NEWS.md

nlmixr2est 3.0.2

• Fix bug where models where omega boundary warnings caused problems in estimation (#490)

• Created a new api for pre-processing ui, allowing adding arbitrary hooks. As written now, this includes literal fix and zero omega as well as added the new rxode2 ui processing.

• Fixed compilation to only use -I in most systems for maximum compatibility

nlmixr2est 3.0.1

New features

• Now when optimizing only a single parameter with focei-family, will change to use stats::optimize() for the outer problem (#481)

• When estimating with all fixed population parameters, do a posthoc estimation.

• Internally removed assignInMyNamespace() replacing with nlmixr2global, which fixes some edge case bugs where the nlmixr2 environment was not reset properly.

• Treated edge case where all initial parameters are zero and change scaling from scaled to unscaled (#486)

• Added mu4 referencing that will change string expressions to rxode2 numeric values. This allows derived strings to also be treated as mu expressions (#484)

Bug Fixes

• Fix focei covariance step when many omega values are fixed #482

nlmixr2est 3.0.0

• No binary linking to rxode2, lbfgsb3c and n1q1, which means that updating these will not make nlmixr2est crash without recompiling.

• New mu3 referencing will take context from the model to see if the algebraic expression can be completed from defined model variables; These variable would have to be unique.

nlmixr2est 2.2.2

Breaking changes

• Saem non-mu reference input parameters/covariates were fixed so they work correctly with fixed parameters (Issue #445)

• Focei changed back to having a lower bound for standard deviations when not specified. This means that best model fits may change. You can revert to the old settings by using foceiControl(sdLowerFact=0.0). You can also change the factors to other values than the default value, that is foceiControl(sdLowerFact=0.000001) for instance which would multiply the initial value by 0.000001 when either the lower bound isn't specified or the lower bound is specified as zero for the error estimates related to error-based standard deviations.

• In nlmixr2, expressions are optimized. Because of that optimization, numerical rounding differences can cause different directions in optimization when fixing parameters in the model vs. fixing the parameters manually.

  This means that the fixed parameters in a model vs hard-coded fixed parameters could give different values in the final model.

  A new option literalFix was introduced which change the fixed population parameters to constants in the model while running the optimization. This makes the output of fixing within the model and fixing manually the same (which is what is likely expected). The default is for this to be turned on (ie. literalFix=TRUE). You can get back the old behavior by using the option literalFix=FALSE.

• In saem, the monte-carlo sampling occurs for all parameters including non-informative ETAs. A fix ensure that non-informative etas in saem are fixed to zero while sampling the phi values. This may change results for models with uninformative etas. To ignore the uninformative etas with saem you ca use use the prior saem handling with saemControl(handleUninformativeEtas=FALSE).

New features

• Gracefully degrade when $cov is not in the right form (see #423)

• Add support for PopED in place solving (used in babelmixr2)

• If est=foceiControl() or other nlmixr2 control with the class foceiControl infer the estimation method is focei

• Add back the warnings when estimation methods ignore the boundaries

• When using rxSolve, now respects the values from tableControl() (#465 and #297)

Bug fixes

• Will emit warnings when the return object is not a nlmixr2 fit (#453)

Other things

• Moved actual code of some matrix libraries to lotri and import them via function pointers

nlmixr2est 2.2.1

• Align with the possibility that linCmt sensitivities may not be present (like intel c++)

Bug fix

• focei cache needs to be based on the parameter order as well as the model information (#415)

nlmixr2est 2.2.0

New Features

• Algebraic mu referencing has been implemented in nlme and saem.

• New estimation method "nlm" has been added to estimate population only likelihoods using stats::nlm and possibly return a standardized nlmixr2 fit.

• New estimation method "nls" has been added to estimate population only problems. This uses minpack.lm::nlsNM by default if present, or the stats::nls

• New estimation method "optim" has been added to estimate population only likelihoods. This uses stats::optim and returns a standardized nlmixr2 fit.

• New estimation method "nlminb" has been added to estimate population only likelihoods. This uses stats::nlminb and returns a standardized nlmixr2 fit.

• New estimation methods from the minqa package: "bobyqa", "uobyqa" and "newuoa" have been added to estimate population only likelihoods. These methods returns a standardized nlmixr2 fit.

• New estimation method "lbfgsb3c" to estimate population only likelihoods. This returns a standardized nlmixr2 fit.

• New estimation method "n1qn1" to estimate population only likelihoods. This returns a standardized nlmixr2 fit.

• Added new feature for vpcSim() where a minimum number of subjects are simulated from the model when trying to fill in ODEs that were not solved successfully. By default this is 10. This also works-around a bug when there is only one subject simulated and the data.frame has a slightly different output.

