Author: Edouard F. Bonneville
Date: 2020-12-17

# Visualising multi-state models using mstate

#### Edouard F. Bonneville

#### 17 december 2020

# Preamble

The purpose of the present vignette is to demonstrate the visualisation capacities of mstate, using both base R graphics and the ggplot2 package (Wickham 2016). To do so, we will use the dataset used to illustrate competing risks analyses in Section 3 of the Tutorial by Putter, Fiocco, and Geskus (2007) . The dataset is available in mstate under the object name `aidssi`.

We can begin by loading both the mstate and ggplot2 libraries, and set a general theme for our plots:

    # Load libraries
    library(mstate)
    #> Loading required package: survival
    library(ggplot2)

    # Set general ggplot2 theme
    theme_set(theme_bw(base_size = 14))

We can then proceed to load the dataset, and prepare it for a competing risks analysis using `msprep()`. The steps are described in more detail in the main vignette.

    # Load data
    data("aidssi")
    head(aidssi)
    #>   patnr   time status      cause ccr5
    #> 1     1  9.106      1       AIDS   WW
    #> 2     2 11.039      0 event-free   WM
    #> 3     3  2.234      1       AIDS   WW
    #> 4     4  9.878      2         SI   WM
    #> 5     5  3.819      1       AIDS   WW
    #> 6     6  6.801      1       AIDS   WW

    # Shorter name
    si <- aidssi

    # Prepare transition matrix
    tmat <- trans.comprisk(2, names = c("event-free", "AIDS", "SI"))
    tmat
    #>             to
    #> from         event-free AIDS SI
    #>   event-free         NA    1  2
    #>   AIDS               NA   NA NA
    #>   SI                 NA   NA NA

    # Run msprep
    si$stat1 <- as.numeric(si$status == 1)
    si$stat2 <- as.numeric(si$status == 2)

    silong <- msprep(
      time = c(NA, "time", "time"),
      status = c(NA, "stat1", "stat2"),
      data = si,
      keep = "ccr5",
      trans = tmat
    )

    # Run cox model
    silong <- expand.covs(silong, "ccr5")

    c1 <- coxph(Surv(time, status) ~ ccr5WM.1 + ccr5WM.2 + strata(trans),
                data = silong)

# Visualising cumulative baseline hazards using `plot.msfit()`

Using `msfit()`, we can obtain patient-specific transition hazards. We look here at a patient with a CCR5 genotype “WW” (wild type allele on both chromosomes).

    # Data to predict
    WW <- data.frame(
      ccr5WM.1 = c(0, 0),
      ccr5WM.2 = c(0, 0),
      trans = c(1, 2),
      strata = c(1, 2)
    )

    # Make msfit object
    msf.WW <- msfit(
      object = c1,
      newdata = WW,
      trans = tmat
    )

The cumulative baseline hazards can be plotted simply by using:

    plot(msf.WW)

If we specify the argument `use.ggplot = TRUE`, the `plot` method will return a ggplot object.

    plot(msf.WW, use.ggplot = TRUE)

When using the argument `type = "separate"`, the base R plot will return a separate plot for each transition:

    par(mfrow = c(1, 2))
    plot(msf.WW, type = "separate")

The ggplot2 version will return a facetted plot, where the axis scales can either be kept “fixed”, or “free” using the `scale_type` argument. It is essentially the same argument as `scales` from the `facet_wrap()` function of ggplot2, see `?ggplot2::facet_wrap`.

    # Fixed scales
    plot(msf.WW, type = "separate", use.ggplot = TRUE, scale_type = "fixed")

    # Free scales
    plot(msf.WW, type = "separate", use.ggplot = TRUE, scale_type = "free", xlim = c(0, 15))

The remaining arguments are standard plotting adjustments, which will work for both the ggplot2 and base R version of the plots. For details, see `?mstate::plot.msfit`. Any further adjustments that are not available through the function arguments (such as plot title) can simply be added using standard ggplot2 syntax using `+`, or graphics functions such as `title()`. The following is a customised example:

    par(mfrow = c(1, 1))
    # A base R customised plot
    plot(
      msf.WW,
      type = "single",
      cols = c("blue", "black"), # or numeric e.g. c(1, 2)
      xlim = c(0, 15),
      legend.pos = "top",
      lty = c("dashed", "solid"),
      use.ggplot = FALSE
    )
    title("Cumulative baseline hazards")

