# In certara/survivalnma: network meta-analyses of survival data

knitr::opts_chunk$set( collapse = TRUE, comment = "#>" ) set.seed(1990) knitr::opts_chunk$set(echo = TRUE)
library(knitr)
library(survivalnma)
library(dplyr)
# collect filepaths
nmalist.rds <- system.file("extdata", "nmalist.RDS",
package = "survivalnma", mustWork = TRUE)
dataframe <- data.frame(
stringsAsFactors = FALSE,
"treatment" = c("Suni", "Ifn", "Suni", "Pazo"),
"study" = c("Study 1", "Study 1", "Study 2", "Study 2"),
"baseline" = c("Suni", "Suni", "Suni", "Suni"),
"filepath" = sapply(c("Mota_OS_Suni_KM.txt",
"Mota_OS_Ifn_KM.txt",
"Mot_OS_Suni_KM.txt",
"Mot_OS_Pazo_KM.txt"), function(x)
system.file("extdata", "narrow", x, package="survivalnma", mustWork=TRUE)))

# Introduction

This vignette is intended as a walkthrough for the basic features of the survivalnma package and explain some concepts behind network meta-analysis of survival data to new users. We concentrate on an example of a single model with a simple analysis dataset. Note that all functions mentioned here have R documentation, e.g.

library(survivalnma)
?survnma

For experienced WinBUGS users, all included models can be viewed

survivalnma::survnma_model("weibull", "fixed") #will open a text file

To introduce our approach, see below the code for a complete (albeit simplified) analysis, which in four lines of code loads data, conducts analysis and outputs it all into a Word document.

df <- filter(df, outcome == "os") #only analyse one of the outcomes
fit <- survnma(df, model = "weibull", type = "random") #estimate NMA parameters
generate_markdown(fit, output = "my_word_document.docx") #generate plots and tables, write them to Word

In this vignette we will walk through these features on a practical example.

## Network meta-analysis of parametric survival curves

We follow the approach originally by Ouwens et al (1). Our objective is to meta-analyse survival data for many treatments by assuming that the true survival function follows some parameteric distribution (such as Weibull, Gompertz etc. etc.). In contrast to a "classical" (network) meta-analysis of survival data, we do not assume proportional hazards (which would lead to the meta-analysis of study-reported HR values) but analyse whole survival curves extracted from publications.

The survivalnma package is supposed to make this process fast and replicable. The underlying Bayesian NMA code has been replicated from (1) and (2) and uses WinBUGS; our contribution lies in making these models accessible and in providing a consistent analytic workflow.

## Network meta-analysis of hazard ratios

Network meta-analysis of survival data is often based on the reported hazard ratio, which relies on the proportional hazards assumption. This assumption is not only often implausible, but can have a huge impact on decisions based on cost-effectiveness analysis. In extreme cases survival curves intersect and the hazard ratio is not constant. Furthermore, even if survival functions do not intersect, the hazard functions might and the assumption is violated.

We follow the approach originally by Jensen et al (2). Patient-level data were reconstructed as described by Guyot et al (3). A variety of first-order and second-order fractional polynomials with different power functions and models with fixed scale and shape, random scale and fixed shape, and random scale and random shape were conducted.

## Models available in survivalnma

### Typical parametric models

The distributions in the following table are implemented in survivalnma. We summarise here for reader's understanding what the $h(t)$ and $S(t)$ functions are in each case.

