library(BayesianMCPMod)
library(clinDR)
library(dplyr)
set.seed(7015)In this vignette, we will show the use of the
BayesianMCPMod R package for trial planning for
continuously distributed data. As in the analysis example vignette, we focus on
the indication MDD and make use of historical data that is included in
the clinDR package. More specifically, trial results for BRINTELLIX will
be utilized to establish an informative prior for the control group.
A more general overview of the R package was provided with a poster presented during the PSI 2024 Conference.
This package makes use of the future framework for parallel processing, which can be set up as follows:
future::plan(future::multisession)In a first step, a meta analytic predictive prior will be calculated using historical data from 5 trials with main endpoint Change from baseline in MADRS score after 8 weeks. Please note that only information from the control group will be integrated leading to an informative mixture prior for the control group, while for the active groups a non-informative prior will be specified.
data("metaData")
testdata <- as.data.frame(metaData)
dataset <- filter(testdata, bname == "BRINTELLIX")
histcontrol <- filter(dataset, dose == 0, primtime == 8, indication == "MAJOR DEPRESSIVE DISORDER")
hist_data <- data.frame(
trial = histcontrol$nctno,
est = histcontrol$rslt,
se = histcontrol$se,
sd = histcontrol$sd,
n = histcontrol$sampsize)
sd_tot <- with(hist_data, sum(sd * n) / sum(n))We will make use of the same getPriorList() function as
in the analysis example vignette to
create a MAP prior.
dose_levels <- c(0, 2.5, 5, 10, 20)
prior_list <- getPriorList(
hist_data = hist_data,
dose_levels = dose_levels,
robust_weight = 0.3)For the hypothetical new trial, we plan with 4 active dose levels and
we specify a broad set of potential dose-response relationships,
including a linear, an exponential, an emax and 2 sigEMAX models.
Furthermore, we assume a maximum effect of -3 on top of control
(i.e. assuming that active treatment can reduce the MADRS score after 8
weeks by up to 15.8) and plan a trial with 80 patients for all active
groups and 60 patients for control.
exp <- DoseFinding::guesst(
d = 5,
p = c(0.2),
model = "exponential",
Maxd = max(dose_levels))
emax <- DoseFinding::guesst(
d = 2.5,
p = c(0.9),
model = "emax")
sigemax <- DoseFinding::guesst(
d = c(2.5, 5),
p = c(0.1, 0.6),
model = "sigEmax")
sigemax2 <- DoseFinding::guesst(
d = c(2, 4),
p = c(0.3, 0.8),
model = "sigEmax")
mods <- DoseFinding::Mods(
linear = NULL,
emax = emax,
exponential = exp,
sigEmax = rbind(sigemax, sigemax2),
doses = dose_levels,
maxEff = -3,
placEff = -12.8)
n_patients <- c(60, 80, 80, 80, 80)To calculate success probabilities for the different assumed dose-response models and the specified trial design we will apply the assessDesign function. For illustration purposes, the number of simulated trial results is reduced to 100 in this example.
success_probabilities <- assessDesign(
n_patients = n_patients,
mods = mods,
prior_list = prior_list,
sd = sd_tot,
n_sim = 100) # speed up example run-time
success_probabilities
#> $linear
#> Bayesian Multiple Comparison Procedure
#> Estimated Success Rate: 0.68
#> N Simulations: 100
#> Model Shape: lin emax exp sigE1 sigE2
#> Significance Freq: 0.59 0.21 0.59 0.48 0.36
#>
#> $emax
#> Bayesian Multiple Comparison Procedure
#> Estimated Success Rate: 0.82
#> N Simulations: 100
#> Model Shape: lin emax exp sigE1 sigE2
#> Significance Freq: 0.26 0.78 0.23 0.36 0.65
#>
#> $exponential
#> Bayesian Multiple Comparison Procedure
#> Estimated Success Rate: 0.63
#> N Simulations: 100
#> Model Shape: lin emax exp sigE1 sigE2
#> Significance Freq: 0.61 0.16 0.60 0.42 0.30
#>
#> $sigEmax1
#> Bayesian Multiple Comparison Procedure
#> Estimated Success Rate: 0.82
#> N Simulations: 100
#> Model Shape: lin emax exp sigE1 sigE2
#> Significance Freq: 0.63 0.52 0.58 0.73 0.76
#>
#> $sigEmax2
#> Bayesian Multiple Comparison Procedure
#> Estimated Success Rate: 0.84
#> N Simulations: 100
#> Model Shape: lin emax exp sigE1 sigE2
#> Significance Freq: 0.43 0.73 0.37 0.61 0.77
#>
#> attr(,"avgSuccessRate")
#> [1] 0.758
#> attr(,"placEff")
#> [1] -12.8
#> attr(,"maxEff")
#> [1] -3
#> attr(,"sampleSize")
#> [1] 60 80 80 80 80
#> attr(,"priorESS")
#> Ctr DG_1 DG_2 DG_3 DG_4
#> 20.6 1.0 1.0 1.0 1.0As an alternative, we will evaluate a design with the same overall sample size but allocating more patients on the highest dose group and control.
