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+utils::globalVariables(c("predicted", "std"))
+
+#' Fit nonlinear mixed models with SAEM
+#'
+#' This function uses [saemix::saemix()] as a backend for fitting nonlinear mixed
+#' effects models created from [mmkin] row objects using the Stochastic Approximation
+#' Expectation Maximisation algorithm (SAEM).
+#'
+#' An mmkin row object is essentially a list of mkinfit objects that have been
+#' obtained by fitting the same model to a list of datasets using [mkinfit].
+#'
+#' Starting values for the fixed effects (population mean parameters, argument
+#' psi0 of [saemix::saemixModel()] are the mean values of the parameters found
+#' using [mmkin].
+#'
+#' @param object An [mmkin] row object containing several fits of the same
+#' [mkinmod] model to different datasets
+#' @param verbose Should we print information about created objects of
+#' type [saemix::SaemixModel] and [saemix::SaemixData]?
+#' @param transformations Per default, all parameter transformations are done
+#' in mkin. If this argument is set to 'saemix', parameter transformations
+#' are done in 'saemix' for the supported cases. Currently this is only
+#' supported in cases where the initial concentration of the parent is not fixed,
+#' SFO or DFOP is used for the parent and there is either no metabolite or one.
+#' @param degparms_start Parameter values given as a named numeric vector will
+#' be used to override the starting values obtained from the 'mmkin' object.
+#' @param test_log_parms If TRUE, an attempt is made to use more robust starting
+#' values for population parameters fitted as log parameters in mkin (like
+#' rate constants) by only considering rate constants that pass the t-test
+#' when calculating mean degradation parameters using [mean_degparms].
+#' @param conf.level Possibility to adjust the required confidence level
+#' for parameter that are tested if requested by 'test_log_parms'.
+#' @param solution_type Possibility to specify the solution type in case the
+#' automatic choice is not desired
+#' @param fail_with_errors Should a failure to compute standard errors
+#' from the inverse of the Fisher Information Matrix be a failure?
+#' @param quiet Should we suppress the messages saemix prints at the beginning
+#' and the end of the optimisation process?
+#' @param nbiter.saemix Convenience option to increase the number of
+#' iterations
+#' @param control Passed to [saemix::saemix].
+#' @param \dots Further parameters passed to [saemix::saemixModel].
+#' @return An S3 object of class 'saem.mmkin', containing the fitted
+#' [saemix::SaemixObject] as a list component named 'so'. The
+#' object also inherits from 'mixed.mmkin'.
+#' @seealso [summary.saem.mmkin] [plot.mixed.mmkin]
+#' @examples
+#' \dontrun{
+#' ds <- lapply(experimental_data_for_UBA_2019[6:10],
+#' function(x) subset(x$data[c("name", "time", "value")]))
+#' names(ds) <- paste("Dataset", 6:10)
+#' f_mmkin_parent_p0_fixed <- mmkin("FOMC", ds,
+#' state.ini = c(parent = 100), fixed_initials = "parent", quiet = TRUE)
+#' f_saem_p0_fixed <- saem(f_mmkin_parent_p0_fixed)
+#'
+#' f_mmkin_parent <- mmkin(c("SFO", "FOMC", "DFOP"), ds, quiet = TRUE)
+#' f_saem_sfo <- saem(f_mmkin_parent["SFO", ])
+#' f_saem_fomc <- saem(f_mmkin_parent["FOMC", ])
+#' f_saem_dfop <- saem(f_mmkin_parent["DFOP", ])
+#'
+#' # The returned saem.mmkin object contains an SaemixObject, therefore we can use
+#' # functions from saemix
+#' library(saemix)
+#' compare.saemix(f_saem_sfo$so, f_saem_fomc$so, f_saem_dfop$so)
+#' plot(f_saem_fomc$so, plot.type = "convergence")
+#' plot(f_saem_fomc$so, plot.type = "individual.fit")
+#' plot(f_saem_fomc$so, plot.type = "npde")
+#' plot(f_saem_fomc$so, plot.type = "vpc")
+#'
+#' f_mmkin_parent_tc <- update(f_mmkin_parent, error_model = "tc")
+#' f_saem_fomc_tc <- saem(f_mmkin_parent_tc["FOMC", ])
+#' compare.saemix(f_saem_fomc$so, f_saem_fomc_tc$so)
+#'
+#' sfo_sfo <- mkinmod(parent = mkinsub("SFO", "A1"),
+#' A1 = mkinsub("SFO"))
+#' fomc_sfo <- mkinmod(parent = mkinsub("FOMC", "A1"),
+#' A1 = mkinsub("SFO"))
+#' dfop_sfo <- mkinmod(parent = mkinsub("DFOP", "A1"),
+#' A1 = mkinsub("SFO"))
+#' # The following fit uses analytical solutions for SFO-SFO and DFOP-SFO,
+#' # and compiled ODEs for FOMC that are much slower
+#' f_mmkin <- mmkin(list(
+#' "SFO-SFO" = sfo_sfo, "FOMC-SFO" = fomc_sfo, "DFOP-SFO" = dfop_sfo),
+#' ds, quiet = TRUE)
+#' # saem fits of SFO-SFO and DFOP-SFO to these data take about five seconds
+#' # each on this system, as we use analytical solutions written for saemix.
