`README.md`

,`vignettes/mkin.Rmd`

: URLs were updated`synthetic_data_for_UBA`

: Add the code used to generate the data in the interest of reproducibility

Converted the vignette FOCUS_Z from tex/pdf to markdown/html

`DESCRIPTION`

: Add ORCID

`plot.mkinfit`

: Fix scaling of residual plots for the case of separate plots for each observed variable`plot.mkinfit`

: Use all data points of the fitted curve for y axis scaling for the case of separate plots for each observed variableDocumentation updates

- Remove
`test_FOMC_ill-defined.R`

as it is too platform dependent

Rename

`twa`

to`max_twa_parent`

to avoid conflict with`twa`

from my`pfm`

packageUpdate URLs in documentation

Limit test code to one core to pass on windows

Switch from

`microbenchmark`

to`rbenchmark`

as the former is not supported on all platforms

- A
`twa`

function, calculating maximum time weighted average concentrations for the parent (SFO, FOMC and DFOP).

`plot.mkinfit`

and`plot.mmkin`

: If the plotting device is`tikz`

, LaTeX markup is being used for the chi2 error in the graphs.Use

`pkgdown`

, the successor of`staticdocs`

for generating static HTML documentation. Include example output and graphs also for`dontrun`

sections.`plot.mkinfit`

: Plotting does not fail any more when the compiled model is not available, e.g. because it was removed from the temporary directory. In this case, the uncompiled model is now used for plotting

- The test
`test_FOMC_ill-defined`

failed on several architectures, so the test is now skipped

The title was changed to

`Kinetic evaluations of chemical degradation data`

`plot.mkinfit`

: Add the possibility to show fits (and residual plots if requested) separately for the observed variables`plot.mkinfit`

: Add the possibility to show the chi2 error levels in the plot, similar to the way they are shown in`plot.mmkin`

`plot_sep`

: Add this function as a convenience wrapper for plotting observed variables of mkinfit objects separately, with chi2 error values and residual plots.Vignettes: The main vignette

`mkin`

was converted to R markdown and updated. The other vignettes were also updated to show current improved functionality.The function

`add_err`

was added to the package, making it easy to generate simulated data using an error model based on the normal distribution

Remove an outdated reference to the inline package in the

`compiled_models`

vignette`mkinfit`

: Do not error out in cases where the fit converges, but the Jacobian for the untransformed model cost can not be estimated. Give a warning instead and return NA for the t-test results.`summary.mkinfit`

: Give a warning message when the covariance matrix can not be obtained.A test has been added to containing a corresponding edge case to check that the warnings are correctly issued and the fit does not terminate.

`plot.mmkin`

: Round the chi2 error value to three significant digits, instead of two decimal digits.`mkinfit`

: Return the`err`

values used on weighted fits as a column named`err`

. Also include these inverse weights when the column`value`

in the observed data is used, which is returned as`observed`

in the data component of the mkinfit object.

`endpoints`

: When the name of a substance degrading to a metabolite (e.g. a parent compound) used in the model formulation ended in the letter`f`

, some rate parameters could be listed as formation fractions with mixed up names. These would also appear in the summary.`mkinfit`

: Check for all observed variables when checking if the user tried to fix formation fractions when fitting them using ilr transformation.`plot.mmkin`

: Set the plot margins correctly, also in the case of a single fit to be plotted, so the main title is placed in a reasonable way.`plot.mkinfit`

: Correct default values for`col_obs`

,`pch_obs`

and`lty_obs`

for the case that`obs_vars`

is specified.

