---
title: "Overview"
output: rmarkdown::html_vignette
vignette: >
  %\VignetteIndexEntry{Overview}
  %\VignetteEngine{knitr::rmarkdown}
  %\VignetteEncoding{UTF-8}
---

```{r, include = FALSE}
knitr::opts_chunk$set(
  collapse = TRUE,
  comment = "#>",
  fig.align = "center",
  fig.width = 6
)
```

The `adaptr` package simulates adaptive (multi-arm, multi-stage) clinical trials
using adaptive stopping, adaptive arm dropping and/or response-adaptive
randomisation.

The package has been developed as part of the
[INCEPT (Intensive Care Platform Trial) project](https://incept.dk/), primarily
supported by a grant from [Sygeforsikringen "danmark"](https://www.sygeforsikring.dk/).

Additional guidance on the key methodological considerations when planning and
comparing adaptive clinical trials can be found in the open access article
*"[An overview of methodological considerations regarding adaptive stopping, arm dropping and randomisation in clinical trials](https://doi.org/10.1016/j.jclinepi.2022.11.002)"*
available in Journal of Clinical Epidemiology.

## Usage and workflow overview

The central functionality of `adaptr` and the typical workflow is illustrated
here.

### Setup

First, the package is loaded and a cluster of parallel workers is initiated by
the `setup_cluster()` function to facilitate parallel computing:

```{r}
library(adaptr)

setup_cluster(2)
```

Parallelisation is supported in many `adaptr` functions, and a cluster of
parallel workers can be setup for the entire session using `setup_cluster()`
early in the script as in this example. Alternatively, parallelisation
can be controlled by the global `"mc.cores"` option (set by calling
`options(mc.cores = <number>)`) or the `cores` argument of many functions.

### Specify trial design

Setup a trial specification (defining the trial design and scenario) using
the general `setup_trial()` function, or one of the special case variants using
default priors `setup_trial_binom()` (for binary, binomially distributed
outcomes; used in this example) or `setup_trial_norm()` (for continuous,
normally distributed outcomes).

The example trial specification has the following characteristics:

- A binary, binomially distributed, undesirable (default) outcome
- Three arms with no designated common control
- Identical underlying outcome probabilities of 25% in each arm
- Analyses conducted when specific number of patients have outcome data
available, with more patients randomised at all but the last look (lag due to
follow-up and data collection/verification)
- No explicitly defined stopping thresholds for `inferiority` or `superiority`
(default thresholds of < 1% and > 99%, respectively, apply)
- Equivalence stopping rule defined as > 90% probability (`equivalence_prob`) of
between-arm differences of all remaining arms being < 5 %-points
- Response-adaptive randomisation with minimum allocation probabilities of 20%
and softening of allocation ratios by a constant factor (`soften_power`)

See `?setup_trial()` for details on all the arguments or
`vignette("Basic-examples", "adaptr")` for **basic** example trial
specifications and a thorough review of the general trial specification
settings, and `vignette("Advanced-example", "adaptr")` for an **advanced**
example including details on how to specify user-written functions for
generating outcomes and posterior draws.

Below, the trial specification is setup and a human-readable overview printed:

```{r}
binom_trial <- setup_trial_binom(
  arms = c("Arm A", "Arm B", "Arm C"),
  true_ys = c(0.25, 0.25, 0.25),
  min_probs = rep(0.20, 3),
  data_looks = seq(from = 300, to = 2000, by = 100),
  randomised_at_looks = c(seq(from = 400, to = 2000, by = 100), 2000),
  equivalence_prob = 0.9,
  equivalence_diff = 0.05,
  soften_power = 0.5
)

print(binom_trial, prob_digits = 3)
```

By default, (most) probabilities are shown with 3 decimals. This can be changed
by explicitly `print()`ing the specification with the `prob_digits` arguments,
for example:

```{r}
print(binom_trial, prob_digits = 2)
```

### Calibration

In the example trial specification, there are no true between-arm differences,
and stopping rules for inferiority and superiority are not explicitly defined.
This is intentional, as these stopping rules will be calibrated to obtain a
desired probability of stopping for superiority in the scenario with no
between-arm differences (corresponding to the Bayesian type 1 error rate). Trial
specifications do not necessarily have to be calibrated. Instead,simulations can
be run directly using the `run_trials()` function covered below (or
`run_trial()` for a single simulation). This can be followed by assessment of
performance metrics, and manually changing the specification (including the
stopping rules) until performance metrics are considered acceptable. In this
example, a full calibration procedure is performed.

