---
title: "MBNMAdose: Perform a Model-Based Network Meta-Analysis (MBNMA)"
author: "Hugo Pedder"
date: "`r Sys.Date()`"
output:
  knitr:::html_vignette:
    toc: TRUE
bibliography: REFERENCES.bib
vignette: >
  %\VignetteIndexEntry{MBNMAdose: Perform a Model-Based Network Meta-Analysis (MBNMA)}
  %\VignetteEngine{knitr::rmarkdown}
  %\VignetteEncoding{UTF-8}
---

```{r setup, include = FALSE}
library(MBNMAdose)
library(rmarkdown)
library(knitr)
library(dplyr)
library(ggplot2)

knitr::opts_chunk$set(
  collapse = TRUE,
  comment = "#>",
  fig.width = 7,
  fig.height = 5,
  include=TRUE,
  tidy.opts=list(width.cutoff=80),
  tidy=TRUE
)
```

# Analysis using `mbnma.run()`

MBNMA is performed in `MBNMAdose` by applying `mbnma.run()`. A
`"mbnma.network"` object must be provided as the data for `mbnma.run()`.
The key arguments within `mbnma.run()` involve specifying the functional
form used to model the dose-response, and the dose-response parameters
that comprise that functional form.

## Dose-response functions

Various functional forms are implemented within `MBNMAdose`, that allow
a variety of parameterizations and dose-response shapes. These are
provided as an object of class `"dosefun"` to the `fun` argument in
`mbnma.run()`. The interpretation of the dose-response parameter
estimates will therefore depend on the dose-response function used. In
previous versions of `MBNMAdose` (prior to version 0.4.0), wrapper
functions were provided for each of the commonly used dose-response
functions in `mbnma.run()`. For example, `mbnma.emax()` is equivalent to
`mbnma.run(fun=demax())`. This will be deprecated in future versions.

For the following functions $x_{i,k}$ refers to the dose and $t_{i,k}$
to the agent in arm $k$ of study $i$.

**Log-linear (`dloglin()`)**
$$f(x_{i,k}, t_{i,k})=\lambda_{t_{i,k}} \times ln(x_{i,k} + 1)$$ 
where $lambda$ controls the gradient of the dose-response relationship.

**Exponential (`dexp()`)**
$$f(x_{i,k}, t_{i,k})=Emax_{t_{i,k}} (1 - e^{-x_{i,k}})$$
where $Emax$ is the maximum efficacy of an agent.

**Emax (`demax()`)**
$$f(x_{i,k}, t_{i,k})=\dfrac{Emax_{t_{i,k}} \times {x_{i,k}^{\gamma_{t_{i,k}}}}} {ED50_{t_{i,k}}^{\gamma_{t_{i,k}}} + x_{i,k}^{\gamma_{t_{i,k}}}}$$
where $Emax$ is the maximum efficacy that can be achieved, $ED50$ is the dose at which 50% of the maximum efficacy is achieved, and $\gamma$ is the Hill parameter that controls the sigmoidal shape of the function. By default, `demax()` fits a 2-parameter Emax function in which $\gamma_{t_{i,k}}=1$ (`hill=NULL` in function argument).

**Polynomial (e.g. linear) (`dpoly()`)**
$$f(x_{i,k}, t_{i,k})=\beta_{1_{t_{i,k}}}x_{i,k}+...+\beta_{p_{t_{i,k}}}x^p_{i,k}$$
where $p$ is the degree of the polynomial (e.g. 1 for linear) and $\beta_p$ are the coefficients

**Fractional polynomial (`dfpoly()`)**
$$f(x_{i,k}, t_{i,k})=\beta_{1_{t_{i,k}}}x_{i,k}^{\gamma_1}+...+\beta_{p_{t_{i,k}}}x^{\gamma_p}_{i,k}$$
where $p$ is the degree of the polynomial, $\beta_p$ are the coefficients, and $x_{i,k}^{\gamma_p}$ is a regular power except where $\gamma_p=0$ where ${x_{i,k}^{(0)}=ln(x_{i,k})}$. If a fractional polynomial power ${\gamma_p}$ repeats within the function it is multiplied by another ${ln(x_{i,k})}$.

**Spline functions (`dspline()`)** 
B-splines (`type="bs"`) and natural cubic splines (`type="ns"`) can be fitted. Piecewise linear splines can be fitted using `type="bs"` with `degree=1` (following deprecation of `type="ls"`).
$$f(x_{i,k}, t_{i,k})=\sum_{p=1}^{P} \beta_{p,t_{i,k}} X_{p,i,k}$$
where $\beta_{p,t_{i,k}}$ is the regression coefficient for the $p^{th}$ spline and $X_{1:P,i,k}$ is the basis matrix for the spline, defined by the spline type.

