Nothing
R/MultAdj.r
In MedianaDesigner: Power and Sample Size Calculations for Clinical Trials
Defines functions
MultAdj3SingleCore
MultAdj3NCores
MultAdj2SingleCore
MultAdj2NCores
MultAdj1SingleCore
MultAdj1NCores
MultAdjReportDoc
MultAdj
Documented in
MultAdj
MultAdj1SingleCore
MultAdjReportDoc
MultAdj = function(parameters) {
# Error checks
if (typeof(parameters) != "list") stop("Function parameters must be a list of named values.", call. = FALSE)
if (is.null(parameters$random_seed)) {
random_seed = 49283
} else {
random_seed = ContinuousErrorCheck(parameters$random_seed,
1,
lower_values = 1,
lower_values_sign = c(">="),
upper_values = 100000,
upper_values_sign = c("<="),
"Seed for the random number generator (random_seed)",
c("Value"),
"int",
NA)
}
parameters$random_seed = random_seed
# Set the seed of R's random number generator.
# It also takes effect to Rcpp random generation functions.
# https://stackoverflow.com/questions/60119621/get-the-same-sample-of-integers-from-rcpp-as-base-r
suppressWarnings(RNGkind(sample.kind = "Rounding"))
set.seed(random_seed)
if (is.null(parameters$endpoint_type)) stop("Endpoint type (endpoint_type): Value must be specified.", call. = FALSE)
if (!tolower(parameters$endpoint_type) %in% tolower(c("normal", "binary"))) stop("Endpoint type (endpoint_type): Value must be Normal or Binary.", call. = FALSE)
if (tolower(parameters$endpoint_type) == "normal") endpoint_index = 1
if (tolower(parameters$endpoint_type) == "binary") endpoint_index = 2
parameters$endpoint_index = endpoint_index
# Default value of direction
if (is.null(parameters$direction)) {
parameters$direction = "Higher"
parameters$direction_index = 1
} else {
direction_list = c("Higher", "Lower")
if (!tolower(parameters$direction) %in% tolower(direction_list)) stop("Direction of beneficial effect (direction): Value must be Higher or Lower.", call. = FALSE)
for (i in 1:length(direction_list)) {
if (tolower(direction_list[i]) == tolower(parameters$direction)) parameters$direction_index = i
}
}
if (is.null(parameters$n_comparisons)) stop("Number of dose-control comparisons (n_comparisons): Value must be specified.", call. = FALSE)
n_comparisons = ContinuousErrorCheck(parameters$n_comparisons,
1,
lower_values = 1,
lower_values_sign = ">=",
upper_values = 10,
upper_values_sign = "<=",
"Number of dose-control comparisons (n_comparisons)",
NA,
"int",
NA)
if (is.null(parameters$n_endpoints)) stop("Number of endpoints (n_endpoints): Value must be specified.", call. = FALSE)
n_endpoints = ContinuousErrorCheck(parameters$n_endpoints,
1,
lower_values = 1,
lower_values_sign = ">=",
upper_values = 10,
upper_values_sign = "<=",
"Number of endpoints (n_endpoints)",
NA,
"int",
NA)
if (n_comparisons == 1 & n_endpoints == 1) stop("Number of dose-control comparisons (n_comparisons) must be greater than 1 or Number of endpoints (n_endpoints) must be greater than 1.", call. = FALSE)
if (is.null(parameters$sample_size)) stop("Number of enrolled patients (sample_size): Value must be specified.", call. = FALSE)
sample_size = ContinuousErrorCheck(parameters$sample_size,
n_comparisons + 1,
lower_values = 0,
lower_values_sign = ">",
upper_values = 10000,
upper_values_sign = "<=",
"Number of enrolled patients (sample_size)",
NA,
"int",
NA)
if (is.null(parameters$dropout_rate)) {
parameters$dropout_rate = 0
}
dropout_rate =
ContinuousErrorCheck(parameters$dropout_rate,
1,
lower_values = c(0),
lower_values_sign = c(">="),
upper_values = c(1),
upper_values_sign = c("<"),
"Patient dropout rate (dropout_rate)",
c("Value"),
"double",
NA)
if (is.null(parameters$nsims)) {
parameters$nsims = 1000
}
nsims =
ContinuousErrorCheck(parameters$nsims,
1,
lower_values = c(10),
lower_values_sign = c(">="),
upper_values = c(10000),
upper_values_sign = c("<="),
"Number of simulations (nsims)",
c("Value"),
"int",
NA)
if (!is.null(parameters$ncores)) {
# nocov start
# Maximum number of cores
max_ncores = parallel::detectCores()
ncores =
ContinuousErrorCheck(parameters$ncores,
1,
lower_values = c(1),
lower_values_sign = c(">="),
upper_values = c(max_ncores),
upper_values_sign = c("<="),
"Number of cores for parallel calculations (ncores)",
c("Value"),
"int",
NA)
if (!is.doRGN && ncores > 1) {
warning("Please install the doRNG package to use multi-core simulation. Only one core will be used.")
ncores = 1
}
parameters$ncores = ncores
# nocov end
} else {
parameters$ncores = 1
}
# Number of simulations per core
parameters$nsims_per_core = ceiling(parameters$nsims / parameters$ncores)
if (is.null(parameters$alpha)) {
parameters$alpha = 0.025
}
alpha =
ContinuousErrorCheck(parameters$alpha,
1,
lower_values = c(0.001),
lower_values_sign = c(">"),
upper_values = c(0.5),
upper_values_sign = c("<"),
"One-sided Type I error rate (alpha)",
c("Value"),
"double",
NA)
# Treatment effect assumptions
if (endpoint_index == 1) {
if (is.null(parameters$control_mean)) stop("Mean effect in the control arm (control_mean): Value must be specified.", call. = FALSE)
control_mean =
ContinuousErrorCheck(parameters$control_mean,
n_endpoints,
lower_values = c(NA),
lower_values_sign = c(NA),
upper_values = c(NA),
upper_values_sign = c(NA),
"Mean effect in the control arm (control_mean)",
c("Value"),
"double",
NA)
if (is.null(parameters$treatment_mean)) stop("Mean effect in the treatment arm or arms (treatment_mean): Value must be specified.", call. = FALSE)
treatment_mean =
ContinuousErrorCheck(parameters$treatment_mean,
n_comparisons * n_endpoints,
lower_values = c(NA),
lower_values_sign = c(NA),
upper_values = c(NA),
upper_values_sign = c(NA),
"Mean effect in the treatment arm (treatment_mean)",
c("Value"),
"double",
NA)
if (n_comparisons >= 2 & n_endpoints >= 2) {
if (!is.matrix(parameters$treatment_mean)) stop("Mean effect in the treatment arm (treatment_mean) must be a matrix.", call. = FALSE)
if (any(dim(parameters$treatment_mean) != c(n_endpoints, n_comparisons))) stop("Mean effect in the treatment arm (treatment_mean) does not have the correction dimensions.", call. = FALSE)
}
if (is.null(parameters$control_sd)) stop("Standard deviation in the control arm (control_sd): Value must be specified.", call. = FALSE)
control_sd =
ContinuousErrorCheck(parameters$control_sd,
n_endpoints,
lower_values = c(0),
lower_values_sign = c(">"),
upper_values = c(NA),
upper_values_sign = c(NA),
"Standard deviation in the control arm (control_sd)",
c("Value"),
"double",
NA)
if (is.null(parameters$treatment_sd)) stop("Standard deviation in the treatment arm or arms (treatment_sd): Value must be specified.", call. = FALSE)
treatment_sd =
ContinuousErrorCheck(parameters$treatment_sd,
n_comparisons * n_endpoints,
lower_values = c(0),
lower_values_sign = c(">"),
upper_values = c(NA),
upper_values_sign = c(NA),
"Standard deviation in the treatment arm (treatment_sd)",
c("Value"),
"double",
NA)
if (n_comparisons >= 2 & n_endpoints >= 2) {
if (!is.matrix(parameters$treatment_sd)) stop("Standard deviation in the treatment arm (treatment_sd) must be a matrix.", call. = FALSE)
if (any(dim(parameters$treatment_sd) != c(n_endpoints, n_comparisons))) stop("Standard deviation in the treatment arm (treatment_sd) does not have the correction dimensions.", call. = FALSE)
}
}
if (endpoint_index == 2) {
if (is.null(parameters$control_rate)) stop("Response rate in the control arm (control_rate): Value must be specified.", call. = FALSE)
control_rate =
ContinuousErrorCheck(parameters$control_rate,
n_endpoints,
lower_values = c(0),
lower_values_sign = c(">"),
upper_values = c(1),
upper_values_sign = c("<"),
"Response rate in the control arm (control_rate)",
c("Value"),
"double",
NA)
if (is.null(parameters$treatment_rate)) stop("Response rate in the treatment arm (treatment_rate): Value must be specified.", call. = FALSE)
treatment_rate =
ContinuousErrorCheck(parameters$treatment_rate,
n_comparisons * n_endpoints,
lower_values = c(0),
lower_values_sign = c(">"),
upper_values = c(1),
upper_values_sign = c("<"),
"Response rate in the treatment arm (treatment_rate)",
c("Value"),
"double",
NA)
if (n_comparisons >= 2 & n_endpoints >= 2) {
if (!is.matrix(parameters$treatment_rate)) stop("Response rate in the treatment arm (treatment_rate) must be a matrix.", call. = FALSE)
if (any(dim(parameters$treatment_rate) != c(n_endpoints, n_comparisons))) stop("Response rate in the treatment arm (treatment_rate) does not have the correction dimensions.", call. = FALSE)
}
}
if (n_comparisons >= 2 & n_endpoints == 1) {
# Analysis of multiple treatment-control comparisons
parameters$mult_test_type = 1
n_hypotheses = n_comparisons
mult_test_list = c("Bonferroni", "Holm", "Hochberg", "Hommel", "Fixed-sequence", "Chain")