+#' # When using the analytical solutions written for mkin this took around
+#' # four minutes
+#' f_saem_sfo_sfo <- saem(f_mmkin["SFO-SFO", ])
+#' f_saem_dfop_sfo <- saem(f_mmkin["DFOP-SFO", ])
+#' # We can use print, plot and summary methods to check the results
+#' print(f_saem_dfop_sfo)
+#' plot(f_saem_dfop_sfo)
+#' summary(f_saem_dfop_sfo, data = TRUE)
+#'
+#' # The following takes about 6 minutes
+#' #f_saem_dfop_sfo_deSolve <- saem(f_mmkin["DFOP-SFO", ], solution_type = "deSolve",
+#' # control = list(nbiter.saemix = c(200, 80), nbdisplay = 10))
+#'
+#' #saemix::compare.saemix(list(
+#' # f_saem_dfop_sfo$so,
+#' # f_saem_dfop_sfo_deSolve$so))
+#'
+#' # If the model supports it, we can also use eigenvalue based solutions, which
+#' # take a similar amount of time
+#' #f_saem_sfo_sfo_eigen <- saem(f_mmkin["SFO-SFO", ], solution_type = "eigen",
+#' # control = list(nbiter.saemix = c(200, 80), nbdisplay = 10))
+#' }
+#' @export
+saem <- function(object, ...) UseMethod("saem")
+
+#' @rdname saem
+#' @export
+saem.mmkin <- function(object,
+ transformations = c("mkin", "saemix"),
+ degparms_start = numeric(),
+ test_log_parms = FALSE,
+ conf.level = 0.6,
+ solution_type = "auto",
+ nbiter.saemix = c(300, 100),
+ control = list(displayProgress = FALSE, print = FALSE,
+ nbiter.saemix = nbiter.saemix,
+ save = FALSE, save.graphs = FALSE),
+ fail_with_errors = TRUE,
+ verbose = FALSE, quiet = FALSE, ...)
+{
+ transformations <- match.arg(transformations)
+ m_saemix <- saemix_model(object, verbose = verbose,
+ degparms_start = degparms_start,
+ test_log_parms = test_log_parms, conf.level = conf.level,
+ solution_type = solution_type,
+ transformations = transformations, ...)