**Non-parametric monotonic function (`dnonparam()`)** 
Follows the approach of Owen et al. [-@owen2015]. The `direction` can bespecified as `"increasing"` or `"decreasing"`.

**User-defined function (`duser()`)** 
Any function that can be explicitly defined by the user within (see [User-defined dose-response function])

**Agent-specific functions (`dmulti()`)**
Allows for a separate dose-response function to be fitted to each agent in the network (see [Agent-specific dose-response functions])


## Dose-response parameters

Dose-response parameters can be specified in different ways which
affects the key parameters estimated by the model and implies different
modelling assumptions. Three different specifications are available for
each parameter:

-   `"rel"` indicates that relative effects should be pooled for this
    dose-response parameter separately for each agent in the network.
    This preserves randomisation within included studies and is likely
    to vary less between studies (only due to effect modification).
-   `"common"` indicates that a single absolute value for this
    dose-response parameter should be estimated across the whole network
    *that does not vary by agent*. This is particularly useful for
    parameters expected to be constant (e.g. Hill parameters in
    `demax()` or fractional polynomial power parameters in `fpoly()`).
-   `"random"` indicates that a single absolute value should be
    estimated separately for each agent, but that all the agent values
    vary randomly around a single mean absolute network effect. It is
    similar to `"common"` but makes slightly less strong assumptions.
-   `numeric()` Assigned a numeric value - this is similar to assigning
    `"common"`, but the single absolute value is assigned as a numeric
    value by the user, rather than estimated from the data.

In `mbnma.run()`, an additional argument, `method`, indicates what
method to use for pooling relative effects and can take either the
values `"common"`, implying that all studies estimate the same true
effect (akin to a "fixed effect" meta-analysis), or `"random"`, implying
that all studies estimate a separate true effect, but that each of these
true effects vary randomly around a true mean effect. This approach
allows for modelling of between-study heterogeneity.


## Output

`mbnma.run()` returns an object of class `c("rjags", "mbnma")`.
`summary()` provides posterior medians and 95% credible intervals
(95%CrI) for different parameters in the model, naming them by agent and
giving some explanation of the way they have been specified in the
model. `print()` can also be used to give full summary statistics of the
posterior distributions for monitored nodes in the JAGS model. Estimates
are automatically reported for parameters of interest depending on the
model specification (unless otherwise specified in
`parameters.to.save`).

Dose-response parameters will be named in the output, with a separate
coefficient for each agent (if specified as `"rel"`). If class effects
are modelled, parameters for classes are represented by the upper case
name of the dose-response parameter they correspond to (e.g. `EMAX` will
be the class effects on `emax`). The SD of the class effect (e.g.
`sd.EMAX`, `sd.BETA.1`) is the SD of agents within a class for the
dose-response parameter they correspond to.

`sd` corresponds to the between-study SD. However, `sd.` followed by a
dose-response parameter name (e.g. `sd.emax`, `sd.beta.1`) is the
between-agent SD for dose response parameters modeled using `"common"`
or `"random"`.

`totresdev` is the residual deviance, and `deviance` the deviance of the
model. Model fit statistics for `pD` (effective number of parameters)
and `DIC` (Deviance Information Criterion) are also reported, with an
explanation as to how they have been calculated.

## Examples

An example MBNMA of the triptans dataset using an Emax dose-response
function and common treatment effects that pool relative effects for
each agent separately on both Emax and ED50 parameters follows:

```{r, results="hide", warning=FALSE}
# Prepare data using the triptans dataset
tripnet <- mbnma.network(triptans)

# Run an Emax dose-response MBNMA
mbnma <- mbnma.run(tripnet, fun=demax(emax="rel", ed50="rel"), 
                   method="random")
```

```{r, message=FALSE, warning=FALSE}
# Print neat summary of output
summary(mbnma)
```

In this example the `emax` parameters are the maximum efficacy that can
be achieved for each agent. The `ed50` parameters are the the dose at
which 50% of the maximum efficacy is achieved for each agent. Results
for ED50 are given on the log scale as it is constrained to be greater
than zero. `sd` corresponds to the between-study SD (included because
`method="random"`).

