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diff --git a/docs/index.html b/docs/index.html index bb14906d..01300749 100644 --- a/docs/index.html +++ b/docs/index.html @@ -19,11 +19,11 @@ equation models are solved using automatically generated C functions. Heteroscedasticity can be taken into account using variance by variable or two-component error models as described by Ranke and Meinecke (2018) - <doi:10.3390/environments6120124>. Interfaces to several nonlinear - mixed-effects model packages are available, some of which are described by - Ranke et al. (2021) <doi:10.3390/environments8080071>. Please note that no - warranty is implied for correctness of results or fitness for a particular - purpose."> + <doi:10.3390/environments6120124>. Hierarchical degradation models can + be fitted using nonlinear mixed-effects model packages as a back end as + described by Ranke et al. (2021) <doi:10.3390/environments8080071>. Please + note that no warranty is implied for correctness of results or fitness for a + particular purpose."> <!-- mathjax --><script src="https://cdnjs.cloudflare.com/ajax/libs/mathjax/2.7.5/MathJax.js" integrity="sha256-nvJJv9wWKEm88qvoQl9ekL2J+k/RWIsaSScxxlsrv8k=" crossorigin="anonymous"></script><script src="https://cdnjs.cloudflare.com/ajax/libs/mathjax/2.7.5/config/TeX-AMS-MML_HTMLorMML.js" integrity="sha256-84DKXVJXs0/F8OTMzX4UR909+jtl4G7SPypPavF+GfA=" crossorigin="anonymous"></script><!--[if lt IE 9]> <script src="https://oss.maxcdn.com/html5shiv/3.7.3/html5shiv.min.js"></script> <script src="https://oss.maxcdn.com/respond/1.4.2/respond.min.js"></script> @@ -44,14 +44,14 @@ </button> <span class="navbar-brand"> <a class="navbar-link" href="index.html">mkin</a> - <span class="version label label-default" data-toggle="tooltip" data-placement="bottom" title="Released version">1.2.1</span> + <span class="version label label-default" data-toggle="tooltip" data-placement="bottom" title="Released version">1.2.3.1</span> </span> </div> <div id="navbar" class="navbar-collapse collapse"> <ul class="nav navbar-nav"> <li> - <a href="reference/index.html">Functions and data</a> + <a href="reference/index.html">Reference</a> </li> <li class="dropdown"> <a href="#" class="dropdown-toggle" data-toggle="dropdown" role="button" data-bs-toggle="dropdown" aria-expanded="false"> @@ -63,6 +63,9 @@ <li> <a href="articles/mkin.html">Introduction to mkin</a> </li> + <li class="divider"> + </li> +<li class="dropdown-header">Example evaluations with (generalised) nonlinear least squares</li> <li> <a href="articles/FOCUS_D.html">Example evaluation of FOCUS Example Dataset D</a> </li> @@ -70,22 +73,31 @@ <a href="articles/FOCUS_L.html">Example evaluation of FOCUS Laboratory Data L1 to L3</a> </li> <li> - <a href="articles/web_only/dimethenamid_2018.html">Example evaluations of dimethenamid data from 2018 with nonlinear mixed-effects models</a> + <a href="articles/web_only/FOCUS_Z.html">Example evaluation of FOCUS Example Dataset Z</a> + </li> + <li class="divider"> </li> +<li class="dropdown-header">Example evaluations with hierarchical models (nonlinear mixed-effects models)</li> <li> - <a href="articles/web_only/multistart.html">Short demo of the multistart method</a> + <a href="articles/prebuilt/2022_dmta_parent.html">Testing hierarchical parent degradation kinetics with residue data on dimethenamid and dimethenamid-P</a> </li> <li> - <a href="articles/web_only/compiled_models.html">Performance benefit by using compiled model definitions in mkin</a> + <a href="articles/prebuilt/2022_dmta_pathway.html">Testing hierarchical pathway kinetics with residue data on dimethenamid and dimethenamid-P</a> </li> <li> - <a href="articles/web_only/FOCUS_Z.html">Example evaluation of FOCUS Example Dataset Z</a> + <a href="articles/prebuilt/2022_cyan_pathway.html">Testing hierarchical pathway kinetics with residue data on