- function(data)
	{
	for(i in 1:nrow(data)){
	if(is.na(data$all.nonspecab)[i])
	data$all.nonspecab[i]<-"N"
	}
	eegfour <- rep(3,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.eegabnormal[i]=="NR")
	eegfour[i]<-1
	if(data$all.eegabnormal[i]=="N")
	eegfour[i]<-0
	if(data$all.eegabnormal[i]=="Y" && data$all.nonspecab[i]=="Y")
	eegfour[i]<-2
	}
	return(eegfour)
	}
eeg1 <- function(data)
	{
	for(i in 1:nrow(data)){
	if(is.na(data$all.nonspecab)[i])
	data$all.nonspecab[i]<-"N"
	}
	eegfour <- rep(-1/4,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.eegabnormal[i]=="NR")
	eegfour[i]<-3/4
	if(data$all.eegabnormal[i]=="N")
	eegfour[i]<--1/4
	if(data$all.eegabnormal[i]=="Y" && data$all.nonspecab[i]=="Y")
	eegfour[i]<--1/4
	}
	return(eegfour)
	}
eeg2 <- function(data)
	{
	for(i in 1:nrow(data)){
	if(is.na(data$all.nonspecab)[i])
	data$all.nonspecab[i]<-"N"
	}
	eegfour <- rep(-1/4,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.eegabnormal[i]=="NR")
	eegfour[i]<--1/4
	if(data$all.eegabnormal[i]=="N")
	eegfour[i]<--1/4
	if(data$all.eegabnormal[i]=="Y" && data$all.nonspecab[i]=="Y")
	eegfour[i]<-3/4
	}
	return(eegfour)
	}
eeg3 <- function(data)
	{
	for(i in 1:nrow(data)){
	if(is.na(data$all.nonspecab)[i])
	data$all.nonspecab[i]<-"N"
	}
	eegfour <- rep(3/4,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.eegabnormal[i]=="NR")
	eegfour[i]<--1/4
	if(data$all.eegabnormal[i]=="N")
	eegfour[i]<--1/4
	if(data$all.eegabnormal[i]=="Y" && data$all.nonspecab[i]=="Y")
	eegfour[i]<--1/4
	}
	return(eegfour)
	}
coxfita=coxph(Surv(rembreak.remtime,rembreak.rcens)~eeg1(sdat2)+eeg2(sdat2)+eeg3(sdat2)+strata(with.Arm),data=sdat2)
coxfita
exp(coxfita$coefficients)
exp(confint(coxfita))

# CT/MR Results #
ctmr1 <- function(data)
	{
	ctmr <- rep(-1/3,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.ctabnormal[i]=="Y")
	ctmr[i] <- 2/3
	if(data$all.ctabnormal[i]=="NR")
	ctmr[i] <- -1/3
	}
	return(ctmr)
	}
ctmr2 <- function(data)
	{
	ctmr <- rep(-1/3,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.ctabnormal[i]=="Y")
	ctmr[i] <- -1/3
	if(data$all.ctabnormal[i]=="NR")
	ctmr[i] <- 2/3
	}
	return(ctmr)
	}
coxfita=coxph(Surv(rembreak.remtime,rembreak.rcens)~ctmr1(sdat2)+ctmr2(sdat2)+strata(with.Arm),data=sdat2)
coxfita
exp(coxfita$coefficients)
exp(confint(coxfita))