if (!tolower(parameters$mult_test) %in% tolower(mult_test_list)) stop("Multiple testing procedure (mult_test): Value must be Bonferroni, Holm, Hochberg, Hommel, Fixed-sequence or Chain.", call. = FALSE)
for (i in 1:length(mult_test_list)) {
if (tolower(mult_test_list[i]) == tolower(parameters$mult_test)) mult_test_index = i
}
parameters$mult_test_index = mult_test_index
}
if (n_comparisons == 1 & n_endpoints >= 2) {
# Analysis of multiple endpoints
parameters$mult_test_type = 2
n_hypotheses = n_endpoints
mult_test_list = c("Bonferroni", "Holm", "Hochberg", "Hommel", "Fixed-sequence", "Chain", "O'Brien")
if (!tolower(parameters$mult_test) %in% tolower(mult_test_list)) stop("Multiple testing procedure (mult_test): Value must be Bonferroni, Holm, Hochberg, Hommel, Fixed-sequence, Chain or O'Brien.", call. = FALSE)
for (i in 1:length(mult_test_list)) {
if (tolower(mult_test_list[i]) == tolower(parameters$mult_test)) mult_test_index = i
}
parameters$mult_test_index = mult_test_index
}
if (n_comparisons >= 2 & n_endpoints >= 2) {
# Analysis of multiple endpoints and multiple treatment-control comparisons
parameters$mult_test_type = 3
n_hypotheses = n_comparisons * n_endpoints
mult_test_list = c("Holm", "Hochberg", "Hommel")
if (!tolower(parameters$mult_test) %in% tolower(mult_test_list)) stop("Multiple testing procedure (mult_test): Value must be Holm, Hochberg or Hommel.", call. = FALSE)
for (i in 1:length(mult_test_list)) {
if (tolower(mult_test_list[i]) == tolower(parameters$mult_test)) mult_test_index = i
}
parameters$mult_test_index = mult_test_index
}
if (parameters$mult_test_type %in% c(1, 2)) {
# Chain procedure
if (mult_test_index == 6) {
if (is.null(parameters$weights)) {
weights = rep(1 / n_hypotheses, n_hypotheses)
} else {
weights =
ContinuousErrorCheck(parameters$weights,
n_hypotheses,
lower_values = c(0),
lower_values_sign = c(">="),
upper_values = c(1),
upper_values_sign = c("<="),
"Hypothesis weights (weights)",
c("Value"),
"double",
NA)
}
if (sum(weights) > 1) stop("Hypothesis weights (weights): Sum of weights must be less than or equal to 1.", call. = FALSE)
parameters$weights = weights
transition =
ContinuousErrorCheck(as.vector(parameters$transition),
n_hypotheses * n_hypotheses,
lower_values = c(0),
lower_values_sign = c(">="),
upper_values = c(1),
upper_values_sign = c("<="),
"Hypothesis transition matrix (transition)",
c("Value"),
"double",
NA)
if (!is.matrix(parameters$transition)) stop("Hypothesis transition matrix (transition) must be a matrix.", call. = FALSE)
if (any(dim(parameters$transition) != c(n_hypotheses, n_hypotheses))) stop("Hypothesis transition matrix (transition) does not have the correction dimensions.", call. = FALSE)
for (i in 1:n_hypotheses) if (sum(parameters$transition[i, ]) > 1) stop("Hypothesis transition matrix (transition): The sum of elements in each row must be less than or equal to 1.", call. = FALSE)
parameters$ctransition = t(parameters$transition)
}
# All other procedures but fixed-sequence or chain
if (mult_test_index %in% c(1, 2, 3, 4)) {
if (is.null(parameters$weights)) {
weights = rep(1 / n_hypotheses, n_hypotheses)
} else {
weights =
ContinuousErrorCheck(parameters$weights,
n_hypotheses,
lower_values = c(0),
lower_values_sign = c(">"),
upper_values = c(1),
upper_values_sign = c("<"),
"Hypothesis weights (weights)",
c("Value"),
"double",
NA)
}
if (sum(weights) > 1) stop("Sum of hypothesis weights (weights) must be less than or equal to 1.", call. = FALSE)
parameters$weights = weights
parameters$transition = 0
parameters$ctransition = 0
}
# Fixed-sequence procedure
if (mult_test_index == 5) {
sequence =
ContinuousErrorCheck(parameters$sequence,
n_hypotheses,
lower_values = c(1),
lower_values_sign = c(">="),
upper_values = c(n_hypotheses),
upper_values_sign = c("<="),
"Hypothesis testing sequence (sequence)",
c("Value"),
"int",
NA)
if (any(sort(parameters$sequence) != 1:n_hypotheses)) stop("Hypothesis testing sequence for the fixed-sequence procedure (sequence) is not correctly specified.", call. = FALSE)
parameters$weights = parameters$sequence
parameters$transition = 0
parameters$ctransition = 0
}
# Global test
if (mult_test_index == 7) {
parameters$weights = 0
parameters$transition = 0
parameters$ctransition = 0
}
}
if (parameters$mult_test_type == 3) {
mult_method_list = c("Standard", "Modified", "Enhanced")
if (!tolower(parameters$mult_method) %in% tolower(mult_method_list)) stop("Mixture method (mult_method): Value must be Standard, Modified or Enhanced.", call. = FALSE)
for (i in 1:length(mult_method_list)) {
if (tolower(mult_method_list[i]) == tolower(parameters$mult_method)) mult_method_index = i
}
parameters$mult_method_index = mult_method_index
# Truncation parameters
mult_test_gamma =
ContinuousErrorCheck(as.vector(parameters$mult_test_gamma),
n_endpoints,
lower_values = c(0),
lower_values_sign = c(">"),
upper_values = c(1),
upper_values_sign = c("<="),
"Truncation parameters (mult_test_gamma)",
c("Value"),
"double",
NA)
for (i in 1:(n_endpoints - 1)) {
if (mult_test_gamma[i] == 1) stop("Truncation parameters (mult_test_gamma): Value must be less than 1 in all families except for the last one.", call. = FALSE)
}
parameters$mult_test_gamma[n_endpoints] = 1
}
if (parameters$mult_test_type %in% c(2, 3)) {
# Correlation matrix
endpoint_correlation =
ContinuousErrorCheck(as.vector(parameters$endpoint_correlation),
n_endpoints * n_endpoints,
lower_values = c(0),
lower_values_sign = c(">="),
upper_values = c(1),
upper_values_sign = c("<="),
"Endpoint correlation matrix (endpoint_correlation)",
c("Value"),
"double",
NA)
parameters$corr_sum = sum(parameters$endpoint_correlation)
if (!is.matrix(parameters$endpoint_correlation)) stop("Endpoint correlation matrix (endpoint_correlation) must be a matrix.", call. = FALSE)
if (any(dim(parameters$endpoint_correlation) != c(n_endpoints, n_endpoints))) stop("Endpoint correlation matrix (endpoint_correlation) does not have the correction dimensions.", call. = FALSE)
if (det(parameters$endpoint_correlation) <= 0) stop("Endpoint correlation matrix (endpoint_correlation) must be positive definite.", call. = FALSE)
}
#############################################
parameters$n_hypotheses = n_hypotheses
parameters$means = 0
parameters$sds = 0
parameters$rates = 0
parameters$hazard_rates = 0
parameters$dropout_parameter = 0
parameters$enrollment_distribution = 2
# All means and SDs
if (endpoint_index == 1) {
parameters$means = c(parameters$control_mean, parameters$treatment_mean)
parameters$sds = c(parameters$control_sd, parameters$treatment_sd)
parameters$enrollment_period = 0
parameters$enrollment_parameter = 0
parameters$event_count = 0
parameters$control_rate = 0
if (parameters$mult_test_type != 3) parameters$treatment_rate = 0 else parameters$treatment_rate = matrix(0, 1, 1)
parameters$control_hazard_rate = 0
if (parameters$mult_test_type != 3) parameters$treatment_hazard_rate = 0 else parameters$treatment_hazard_rate = matrix(0, 1, 1)
}
# All rates
if (endpoint_index == 2) {
parameters$rates = c(parameters$control_rate, parameters$treatment_rate)
parameters$enrollment_period = 0
parameters$enrollment_parameter = 0
parameters$event_count = 0
parameters$control_mean = rep(0, n_endpoints)
if (parameters$mult_test_type != 3) parameters$treatment_mean = rep(0, n_endpoints) else parameters$treatment_mean = matrix(rep(0, n_endpoints), 1, n_endpoints)
parameters$control_sd = rep(1, n_endpoints)
if (parameters$mult_test_type != 3) parameters$treatment_sd = rep(1, n_endpoints) else parameters$treatment_sd = matrix(rep(1, n_endpoints), 1, n_endpoints)
parameters$control_hazard_rate = 0
if (parameters$mult_test_type != 3) parameters$treatment_hazard_rate = 0 else parameters$treatment_hazard_rate = matrix(0, 1, 1)
}
# Total sample size after accounting for dropout rates
if (endpoint_index != 3) {
parameters$sample_size_adj = floor(parameters$sample_size * (1 - parameters$dropout_rate))
} else {
parameters$sample_size_adj = parameters$sample_size
}
parameters$max_sample_size = max(parameters$sample_size_adj)
###########################################################
# Run simulations to compute key characteristics
# Analysis of multiple treatment-control comparisons
if (parameters$mult_test_type == 1) {
simulations = MultAdj1NCores(parameters)
sim_results = simulations$sim_results
# Add column names
column_names = NULL
for (i in 1:n_comparisons) column_names = c(column_names, paste0("pvalue", i))
for (i in 1:n_comparisons) column_names = c(column_names, paste0("adjpvalue", i))
colnames(sim_results) = column_names
sim_summary = list()
# Unadjusted power
pvalue = sim_results[, 1:n_comparisons]
sim_summary$power = colMeans(pvalue <= alpha)
