mmrm

Daniel Sabanes Bove

(Statistical Engineering, Pharma Product Development Data Sciences, Roche)

2022-12-08

Acknowledgments

Authors:

• Kevin Kunzmann (Boehringer Ingelheim)
• Brian Matthew Lang (MSD)
• Ya Wang (Gilead)
• Julia Dedic (Roche)
• Doug Kelkhoff (Roche)
• Liming Li (Roche)

Thanks to:

• Ben Bolker (McMaster University)
• Software Engineering working group (SWE WG)
• Gonzalo Duran Pacheco (Roche)
• Craig Gower-Page (Roche)
• Dinakar Kulkarni (Roche)
• Davide Garolini (Roche)

Motivation

• 2 years ago, we thought we had solved the MMRM problem, using lme4 and lmerTest
• However in March this year, Gonzalo and Julia told us the bad news: this approach failed on their Ophthalmology data sets (slow, did not converge)
• nlme does not give Satterthwaite adjusted degrees of freedom, has convergence issues, and with emmeans it is only approximate
• Next we tried to extend glmmTMB to calculate Satterthwaite adjusted degrees of freedom, but it did not work

Idea

• Because glmmTMB is always using a random effects representation, we cannot have a real unstructured model (uses \(\sigma = \varepsilon > 0\) trick)
• We only want to fit a fixed effects model with a structured covariance matrix for each subject
• The idea is then to use the Template Model Builder (TMB) directly - as it is also underlying glmmTMB - but code the exact model we want
• We do this by implementing the log-likelihood in C++ using the TMB provided libraries

Advantages of TMB

• Fast C++ framework for defining objective functions (Rcpp would have been alternative interface)
• Automatic differentiation of the log-likelihood as a function of the variance parameters
• We get the gradient and Hessian exactly and without additional coding
• This can be used from the R side with the TMB interface and plugged into optimizers

Cross-industry collaboration

• We created an initial prototype quickly and open sourced it on github.com/openpharma/mmrm
• In parallel we assembled multiple other companies - many of them had also struggled to implement MMRM in R (crucial gap in toolbox so far)
• This was the start of the Software Engineering working group (SWE WG)
  • Read more at rconsortium.github.io/asa-biop-swe-wg
  • Official working group of the ASA Biopharmaceutical section

Features

• Linear model for dependent observations within independent subjects
• Covariance structures for the dependent observations:
  • Unstructured, Toeplitz, AR1, compound symmetry, ante-dependence, spatial exponential
  • Allows group specific covariance estimates and weights
• REML or ML estimation, using multiple optimizers if needed
• emmeans interface for least square means
• Satterthwaite adjusted degrees of freedom

Getting started

• mmrm is on CRAN - use this as a starting point:

install.packages("mmrm")
library(mmrm)
fit <- mmrm(
  formula = FEV1 ~ RACE + SEX + ARMCD * AVISIT + us(AVISIT | USUBJID),
  data = fev_data
)
summary(fit)
library(emmeans)
emmeans(fit, ~ ARMCD | AVISIT)

• Visit openpharma.github.io/mmrm for detailed docs including vignettes
• Consider tern.mmrm for high-level clinical reporting interface, incl. standard tables and graphs

Outlook

• We still have major features on our backlog:
  • Kenward-Roger (improved variance-covariance matrix, degrees of freedom)
  • Robust sandwich estimator for covariance matrix (important when not using unstructured covariance)
  • Type II and type III ANOVA tests
• Working on comparison to other implementations
  • Parameter estimates, computation time, convergence, …
• Please let us know what is missing in mmrm for you! And try it out :-)

Thank you! Questions?