---
title: "Maraca Plots - Basic Usage"
author: "Martin Karpefors, Samvel B. Gasparyan, Stefano Borini"
date: "`r Sys.Date()`"
output: rmarkdown::html_vignette
vignette: >
  %\VignetteIndexEntry{Maraca Plots - Basic Usage}
  %\VignetteEngine{knitr::rmarkdown}
  \usepackage[utf8]{inputenc}
---

```{r setup, include = FALSE}
knitr::opts_chunk$set(echo = TRUE, collapse = TRUE)
library(dplyr)
library(ggplot2)
library(maraca)
```

This vignette is largely based on the
publication 'The maraca plot -- a novel visualization of hierarchical composite endpoints'
<a href="https://doi.org/10.1177/17407745221134949" target="_blank">doi:10.1177/17407745221134949</a> as well as
pages 1-6 of the <a href="https://doi.org/10.25384/SAGE.21558565.v1" 
target="_blank">supplement</a>.

# Introduction

Hierarchical composite endpoints (HCE) are complex endpoints combining events of different clinical importance into an ordinal outcome that prioritize the most severe event of a patient. Up to now, one of the difficulties in interpreting HCEs has been the lack of proper tools for visualizing the treatment effect captured by HCE. This package makes it possible to visualize endpoints consisting of the combination of one to several time-to-event (TTE) outcomes (like Death, Hospitalization for heart failure, …) with one continuous outcome (like a symptom score).

The maraca plot captures all important features of how the HCE measures the treatment effect:\n
*1.* the percentage of time-to-event outcomes in the overall population,
*2.* the treatment effect on the combined and individual time-to-event outcomes, and 
*3.* the treatment effect on the continuous component.

# Basic usage

Plotting with maraca requires to have the data in an appropriate format.
We provide a few scenarios in the package, named `hce_scenario_a`,
`hce_scenario_b`, `hce_scenario_c` and `hce_scenario_d`. These scenarios cover four cases: a) Treatment effect is driven by a combination of TTE outcomes and continuous outcome, b) No treatment effect on neither the TTE outcomes nor on the continuous outcome, c) A large treatment effect on time-to-event outcomes, but no effect on continuous outcome, and finally d) A small treatment effect on time-to-event outcomes, with a larger effect on continuous outcomes, respectively. 
Other HCE scenarios can easily be simulated with the [hce package](https://cran.r-project.org/package=hce). The hce package is also used for win odds calculations in the maraca package.

```{r maraca1, eval = TRUE}
library(maraca)

data(hce_scenario_a, package = "maraca")

data <- hce_scenario_a
head(data)
```

The `data` data frame contains information on various columns. These columns
may have arbitrary names, so the `maraca` function allows you to specify
these names and how they map to the internal nomenclature using the
`column_names` parameter. This parameter is a named character vector, mapping
the standard names used by maraca with the column names in your dataset.

```{r maraca2, eval = TRUE}
column_names <- c(
    outcome = "GROUP",
    arm = "TRTP",
    value = "AVAL0"
)
```

the `outcome` column must be a character column containing the outcome
for each entry.

```{r maraca3, eval = TRUE}
unique(data[["GROUP"]])
```

The strings associated to each entry are arbitrary, so maraca
allows you to specify them in the `step_outcomes` and `last_outcome`
parameters. Make sure to specify the TTE outcomes in the correct order, starting from the most severe outcome to the least severe outcome. There can only be one continuous outcome.

```{r maraca4, eval = TRUE}
step_outcomes <- c(
  "Outcome I", "Outcome II", "Outcome III", "Outcome IV"
)
last_outcome <- "Continuous outcome"
```

the `arm` column must also be a character column describing to which arm
each row belongs.

```{r maraca5, eval = TRUE}
unique(data[["TRTP"]])
```

The strings associated to each entry are arbitrary, so maraca
allows you to specify them in the `arm_levels` parameter, as a named
vector of character strings. In this example, our file contains "Active"
and "Control" as identifiers, as seen in the output above, so we will specify

```{r maraca6, eval = TRUE}
arm_levels = c(active = "Active", control = "Control")
```

Finally, the `original` column must contain numerical values.

We also need to specify the follow-up time for the time-to event outcomes.
This can be one single timepoint (integer) for all time-to event outcomes
or individual timepoints for each.
Note that there can be no observed events in the data after the follow-up
time specified.