+ d_saemix <- saemix_data(object, verbose = verbose)
+
+ fit_time <- system.time({
+ utils::capture.output(f_saemix <- saemix::saemix(m_saemix, d_saemix, control), split = !quiet)
+ FIM_failed <- NULL
+ if (any(is.na(f_saemix@results@se.fixed))) FIM_failed <- c(FIM_failed, "fixed effects")
+ if (any(is.na(c(f_saemix@results@se.omega, f_saemix@results@se.respar)))) {
+ FIM_failed <- c(FIM_failed, "random effects and residual error parameters")
+ }
+ if (!is.null(FIM_failed) & fail_with_errors) {
+ stop("Could not invert FIM for ", paste(FIM_failed, collapse = " and "))
+ }
+ })
+
+ transparms_optim <- f_saemix@results@fixed.effects
+ names(transparms_optim) <- f_saemix@results@name.fixed
+
+ if (transformations == "mkin") {
+ bparms_optim <- backtransform_odeparms(transparms_optim,
+ object[[1]]$mkinmod,
+ object[[1]]$transform_rates,
+ object[[1]]$transform_fractions)
+ } else {
+ bparms_optim <- transparms_optim
+ }
+
+ return_data <- nlme_data(object)
+
+ return_data$predicted <- f_saemix@model@model(
+ psi = saemix::psi(f_saemix),
+ id = as.numeric(return_data$ds),
+ xidep = return_data[c("time", "name")])
+
+ return_data <- transform(return_data,
+ residual = value - predicted,
+ std = sigma_twocomp(predicted,
+ f_saemix@results@respar[1], f_saemix@results@respar[2]))
+ return_data <- transform(return_data,
+ standardized = residual / std)
+
+ result <- list(
+ mkinmod = object[[1]]$mkinmod,
+ mmkin = object,
+ solution_type = object[[1]]$solution_type,
+ transformations = transformations,
+ transform_rates = object[[1]]$transform_rates,
+ transform_fractions = object[[1]]$transform_fractions,
+ so = f_saemix,
+ time = fit_time,
+ mean_dp_start = attr(m_saemix, "mean_dp_start"),
+ bparms.optim = bparms_optim,
+ bparms.fixed = object[[1]]$bparms.fixed,
+ data = return_data,
+ err_mod = object[[1]]$err_mod,
+ date.fit = date(),
+ saemixversion = as.character(utils::packageVersion("saemix")),
+ mkinversion = as.character(utils::packageVersion("mkin")),
+ Rversion = paste(R.version$major, R.version$minor, sep=".")
+ )
+
+ class(result) <- c("saem.mmkin", "mixed.mmkin")
+ return(result)
+}
+
+#' @export
+#' @rdname saem
+#' @param x An saem.mmkin object to print
+#' @param digits Number of digits to use for printing
+print.saem.mmkin <- function(x, digits = max(3, getOption("digits") - 3), ...) {
+ cat( "Kinetic nonlinear mixed-effects model fit by SAEM" )
+ cat("\nStructural model:\n")
+ diffs <- x$mmkin[[1]]$mkinmod$diffs
+ nice_diffs <- gsub("^(d.*) =", "\\1/dt =", diffs)
+ writeLines(strwrap(nice_diffs, exdent = 11))
+ cat("\nData:\n")
+ cat(nrow(x$data), "observations of",
+ length(unique(x$data$name)), "variable(s) grouped in",
+ length(unique(x$data$ds)), "datasets\n")
+
+ cat("\nLikelihood computed by importance sampling\n")
+ print(data.frame(
+ AIC = AIC(x$so, type = "is"),
+ BIC = BIC(x$so, type = "is"),
+ logLik = logLik(x$so, type = "is"),
+ row.names = " "), digits = digits)
+
+ cat("\nFitted parameters:\n")
+ conf.int <- x$so@results@conf.int[c("estimate", "lower", "upper")]
+ rownames(conf.int) <- x$so@results@conf.int[["name"]]
+ print(conf.int, digits = digits)
+
+ invisible(x)
+}
+
+#' @rdname saem
+#' @return An [saemix::SaemixModel] object.
+#' @export
+saemix_model <- function(object, solution_type = "auto", transformations = c("mkin", "saemix"),
+ degparms_start = numeric(), test_log_parms = FALSE, verbose = FALSE, ...)