Instead of estimating a separate relative effect for each agent, a
simpler dose-response model that makes stronger assumptions could
estimate a single parameter across the whole network for ED50, but still
estimate a separate effect for each agent for Emax:

```{r, results="hide"}
# Emax model with single parameter estimated for Emax
emax <- mbnma.run(tripnet, fun=demax(emax="rel", ed50="common"), 
                  method="random")
```

```{r}
summary(emax)
```

In this example `ed50` only has a single parameter, which corresponds to
the dose at which 50% of the maximum efficacy is achieved, assumed to be
equal across all agents in the network.

## Parameter interpretation

Parameter interpretation depends both on the link scale on which the
outcome is modeled, and on the dose-response function used in the model.

For example for a binomial outcome modeled using a logit link function
and an Emax dose-response function, the `emax` parameter represents the
maximum efficacy on the logit scale - it is modeled on the outcome scale
and hence is dependent on the link function. As indicated in the help
file (`?demax()`), the `ed50` parameter is modeled on the log-scale to
ensure that it takes positive values on the natural scale, but is not
modeled on the outcome scale so is not dependent on the link function.
Therefore it can be interpreted as the log-dose at which 50% of the
maximum efficacy is achieved. The `hill` parameter is also modeled on
the log-scale, and it can be interpreted as a log-value that controls
the sigmoidicity of the dose-response function for the outcome on the
logit scale.

For a continuous outcome modeled using `link="smd"`, whilst not a true
link function it implies modelling Standardised Mean Differences (SMD).
For a linear dose-response function (`dpoly(degree=1)`), `beta.1`
represents the change in SMD for each additional unit of dose. For a
quadratic dose-response function (`dpoly(degree=2)`), `beta.2`
represents the change in `beta.1` for each additional unit of dose.

With some dose-response functions (e.g. splines, fractional polynomials)
parameter interpretation can be challenging. The `get.relative()`
function can make this easier as this allows relative effects to be
estimated between agents at specific doses, which is typically much more
easily understandable and presentable (see [Estimating relative
effects]).

## Additional arguments for `mbnma.run()`

Several additional arguments can be given to `mbnma.run()` that require
further explanation.

### Link functions for `likelihood=="normal"`

For data with normal likelihood, users are likely to typically analyse
data using an identity link function, the default given to the `link`
argument in `mbnma.run()` when `likelihood="normal"`. This assumes an
additive treatment effect (e.g. mean difference).

However, by specifying `link="log"` a user can model a log link and
therefore assume a multiplicative treatment effect. For continuous data
this models the treatment effect as a Ratio of Means (RoM)
[@friedrich2011]. This also provides an advantage as the treatment
effect is scale independent (i.e. studies measuring the same outcome
using different measurement scales can be analysed simultaneously).
However, within-study treatment effects must all be of the same
direction (either positive or negative), and change from baseline
measures must be adjusted so that they are also expressed as RoMs
(log(follow-up) - log(baseline)) to avoid combining additive and
multiplicative assumptions within the same analysis.

An alternative approach for modelling a measurement scale-independent
treatment effect whilst still assuming additive treatment effects is to
perform the analysis using Standardised Mean Differences (SMD). Whilst
not strictly a different link function, this can be specified using
`link="smd"`. The resulting treatment effects are reported in units of SD as SMDs.

By default, `MBNMAdose` standardises treatment effects
using the pooled standard deviation (SD) in each study ("study-specific" SDs). However, a more robust approach to minimise bias from estimation of study-specific SD is to use a "reference" SD that is the same for each scale included in the dataset. Such a reference could be estimated from all the included studies within the dataset that report outcomes on the scale (an "internal reference SD"), but the best approach is to obtain a SD from an observational study *that is specific to the target population of interest*.

Once this has been obtained for each scale, it can be included in the original data frame as an additional variable, `standsd`. For the analysis to be meaningful, `stansd` should be the same for all arms within a study and for all studies that report the same outcome. If this has been included in the dataset used to create an `"mbnma.network"` object, then `sdscale=TRUE` argument can be specified in `mbnma.run()` to indicate that this variable should be used to standardise SMDs. 

Note that for outputting results from a model using SMDs, results should be back-transformed to a clinically relevant scale to make robust interpretation. This can be done by multiplying the effect estimates or predictions by the standard deviation of the relevant scale in the population of interest. For further details of analysis of continuous data that include discussion of both RoM and SMD see [@GMD2].

### Class effects

Similar effects between agents within the network can be modelled using
class effects. This requires assuming that different agents have some
sort of common class effect, perhaps due to similar mechanisms of
action. Advantages of this is that class effects can be used to connect
agents that might otherwise be disconnected from the network, and they
can also provide additional information on agents that might otherwise
have insufficient data available to estimate a desired dose-response.
The drawback is that this requires making additional assumptions
regarding similarity of efficacy.