    # A ggplot2 customised plot
    plot(
      msf.WW,
      type = "single",
      cols = c("blue", "black"), # or numeric e.g. c(1, 2)
      xlim = c(0, 15),
      lty = c("dashed", "solid"),
      legend.pos = "bottom",
      use.ggplot = TRUE
    ) +

      # Add title and center
      ggtitle("Cumulative baseline hazards") +
      theme(plot.title = element_text(hjust = 0.5))

# Visualising transition probabilities using `plot.probtrans()`

The transition hazards obtained in the previous section can be used to obtain patient-specific transition probabilities using `probtrans()`. Here, we would like to predict from the beginning of follow-up (`predt = 0`).

    # Run probtrans
    pt.WW <- probtrans(msf.WW, predt = 0)

    # Example predict at different times
    summary(pt.WW, times = c(1, 5, 10))
    #>
    #> Prediction from state 1 :
    #>   times   pstate1   pstate2    pstate3         se1        se2         se3
    #> 1     1 0.9805172 0.0000000 0.01948279 0.007899257 0.00000000 0.007899257
    #> 2     5 0.6887491 0.1471596 0.16409130 0.028250825 0.02189893 0.022200323
    #> 3    10 0.2772999 0.3870165 0.33568358 0.030015241 0.03202897 0.030204083
    #>      lower1    lower2      lower3    upper1    upper2     upper3
    #> 1 0.9651565 0.0000000 0.008801028 0.9961223 0.0000000 0.04312897
    #> 2 0.6355458 0.1099311 0.125870614 0.7464063 0.1969956 0.21391771
    #> 3 0.2242925 0.3290677 0.281410843 0.3428346 0.4551702 0.40042333

The `plot` method for `probtrans` objects allows to visualise the transition probabilities in various ways, using both functionality from base R graphics and ggplot2.

## Filled/stacked plots

The default is a so-called “filled” plot, where the transition probabilities are represented by coloured areas. The `from` argument allows the user to choose the state to predict from (default is 1, the first state).

    plot(pt.WW, from = 1)

Again, the `use.ggplot = TRUE` argument can be used to return a ggplot object instead:

    # from = 1 implied
    plot(pt.WW, use.ggplot = TRUE)

Note that the ggplot2 version of the plot places the state labels in a legend rather than labels in the plot itself. If we prefer the latter, we can specify `label = annotate` instead - and change the size of the labels with cex.

    plot(pt.WW, use.ggplot = TRUE, label = "annotate", cex = 6)

More generally, we can also adjust the stacking order using the `ord` argument, which takes a numeric vector equal to the number of states, in the desired stacking order (bottom to top).

    # Check state order again from transition matrix
    tmat
    #>             to
    #> from         event-free AIDS SI
    #>   event-free         NA    1  2
    #>   AIDS               NA   NA NA
    #>   SI                 NA   NA NA

    # Plot aids (state 2), then event-free (state 1), and SI on top (state 3)
    plot(pt.WW, use.ggplot = TRUE, ord = c(2, 1, 3))

You can also choose to forgo the colour, and specify `type = "stacked"` instead:

    plot(pt.WW, use.ggplot = TRUE, type = "stacked")

## Single and separate plots, confidence intervals

Instead of visualising the probabilities using stacked areas, we can go the traditional route and use a single line per state. Confidence intervals can then be added.

By specifying `type = "separate"`, the base R plot will return a separate plot for all three states.

    par(mfrow = c(1, 3))
    plot(pt.WW, type = "separate")

The ggplot2 version will return a facetted plot, with one state per facet. It also accommodates confidence intervals, which are either of type “log” (default) or “plain”.

    plot(
      pt.WW,
      use.ggplot = TRUE,
      type = "separate",
      conf.int = 0.95, # 95% level
      conf.type = "log"
    )

These confidence intervals can be omitted using `conf.type = "none"`.