cyantraniliprole</a> </li> <li> - <a href="articles/twa.html">Calculation of time weighted average concentrations with mkin</a> + <a href="articles/web_only/dimethenamid_2018.html">Comparison of saemix and nlme evaluations of dimethenamid data from 2018</a> </li> <li> - <a href="articles/web_only/NAFTA_examples.html">Example evaluation of NAFTA SOP Attachment examples</a> + <a href="articles/web_only/multistart.html">Short demo of the multistart method</a> + </li> + <li class="divider"> + </li> +<li class="dropdown-header">Performance</li> + <li> + <a href="articles/web_only/compiled_models.html">Performance benefit by using compiled model definitions in mkin</a> </li> <li> <a href="articles/web_only/benchmarks.html">Benchmark timings for mkin</a> @@ -93,6 +105,15 @@ <li> <a href="articles/web_only/saem_benchmarks.html">Benchmark timings for saem.mmkin</a> </li> + <li class="divider"> + </li> +<li class="dropdown-header">Miscellaneous</li> + <li> + <a href="articles/twa.html">Calculation of time weighted average concentrations with mkin</a> + </li> + <li> + <a href="articles/web_only/NAFTA_examples.html">Example evaluation of NAFTA SOP Attachment examples</a> + </li> </ul> </li> <li> @@ -121,8 +142,8 @@ <div class="section level1"> <div class="page-header"><h1 id="mkin">mkin<a class="anchor" aria-label="anchor" href="#mkin"></a> </h1></div> - -<p>The R package <strong>mkin</strong> provides calculation routines for the analysis of chemical degradation data, including <b>m</b>ulticompartment <b>kin</b>etics as needed for modelling the formation and decline of transformation products, or if several degradation compartments are involved.</p> +<p><a href="https://cran.r-project.org/package=mkin" class="external-link"><img src="https://www.r-pkg.org/badges/version/mkin"></a> <a href="https://jranke.r-universe.dev/ui/#package:mkin" class="external-link"><img src="https://jranke.r-universe.dev/badges/mkin" alt="mkin status badge"></a> <a href="https://app.travis-ci.com/github/jranke/mkin" class="external-link"><img src="https://travis-ci.com/jranke/mkin.svg?branch=main" alt="Build Status"></a> <a href="https://app.codecov.io/gh/jranke/mkin" class="external-link"><img src="https://codecov.io/github/jranke/mkin/branch/main/graphs/badge.svg" alt="codecov"></a></p> +<p>The <a href="https://www.r-project.org" class="external-link">R</a> package <strong>mkin</strong> provides calculation routines for the analysis of chemical degradation data, including <b>m</b>ulticompartment <b>kin</b>etics as needed for modelling the formation and decline of transformation products, or if several degradation compartments are involved. It provides stable functionality for kinetic evaluations according to the FOCUS guidance (see below for details). In addition, it provides functionality to do hierarchical kinetics based on nonlinear mixed-effects models.</p> <div class="section level2"> <h2 id="installation">Installation<a class="anchor" aria-label="anchor" href="#installation"></a> </h2> @@ -133,17 +154,18 @@ <div class="section level2"> <h2 id="background">Background<a class="anchor" aria-label="anchor" href="#background"></a> </h2> -<p>In the regulatory evaluation of chemical substances like plant protection products (pesticides), biocides and other chemicals, degradation data play an important role. For the evaluation of pesticide degradation experiments, detailed guidance and helpful tools have been developed as detailed in ‘Credits and historical remarks’ below.</p> +<p>In the regulatory evaluation of chemical substances like plant protection products (pesticides), biocides and other chemicals, degradation data play an important role. For the evaluation of pesticide degradation experiments, detailed guidance and various helpful tools have been developed as detailed in ‘Credits and historical remarks’ below. This package aims to provide a one stop solution for degradation kinetics, addressing modellers that are willing to, or even prefer to work with R.