# Treatment #
treat <- function(data)
	{
	treat <- rep(0,nrow(data))
	for(i in 1:nrow(data)){
	if(data$with.Treat[i]=="CBZ")
	treat[i] <- 1
	if(data$with.Treat[i]=="GBP")
	treat[i] <- 2
	if(data$with.Treat[i]=="LTG")
	treat[i] <- 3
	if(data$with.Treat[i]=="OXC")
	treat[i] <- 4
	if(data$with.Treat[i]=="TPM")
	treat[i] <- 5
	if(data$with.Treat[i]=="VPS")
	treat[i] <- 6
	}
	return(treat)
	}
treat1 <- function(data)
	{
	treat <- rep(0,nrow(data))
	for(i in 1:nrow(data)){
	if(data$with.Treat[i]=="CBZ")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="GBP")
	treat[i] <- 5/6
	if(data$with.Treat[i]=="LTG")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="OXC")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="TPM")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="VPS")
	treat[i] <- -1/6
	}
	return(treat)
	}
treat2 <- function(data)
	{
	treat <- rep(0,nrow(data))
	for(i in 1:nrow(data)){
	if(data$with.Treat[i]=="CBZ")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="GBP")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="LTG")
	treat[i] <- 5/6
	if(data$with.Treat[i]=="OXC")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="TPM")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="VPS")
	treat[i] <- -1/6
	}
	return(treat)
	}
treat3 <- function(data)
	{
	treat <- rep(0,nrow(data))
	for(i in 1:nrow(data)){
	if(data$with.Treat[i]=="CBZ")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="GBP")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="LTG")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="OXC")
	treat[i] <- 5/6
	if(data$with.Treat[i]=="TPM")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="VPS")
	treat[i] <- -1/6
	}
	return(treat)
	}
treat4 <- function(data)
	{
	treat <- rep(0,nrow(data))
	for(i in 1:nrow(data)){
	if(data$with.Treat[i]=="CBZ")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="GBP")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="LTG")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="OXC")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="TPM")
	treat[i] <- 5/6
	if(data$with.Treat[i]=="VPS")
	treat[i] <- -1/6
	}
	return(treat)
	}
treat5 <- function(data)
	{
	treat <- rep(0,nrow(data))
	for(i in 1:nrow(data)){
	if(data$with.Treat[i]=="CBZ")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="GBP")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="LTG")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="OXC")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="TPM")
	treat[i] <- -1/6
	if(data$with.Treat[i]=="VPS")
	treat[i] <- 5/6
	}
	return(treat)
	}
coxfita=coxph(Surv(rembreak.remtime,rembreak.rcens)~treat1(sdat2)+treat2(sdat2)+treat3(sdat2)+treat4(sdat2)+treat5(sdat2)+strata(with.Arm),data=sdat2)
coxfita
exp(coxfita$coefficients)
exp(confint(coxfita))

# Monotherapy to achieve remission #
mono <- function(data)
	{
	for(i in 1:nrow(data)){
	if(is.na(data$drugs.nodrugs)[i])
	data$drugs.nodrugs[i]<-0
	}
	mono <- rep(0,nrow(data))
	for(i in 1:nrow(data)){
	if(data$drugs.nodrugs[i]<=1)
	mono[i] <- 0
	if(data$drugs.nodrugs[i]>=2)
	mono[i] <- 1
	}
	return(mono)
	}
monodat <- mono(sdat2)
mntp <- function(data)
	{
	mntp <- rep(-1/2,length(data))
	for(i in 1:length(data)){
	if(data[i]==1)
	mntp[i] <- 1/2
	}
	return(mntp)
	}
coxfita=coxph(Surv(rembreak.remtime,rembreak.rcens)~mntp(monodat)+strata(with.Arm),data=sdat2)
coxfita
exp(coxfita$coefficients)
exp(confint(coxfita))

# Post-seizure treatment decision #
post1 <- function(data)
	{
	for(i in 1:nrow(data)){
	if(is.na(data$ttss.postdec)[i])
	data$ttss.postdec[i]<-4
	}
	post1 <- rep(-1/3,nrow(data))
	for(i in 1:nrow(data)){
	if(data$ttss.postdec[i]==1)
	post1[i] <- -1/3
	if(data$ttss.postdec[i]==2)
	post1[i] <- 2/3
	if(data$ttss.postdec[i]==3)
	post1[i] <- -1/3
	if(data$ttss.postdec[i]==4)
	post1[i] <- -1/3
	}
	return(post1)
	}
post2 <- function(data)
	{
	for(i in 1:nrow(data)){
	if(is.na(data$ttss.postdec)[i])
	data$ttss.postdec[i]<-4
	}
	post2 <- rep(-1/3,nrow(data))
	for(i in 1:nrow(data)){
	if(data$ttss.postdec[i]==1)
	post2[i] <- -1/3
	if(data$ttss.postdec[i]==2)
	post2[i] <- -1/3
	if(data$ttss.postdec[i]==3)
	post2[i] <- 2/3
	if(data$ttss.postdec[i]==4)
	post2[i] <- 2/3
	}
	return(post2)
	}
coxfita=coxph(Surv(rembreak.remtime,rembreak.rcens)~post1(sdat2)+post2(sdat2)+strata(with.Arm),data=sdat2)
coxfita
exp(coxfita$coefficients)
exp(confint(coxfita))

