Updated: covariateEffect_IQRnlmeProject received new argument CImethod to choose between methods for the confidence interval calculation. That involves a method correcting for the multiple-testing problem.
New: simultaneousCI_IQRnlmeProject returns confidence intervals of covariate effects corrected for the multiple testing problem
Added algOpt.NONMEM.IMP_ISAMPLE argument to IQRnlmeProject
IQRnlmeProject: sets $SIZES PC= to acceptable values. This is now needed for NONMEM 7.5.
Fixed "M4" method handling for MONOLIX when LIMIT column not available
Remove "Baseline" from naming covariates in GDF export define and XPT
Automatic setting MUM option in NONMEM control file to better handle estimation of parameters without random effects in SAEM.
Update summary obs tables with N patients overall and N patients with at least one MDV=0 sample
Small bug fixes
7.2 V1.9.0 February 01, 2022
Remove STAT.SIGNIF.05 from covariate protocol summary.IQRnlmeProjectMulti()
Updated diagnostic plots with more informative captions
Updates needed to use MRAN snapshot 2021-12-13
Improvements to VPC functions
Added optional argument to IQRloadCSVdata to allow reading in columns as characters
Added function to compute terminal elmination halflife (halflife_IQRnlmeProject)
7.3 V1.8.0 October 16, 2021
Improved AE analysis functions
Added summary_IQRaedataER()
First version of scm_IQRnlmeProject()
Added read_IQRoutputTable() function to parse IQRoutputTable text files as IQRoutputTable objects
Added "M4" option for MONOLIX when generating IQRnlmeProjects
Smaller bug fixes
7.4 V1.7.2 September 15, 2021
AE analysis
Added plotIndivAE_IQRdataGENERAL()
Added summary_IQRaedataER()
vpc_IQRdataVPC: for binning by default BIN.groupsize = round(Nsubj/2) is used
MONOLIX 2020R1: adaptation to changes in output from Lixoft
IQRoutputFigure: adding FLAGdraft to allow some watermark for draft results
Smaller bug fixes
7.5 V1.7.1 May 4, 2021
Added a flag ".ALLOW_SPACES_IN_PATH" into setup_options_IQRtools.R. By default it is FALSE. If you set it to TRUE then no error is thrown if spaces appear in paths. Use with care, as NONMEM will not work with it.
7.6 V1.7.0 April 10, 2021
Added sample_IQRgpf function as main interface to the GPF sampling API
Added function getNamesCovariates to extract covariate names from a GPF or an IQRnlmeParamSpec object
Added a NEWS.md file to track changes to the package and for a more convenient book generation
Complete revision of function createSubmissionPack to produce FDA compliant submission package
parameters argument in sim_IQRmodel can now contain ID and USUBJID entries which will be ignored for simulation#
Added a sample_GPF function to allow similar sampling from GPF as from NLME projects with sample_IQRnlmeProject
Harmonized output structure of sample_IQRnlmeProject with sample_GPF function
Renamed list elements in output of sample_IQRnlmeProject function to be shorter
7.7 V1.6.0 February 18, 2021
Added geom_uperrorbar
Legend in rmdFIGURE now works better with line breaks
Improved robustness of post-processing also when NONMEM crashes
"keepNext" in DOCX dataset define file generation
MONOLIX 2020R1
MONOLIX bug with linear model compilation has been worked around. Hoping for a fix in next MONOLIX version.
Handling of multiple MONOLIX installations >=2019R1
NCA functions removed. NCA moved out of IQR Tools and into IQnca
Use haven instead of SASxport for XPT output and loading. About >100 times faster
Setting CONSTRAIN=7 for EM methods in NONMEM as default
Improved some NONMEM and MONOLIX handling in case of if then else (piecewise) statements
Added SBML export (L2V4) - working on IQdesktop only
And finally: moving to Open Source (GNU AGPL-3)
7.8 V1.5.0 October 23, 2020
New module General Parameter Format (GPF), including functions for export/import of MONOLIX/NONMEM/SYSFIT project estimates into/from a GPF excel file. For more information, refer to https://iqrtools.intiquan.com/doc/book/GPF.html.