# Adjusted overall power
adj_pvalue = sim_results[, (n_comparisons + 1):(2 * n_comparisons)]
sim_summary$adj_power = colMeans(adj_pvalue <= alpha)
# Disjunctive and conjunctive power
disj_power = 0
conj_power = 0
for (i in 1:nsims) {
disj_power = disj_power + any(adj_pvalue[i, ] <= alpha)
conj_power = conj_power + all(adj_pvalue[i, ] <= alpha)
}
sim_summary$disj_power = disj_power / nsims
sim_summary$conj_power = conj_power / nsims
}
# Analysis of multiple endpoints
if (parameters$mult_test_type == 2) {
simulations = MultAdj2NCores(parameters)
sim_results = simulations$sim_results
# Add column names
column_names = NULL
for (i in 1:n_endpoints) column_names = c(column_names, paste0("pvalue", i))
for (i in 1:n_endpoints) column_names = c(column_names, paste0("adjpvalue", i))
colnames(sim_results) = column_names
sim_summary = list()
# Unadjusted power
pvalue = sim_results[, 1:n_endpoints]
sim_summary$power = colMeans(pvalue <= alpha)
# Adjusted marginal power
if (parameters$mult_test_index <= 6) {
adj_pvalue = sim_results[, (n_endpoints + 1):(2 * n_endpoints)]
sim_summary$adj_power = colMeans(adj_pvalue <= alpha)
# Disjunctive and conjunctive power
disj_power = 0
conj_power = 0
for (i in 1:nsims) {
disj_power = disj_power + any(adj_pvalue[i, ] <= alpha)
conj_power = conj_power + all(adj_pvalue[i, ] <= alpha)
}
sim_summary$disj_power = disj_power / nsims
sim_summary$conj_power = conj_power / nsims
}
# Adjusted overall power
if (parameters$mult_test_index == 7) {
adj_pvalue = sim_results[, n_endpoints + 1]
sim_summary$adj_power = mean(adj_pvalue <= alpha)
}
}
# Analysis of multiple treatment-control comparisons and multiple endpoints
if (parameters$mult_test_type == 3) {
simulations = MultAdj3NCores(parameters)
sim_results = simulations$sim_results
# Add column names
column_names = NULL
for (i in 1:n_hypotheses) column_names = c(column_names, paste0("pvalue", i))
for (i in 1:n_hypotheses) column_names = c(column_names, paste0("adjpvalue", i))
colnames(sim_results) = column_names
sim_summary = list()
# Unadjusted power
pvalue = sim_results[, 1:n_hypotheses]
sim_summary$power = colMeans(pvalue <= alpha)
# Adjusted overall power
adj_pvalue = sim_results[, (n_hypotheses + 1):(2 * n_hypotheses)]
sim_summary$adj_power = colMeans(adj_pvalue <= alpha)
# Disjunctive and conjunctive power for each endpoint
disj_power = rep(0, n_endpoints)
conj_power = rep(0, n_endpoints)
for (i in 1:nsims) {
k = 0
for (j in 1:n_endpoints) {
disj_power[j] = disj_power[j] + any(adj_pvalue[i, (k + 1):(k + n_comparisons)] <= alpha)
conj_power[j] = conj_power[j] + all(adj_pvalue[i, (k + 1):(k + n_comparisons)] <= alpha)
k = k + n_comparisons
}
}
sim_summary$disj_power = disj_power / nsims
sim_summary$conj_power = conj_power / nsims
}
results = list(parameters = parameters,
sim_results = sim_results,
sim_summary = sim_summary)
class(results) = "MultAdjResults"
return(results)
}
MultAdjReportDoc = function(results) {
#############################################################################
# Error checks
if (!is(results, "MultAdjResults")) stop("The object was not created by the MultAdj function", call. = FALSE)
#############################################################################
# Empty list of tables to be included in the report
item_list = list()
item_index = 1
table_index = 1
figure_index = 1
width = 6.5
height = 5
parameters = results$parameters
sim_summary = results$sim_summary
endpoint_index = parameters$endpoint_index
ncomparisons = parameters$n_comparisons
nendpoints = parameters$n_endpoints
nhypotheses = parameters$n_hypotheses
mult_test_type = parameters$mult_test_type
mult_test_index = parameters$mult_test_index
# Trial arms
trial_arms = "Control"
if (ncomparisons >= 2) {
for (i in 1:ncomparisons) trial_arms = c(trial_arms, paste0("Treatment ", i))
} else {
trial_arms = c(trial_arms, "Treatment")
}
# Endpoints
endpoints = rep("", nendpoints)
if (nendpoints >= 2) {
for (i in 1:nendpoints) endpoints[i] = paste0("Endpoint ", i)
}
# Hypotheses
short_hypotheses = rep("", nhypotheses)
for (i in 1:nhypotheses) short_hypotheses[i] = paste0("H", i)
hypotheses = rep("", nhypotheses)
for (i in 1:nhypotheses) hypotheses[i] = paste0("Hypothesis ", i)
# Treatment effect assumptions
if (mult_test_type %in% c(1, 2)) {
# All means and SDs
if (endpoint_index == 1) {
means = c(parameters$control_mean, parameters$treatment_mean)
sds = c(parameters$control_sd, parameters$treatment_sd)
}
# All rates
if (endpoint_index == 2) {
rates = c(parameters$control_rate, parameters$treatment_rate)
}
}
# Treatment effect assumptions
if (mult_test_type == 3) {
# All means and SDs
if (endpoint_index == 1) {
means = cbind(parameters$control_mean, parameters$treatment_mean)
sds = cbind(parameters$control_sd, parameters$treatment_sd)
}
# All rates
if (endpoint_index == 2) {
rates = cbind(parameters$control_rate, parameters$treatment_rate)
}
}
#############################################################################
report_title = "Traditional design with multiple objectives"
endpoint_labels = c("normally distributed", "binary")
if (mult_test_type == 1) item_list[[item_index]] = list(type = "paragraph", label = "Description", value = paste0("The simulation report presents key operating characteristics of a multiplicity adjustment for multiple treatment-control comparisons in a trial with a ", tolower(endpoint_labels[endpoint_index]), " endpoint."))
if (mult_test_type == 2) item_list[[item_index]] = list(type = "paragraph", label = "Description", value = paste0("The simulation report presents key operating characteristics of a multiplicity adjustment or a global testing procedure for multiple endpoints in a trial with a ", tolower(endpoint_labels[endpoint_index]), " endpoint."))
if (mult_test_type == 3) item_list[[item_index]] = list(type = "paragraph", label = "Description", value = paste0("The simulation report presents key operating characteristics of a multiple testing procedure (gatekeeping procedure) for multiple endpoints and multiple treatment-control comparisons in a trial with a ", tolower(endpoint_labels[endpoint_index]), " endpoint."))
item_index = item_index + 1
#############################################################################
column_names = c("Trial arm", "Sample size")
col1 = trial_arms
col2 = parameters$sample_size
data_frame = data.frame(col1, col2)
title = paste0("Table ", table_index, ". Number of enrolled patients")
column_width = c(5, 1.5)
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
#############################################################################
if (mult_test_type == 1) {
column_names = c("Trial arm", "Parameter", "Value")
col1 = NULL
col2 = NULL
col3 = NULL
for (i in 1:(ncomparisons + 1)) {
if (endpoint_index == 1) {
col1 = c(col1, trial_arms[i], "")
col2 = c(col2, "Mean", "SD")
col3 = c(col3, means[i], sds[i])
}
if (endpoint_index == 2) {
col1 = c(col1, trial_arms[i])
col2 = c(col2, "Rate (%)")
col3 = c(col3, 100 * rates[i])
}
}
data_frame = data.frame(col1, col2, col3)
column_width = c(2.5, 2.5, 1.5)
}
if (mult_test_type == 2) {
column_names = c("Endpoint", "Trial arm", "Parameter", "Value")
col1 = NULL
col2 = NULL
col3 = NULL
col4 = NULL
for (i in 1:nendpoints) {
if (endpoint_index == 1) {
col1 = c(col1, endpoints[i], rep("", 3))
col2 = c(col2, "Control", "", "Treatment", "")
col3 = c(col3, "Mean", "SD", "Mean", "SD")
col4 = c(col4, parameters$control_mean[i], parameters$control_sd[i], parameters$treatment_mean[i], parameters$treatment_sd[i])
}
if (endpoint_index == 2) {
col1 = c(col1, endpoints[i], "")
col2 = c(col2, "Control", "Treatment")
col3 = c(col3, "Rate (%)", "Rate (%)")
col4 = c(col4, 100 * parameters$control_rate[i], 100 * parameters$treatment_rate[i])
}
}
data_frame = data.frame(col1, col2, col3, col4)
column_width = c(1.5, 1.5, 2, 1.5)
}
if (mult_test_type == 3) {
column_names = c("Endpoint", "Trial arm", "Parameter", "Value")
col1 = NULL
col2 = NULL
col3 = NULL
col4 = NULL
for (i in 1:nendpoints) {
for (j in 1:(ncomparisons + 1)) {
if (endpoint_index == 1) {
col1 = c(col1, endpoints[i], "")
col2 = c(col2, trial_arms[j], "")
col3 = c(col3, "Mean", "SD")
col4 = c(col4, means[i, j], sds[i, j])
}
if (endpoint_index == 2) {
col1 = c(col1, endpoints[i])
col2 = c(col2, trial_arms[j])
col3 = c(col3, "Rate (%)")
col4 = c(col4, 100 * rates[i, j])
}
}
}
data_frame = data.frame(col1, col2, col3, col4)
column_width = c(1.5, 1.5, 2, 1.5)
}
if (parameters$direction_index == 1) footnote = "A higher value of the endpoint indicates a beneficial effect."
if (parameters$direction_index == 2) footnote = "A lower value of the endpoint indicates a beneficial effect."