# Number of tonic-clonic seizures #
library(mfp)
library(Hmisc)
fit1 <- coxph(Surv(rembreak.remtime,rembreak.rcens)~newtc+strata(with.Arm),data=sdat2)
extractAIC(fit1)
fit2 <- coxph(Surv(rembreak.remtime,rembreak.rcens)~log(newtc+1)+strata(with.Arm),data=sdat2)
extractAIC(fit2)
fit3 <- mfp(Surv(rembreak.remtime,rembreak.rcens)~fp(newtc)+strata(with.Arm),family=cox,data=sdat2,select=0.05,verbose=TRUE)
extractAIC(fit3)
summary(fit2)
summary(sdat2$newtc)

# Age at first breakthrough #
fit1 <- coxph(Surv(rembreak.remtime,rembreak.rcens)~newage+strata(with.Arm),data=sdat2)
extractAIC(fit1)
fit2 <- coxph(Surv(rembreak.remtime,rembreak.rcens)~log(newage)+strata(with.Arm),data=sdat2)
extractAIC(fit2)
coxfitf1 <- mfp(Surv(rembreak.remtime,rembreak.rcens)~fp(newage)+strata(with.Arm),family=cox,data=sdat2,select=0.05,verbose=TRUE)
extractAIC(coxfitf1)

summary(fit2)
summary(sdat2$newage)

# Time to achieve first period of 12 month remission #
fit1 <- coxph(Surv(rembreak.remtime,rembreak.rcens)~rem.Remtime+strata(with.Arm),data=sdat2)
extractAIC(fit1)
fit2 <- coxph(Surv(rembreak.remtime,rembreak.rcens)~log(rem.Remtime)+strata(with.Arm),data=sdat2)
extractAIC(fit2)
coxfitf1 <- mfp(Surv(rembreak.remtime,rembreak.rcens)~fp(rem.Remtime)+strata(with.Arm),family=cox,data=sdat2,select=0.05,verbose=TRUE)
extractAIC(coxfitf1)

summary(fit1)
summary(sdat2$rem.Remtime)

# Time on randomised treatment #
fit1 <- coxph(Surv(rembreak.remtime,rembreak.rcens)~with.Withtime+strata(with.Arm),data=sdat2)
extractAIC(fit1)
fit2 <- coxph(Surv(rembreak.remtime,rembreak.rcens)~log(with.Withtime)+strata(with.Arm),data=sdat2)
extractAIC(fit2)
coxfitf1 <- mfp(Surv(rembreak.remtime,rembreak.rcens)~fp(with.Withtime)+strata(with.Arm),family=cox,data=sdat2,select=0.05,verbose=TRUE)
extractAIC(coxfitf1)

summary(fit1)
summary(sdat2$with.Withtime)

