## -----------------------------------------------------------------------------
library(rdecision)

## -----------------------------------------------------------------------------
# create Markov states
sA <- MarkovState$new("A")
sB <- MarkovState$new("B")
sC <- MarkovState$new("C")
sD <- MarkovState$new("D", utility = 0.0)
# create transitions
tAA <- Transition$new(sA, sA)
tAB <- Transition$new(sA, sB)
tAC <- Transition$new(sA, sC)
tAD <- Transition$new(sA, sD)
tBB <- Transition$new(sB, sB)
tBC <- Transition$new(sB, sC)
tBD <- Transition$new(sB, sD)
tCC <- Transition$new(sC, sC)
tCD <- Transition$new(sC, sD)
tDD <- Transition$new(sD, sD)
# set discount rates
cDR <- 6.0 # annual discount rate, costs (%)
oDR <- 0.0 # annual discount rate, benefits (%)
# construct the model
m <- SemiMarkovModel$new(
  V = list(sA, sB, sC, sD),
  E = list(tAA, tAB, tAC, tAD, tBB, tBC, tBD, tCC, tCD, tDD),
  discount.cost = cDR / 100.0,
  discount.utility = oDR / 100.0
)

## -----------------------------------------------------------------------------
# drug costs
cAZT <- 2278.0 # zidovudine drug cost
cLam <- 2087.0 # lamivudine drug cost

# direct medical and community costs
dmca <- 1701.0 # direct medical costs associated with state A
dmcb <- 1774.0 # direct medical costs associated with state B
dmcc <- 6948.0 # direct medical costs associated with state C
ccca <- 1055.0 # Community care costs associated with state A
cccb <- 1278.0 # Community care costs associated with state B
cccc <- 2059.0 # Community care costs associated with state C

# occupancy costs with monotherapy
cAm <- dmca + ccca + cAZT
cBm <- dmcb + cccb + cAZT
cCm <- dmcc + cccc + cAZT

# occupancy costs with combination therapy
cAc <- dmca + ccca + cAZT + cLam
cBc <- dmcb + cccb + cAZT + cLam
cCc <- dmcc + cccc + cAZT + cLam

## -----------------------------------------------------------------------------
RR <- 0.509

## -----------------------------------------------------------------------------
# transition counts
nAA <- 1251L
nAB <- 350L
nAC <- 116L
nAD <- 17L
nBB <- 731L
nBC <- 512L
nBD <- 15L
nCC <- 1312L
nCD <- 437L
# create transition matrix
nA <- nAA + nAB + nAC + nAD
nB <- nBB + nBC + nBD
nC <- nCC + nCD
Ptm <- matrix(
  c(nAA / nA, nAB / nA, nAC / nA, nAD / nA,
    0.0, nBB / nB, nBC / nB, nBD / nB,
    0.0,      0.0, nCC / nC, nCD / nC,
    0.0,      0.0,      0.0,      1.0),
  nrow = 4L, byrow = TRUE,
  dimnames = list(
    source = c("A", "B", "C", "D"), target = c("A", "B", "C", "D")
  )
)