Family of distribution | Parameters | Reparameterisation | Hazard function $h(t)$ | Survival function $S(t)$ ------------------------|------------------|--------------------|---------------------------|-------------------------------- Exponential | $\alpha$ |$\nu = \log(\alpha)$|$h(t) = \alpha$| $S(t) = \exp(-\alpha t)$| Weibull | $\alpha > 0$,$\beta > 0$ |$\nu = \log(\frac{\alpha}{\beta^\alpha})$ $\theta = (\alpha - 1)$ | $h(t) = \exp({\nu+\theta log(t)})$ | $S(t) = \exp( -( \frac{\exp(nu)}{\theta +1})t^{\theta+1})$ Gompertz |$\alpha > 0$, $\beta > 0$|$\nu = \log(a)$, $\theta = \beta$|$h(t) = \exp(\nu + {\theta t})$| $S(t) = \exp {\big[{\frac{log(\nu)}{\theta}(1-\exp({\theta t})}\Big]}$ Log-Normal | $\alpha > 0$, $\beta^2 >0$|$\nu = \alpha$, $\theta = \log(\beta)$ |$h(t) = \frac{\phi \left( \frac{\log(t)}{\sigma} \right)}{\sigma t \left[1 - \Phi \left( \frac{\log(t)}{\sigma} \right)\right]}$| $S(t) = 1 - \Phi \left( \frac{\log(t) - \nu}{\exp(\theta)} \right)$ Log-Logistic | $\alpha$,$\beta$ |$\nu = \log(\alpha^\frac{-1}{\beta})$,$\theta = \log(\beta)$| $h(t)= \frac{\exp^{\theta - \nu}(t\exp^{-\nu})^{\exp^{\theta}-1}}{1+(t\exp^{-\nu})^{\exp^{\theta}}}$ | $S(t)=\frac{1}{1+(t\exp(-\nu))^{\exp(\theta)}}$

• $\Phi(x)$ represents the incomplete normal integral $\int_{-\infty}^{x}{\phi(s)ds}$ with $\phi(x)={\frac{1}{\sqrt{2\pi}}{\exp{\frac{x^2}{2}}}}$ being the probability density function of the standard normal distribution.
• Some distributions, especially Weibull and Gompertz have been or can be reparametrised for ease of use. Please refer to relevant information here
• The Gamma distribution has been omitted due to the lack of a closed form expression (contains incomplete gamma integral) which imposes computational problems. It is of limited interest but more information can be found at the link above.
• Log-Normal distribution also relies on the incomplete normal integral making computations quickly formidable. Nevertheless, there are diverse situations where it can be of use and thus has been included.

### Fractional polynomials

We consider a range of first and second order fractional polynomials. A fractional polynomial is just a polynomial with non integer powers. Typically we consider five models for both orders, but this is not necessary.

Polynomial | Model 1 | Model 2 | Model 3 | Model 4 | Model 5 ----------|----------|---------|-------- |---------|----------- First Order | $P = 0$ | $P = 1$| $P = 0.5$ | $P = -1$ | $P = -0.5$ | | | | | Second Order | $P1 = -0.5,\ P2 = 0$| $P1 = -1,\ P2 = 0$ | $P1 = -1,\ P2 = 1$|$P1 = -1,\ P2 = -1$ |$P1 = -1,\ P2 = 0.5$

With the above set of polynomial powers you can achieve many different shapes for the hazard functions. Such shapes can mimic a constant hazard over time, a linear increasing or decreasing hazard over time and bathtub shaped hazard.

Specifically for first order polynomials of the form $\ln(h_{kt}) = \beta_{0k} + \beta_{1k} t^p$ with $t^0 = log(t)$:

• If you set the coeffcient $\beta_1$ equal to 0, a constant loghazard function is obtained, reflecting exponentially distributed survival times.
• If $\beta_1 \neq 0$ and $p = 1$ a linear hazard function is obtained which corresponds to a Gompertz survival function.
• If $\beta_1 \neq 0$ and $p = 0$ a Weibull hazard function is obtained, and $\pmatrix{ d_0 \ d_1}$ reflects the difference in respectively the scale and shape of the Weibull log hazard curve for treatment B relative to A.

Extending the first order fractional polynomial hazard function to a second-order fractional polynomial increases the possible (differences in) shapes even further.

# Data and network preparation

## NMA of HRs

[This is currently not supported within the package. We will expand this guide with details on HR analysis later.]

## Curve extraction

Typically aggregate survival data is obtained from published Kaplan-Meier curves by using digitizing software. This is an example of curve obtained from an oncology trial (see (4)):

We typically use DigitizeIt to extract the curve. It requires a published Kaplan Meier curve as input (usually in png or pdf format). After defining axis start/end points, the analyst is required to either manually select plot points or use the softwares recognition tools to "scan" the curve. This provides an accurate estimate of the curve's path, but the result is dependent on the analyst's accuracy.

The software then supplies a digitized version of the curve, in a text format. A final step is required before we can use the data. Analyst modifies the data (e.g. in Excel) by adding numbers at risk where available. This is crucial in the analysis.

By default we assume that the user will supply text files corresponding to individual Kaplan-Meier curves. That is, each file will have columns corresponding to "time", "n.risk", "n.event", "n.censor". Note that the columns do not have to follow this naming convention, but have to follow this ordering.)