### Multivariable Model ###
neuro <- function(data)
	{
	neuro <- rep(0,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.neur[i]=="Y")
	neuro[i] <- 1
	}
	return(neuro)
	}
neuroa <- neuro(sdat2)
learn <- function(data)
	{
	learn <- rep(0,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.learn[i]=="Y")
	learn[i] <- 1
	}
	return(learn)
	}
learna <- learn(sdat2)
nsigna <- neuroa + learna
nsign <- function(data)
	{
	nsign <- rep(0,length(data))
	for(i in 1:length(data)){
	if(data[i]>0)
	nsign[i] <- 1
	}
	return(nsign)
	}
stype <- function(data) 
	{
	for(i in 1:nrow(data)){
	if(is.na(data$all.sp)[i])
	data$all.sp[i]<-0
	if(is.na(data$all.cp)[i])
	data$all.cp[i]<-0
	if(is.na(data$all.scgtc)[i])
	data$all.scgtc[i]<-0
	if(is.na(data$all.tc)[i])
	data$all.tc[i] <- 0
	if(is.na(data$all.ta)[i])
	data$all.ta[i] <- 0
	if(is.na(data$all.aa)[i])
	data$all.aa[i] <- 0
	if(is.na(data$all.m)[i])
	data$all.m[i] <- 0
	if(is.na(data$all.otc)[i])
	data$all.otc[i] <- 0
	if(is.na(data$all.o)[i])
	data$all.o[i] <- 0
	}
	stype <- rep(7,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.sp[i]>=1 && data$all.scgtc[i]==0)
	stype[i] <- 2
	if(data$all.cp[i]>=1  && data$all.scgtc[i]==0)
	stype[i] <- 2
	if(data$all.sp[i]>=1 && data$all.scgtc[i]>=1)
	stype[i] <- 1
	if(data$all.cp[i]>=1  && data$all.scgtc[i]>=1)
	stype[i] <- 1
	if(data$all.scgtc[i]>=1)
	stype[i] <- 1	
	if(data$all.tc[i]>=1 && data$all.aa[i]==0 && data$all.ta[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- 3
	if(data$all.aa[i]>=1 && data$all.tc[i]==0 && data$all.ta[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- 4
	if(data$all.ta[i]>=1 && data$all.tc[i]==0 && data$all.aa[i]==0 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- 4
	if(data$all.ta[i]>=1 && data$all.tc[i]==0 && data$all.aa[i]>=1 && data$all.m[i]==0 && data$all.otc[i]==0 && data$all.o[i]==0)
	stype[i] <- 4 
	if(data$all.m[i]>=1 && data$all.ta[i]>=1)
	stype[i] <- 4
	if(data$all.m[i]>=1 && data$all.aa[i]>=1)
	stype[i] <- 4
	if(data$all.aa[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- 5
	if(data$all.m[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- 5
	if(data$all.ta[i]>=1 && data$all.tc[i]>=1)
	stype[i] <- 5
	if(data$all.otc[i]>=1)
	stype[i] <- 6
	if(data$all.o[i]>=1)
	stype[i] <- 7
	}
	return(stype)
	}
eegfour <- function(data)
	{
	for(i in 1:nrow(data)){
	if(is.na(data$all.nonspecab)[i])
	data$all.nonspecab[i]<-"N"
	}
	eegfour <- rep(3,nrow(data))
	for(i in 1:nrow(data)){
	if(data$all.eegabnormal[i]=="NR")
	eegfour[i]<-1
	if(data$all.eegabnormal[i]=="N")
	eegfour[i]<-0
	if(data$all.eegabnormal[i]=="Y" && data$all.nonspecab[i]=="Y")
	eegfour[i]<-2
	}
	return(eegfour)
	}
post1a <- function(data)
		{
		for(i in 1:nrow(data)){
		if(is.na(data$ttss.postdec)[i])
		data$ttss.postdec[i] <- 4
		}
		post1a <- rep(0,nrow(data)) 
		for(i in 1:nrow(data)){
		if(data$ttss.postdec[i]==1)
		post1a[i] <- 1
		if(data$ttss.postdec[i]==2)
		post1a[i] <- 2
		if(data$ttss.postdec[i]==3)
		post1a[i] <- 3
		if(data$ttss.postdec[i]==4)
		post1a[i] <- 3
		}
		return(post1a)
		}
aeds1a <- function(data)
	{
	aeda <- rep(0,nrow(data))
	for(i in 1:nrow(data)){
	if(is.na(data$drugs.nodrugs)[i])
	data$drugs.nodrugs[i]<-0
	}
	for(i in 1:nrow(data)){
	if(data$drugs.nodrugs[i]==2)
	aeda[i] <- 1
	if(data$drugs.nodrugs[i]==3)
	aeda[i] <- 1
	}
	return(aeda)
	}

coxfitb=coxph(Surv(rembreak.remtime,rembreak.rcens)~all.sex+all.feb+all.rels+nsign(nsigna)+factor(stype(sdat2))+factor(eegfour(sdat2))+factor(all.ctabnormal)+aeds1a(sdat2)+log(newtc+1)+log(newage)+rem.Remtime+factor(post1a(sdat2))+strata(with.Arm),data=sdat2)
rema.step=stepAIC(coxfitb,scope=list(upper=~all.sex+all.feb+all.rels+nsign(nsigna)+factor(stype(sdat2))+factor(eegfour(sdat2))+factor(all.ctabnormal)+aeds1a(sdat2)+log(newtc+1)+log(newage)+rem.Remtime+factor(post1a(sdat2))+strata(with.Arm)),direction="backward",trace=FALSE)
rema.step

