---
title: "Multiple Regimen MCP-Mod"
output: rmarkdown::html_vignette
bibliography: refs.bib
link-citations: yes
csl: american-statistical-association.csl
vignette: >
  %\VignetteIndexEntry{Analysis template: MCP-Mod with multiple regimen}
  %\VignetteEngine{knitr::rmarkdown}
  %\VignetteEncoding{UTF-8}
---

```{r setup, child="children/settings.txt"}
```

## Background

Often more than one regimen is studied in dose-finding studies. If there
are enough doses within each regimen, one may still utilize MCP-Mod.
But specific assumptions are needed, and it depends on the situation,
whether or not these are appropriate (and thus usage of MCP-Mod).

The first idea is to bring the doses for each regimen on a common
scale (total dose per time unit). For example if once daily (od)
dosing and twice daily (bid) dosing are used in a study, one might
utilize the total daily dose.

It is usually not appropriate to then perform MCP-Mod on the total daily
dose (ignoring from which regimen the doses originate): The study
investigated more than one regimen, so assessing the difference
between regimen (for example for the same total daily dose) is of
interest. This would not be possible with a modelling approach
that ignores the regimen.

The most general approach would be to perform MCP-Mod separately by
regimen, and for example to adjust p-values originating from the
MCP-part using a Bonferroni correction. This approach assumes that the
regimen don't share any similarity. Due to the double-blind nature of
trials, all patients would receive two administrations per day
(patients in the od group receive one placebo per day), so that there
is no real od group and in particular no separate placebo od group.
So it often makes more sense to assume that the placebo group is
common to both the od and bid dose-response curve. For the MCP-step
contrasts for both od and bid are taken with respect to the same
placebo group and in the modelling step one would assume the intercept
to be the same across regimen, but all other parameters separate.

One could also assume further parameters to be common across regimen
(for example the Emax or the ED50 parameter for the Emax model), but
in the following example no such assumption is made.

The motivation for the simulated data below is taken from a recently
completed dose-finding study, where the dose-response of the drug
Licogliflozin was assessed for the od and bid regimen [@bays2020],
see also the [corresponding page at clinicaltrials.gov](https://clinicaltrials.gov/ct2/show/results/NCT03100058).

Note that this study used MCP-Mod, but the analysis presented here has
been modified and simplified (in terms of candidate models and
dose-response modelling strategy).

For most of the following code it is useful to structure the first-stage estimates like this:
\[
\hat\mu=(\hat\mu_{\mathrm{placebo}}, \hat\mu_{\mathrm{od}}, \hat\mu_{\mathrm{bid}})
\]
The length of the sub-vectors $\hat\mu_{\mathrm{od}}$ and $\hat\mu_{\mathrm{bid}}$ correspond to the number of different doses in the two regimens.
They can be different, but in our example both have 4 elements.

Also as discussed above everything is modeled on the total daily dose scale.

```{r, data}
library(DoseFinding)
library(ggplot2)
## collect estimates and dosage information in one place
example_estimates <- function() {
  ## ANOVA mean estimates and ci bounds extracted from fig. 3 of Bays (2020).
  ## clinicaltrials.gov page already seems to contain values from the dose-response model fit
  mn <- c(-0.55, -1.78, -1.95, -3.29, -4.43, -1.14, -2.74, -4.03, -4.47)
  lb <- c(-1.56, -3.15, -3.36, -4.85, -5.40, -2.49, -4.10, -5.50, -5.50)
  ub <- c( 0.40, -0.30, -0.54, -1.76, -3.48, 0.24, -1.38, -2.65, -3.44)
  se <- (ub - lb)/(2*qnorm(0.975)) # approximate standard error
  return(list(mu_hat = mn,
              daily_dose = c(0, 2.5, 10, 50, 150, 5, 10, 50, 100),
              S_hat = diag(se^2),
              # keep track of which elements correspond to which regimen:
              index = list(placebo = 1, od = 2:5, bid = 6:9)))
}

## restructure estimates for easy plotting with ggplot
tidy_estimates <- function(est) {
  se <- sqrt(diag(est$S_hat))
  tidy <- data.frame(daily_dose = est$daily_dose, mu_hat = est$mu_hat,
                     ub = est$mu_hat + qnorm(0.975) * se, lb = est$mu_hat - qnorm(0.975) * se)
  tidy <- rbind(tidy[1, ], tidy) # duplicate placebo
  tidy$regimen <- c("od", "bid", rep("od", length(est$index$od)), rep("bid", length(est$index$bid)))
  return(tidy)
}

plot_estimates <- function(est) {
  df <- tidy_estimates(est)
  ggplot(df, aes(daily_dose, mu_hat)) + geom_point() +
    geom_errorbar(aes(ymin = lb, ymax = ub)) +
    facet_wrap(vars(regimen), labeller = label_both) +
    xlab("daily dose") + ylab("percent body weight cange") +
    labs(title = "ANOVA estimates with 95% confindence intervals")
}

est <- example_estimates()
plot_estimates(est)
```