Introduction of time-varying stratification to VPC functionality (FLAGuseObsTimes replaced by simtimeOption)
NEW: user-defined simulation time vector for VPC simulations
NEW: user-defined observation time binning for VPC either using dataset column (BIN.column) or vector of bin borders (BIN.breaks)
Fixed non-appropriate binning when using simulation times with time after dose for VPC
themeIQRtools() available to all
New log-scale functionality with scale_y_log10_IQRtools()
Support for stratified shrinkage in parameter estimation table
Optional removal of small ETA values in random effects plots and ramdom effects vs covariates plots
Better support for stratification and selection/exclusion of parameters in random effects plots and random effects vs covariates plots
IQRoutputTable() accepts vector argument as footer (automatic line break between elements)
IQRoutputFigure() with improved functionality
Fixed TIME/TIME2/OFFSET bug in NONMEM that was impacting analytic (non-ODE) models with TIME as a variable
Definition of .LIBPATHS_FIRSTONLY option in the setup_options_IQRtools.R file allowing to search only the first entry returned from .libpaths() when looking for includes
Small bug fixes
7.9 V1.4.0 August 21, 2020
IOV handling in IQRnlmeProjects (for NONMEM only)
vpc_IQRnlmeProject() function now does the same as the createDataVPC_IQRnlmeProject() function (alias) over time the createDataVPC_IQRnlmeProject() function likely will disappear.
Removed function createVPC_IQRnlmeProject() - Reason the split approach with simulation and subsequently plotting is just more powerful.
Considerably improved error check for covariate definitions giving much better feedback to the user.
Added reference covariate value into the summary table for IQRnlmeProjects (continuous covariates only)
Fixed TTE VPC (adjusting for constant changes in MONOLIX output files over the different versions ...)
Removed SAEM warning if SysFit is used
Added "PRINT=E" in $COVARIANCE for NONMEM as it provides additional output that might come in handy
Allowed MATRIX=S, R, RSR (NONMEM default when unspecified) for $COV step. IQR Tools by default uses "S"
Improved check of parameter names in modelSpec arguments
7.10 V1.3.2 July 5, 2020
Improved NCA functions (mean+-sd lin and log10), better subsetting for summary function
Fixed IIV check in IQRnlmeEst. Allow IIVestimate=2 when covariance definition
NONMEM convergence tracjectories: sqrt(errors) fixed for display
tempdirIQR() and tempfileIQR() functions available
Allow data.frame as data$datafile for NLME projects, instead of path
IQRdataGENERAL more verbose (messages if adding columns and sorting)
SysFit now supports time varying regressors!
Small bug fixes
7.11 V1.3.1 May 20, 2020
Small bug fix in Sysfit
Improved handling of numerics when generating convergence trajectory plots for NONMEM
Added function for convenient mapping of categorical levels to their meaning
7.12 V1.3.0 May 01, 2020
IQRdataGENERAL: improved handling of general dataset format. Not necessary columns will not be created if not already present in the dataset. This lead to considerably leaner datasets. The approach is backward compatible with the old version. More information on new format available here.
Added function exportDEFINEpdf_IQRdataGENERAL().
Small bug fixes
7.13 V1.2.1 March 08, 2020
NONMEM: Use SIGMA instead of THETA for error parameters => far more stable SAEM results on multiple cores
NONMEM: Add FOCEIOFV as option to IQRnlmeProject, allowing to use a MAXEVAL=0 FOCEI step for OFV determination. IMP MAPITER=0 is just not reproducible when running on ncores>1
7.14 V1.2.0 March 02, 2020
New function pred_IQRnlmeProject() for generation of predictions based on an IQRnlmeProject
Limiting default number of cores for functions to smaller than max number (1)
Allowing multiple activation key license files
Option to set path for license file (default in home directory)
Bug fixes
7.15 V1.1.1 January 31, 2020 (Brexit Day)
Do not count CENS=1 records in non-zero pre first dose numbers in summaryObservations table.