- Add the argument
`from_max_mean`

to`mkinfit`

, for fitting only the decline from the maximum observed value for models with a single observed variable

Add plots to

`compiled_models`

vignetteGive an explanatory error message when mkinmod fails due to a missing definition of a target variable

`print.mkinmod()`

: Improve formatting when printing mkinmod model definitions

Add an R6 class

`mkinds`

representing datasets with a printing methodAdd a printing method for mkinmod objects

Make it possible to specify arbitrary strings as names for the compounds in

`mkinmod`

, and show them in the plotUse an index.r file to group help topics in static documentation

`print.summary.mkinfit()`

: Avoid an error that occurred when printing summaries generated with mkin versions before 0.9-36

`endpoints()`

: For DFOP and SFORB models, where`optimize()`

is used, make use of the fact that the DT50 must be between DT50_k1 and DT50_k2 (DFOP) or DT50_b1 and DT50_b2 (SFORB), as`optimize()`

sometimes did not find the minimum. Likewise for finding DT90 values. Also fit on the log scale to make the function more efficient.

`DESCRIPTION`

,`NAMESPACE`

,`R/*.R`

: Import (from) stats, graphics and methods packages, and qualify some function calls for non-base packages installed with R to avoid NOTES made by R CMD check –as-cran with upcoming R versions.

New function

`mmkin()`

: This function takes a character vector of model shorthand names, or alternatively a list of mkinmod models, as well as a list of dataset as main arguments. It returns a matrix of mkinfit objects, with a row for each model and a column for each dataset. A subsetting method with single brackets is available. Fitting the models in parallel using the`parallel`

package is supported.New function

`plot.mmkin()`

: Plots single-row or single-column`mmkin`

objects including residual plots.

`mkinparplot()`

: Fix the x axis scaling for rate constants and formation fractions that got confused by the introduction of the t-values of transformed parameters.

`vignettes/compiled_models.html`

: Show the performance improvement factor actually obtained when building the vignette, as well as mkin version, some system info and the CPU model used for building the vignette.`GNUMakefile`

,`vignettes/*`

: Clean up vignette generation and include table of contents in HTML vignettes.

`mkinmod()`

: When generating the C code for the derivatives, only declare the time variable when it is needed and remove the ‘-W-no-unused-variable’ compiler flag as the C compiler used in the CRAN checks on Solaris does not know it.

`summary.mkinfit()`

: A one-sided t-test for significant difference of untransformed parameters from zero is now always shown, based on the assumption of normal distribution for estimators of all untransformed parameters. Use with caution, as this assumption is unrealistic e.g. for rate constants in these nonlinear kinetic models.If a compiler (gcc) is installed, use a version of the differential equation model compiled from C code, which is a huge performance boost for models where only the deSolve method works.

`mkinmod()`

: Create a list component $cf (of class CFuncList) in the list returned by mkinmod, if a version can be compiled from autogenerated C code (see above).`mkinfit()`

: Set the default`solution_type`

to`deSolve`

when a compiled version of the model is present, except when an analytical solution is possible.

- Added a simple showcase vignette with an evaluation of FOCUS example dataset D

- Switch from RUnit to testthat for testing

`mkinparplot()`

: Avoid warnings that occurred when not all confidence intervals were available in the summary of the fit`print.summary.mkinfit()`

: Fix printing the summary for the case that the number of iterations is not availableNAMESPACE: export S3 methods plot.mkinfit, summary.mkinfit and print.summary.mkinfit to satisfy R CMD check on R-devel

`mkinparplot()`

: Avoid warning in R CMD check about undeclared global variable`Lower`

`mkinfit()`

: Report successful termination when quiet = FALSE. This is helpful for more difficult problems fitted with reweight.method = obs, as no progress is often indicated during the reweighting.A first test using results established in the expertise written for the German Federal Environmental Agency (UBA) was added.

Add synthetic datasets generated for expertise written for the German Federal Environmental Agency UBA

Add tests based on these datasets

Add the convenience function

`mkinsub()`

for creating the lists used in`mkinmod()`

Add the possibility to fit indeterminate order rate equation (IORE) models using an analytical solution (parent only) or a numeric solution. Paths from IORE compounds to metabolites are supported when using formation fractions (use_of_ff = ‘max’). Note that the numerical solution (method.ode = ‘deSolve’) of the IORE differential equations sometimes fails due to numerical problems.