## Data preparation

Before conducting analysis, inputs need to be formatted correctly. The function will require a data.frame with 4 columns: treatment, study, baseline and filepath. Their meaning is self-explanatory. Each row corresponds to a single arm (single extracted curve).

Each linked file via filepath should be the corresponding data extracted from the Kaplan Meier plots, as explained above.

Only two-arm studies are supported at the moment.

### Automated data preparation

[Currently this feature has not been included in the public release of the package – we will consider it for release in the future versions.]

### Defining baselines

Defining the baseline for each study/treatment pair is important. Although this can be done manually, we supply a function, add_baseline_column that does so automatically. Choice of baseline needs to be consistent with the selection of studies supplied. It needs to connect treatments, forming a network for the comparisons to make sense. Usually, treatments are given an identification number, and the lowest integer identifier is chosen as that study's baseline. This guarantees that all present studies will have a baseline treatment present in another study.

For this example we will be using a premade dataframe we supply together with the package. Normally, you would have a folder that would contain all the text (.txt) files of your data. You would then use read_km_folder to automatically read the folder to a more managable dataframe in R.

Let's see what the dataframes supplied look like. As they come with the package you can access them via survivalnma::mrcc_small.

# This is the short dataset
print(survivalnma::mrcc_small)

# Plots

## Plotting the network

[Currently this feature has not been included in the public release of the package – we will consider it for release in the future versions.]

## Plotting Kaplan Meier curve

Plotting Kaplan-Meier curves relies on external packages survival and survminer (function ggsurvplot). These will NOT be installed automatically when user installs survivalnma.

1. KM survfit object. This is the output of the survival::survfit function
2. IPD data used to generate the above survfit object

It then outputs a standard Kaplan-Meier curve

package = "survivalnma", mustWork = TRUE))
colnames(IPD.data) <- c("time", "event", "arm")

# run survfit to create survival object
KM.est <- survival::survfit(survival::Surv(time, event)~1,
data=IPD.data,
type="kaplan-meier")
# This is what survminer plots for KM curves
survminer::ggsurvplot(KM.est, data = IPD.data, legend.labs = "Kaplan Meier")

## Testing proportionality of hazards

[Currently this feature has not been included in the public release of the package – we will consider it for release in the future versions.]

# NMA model via survnma() function

## Setting up WinBUGS

The survivalnma package uses the WinBUGS software and the R2WinBUGS package. The default location for the program files of WinBUGS is expected to be stored in the root directory "C:\WinBUGS14". If you have your own filing system and want to change the location of this directory then you need to inform survivalnma.

This alteration is easy. When running survnma() make sure to pass the additional parameter bugs.directory = "PATH TO WINBUGS".

For example, if you stored WinBUGS at "C:\Program Files (x86)\" then when calling survnma you should do the following:

fit <- survnma(nma_df = mrcc_small, model = "weibull", bugs.directory = "C:/Program Files (x86)/WinBUGS14")

We recommend that you save WinBUGS at C:/WinBUGS14/ to avoid this extra work.

## survnma() function

The survnma function is the fundamental function in the survivalnma package. It runs WinBUGS NMA models and formats the outputs to make them user-friendly for later analysis.

input variable | description ---------------|-------------------------------------------------------- nma_df | data.frame with studies, treatments, baselines and paths to files (see above) model | string specifying the model type: for now we have "weibull", "gompertz", "exponential", "loglogistic", "lognormal", "fp1", "fp2" type | "fixed" or "random" effects (default is fixed) prior | prior distribution of parameters. List of prior values with elements mean, prec2, and R to be passed to WinBUGS. If NULL, the defaults are used. Dimensionality depends on distribution family: 1 for exponential, 3 for fp2 and 2 for all others. inits | Initial values for chain. If left NULL WinBUGS will generate, if set to generate initial values will be generated within R. P | powers to be used with the fractional polynomials (one or two values) ... | more optional arugments; you can use WinBUGS arguments such as n.chains, n.iter

Observe the simple Weibull model below. (Note that the results are likely wrong as we purposefully ran the model for a very short time.)