Change aux_na_locf() to be able to handle DOSE and time varying covariate creations for GDF correctly with updating earlier records with same time.
Stability improvements new VPC functionality.
aux_version() can check IQdesktop version
install_workshop() to conveniently install workshop material
7.16 V1.1.0 December 23, 2019
Fixed issues with NCA that appeared in 1.0.9
Added many functions related to QSP modeling (export of virtual subjects and populations, simulation, etc.)
Improved QSP modeling
Same output table format in QSP as in NLME
Improved simulation speed with eventTable
Improved test functions
Bug fixes
7.17 V1.0.9 October 13, 2019
Improved NCA and made unit handling more robust
Added exportVariant_IQRmodel and importVariant_IQRmodel for QSP modeling
Improved QSP modeling with flexible output assignments to support modeling in a multi observation setting
Improved robustness of pcVPC functions
Small additional fixes
7.18 V1.0.8 September 13, 2019
Added handling of initial assignments to allow compatibility with SimBiology models
Added functions to handle parameterization updates in IQRmodels to allow compatibility with typical SimBiology models
Improved robustness of QSP functionality with more informative warnings and error messages
Removed dosing argument from sim_IQRsysModel() for usability reasons
Allowed QSP data to include ADDL and II columns as well
Improved annotation of output from sim_IQRsysModel()
QSP parameter estimation now outputs trace information while doing the optimization into CSV files
Added functions to postprocess the QSP estimation trace information (including plotting)
IQRmodel: changed default setting from FLAGsym = TRUE to FALSE
Deprecated IQRoutputPDFstart and IQRoutputPDFend. The functionality is now replaced by IQRoutputPDF which can now take lists of plots and has added features such as arranging into a grid, multi-page output, scaling width, height, overall
"RDS mode" If set to TRUE then plot and table objects are stored in addition as RDS files when using IQRoutput* functions
Added IQRsim Shiny App for easy exploration of models
7.19 V1.0.7 September 2, 2019
Improved QSP modeling - allowing also derivative free algorithms for special applications
Prediction corrected VPC functionality
Allow selection of RES, WRES, PRED values in NONMEM runs
Added cov and cat table functions for exposure response
Added XPT and define file generation for general data.frames
Added getModel_IQRnlmeProject(), and getEst_IQRnlmeProject()
sample_IQRnlmeProject() now handles different from Nsamples row numbers in covariates
Further improvements
7.20 V1.0.6 May 28, 2019
Improved QSP modeling
Further improvements
7.21 V1.0.5 May 20, 2019
Improved QSP modeling
QSP functionality documentation in IQR Tools Book included
Bug fix in addIndivRegressors_IQRdataGENERAL()
Further improvements
7.22 V1.0.4 April 19, 2019
Compatibility R 3.5.2 and R 3.5.3
Fix in statXY function
Better support of MacOS Monolix path setup
Added compatibility with new Monolix 2019R1
7.23 V1.0.3 April 3, 2019
Handle not present outputs in data when doing VPC
Back-transform exp data when doing VPC
Added getHeader_IQRnlmeProject()
Allowed definition of SIGL for NONMEM gradient runs
Stratified GOF plots for ETAs and ETA vs COV plots
Add residual diagnostic plots to logistic regression
New function to add covariate relationships to model specification
QSP SysFit:
Compatibility with Microsoft Open R
Profiles for fixed parameters
Allow additional integrator options in IQRsysProject
Allow "." in condition names
7.24 V1.0.2 March 18, 2019
Improved NCA functionality now also handling SS data
Improved survival analysis functionality
Allow removal of confidence interval
Allow different xticks (equidistant to last data point or max(xlim))
Add cox regression information for selected strata
Display cox regression as table and return
Add Schoenfeldt cox.zph() test results to cox-table! - somehow - do not do plots at this time?!