title = paste0("Table ", table_index, ". Treatment effect assumptions")
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE, footnote)
item_index = item_index + 1
table_index = table_index + 1
#############################################################################
if (mult_test_type == 1) {
column_names = c("Hypothesis", "Definition")
col1 = hypotheses
col2 = rep("", ncomparisons)
for (i in 1:ncomparisons) col2[i] = paste0("Null hypothesis of no difference between Treatment ", i, " and control")
data_frame = data.frame(col1, col2)
column_width = c(1.5, 5)
title = paste0("Table ", table_index, ". Hypothesis definitions")
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
}
if (mult_test_type == 2) {
column_names = c("Hypothesis", "Definition")
col1 = hypotheses
col2 = rep("", nendpoints)
for (i in 1:nendpoints) col2[i] = paste0("Null hypothesis of no difference between the treatment and control with respect to Endpoint ", i)
data_frame = data.frame(col1, col2)
column_width = c(1.5, 5)
title = paste0("Table ", table_index, ". Hypothesis definitions")
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
}
if (mult_test_type == 3) {
column_names = c("Hypothesis", "Definition")
col1 = hypotheses
col2 = rep("", ncomparisons * nendpoints)
k = 1
for (i in 1:nendpoints) {
for (j in 1:ncomparisons) {
col2[k] = paste0("Null hypothesis of no difference between Treatment ", j, " and control with respect to Endpoint ", i)
k = k + 1
}
}
data_frame = data.frame(col1, col2)
column_width = c(1.5, 5)
title = paste0("Table ", table_index, ". Hypothesis definitions")
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
}
#############################################################################
if (mult_test_type %in% c(2, 3)) {
column_names = c("Endpoint", endpoints)
data_frame = cbind(endpoints, parameters$endpoint_correlation)
column_width = c(1, rep(5.5 / nendpoints, nendpoints))
title = paste0("Table ", table_index, ". Endpoint correlation matrix")
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
}
#############################################################################
if (mult_test_type %in% c(1, 2)) {
if (mult_test_index <= 6) {
column_names = c("Parameter", "Value")
col1 = c("Multiple testing procedure")
col2 = c(parameters$mult_test)
data_frame = data.frame(col1, col2)
column_width = c(5, 1.5)
title = paste0("Table ", table_index, ". Multiple testing procedure")
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
# Fixed-sequence procedure
if (mult_test_index == 5) {
column_names = short_hypotheses
data_frame = as.data.frame(matrix(0, 1, nhypotheses))
data_frame[1, ] = round(parameters$sequence)
title = paste0("Table ", table_index, ". Multiple testing procedure: Hypothesis testing sequence")
column_width = c(rep(6.5 / nhypotheses, nhypotheses))
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
}
# All other procedures but fixed-sequence
if (mult_test_index %in% c(1, 2, 3, 4, 6)) {
column_names = short_hypotheses
data_frame = as.data.frame(matrix(0, 1, nhypotheses))
data_frame[1, ] = round(parameters$weights, 4)
title = paste0("Table ", table_index, ". Multiple testing procedure: Initial hypothesis weights")
column_width = c(rep(6.5 / nhypotheses, nhypotheses))
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
}
# Chain procedure
if (mult_test_index == 6) {
data_frame = as.data.frame(matrix(0, nhypotheses, nhypotheses + 1))
data_frame[, 1] = hypotheses
temp = round(parameters$transition, 4)
temp = matrix(temp, nhypotheses, nhypotheses)
data_frame[, 2:(nhypotheses + 1)] = temp
column_names = c("Hypothesis", short_hypotheses)
title = paste0("Table ", table_index, ". Multiple testing procedure: Transition parameters")
column_width = c(1.25, rep(5.25 / nhypotheses, nhypotheses))
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
}
}
if (mult_test_index == 7) {
column_names = c("Parameter", "Value")
col1 = c("Global testing procedure")
col2 = c(parameters$mult_test)
data_frame = data.frame(col1, col2)
column_width = c(5, 1.5)
title = paste0("Table ", table_index, ". Global testing procedure")
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
}
}
if (mult_test_type == 3) {
column_names = c("Parameter", "Value")
col1 = c("Component procedure", "Mixture method", "Truncation parameters")
col2 = c(parameters$mult_test, parameters$mult_method, paste0(parameters$mult_test_gamma, collapse = ", "))
data_frame = data.frame(col1, col2)
column_width = c(5, 1.5)
title = paste0("Table ", table_index, ". Multiple testing procedure (Gatekeeping procedure)")
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
}
#############################################################################
column_names = c("Parameter", "Value")
if (endpoint_index %in% c(1, 2)) {
col1 = c("Dropout rate (%)")
col2 = c(100 * parameters$dropout_rate)
}
data_frame = data.frame(col1, col2)
title = paste0("Table ", table_index, ". Other design parameters")
column_width = c(5, 1.5)
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
#############################################################################
column_names = c("Parameter", "Value")
col1 = c("One-sided Type I error rate", "Number of simulations")
col2 = c(sprintf("%0.3f", sum(parameters$alpha)),
sprintf("%d", parameters$nsims))
data_frame = data.frame(col1, col2)
title = paste0("Table ", table_index, ". Simulation parameters")
column_width = c(5, 1.5)
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, TRUE)
item_index = item_index + 1
table_index = table_index + 1
#############################################################################
# Traditional multiplicity adjustments or gatekeeping procedures
if (mult_test_type == 1 | (mult_test_type == 2 & mult_test_index <= 6) | mult_test_type == 3) {
column_names = c("Hypothesis", "Power (%)", "Adjusted power (%)")
col1 = hypotheses
col2 = round(100 * sim_summary$power, 1)
col3 = round(100 * sim_summary$adj_power, 1)
data_frame = data.frame(col1, col2, col3)
title = paste0("Table ", table_index, ". Simulation results: Hypothesis-specific power")
column_width = c(2.5, 2, 2)
footnote = "Power: Probability of rejecting each hypothesis of no effect without a multiplicity adjustment. Adjusted power: Probability of rejecting each hypothesis of no effect using a multiplicity adjustment based on the specified multiple testing procedure."
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE, footnote)
item_index = item_index + 1
table_index = table_index + 1
}
# Global testing procedure
if (mult_test_type == 2 & mult_test_index == 7) {
column_names = c("Hypothesis", "Power (%)")
col1 = hypotheses
col2 = round(100 * sim_summary$power, 1)
data_frame = data.frame(col1, col2)
title = paste0("Table ", table_index, ". Simulation results: Hypothesis-specific power")
column_width = c(2.5, 4)
footnote = "Power: Probability of rejecting each hypothesis of no effect without a multiplicity adjustment."
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE, footnote)
item_index = item_index + 1
table_index = table_index + 1
column_names = c("Overall power", "Power (%)")
col1 = c("Global power")
col2 = round(100 * sim_summary$adj_power, 1)
data_frame = data.frame(col1, col2)
title = paste0("Table ", table_index, ". Simulation results: Overall power")
column_width = c(2.5, 4)
footnote = "Global power: Probability of rejecting at least one hypothesis of no effect using the specified global testing approach."
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE, footnote)
item_index = item_index + 1
table_index = table_index + 1
}
# Traditional multiplicity adjustments
if (mult_test_type == 1 | (mult_test_type == 2 & mult_test_index <= 6)) {
column_names = c("Overall power", "Power (%)")
col1 = c("Disjunctive power", "Conjunctive power")
col2 = c(round(100 * sim_summary$disj_power, 1), round(100 * sim_summary$conj_power, 1))
data_frame = data.frame(col1, col2)
title = paste0("Table ", table_index, ". Simulation results: Overall power")
column_width = c(2.5, 4)
footnote = "Disjunctive power: Probability of rejecting at least one hypothesis of no effect using a multiplicity adjustment based on the specified multiple testing procedure. Conjunctive power: Probability of rejecting all hypotheses of no effect using a multiplicity adjustment based on the specified multiple testing procedure."
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE, footnote)
item_index = item_index + 1
table_index = table_index + 1
}
# Gatekeeping procedures
if (mult_test_type == 3) {
column_names = c("Endpoint family", "Overall power", "Power (%)")
col1 = NULL
col2 = NULL
col3 = NULL
for (i in 1:nendpoints) {
col1 = c(col1, paste0("Endpoint ", i), "")
col2 = c(col2, "Disjunctive power", "Conjunctive power")
col3 = c(col3, round(100 * sim_summary$disj_power[i], 1), round(100 * sim_summary$conj_power[i], 1))
}
data_frame = data.frame(col1, col2, col3)
title = paste0("Table ", table_index, ". Simulation results: Overall power")
column_width = c(2.5, 2, 2)
footnote = "Disjunctive power: Probability of rejecting at least one hypothesis of no effect within each endpoint family using a multiplicity adjustment based on the specified multiple testing procedure. Conjunctive power: Probability of rejecting all hypotheses of no effect within each endpoint family using a multiplicity adjustment based on the specified multiple testing procedure."
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE, footnote)
item_index = item_index + 1
table_index = table_index + 1
}
#############################################################################
report = item_list
doc = SaveReport(report, report_title)
return(doc)
}
# End of MultAdjReportDoc
# --==[ MultAdj1 ]==--
MultAdj1NCores = function(parameters) {
ncores = parameters$ncores
# Run simulations on multiple cores to compute key characteristics
if (ncores > 1) {
# nocov start
cl = parallel::makeCluster(ncores)
# Export all functions in the global environment to each node
parallel::clusterExport(cl, ls(envir = .GlobalEnv))
doParallel::registerDoParallel(cl)
simulation_list = foreach(counter=(1:ncores), .packages = c("MedianaDesigner")) %dorng% {
MultAdj1SingleCore(parameters)
}
stopCluster(cl)
# Combine the simulation results across the cores
sim_results = NULL
for (i in 1:ncores) {
sim_results = rbind(sim_results, simulation_list[[i]]$sim_results)
}
simulations = list(sim_results = sim_results)
# nocov end
} else {
simulations = MultAdj1SingleCore(parameters)
}
return(simulations)
}
MultAdj1SingleCore = function(parameters) {
params_for_core = parameters
params_for_core$nsims = parameters$nsims_per_core
simulations = MultAdjC1(params_for_core)
return(simulations)
}
# --==[ MultAdj2 ]==--
MultAdj2NCores = function(parameters) {
ncores = parameters$ncores
# Run simulations on multiple cores to compute key characteristics
if (ncores > 1) {
# nocov start
cl = parallel::makeCluster(ncores)
# Export all functions in the global environment to each node
parallel::clusterExport(cl, ls(envir = .GlobalEnv))
doParallel::registerDoParallel(cl)
simulation_list = foreach(counter=(1:ncores), .packages = c("MedianaDesigner")) %dorng% {
MultAdj2SingleCore(parameters)
}
stopCluster(cl)
# Combine the simulation results across the cores
sim_results = NULL
for (i in 1:ncores) {
sim_results = rbind(sim_results, simulation_list[[i]]$sim_results)
}
simulations = list(sim_results = sim_results)
# nocov end
} else {
simulations = MultAdj2SingleCore(parameters)
}
return(simulations)
}
MultAdj2SingleCore = function(parameters) {
params_for_core = parameters
params_for_core$nsims = parameters$nsims_per_core
simulations = MultAdjC2(params_for_core)
return(simulations)
}
# --==[ MultAdj3 ]==--
MultAdj3NCores = function(parameters) {
ncores = parameters$ncores
# Run simulations on multiple cores to compute key characteristics
if (ncores > 1) {
# nocov start
cl = parallel::makeCluster(ncores)
# Export all functions in the global environment to each node
parallel::clusterExport(cl, ls(envir = .GlobalEnv))
doParallel::registerDoParallel(cl)
simulation_list = foreach(counter=(1:ncores), .packages = c("MedianaDesigner")) %dorng% {
MultAdj3SingleCore(parameters)
}
stopCluster(cl)
# Combine the simulation results across the cores
sim_results = NULL
for (i in 1:ncores) {
sim_results = rbind(sim_results, simulation_list[[i]]$sim_results)
}
simulations = list(sim_results = sim_results)
# nocov end
} else {
simulations = MultAdj3SingleCore(parameters)
}
return(simulations)
}
MultAdj3SingleCore = function(parameters) {
params_for_core = parameters
params_for_core$nsims = parameters$nsims_per_core
simulations = MultAdjC3(params_for_core)
return(simulations)
}
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Defines functions MultAdj3SingleCore MultAdj3NCores MultAdj2SingleCore MultAdj2NCores MultAdj1SingleCore MultAdj1NCores MultAdjReportDoc MultAdj
Documented in MultAdj MultAdj1SingleCore MultAdjReportDoc
MultAdj = function(parameters) {
# Error checks
if (typeof(parameters) != "list") stop("Function parameters must be a list of named values.", call. = FALSE)
if (is.null(parameters$random_seed)) {
random_seed = 49283
} else {
random_seed = ContinuousErrorCheck(parameters$random_seed,
1,
lower_values = 1,
lower_values_sign = c(">="),
upper_values = 100000,
upper_values_sign = c("<="),
"Seed for the random number generator (random_seed)",
c("Value"),
"int",
NA)