Switch to using the Port algorithm (using a model/trust region approach) per default. While needing more iterations than the Levenberg-Marquardt algorithm previously used per default, it is less sensitive to starting parameters.

The formatting of differential equations in the summary was further improved

Always include 0 on y axis when plotting during the fit

The initial value (state.ini) for the observed variable with the highest observed residue is set to 100 in case it has no time zero observation and

`state.ini = "auto"`

A basic unit test for

`mkinerrmin()`

was written

`mkinfit()`

: The internally fitted parameter for`g`

was named`g_ilr`

even when`transform_fractions=FALSE`

`mkinfit()`

: The initial value (state.ini) for the parent compound was not set when the parent was not the (only) variable with the highest value in the observed data.`mkinerrmin()`

: When checking for degrees of freedom for metabolites, check if their time zero value is fixed instead of checking if the observed value is zero. This ensures correct calculation of degrees of freedom also in cases where the metabolite residue at time zero is greater zero.`plot.mkinfit()`

: Avoid a warning message about only using the first component of ylim that occurred when ylim was specified explicitly

The formatting of differential equations in the summary was improved by wrapping overly long lines

The FOCUS_Z vignette was rebuilt with the above improvement and using a width of 70 to avoid output outside of the grey area

`print.summary.mkinfit()`

: Avoid a warning that occurred when gmkin showed summaries ofinitial fits without iterations`mkinfit()`

: Avoid a warning that occurred when summarising a fit that was performed with maxitmodFit = 0 as done in gmkin for configuring new fits.

The number of degrees of freedom is difficult to define in the case of ilr transformation of formation fractions. Now for each source compartment the number of ilr parameters (=number of optimised parameters) is divided by the number of pathways to metabolites (=number of affected data series) which leads to fractional degrees of freedom in some cases.

The default for the initial value for the first state value is now taken from the mean of the observations at time zero, if available.

The kinetic model can alternatively be specified with a shorthand name for parent only degradation models, e.g.

`SFO`

, or`DFOP`

.Optimisation method, number of model evaluations and time elapsed during optimisation are given in the summary of mkinfit objects.

The maximum number of iterations in the optimisation algorithm can be specified using the argument

`maxit.modFit`

to the mkinfit function.mkinfit gives a warning when the fit does not converge (does not apply to SANN method). This warning is included in the summary.

Avoid plotting an artifical 0 residual at time zero in

`mkinresplot`

In the determination of the degrees of freedom in

`mkinerrmin`

, formation fractions were accounted for multiple times in the case of parallel formation of metabolites. See the new feature described above for the solution.`transform_rates=FALSE`

in`mkinfit`

now also works for FOMC and HS models.Initial values for formation fractions were not set in all cases.

No warning was given when the fit did not converge when a method other than the default Levenberg-Marquardt method

`Marq`

was used.

Vignettes were rebuilt to reflect the changes in the summary method.

Algorithm

`Pseudo`

was excluded because it needs user-defined parameter limits which are not supported.Algorithm

`Newton`

was excluded because of its different way to specify the maximum number of iterations and because it does not appear to provide additional benefits.

- The internal renaming of optimised parameters in Version 0.9-30 led to errors in the determination of the degrees of freedom for the chi2 error level calulations in
`mkinerrmin()`

used by the summary function.

- It is now possible to use formation fractions in combination with turning off the sink in
`mkinmod()`

.

The original and the transformed parameters now have different names (e.g.

`k_parent`

and`log_k_parent`

. They also differ in how many they are when we have formation fractions but no pathway to sink.The order of some of the information blocks in

`print.summary.mkinfit.R()`

has been ordered in a more logical way.