Show quantile values
Improved QSP modeling
Small additional fixes
7.25 V1.0.1 February 23, 2019
Improved QSP modeling functionality
vpc_IQRnlmeProject parallelized also for Windows
Fixed CENS information in converted project_pred.csv file when using MONOLIX
Small fixes
7.26 V1.0.0 February 8, 2019
QSP modeling backend has been exchanged
Allowing random effects
Handling BLOQ data
Improved convergence and profile likelihood computation
Faster on Windows (parallelized pLL computation)
Changed syntax to be identical to NLME project setup
Improved logistic regression modeling
Small fixes
7.27 V0.9.999 January 16, 2019
Improved logistic regression functionality
Date/time conversion functions supporting data programming
IQRoutputRDS available and producing log file for traceability information
Event table generation functions
Shiny app for NLME modeling now included in IQR Tools
Smaller fixes
7.28 V0.9.99 December 06, 2018
Update to PopED 0.4.0
Providing convenient installers for
Rtools
IQReport
IQRsbml
Providing installation test functions for
Rtools, IQReport, IQRsbml
MONOLIX and NONMEM
7.29 V0.9.9 November 27, 2018
Removed support for MONOLIX old version 2016R1
Bookdown-style full documentation accessed with "doc_IQRtools()"
Factored NLME project storage
All plot functions now return ggplot objects with plot data as attributes
Improved IQRoutputTable handling and modification
Replaced IQRexportCSVdata with IQRsaveCSVdata. The new function also stores potential non-standard attributes of a data.frame as an .atr file. The IQRloadCSVdata function restores these attributes, if present.
Made following functions for NLME diagnostic plots available to the user:
plotETA_NLME()
plotETACOV_NLME()
plotINDIV_NLME()
plotGOF_IQRnlmeProject()
printOutlier_NLME()
Allowed "comment" argument in IQRnlmeProject() function call to annotate a model
Added summaryComments_IQRnlmeProjectMulti function showing the AIC, BIC, OBJ, and the user provided comments by "comment"
Shrinkage in parameter table for fixed IIVs
"results_MONOLIX()" function added allowing to generate results for models built in the GUI, rather than in IQR Tools
7.30 V0.9.3 October 25, 2018
Fixed as_IQRnlmeProjectMulti to work correctly with MONOLIX >2018R1 when using recursion (exclusion of .Internals folders)
Allow VPC to not show the data points
Allow VPC to set alpha/transparency for the data points
Fixed issue in NONMEM and NLMIXR results table with long expressions
Allow multi-column stratification in bootstrap_IQRnlmeProject function
7.31 V0.9.2 October 18, 2018
Enforced NRCHAINS if below 50 subjects
IQRoutputPNG/PDF now first close PNG and PDF devices before opening and printing
VPC: FLAGindivSimtimeMax on TRUE by default
More informative information text showing license activity, etc.
7.32 V0.9.1 October 07, 2018
Improved NCA
Advanced grouping of results
Allowing non-numeric profile numbers
Allowed IQRdataNCA to be exported to CSV and imported again as IQRdataNCA object
Added modelSpec_IQRest function to allow easier definition of a modelSpec argument for the estimation object generation
Added data_IQRest function to allow easier definition of a data argument for the estimation object generation
Added dosing_IQRest function to allow easier definition of a dosing argument for the estimation object generation
Allowed MONOLIX 2018R2
Fixed interface to work with both NLMIXR 0.9.1.3 and 1.0.0.7 - now also allowing FOCEI
Updated installer for NLMIXR and RxODE
Summary function for IQRnlmeProject now provides units for error parameters and improved comments
Remove min-max range bars from covariate forest-tree plots
7.33 V0.9.0 September 03, 2018
Improved the NCA functionality to better group subjects (e.g. weight-based dosing groups)
Allow in NONMEM/BAYES interface to provide a vector for the DF of the omegas
PopED interface improved
Updated NLMIXR interface
Small fixes
7.34 V0.8.1 August 7, 2018
packageR_IQRtools() function allowing to package a whole R installation for reproducibility purposes