+{
+ if (nrow(object) > 1) stop("Only row objects allowed")
+
+ mkin_model <- object[[1]]$mkinmod
+
+ degparms_optim <- mean_degparms(object, test_log_parms = test_log_parms)
+ if (transformations == "saemix") {
+ degparms_optim <- backtransform_odeparms(degparms_optim,
+ object[[1]]$mkinmod,
+ object[[1]]$transform_rates,
+ object[[1]]$transform_fractions)
+ }
+ degparms_fixed <- object[[1]]$bparms.fixed
+
+ # Transformations are done in the degradation function
+ transform.par = rep(0, length(degparms_optim))
+
+ odeini_optim_parm_names <- grep('_0$', names(degparms_optim), value = TRUE)
+ odeini_fixed_parm_names <- grep('_0$', names(degparms_fixed), value = TRUE)
+
+ odeparms_fixed_names <- setdiff(names(degparms_fixed), odeini_fixed_parm_names)
+ odeparms_fixed <- degparms_fixed[odeparms_fixed_names]
+
+ odeini_fixed <- degparms_fixed[odeini_fixed_parm_names]
+ names(odeini_fixed) <- gsub('_0$', '', odeini_fixed_parm_names)
+
+ model_function <- FALSE
+
+ # Model functions with analytical solutions
+ # Fixed parameters, use_of_ff = "min" and turning off sinks currently not supported here
+ # In general, we need to consider exactly how the parameters in mkinfit were specified,
+ # as the parameters are currently mapped by position in these solutions
+ sinks <- sapply(mkin_model$spec, function(x) x$sink)
+ if (length(odeparms_fixed) == 0 & mkin_model$use_of_ff == "max" & all(sinks)) {
+ # Parent only
+ if (length(mkin_model$spec) == 1) {
+ parent_type <- mkin_model$spec[[1]]$type
+ if (length(odeini_fixed) == 1) {
+ if (parent_type == "SFO") {
+ stop("saemix needs at least two parameters to work on.")
+ }
+ if (parent_type == "FOMC") {
+ model_function <- function(psi, id, xidep) {
+ odeini_fixed / (xidep[, "time"]/exp(psi[id, 2]) + 1)^exp(psi[id, 1])
+ }
+ }
+ if (parent_type == "DFOP") {
+ model_function <- function(psi, id, xidep) {
+ g <- plogis(psi[id, 3])
+ t <- xidep[, "time"]
+ odeini_fixed * (g * exp(- exp(psi[id, 1]) * t) +
+ (1 - g) * exp(- exp(psi[id, 2]) * t))
+ }
+ }
+ if (parent_type == "HS") {
+ model_function <- function(psi, id, xidep) {
+ tb <- exp(psi[id, 3])
+ t <- xidep[, "time"]
+ k1 = exp(psi[id, 1])
+ odeini_fixed * ifelse(t <= tb,
+ exp(- k1 * t),
+ exp(- k1 * tb) * exp(- exp(psi[id, 2]) * (t - tb)))
+ }
+ }
+ } else {
+ if (parent_type == "SFO") {
+ if (transformations == "mkin") {
+ model_function <- function(psi, id, xidep) {
+ psi[id, 1] * exp( - exp(psi[id, 2]) * xidep[, "time"])
+ }
+ } else {
+ model_function <- function(psi, id, xidep) {
+ psi[id, 1] * exp( - psi[id, 2] * xidep[, "time"])
+ }
+ transform.par = c(0, 1)
+ }
+ }
+ if (parent_type == "FOMC") {
+ model_function <- function(psi, id, xidep) {
+ psi[id, 1] / (xidep[, "time"]/exp(psi[id, 3]) + 1)^exp(psi[id, 2])
+ }
+ }
+ if (parent_type == "DFOP") {
+ if (transformations == "mkin") {
+ model_function <- function(psi, id, xidep) {
+ g <- plogis(psi[id, 4])
+ t <- xidep[, "time"]
+ psi[id, 1] * (g * exp(- exp(psi[id, 2]) * t) +
+ (1 - g) * exp(- exp(psi[id, 3]) * t))
+ }
+ } else {
+ model_function <- function(psi, id, xidep) {
+ g <- psi[id, 4]
+ t <- xidep[, "time"]
+ psi[id, 1] * (g * exp(- psi[id, 2] * t) +
+ (1 - g) * exp(- psi[id, 3] * t))