success_probabilities_uneq <- assessDesign(
n_patients = c(80, 60, 60, 60, 120),
mods = mods,
prior_list = prior_list,
sd = sd_tot,
n_sim = 100) # speed up example run-time
success_probabilities_uneq
#> $linear
#> Bayesian Multiple Comparison Procedure
#> Estimated Success Rate: 0.8
#> N Simulations: 100
#> Model Shape: lin emax exp sigE1 sigE2
#> Significance Freq: 0.76 0.50 0.75 0.65 0.61
#>
#> $emax
#> Bayesian Multiple Comparison Procedure
#> Estimated Success Rate: 0.84
#> N Simulations: 100
#> Model Shape: lin emax exp sigE1 sigE2
#> Significance Freq: 0.39 0.83 0.34 0.59 0.76
#>
#> $exponential
#> Bayesian Multiple Comparison Procedure
#> Estimated Success Rate: 0.81
#> N Simulations: 100
#> Model Shape: lin emax exp sigE1 sigE2
#> Significance Freq: 0.76 0.48 0.76 0.64 0.59
#>
#> $sigEmax1
#> Bayesian Multiple Comparison Procedure
#> Estimated Success Rate: 0.87
#> N Simulations: 100
#> Model Shape: lin emax exp sigE1 sigE2
#> Significance Freq: 0.73 0.66 0.71 0.84 0.80
#>
#> $sigEmax2
#> Bayesian Multiple Comparison Procedure
#> Estimated Success Rate: 0.86
#> N Simulations: 100
#> Model Shape: lin emax exp sigE1 sigE2
#> Significance Freq: 0.58 0.79 0.52 0.75 0.81
#>
#> attr(,"avgSuccessRate")
#> [1] 0.836
#> attr(,"placEff")
#> [1] -12.8
#> attr(,"maxEff")
#> [1] -3
#> attr(,"sampleSize")
#> [1] 80 60 60 60 120
#> attr(,"priorESS")
#> Ctr DG_1 DG_2 DG_3 DG_4
#> 20.6 1.0 1.0 1.0 1.0For this specific trial setting the adapted allocation ratio leads to increased success probabilities under all assumed dose response relationships.
Instead of specifying the assumed effects via the models, it is also possible to directly specify the effects for the individual dose levels via the dr_means input. This allows e.g. also the simulation of scenarios with a prior-data conflict.
success_probabilities <- assessDesign(
n_patients = c(60, 80, 80, 80, 80),
mods = mods,
prior_list = prior_list,
sd = sd_tot,
dr_means = c(-12, -14, -15, -16, -17),
n_sim = 100) # speed up example run-time
success_probabilities
#> $dose_resp
#> Bayesian Multiple Comparison Procedure
#> Estimated Success Rate: 0.99
#> N Simulations: 100
#> Model Shape: lin emax exp sigE1 sigE2
#> Significance Freq: 0.90 0.89 0.88 0.88 0.91
#>
#> attr(,"avgSuccessRate")
#> [1] 0.99
#> attr(,"placEff")
#> [1] -12
#> attr(,"maxEff")
#> [1] 5
#> attr(,"sampleSize")
#> [1] 60 80 80 80 80
#> attr(,"priorESS")
#> Ctr DG_1 DG_2 DG_3 DG_4
#> 20.6 1.0 1.0 1.0 1.0The assessment of the Minimally Efficacious Dose (MED) is integrated
in the assessDesign() function via the arguments
delta and evidence_level. If only the argument
delta is provided, the estimated model shapes will be used
to assess the MED. If both the arguments delta and
evidence_level are provided, a Bayesian decision rule of
the form \[\widehat{\text{MED}} = \text{arg
min}_{d\in\{d_1, \dots, d_k\}} \left\{ \text{Pr}\left(f(d, \hat\theta) -
f(d_1, \hat\theta) > \Delta\right) > \gamma \right\}\] will
be applied, see also ?getMED(). The computational cost for
the Bayesian decision rule within the assessDesign()
function is rather high depending on the number of simulated trial
outcomes, as the required quantiles need to be bootstrapped for each
true model shape and each simulated outcome. Thus, using the Bayesian
decision rule when assessing the trial’s design is only recommended when
using parallel computing.