}
parameters$random_seed = random_seed
# Set the seed of R's random number generator.
# It also takes effect to Rcpp random generation functions.
# https://stackoverflow.com/questions/60119621/get-the-same-sample-of-integers-from-rcpp-as-base-r
suppressWarnings(RNGkind(sample.kind = "Rounding"))
set.seed(random_seed)
if (is.null(parameters$endpoint_type)) stop("Endpoint type (endpoint_type): Value must be specified.", call. = FALSE)
if (!tolower(parameters$endpoint_type) %in% tolower(c("normal", "binary"))) stop("Endpoint type (endpoint_type): Value must be Normal or Binary.", call. = FALSE)
if (tolower(parameters$endpoint_type) == "normal") endpoint_index = 1
if (tolower(parameters$endpoint_type) == "binary") endpoint_index = 2
parameters$endpoint_index = endpoint_index
# Default value of direction
if (is.null(parameters$direction)) {
parameters$direction = "Higher"
parameters$direction_index = 1
} else {
direction_list = c("Higher", "Lower")
if (!tolower(parameters$direction) %in% tolower(direction_list)) stop("Direction of beneficial effect (direction): Value must be Higher or Lower.", call. = FALSE)
for (i in 1:length(direction_list)) {
if (tolower(direction_list[i]) == tolower(parameters$direction)) parameters$direction_index = i
}
}
if (is.null(parameters$n_comparisons)) stop("Number of dose-control comparisons (n_comparisons): Value must be specified.", call. = FALSE)
n_comparisons = ContinuousErrorCheck(parameters$n_comparisons,
1,
lower_values = 1,
lower_values_sign = ">=",
upper_values = 10,
upper_values_sign = "<=",
"Number of dose-control comparisons (n_comparisons)",
NA,
"int",
NA)
if (is.null(parameters$n_endpoints)) stop("Number of endpoints (n_endpoints): Value must be specified.", call. = FALSE)
n_endpoints = ContinuousErrorCheck(parameters$n_endpoints,
1,
lower_values = 1,
lower_values_sign = ">=",
upper_values = 10,
upper_values_sign = "<=",
"Number of endpoints (n_endpoints)",
NA,
"int",
NA)
if (n_comparisons == 1 & n_endpoints == 1) stop("Number of dose-control comparisons (n_comparisons) must be greater than 1 or Number of endpoints (n_endpoints) must be greater than 1.", call. = FALSE)
if (is.null(parameters$sample_size)) stop("Number of enrolled patients (sample_size): Value must be specified.", call. = FALSE)
sample_size = ContinuousErrorCheck(parameters$sample_size,
n_comparisons + 1,
lower_values = 0,
lower_values_sign = ">",
upper_values = 10000,
upper_values_sign = "<=",
"Number of enrolled patients (sample_size)",
NA,
"int",
NA)
if (is.null(parameters$dropout_rate)) {
parameters$dropout_rate = 0
}
dropout_rate =
ContinuousErrorCheck(parameters$dropout_rate,
1,
lower_values = c(0),
lower_values_sign = c(">="),
upper_values = c(1),
upper_values_sign = c("<"),
"Patient dropout rate (dropout_rate)",
c("Value"),
"double",
NA)
if (is.null(parameters$nsims)) {
parameters$nsims = 1000
}
nsims =
ContinuousErrorCheck(parameters$nsims,
1,
lower_values = c(10),
lower_values_sign = c(">="),
upper_values = c(10000),
upper_values_sign = c("<="),
"Number of simulations (nsims)",
c("Value"),
"int",
NA)
if (!is.null(parameters$ncores)) {
# nocov start
# Maximum number of cores
max_ncores = parallel::detectCores()
ncores =
ContinuousErrorCheck(parameters$ncores,
1,
lower_values = c(1),
lower_values_sign = c(">="),
upper_values = c(max_ncores),
upper_values_sign = c("<="),
"Number of cores for parallel calculations (ncores)",
c("Value"),
"int",
NA)
if (!is.doRGN && ncores > 1) {
warning("Please install the doRNG package to use multi-core simulation. Only one core will be used.")
ncores = 1
}
parameters$ncores = ncores
# nocov end
} else {
parameters$ncores = 1
}
# Number of simulations per core
parameters$nsims_per_core = ceiling(parameters$nsims / parameters$ncores)
if (is.null(parameters$alpha)) {
parameters$alpha = 0.025
}
alpha =
ContinuousErrorCheck(parameters$alpha,
1,
lower_values = c(0.001),
lower_values_sign = c(">"),
upper_values = c(0.5),
upper_values_sign = c("<"),
"One-sided Type I error rate (alpha)",
c("Value"),
"double",
NA)
# Treatment effect assumptions
if (endpoint_index == 1) {
if (is.null(parameters$control_mean)) stop("Mean effect in the control arm (control_mean): Value must be specified.", call. = FALSE)
control_mean =
ContinuousErrorCheck(parameters$control_mean,
n_endpoints,
lower_values = c(NA),
lower_values_sign = c(NA),
upper_values = c(NA),
upper_values_sign = c(NA),
"Mean effect in the control arm (control_mean)",
c("Value"),
"double",
NA)
if (is.null(parameters$treatment_mean)) stop("Mean effect in the treatment arm or arms (treatment_mean): Value must be specified.", call. = FALSE)
treatment_mean =
ContinuousErrorCheck(parameters$treatment_mean,
n_comparisons * n_endpoints,
lower_values = c(NA),
lower_values_sign = c(NA),
upper_values = c(NA),
upper_values_sign = c(NA),
"Mean effect in the treatment arm (treatment_mean)",
c("Value"),
"double",
NA)
if (n_comparisons >= 2 & n_endpoints >= 2) {
if (!is.matrix(parameters$treatment_mean)) stop("Mean effect in the treatment arm (treatment_mean) must be a matrix.", call. = FALSE)
if (any(dim(parameters$treatment_mean) != c(n_endpoints, n_comparisons))) stop("Mean effect in the treatment arm (treatment_mean) does not have the correction dimensions.", call. = FALSE)
}
if (is.null(parameters$control_sd)) stop("Standard deviation in the control arm (control_sd): Value must be specified.", call. = FALSE)
control_sd =
ContinuousErrorCheck(parameters$control_sd,
n_endpoints,
lower_values = c(0),
lower_values_sign = c(">"),
upper_values = c(NA),
upper_values_sign = c(NA),
"Standard deviation in the control arm (control_sd)",
c("Value"),
"double",
NA)
if (is.null(parameters$treatment_sd)) stop("Standard deviation in the treatment arm or arms (treatment_sd): Value must be specified.", call. = FALSE)
treatment_sd =
ContinuousErrorCheck(parameters$treatment_sd,
n_comparisons * n_endpoints,
lower_values = c(0),
lower_values_sign = c(">"),
upper_values = c(NA),
upper_values_sign = c(NA),
"Standard deviation in the treatment arm (treatment_sd)",
c("Value"),
"double",
NA)
if (n_comparisons >= 2 & n_endpoints >= 2) {
if (!is.matrix(parameters$treatment_sd)) stop("Standard deviation in the treatment arm (treatment_sd) must be a matrix.", call. = FALSE)
if (any(dim(parameters$treatment_sd) != c(n_endpoints, n_comparisons))) stop("Standard deviation in the treatment arm (treatment_sd) does not have the correction dimensions.", call. = FALSE)
}
}
if (endpoint_index == 2) {
if (is.null(parameters$control_rate)) stop("Response rate in the control arm (control_rate): Value must be specified.", call. = FALSE)
control_rate =
ContinuousErrorCheck(parameters$control_rate,
n_endpoints,
lower_values = c(0),
lower_values_sign = c(">"),
upper_values = c(1),
upper_values_sign = c("<"),
"Response rate in the control arm (control_rate)",
c("Value"),
"double",
NA)
if (is.null(parameters$treatment_rate)) stop("Response rate in the treatment arm (treatment_rate): Value must be specified.", call. = FALSE)
treatment_rate =
ContinuousErrorCheck(parameters$treatment_rate,
n_comparisons * n_endpoints,
lower_values = c(0),
lower_values_sign = c(">"),
upper_values = c(1),
upper_values_sign = c("<"),
"Response rate in the treatment arm (treatment_rate)",
c("Value"),
"double",
NA)
if (n_comparisons >= 2 & n_endpoints >= 2) {
if (!is.matrix(parameters$treatment_rate)) stop("Response rate in the treatment arm (treatment_rate) must be a matrix.", call. = FALSE)
if (any(dim(parameters$treatment_rate) != c(n_endpoints, n_comparisons))) stop("Response rate in the treatment arm (treatment_rate) does not have the correction dimensions.", call. = FALSE)
}
}
if (n_comparisons >= 2 & n_endpoints == 1) {
# Analysis of multiple treatment-control comparisons
parameters$mult_test_type = 1
n_hypotheses = n_comparisons
mult_test_list = c("Bonferroni", "Holm", "Hochberg", "Hommel", "Fixed-sequence", "Chain")
if (!tolower(parameters$mult_test) %in% tolower(mult_test_list)) stop("Multiple testing procedure (mult_test): Value must be Bonferroni, Holm, Hochberg, Hommel, Fixed-sequence or Chain.", call. = FALSE)
for (i in 1:length(mult_test_list)) {
if (tolower(mult_test_list[i]) == tolower(parameters$mult_test)) mult_test_index = i
}
parameters$mult_test_index = mult_test_index
}
if (n_comparisons == 1 & n_endpoints >= 2) {
# Analysis of multiple endpoints
parameters$mult_test_type = 2
n_hypotheses = n_endpoints