+ }
+ transform.par = c(0, 1, 1, 3)
+ }
+ }
+ if (parent_type == "HS") {
+ model_function <- function(psi, id, xidep) {
+ tb <- exp(psi[id, 4])
+ t <- xidep[, "time"]
+ k1 = exp(psi[id, 2])
+ psi[id, 1] * ifelse(t <= tb,
+ exp(- k1 * t),
+ exp(- k1 * tb) * exp(- exp(psi[id, 3]) * (t - tb)))
+ }
+ }
+ }
+ }
+
+ # Parent with one metabolite
+ # Parameter names used in the model functions are as in
+ # https://nbviewer.jupyter.org/urls/jrwb.de/nb/Symbolic%20ODE%20solutions%20for%20mkin.ipynb
+ types <- unname(sapply(mkin_model$spec, function(x) x$type))
+ if (length(mkin_model$spec) == 2 &! "SFORB" %in% types ) {
+ # Initial value for the metabolite (n20) must be fixed
+ if (names(odeini_fixed) == names(mkin_model$spec)[2]) {
+ n20 <- odeini_fixed
+ parent_name <- names(mkin_model$spec)[1]
+ if (identical(types, c("SFO", "SFO"))) {
+ if (transformations == "mkin") {
+ model_function <- function(psi, id, xidep) {
+ t <- xidep[, "time"]
+ n10 <- psi[id, 1]
+ k1 <- exp(psi[id, 2])
+ k2 <- exp(psi[id, 3])
+ f12 <- plogis(psi[id, 4])
+ ifelse(xidep[, "name"] == parent_name,
+ n10 * exp(- k1 * t),
+ (((k2 - k1) * n20 - f12 * k1 * n10) * exp(- k2 * t)) / (k2 - k1) +
+ (f12 * k1 * n10 * exp(- k1 * t)) / (k2 - k1)
+ )
+ }
+ } else {
+ model_function <- function(psi, id, xidep) {
+ t <- xidep[, "time"]
+ n10 <- psi[id, 1]
+ k1 <- psi[id, 2]
+ k2 <- psi[id, 3]
+ f12 <- psi[id, 4]
+ ifelse(xidep[, "name"] == parent_name,
+ n10 * exp(- k1 * t),
+ (((k2 - k1) * n20 - f12 * k1 * n10) * exp(- k2 * t)) / (k2 - k1) +
+ (f12 * k1 * n10 * exp(- k1 * t)) / (k2 - k1)
+ )
+ }
+ transform.par = c(0, 1, 1, 3)
+ }
+ }
+ if (identical(types, c("DFOP", "SFO"))) {
+ if (transformations == "mkin") {
+ model_function <- function(psi, id, xidep) {
+ t <- xidep[, "time"]
+ n10 <- psi[id, 1]
+ k2 <- exp(psi[id, 2])
+ f12 <- plogis(psi[id, 3])
+ l1 <- exp(psi[id, 4])
+ l2 <- exp(psi[id, 5])
+ g <- plogis(psi[id, 6])
+ ifelse(xidep[, "name"] == parent_name,
+ n10 * (g * exp(- l1 * t) + (1 - g) * exp(- l2 * t)),
+ ((f12 * g - f12) * l2 * n10 * exp(- l2 * t)) / (l2 - k2) -
+ (f12 * g * l1 * n10 * exp(- l1 * t)) / (l1 - k2) +
+ ((((l1 - k2) * l2 - k2 * l1 + k2^2) * n20 +
+ ((f12 * l1 + (f12 * g - f12) * k2) * l2 -
+ f12 * g * k2 * l1) * n10) * exp( - k2 * t)) /
+ ((l1 - k2) * l2 - k2 * l1 + k2^2)
+ )
+ }
+ } else {
+ model_function <- function(psi, id, xidep) {
+ t <- xidep[, "time"]
+ n10 <- psi[id, 1]
+ k2 <- psi[id, 2]
+ f12 <- psi[id, 3]
+ l1 <- psi[id, 4]
+ l2 <- psi[id, 5]
+ g <- psi[id, 6]
+ ifelse(xidep[, "name"] == parent_name,
+ n10 * (g * exp(- l1 * t) + (1 - g) * exp(- l2 * t)),
+ ((f12 * g - f12) * l2 * n10 * exp(- l2 * t)) / (l2 - k2) -
+ (f12 * g * l1 * n10 * exp(- l1 * t)) / (l1 - k2) +
+ ((((l1 - k2) * l2 - k2 * l1 + k2^2) * n20 +
+ ((f12 * l1 + (f12 * g - f12) * k2) * l2 -
+ f12 * g * k2 * l1) * n10) * exp( - k2 * t)) /
+ ((l1 - k2) * l2 - k2 * l1 + k2^2)
+ )
+ }
+ transform.par = c(0, 1, 3, 1, 1, 3)
+ }
+ }
+ }
+ }
+ }
+
+ if (is.function(model_function) & solution_type == "auto") {
+ solution_type = "analytical saemix"
+ } else {
+
+ if (solution_type == "auto")
+ solution_type <- object[[1]]$solution_type
+
