library("survival")
library("nlme")
library("GLMMadaptive")
library("splines")
data("pbc2", package = "JM")
data("pbc2.id", package = "JM")
source(file.path(getwd(), "R/jm.R"))
source(file.path(getwd(), "R/help_functions.R"))
source(file.path(getwd(), "Development/jm/R_to_Cpp.R"))
source(file.path(getwd(), "Development/jm/PBC_data.R"))
source(file.path(getwd(), "Development/MCMC/Surv_Model/sample_Surv_Funs.R"))
simulateJoint <- function (alpha = 0.5, Dalpha = 0, n = 1000,
mean.Cens = 7) {
# if alpha = 0, mean.Cens = 35
library("splines")
library("MASS")
K <- 15 # number of planned repeated measurements per subject, per outcome
t.max <- 10 # maximum follow-up time
################################################
# parameters for the linear mixed effects model
betas <- c("Intercept" = 6.94, "Time1" = 1.30, "Time2" = 1.84, "Time3" = 1.82)
sigma.y <- 0.6 # measurement error standard deviation
# parameters for the survival model
gammas <- c("(Intercept)" = -9.2, "Group" = 0.5, "Age" = 0.05)
phi <- 2
D <- matrix(0, 4, 4)
D[lower.tri(D, TRUE)] <- c(0.71, 0.33, 0.07, 1.26, 2.68, 3.81, 4.35, 7.62, 5.4, 8)
D <- D + t(D)
diag(D) <- diag(D) * 0.5
################################################
Bkn <- c(0, 9)
kn <- c(2.1, 3.5)
# design matrices for the longitudinal measurement model
times <- c(replicate(n, c(0, 0.5, 1, sort(runif(K - 3, 1, t.max)))))
group <- rep(0:1, each = n/2)
age <- runif(n, 30, 70)
DF <- data.frame(time = times)
X <- model.matrix(~ ns(time, knots = kn, Boundary.knots = Bkn),
data = DF)
Z <- model.matrix(~ ns(time, knots = kn, Boundary.knots = Bkn), data = DF)
# design matrix for the survival model
W <- cbind("(Intercept)" = 1, "Group" = group, "Age" = age)
################################################
# simulate random effects
b <- mvrnorm(n, rep(0, nrow(D)), D)
# simulate longitudinal responses
id <- rep(1:n, each = K)
eta.y <- as.vector(X %*% betas + rowSums(Z * b[id, ]))
y <- rnorm(n * K, eta.y, sigma.y)
# simulate event times
eta.t <- as.vector(W %*% gammas)
invS <- function (t, u, i) {
h <- function (s) {
NS <- ns(s, knots = kn, Boundary.knots = Bkn)
DNS <- JMbayes:::dns(s, knots = kn, Boundary.knots = Bkn)
XX <- cbind(1, NS)
ZZ <- cbind(1, NS)
XXd <- DNS
ZZd <- DNS
f1 <- as.vector(XX %*% betas + rowSums(ZZ * b[rep(i, nrow(ZZ)), ]))
f2 <- as.vector(XXd %*% betas[2:4] + rowSums(ZZd * b[rep(i, nrow(ZZd)), 2:4]))
exp(log(phi) + (phi - 1) * log(s) + eta.t[i] + f1 * alpha + f2 * Dalpha)
}
integrate(h, lower = 0, upper = t)$value + log(u)
}
u <- runif(n)
trueTimes <- numeric(n)
for (i in 1:n) {
Up <- 50
tries <- 5
Root <- try(uniroot(invS, interval = c(1e-05, Up), u = u[i], i = i)$root, TRUE)
while(inherits(Root, "try-error") && tries > 0) {
tries <- tries - 1
Up <- Up + 50
Root <- try(uniroot(invS, interval = c(1e-05, Up), u = u[i], i = i)$root, TRUE)
}
trueTimes[i] <- if (!inherits(Root, "try-error")) Root else NA
}
na.ind <- !is.na(trueTimes)
trueTimes <- trueTimes[na.ind]
W <- W[na.ind, , drop = FALSE]
long.na.ind <- rep(na.ind, each = K)
y <- y[long.na.ind]
X <- X[long.na.ind, , drop = FALSE]
Z <- Z[long.na.ind, , drop = FALSE]
DF <- DF[long.na.ind, , drop = FALSE]
n <- length(trueTimes)
Ctimes <- runif(n, 0, 2 * mean.Cens)
Time <- pmin(trueTimes, Ctimes)