One difficult of this modelling aspect in particular is that the scales
for dose-response parameters must be the same across different agents
within a class for this assumption to be valid. For example, in an Emax
model it may be reasonable to assume a class effect on the Emax
parameter, as this is parameterised on the response scale and so could
be similar across agents of the same class. However, the ED50 parameter
is parameterised on the dose scale, which is likely to differ for each
agent and so an assumption of similarity between agents for this
parameter may be less valid. One way to try to account for this issue
and make dose scales more consistent across agents is to standardise
doses for each agent relative to its "common" dose (see Thorlund et al.
[-@thorlund2014]), though we expect that this may lead to bias if the
common dose is located at a different point along the dose-response
curve.

Class effects can only be applied to dose-response parameters which vary
by agent. In `mbnma.run()` they are supplied as a list, in which each
element is named following the name of the corresponding dose-response
parameter as defined in the dose-response function. The names will
therefore differ when using wrapper functions for `mbnma.run()`. The
class effect for each dose-response parameter can be either `"common"`,
in which the effects for each agent within the same class are
constrained to a common class effect, or `"random"`, in which the
effects for each agent within the same class are assumed to be randomly
distributed around a shared class mean.

When working with class effects in `MBNMAdose` a variable named `class`
must be included in the original data frame provided to
`mbnma.network()`. Below we assign a class for two similar agents in the
dataset - Naproxcinod and Naproxen. We will estimate separate effects
for all other agents, so we set their classes to be equal to their
agents.

```{r, results="hide", message=FALSE, warning=FALSE}
# Using the osteoarthritis dataset
pain.df <- osteopain

# Set class equal to agent for all agents
pain.df$class <- pain.df$class

# Set a shared class (NSAID) only for Naproxcinod and Naproxen
pain.df$class[pain.df$agent %in% c("Naproxcinod", "Naproxen")] <- 
  "NSAID"

# Run a restricted cubic spline MBNMA with a random class effect on beta.1
painnet <- mbnma.network(pain.df)
splines <- mbnma.run(painnet, fun=dspline(type="bs", knots=2), class.effect = list(beta.1="random"))
```

Mean class effects are given in the output as `D.ed50`/`D.1` parameters.
These can be interpreted as the effect of each class for Emax parameters
(`beta.1`). Note the number of `D.ed50` parameters is therefore equal to
the number of classes defined in the dataset.

If we had specified that the class effects were `"random"`, each
treatment effect for Emax (`beta.1`) would be assumed to be randomly
distributed around its class mean with SD given in the output as
`sd.D.ed50`/`sd.D.1`.

Mean class effects are represented in the output by the upper case name
of the dose-response parameter they correspond to. In this case,
`BETA.1` is the class effects on `beta.1`, the first spline coefficient.
The SD of the class effect is the SD of agents within a class for the
dose-response parameter they correspond to. In this case `sd.BETA.1` is
the within-class SD for `beta.1`.

### User-defined dose-response function

Users can define their own dose-response function using `duser()` rather
than using one of the functions provided in `MBNMAdose`. The
dose-response is specified in terms of `beta` parameters and `dose`.
This allows a huge degree of flexibility when defining the dose-response
relationship.

The function assigned needs to fulfil a few criteria to be valid: \*
`dose` must always be included in the function \* At least one `beta`
dose-response parameter must be specified, up to a maximum of four.
These must always be named `beta.1`, `beta.2`, `beta.3` and `beta.4`,
and must be included sequentially (i.e. don't include `beta.3` if
`beta.2` is not included) \* Indices used by JAGS should *not* be added
(e.g. use `dose` rather than `dose[i,k]`) \* Any mathematical/logical
operators that can be implemented in JAGS can be added to the function
(e.g. `exp()`, `ifelse()`). See the JAGS manual [-@jags] for further
details.

```{r, eval=FALSE}
# Using the depression SSRI dataset
depnet <- mbnma.network(ssri)

# An example specifying a quadratic dose-response function
quadfun <- ~ (beta.1 * dose) + (beta.2 * (dose^2))

quad <- mbnma.run(depnet, fun=duser(fun=quadfun, beta.1 = "rel", beta.2 = "rel"))
```

### Agent-specific dose-response functions

Different dose-response functions can be used for different agents
within the network. This allows for the modelling of more complex
dose-response functions in agents for which there are many doses
available, and less complex functions in agents for which there are
fewer doses available. Note that these models are typically less
computationally stable than single dose-response function models, and
they are likely to benefit less from modelling correlation between
multiple dose-response parameters since there are fewer agents informing
correlations between each dose-response parameter.