getRepos() function to facilitate installation of packages from the MRAN time machine
Improved VPC function
Initial Interface popED 0.3.2 with IQRtools
Survival analysis (KM)
Logistic regression function
Added info in IQRnlmeProject output tables that omegas are in standard deviation
Small fixes
7.35 V0.8.0 June 25, 2018
BAYES NONMEM estimation
Selector for NM and MLX versions
Added unit tests for MONOLIX 2018R1
Fixed bug with NONMEM 7.4 on Windows when running from R
Rename NPROCESSORS to ncores and NPROCESSORSpar to Nparallel
Handle ncores for MONOLIX 2018R1
Fixed bug in initial guesses covariates in combination with covariance reordering - NONMEM code generation
Additional tests for covariates and correlations and BAYES method in NONMEM
Improved stability of NCA
Allowed to provide individual simtime vectors when doing eventTable simulations
Allowed VPCs for models without INPUTs
Improved VPC to consider consider individual time periods
Added IQRtteProject and associated functions for TTE modeling (MONOLIX only)
Rename setup_options.R to setup_options_IQRtools.R
The inference if old (2016R1) or new (2018R1) MONOLIX is used is not anymore done by the path name but by the list entry name in the setup_options_IQRtools.R file
A local / user setup_options_IQRtools.R file can be placed in the users home folder to define settings that should be overridden from the global definition.
Allowed to set number of simulated individual parameters for MONOLIX runs (2018R1 only)
Deprecated MONOLIX 2016R1 ... will disappear end of the year
IQRnlmeProject now allows to set the TOL option for NONMEM ADVAN13
Better handling and documentation of the RATE/TINF column pair for NONMEM and MONOLIX MONOLIX only uses the TINF column NONMEM uses RATE=0 for bolus, RATE=-2 for using TINF or ABSORPTION0 TINF estimation.
Joint Modelling (Longitudinal / TTE) using MONOLIX 2018R1
Allow non full covariance matrices for BAYES
Parallel NLME fits on Windows in addition to Linux
Better error messages if identifiers are missing in IQRmodel files
Small fixes
7.36 V0.7.2 May 10, 2018
Parallelized IQRsysFit on Windows
Update the objective function for IQRsysFit to improve performance of optimization
Improved dose handling for sensitivity calculations
Fixed bug in sampling initial guesses for logit transformed parameters in IQRnlmeProject
Small fixes
7.37 V0.7.0 April 23, 2018
Fixed issue with more than 9 model outputs
Added convenience functions for testing, setup, license and examples
Fix state-parameter sensitivities to 0 when event is fired
Updated derivative computation in QSP modeling objective function
Use sensitivity equations instead of CVODE sensitivities by default to allow estimation of bioavailability in IQRsysFit
Updated simulation time vector definition in QSP modeling objective function
NCA data mean plots also shown now for single subjects in a dose group
Small additional fixes
7.38 V0.6.6 April 16, 2018
Added vpc_IQRnlmeProject function ... still limited and should not be used for infusion data yet
Added regenerate_IQRmodel as exported.
Added additional NCA functions
Small fixes
7.39 V0.6.4 March 16, 2018
Support of MONOLIX 2018R1
Removal of pander as a dependency
Interfacing with new version of IQReport
Small bug fixes
7.40 V0.6.3 March 08, 2018
Added eigenvalue calculation function for IQRnlmeProjects to quickly assess the terminal elimination half-life
Allowed NLME projects without dosing inputs
Export or IQRnlmeEst object as file in NLME project folder
Added plotGOF_IQRnlmeProject function
Improved annotation of GOF plots
Bug fixes
7.41 V0.6.2 February 08, 2018
Updated NCA code to result in same results as Phoenix/Winnonlin
Improved NCA report generation to stratify dose groups
Updated print and summary functions for IQRnca objects to allow stratification by dose group
7.42 V0.6.1 January 26, 2018
Improved installability across R 3.3.0 -> R 3.4.3
Removed doParallel and foreach dependencies (result in IQRsysFit not running in parallel on Windows, but Linux is anyway better for heavy computation ...)
