Mixed models repeated measures (mmrm) package for R

I was recently made aware of the release of the mmrm package in R. It has been developed by a group of programmers and statisticians at a number of pharmaceutical companies, led by Daniel Sabanes Bove at Roche, as part of the ASA Biopharmaceutical Section Software Engineering Working Group. I’ve written previously about fitting mixed models for repeated measures (MMRM) using R, Stata and SAS. In R, this can be done using the gls function in the nlme package, but there are a number of limitations with this approach. For example, it is difficult (or impossible) to fit models where you allow the covariance parameters to be distinct between treatment groups. In this post, I’ll take a very quick look at the new mmrm package in R.

To demonstrate the typical use of the mmrm package, I reload the simulated dataset generated in this previous post. This is a dataset with a baseline measurement y0 and three follow-up measurements, as shown in the following summary of the wide version of the data:

summary(wideData)
       id             trt              y0                 y1                y2                y3         
 Min.   :  1.0   Min.   :0.000   Min.   :-3.00794   Min.   :-3.2529   Min.   :-3.0906   Min.   :-2.8766  
 1st Qu.:125.8   1st Qu.:0.000   1st Qu.:-0.85620   1st Qu.:-0.6638   1st Qu.:-0.4164   1st Qu.:-0.2294  
 Median :250.5   Median :0.000   Median :-0.08929   Median : 0.2174   Median : 0.5147   Median : 0.7423  
 Mean   :250.5   Mean   :0.488   Mean   :-0.03882   Mean   : 0.1731   Mean   : 0.4559   Mean   : 0.7058  
 3rd Qu.:375.2   3rd Qu.:1.000   3rd Qu.: 0.86261   3rd Qu.: 1.0390   3rd Qu.: 1.4003   3rd Qu.: 1.6568  
 Max.   :500.0   Max.   :1.000   Max.   : 4.40421   Max.   : 3.6834   Max.   : 4.1396   Max.   : 4.6730  
                                                    NA's   :42        NA's   :75        NA's   :113  

MMRM using the nlme package

To fit this model using the older nlme package, in my previous code I used the following syntax:

library(nlme)
mmrm <- nlme::gls(y~y0*factor(time)+trt*factor(time),
          na.action=na.omit, data=longData,
          correlation=nlme::corSymm(form=~time | id),
          weights=nlme::varIdent(form=~1|time))

The values passed to the correlation and weights arguments are needed to specify that we wanted an unstructured variance covariance matrix across the time points (visits).

MMRM using the mmrm package

To fit the same model using the new mmrm package, I discovered I first needed to convert the id, time and trt variables to factors. I then fitted the MMRM model using:

library(mmrm)
mmrm2 <- mmrm(y~y0*time+trt*time+us(time|id), data=longData)

Note the simpler syntax for specifying an unstructured covariance matrix. Comparing the estimates (not shown here) I obtained from this fit to those from gls, they were essentially identical, with the tiny differences presumably due to differences in the way the two functions/packages are maximising the likelihood function.

Separate covariance matrices by treatment arm

One of the things that is not possible to do with the nlme/gls route is to allow the parameters of the residual covariance matrix to differ by treatment arms. This is something that is very easy to do in the mmrm package by modifying the us() argument as follows:

mmrm3 <- mmrm(y~y0*time+trt*time+us(time| trt/id), data=longData)

I have only just brushed the surface of what the package is capable I think, but it looks like a fantastic development for anyone who is interested in fitting mixed models to repeated measures data. For more on the package, see this blog post by the working group who developed the package and of course the package's page at CRAN, from which there are links to various vignettes and the package manual.