In openpharma/mmrm: Mixed Models for Repeated Measures

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library(mmrm)

Prediction of conditional mean

Mathematical Derivations

Since residuals can be correlated, potentially existing observed outcomes of the same individual can be informative for predicting the unobserved valued of the same individual.

Assume that the data is sorted such that $Y_{ij} = y_{ij}, j = k+1, k+2, \dots, p$ are observed and $Y_{ij}, j = 1, 2, \dots, k$ are not. The special case of all outcomes being unobserved (new individual) is covered with $k=p$.

Let further $$ \Sigma_i(X_i, \theta) = \begin{pmatrix} \Sigma_i^{new,new}(X_i,\theta) & \Sigma_i^{new,old}(X_i,\theta)\ \Sigma_i^{old,new}(X_i,\theta) & \Sigma_i^{old,old}(X_i,\theta)\end{pmatrix} $$

be a block decomposition where $\Sigma_i^{new,new}(X_i,\theta) = \Big(\big(\Sigma_i(X_i,\theta)\big){j,l}\Big){j = 1\dots k,\, l = 1\ldots k}$ and similarly for the other blocks.

Predictions can then be made based on the conditional distribution $$ Y_{i, 1\ldots k}\,|\,X_i,Y_{i,k+1\ldots p}=y_{i, k+1\ldots p}\sim\mathcal{N}(\mu_i, A_i) $$

with

$$ \mu_i(\beta,\theta) = (X_i \ \beta){1\ldots k} + \Sigma_i^{new,old}(X_i,\theta) \, \Big(\big(\Sigma_i^{old,old}(X_i,\theta)\big)^{-1} \big(y_i^{k+1\ldots p} - (X_i \ \beta){k+1\ldots p}\big)\Big) $$ and

$$ A_i(\beta, \theta) = \Sigma_i^{new,new}(X_i,\theta) - \Sigma_i^{old,new}(X_i,\theta) \Big(\Sigma_i^{old,old}(X_i,\theta)\Big)^{-1} \Sigma_i^{new,old}(X_i,\theta) \ . $$ Note that $A_i$ does not depend on $\beta$.

Implementation of predict

For implementing predict(), only $\widehat{\mu}_i:=\mu_i(\widehat{\beta},\widehat{\theta})$ is required.

For predict(interval = "confidence") additionally standard errors are required. These could be derived using the delta methods since $\mu_i$ is a function of the estimated model parameters $\beta$ and $\theta$. This would require the Jacobian $\nabla\mu_i(\beta,\theta)|{\big(\widehat{\beta},\widehat{\theta}\big)}$ in addition to the estimated variance covariance matrix of the parameter estimate $\big(\widehat{\beta},\widehat{\theta}\big)$, $\widehat{S}$. Standard errors for $\widehat{\mu}^{\,(i)}$ are then given by the square root of the diagonal elements of $$ \Big(\nabla\mu_i(\beta,\theta)|{\big(\widehat{\beta},\widehat{\theta}\big)}\Big)^\top\quad \widehat{S} \quad \Big(\nabla\mu_i(\beta,\theta)|_{\big(\widehat{\beta},\widehat{\theta}\big)}\Big) $$ For predict(interval = "prediction") one would use the square root of the diagonal elements of $A_i\big(\widehat{\beta},\widehat{\theta}\big)$ instead. The delta method could again be used to make upper and lower boundaries reflect parameter estimation uncertainty.

Alternatively, both intervals can be derived using a parametric bootstrap sample of the unrestricted parameters $\theta$. This would probably also be easier for the interval = "prediction" case.

Please note that for these intervals, we assume that the distribution is approximately normal: we use $\mu_{i,j}(\hat\beta, \hat\theta) \pm Z_{\alpha} * sqrt(A_{i, j, j}(\hat\beta, \hat\theta))$ to construct it, where $\mu_{i,j}(\hat\beta, \hat\theta)$ is the $j$th element of $\mu_i(\hat\beta, \hat\theta)$, and $A_{i, j, j}(\hat\beta, \hat\theta)$ is the $j,j$ element of $A_i(\hat\beta, \hat\theta)$.

Parametric Sampling for Prediction Interval

With the conditional variance formula

[ Var(Y_i) = Var(E(Y_i|\theta)) + E(Var(Y_i|\theta)) ]

and the conditional expectation $E(Y_i|\theta)$ and the conditional variance $Var(Y_i|\theta)$ being already described as

[ E(Y_i|\theta) = \mu_i(\beta, \theta) ]

and

[ Var(Y_i|\theta) = A_i(\beta, \theta), ]

we can sample on $\theta$ and obtain $\beta$, then calculate the variance of conditional mean and the mean of conditional variance.

Prediction of Conditional Mean for New Subjects

If there are no observations for a subject, then the prediction is quite simple:

[ Y_i = X_i \hat\beta ]

Simulate response

To create simulation of responses from a fitted model, we have multiple situations: whether this simulation is conditional on both $\theta$ and $\beta$ estimates, or it is marginal?

Conditional Simulation

Under conditional simulation setting, the variance-covariance matrix, and the expectation of $Y_i$ are already given in Mathematical Derivations.

Please note that in implementation of predict function, we only use the diagonal elements of $A_i$, however, here we need to make use of the full matrix $A_i$ to obtain correctly correlated simulated observations.