What if we wanted all of these in one plot? For that, we can use the `type = single` option:

    plot(
      pt.WW,
      use.ggplot = TRUE,
      type = "single",
      conf.int = 0.95, # 95% level
      conf.type = "log"
    )

As before, the confidence intervals can be omitted.

    plot(
      pt.WW,
      use.ggplot = TRUE,
      type = "single",
      conf.type = "none",
      lty = c(1, 2, 3), # change the linetype
      lwd = 1.5,
    )

If the multi-state model is large, we may be only interested in plotting the probabilities for a subset of states together. This subset will not sum up to 1, so the stacked/filled plots are not appropriate. There is no set function to do this, but it can be done by extracting the data from a `plot.probtrans()`-based ggplot object as follows:

    # Run plot and extract data using $data
    dat_plot <- plot(x = pt.WW, use.ggplot = TRUE, type = "single")$data

    # Begin new plot - Exclude or select states to be plotted
    ggplot(data = dat_plot[state != "event-free", ], aes(
      x = time,
      y = prob,
      ymin = CI_low,
      ymax = CI_upp,
      group = state,
      linetype = state,
      col = state
    )) +

      # Add CI and lines; change fill = NA to remove CIs
      geom_ribbon(col = NA, fill = "gray", alpha = 0.5) +
      geom_line() +

      # Remaining details
      labs(x = "Time", y = "Cumulative Incidence") +
      coord_cartesian(ylim = c(0, 1), xlim = c(0, 14), expand = 0)

If interest lies in plotting the probability of a single state, the procedure above can be used, or the `vis.multiple.pt()` function presented further could be used directly.

# Plotting non-parametric cumulative incidence functions

The `Cuminc()` function in mstate produces (for competing risks data) the non-parametric Aalen-Johansen estimates of the cumulative incidence functions. This is the same as is obtained in the cmrpsk package with the function `cuminc()`.

In mstate, an object of class “Cuminc” can also be plotted as follows:

    cum_incid <- Cuminc(
      time = "time",
      status = "status",
      data = si
    )

    plot(
      x = cum_incid,
      use.ggplot = TRUE,
      conf.type = "none",
      lty = 1:2,
      conf.int = 0.95,
    )

In the case where this a grouping variable:

    cum_incid_grp <- Cuminc(
      time = "time",
      status = "status",
      group = "ccr5",
      data = si
    )

    plot(
      x = cum_incid_grp,
      use.ggplot = TRUE,
      conf.type = "none",
      lty = 1:4,
      facet = FALSE
    )

    plot(
      x = cum_incid_grp,
      use.ggplot = TRUE,
      conf.type = "none",
      lty = 1:4,
      facet = TRUE
    )

# Visualising multiple probtrans objects

We may also be interested in comparing the predicted probabilities for multiple reference patients. First, we need to create as many msfit/probtrans objects as there are reference patients of interest:

    # 1. Prepare patient data - both CCR5 genotypes
    WW <- data.frame(
      ccr5WM.1 = c(0, 0),
      ccr5WM.2 = c(0, 0),
      trans = c(1, 2),
      strata = c(1, 2)
    )

    WM <- data.frame(
      ccr5WM.1 = c(1, 0),
      ccr5WM.2 = c(0, 1),
      trans = c(1, 2),
      strata = c(1, 2)
    )

    # 2. Make msfit objects
    msf.WW <- msfit(c1, WW, trans = tmat)
    msf.WM <- msfit(c1, WM, trans = tmat)

    # 3. Make probtrans objects
    pt.WW <- probtrans(msf.WW, predt = 0)
    pt.WM <- probtrans(msf.WM, predt = 0)

Afterwards, we can supply the probtrans objects in a list into the `vis.multiple.pt()` function. This will visualise the probability of being in state number `to` over time, given the reference patient was in state number `from` at the `predt` time supplied in `probtrans()`.

The example below visualises the probability of being in state AIDS, given event-free at time 0. The two lines/associated confidence intervals correspond to the reference patients - both with a different CCR5 genotype (“WW” or “WM”).

    vis.multiple.pt(
      x = list(pt.WW, pt.WM),
      from = 1,
      to = 2,
      conf.type = "log",
      cols = c(1, 2),
      labels = c("Pat WW", "Pat WM"),
      legend.title = "Ref patients"
    )

This function could just as well be used for a single probtrans object:

    vis.multiple.pt(
      x = list(pt.WW),
      from = 1,
      to = 2,
      conf.type = "log",
      cols = c(1, 2),
      labels = c("Pat WW", "Pat WM"),
      legend.title = "Ref patients"
    )

Note this function is only available in the ggplot format.