Breaking changes

• Removed fit$saemTransformedData since it isn't actually used in saem anymore (but will break anyone's code who is using it)

• Now the internal function .foceiPreProcessData() requires the rxode2 control rxControl() because some of the new steady state lag features need to translate the data differently based on rxControl() options.

Bug fixes

• Printing models with correlated omega values and omega values fixed to zero no longer fails (#359)

• Add back values for $parHistData (#368)

• This requires a new rxode2 which will fix multiple endpoint issues observed (#394)

• Manual back-transformed values in $parFixed are now displaying correctly and are calculated based on the confidence interval in the control instead of 95% confidence no matter what (#397)

Other changes

• An as.rxUi() method was added for fit models (#377)

nlmixr2est 2.1.8

• Version bump and a minor documentation update (same as nlmixr2est 2.1.7). This version bump is to simply allow correct binary linkage to rxode2 2.0.14. Otherwise nlmixr2 models will crash R.

nlmixr2est 2.1.7

• As requested by CRAN, remove Rvmmin

• Values in $parFixed for BSV without exponential transformation are now correctly shown (#366)

nlmixr2est 2.1.6

Breaking changes

• Since rxode2 now allows simulation with omega having diagonal zero elements, $omega and $omegaR now reflects this information including the zero omega elements in the output. On the other hand, the other eta-information and standard error information for zero etas are still excluded in $phiR, $phiSE, $eta etc.

Bug fixes

• vpcSim() works when an eta value is fixed to 0 (#341)

• augPred() now consistently uses the simulation model (instead of the inner model used for CWRES calculation).

Other changes

• Dropped dependence on orphaned package ucminf

nlmixr2est 2.1.5

• Add $fitMergeFull, $fitMergInner, $fitMergeLeft, $fitMergeRight as a complement to $dataMergeFull, $dataMergInner, $dataMergeLeft, $dataMergeRight. The fit variants prefer columns in the fit dataset instead of the original dataset. This is useful for goodness of fit plots with censoring since the DV in the fit simulates values under the ipred/residual assumption and will give more appropriate goodness of fits, otherwise these values are the limit of whatever censoring is applied

• Moved the mu reference fix for the split mu referenced model here (from babelmixr2)

nlmixr2est 2.1.4

• Breaking change, now calculate condition number based on covariance and correlation, the names have changed to be more explicit. conditionNumber changed to conditionNumberCov and a new metric conditionNumberCor has been added.

• A bug in boundary value detection prevented automatic covariance calculation with FOCEi estimation (#318)

• Fix vpcSim so that it will be a bit more robust when it is difficult to simulate.

• A bug in model piping which did not allow models to be appended to was fixed (rxode2#364)

• An internal change was made in nlmixr2.rxUi() to better support the babelmixr2 PKNCA estimation method (babelmixr2#75)

• Fixed bug where $iniUi did not return the initial ui when running non focei related methods. Also added alias of $uiIni to the same function.

• Dropped Stan headers for this package, also updated to C++17

nlmixr2est 2.1.3

• Allows $etaH and related family to be integrated into a saem fit if cwres is calculated.

• Fixed a bug where nlmixrLlikObs in the merged dataset is sometimes named llikObs, now it is always named nlmixrLlikObs

• Fixed a bug where nlmixrLlikObs shows up in merged dataset when cwres is not calculated (it was always 0), also allow cwres calculation to pick up nlmixrLlikObs in merged dataset.

• Dropped dparser dependency

nlmixr2est 2.1.2

• Fixes $etaH memory corruption so the standard errors of etas are now correct

• Removed the memory requirements for focei by neta*neta*nsub

• Fixed character based covariates so the work correctly (again) with focei. Added a test for this as well.

nlmixr2est 2.1.1

• Fixes $dataMergeInner so that observation-based log-likelihoods work with infusions. Should fix tests with ggPMX

• Fixes $etaSE and $etaRSE to work correctly when there is only 1 eta.

• Fixes npde valgrind observed on CRAN machines

nlmixr2est 2.1.0

Breaking changes

FOCEi

• Gill forward differences will not repeat now (by default), You can change back to prior behavior with foceiControl(repeatGillMax=3)

• Number of sticky recalculation is reduced to 4; to have the old behavior use foceiControl(stickyRecalcN=5)

• n2ll has been changed to ll to specify individual log-likelihoods. This was only used in simulation and was not well documented.

• Generalized log-likelihood is only supported with rxode2 2.0.8 or later.