## -----------------------------------------------------------------------------
local({
  # create an igraph object
  gml <- m$as_gml()
  gmlfile <- tempfile(fileext = ".gml")
  writeLines(gml, con = gmlfile)
  ig <- igraph::read_graph(gmlfile, format = "gml")
  # define vertex positions
  yv <- c(A = 1.0, B = 1.0 / 3.0, C = -1.0 / 3.0, D = -1.0)
  # set vertex positions
  layout <- matrix(
    data = c(
      0L, 0L, 0L, 0L,
      vapply(X = igraph::V(ig), FUN.VALUE = 1.0, FUN = function(v) {
        lbl <- igraph::vertex_attr(ig, "label", v)
        return(yv[[lbl]])
      })
    ),
    byrow = FALSE,
    ncol = 2L
  )
  # define edge curvatures
  cm <- matrix(
    data = 0.0, nrow = 4L, ncol = 4L,
    dimnames = list(LETTERS[seq(4L)], LETTERS[seq(4L)])
  )
  cm[["A", "D"]] <- 1.5
  cm[["A", "C"]] <- 1.0
  cm[["B", "D"]] <- -1.0
  # set edge curvatures
  curves <- vapply(X = igraph::E(ig), FUN.VALUE = 1.0, FUN = function(e) {
    # find source and target labels
    trg <- igraph::head_of(ig, e)
    trgl <- igraph::vertex_attr(ig, name = "label", index = trg)
    src <- igraph::tail_of(ig, e)
    srcl <- igraph::vertex_attr(ig, name = "label", index = src)
    cr <- cm[[srcl, trgl]]
    return(cr)
  })
  # plot the igraph
  withr::with_par(
    new = list(
      oma = c(1L, 1L, 1L, 1L),
      mar = c(1L, 1L, 1L, 1L),
      xpd = NA
    ),
    code = {
      plot(
        ig,
        rescale = FALSE, asp = 0L,
        vertex.color = "white", vertex.label.color = "black",
        edge.color = "black", edge.curved = curves,
        edge.arrow.size = 0.75,
        frame = FALSE,
        layout = layout,
        loop.size = 0.8
      )
    }
  )
})

## -----------------------------------------------------------------------------
with(data = as.data.frame(Ptm), expr = {
  data.frame(
    A = round(A, digits = 3L),
    B = round(B, digits = 3L),
    C = round(C, digits = 3L),
    D = round(D, digits = 3L),
    row.names = row.names(Ptm),
    stringsAsFactors = FALSE
  )
})

## -----------------------------------------------------------------------------
# function to run model for 20 years of monotherapy
run_mono <- function(Ptm, cAm, cBm, cCm, hcc = FALSE) {
  # create starting populations
  N <- 1000L
  populations <- c(A = N, B = 0L, C = 0L, D = 0L)
  m$reset(populations)
  # set costs
  sA$set_cost(cAm)
  sB$set_cost(cBm)
  sC$set_cost(cCm)
  # set transition probabilities
  m$set_probabilities(Ptm)
  # run 20 cycles
  tr <- m$cycles(
    ncycles = 20L, hcc.pop = hcc, hcc.cost = FALSE, hcc.QALY = hcc
  )
  return(tr)
}

## -----------------------------------------------------------------------------
MT.mono <- run_mono(Ptm, cAm, cBm, cCm)
el.mono <- sum(MT.mono$QALY)
cost.mono <- sum(MT.mono$Cost)

## -----------------------------------------------------------------------------
with(data = MT.mono, expr = {
  data.frame(
    Years = Years,
    A = round(A, digits = 0L),
    B = round(B, digits = 0L),
    C = round(C, digits = 0L),
    D = round(D, digits = 0L),
    Cost = round(Cost, digits = 0L),
    QALY = round(QALY, digits = 3L),
    stringsAsFactors = FALSE
  )
})

## -----------------------------------------------------------------------------
# annual probabilities modified by treatment effect
pAB <- RR * nAB / nA
pAC <- RR * nAC / nC
pAD <- RR * nAD / nA
pBC <- RR * nBC / nB
pBD <- RR * nBD / nB
pCD <- RR * nCD / nC
# annual transition probability matrix
Ptc <- matrix(
  c(1.0 - pAB - pAC - pAD,               pAB,         pAC, pAD,
    0.0, (1.0 - pBC - pBD),         pBC, pBD,
    0.0,               0.0, (1.0 - pCD), pCD,
    0.0,               0.0,         0.0, 1.0),
  nrow = 4L, byrow = TRUE,
  dimnames = list(
    source = c("A", "B", "C", "D"), target = c("A", "B", "C", "D")
  )
)

## -----------------------------------------------------------------------------
with(data = as.data.frame(Ptc), expr = {
  data.frame(
    A = round(A, digits = 3L),
    B = round(B, digits = 3L),
    C = round(C, digits = 3L),
    D = round(D, digits = 3L),
    row.names = row.names(Ptc),
    stringsAsFactors = FALSE
  )
})