This can be modeled using the `dmulti()` dose-response function and
assigning a list of objects of class `"dosefun"` to it. Each element in
the list corresponds to an agent in the network (the order of which
should be the same as the order of agents in the `"mbnma.network"`
object). A dose-response function for Placebo should be included in the
list, though which function is used is typically irrelevant since
evaluating the function at dose=0 will typically equal 0.

```{r, eval=FALSE}
# Using the depression SSRI dataset
depnet <- mbnma.network(ssri)

dr.funs <- dmulti(list(
  "Placebo"=dfpoly(degree=2),
  "citalopram"=dfpoly(degree=2),
  "escitalopram"=dfpoly(degree=2),
  "fluoxetine"=dspline(type="ns",knots=2),
  "paroxetine"=dfpoly(degree=2),
  "sertraline"=dspline(type="ns",knots=2)
  ))

multifun <- mbnma.run(depnet, fun=dr.funs, method="common", n.iter=50000)
summary(multifun)
```

### Incorporating agents/interventions without a dose-response

Because an MBNMA model with a linear dose-response function
(`dpoly(degree=1)`) is mathematically equivalent to a standard NMA
model, using agent-specific dose-response functions allows analysis of
datasets that both include multiple doses of different drugs *and*
interventions for which a dose-response relationship is not realistic
(e.g. surgery) or difficult to assume (e.g. psychotherapy, exercise
interventions). Interventions without a dose-response relationship can
be coded in the dataset as different agents, each of which should be
assigned a dose of 1, and these can then be modeled using a linear
dose-response relationship, whilst agents with a plausible dose-response
can be assigned a function that appropriately captures their
dose-response relationship. Further details of this approach can be
found in the vignette on [NMA in MBNMAdose](nma_in_mbnmadose.html)

### Splines and `knots`

For a more flexible dose-response shape, various different splines can
be fitted to the data by using `dspline()`. This model is very flexible
and can allow for a variety of non-monotonic dose-response
relationships, though parameters can be difficult to interpret and the
resulting dose-response shape is often best visualised by calculating
and plotting predictions ([Predictions](predictions-5.html).

To fit this model, the number/location of `knots` (the points at which
the different spline pieces meet) should be specified. If a single
number is given, it represents the the number of knots to be equally
spaced across the dose range of each agent. Alternatively several
probabilities can be given that represent the quantiles of the dose
range for each agent at which knots should be located. Note that by default, a boundary knot will be placed at the maximum of the dose range to limit the function extrapolating to extreme values.

```{r, eval=FALSE}
dspline(type="bs", knots=3)
# ...is equivalent to 
dspline(type="bs", knots=c(0.25,0.5,0.75))

# Using a natural cubic spline on the SSRI dataset
depnet <- mbnma.network(ssri)
ns <- mbnma.run(depnet, fun=dspline(type="ns", knots=c(0.25,0.5,0.75)))
```


### Correlation between dose-response parameters

`mbnma.run()` can model correlation between relative effects
dose-response parameters, allowing information on one parameter to inform the other(s). 
This can be implemented by specifying `cor=TRUE` in `mbnma.run()`. The correlation is modeled using a vague Wishart prior. However, note that even a vague Wishart prior may be somewhat influential, given
that there is typically limited data to inform the dose-response parameter correlations. The prior can be made more informative by specifying a scale matrix for it. This corresponds to the expectation of the Wishart prior. A different scale matrix can be given to the model in
`omega`. Each row of the scale matrix corresponds to the 1st, 2nd, 3rd,
etc. dose-response parameter that has been modeled using relative
effects (as specified in the dose-response function).

### Priors

Default vague priors for the model are as follows:

$$
\begin{aligned}
  &d_{p,a} \sim N(0,10000)\\
  &beta_{p} \sim N(0,10000)\\
  &\sigma \sim N(0,400) \text{  limited to  } x \in [0,\infty]\\
  &\sigma_{p} \sim N(0,400) \text{  limited to  } x \in [0,\infty]\\
  &D_{p,c} \sim N(0,1000)\\
  &\sigma^D_{p} \sim N(0,400) \text{ limited to } x \in [0,\infty]\\
\end{aligned}
$$

...where $p$ is an identifier for the dose-response parameter (e.g. 1
for Emax and 2 for ED50), $a$ is an agent identifier and $c$ is a class
identifier.

For dose-response parameters that are constrained to be non-negative
(`ed50`, `hill`, `onset`), default prior distributions are truncated
(normal). An alternative is to model these parameters using a log-normal
distribution (`"dlnorm(mean, prec)"`).