+ model_function <- function(psi, id, xidep) {
+
+ uid <- unique(id)
+
+ res_list <- lapply(uid, function(i) {
+
+ transparms_optim <- as.numeric(psi[i, ]) # psi[i, ] is a dataframe when called in saemix.predict
+ names(transparms_optim) <- names(degparms_optim)
+
+ odeini_optim <- transparms_optim[odeini_optim_parm_names]
+ names(odeini_optim) <- gsub('_0$', '', odeini_optim_parm_names)
+
+ odeini <- c(odeini_optim, odeini_fixed)[names(mkin_model$diffs)]
+
+ ode_transparms_optim_names <- setdiff(names(transparms_optim), odeini_optim_parm_names)
+ odeparms_optim <- backtransform_odeparms(transparms_optim[ode_transparms_optim_names], mkin_model,
+ transform_rates = object[[1]]$transform_rates,
+ transform_fractions = object[[1]]$transform_fractions)
+ odeparms <- c(odeparms_optim, odeparms_fixed)
+
+ xidep_i <- subset(xidep, id == i)
+
+ if (solution_type == "analytical") {
+ out_values <- mkin_model$deg_func(xidep_i, odeini, odeparms)
+ } else {
+
+ i_time <- xidep_i$time
+ i_name <- xidep_i$name
+
+ out_wide <- mkinpredict(mkin_model,
+ odeparms = odeparms, odeini = odeini,
+ solution_type = solution_type,
+ outtimes = sort(unique(i_time)),
+ na_stop = FALSE
+ )
+
+ out_index <- cbind(as.character(i_time), as.character(i_name))
+ out_values <- out_wide[out_index]
+ }
+ return(out_values)
+ })
+ res <- unlist(res_list)
+ return(res)
+ }
+ }
+
+ error.model <- switch(object[[1]]$err_mod,
+ const = "constant",
+ tc = "combined",
+ obs = "constant")
+
+ if (object[[1]]$err_mod == "obs") {
+ warning("The error model 'obs' (variance by variable) can currently not be transferred to an saemix model")
+ }
+
+ error.init <- switch(object[[1]]$err_mod,
+ const = c(a = mean(sapply(object, function(x) x$errparms)), b = 1),
+ tc = c(a = mean(sapply(object, function(x) x$errparms[1])),
+ b = mean(sapply(object, function(x) x$errparms[2]))),
+ obs = c(a = mean(sapply(object, function(x) x$errparms)), b = 1))
+
+ degparms_psi0 <- degparms_optim
+ degparms_psi0[names(degparms_start)] <- degparms_start
+ psi0_matrix <- matrix(degparms_psi0, nrow = 1)
+ colnames(psi0_matrix) <- names(degparms_psi0)
+
+ res <- saemix::saemixModel(model_function,
+ psi0 = psi0_matrix,
+ "Mixed model generated from mmkin object",
+ transform.par = transform.par,
+ error.model = error.model,
+ verbose = verbose
+ )
+ attr(res, "mean_dp_start") <- degparms_optim
+ return(res)
+}
+
+#' @rdname saem
+#' @return An [saemix::SaemixData] object.
+#' @export
+saemix_data <- function(object, verbose = FALSE, ...) {
+ if (nrow(object) > 1) stop("Only row objects allowed")
+ ds_names <- colnames(object)
+
+ ds_list <- lapply(object, function(x) x$data[c("time", "variable", "observed")])
+ names(ds_list) <- ds_names
+ ds_saemix_all <- purrr::map_dfr(ds_list, function(x) x, .id = "ds")
+ ds_saemix <- data.frame(ds = ds_saemix_all$ds,
+ name = as.character(ds_saemix_all$variable),
+ time = ds_saemix_all$time,
+ value = ds_saemix_all$observed,
+ stringsAsFactors = FALSE)
+
+ res <- saemix::saemixData(ds_saemix,
+ name.group = "ds",
+ name.predictors = c("time", "name"),
+ name.response = "value",
+ verbose = verbose,
+ ...)
+ return(res)
+}

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