The vignette FOCUS_Z has been simplified to use formation fractions with turning off the sink, and slightly amended to use the new versions of DT50 values calculated since mkin 0.9-29.

All vignettes have been rebuilt so they reflect all changes.

The ChangeLog was renamed to NEWS.md and the entries were converted to markdown syntax compatible with the

`tools::news()`

function built into R.The test suite was overhauled. Tests of the DFOP and SFORB models with dataset FOCUS_2006_A were removed, as they were too much dependent on the optimisation algorithm and/or starting parameters, because the dataset is SFO (compare kinfit vignette).

Also, the Schaefer complex case can now be fitted using formation fractions, and with the ‘Port’ optimisation method we also fit A2 in the same way as published in the Piacenza paper.

Some more checks were introduced to

`mkinfit()`

, leading to warnings or stopping execution if unsupported combinations of methods and parameters are requested.

R/mkinresplot.R: Make it possible to specify

`xlim`

R/geometric_mean.R, man/geometric_mean.Rd: Add geometric mean function

R/endpoints.R, man/endpoints.Rd: Calculate additional (pseudo)-DT50 values for FOMC, DFOP, HS and SFORB. Avoid calculation of formation fractions from rate constants when they are directly fitted

Do not backtransform confidence intervals for formation fractions if more than one compound is formed, as such parameters only define the pathways as a set

Add historical remarks and some background to the main package vignette

Correct ‘isotropic’ into ‘isometric’ for the ilr transformation

Fork the GUI into a separate package gmkin

DESCRIPTION, NAMESPACE, TODO: Adapt and add copyright information

Remove files belonging to the GUI

Possibility to fit without parameter transformations, using bounds as implemented in FME

Add McCall 2,4,5-T dataset

Enable selection of observed variables in plotting

Add possibility to show residual plot in

`plot.mkinfit`

R/mkinparplot.R, man/mkinparplot.Rd: plot parameters with confidence intervals

Change vignette format from Sweave to knitr

Split examples vignette to FOCUS_L and FOCUS_Z

Remove warning about constant formation fractions in mkinmod as it was based on a misconception

Restrict the unit test with the Schaefer data to parent and primary metabolites as formation fraction and DT50 for A2 are higly correlated and passing the test is platform dependent. For example, the test fails in 1 out of 14 platforms on CRAN as of today.

Add Eurofins Regulatory AG copyright notices

Import FME and deSolve instead of depending on them to have clean startup

Add a starter function for the GUI:

`gmkin()`

Change the format of the workspace files of gmkin so they can be distributed and documented in the package

Add gmkin workspace datasets FOCUS_2006_gmkin and FOCUS_2006_Z_gmkin

Bugfix re-enabling the fixing of any combination of initial values for state variables

Default values for kinetic rate constants are not all 0.1 any more but are “salted” with a small increment to avoid numeric artefacts with the eigenvalue based solutions

Backtransform fixed ODE parameters for the summary

Get rid of the optimisation step in

`mkinerrmin`

- this was unnecessary. Thanks to KinGUII for the inspiration - actually this is equation 6-2 in FOCUS kinetics p. 91 that I had overlooked originallyFix

`plot.mkinfit`

as it passed graphical arguments like main to the solverDo not use

`plot=TRUE`

in`mkinfit()`

exampleThe first successful fits in the not so simple GUI

Fix iteratively reweighted least squares for the case of many metabolites

Unify naming of initial values of state variables

Unify naming in dataframes of optimised and fixed parameters in the summary

Show the weighting method for residuals in the summary

Correct the output of the data in the case of manual weighting

Implement IRLS assuming different variances for observed variables

Do not use 0 values at time zero for chi2 error level calculations. This is the way it is done in KinGUII and it makes sense. It does impact the chi2 error levels in the output. Generally they seem to be lower for metabolites now, presumably because the mean of the observed values is higher

For a detailed list of changes to the mkin source please consult the commit history on http://github.com/jranke/mkin