Users may wish to change these, perhaps in order to use more/less
informative priors. For default prior distributions on some parameters
this may lead to errors when compiling/updating models due to
implausibly high values. Or in some cases they can constrain the
posterior distribution when the user may wish to allow for a wider range
of values.

If the model fails during compilation/updating (i.e. due to a problem in
JAGS), `mbnma.run()` will generate an error and return a list of
arguments that `mbnma.run()` used to generate the model. Within this (as
within a model that has run successfully), the priors used by the model
(in JAGS syntax) are stored within `"model.arg"`:

```{r}
print(mbnma$model.arg$priors)
```

In this way a model can first be run with vague priors and then rerun
with different priors, perhaps to allow successful computation, perhaps
to provide more informative priors, or perhaps to run a sensitivity
analysis with different priors. Increasing the precision of prior
distributions only a little can also often improve convergence
considerably.

To change priors within a model, a list of replacements can be provided
to `priors` in `mbnma.run()`. The name of each element is the name of
the parameter to change (without indices) and the value of the element
is the JAGS distribution to use for the prior. This can include
censoring or truncation if desired. Only the priors to be changed need
to be specified - priors for parameters that aren't specified will take
default values.

For example, if we want to use tighter priors for the half-normal SD
parameters we could increase the precision:

```{r, eval=FALSE}
# Define replacement prior
new.priors <- list(
  sd = "dnorm(0, 1) T(0,)"
  )

# Run an MBNMA model with new priors
emax <- mbnma.run(alognet, fun=demax(), method="random",
                   priors=new.priors)
```

Different prior distributions can be assigned for different indices of a parameter by specifying the list element for a parameter as a character vector. This allows (for example) for the user to fit specific priors for specific agents. The length of this vector must be equal to the number of indices of the parameter. The ordering will also be important - for example for agent-specific priors the order of the elements within the vector must match the order of the agents in the network.

For example for an Emax function we may have different prior beliefs about the ED50 parameter, as the dose scale will be different for different agents:

```{r, eval=FALSE}
ed50.priors <- list(ed50 = c(
  Celebrex="dnorm(100, 0.0025) T(0,)", 
  Etoricoxib="dnorm(20, 0.01) T(0,)", 
  Lumiracoxib="dnorm(50, 0.0025) T(0,)", 
  Naproxcinod="dnorm(500, 0.0004) T(0,)", 
  Naproxen="dnorm(500, 0.0004) T(0,)",
  Rofecoxib="dnorm(35, 0.04) T(0,)",
  Tramadol="dnorm(200, 0.0004) T(0,)",
  Valdecoxib="dnorm(4, 0.04) T(0,)"
  ))

# Using the osteoarthritis dataset
mbnma <- mbnma.run(painnet, fun=demax(emax="rel", ed50="rel"),
                   priors=ed50.priors)
```


### pD (effective number of parameters)

The default value in for `pD` in `mbnma.run()` uses the Kullback-Leibler divergence to estimate
pD [@plummer2008]. However, since it requires running additional MCMC samples, it can be set to
`FALSE` to force the model to estimate pV, where `pv = var(deviance)/2`. Whilst this is easy to calculate, it is numerically less stable than the Kullback-Leibler divergence estimation, and may perform more poorly in certain conditions [@gelman2014].


### Arguments to be sent to JAGS

In addition to the arguments specific to `mbnma.run()` it is also
possible to use any arguments to be sent to `R2jags::jags()`. Most of
these are likely to relate to improving the performance of MCMC
simulations in JAGS and may help with parameter convergence (see
[Convergence]). Some of the key arguments that may be of interest are:

-   `n.chains` The number of Markov chains to run (default is 3)
-   `n.iter` The total number of iterations per MCMC chain
-   `n.burnin` The number of iterations that are discarded to ensure
    iterations are only saved once chains have converged
-   `n.thin` The thinning rate which ensures that results are only saved
    for 1 in every `n.thin` iterations per chain. This can be increased
    to reduce autocorrelation

## Connecting networks via the dose-response relationship

One of the strengths of dose-response MBNMA is that it allows treatments
to be connected in a network that might otherwise be disconnected, by
linking up different doses of the same agent via the dose-response
relationship [@pedder2021]. To illustrate this we can generate a version
of the gout dataset which excludes placebo (to artificially disconnect
the network):

```{r, message=FALSE, warning=FALSE}
# Generate dataset without placebo
noplac.gout <- 
  gout[!gout$studyID %in% c(2001, 3102),] # Drop two-arm placebo studies
noplac.gout <- 
  noplac.gout[noplac.gout$agent!="Plac",] # Drop placebo arm from multi-arm studies

# Create mbnma.network object
noplac.net <- mbnma.network(noplac.gout)
```

```{r}
# Plot network
plot(noplac.net, label.distance=5)
```

