## Date: 2015-03-03
## Purpose: To do the solution for Biostat III exercise 9 in R
## Author: Annika Tillander,  Johan Zetterqvist
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## ## Install needed packages only need to be done once
## Install needed packages only need to be done once

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## Exercise 9
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## @knitr loadDependencies

library(biostat3)
library(dplyr)    # for data manipulation
library(splines)   # ns (recommended package)

## @knitr loadPreprocess
## Read melanoma data, select subcohorts and create a death indicator
melanoma.l <- biostat3::melanoma |>
    subset(stage=="Localised") |>
    transform(death_cancer = as.numeric(status=="Dead: cancer"))

melanoma.l2 <-
    transform(melanoma.l,
              ## Create a death indicator (only count deaths within 120 months)
              death_cancer = ifelse(surv_mm<=120, death_cancer, 0),
              ## Create a new time variable
              surv_mm = pmin(surv_mm, 120))

## @knitr 9.a

summary(coxph(Surv(surv_mm, death_cancer) ~ year8594,
              data = melanoma.l2))

## @knitr 9.b

survdiff(Surv(surv_mm, death_cancer) ~ year8594, data = melanoma.l)
summary(coxph(Surv(surv_mm, death_cancer) ~ year8594,
              data = melanoma.l))

## @knitr 9.c

summary(coxfit9c <- coxph(Surv(surv_mm, death_cancer) ~ year8594 + sex + agegrp,
                          data = melanoma.l2))

## Test if the effect of age is significant
## Use a Wald test with the car package
library(car)
linearHypothesis(coxfit9c,c("agegrp45-59 = 0","agegrp60-74 = 0","agegrp75+ = 0"))

## @knitr 9.d

## Test if the effect of age is significant
## Use an LR test with the anova function
## The model without agegrp
summary(coxfit9d <- coxph(Surv(surv_mm, death_cancer) ~ year8594 + sex,
                          data = melanoma.l2))
## LR test
anova(coxfit9c, coxfit9d)
anova(coxfit9c)
## @knitr 9.e

summary(coxfit9e <- coxph(Surv(surv_mm, death_cancer) ~ year8594 + sex + agegrp,
                          data = melanoma.l2))

## Split follow up by year
melanoma.spl <- survSplit(melanoma.l2, cut=12*(0:10), end="surv_mm", start="start",
                           event="death_cancer")

## Calculate persontime and
## recode start time as a factor
melanoma.spl <- transform(melanoma.spl,
                          pt = surv_mm - start,
                          fu = as.factor(start))

## Run Poisson regression
summary(poisson9e <- glm(death_cancer ~ fu + year8594 + sex + agegrp + offset(log(pt)),
                         family = poisson,
                         data = melanoma.spl))

eform(poisson9e)

## @knitr 9.f

sfit9f <- survfit(Surv(surv_mm, event=death_cancer) ~ 1,
                  data = melanoma.l2 )
## Have a look at the fitted object
str(sfit9f, 1)

head(sfit9f$time)

## Split follow up by event times
melanoma.spl2 <- survSplit(melanoma.l2, cut=sfit9f$time, end="surv_mm", start="start",
                           event="death_cancer")

## Calculate persontime and
## recode start time as a factor
melanoma.spl2 <- transform(melanoma.spl2,
                           pt = surv_mm - start,
                           fu = as.factor(start))

## Collapse
library(dplyr)
melanoma.spl3 <- melanoma.spl2 |>
    group_by(fu,year8594,sex,agegrp) |>
    summarise(pt=sum(pt), death_cancer=sum(death_cancer)) |>
    data.frame()

## Run Poisson regression
poisson9f <- glm(death_cancer ~ fu + year8594 + sex + agegrp + offset(log(pt)),
                 family = poisson,
                 data = melanoma.spl3 )

## IRR
coef9f <- eform(poisson9f)
## We are not interested in nuisance parameters fu1, fu2, etc
npar <- nrow(coef9f)
pars <- (npar-4):npar
coef9f[pars,]

summary(coxfit9e)


## @knitr 9.g
## split and collapse
library(dplyr)
cuts.splines <- seq(0,max(sfit9f$time),by=3)
mid.splines <- cuts.splines + 1.5
melanoma.spl4 <-
    survSplit(Surv(surv_mm,death_cancer)~., data=melanoma.l2, cut=cuts.splines,
              start="tstart", end="tstop") |>
    mutate(cut=cut(tstop,cuts.splines),
              mid=mid.splines[unclass(cut)]) |>
    group_by(mid,year8594,sex,agegrp) |>
    summarise(pt=sum(tstop-tstart), death_cancer=sum(death_cancer), .groups="keep")

poisson9g <- glm( death_cancer ~ ns(mid,df=3) + year8594 + sex + agegrp,
                 offset=log(pt), # for effects::Effect() - rather than in the formula
                 family = poisson,
                 data = melanoma.spl4 )
summary(poisson9g)
eform(poisson9g)

times <- seq(0,max(cuts.splines),length=1000)
delta <- times[2]-times[1]
newdata <- data.frame(mid=times, year8594="Diagnosed 85-94",
                      sex="Male", agegrp="45-59",
                      pt=1)
## plot predicted rates and 95% CI
library(tinyplot)
cbind(newdata,
      predict(poisson9g, newdata=newdata, se.fit=TRUE) |> as.data.frame()) |>
    transform(rate = exp(fit),
              lower = exp(fit-1.96*se.fit),
              upper = exp(fit+1.96*se.fit)) |>
	with(plt(rate~mid, type="ribbon",
             ymin=lower, ymax=upper,
             xlab="Time since diagnosis (months)",
             ylab="Rate", main="Males aged 45-59 years diagnosed 1985-94"))

## predict survival and 95% CI
library(rstpm2)
logcumhaz <-
    rstpm2::predictnl(poisson9g,
                      fun=function(fit,newdata)
                          log(cumsum(delta*predict(fit, newdata, type="response"))),
                      newdata=newdata) |>
    transform(surv = exp(-exp(Estimate)),
              lower.ci=exp(-exp(cbind(Estimate-1.96*SE))),
              upper.ci=exp(-exp(cbind(Estimate+1.96*SE)))) |>
    cbind(newdata)
with(logcumhaz, plt(surv~mid, ymin=lower.ci, ymax=upper.ci, type="ribbon",
                    xlab="Time since diagnosis (months)",
                    ylab="Survival", main="Males aged 45-59 years diagnosed 1985-94"))


## @knitr 9.g
coxfit9e <- coxph(Surv(surv_mm/12, death_cancer) ~ year8594 + sex + agegrp,
                  data = melanoma.l2)
plot(survfit(coxfit9e, newdata=newdata[1,]),
     xlab="Time from diagnosis (years)", ylab="Survival")
