v2.0.6

nlmixr 2.0.6

• Fix focei subject initialization, see #566

Version 2.0.5

• Fix for nlmixrSim CMT to have a factor that matches the RxODE
  definition (issue #501)

• Give instructions on how to reinstall nlmixr if it is linked to a
  different version of RxODE. (#555)

• Now inform which parameters are near the boundary (#544)

• The saem estimation routine will now increase the tolerance when
  ODE solving is difficult; This can be controlled with
  odeRecalcFactors and maxOdeRecalc. This is similar to the
  handling that focei already uses.

• For focei family estimation methods:

  • If the inner problem couldn't solve the ODE using the forward
    sensitivities, try using numerical differences to approximate the
    derivatives needed for the focei problem. A warning will be
    issued when this occurs. This requires RxODE 1.1.0 that always
    generates the finite difference prediction model. If RxODE is an
    earlier version, only apply this when the finite differences are
    supplied to nlmixr. This occurs when there are ETAs on the dose
    based events like duration, lag time, bioavaibility etc.

  • If eta nudge is non-zero, when resetting an ETA estimate, try the
    zero estimate first, and then the nudged locations.

  • When there is an ODE system for an individual that cannot be
    optimized in the inner problem, adjust that individual's objective
    function by 100 points. This can be controlled by
    foceiControl(badSolveObjfAdj=100)

  • Theta reset now will now make sure the parameter is estimated and
    between the proper bounds before resetting.

• $simInfo non longer tries to generate the covariance step, and
  will simply have a $simInfo$thetaMat entry of NULL if the
  covariance step was unsuccessful.

• With vpc() if the cmt conversion isn't working correctly, fall
  back to compartment numbers.

• Take out symbol stripping based on CRAN policies

• Fall back gracefully when rbind doesn't work in parameter
  histories.

• Correctly print out the number of compartments based on the new
  RxODE linCmt() that was updated to support solved systems in
  focei. (Reported by Bill Denney #537).

• Use strict headers since Rcpp now is moving toward strict headers.
  Also changed all the Calloc to R_Calloc, Free to R_Free,
  and DOUBLE_EPS to DBL_EPSILON.

• gnlmm no longer imports the data.frame to an RxODE event table.
  This should speed up the routine slightly and (more importantly)
  make it easier to specify time varying covariates.

nlmixr 2.0.4

• Now can use the following for combinde error models:
  foceiControl(addProp=1) foceiControl(addProp=2)
saemControl(addProp=1) saemControl(addProp=2)

• Bug-fix for SAEM add+prop and other error models that are optimized
  with nelder mead simplex (#503)

• Bug-fix for more complex SAEM models that were not parsing and running. (Issue
  #502, #501)

• Issue the "NaN in prediction" once per SAEM problem (#500)

v2.0.4

• Now can use the following for combinde error models:
  foceiControl(addProp=1) foceiControl(addProp=2)
saemControl(addProp=1) saemControl(addProp=2)

• Bug-fix for SAEM add+prop and other error models that are optimized
  with nelder mead simplex (#503)

• Bug-fix for more complex SAEM models that were not parsing and running. (Issue
  #502, #501)

• Issue the "NaN in prediction" once per SAEM problem (#500)

v2.0.3

User interface changes

• Detection of initial conditions was rewritten to enable additional features
  in the initial conditions (#322). The most important user-facing change is
  that now arbitrary R expressions can be used when setting initial conditions
  such as tvCL <- log(c(2,3,4)) (#253) instead of simply tvCL <- log(3)

• The function as.nlmixrBounds() now supports adding the columns that are
  missing into the input data.frame.

• omega definitions can be correlation matrices (#338)

• Can specify keep= and drop= in the nlmixr function to keep and
  drop columns in nlmixr output. Can also specify
  control=list(keep=,drop=) or nlmixr(...,keep=,drop=) to
  keep/drop columns (#260)

focei changes:

• Uses RxODE to re-arrange the problem so it does not include
  if/else in the model (ie. un-branched code). This allows
  sensitivities to be calculated in one pass saving time for multiple
  endpoint models and models with if/else in them.

• linCmt() now uses solved systems instead of translating to ODEs.

  • Uses RxODE/stan's math headers to calculate the sensitivities
    of the super-positioned linCmt() solutions.
  • This uses the advan solutions and hence supports
    support time-varying covariates.

• focei now supports censoring in the same way monolix does, with
  cens and limit columns

• focei now allows etas on dose-related modeled events like
  alag, f, etc by finite difference sensitivities.