## A mirrored plot

Multiple probtrans objects can also be compared by means of a mirrored plot. The idea is to compare the probabilities of being in (all) states between two references patients at a particular horizon. In addition to reference patients, different subsets of the data could equally be compared.

    vis.mirror.pt(
      x = list(pt.WW, pt.WM),
      titles = c("WW", "WM"),
      horizon = 10
    )

Omitting the `horizon` argument will default to plotting both sides with their respective maximum follow-up time, so it may be asymmetric. We thus recomment to always use the `horizon` argument.

If for example time is in years, and follow-up is extremely short, you may want to override the breaks on the x-axis. This can be done using the `breaks_x_left` and `breaks_x_right` arguments.

    vis.mirror.pt(
      x = list(pt.WW, pt.WM),
      titles = c("WW", "WM"),
      size_titles = 8,
      horizon = 3,
      breaks_x_left = c(0, 1, 2, 3),
      breaks_x_right = c(0, 1, 2),
      ord = c(3, 2, 1)
    )

# Saving outputs

Any plots made with mstate using the `use.ggplot = TRUE` will return a ggplot object, which can be saved to a desired format by using `ggplot2::ggsave()`. Please refer to the article written by the ggplot2 team on using `ggplot2::ggsave()`.

    # Saving a ggplot2 plot
    p <- plot(pt.WW, use.ggplot = TRUE)
    ggplot2::ggsave("my_ggplot2_plot.png")

    # Standard graphics plot
    png("my_standard_plot.png")
    plot(pt.WW, use.ggplot = FALSE)
    dev.off()

# Reproducibility

Reproducibility receipt

    # Date/time
    Sys.time()
    #> [1] "2020-12-17 12:17:02 CET"

    # Environment
    sessionInfo()
    #> R version 4.0.3 (2020-10-10)
    #> Platform: x86_64-w64-mingw32/x64 (64-bit)
    #> Running under: Windows 10 x64 (build 17134)
    #>
    #> Matrix products: default
    #>
    #> locale:
    #> [1] LC_COLLATE=C                       LC_CTYPE=Dutch_Netherlands.1252
    #> [3] LC_MONETARY=Dutch_Netherlands.1252 LC_NUMERIC=C
    #> [5] LC_TIME=Dutch_Netherlands.1252
    #>
    #> attached base packages:
    #> [1] stats     graphics  grDevices utils     datasets  methods   base
    #>
    #> other attached packages:
    #> [1] ggplot2_3.3.1   mstate_0.3.1    survival_3.1-12
    #>
    #> loaded via a namespace (and not attached):
    #>  [1] Rcpp_1.0.4.6       compiler_4.0.3     pillar_1.4.4       RColorBrewer_1.1-2
    #>  [5] viridis_0.5.1      tools_4.0.3        digest_0.6.25      viridisLite_0.3.0
    #>  [9] evaluate_0.14      lifecycle_0.2.0    tibble_3.0.1       gtable_0.3.0
    #> [13] lattice_0.20-41    pkgconfig_2.0.3    rlang_0.4.6        Matrix_1.2-18
    #> [17] yaml_2.2.1         xfun_0.17          gridExtra_2.3      withr_2.2.0
    #> [21] stringr_1.4.0      dplyr_1.0.0        knitr_1.29         generics_0.0.2
    #> [25] vctrs_0.3.1        grid_4.0.3         tidyselect_1.1.0   glue_1.4.1
    #> [29] data.table_1.12.8  R6_2.4.1           rmarkdown_2.2      farver_2.0.3
    #> [33] purrr_0.3.4        magrittr_1.5       scales_1.1.1       htmltools_0.4.0
    #> [37] ellipsis_0.3.1     splines_4.0.3      colorspace_1.4-1   labeling_0.3
    #> [41] stringi_1.4.6      munsell_0.5.0      crayon_1.3.4

# References

Putter, H., M. Fiocco, and R. B. Geskus. 2007. “Tutorial in Biostatistics: Competing Risks and Multi-State Models.” Statist Med 26: 2389–2430.

Wickham, Hadley. 2016. Ggplot2: Elegant Graphics for Data Analysis. Springer-Verlag New York. https://ggplot2.tidyverse.org.