remb.step=stepAIC(coxfitb,scope=list(upper=~all.sex+all.feb+all.rels+nsign(nsigna)+factor(stype(sdat2))+factor(eegfour(sdat2))+factor(all.ctabnormal)+aeds1a(sdat2)+log(newtc+1)+log(newage)+rem.Remtime+factor(post1a(sdat2))+strata(with.Arm)),direction="both",trace=FALSE)
remb.step

remamod = coxph(Surv(rembreak.remtime,rembreak.rcens)~all.sex+log(newage)+rem.Remtime+factor(post1a(sdat2))+strata(with.Arm),data=sdat2)
summary(remamod)
exp(remamod$coef)
exp(confint(remamod))


## Forest Plot #
library(grid)

# read in relevant dataset #
rem <- read.table("Risk Factor Combos - Remission.txt",header=TRUE)

Ys=seq(from=1,to=nrow(rem),by=1)
par(mfrow=c(1,3),mar=c(5,1,1,1))
plot(0,0,xlim=c(0,100),ylim=c(0,nrow(rem)+3),type="n",axes=F,xlab="",ylab="",main="")
text(10,Ys,rev(rem$sexn),cex=0.7)
text(37.5,Ys,rev(rem$pdec),cex=0.7)
text(62.5,Ys,rev(rem$newage2),cex=0.7)
text(90,Ys,rev(rem$remtime),cex=0.7)
text(10,nrow(rem)+3,"Gender",font=2,cex=0.7)
text(37.5,nrow(rem)+3,"Treatment",font=2,cex=0.7)
text(37.5,nrow(rem)+2,"decision",font=2,cex=0.7)
text(62.5,nrow(rem)+3,"Age",font=2,cex=0.7)
text(62.5,nrow(rem)+2,"(years)",font=2,cex=0.7)
text(90,nrow(rem)+3,"Time to",font=2,cex=0.7)
text(90,nrow(rem)+2,"remission",font=2,cex=0.7)
text(90,nrow(rem)+1,"(years)",font=2,cex=0.7)
abline(h=18.5)
abline(h=9.5,lty=2)
abline(h=27.5,lty=2)

plot(0,0,xlim=c(0,100),ylim=c(0,nrow(rem)+3),type="n",axes=F,xlab="Chance of 12 Month Remission 1 year after Breakthrough (%)",ylab="",main="",cex.lab=0.7)
estimate1y <- rev(rem$HR1)*100
lower1y <- rev(rem$Lower1)*100
upper1y <- rev(rem$Upper1)*100
points(estimate1y,Ys,pch=15,cex=1.5,)
for(i in 1:length(Ys)){
lines(c(lower1y[i],upper1y[i]),rep(Ys[i],2),lwd=1.0)
}
axis(1,at=c(0,10,20,30,40,50,60,70,80,90,100),c(0,10,20,30,40,50,60,70,80,90,100),cex.axis=0.7)
abline(h=18.5)
abline(h=9.5,lty=2)
abline(h=27.5,lty=2)

plot(0,0,xlim=c(0,100),ylim=c(0,nrow(rem)+3),type="n",axes=F,xlab="Chance of 12 Month Remission 2 years after Breakthrough (%)",ylab="",main="",cex.lab=0.7)
estimate2y <- rev(rem$HR2)*100
lower2y <- rev(rem$Lower2)*100
upper2y <- rev(rem$Upper2)*100
points(estimate2y,Ys,pch=15,cex=1.5,)
for(i in 1:length(Ys)){
lines(c(lower2y[i],upper2y[i]),rep(Ys[i],2),lwd=1.0)
}
axis(1,at=c(0,10,20,30,40,50,60,70,80,90,100),c(0,10,20,30,40,50,60,70,80,90,100),cex.axis=0.7)
abline(h=18.5)
abline(h=9.5,lty=2)
abline(h=27.5,lty=2)