mult_test_list = c("Bonferroni", "Holm", "Hochberg", "Hommel", "Fixed-sequence", "Chain", "O'Brien")
if (!tolower(parameters$mult_test) %in% tolower(mult_test_list)) stop("Multiple testing procedure (mult_test): Value must be Bonferroni, Holm, Hochberg, Hommel, Fixed-sequence, Chain or O'Brien.", call. = FALSE)
for (i in 1:length(mult_test_list)) {
if (tolower(mult_test_list[i]) == tolower(parameters$mult_test)) mult_test_index = i
}
parameters$mult_test_index = mult_test_index
}
if (n_comparisons >= 2 & n_endpoints >= 2) {
# Analysis of multiple endpoints and multiple treatment-control comparisons
parameters$mult_test_type = 3
n_hypotheses = n_comparisons * n_endpoints
mult_test_list = c("Holm", "Hochberg", "Hommel")
if (!tolower(parameters$mult_test) %in% tolower(mult_test_list)) stop("Multiple testing procedure (mult_test): Value must be Holm, Hochberg or Hommel.", call. = FALSE)
for (i in 1:length(mult_test_list)) {
if (tolower(mult_test_list[i]) == tolower(parameters$mult_test)) mult_test_index = i
}
parameters$mult_test_index = mult_test_index
}
if (parameters$mult_test_type %in% c(1, 2)) {
# Chain procedure
if (mult_test_index == 6) {
if (is.null(parameters$weights)) {
weights = rep(1 / n_hypotheses, n_hypotheses)
} else {
weights =
ContinuousErrorCheck(parameters$weights,
n_hypotheses,
lower_values = c(0),
lower_values_sign = c(">="),
upper_values = c(1),
upper_values_sign = c("<="),
"Hypothesis weights (weights)",
c("Value"),
"double",
NA)
}
if (sum(weights) > 1) stop("Hypothesis weights (weights): Sum of weights must be less than or equal to 1.", call. = FALSE)
parameters$weights = weights
transition =
ContinuousErrorCheck(as.vector(parameters$transition),
n_hypotheses * n_hypotheses,
lower_values = c(0),
lower_values_sign = c(">="),
upper_values = c(1),
upper_values_sign = c("<="),
"Hypothesis transition matrix (transition)",
c("Value"),
"double",
NA)
if (!is.matrix(parameters$transition)) stop("Hypothesis transition matrix (transition) must be a matrix.", call. = FALSE)
if (any(dim(parameters$transition) != c(n_hypotheses, n_hypotheses))) stop("Hypothesis transition matrix (transition) does not have the correction dimensions.", call. = FALSE)
for (i in 1:n_hypotheses) if (sum(parameters$transition[i, ]) > 1) stop("Hypothesis transition matrix (transition): The sum of elements in each row must be less than or equal to 1.", call. = FALSE)
parameters$ctransition = t(parameters$transition)
}
# All other procedures but fixed-sequence or chain
if (mult_test_index %in% c(1, 2, 3, 4)) {
if (is.null(parameters$weights)) {
weights = rep(1 / n_hypotheses, n_hypotheses)
} else {
weights =
ContinuousErrorCheck(parameters$weights,
n_hypotheses,
lower_values = c(0),
lower_values_sign = c(">"),
upper_values = c(1),
upper_values_sign = c("<"),
"Hypothesis weights (weights)",
c("Value"),
"double",
NA)
}
if (sum(weights) > 1) stop("Sum of hypothesis weights (weights) must be less than or equal to 1.", call. = FALSE)
parameters$weights = weights
parameters$transition = 0
parameters$ctransition = 0
}
# Fixed-sequence procedure
if (mult_test_index == 5) {
sequence =
ContinuousErrorCheck(parameters$sequence,
n_hypotheses,
lower_values = c(1),
lower_values_sign = c(">="),
upper_values = c(n_hypotheses),
upper_values_sign = c("<="),
"Hypothesis testing sequence (sequence)",
c("Value"),
"int",
NA)
if (any(sort(parameters$sequence) != 1:n_hypotheses)) stop("Hypothesis testing sequence for the fixed-sequence procedure (sequence) is not correctly specified.", call. = FALSE)
parameters$weights = parameters$sequence
parameters$transition = 0
parameters$ctransition = 0
}
# Global test
if (mult_test_index == 7) {
parameters$weights = 0
parameters$transition = 0
parameters$ctransition = 0
}
}
if (parameters$mult_test_type == 3) {
mult_method_list = c("Standard", "Modified", "Enhanced")
if (!tolower(parameters$mult_method) %in% tolower(mult_method_list)) stop("Mixture method (mult_method): Value must be Standard, Modified or Enhanced.", call. = FALSE)
for (i in 1:length(mult_method_list)) {
if (tolower(mult_method_list[i]) == tolower(parameters$mult_method)) mult_method_index = i
}
parameters$mult_method_index = mult_method_index
# Truncation parameters
mult_test_gamma =
ContinuousErrorCheck(as.vector(parameters$mult_test_gamma),
n_endpoints,
lower_values = c(0),
lower_values_sign = c(">"),
upper_values = c(1),
upper_values_sign = c("<="),
"Truncation parameters (mult_test_gamma)",
c("Value"),
"double",
NA)
for (i in 1:(n_endpoints - 1)) {
if (mult_test_gamma[i] == 1) stop("Truncation parameters (mult_test_gamma): Value must be less than 1 in all families except for the last one.", call. = FALSE)
}
parameters$mult_test_gamma[n_endpoints] = 1
}
if (parameters$mult_test_type %in% c(2, 3)) {
# Correlation matrix
endpoint_correlation =
ContinuousErrorCheck(as.vector(parameters$endpoint_correlation),
n_endpoints * n_endpoints,
lower_values = c(0),
lower_values_sign = c(">="),
upper_values = c(1),
upper_values_sign = c("<="),
"Endpoint correlation matrix (endpoint_correlation)",
c("Value"),
"double",
NA)
parameters$corr_sum = sum(parameters$endpoint_correlation)
if (!is.matrix(parameters$endpoint_correlation)) stop("Endpoint correlation matrix (endpoint_correlation) must be a matrix.", call. = FALSE)
if (any(dim(parameters$endpoint_correlation) != c(n_endpoints, n_endpoints))) stop("Endpoint correlation matrix (endpoint_correlation) does not have the correction dimensions.", call. = FALSE)
if (det(parameters$endpoint_correlation) <= 0) stop("Endpoint correlation matrix (endpoint_correlation) must be positive definite.", call. = FALSE)
}
#############################################
parameters$n_hypotheses = n_hypotheses
parameters$means = 0
parameters$sds = 0
parameters$rates = 0
parameters$hazard_rates = 0
parameters$dropout_parameter = 0
parameters$enrollment_distribution = 2
# All means and SDs
if (endpoint_index == 1) {
parameters$means = c(parameters$control_mean, parameters$treatment_mean)
parameters$sds = c(parameters$control_sd, parameters$treatment_sd)
parameters$enrollment_period = 0
parameters$enrollment_parameter = 0
parameters$event_count = 0
parameters$control_rate = 0
if (parameters$mult_test_type != 3) parameters$treatment_rate = 0 else parameters$treatment_rate = matrix(0, 1, 1)
parameters$control_hazard_rate = 0
if (parameters$mult_test_type != 3) parameters$treatment_hazard_rate = 0 else parameters$treatment_hazard_rate = matrix(0, 1, 1)
}
# All rates
if (endpoint_index == 2) {
parameters$rates = c(parameters$control_rate, parameters$treatment_rate)
parameters$enrollment_period = 0
parameters$enrollment_parameter = 0
parameters$event_count = 0
parameters$control_mean = rep(0, n_endpoints)
if (parameters$mult_test_type != 3) parameters$treatment_mean = rep(0, n_endpoints) else parameters$treatment_mean = matrix(rep(0, n_endpoints), 1, n_endpoints)
parameters$control_sd = rep(1, n_endpoints)
if (parameters$mult_test_type != 3) parameters$treatment_sd = rep(1, n_endpoints) else parameters$treatment_sd = matrix(rep(1, n_endpoints), 1, n_endpoints)
parameters$control_hazard_rate = 0
if (parameters$mult_test_type != 3) parameters$treatment_hazard_rate = 0 else parameters$treatment_hazard_rate = matrix(0, 1, 1)
}
# Total sample size after accounting for dropout rates
if (endpoint_index != 3) {
parameters$sample_size_adj = floor(parameters$sample_size * (1 - parameters$dropout_rate))
} else {
parameters$sample_size_adj = parameters$sample_size
}
parameters$max_sample_size = max(parameters$sample_size_adj)
###########################################################
# Run simulations to compute key characteristics
# Analysis of multiple treatment-control comparisons
if (parameters$mult_test_type == 1) {
simulations = MultAdj1NCores(parameters)
sim_results = simulations$sim_results
# Add column names
column_names = NULL
for (i in 1:n_comparisons) column_names = c(column_names, paste0("pvalue", i))
for (i in 1:n_comparisons) column_names = c(column_names, paste0("adjpvalue", i))
colnames(sim_results) = column_names
sim_summary = list()
# Unadjusted power
pvalue = sim_results[, 1:n_comparisons]
sim_summary$power = colMeans(pvalue <= alpha)
# Adjusted overall power
adj_pvalue = sim_results[, (n_comparisons + 1):(2 * n_comparisons)]
sim_summary$adj_power = colMeans(adj_pvalue <= alpha)
# Disjunctive and conjunctive power
disj_power = 0
conj_power = 0
for (i in 1:nsims) {