Calibration of a trial specification is done using the `calibrate_trial()`
function, which defaults to calibrate constant, symmetrical stopping rules
for inferiority and superiority (expecting a trial specification with
identical outcomes in each arm), but can be used to calibrate any parameter in a
trial specification towards any performance metric if a user-defined calibration
function (`fun`) is specified.

To perform the calibration, a `target` value, a `search_range`, a tolerance
value (`tol`), and the allowed direction of the tolerance value (`dir`) must be
specified (or alternatively, the defaults can be used). Of note, the number of
simulations in each calibration step here is lower than generally recommended
(to reduce the time required to build this vignette):

```{r}
# Calibrate the trial specification
calibrated_binom_trial <- calibrate_trial(
  trial_spec = binom_trial,
  n_rep = 1000, # 1000 simulations for each step (more generally recommended)
  base_seed = 4131, # Base random seed (for reproducible results)
  target = 0.05, # Target value for calibrated metric (default value)
  search_range = c(0.9, 1), # Search range for superiority stopping threshold
  tol = 0.01, # Tolerance range
  dir = -1 # Tolerance range only applies below target
)

# Print result (to check if calibration is successful)
calibrated_binom_trial
```

The calibration is successful (if not, results should not be used, and the
calibration settings should be changed and the calibration repeated).
The calibrated, constant stopping threshold for superiority is printed with the
results (`r calibrated_binom_trial$best_x`) and can be extracted using
`calibrated_binom_trial$best_x`. Using the default calibration functionality,
the calibrated, constant stopping threshold for inferiority is symmetrical,
i.e., `1 - stopping threshold for superiority`
(`r 1 - calibrated_binom_trial$best_x`). The calibrated trial specification
may be extracted using `calibrated_binom_trial$best_trial_spec` and, if printed,
will also include the calibrated stopping thresholds.

Calibration results may be saved and reloaded by using the `path` argument, to
avoid unnecessary repeated simulations.


### Summarising results

The results of the simulations using the calibrated trial specification
conducted during the calibration procedure may be extracted using
`calibrated_binom_trial$best_sims`. These results can be summarised with several
functions. Most of these functions support different 'selection strategies' for
simulations not ending with superiority, i.e., performance metrics can be
calculated assuming different arms would be used in clinical practice if no arm
is ultimately superior.

The `check_performance()` function summarises performance metrics in a tidy
`data.frame`, with uncertainty measures (bootstrapped confidence intervals) if
requested. Here, performance metrics are calculated considering the 'best' arm
(i.e., the one with the highest probability of being overall best) selected in
simulations not ending with superiority:

```{r}
# Calculate performance metrics with uncertainty measures
binom_trial_performance <- check_performance(
  calibrated_binom_trial$best_sims,
  select_strategy = "best",
  uncertainty = TRUE, # Calculate uncertainty measures
  n_boot = 1000, # 1000 bootstrap samples (more typically recommended)
  ci_width = 0.95, # 95% confidence intervals (default)
  boot_seed = "base" # Use same random seed for bootstrapping as for simulations
)

# Print results 
print(binom_trial_performance, digits = 2)
```

Similar results in `list` format (without uncertainty measures) can be obtained
using the `summary()` method (as known from, e.g., regression models in`R`),
which comes with a `print()` method providing formatted results. If the
simulation results are printed directly, this function is called with the
default arguments (all arguments, e.g., selection strategies may also be
directly supplied to the `print()` method).

```{r}
binom_trial_summary <- summary(
  calibrated_binom_trial$best_sims,
  select_strategy = "best"
)

print(binom_trial_summary, digits = 2)
```

Individual simulation results can be extracted in a tidy `data.frame` using
`extract_results()`:

```{r}
binom_trial_results <- extract_results(
  calibrated_binom_trial$best_sims,
  select_strategy = "best"
)

nrow(binom_trial_results) # Number of rows/simulations

head(binom_trial_results) # Print the first rows
```

Finally, the probabilities of different remaining arms and
their statuses (with uncertainty) at the last adaptive analysis can be
summarised using the `check_remaining_arms()` function (dropped arms will
be shown with an empty text string):

```{r}
check_remaining_arms(
  calibrated_binom_trial$best_sims,
  ci_width = 0.95 # 95% confidence intervals (default)
)
```

### Visualising results

Several visualisation functions are included (all are optional, and all require
the `ggplot2` package installed).