FOCEi covariance calculation

• The S matrix calculation was made a bit more robust to errors in individual gradients. When there are errors in the individual gradient calculation, assume the gradient is the same as the overall gradient. In the tests cases, were reasonable using this adjusted S matrix. This means if some individuals do not have very much data to support a specific parameter, a S matrix calculation for the population will still be generated. When there is some patients/subject combinations that do not have sufficient data, we will add the following to the run information: S matrix had problems solving for some subject and parameters. The S matrix calculation will still fail if the percentage of parameters that are being reset is lower than foceiControl(smatPer=0.6) or whatever you specify.

• The r,s covariance matrix will now also check for unreasonably small values (controlled by foceiControl(covSmall=...)) and select a different covariance estimate method even when the "r" and "s" matrices are calculated "correctly".

New features

• What type(s) censoring (if any) is now stored in fit$censInformation

• Standard errors of $etas can now be obtained with fit$phiSE, also available are fit$phiRSE (relative standard error), fit$phiH, (individual hessian), fit$phiC (individual covariances), fit$phiR (individual correlation matrices)

• Can also use Shi 2021 differences in addition to Gill differences. In our tests (using the same datasets as CPT) these produced worse estimates than the Gill 1983, though it is unclear why since it should be a faster more accurate method. A modified version is used in calculating the individual Hessians of numerically for the generalized likelihood approach.

• Generalized likelihood estimation is now present in nlmixr2est for focei, foce and posthoc

• nmNearPD() is a function you may use for nearest positive definite matrix. This is derived from Matrix::nearPD() but is implemented in C/C++ to be used in (possibly threaded) optimization.

• Individual Hessians can be accessed by $phiH, covariance by $phiC, eta standard errors by $phiSE and eta RSEs can be accessed by $phiRSE. There are eta aliases for these as well ($etaH, $etaC, $etaSE, and $etaRSE).

• Can now access the individual point's contribution to the overall likelihood when merging to the original dataset. These merges can be accessed with $dataMergeFull, $dataMergeLeft, $dataMergeRight, and $dataMergeInner. The columns with the individual data column is nlmixrLlikObs.

  To calculate the total focei/foce objective function, the sum of the likelihoods still need to be adjusted by the omega/eta contribution, and the individual Hessians, and possibly the NONMEM objective function offset constant.

Censoring fixes

• Fixed bug where datasets with censoring that are not lower case cens and limit do not produce the correct table output (#180)

FOCEi updates

• Resets now scale properly when a value is simulated outside the limit
• Models with zero gradients on the first step now switch to bobyqa by default. With this, it is more important to examine the model parameters and fits for plausibility.

nlmixr2est 2.0.8

New features

• Add pd/npd as an output as well as npd/npde

SAEM bug fix

• When loading a nlmixr2 "saem" fit from another R session, nlmixr2 will no longer crash with fit$objf

NPDE/NPD fixes

• NPDE was identical to NPD even with correlated models, this was fixed (prior output was actually NPDE).

Censoring fixes

• FOCEi censoring fixes:

  • M4 method equation bug fix
  • M4 method derivative change based on equation fix
  • M2 method added missing derivative
  • Censoring already dTBS

• SAEM Censoring fixes:

  • SAEM method M4 method equation bug fix
  • Censoring limit changed to dTBS

• Censoring handling was unified

Internal changes

• Added ui$getSplitMuModel which is used in babelmixr2 and will be used in the refined stepwise covariate selection of nlmixr2extra

• Added work-around to remove _nlmixr2est_RcppExport_registerCCallable since the registering of C callable are handled manually at the moment.

nlmixr2est 2.0.7

• Use .zeros() for the matrices in armadillo in addition to relying on calloc to give zero matrices.

• Fixed one uninitialized object

• Fix for augPred so it works on population only models

• nlme no longer sets options to treat all covariates as non mu-referenced covariates, but directly calls a function that can turn on or off the mu-reference covariate selection.

• vpcSim now tries to simulate IDs that didn't simulate correctly (with a warning)

• Export nmObjHandleControlObject

nlmixr2est 2.0.6 -- new package

nlmixr2est contains the estimation functions within nlmixr2.

FOCEI family changes

• Remove lower level foceiFit function. Focei, foce, fo, foi, and posthoc now directly takes rxode2 ui objects

• New error types are supported in focei including mixing theta and etas in residual errors and different types of proportional errors

• Different types of additive and proportional errors can be used for each endpoint using + combined1() or + combined2() otherwise it takes the supplied addProp option to figure out which type of combined model is run (by default combined2())

• Focei model cache is now named focei-md5Digest.qs and uses qs compression/saving/loading.

• foceiControl() aligned between other methods.

• foceiControl(adjLik=TRUE) uses the NONMEM-style objective function throughout. foceiControl(adjLik=FALSE) uses the adjusted objective function throughout, and adjusts it back to the NONMEM objective function.