This results in a very disconnected network, and if we were to conduct a
conventional "split" NMA (whereby different doses of an agent are
considered to be independent), we would only be able to estimate
relative effects for a very small number of treatments. However, if we
assume a dose-response relationship then these different doses can be
connected via this relationship, and we can connect up more treatments
and agents in the network.

```{r}
# Network plot at the agent level illustrates how doses can connect using MBNMA
plot(noplac.net, level="agent", remove.loops = TRUE, label.distance = 4)
```

There are still two agents that do not connect to the network because
they involve comparisons of different doses of the same agent. However,
multiple doses of an agent within a study allow us to estimate the
dose-response relationship and tell us something about the placebo (dose
= 0) response - the number of different doses of an agent within a study
will determine the degrees of freedom with which we are able to estimate
a given dose-response function. Although the placebo response is not
estimated directly in the MBNMA framework (it is modelled as a nuisance
parameter), it allows us to connect the dose-response function estimated
for an agent in one study, with that in another.

To visualise this, we can use the `doselink` argument in
`plot(mbnma.network)`. The integer given to this argument indicates the
minimum number of doses from which a dose-response function could be
estimated, and is equivalent to the number of parameters in the desired
dose-response function plus one. For example for an exponential
function, we would require at least two doses on a dose-response curve
(including placebo), since this would allow one degree of freedom with
which to estimate the one-parameter dose-response function. By modifying
the `doselink` argument we can determine the complexity of a
dose-response function that we might expect to be able to estimate
whilst still connecting all agents within the network.

If placebo is not included in the original dataset then this argument
will also add a node for placebo to illustrate the connection.

```{r}
# Network plot assuming connectivity via two doses
# Allows estimation of a single-parameter dose-response function
plot(noplac.net, level="agent", remove.loops = TRUE, label.distance = 4,
     doselink=2)

# Network plot assuming connectivity via three doses
# Allows estimation of a two-parameter dose-response function
plot(noplac.net, level="agent", remove.loops = TRUE, label.distance = 4,
     doselink=3)
```

In this way we can fully connect up treatments in an otherwise
disconnected network, though unless informative prior information is
used this will be limited by the number of doses of agents within
included studies. See Pedder et al. [-@pedder2021] for more details on
this.

## Non-parametric dose-response functions

In addition to the parametric dose-response functions described above, a
non-parametric monotonic dose-response relationship can also be
specified in `mbnma.run()`. `fun=dnonparam()` can be used to specify a
monotonically increasing (`direction="increasing"`) or decreasing
(`direction="decreasing"`) dose-response respectively. This is achieved
in the model by imposing restrictions on the prior distributions of
treatment effects that ensure that each increasing dose of an agent has
an effect that is either the same or greater than the previous dose. The
approach results in a similar model to that developed by Owen et al.
[-@owen2015].

By making this assumption, this model is slightly more informative, and
can lead to some slight gains in precision if relative effects are
otherwise imprecisely estimated. However, because a functional form for
the dose-response is not modeled, it cannot be used to connect networks
that are disconnected at the treatment-level, unlike a parametric MBNMA.

In the case of MBNMA, it may be useful to compare the fit of a
non-parametric model to that of a parametric dose-response function, to
ensure that fitting a parametric dose-response function does not lead to
significantly poorer model fit.

When fitting a non-parametric dose-response model, it is important to
correctly choose the expected `direction` of the monotonic response,
otherwise it can lead to computation error.

```{r, nonparam, results="hide"}
nonparam <- mbnma.run(tripnet, fun=dnonparam(direction="increasing"), method="random")
```

```{r}
print(nonparam)
```

In the output from non-parametric models, `d.1` parameters represent the
relative effect for each treatment (specific dose of a specific agent)
versus the reference treatment, similar to in a standard Network
Meta-Analysis. The first index of `d` represents the dose identifier,
and the second index represents the agent identifier. Information on the
specific values of the doses is not included in the model, as only the
ordering of them (lowest to highest) is important.

Note that some post-estimation functions (e.g. ranking, prediction)
cannot be performed on non-parametric models within the package.