success_probabilities_med <- assessDesign(
n_patients = c(60, 80, 80, 80, 80),
mods = mods,
prior_list = prior_list,
sd = sd_tot,
delta = 2,
n_sim = 100) # speed up example run-time
success_probabilities_med
#> $linear
#> Bayesian Multiple Comparison Procedure
#> Estimated Success Rate: 0.71
#> N Simulations: 100
#> Model Shape: lin emax exp sigE1 sigE2
#> Significance Freq: 0.61 0.27 0.61 0.53 0.43
#> MED Assessment
#> Selection Method: avgFit
#> Identification Rate: 0.71
#> Dose Level: 2.5 5.0 10.0 20.0
#> MED Freq: 0.01 0.03 0.22 0.45
#> MED not reached Freq: 0
#> No success in MCP step Freq: 0.29
#>
#> $emax
#> Bayesian Multiple Comparison Procedure
#> Estimated Success Rate: 0.83
#> N Simulations: 100
#> Model Shape: lin emax exp sigE1 sigE2
#> Significance Freq: 0.27 0.81 0.24 0.44 0.69
#> MED Assessment
#> Selection Method: avgFit
#> Identification Rate: 0.83
#> Dose Level: 2.5 5.0 10.0 20.0
#> MED Freq: 0.48 0.11 0.13 0.11
#> MED not reached Freq: 0
#> No success in MCP step Freq: 0.17
#>
#> $exponential
#> Bayesian Multiple Comparison Procedure
#> Estimated Success Rate: 0.71
#> N Simulations: 100
#> Model Shape: lin emax exp sigE1 sigE2
#> Significance Freq: 0.61 0.20 0.63 0.52 0.39
#> MED Assessment
#> Selection Method: avgFit
#> Identification Rate: 0.71
#> Dose Level: 2.5 5.0 10.0 20.0
#> MED Freq: 0.00 0.04 0.20 0.47
#> MED not reached Freq: 0
#> No success in MCP step Freq: 0.29
#>
#> $sigEmax1
#> Bayesian Multiple Comparison Procedure
#> Estimated Success Rate: 0.87
#> N Simulations: 100
#> Model Shape: lin emax exp sigE1 sigE2
#> Significance Freq: 0.64 0.52 0.61 0.84 0.79
#> MED Assessment
#> Selection Method: avgFit
#> Identification Rate: 0.84
#> Dose Level: 2.5 5.0 10.0 20.0
#> MED Freq: 0.04 0.16 0.44 0.20
#> MED not reached Freq: 0.03
#> No success in MCP step Freq: 0.13
#>
#> $sigEmax2
#> Bayesian Multiple Comparison Procedure
#> Estimated Success Rate: 0.85
#> N Simulations: 100
#> Model Shape: lin emax exp sigE1 sigE2
#> Significance Freq: 0.45 0.71 0.42 0.70 0.79
#> MED Assessment
#> Selection Method: avgFit
#> Identification Rate: 0.85
#> Dose Level: 2.5 5.0 10.0 20.0
#> MED Freq: 0.19 0.23 0.26 0.17
#> MED not reached Freq: 0
#> No success in MCP step Freq: 0.15
#>
#> attr(,"avgSuccessRate")
#> [1] 0.794
#> attr(,"placEff")
#> [1] -12.8
#> attr(,"maxEff")
#> [1] -3
#> attr(,"sampleSize")
#> [1] 60 80 80 80 80
#> attr(,"priorESS")
#> Ctr DG_1 DG_2 DG_3 DG_4
#> 20.6 1.0 1.0 1.0 1.0