# Construct the survnma object
weibull.nma <- survnma(nma_df = dataframe, "weibull", type = "fixed", n.iter = 500, min_time_change = 0.05)

# The object has stored the following attributes
attributes(weibull.nma)

# WinBUGS model is included in our NMA result
# And it's shown by default:
weibull.nma
# Construct the survnma object
temppath <- system.file("extdata", "weibull_nma.Rds", package = "survivalnma", mustWork = TRUE)

# The object has stored the following attributes
attributes(weibull.nma)

# WinBUGS model is included in our NMA result
# And it's shown by default:
weibull.nma

More complicated models like fractional polynomials or random-effect models are all ran with the same function (once again it will not converge during this short run):

fp1.nma <- survnma(mrcc_small,
"fp1", P = 1,
type = "fixed", min_time_change = 0.05)

fp2.nma <- survnma(mrcc_small,
"fp2", P = c(2.3, 0.23),
type = "random", min_time_change = 0.05)

# Extract model name
fp2.nma$model # Extract powers used fp2.nma$P

## Automatic convergence for the models

The package survivalnma also has the ability to continuously run a model until convergence has been reached. This is determined by checking the largest Rhat value (a measurement of fitness). If you specify auto_restart = TRUE while generating your survnma object, then it will automatically re-run the operation at most 5 times or until Rhat is less than 1.05

By default, the option for warnings is automatically enabled, informing you whether the model has converged or the limit of iterations has been reached. To disable this, just pass r warnings = FALSE when calling survnma

#AUTO RESTART ON
survnma.object <- survnma(nma_df = data,
model = "weibull",
auto_restart = TRUE,
warnings = FALSE)

# We enable auto_restart but disable the warnings

Regardless whether you specified auto_restart = TRUE or not, you will be warned if Rhat > 1.05 given that warnings = TRUE

## Interlude: understanding model parameters

This is a technical note you can skip: as you can see from the WinBUGS result above, we can identify the parameters of each unique treatment effect (d) and each study baseline (mu).

For example, considering mu[i, j]:

• [i] represents the treatment, in this case there are 3 treatments so [i] spans from one to three

• [j] represents the parameters of the model, as we are considering a second order fractional polynomial which has parameters b0, b1 and b2; these are in positions mu[i, 1], mu[i, 2] and mu[i, 3]

The same holds for d[i,j] where the d vector reflects the difference for scale nu and shape theta of log-hazard curves for treatment B versus A. See (1) for details.

# Working with the NMA results

In survivalnma we provide the ability to calculate and plot the survival function of all models.

## Survival curve results

In the survival curve NMA framework, survival curves can only be plotted in relation to baseline value of mu (study-specific baseline).

You can plot with survival_plot.

# You have to specify study to "adjust to"
# As default all treatments are plotted
survival_plot(weibull.nma, study = "mot",
timesteps = seq(0,30))

Setting a short timesteps interval will result in more "jagged" plots but will speed up calculations. See ?survival_plot for various arguments to customise your plots.

Note: We provide two functions for survival curves, one for calculation and one for plotting. The reason for this is that some of survival calculations take a long time, so sometimes you may want to precalculate the results and save them for later use.

curve_data <- prep_all_survivals(weibull.nma, study = "Study 1")
survival_plot(curve_data)
#would generate the same result

## Hazard ratio results

For HR the derivation and plotting is similar as for survival curves. For HR no study is needed to adjust to, as we deal with relative quantities.

Again you can either pre-calculate the hazard ratios using prep_all_hazards or just pass directly into hazard_plot a survnma object together with the corresponding study, treatments and reference for the internal calculation.

# if you precalculated
hazard_data <- prep_all_hazards(nmafit = weibull.nma,
treatments = c("Ifn", "Suni", "Pazo"),
reference = "Suni")
hazard_plot(data = hazard_data)

# OR alternatively

hazard_plot(data = survnma.object,
treatments = c("trt1", "trt2", "trt3", "trt4"),
reference = "trtX")
hazard_plot(weibull.nma, reference = "suni")

## Assessing fit to data (WIP)

The Kaplan-Meier plots can be compared against the fitted data via kaplan_plot(). It uses the survnma object altogether with IPD data.

[Currently this feature has not been included in the public release of the package – we will consider it for release in the future versions.]

## Gelman-Rubin (R-hat) and its interpretation

The Gelman-Rubin diagnostic, ($\hat{R}$), is a measure of convergence for a list of MCMC sequences. Without getting into details, it uses the Within-Chain and Between-Chain variances of the MCMC to conclude whether the collection of chains has converged to the target posterior distribution.