## Assessment of model fit

For looking at model fit we will demonstrate using
results from an Emax MBNMA on the triptans dataset:

```{r, results="hide"}
tripnet <- mbnma.network(triptans)
trip.emax <- mbnma.run(tripnet, fun=demax(emax="rel", ed50="rel")) 
```

### Deviance plots

To assess how well a model fits the data, it can be useful to look at a
plot of the contributions of each data point to the residual deviance.
This can be done using `devplot()`. As individual deviance contributions
are not automatically monitored in `parameters.to.save`, this might
require the model to be automatically run for additional iterations.

Results can be plotted either as a scatter plot (`plot.type="scatter"`)
or a series of boxplots (`plot.type="box"`).

```{r, results="hide"}
# Plot boxplots of residual deviance contributions (scatterplot is the default)
devplot(trip.emax, plot.type = "box")
```

From these plots we can see that whilst the model fit does not seem to
be systematically non-linear (which would suggest an alternative
dose-response function may be a better fit), residual deviance is high
at a dose of 1 for eletriptan, and at 2 for sumatriptan. This may
indicate that fitting random effects may allow for additional
variability in response which may improve the model fit.

If saved to an object, the output of `devplot()` contains the results
for individual deviance contributions, and this can be used to identify
any extreme outliers.

### Fitted values

Another approach for assessing model fit can be to plot the fitted
values, using `fitplot()`. As with `devplot()`, this may require running
additional model iterations to monitor `theta`.

```{r, results="hide", warning=FALSE}
# Plot fitted and observed values with treatment labels
fitplot(trip.emax)
```

Fitted values are plotted as connecting lines and observed values in the
original dataset are plotted as points. These plots can be used to
identify if the model fits the data well for different agents and at
different doses along the dose-response function.


## Model Selection

Detailed description of model selection based on statistical measures
such as Deviance Information Criterion (DIC) and residual deviance is
outside the scope of this vignette. However, the following approach for
model identification and selection is recommended, which also gives
details on model fit statistics used for comparison:

1.  Identify candidate dose-response functions based on plotted results
    of split NMA (`plot.nma()`) and clinical/biological reasoning
2.  Compare candidate dose-response functions fitted with common
    relative treatment effects (`mbnma.run(..., method="common")`)
3.  If no candidate dose-response functions converge successfully,
    additional modelling assumptions can be made to strengthen
    inference, provided they are clinically justifiable (e.g. class
    effects, agent-specific dose-response functions, correlation between
    dose-response parameters)
4.  Compare selected common effects model to the same model fitted with
    random effects (`mbnma.run(..., method="random")`)

Finally the validity of the consistency assumption should be explored in
the selected final model (see [Consistency Testing] and Pedder et al.
[-@pedder2021cons]).

## MCMC Convergence

`MBNMAdose` runs Bayesian models in JAGS, which uses Markov Chain Monte
Carlo (MCMC) simulation. However, the validity of results is reliant on
the MCMC chains having converged successfully on the posterior densities
of all parameters in the model. For highly parameterised models run on
relatively limited data, as is often the case with MBNMA models,
convergence can often be an challenge. Note that convergence is
*necessary* to be able to compare models and evaluate model fit.
However, successful convergence *does not* imply good model fit.

A full explanation of how to facilitate and to check for convergence is
outside the scope of this vignette, but below are some simple steps for
checking convergence. None of these steps alone ensures convergence has
been successful, but interpretation of them jointly can provide strong
evidence of it.

-   Rhat values close to 1 (\<1.1 is considered acceptable by some).
    These are shown for monitored parameters in the summary statistics
    table when an `"mbnma"` or `"nma"` object is printed.
-   Trace plots that have a "fuzzy caterpillar" look that shows good
    mixing of MCMC chains
-   Density plots that show a smooth posterior distribution that is
    similar across all chains
-   Autocorrelation plots that show low autocorrelation between
    neighbouring MCMC iterations (i.e. low correlation at higher lags)

Convergence plots for all parameters in the model can be generated using
functions from the `coda` package (e.g. `coda::traceplot()`,
`coda::densplot()` and `coda::autocorr.plot()`) applied to the model
output via `coda::as.mcmc()`.

Two steps may improve convergence when using `MBNMAdose`. One step is to
run models for more iterations (this can be done using the `n.iter`
argument in `mbnma.run()`). It can take time for MCMC chains to
converge, particularly for non-linear models with limited data. It is
important to note that chains should only be monitored *after* they have
converged - increasing the number of burn-in iterations ensures that
this is the case (using the `n.burnin` argument in `mbnma.run()`).
Another method to improve convergence is by providing more information
to the model via informative priors.

For a detailed review of MCMC convergence assessment see Sinharay
[-@sinharay].


## References