Marginal Simulation

To simulate marginally, we take the variance of $\hat\theta$ and $\hat\beta$ into consideration. For each simulation, we first generate $\theta$ assuming it approximately follows a multivariate normal distribution. Then, conditional on the $\theta$ we sampled, we generate $\beta$ also assuming it approximately follows a multivariate normal distribution.

Now we have $\theta$ and $\beta$ estimates, and we just follow the conditional simulation.

Implementation of simulate

To implement simulate function, we first ensure that the expectation ($\mu$) and variance-covariance matrix ($A$) are generated in predict function, for each of the subjects.

For simulate(method = "conditional"), we use the estimated $\theta$ and $\beta$ to construct the $\mu$ and $A$ directly, and generate response with $N(\mu, A)$ distribution.

For simulate(method = "marginal"), for each repetition of simulation, we generate $\theta_{new}$ from the mmrm fit, where the estimate of $\theta$ and variance-covariance matrix of $\theta$ are provided. Using the generated $\theta_{new}$, we then obtain the $\beta_{new}$ and its variance-covariance matrix, with $\theta_{new}$ and the data used in fit.

Then we sample $\beta$ as follows. We note that on the C++ side we already have the robust Cholesky decomposition of the inverse of its asymptotic covariance matrix: [ cov(\hat\beta) = (X^\top W X)^{-1} = (LDL^\top)^{-1} ] Hence we make sure to report the lower triangular matrix $L$ and the diagonal matrix $D$ back to the R side, and afterwards we can generate $\beta$ samples as follows: [ \beta_{sample} = \beta_{new} + L^{-\top}D^{-1/2}z_{sample} ] where $z_{sample}$ is drawn from the standard multivariate normal distribution, since [ cov(L^{-\top}D^{-1/2}z_{sample}) = L^{-\top}D^{-1/2} I_p D^{-1/2} L^{-1} = L^{-\top}D^{-1}L^{-1} = (LDL^\top)^{-1} = cov(\hat\beta) ] We note that calculating $w = L^{-\top}D^{-1/2}z_{sample}$ is efficient via backwards solving [ L^\top w = D^{-1/2}z_{sample} ] since $L^\top$ is upper right triangular.

Then we simulate the observations once with simulate(method = "conditional", beta = beta_sample, theta = theta_new). We pool all the repetitions together and thus obtain the marginal simulation results.

Relationship Between predict and simulate Results

We summarize the different options for predict and simulate methods and explain how they relate to each other.

predict options

1. predict(type = "confidence") gives the variance of the predictions conditional on the $\theta$ estimate, taking into account the uncertainty of estimating $\beta$. So here we ignore the uncertainty in estimating $\theta$. It also does not add measurement error $\epsilon$. We can use this prediction when we are only interested in predicting the mean of the unobserved $y_i$, assuming the estimated $\theta$ as the true variance parameters.
2. predict(type = "prediction") in contrast takes into account the full uncertainty, including the variance of $\theta$ and the measurement error $\epsilon$. We can use this prediction when we are interested in reliable confidence intervals for the unobserved $y_i$ as well as the observed $y_i$, assuming we would like to predict repeated observations from the same subjects and time points.

simulate options

1. simulate(type = "conditional") simulates observations while keeping the $\theta$ and $\beta$ estimates fixed. It adds measurement errors $\epsilon$ when generating the simulated values. Hence the mean of the simulated values will be within the confidence intervals from predict(type = "conditional").
2. simulate(type = "marginal") simulates observations while taking into account the uncertainty of $\beta$ and $\theta$ through sampling from their asymptotic frequentist distributions. On top of that, it also adds measurement errors $\epsilon$. This hence is using the same distribution as predict(type = "prediction").

Comparison with SAS

In SAS, from proc mixed, we are able to generate predictions using the outp argument in the model statement. For example:

{sas eval=FALSE} PROC MIXED DATA = fev_data method=reml; CLASS RACE(ref = 'Asian') AVISIT(ref = 'VIS4') SEX(ref = 'Male') ARMCD(ref = 'PBO') USUBJID; MODEL FEV1 = ARMCD / ddfm=Satterthewaite solution chisq outp=pred; REPEATED AVISIT / subject=USUBJID type=un r rcorr; LSMEANS ARMCD / pdiff=all cl alpha=0.05 slice=AVISIT; RUN;

However, there are some differences between the SAS implementation and our mmrm package, described as follows:

1. While mmrm and SAS both provide predicted means (conditional on other observations) for unobserved records, SAS also provides predicted means for observed records while mmrm does not. The rationale is that in the mmrm package we want to be consistent with the notion of predictions conditional on the observed records - which means that observed records are observed and therefore there is no prediction uncertainty anymore.
2. The prediction standard error is different between mmrm and SAS. While in SAS the prediction standard error is conditional on the estimated variance parameters $\theta$, in mmrm the marginal prediction standard error is provided. The rationale is that in the mmrm package we want to take into account the full uncertainty about parameter estimates including $\theta$.
3. The prediction intervals in SAS are based on the t distribution, while currently in mmrm we use the normal distribution. We will be considering an extension towards using the t distribution in the future and welcome feedback on this detail.

openpharma/mmrm documentation built on April 14, 2025, 2:10 a.m.