Following Gelman and Rubin's suggestion of utilising the potential scale reduction factor, MCMC convergence should yield an $\hat{R}$ value of close to 1.

## Tabular outputs

The function hazard_table() can produce multiple hazard-ratio tables for every consequtive month. It requires an input of a survnma object together with specified study, treatments, reference and timesteps. Timesteps should be the times you want the evaluation to occur at.

It can also utilise pre-calculated hazards. If it happens that you have already calculated hazards, you can pass directly the hazard object, which would decrease the computation time drastically.

# if you calculate hazards previously,
survnma.object <- survnma(nma_df = mrcc_big, model = "weibull")
hazards <- prep_all_hazards(survnma.object,
treatments = c("trt1", "trt2"),
reference = "ref", timesteps = seq(0, 30, 3))

hazard_table(survnma.object, hazards = hazards, print = TRUE)

# if you want to do it internally
survnma.object <- survnma(nma_df = mrcc_big, model = "weibull")
hazard_table(survnma.object, c("trt1", "trt2"), "ref", timesteps = seq(0, 30, 3), print = TRUE)
data <- hazard_table(weibull.nma, c("ifn", "pazo"), reference = "suni", print = FALSE, timesteps = seq(0, 30, 3))
kable(data[1:6,], caption = "3-Month Hazard Ratio Table", digits = 2)

Similarly, the function survival_table() evaluates the survival rate at multiple time points for any treatment specified. Again, you are required to supply a survnma object together with the study of interest, treatments and timesteps which determines when the survivals are evaluated.

If you have pre-calculated any survivals you can pass them directly, by supplying them in the survivals argument. Changing print to FALSE will not print results to console.

# if you calculate hazards previously,
survnma.object <- survnma(nma_df = mrcc_big, model = "weibull")
survivals <- prep_all_survivals(survnma.object,
study = "Study 1",
treatments = c("trt1", "trt2"),
timesteps = seq(0,30))

survival_table(survnma.object, survivals = survivals, print = TRUE)

# if you want to do it internally
survnma.object <- survnma(nma_df = mrcc_big, model = "weibull")
survival_table(survnma.object, "Study 1", c("trt1", "trt2"), timesteps = seq(0,30), print = TRUE)
data <- survival_table(weibull.nma, "mot", c("ifn", "suni", "pazo"), timesteps = seq(0,30),print = FALSE)
kable(data[1:10,], caption = "Monthly Survivals Table")

## Automatic reporting of results

We have constructed a script that automatically generates a Word document (can be changed to html/pdf) of your analysis.

[Currently this feature has not been included in the public release of the package – we will consider it for release in the future versions.]

# References & credits

Vignettes and code in the survnma has been created at Analytica Laser, a Certara company by Witold Wiecek and Savvas Pafitis with modelling contributions and comments from Shuai Fu, Johanna Lister and Jie Meng. Original parametric curve models are sourced from work cited in references, primarily by MJ Ouwens and JP Jansen.

(1) Ouwens, Mario J. N. M., Zoe Philips, and Jeroen P. Jansen. “Network Meta-Analysis of Parametric Survival Curves.” Research Synthesis Methods 1, no. 3–4 (July 2010): 258–71. https://doi.org/10.1002/jrsm.25.

(2) Jansen, Jeroen P. “Network Meta-Analysis of Survival Data with Fractional Polynomials.” BMC Medical Research Methodology 11, no. 1 (May 6, 2011): 61. https://doi.org/10.1186/1471-2288-11-61.

(3) Guyot, Patricia, AE Ades, Mario JNM Ouwens, and Nicky J. Welton. “Enhanced Secondary Analysis of Survival Data: Reconstructing the Data from Published Kaplan-Meier Survival Curves.” BMC Medical Research Methodology 12, no. 1 (February 1, 2012): 9. https://doi.org/10.1186/1471-2288-12-9.

(4) Motzer, Robert J., Bernard Escudier, David F. McDermott, Saby George, Hans J. Hammers, Sandhya Srinivas, Scott S. Tykodi, et al. “Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.” New England Journal of Medicine 373, no. 19 (September 25, 2015): 1803–13. https://doi.org/10.1056/NEJMoa1510665.

certara/survivalnma documentation built on June 5, 2019, 11:02 a.m.