## Candidate models

Even though not necessary and not always desired we will use the same
candidate models for both regimen here.

```{r, candidate_models}
mods <- list(
  od = Mods(emax = c(5, 50),
            sigEmax = rbind(c(75, 3.5), c(25, 0.7)),
            maxEff = -1,
            doses = est$daily_dose[c(est$index$placebo, est$index$od)]),
  bid = Mods(emax = c(5, 50),
             sigEmax = rbind(c(75, 3.5), c(25, 0.7)),
             maxEff = -1,
             doses=est$daily_dose[c(est$index$placebo, est$index$bid)]))

plotMods(mods$od, superpose = TRUE, xlab = "daily dose")
plotMods(mods$bid, superpose = TRUE, xlab = "daily dose")
```

## Multiple contrast test

The matrix of contrasts is built up from a separate matrix for each regimen.
We stick them together in such a way
that we compare $\hat\mu_{\mathrm{od}}$ and $\hat\mu_{\mathrm{bid}}$
with the common placebo response estimate $\hat\mu_{\mathrm{placebo}}$.

```{r, contrasts}
calculate_contrasts <- function(est, mods) {
  S_hat <- est$S_hat
  i <- est$index
  cm_od <- optContr(mods$od, S=S_hat[c(i$placebo, i$od), c(i$placebo, i$od)])$contMat
  cm_bid <- optContr(mods$bid, S=S_hat[c(i$placebo, i$bid), c(i$placebo, i$bid)])$contMat
  colnames(cm_od) <- paste0("od_", colnames(cm_od))
  rownames(cm_od)[-1] <- paste0("od_", rownames(cm_od)[-1])
  colnames(cm_bid) <- paste0("bid_", colnames(cm_bid))
  rownames(cm_bid)[-1] <- paste0("bid_", rownames(cm_bid)[-1])
  # now build a block matrix (contrasts in columns) like this:
  # [ row of placebo coefficients od   | row of placebo coefficients bid   ]
  # [----------------------------------+-----------------------------------]
  # [ remaining doses' coefficents od  | fill with all zeros               ]
  # [----------------------------------+-----------------------------------]
  # [ fill with all zeros              | remaining doses' coefficients bid ]
  cm_full <- rbind(
    "0"=c(cm_od[1,],                                cm_bid[1,]                              ),
    cbind(cm_od[-1,],                               matrix(0, nrow(cm_od) - 1, ncol(cm_bid))),
    cbind(matrix(0, nrow(cm_bid) - 1, ncol(cm_od)), cm_bid[-1, ]                            ))
  return(cm_full)
}

cont_mat <- calculate_contrasts(est, mods)
print(round(cont_mat, 2))
```

We also need to calculate the test statistics by hand.

```{r, test}
mct_test <- function(cont_mat, est) {
  cont_cov <- t(cont_mat) %*% est$S_hat %*% cont_mat
  t_stat <- drop(est$mu_hat %*% cont_mat) / sqrt(diag(cont_cov))
  # FIXME: calling non-exported function
  p <- MCTpval(contMat = cont_mat, corMat = cov2cor(cont_cov),
               df=Inf, tStat=t_stat, alternative = "one.sided")
  ord <- rev(order(t_stat))
  return(data.frame(tStat = t_stat[ord], pVals = p[ord]))
}
mct_test(cont_mat, est)
```

A clear dose-response trend can be established for both regimen.

## Dose-response modelling

Dose-response estimation needs a handful of auxiliary functions.
The model for $\hat\mu$ has a common intercept parameter for both regimen together
and two sets of the remaining parameters of the family in question.
For example, a model based on the Emax family has 5 parameters:
one common `e0`,
`(eMax, ed50)` for the od regimen,
and `(eMax, ed50)` for the bid regimen.

The following function calculates the responses given dose values and a model family.

```{r, estimation_1}
## calculate response under `model` for od/bid with common e0, but separate remaining parameters
## arguments:
## - model: as a string like "emax",
## - i_par: list of vectors named "placebo", "od", "bid", used for indexing `par`
## - par: numeric, model parameter structured as c(e0, pars_od, pars_bid)
## returns: response at placebo, dose_od, dose_bid (in this order)
eval_model_shared_e0 <- function(model, dose_od, dose_bid, par, i_par) {
  resp_placebo <- par[1] # e0
  resp_od <- do.call(model, append(list(dose_od, par[1]), as.list(par[i_par$od])))
  resp_bid <- do.call(model, append(list(dose_bid, par[1]), as.list(par[i_par$bid])))
  resp <- c(resp_placebo, resp_od, resp_bid)
  return(resp)
}
```