disj_power = disj_power + any(adj_pvalue[i, ] <= alpha)
conj_power = conj_power + all(adj_pvalue[i, ] <= alpha)
}
sim_summary$disj_power = disj_power / nsims
sim_summary$conj_power = conj_power / nsims
}
# Analysis of multiple endpoints
if (parameters$mult_test_type == 2) {
simulations = MultAdj2NCores(parameters)
sim_results = simulations$sim_results
# Add column names
column_names = NULL
for (i in 1:n_endpoints) column_names = c(column_names, paste0("pvalue", i))
for (i in 1:n_endpoints) column_names = c(column_names, paste0("adjpvalue", i))
colnames(sim_results) = column_names
sim_summary = list()
# Unadjusted power
pvalue = sim_results[, 1:n_endpoints]
sim_summary$power = colMeans(pvalue <= alpha)
# Adjusted marginal power
if (parameters$mult_test_index <= 6) {
adj_pvalue = sim_results[, (n_endpoints + 1):(2 * n_endpoints)]
sim_summary$adj_power = colMeans(adj_pvalue <= alpha)
# Disjunctive and conjunctive power
disj_power = 0
conj_power = 0
for (i in 1:nsims) {
disj_power = disj_power + any(adj_pvalue[i, ] <= alpha)
conj_power = conj_power + all(adj_pvalue[i, ] <= alpha)
}
sim_summary$disj_power = disj_power / nsims
sim_summary$conj_power = conj_power / nsims
}
# Adjusted overall power
if (parameters$mult_test_index == 7) {
adj_pvalue = sim_results[, n_endpoints + 1]
sim_summary$adj_power = mean(adj_pvalue <= alpha)
}
}
# Analysis of multiple treatment-control comparisons and multiple endpoints
if (parameters$mult_test_type == 3) {
simulations = MultAdj3NCores(parameters)
sim_results = simulations$sim_results
# Add column names
column_names = NULL
for (i in 1:n_hypotheses) column_names = c(column_names, paste0("pvalue", i))
for (i in 1:n_hypotheses) column_names = c(column_names, paste0("adjpvalue", i))
colnames(sim_results) = column_names
sim_summary = list()
# Unadjusted power
pvalue = sim_results[, 1:n_hypotheses]
sim_summary$power = colMeans(pvalue <= alpha)
# Adjusted overall power
adj_pvalue = sim_results[, (n_hypotheses + 1):(2 * n_hypotheses)]
sim_summary$adj_power = colMeans(adj_pvalue <= alpha)
# Disjunctive and conjunctive power for each endpoint
disj_power = rep(0, n_endpoints)
conj_power = rep(0, n_endpoints)
for (i in 1:nsims) {
k = 0
for (j in 1:n_endpoints) {
disj_power[j] = disj_power[j] + any(adj_pvalue[i, (k + 1):(k + n_comparisons)] <= alpha)
conj_power[j] = conj_power[j] + all(adj_pvalue[i, (k + 1):(k + n_comparisons)] <= alpha)
k = k + n_comparisons
}
}
sim_summary$disj_power = disj_power / nsims
sim_summary$conj_power = conj_power / nsims
}
results = list(parameters = parameters,
sim_results = sim_results,
sim_summary = sim_summary)
class(results) = "MultAdjResults"
return(results)
}
MultAdjReportDoc = function(results) {
#############################################################################
# Error checks
if (!is(results, "MultAdjResults")) stop("The object was not created by the MultAdj function", call. = FALSE)
#############################################################################
# Empty list of tables to be included in the report
item_list = list()
item_index = 1
table_index = 1
figure_index = 1
width = 6.5
height = 5
parameters = results$parameters
sim_summary = results$sim_summary
endpoint_index = parameters$endpoint_index
ncomparisons = parameters$n_comparisons
nendpoints = parameters$n_endpoints
nhypotheses = parameters$n_hypotheses
mult_test_type = parameters$mult_test_type
mult_test_index = parameters$mult_test_index
# Trial arms
trial_arms = "Control"
if (ncomparisons >= 2) {
for (i in 1:ncomparisons) trial_arms = c(trial_arms, paste0("Treatment ", i))
} else {
trial_arms = c(trial_arms, "Treatment")
}
# Endpoints
endpoints = rep("", nendpoints)
if (nendpoints >= 2) {
for (i in 1:nendpoints) endpoints[i] = paste0("Endpoint ", i)
}
# Hypotheses
short_hypotheses = rep("", nhypotheses)
for (i in 1:nhypotheses) short_hypotheses[i] = paste0("H", i)
hypotheses = rep("", nhypotheses)
for (i in 1:nhypotheses) hypotheses[i] = paste0("Hypothesis ", i)
# Treatment effect assumptions
if (mult_test_type %in% c(1, 2)) {
# All means and SDs
if (endpoint_index == 1) {
means = c(parameters$control_mean, parameters$treatment_mean)
sds = c(parameters$control_sd, parameters$treatment_sd)
}
# All rates
if (endpoint_index == 2) {
rates = c(parameters$control_rate, parameters$treatment_rate)
}
}
# Treatment effect assumptions
if (mult_test_type == 3) {
# All means and SDs
if (endpoint_index == 1) {
means = cbind(parameters$control_mean, parameters$treatment_mean)
sds = cbind(parameters$control_sd, parameters$treatment_sd)
}
# All rates
if (endpoint_index == 2) {
rates = cbind(parameters$control_rate, parameters$treatment_rate)
}
}
#############################################################################
report_title = "Traditional design with multiple objectives"
endpoint_labels = c("normally distributed", "binary")
if (mult_test_type == 1) item_list[[item_index]] = list(type = "paragraph", label = "Description", value = paste0("The simulation report presents key operating characteristics of a multiplicity adjustment for multiple treatment-control comparisons in a trial with a ", tolower(endpoint_labels[endpoint_index]), " endpoint."))
if (mult_test_type == 2) item_list[[item_index]] = list(type = "paragraph", label = "Description", value = paste0("The simulation report presents key operating characteristics of a multiplicity adjustment or a global testing procedure for multiple endpoints in a trial with a ", tolower(endpoint_labels[endpoint_index]), " endpoint."))
if (mult_test_type == 3) item_list[[item_index]] = list(type = "paragraph", label = "Description", value = paste0("The simulation report presents key operating characteristics of a multiple testing procedure (gatekeeping procedure) for multiple endpoints and multiple treatment-control comparisons in a trial with a ", tolower(endpoint_labels[endpoint_index]), " endpoint."))
item_index = item_index + 1
#############################################################################
column_names = c("Trial arm", "Sample size")
col1 = trial_arms
col2 = parameters$sample_size
data_frame = data.frame(col1, col2)
title = paste0("Table ", table_index, ". Number of enrolled patients")
column_width = c(5, 1.5)
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
#############################################################################
if (mult_test_type == 1) {
column_names = c("Trial arm", "Parameter", "Value")
col1 = NULL
col2 = NULL
col3 = NULL
for (i in 1:(ncomparisons + 1)) {
if (endpoint_index == 1) {
col1 = c(col1, trial_arms[i], "")
col2 = c(col2, "Mean", "SD")
col3 = c(col3, means[i], sds[i])
}
if (endpoint_index == 2) {
col1 = c(col1, trial_arms[i])
col2 = c(col2, "Rate (%)")
col3 = c(col3, 100 * rates[i])
}
}
data_frame = data.frame(col1, col2, col3)
column_width = c(2.5, 2.5, 1.5)
}
if (mult_test_type == 2) {
column_names = c("Endpoint", "Trial arm", "Parameter", "Value")
col1 = NULL
col2 = NULL
col3 = NULL
col4 = NULL
for (i in 1:nendpoints) {
if (endpoint_index == 1) {
col1 = c(col1, endpoints[i], rep("", 3))
col2 = c(col2, "Control", "", "Treatment", "")
col3 = c(col3, "Mean", "SD", "Mean", "SD")
col4 = c(col4, parameters$control_mean[i], parameters$control_sd[i], parameters$treatment_mean[i], parameters$treatment_sd[i])
}
if (endpoint_index == 2) {
col1 = c(col1, endpoints[i], "")
col2 = c(col2, "Control", "Treatment")
col3 = c(col3, "Rate (%)", "Rate (%)")
col4 = c(col4, 100 * parameters$control_rate[i], 100 * parameters$treatment_rate[i])
}
}
data_frame = data.frame(col1, col2, col3, col4)
column_width = c(1.5, 1.5, 2, 1.5)
}
if (mult_test_type == 3) {
column_names = c("Endpoint", "Trial arm", "Parameter", "Value")
col1 = NULL
col2 = NULL
col3 = NULL
col4 = NULL
for (i in 1:nendpoints) {
for (j in 1:(ncomparisons + 1)) {
if (endpoint_index == 1) {
col1 = c(col1, endpoints[i], "")
col2 = c(col2, trial_arms[j], "")
col3 = c(col3, "Mean", "SD")
col4 = c(col4, means[i, j], sds[i, j])
}
if (endpoint_index == 2) {
col1 = c(col1, endpoints[i])
col2 = c(col2, trial_arms[j])
col3 = c(col3, "Rate (%)")
col4 = c(col4, 100 * rates[i, j])
}
}
}
data_frame = data.frame(col1, col2, col3, col4)
column_width = c(1.5, 1.5, 2, 1.5)
}
if (parameters$direction_index == 1) footnote = "A higher value of the endpoint indicates a beneficial effect."
if (parameters$direction_index == 2) footnote = "A lower value of the endpoint indicates a beneficial effect."