• focei now supports 2 combined additive + proportional error
  models;

  • combined1: trans(y) = trans(f) + (a+b*f^c)*err
  • combined2: trans(y) = trans(f) + sqrt(a^2+b^2*f^(2c))*err

• focei etaNudge parameters were changed to use quadrature points
  covering 95% percent of a standard normal.

• With zero gradients, Gill differences are recomputed to try to find
  a non-zero gradient.

• Now when running if a zero gradient is detected, reset the problem
  (theta reset) and re-estimated with outerOpt="bobyqa"

• Now when running a model where the last objective function is not
  the minimum objective function, issue a warning and skip the
  covariance step. (See Issue #403)

• focei proportional and power models are more tolerant of 0
  predictions in your data

SAEM changes

• saem fits now gracefully fall back to the focei likelihood when
  they support files are no longer on the loaded disk

• saem phi pile is now saved in the RxODE::rxTempDir() which can
  be customized to allow the phi file to remain after R has exited

• saem fits now can add in fo, foce and focei likelihood

• saem fits now use liblsoda by default and are multi-threaded when
  running (controlled by RxODE)

• saem now supports time-varying covariates (like clock-time)

• saem now supports 2 combined additive + proportional error models:

  • combined1: trans(y) = trans(f) + (a+b*f^c)*err
  • combined2: trans(y) = trans(f) + sqrt(a^2+b^2*f^(2c))*err

• saem proportional and power models are more tolerant of 0
  predictions in your data

• saem now supports censoring a similar way as monolix does, with
  cens and limit columns

• The default of saem additive + proportional error has been
  switched to combined2, which was the focei default, but you can
  change this back with saemControl(addProp="combined2"). The
  table results will likely be different because in the last release
  the saem calculated combined1 and then used these coefficients
  in the combined2 focei problem.

nlme changes

• nlme will now support 2 combined additive + proportional error models (if the patched version of nlme is used)

  • combined1: y = f + (a+b*f)*err
  • combined2: y = f + sqrt(a^2+b^2*f^2)*err
  • See #428
  • Thanks to Johannes Ranke (@jranke) for the nlme patch and the catch

• Can switch with nlmeControl(addProp="combined1") to use the combined1 type of error model

New Utilities

• bootstrapFit now calculates the bootstrap confidence bands and
  (optionally) will compare with the theoretical chi-squared
  distribution to help assess their adequacy.

• covarSearchAuto now allows automatic forward/backward covariate
  selection

General Changes

• Added auto-completion of nlmixr object properties accessed by
  $. This works for major editors including Rstudio, ESS, and
  Base R itself.

• Changed the way that Rstudio notebooks display nlmixr objects; It
  should be more legible in Rstudio.

• Graphics have been revamped to show censoring (including adding
  ggplot stat/geom geom_cens) as well as use RxODE's ggplot theme
  (rxTheme()). Additionally time after dose is calculated as tad
  for all nlmixr models

• Tables generation has been refactored; npde uses the arma and
  RxODE random number generators which may change results. Also
  the default of ties=TRUE has been changed to ties=FALSE.
  npde calculations have been threaded with OpenMP to speed up
  the calculation as well. This refactoring was required to have the
  dv imputation between cwres and npde use the same method.
  The npde option now calculates the decorrelated npd as well, (which is
  the recommended weighted residual; see Nguyen 2017)

Bug Fixes

• Aligned saem and focei additive + proportional error models, so
  saem additive+proportional outputs will be different using the
  correct focei method

Note this includes all the RxODE changes including dropping python.

CRAN v1.1.1-7

• Update for solaris
• Added clang USBAN fix

CRAN release

• Cran release to fix upcoming R's stringAsFactors change in R 4.0

CRAN Release

This is the CRAN bug-fix release related to R version 4.0

It fixes the documentation and adds completion of the nlmixr object via $.

nlmixr release v1.1.1-3

Compared to v1.1.1-2:

• Some stability fixes for VPC and SAEM
• Changed steady state handling
• Memory allocation consolidated in preparation for threading and for spead increase
• Moved nlmixr vignettes to pkgdown only for now.
• Some augPred enhancements
• Change correlation matrix printout handling
• Fix mu-refereced covariates to be shown more consistently in the nlmixr(.) printout
• Fixes related to new Stan headers

Release Candidate for v1.1.1-3

This is the release candidate for v1.1.1-3

CRAN release

v1.1.1-2

Fix vignette to run by setting up the R cache dir