## -----------------------------------------------------------------------------
# function to run model for 2 years of combination therapy and 18 of monotherapy
run_comb <- function(Ptm, cAm, cBm, cCm, Ptc, cAc, cBc, cCc, hcc = FALSE) {
  # set populations
  N <- 1000L
  populations <- c(A = N, B = 0L, C = 0L, D = 0L)
  m$reset(populations)
  # set the transition probabilities accounting for treatment effect
  m$set_probabilities(Ptc)
  # set the costs including those for the additional drug
  sA$set_cost(cAc)
  sB$set_cost(cBc)
  sC$set_cost(cCc)
  # run first 2 yearly cycles with additional drug costs and tx effect
  tr <- m$cycles(2L, hcc.pop = hcc, hcc.cost = FALSE, hcc.QALY = hcc)
  # save the state populations after 2 years
  populations <- m$get_populations()
  # revert probabilities to those without treatment effect
  m$set_probabilities(Ptm)
  # revert costs to those without the extra drug
  sA$set_cost(cAm)
  sB$set_cost(cBm)
  sC$set_cost(cCm)
  # restart the model with populations from first 2 years with extra drug
  m$reset(
    populations,
    icycle = 2L,
    elapsed = as.difftime(365.25 * 2.0, units = "days")
  )
  # run for next 18 years, combining the traces
  tr <- rbind(
    tr,
    m$cycles(ncycles = 18L, hcc.pop = hcc, hcc.cost = FALSE, hcc.QALY = hcc)
  )
  # return the trace
  return(tr)
}

## -----------------------------------------------------------------------------
MT.comb <- run_comb(Ptm, cAm, cBm, cCm, Ptc, cAc, cBc, cCc)
el.comb <- sum(MT.comb$QALY)
cost.comb <- sum(MT.comb$Cost)
icer <- (cost.comb - cost.mono) / (el.comb - el.mono)

## -----------------------------------------------------------------------------
with(data = MT.comb, expr = {
  data.frame(
    Years = Years,
    A = round(A, digits = 0L),
    B = round(B, digits = 0L),
    C = round(C, digits = 0L),
    D = round(D, digits = 0L),
    Cost = round(Cost, digits = 0L),
    QALY = round(QALY, digits = 3L),
    stringsAsFactors = FALSE
  )
})

## -----------------------------------------------------------------------------
MT.mono.hcc <- run_mono(Ptm, cAm, cBm, cCm, hcc = TRUE)
el.mono.hcc <- sum(MT.mono.hcc$QALY)
cost.mono.hcc <- sum(MT.mono.hcc$Cost)
MT.comb.hcc <- run_comb(Ptm, cAm, cBm, cCm, Ptc, cAc, cBc, cCc, hcc = TRUE)
el.comb.hcc <- sum(MT.comb.hcc$QALY)
cost.comb.hcc <- sum(MT.comb.hcc$Cost)
icer.hcc <- (cost.comb.hcc - cost.mono.hcc) / (el.comb.hcc - el.mono.hcc)

## -----------------------------------------------------------------------------
# direct medical and community costs (modelled as gamma distributions)
dmca <- GammaModVar$new("dmca", "GBP", shape = 1.0, scale = 1701.0)
dmcb <- GammaModVar$new("dmcb", "GBP", shape = 1.0, scale = 1774.0)
dmcc <- GammaModVar$new("dmcc", "GBP", shape = 1.0, scale = 6948.0)
ccca <- GammaModVar$new("ccca", "GBP", shape = 1.0, scale = 1055.0)
cccb <- GammaModVar$new("cccb", "GBP", shape = 1.0, scale = 1278.0)
cccc <- GammaModVar$new("cccc", "GBP", shape = 1.0, scale = 2059.0)