event <- as.numeric(trueTimes <= Ctimes) # event indicator
################################################
# keep the nonmissing cases, i.e., drop the longitudinal measurements
# that were taken after the observed event time for each subject.
ind <- times[long.na.ind] <= rep(Time, each = K)
y <- y[ind]
X <- X[ind, , drop = FALSE]
Z <- Z[ind, , drop = FALSE]
id <- id[long.na.ind][ind]
id <- match(id, unique(id))
dat <- DF[ind, , drop = FALSE]
dat$id <- id
dat$y <- y
dat$Time <- Time[id]
dat$event <- event[id]
dat <- dat[c("id", "y", "time", "Time", "event")]
dat.id <- data.frame(id = unique(dat$id), Time = Time,
event = event, group = W[, 2], age = W[, 3])
dat$group <- dat.id$group[id]
#summary(tapply(id, id, length))
#n
#mean(event)
#summary(dat.id$Time)
#summary(dat$time)
# true values for parameters and random effects
trueValues <- list(betas = betas, tau = 1/sigma.y^2, gammas = gammas,
alphas = alpha, Dalphas = Dalpha, sigma.t = phi,
inv.D = solve(D), b = b)
# return list
list(DF = dat, DF.id = dat.id, trueValues = trueValues)
}
Data <- simulateJoint(alpha = 0.5)
lmeFit <- lme(y ~ ns(time, k = c(2.1, 3.5), B = c(0, 9)), data = Data$DF,
random = list(id = pdDiag(form = ~ ns(time, k = c(2.1, 3.5), B = c(0, 9)))),
control = lmeControl(opt = "optim", niterEM = 45))
coxFit <- coxph(Surv(Time, event) ~ group + age, data = Data$DF.id)
JM2 <- jm(coxFit, list(lmeFit), time_var = "time")
test <- JM2
###########################################################
# parameter values
betas <- test$initial_values$betas
b <- test$initial_values$b
gammas <- test$initial_values$gammas
bs_gammas <- test$initial_values$bs_gammas
alphas <- test$initial_values$alphas
# outcome vectors and design matrices
n <- test$model_data$n
idT <- test$model_data$idT
Time_right <- test$model_data$Time_right
Time_left <- test$model_data$Time_left
Time_start <- test$model_data$Time_start
delta <- test$model_data$delta
which_event <- test$model_data$which_event
which_right <- test$model_data$which_right
which_left <- test$model_data$which_left
which_interval <- test$model_data$which_interval
W0_H <- test$model_data$W0_H
W_H <- test$model_data$W_H
X_H <- test$model_data$X_H
Z_H <- test$model_data$Z_H
U_H <- test$model_data$U_H
W0_h <- test$model_data$W0_h
W_h <- test$model_data$W_h
X_h <- test$model_data$X_h
Z_h <- test$model_data$Z_h
U_h <- test$model_data$U_h
W0_H2 <- test$model_data$W0_H2
W_H2 <- test$model_data$W_H2
X_H2 <- test$model_data$X_H2
Z_H2 <- test$model_data$Z_H2
U_H2 <- test$model_data$U_H2
log_Pwk <- test$model_data$log_Pwk
log_Pwk2 <- test$model_data$log_Pwk2
control <- test$control
functional_forms_per_outcome <- test$model_info$fun_forms$functional_forms_per_outcome
# id_H is used to repeat the random effects of each subject GK_k times
id_H <- lapply(X_H, function (i, n) rep(seq_len(n), each = control$GK_k), n = n)
# this is the linear predictor for the longitudinal outcomes evaluated at the
# Gauss-Kronrod quadrature points
eta_H <- linpred_surv(X_H, betas, Z_H, b, id_H)
# Wlong is the design matrix of all longitudinal outcomes according to the specified
# functional forms per outcome already multiplied with the interaction terms matrix U
Wlong_H <- create_Wlong(eta_H, functional_forms_per_outcome, U_H)
if (length(which_event)) {
id_h <- lapply(X_h, function (x) seq_len(nrow(x[[1]])))
eta_h <- linpred_surv(X_h, betas, Z_h, b, id_h)
Wlong_h <- create_Wlong(eta_h, functional_forms_per_outcome, U_h)
}
if (length(which_interval)) {
id_H2 <- lapply(X_H2, function (i, n) rep(seq_len(n), each = control$GK_k), n = n)
eta_H2 <- linpred_surv(X_H2, betas, Z_H, b, id_H2)
Wlong_H2 <- create_Wlong(eta_H2, functional_forms_per_outcome, U_H2)
} else {
Wlong_H2 <- rep(list(matrix(0.0, length(Time_right), 1)), length(W_H))
}
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