• Lag time and other between subject variability differences no longer calculate an ideal relative step size, but an absolute step size when using Gill differences (default)

• Objective function checks for infinite/NaN/NA values for the entire solving space and ensures no overflow occurs when calculating the inner hessian

SAEM changes

• mu referencing is no longer required for saem; Internally non mu-referenced values are converted to mu referenced values and the converted back when calculating the nlmixr2 object.

• nlmixr2 forced the parameter ordering to (1) population effects, (2) non mu-referenced between subject effects (3) omega estimates and (4) residual effects. This changes the order that nlmixr2 sees the parameters. Since this is based on a random number generator, the optimization trajectory will be different and have different results than nlmixr

• Components of omega can now be fixed.

• Residual error components can also be fixed.

• When optimizing only one residual value, nlmixr2's saem uses nlm from R, which is more efficient than the nealder-meade method.

• Lower level saem functions (like configsaem()) are not exported because they are increasingly difficult to use and convert to something standard; a few methods (like print, summary etc) are maintained to view the lower level object and for debugging it.

• Parameter history and print-out no longer includes fixed parameters.

• The model to calculate the residuals more closely matches the model used for estimation to remove small rounding differences that may occur in the models.

• Different types of additive and proportional errors can be used for each endpoint using + combined1() or + combined2() otherwise it takes the supplied addProp option to figure out which type of combined model is run (by default combined2())

• Parameter history and printout now uses standard deviation for additive only components, matching the estimation of the components.

• rxode2 solving options are now saved in the rxControl part of the saemControl(). That is saemControl(rxControl=rxControl(...)); This fixes any conflicting option names as well as allowing alignment between the control structures in focei, nlme and saem

• saemControl() aligned between other methods.

nlme changes

• nlme has been completely rewritten to directly run from the rxode2 UI

• nlme always tries to use mu-referencing (when available)

• Internally nlme now uses parallel processing for solving so it should be faster.

• nlmixr2NlmeControl() (which will overwrite nlmeControl()) documents and adds more options to nlme. Also aligned with other methods.

• weights, fixed, random can be specified in nlmixr2NlmeControl(). If so, then the nlme object will be returned.

• returnNlme is a new option that will return the nlme object instead of the traditional nlme object.

• nlme_ode and lme_lin_cmpt are both removed.

• rxode2 solving options are now saved in the rxControl part of the saemControl(). That is nlmeControl(rxControl=rxControl(...)); This fixes any conflicting option names as well as allowing alignment between the control structures in focei, nlme and saem

nlmixr2 object change

• With saem, the nlmixr2 function now saves/compresses the phiM information. This means the gaussian and Laplacians likelihoods can be calculated when you save the nlmixr object and then restore it later.

• The nlmixr2 object compresses infrequently used and removes many unneeded objects. Even with compression, the saem objects are often a bit bigger since they include the large phiM object.

• nlmixr2 now supports non-mu referenced ETAs in the fit$parFixed and fit$parFixedDf

nlmixr2 interface change

• nlmixr2 interface changed to use rxode2 UI

• keep and drop are added to tableControl to influence the end data-frame

• $simInfo uses a quoted expression for $rx instead of a string

• $simInfo$sigma is a diagonal matrix since now the normal simulation is controlled by the variability modeled as a population value.

• nlmixr2 now allows etas that have initial omega estimates of zero to be dropped from the model (instead of issuing an error about a non-positive definite $omega matrix)

NPDE changes

• Fixed a bug where the number of simulations for a NPDE calculation are correctly passed by addNpde(fit, table=tableControl(nsim=500))

VPC changes

• vpc function rewritten and split out to vpcSim() and vpcPlot() (which is a replacement for vpc()).

• There were too many mismatches between vpc::vpc and nlmixr::vpc which caused inconsistencies in code based on load order of vpc and nlmixr. This way both coexist, and you can use the vpc simulation for other packages more easily (like ggPMX) without creating or summarizing data since ggPMX has its own methods for summarizing and creating plots.

• VPC now directly uses rxode2::rxSolve

augPred() changes

• augPred() has been written to use the new fit object.

• nlmixr2AugPred was changed to nlmixr2AugPredSolve()

• augPred uses the new interface and supports multiple endpoints. The endpoint name is now always on the plot(augPred(fit)).

getFitMethod() change

• Internally, fit estimation method is saved in fit$est, and now getFitMethod(fit) simply returns fit$est

Delete methods

• Many methods lower level utility functions have been deleted.

• nmDocx, nmLst and nmSave have been removed.

Bug fixes

• Now will reset the cache when items cannot be loaded. In the past error messages like function 'rx_0ba247452048de33b1ffb8af516714fc__calc_lhs' not provided by package 'rx_0ba247452048de33b1ffb8af516714fc_' would cause the estimation to stop. Now rxode2::rxClean() is run when this occurs.