All of the above can be aggregated in the call to create a maraca object from
the given dataset

```{r maraca7, eval = TRUE}
mar <- maraca(
  data, step_outcomes, last_outcome, arm_levels, column_names, 
  fixed_followup_days = 3*365,
  compute_win_odds = TRUE
)
```

The win odds can be calculated and will be annotated in the maraca plot if available. However, it is not calculated by default. Please set the `compute_win_odds = TRUE` to make the calculation. The resulting estimate, 95% confidence levels and p-value will be shown in the maraca object and can also be retrieved with

```{r, eval = TRUE}
mar$win_odds
```


# Plotting the resulting object

To create a maraca plot, simply pass the maraca object as the first argument to the `plot` function. In addition to the maraca object, the user can optionally supply input parameters for selecting the `continuous_grid_spacing`; transforming the x-axis using "sqrt" in the `trans` argument; selecting different representations of the continuous distribution density in the `density_plot_type`; and setting `vline_type` to "mean" or "median".

The following types of plots that are available: "default", "violin", "box", "scatter". The default type is just a nested combination of violin and box plot. Figure 1A-D in reference 1 below, can be recreated through applying the maraca function with subsequent plotting on each of the scenario A-D datasets provided in this package. As an example scenario A is shown in the following plot. 

```{r maraca8, eval = TRUE, fig.width = 7, fig.height = 6}
plot(mar, continuous_grid_spacing_x = 20)
```

\newpage

```{r maraca9, eval = TRUE, fig.width = 7, fig.height = 6}
plot(mar, continuous_grid_spacing_x = 20, density_plot_type = "box")
```

\newpage

```{r maraca10, eval = TRUE, fig.width = 7, fig.height = 6}
plot(mar, continuous_grid_spacing_x = 20, density_plot_type = "scatter", vline_type = "mean")
```

\newpage

The plot_maraca function returns a ggplot2 object. This function will not render the plot immediately so you will have to print() it. 
Conveniently, you can customize your maraca plot with the comprehensive toolbox of ggplot2. For example:

```{r maraca11, eval = TRUE, fig.width = 7, fig.height = 6, message=FALSE, warning=FALSE}
p <- plot_maraca(mar, continuous_grid_spacing_x = 20, density_plot_type = "scatter", vline_type = "mean")
p + 
  scale_color_manual(values = c("#E69F00", "#999999")) + 
  theme(axis.text.x.bottom = element_text(vjust = 0.5, hjust = 0.5))
```

Note that some styling settings are already specified in the default plot version. The maraca package contains different styling
themes for the convenience of the user, including a version without any preset stylings. For more details, please take a look at
the vignette [Maraca Plots - Themes and Styling](themes.html).

The user can also use transformations on the x-axis for the
continuous outcomes in order to make the plot more readable,
such as log-transforming it.
One such transformation is to reverse the x-axis scale by
setting `trans = "reverse"`. This
could be of interest when lower values of the continuous outcome
are better than higher ones. In such a case, one also has to make
sure that the win odds are calculated correctly by 
including the parameter `lowerBetter = TRUE` in the `maraca()` or
`plot.adhce()` function.
```{r fig.width = 7, fig.height = 6}
Rates_A <- c(1.72, 1.74, 0.58, 1.5, 1)
Rates_P <- c(2.47, 2.24, 2.9, 4, 6)
hce_dat <- hce::simHCE(n = 2500, TTE_A = Rates_A, TTE_P = Rates_P,
              CM_A = -6, CM_P = 3, CSD_A = 15, CSD_P = 16, fixedfy = 3,
              seed = 31337)
plot(hce_dat, compute_win_odds = TRUE, lowerBetter = TRUE,
     trans = "reverse")
```

In some cases, there might be outliers that skew the displayed range for the
continuous endpoint. This might make it difficult to visualize the differences
between the treatment arms. There is an option to display the continuous
endpoint without the outliers by setting the parameter `remove_outliers = TRUE`
in the `plot.maraca()` or `plot.adhce()` function.
We define outliers here according to the common boxplot calculation definition:
any data outside the range 25th percentile - 1.5 * IQR (inter-quartile range)
and 75th percentile + 1.5 * IQR.

```{r maraca12, eval = TRUE, fig.width = 7, fig.height = 6}
plot(mar, continuous_grid_spacing_x = 20, remove_outliers = TRUE)
```

# References

Martin Karpefors, Daniel Lindholm and Samvel B. Gasparyan, "The maraca plot -- a novel visualization of hierarchical composite endpoints", Clinical Trials (2022).