title = paste0("Table ", table_index, ". Treatment effect assumptions")
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE, footnote)
item_index = item_index + 1
table_index = table_index + 1
#############################################################################
if (mult_test_type == 1) {
column_names = c("Hypothesis", "Definition")
col1 = hypotheses
col2 = rep("", ncomparisons)
for (i in 1:ncomparisons) col2[i] = paste0("Null hypothesis of no difference between Treatment ", i, " and control")
data_frame = data.frame(col1, col2)
column_width = c(1.5, 5)
title = paste0("Table ", table_index, ". Hypothesis definitions")
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
}
if (mult_test_type == 2) {
column_names = c("Hypothesis", "Definition")
col1 = hypotheses
col2 = rep("", nendpoints)
for (i in 1:nendpoints) col2[i] = paste0("Null hypothesis of no difference between the treatment and control with respect to Endpoint ", i)
data_frame = data.frame(col1, col2)
column_width = c(1.5, 5)
title = paste0("Table ", table_index, ". Hypothesis definitions")
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
}
if (mult_test_type == 3) {
column_names = c("Hypothesis", "Definition")
col1 = hypotheses
col2 = rep("", ncomparisons * nendpoints)
k = 1
for (i in 1:nendpoints) {
for (j in 1:ncomparisons) {
col2[k] = paste0("Null hypothesis of no difference between Treatment ", j, " and control with respect to Endpoint ", i)
k = k + 1
}
}
data_frame = data.frame(col1, col2)
column_width = c(1.5, 5)
title = paste0("Table ", table_index, ". Hypothesis definitions")
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
}
#############################################################################
if (mult_test_type %in% c(2, 3)) {
column_names = c("Endpoint", endpoints)
data_frame = cbind(endpoints, parameters$endpoint_correlation)
column_width = c(1, rep(5.5 / nendpoints, nendpoints))
title = paste0("Table ", table_index, ". Endpoint correlation matrix")
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
}
#############################################################################
if (mult_test_type %in% c(1, 2)) {
if (mult_test_index <= 6) {
column_names = c("Parameter", "Value")
col1 = c("Multiple testing procedure")
col2 = c(parameters$mult_test)
data_frame = data.frame(col1, col2)
column_width = c(5, 1.5)
title = paste0("Table ", table_index, ". Multiple testing procedure")
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
# Fixed-sequence procedure
if (mult_test_index == 5) {
column_names = short_hypotheses
data_frame = as.data.frame(matrix(0, 1, nhypotheses))
data_frame[1, ] = round(parameters$sequence)
title = paste0("Table ", table_index, ". Multiple testing procedure: Hypothesis testing sequence")
column_width = c(rep(6.5 / nhypotheses, nhypotheses))
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
}
# All other procedures but fixed-sequence
if (mult_test_index %in% c(1, 2, 3, 4, 6)) {
column_names = short_hypotheses
data_frame = as.data.frame(matrix(0, 1, nhypotheses))
data_frame[1, ] = round(parameters$weights, 4)
title = paste0("Table ", table_index, ". Multiple testing procedure: Initial hypothesis weights")
column_width = c(rep(6.5 / nhypotheses, nhypotheses))
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
}
# Chain procedure
if (mult_test_index == 6) {
data_frame = as.data.frame(matrix(0, nhypotheses, nhypotheses + 1))
data_frame[, 1] = hypotheses
temp = round(parameters$transition, 4)
temp = matrix(temp, nhypotheses, nhypotheses)
data_frame[, 2:(nhypotheses + 1)] = temp
column_names = c("Hypothesis", short_hypotheses)
title = paste0("Table ", table_index, ". Multiple testing procedure: Transition parameters")
column_width = c(1.25, rep(5.25 / nhypotheses, nhypotheses))
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
}
}
if (mult_test_index == 7) {
column_names = c("Parameter", "Value")
col1 = c("Global testing procedure")
col2 = c(parameters$mult_test)
data_frame = data.frame(col1, col2)
column_width = c(5, 1.5)
title = paste0("Table ", table_index, ". Global testing procedure")
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
}
}
if (mult_test_type == 3) {
column_names = c("Parameter", "Value")
col1 = c("Component procedure", "Mixture method", "Truncation parameters")
col2 = c(parameters$mult_test, parameters$mult_method, paste0(parameters$mult_test_gamma, collapse = ", "))
data_frame = data.frame(col1, col2)
column_width = c(5, 1.5)
title = paste0("Table ", table_index, ". Multiple testing procedure (Gatekeeping procedure)")
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
}
#############################################################################
column_names = c("Parameter", "Value")
if (endpoint_index %in% c(1, 2)) {
col1 = c("Dropout rate (%)")
col2 = c(100 * parameters$dropout_rate)
}
data_frame = data.frame(col1, col2)
title = paste0("Table ", table_index, ". Other design parameters")
column_width = c(5, 1.5)
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE)
item_index = item_index + 1
table_index = table_index + 1
#############################################################################
column_names = c("Parameter", "Value")
col1 = c("One-sided Type I error rate", "Number of simulations")
col2 = c(sprintf("%0.3f", sum(parameters$alpha)),
sprintf("%d", parameters$nsims))
data_frame = data.frame(col1, col2)
title = paste0("Table ", table_index, ". Simulation parameters")
column_width = c(5, 1.5)
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, TRUE)
item_index = item_index + 1
table_index = table_index + 1
#############################################################################
# Traditional multiplicity adjustments or gatekeeping procedures
if (mult_test_type == 1 | (mult_test_type == 2 & mult_test_index <= 6) | mult_test_type == 3) {
column_names = c("Hypothesis", "Power (%)", "Adjusted power (%)")
col1 = hypotheses
col2 = round(100 * sim_summary$power, 1)
col3 = round(100 * sim_summary$adj_power, 1)
data_frame = data.frame(col1, col2, col3)
title = paste0("Table ", table_index, ". Simulation results: Hypothesis-specific power")
column_width = c(2.5, 2, 2)
footnote = "Power: Probability of rejecting each hypothesis of no effect without a multiplicity adjustment. Adjusted power: Probability of rejecting each hypothesis of no effect using a multiplicity adjustment based on the specified multiple testing procedure."
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE, footnote)
item_index = item_index + 1
table_index = table_index + 1
}
# Global testing procedure
if (mult_test_type == 2 & mult_test_index == 7) {
column_names = c("Hypothesis", "Power (%)")
col1 = hypotheses
col2 = round(100 * sim_summary$power, 1)
data_frame = data.frame(col1, col2)
title = paste0("Table ", table_index, ". Simulation results: Hypothesis-specific power")
column_width = c(2.5, 4)
footnote = "Power: Probability of rejecting each hypothesis of no effect without a multiplicity adjustment."
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE, footnote)
item_index = item_index + 1
table_index = table_index + 1
column_names = c("Overall power", "Power (%)")
col1 = c("Global power")
col2 = round(100 * sim_summary$adj_power, 1)
data_frame = data.frame(col1, col2)
title = paste0("Table ", table_index, ". Simulation results: Overall power")
column_width = c(2.5, 4)
footnote = "Global power: Probability of rejecting at least one hypothesis of no effect using the specified global testing approach."
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE, footnote)
item_index = item_index + 1
table_index = table_index + 1
}
# Traditional multiplicity adjustments
if (mult_test_type == 1 | (mult_test_type == 2 & mult_test_index <= 6)) {
column_names = c("Overall power", "Power (%)")
col1 = c("Disjunctive power", "Conjunctive power")
col2 = c(round(100 * sim_summary$disj_power, 1), round(100 * sim_summary$conj_power, 1))
data_frame = data.frame(col1, col2)
title = paste0("Table ", table_index, ". Simulation results: Overall power")
column_width = c(2.5, 4)
footnote = "Disjunctive power: Probability of rejecting at least one hypothesis of no effect using a multiplicity adjustment based on the specified multiple testing procedure. Conjunctive power: Probability of rejecting all hypotheses of no effect using a multiplicity adjustment based on the specified multiple testing procedure."
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE, footnote)
item_index = item_index + 1
table_index = table_index + 1
}
# Gatekeeping procedures
if (mult_test_type == 3) {
column_names = c("Endpoint family", "Overall power", "Power (%)")
col1 = NULL
col2 = NULL
col3 = NULL
for (i in 1:nendpoints) {
col1 = c(col1, paste0("Endpoint ", i), "")
col2 = c(col2, "Disjunctive power", "Conjunctive power")
col3 = c(col3, round(100 * sim_summary$disj_power[i], 1), round(100 * sim_summary$conj_power[i], 1))
}
data_frame = data.frame(col1, col2, col3)
title = paste0("Table ", table_index, ". Simulation results: Overall power")
column_width = c(2.5, 2, 2)
footnote = "Disjunctive power: Probability of rejecting at least one hypothesis of no effect within each endpoint family using a multiplicity adjustment based on the specified multiple testing procedure. Conjunctive power: Probability of rejecting all hypotheses of no effect within each endpoint family using a multiplicity adjustment based on the specified multiple testing procedure."
item_list[[item_index]] = CreateTable(data_frame, column_names, column_width, title, FALSE, footnote)
item_index = item_index + 1
table_index = table_index + 1
}
#############################################################################
report = item_list
doc = SaveReport(report, report_title)
return(doc)
}
# End of MultAdjReportDoc
# --==[ MultAdj1 ]==--
MultAdj1NCores = function(parameters) {
ncores = parameters$ncores
# Run simulations on multiple cores to compute key characteristics
if (ncores > 1) {
# nocov start
cl = parallel::makeCluster(ncores)
# Export all functions in the global environment to each node
parallel::clusterExport(cl, ls(envir = .GlobalEnv))
doParallel::registerDoParallel(cl)
simulation_list = foreach(counter=(1:ncores), .packages = c("MedianaDesigner")) %dorng% {
MultAdj1SingleCore(parameters)
}
stopCluster(cl)
# Combine the simulation results across the cores
sim_results = NULL
for (i in 1:ncores) {
sim_results = rbind(sim_results, simulation_list[[i]]$sim_results)
}
simulations = list(sim_results = sim_results)
# nocov end
} else {
simulations = MultAdj1SingleCore(parameters)
}
return(simulations)
}
MultAdj1SingleCore = function(parameters) {
params_for_core = parameters
params_for_core$nsims = parameters$nsims_per_core
simulations = MultAdjC1(params_for_core)
return(simulations)
}
# --==[ MultAdj2 ]==--
MultAdj2NCores = function(parameters) {
ncores = parameters$ncores
# Run simulations on multiple cores to compute key characteristics
if (ncores > 1) {
# nocov start
cl = parallel::makeCluster(ncores)
# Export all functions in the global environment to each node
parallel::clusterExport(cl, ls(envir = .GlobalEnv))
doParallel::registerDoParallel(cl)
simulation_list = foreach(counter=(1:ncores), .packages = c("MedianaDesigner")) %dorng% {
MultAdj2SingleCore(parameters)
}
stopCluster(cl)
# Combine the simulation results across the cores
sim_results = NULL
for (i in 1:ncores) {
sim_results = rbind(sim_results, simulation_list[[i]]$sim_results)
}
simulations = list(sim_results = sim_results)
# nocov end
} else {
simulations = MultAdj2SingleCore(parameters)
}
return(simulations)
}
MultAdj2SingleCore = function(parameters) {
params_for_core = parameters
params_for_core$nsims = parameters$nsims_per_core
simulations = MultAdjC2(params_for_core)
return(simulations)
}
# --==[ MultAdj3 ]==--
MultAdj3NCores = function(parameters) {
ncores = parameters$ncores
# Run simulations on multiple cores to compute key characteristics
if (ncores > 1) {
# nocov start
cl = parallel::makeCluster(ncores)
# Export all functions in the global environment to each node
parallel::clusterExport(cl, ls(envir = .GlobalEnv))
doParallel::registerDoParallel(cl)
simulation_list = foreach(counter=(1:ncores), .packages = c("MedianaDesigner")) %dorng% {
MultAdj3SingleCore(parameters)
}
stopCluster(cl)
# Combine the simulation results across the cores
sim_results = NULL
for (i in 1:ncores) {
sim_results = rbind(sim_results, simulation_list[[i]]$sim_results)
}
simulations = list(sim_results = sim_results)
# nocov end
} else {
simulations = MultAdj3SingleCore(parameters)
}
return(simulations)
}
MultAdj3SingleCore = function(parameters) {
params_for_core = parameters
params_for_core$nsims = parameters$nsims_per_core
simulations = MultAdjC3(params_for_core)
return(simulations)
}
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