Next, we need to be able to fit a model family to the observed $\hat\mu$.
For this we employ the usual generalized MCP-Mod approach,
i.e. generalized least squares with the estimated covariance matrix $\hat S$
[@pinheiro2014].

```{r, estimation_2}
## find sensible starting values for `fit_model_shared_e0` by fitting separate models,
## index:  list of vectors named "placebo", "od", "bid", used for indexing `dose`
## bounds: passed through to `fitMod`
calc_start_values <- function(model, full_mu, full_S, dose, index, bounds) {
  separate_coefs <- sapply(c("od", "bid"), function(regimen) {
    inds <- c(index$placebo, index[[regimen]])
    coef(fitMod(dose[inds], full_mu[inds], S = full_S[inds, inds],
                type = "general",  model = model, bnds = bounds))[-1] # drop e0 estimate
  })
  ## remove names to prevent error in do.call() in eval_model_shared_e0;
  ## od, bid coefs are in 1st / second column
  start <- c(full_mu[1], as.numeric(separate_coefs), use.names=FALSE)
  return(start)
}

## fits 'model' to mu_hat with GLS (using S_hat_inv as weight matrix), using a common e0 for od and bid regimens.
## i_reg:  list of vectors named "placebo", "od", "bid", used for indexing `dose`
## i_par: passed through to `eval_model_shared_e0`
## dose: numeric with doses for placebo, od, bid
## lower, upper, start: control parameters fro `nlminb`
fit_model_shared_e0 <- function(model, dose, mu_hat, S_hat_inv, lower, upper, start, i_reg, i_par) {
  opt_fun <- function(par) { # make use of lexical scope
    resp <- eval_model_shared_e0(model, dose[i_reg$od], dose[i_reg$bid], par, i_par)
    delta <- resp - mu_hat
    return(drop(t(delta) %*% S_hat_inv %*% delta))
  }
  fit <- nlminb(start, opt_fun, lower = lower, upper = upper)
  return(fit)
}
```

Finally, instead of only fitting a single model,
we use the same bootstrap-plus-averaging approach
that is detailed in the [vignette for analysis of continuous data](analysis_normal.html#dose-response-estimation).

```{r, estimation_3}
## predict population response in each regimen for dose_seq_*
## note: both dose_seq_* vectors should contain a 0 if response at placebo is of interest
one_bootstrap_sample <- function(est, dose_seq_od, dose_seq_bid) {
  mu_new <- drop(rmvnorm(1, est$mu_hat, est$S_hat))
  mod_info <- list(list(name = "emax", bounds = rbind(c(0.15, 225)),
                        i_par = list(od = 2:3, bid = 4:5), n_par_gaic = 5),
                   list(name = "sigEmax", bounds = rbind(c(0.15, 225), c(0.5, 5)),
                        i_par = list(od = 2:4, bid = 5:7), n_par_gaic = 7))
  fit <- lapply(mod_info, function(m) {
    start <- calc_start_values(m$name, mu_new, est$S_hat, est$daily_dose, est$index, m$bounds)
    low <- c(-Inf, -Inf, m$bounds[,1]) # no bounds on e0, eMax
    up <- c(Inf, Inf, m$bounds[,2])
    fit_model_shared_e0(m$name, est$daily_dose, mu_new, solve(est$S_hat), lower = low,  upper = up,
                        start = start, i_reg = est$index, i_par = m$i_par)
  })
  ## calculate gAICs
  gaics <- sapply(fit, `[[`, "objective") + 2 * sapply(mod_info, `[[`, "n_par_gaic")
  sel <- which.min(gaics)
  mod <- mod_info[[sel]]
  ## drop the placebo element
  pred <- eval_model_shared_e0(mod$name, dose_seq_od, dose_seq_bid, fit[[sel]]$par, mod$i_par)[-1]
  return(pred)
}

summarize_bootstrap_samples <- function(samples, probs = c(0.025, 0.25, 0.75, 0.975)) {
  stopifnot(length(probs) == 4)
  med <- apply(samples, 1, median)
  quants <- apply(samples, 1, quantile, probs = probs)
  bs_df <- as.data.frame(cbind(med, t(quants)))
  names(bs_df) <- c("median", "low_out", "low_in", "high_in", "high_out")
  return(bs_df)
}

dose_seq_od <- seq(0, 150, length.out = 21) # do include placebo!
dose_seq_bid <- seq(0, 100, length.out = 21)
set.seed(1, kind = "Mersenne-Twister", sample.kind = "Rejection", normal.kind = "Inversion")
reps <- replicate(1000, one_bootstrap_sample(est, dose_seq_od, dose_seq_bid))
bs_sum <- summarize_bootstrap_samples(reps)
bs_sum$daily_dose <- c(dose_seq_od, dose_seq_bid)
bs_sum$regimen <- c(rep("od", length(dose_seq_od)), rep("bid", length(dose_seq_bid)))

ggplot(bs_sum) + geom_ribbon(aes(daily_dose, ymin=low_out, ymax=high_out), alpha = 0.2) +
  geom_ribbon(aes(daily_dose, ymin=low_in, ymax=high_in), alpha = 0.2) +
  geom_line(aes(daily_dose, median)) +
  geom_point(aes(daily_dose, mu_hat), tidy_estimates(est)) +
  facet_wrap(vars(regimen), labeller = label_both) +
  labs(title = "Bootstrap estimates for population response",
       subtitle = "Least squares estimates plus 50% and 95% confidence bands") +
  xlab("daily dose") + ylab("percent body weigh change") +
  coord_cartesian(ylim = c(-6, 0))
```

## References