Convergence and stability of one or more performance metrics may be visually
assessed using `plot_convergence()` function:

```{r}
plot_convergence(
  calibrated_binom_trial$best_sims,
  metrics = c("size mean", "prob_superior", "prob_equivalence"),
  # select_strategy can be specified, but does not affect the chosen metrics
)
```

Plotting other metrics is possible; see the `plot_convergence()` documentation.
The simulation results may also be split into separate, consecutive batches when
assessing convergence, to further assess the stability:

```{r}
plot_convergence(
  calibrated_binom_trial$best_sims,
  metrics = c("size mean", "prob_superior", "prob_equivalence"),
  n_split = 4
)
```

The status probabilities for the overall trial according to trial progress can
be visualised using the `plot_status()` function:

```{r}
plot_status(
  calibrated_binom_trial$best_sims,
  x_value = "total n" # Total number of randomised patients at X-axis
)
```

Similarly, the status probabilities for one or more specific trial arms can be
visualised:

```{r}
plot_status(
  calibrated_binom_trial$best_sims,
  x_value = "total n",
  arm = NA # NA for all arms or character vector for specific arms
)
```

Finally, various metrics may be summarised over the progress of one or multiple
trial simulations using the `plot_history()` function, which requires non-sparse
results (the `sparse` argument must be `FALSE` in `calibrate_trials()`,
`run_trials()`, or `run_trial()`, leading to additional results being saved -
all other functions work with sparse results). This will be illustrated below.

### Use calibrated stopping thresholds in another scenario

The calibrated stopping thresholds (calibrated in a scenario with no between-arm
differences) may be used to run simulations with the same overall trial
specification, but according to a different scenario (i.e., with between-arm
differences present) to assess performance metrics (including the Bayesian
analogue of power).

First, a new trial specification is setup using the same settings as before,
except for between-arm differences and the calibrated stopping thresholds:

```{r}
binom_trial_calib_diff <- setup_trial_binom(
  arms = c("Arm A", "Arm B", "Arm C"),
  true_ys = c(0.25, 0.20, 0.30), # Different outcomes in the arms
  min_probs = rep(0.20, 3),
  data_looks = seq(from = 300, to = 2000, by = 100),
  randomised_at_looks = c(seq(from = 400, to = 2000, by = 100), 2000),
  # Stopping rules for inferiority/superiority explicitly defined
  # using the calibration results
  inferiority = 1 - calibrated_binom_trial$best_x,
  superiority = calibrated_binom_trial$best_x,
  equivalence_prob = 0.9,
  equivalence_diff = 0.05,
  soften_power = 0.5
)
```

Simulations using the trial specification with calibrated stopping thresholds
and differences present can then be conducted using the `run_trials()` function.
Here, we specify that non-sparse results will be returned (to illustrate the
`plot_history()` function).

```{r}
binom_trial_diff_sims <- run_trials(
  binom_trial_calib_diff,
  n_rep = 1000, # 1000 simulations (more generally recommended)
  base_seed = 1234, # Reproducible results
  sparse = FALSE # Return additional results for visualisation
)
```

Again, simulations may be saved and reloaded using the `path` argument.

We then calculate performance metrics as above:

```{r}
check_performance(
  binom_trial_diff_sims,
  select_strategy = "best",
  uncertainty = TRUE,
  n_boot = 1000, # 1000 bootstrap samples (more typically recommended)
  ci_width = 0.95,
  boot_seed = "base"
)
```

Similarly, overall trial statuses for the scenario with differences are
visualised:

```{r}
plot_status(binom_trial_diff_sims, x_value = "total n")
```

Statuses for each arm in this scenario are also visualised:

```{r}
plot_status(binom_trial_diff_sims, x_value = "total n", arm = NA)
```

We can plot the median and interquartile ranges of allocation probabilities in
each arm over time using the `plot_history()` function (requiring non-sparse
results, leading to substantially larger objects and files if saved):

```{r}
plot_history(
  binom_trial_diff_sims,
  x_value = "total n",
  y_value = "prob"
)
```

Similarly, the median (interquartile range) number of patients allocated to each
arm as the trial progresses can be visualised:

```{r}
plot_history(
  binom_trial_diff_sims,
  x_value = "total n",
  y_value = "n all"
)
```

Plotting other metrics is possible; see the `plot_history()` documentation.

## Citation

If you use the package, please consider citing it:

```{r}
citation(package = "adaptr")
```