# occupancy costs with monotherapy
cAm <- ExprModVar$new("cA", "GBP", rlang::quo(dmca + ccca + cAZT))
cBm <- ExprModVar$new("cB", "GBP", rlang::quo(dmcb + cccb + cAZT))
cCm <- ExprModVar$new("cC", "GBP", rlang::quo(dmcc + cccc + cAZT))

# occupancy costs with combination therapy
cAc <- ExprModVar$new("cAc", "GBP", rlang::quo(dmca + ccca + cAZT + cLam))
cBc <- ExprModVar$new("cBc", "GBP", rlang::quo(dmcb + cccb + cAZT + cLam))
cCc <- ExprModVar$new("cCc", "GBP", rlang::quo(dmcc + cccc + cAZT + cLam))

## -----------------------------------------------------------------------------
RR <- LogNormModVar$new(
  "Tx effect", "RR", p1 = 0.509, p2 = (0.710 - 0.365) / (2.0 * 1.96), "LN7"
)

## -----------------------------------------------------------------------------
# function to generate a probabilistic transition matrix
pt_prob <- function() {
  # create Dirichlet distributions for conditional probabilities
  DA <- DirichletDistribution$new(c(1251L, 350L, 116L, 17L)) # from A # nolint
  DB <- DirichletDistribution$new(c(731L, 512L, 15L))  # from B # nolint
  DC <- DirichletDistribution$new(c(1312L, 437L)) # from C # nolint
  # sample from the Dirichlet distributions
  DA$sample()
  DB$sample()
  DC$sample()
  # create the transition matrix
  Pt <- matrix(
    c(DA$r(), c(0.0, DB$r()), c(0.0, 0.0, DC$r()), c(0.0, 0.0, 0.0, 1.0)),
    byrow = TRUE,
    nrow = 4L,
    dimnames = list(
      source = c("A", "B", "C", "D"), target = c("A", "B", "C", "D")
    )
  )
  return(Pt)
}

## -----------------------------------------------------------------------------
# create matrix to hold the incremental costs and life years for each run
psa <- matrix(
  data = NA_real_, nrow = 1000L, ncol = 5L,
  dimnames = list(
    NULL, c("el.mono", "cost.mono", "el.comb", "cost.comb", "icer")
  )
)

# run the model repeatedly
for (irun in seq_len(nrow(psa))) {

  # sample variables from their uncertainty distributions
  cAm$set("random")
  cBm$set("random")
  cCm$set("random")
  cAc$set("random")
  cBc$set("random")
  cCc$set("random")
  RR$set("random")

  # sample the probability transition matrix from observed counts
  Ptm <- pt_prob()

  # run monotherapy model
  MT.mono <- run_mono(Ptm, cAm, cBm, cCm, hcc = TRUE)
  el.mono <- sum(MT.mono$QALY)
  cost.mono <- sum(MT.mono$Cost)
  psa[[irun, "el.mono"]] <- el.mono
  psa[[irun, "cost.mono"]] <- cost.mono

  # create Pt for combination therapy (Briggs applied the RR to the transition
  # probabilities - not recommended, but done here for reproducibility).
  Ptc <- Ptm
  for (i in 1L:4L) {
    for (j in 1L:4L) {
      Ptc[[i, j]] <- ifelse(i == j, NA, RR$get() * Ptc[[i, j]])
    }
    Ptc[i, which(is.na(Ptc[i, ]))] <- 1.0 - sum(Ptc[i, ], na.rm = TRUE)
  }

  # run combination therapy model
  MT.comb <- run_comb(Ptm, cAm, cBm, cCm, Ptc, cAc, cBc, cCc, hcc = TRUE)
  el.comb <- sum(MT.comb$QALY)
  cost.comb <- sum(MT.comb$Cost)
  psa[[irun, "el.comb"]] <- el.comb
  psa[[irun, "cost.comb"]] <- cost.comb

  # calculate the icer
  psa[[irun, "icer"]] <- (cost.comb - cost.mono) / (el.comb - el.mono)
}