Changed gather() -> gather_() where needed to ensure its working for some time around R 3.4.1 where the tidyr package seems to have changed
7.43 V0.6.0 January 24, 2018
Finalized NCA functions including documentation, testing, and examples
Added function getParameters_IQRnlmeProject()
7.44 V0.5.8 January 19, 2018
Added NCA functions (still without examples)
Removed need for the MASS package
Fixed a bug in regression parameter adding to datasets (made this new version necessary)
7.45 V0.5.7 January 16, 2018
IQRdataGENERAL: non-task events taken out by default
Fixed issue in MONOLIX project generation that was not allowing ADDL/II
Small bug fixes
7.46 V0.5.6 December 14, 2017
Allowed for bioavailability terms in NONMEM infusion/absorption0 models
Smaller improvements (e.g. showing ID in addition to USUBJID in individual PK plots)
Added clustering function for binning and function to generate binned statistics
Small bug fixes
7.47 V0.5.5 December 04, 2017
Handling NONMEM 7.4 bug by automatically setting the MUM=N(...) option when needed
Allow to provide simulatiokn time vector for plot.IQRsysData
Add convergence info steps to trust and IQRsysPharm
Add function setparameters_IQRmodel
Allow not to provide doseNAMES and obsNAMES in IQRdataGENERAL - Handled by identifying doses by !is.na(ROUTE) and the rest as observations.
Addition of a number of graphical data exploration functions
Adding optional columns PROFTIME and PROFNR in the general dataset format
subset_IQRdataGENERAL function
Access to IQRdataGENERAL attributes via "convenience" functions
ETA correlation plots were changed to allow for reasonable formatting when a larger number of parameters available in model
Bug fix and improvement in ETA plots
7.48 V0.5.1 October 14, 2017
ACoP version
Mainly fixing some documentation
7.49 V0.5.0 October 10, 2017
Exchanged "." in all non-S3 methods to "_"
Added functions for generation of graphical exploration plots for IQRdataGENERAL objects
Improved determination of estimated parameters for display purposes
Display selected order metric in summary IQRnlmeProjectMulti tables
Improved test-suite for validation of IQRtools
Minor bug fixed that displayed in print.IQRnlmeEst function the wrong initial guesses for random effects
Fixed all Notes that were important to fix.
Improved ETA and ETA vs. COV plots by adding better titles for plots
Added comparison based on t-test to ETA vs. categorical covariates
7.50 V0.4.2 September 21, 2017
Added function to generate an observation summary table for IQRdataGENERAL objects
Added function rmDosePostLastObs.IQRdataGENERAL
Optional removal of doses post last observation in clean.IQRdataGENERAL
Bootstrap function updated to work with NLMIXR
Simple NLMIXR Test functions
Improved annotation of covariateEffect.IQRnlmeProject
Sampling from uncertainty for MONOLIX results now ensures parameters in correct range (log, logit) without the user needing to take care of it
Minor bug fixes
7.51 V0.4.1 September 14, 2017
NLMIXR has been interfaced with IQRtools ... it is experimental still
Demographics tables generated for IQRdataGENERAL objects
Exported auxiliary functions
Small fixes
Added log for project_model.txt in MONOLIX export and also the graphics.xml one
Removed the ADM=2 for IV by default if single ROUTE ... for single admin ADM=1 will be default if single ROUTE
Write out which covariates are not in the data when importing general dataset
Fixed covariate forest plot if covariate centering was chosen
Added residuals over TAD to GoF plots
Removed required dose names from IQRdataGENERAL
Minor bug fixes where needed
7.52 V0.3.0 August 14, 2017
Support of NONMEM ADVAN 1,3, and 11
Improvement of IQRnlmeProjectMulti summary tables to be fit for reporting
Improvement of IQRnlmeProject summary table for reporting purposes
Small bug fixes
7.53 V0.2.0 July 14, 2017
Small improvements
Diagram representation of model via plot() function
IQRsysPharm Shiny App provided separately which works with V0.2.0