</p> </div> <div class="section level2"> -<h2 id="usage">Usage<a class="anchor" aria-label="anchor" href="#usage"></a> +<h2 id="basic-usage">Basic usage<a class="anchor" aria-label="anchor" href="#basic-usage"></a> </h2> <p>For a start, have a look at the code examples provided for <a href="https://pkgdown.jrwb.de/mkin/reference/plot.mkinfit.html"><code>plot.mkinfit</code></a> and <a href="https://pkgdown.jrwb.de/mkin/reference/plot.mmkin.html"><code>plot.mmkin</code></a>, and at the package vignettes <a href="https://pkgdown.jrwb.de/mkin/articles/FOCUS_L.html"><code>FOCUS L</code></a> and <a href="https://pkgdown.jrwb.de/mkin/articles/FOCUS_D.html"><code>FOCUS D</code></a>.</p> </div> <div class="section level2"> <h2 id="documentation">Documentation<a class="anchor" aria-label="anchor" href="#documentation"></a> </h2> -<p>The HTML documentation of the latest version released to CRAN is available at <a href="https://pkgdown.jrwb.de/mkin/">jrwb.de</a> and <a href="https://jranke.github.io/mkin/" class="external-link">github</a>. Documentation of the development version is found in the <a href="https://pkgdown.jrwb.de/mkin/dev/">‘dev’ subdirectory</a>.</p> +<p>The HTML documentation of the latest version released to CRAN is available at <a href="https://pkgdown.jrwb.de/mkin/">jrwb.de</a> and <a href="https://jranke.github.io/mkin/" class="external-link">github</a>.</p> +<p>Documentation of the development version is found in the <a href="https://pkgdown.jrwb.de/mkin/dev/">‘dev’ subdirectory</a>. In the articles section of this documentation, you can also find demonstrations of the application of nonlinear hierarchical models, also known as nonlinear mixed-effects models, to more complex data, including transformation products and covariates.</p> </div> <div class="section level2"> <h2 id="features">Features<a class="anchor" aria-label="anchor" href="#features"></a> @@ -152,9 +174,9 @@ <h3 id="general">General<a class="anchor" aria-label="anchor" href="#general"></a> </h3> <ul> -<li>Highly flexible model specification using <a href="https://pkgdown.jrwb.de/mkin/reference/mkinmod.html"><code>mkinmod</code></a>, including equilibrium reactions and using the single first-order reversible binding (SFORB) model, which will automatically create two latent state variables for the observed variable.</li> -<li>Model solution (forward modelling) in the function <a href="https://pkgdown.jrwb.de/mkin/reference/mkinpredict.html"><code>mkinpredict</code></a> is performed either using the analytical solution for the case of parent only degradation, an eigenvalue based solution if only simple first-order (SFO) or SFORB kinetics are used in the model, or using a numeric solver from the <code>deSolve</code> package (default is <code>lsoda</code>).</li> -<li>The usual one-sided t-test for significant difference from zero is nevertheless shown based on estimators for the untransformed parameters.</li> +<li>Highly flexible model specification using <a href="https://pkgdown.jrwb.de/mkin/reference/mkinmod.html"><code>mkinmod</code></a>, including equilibrium reactions and using the single first-order reversible binding (SFORB) model, which will automatically create two state variables for the observed variable.</li> +<li>Model solution (forward modelling) in the function <a href="https://pkgdown.jrwb.de/mkin/reference/mkinpredict.html"><code>mkinpredict</code></a> is performed either using the analytical solution for the case of parent only degradation or some simple models involving a single transformation product, , an eigenvalue based solution if only simple first-order (SFO) or SFORB kinetics are used in the model, or using a numeric solver from the <code>deSolve</code> package (default is <code>lsoda</code>).</li> +<li>The usual one-sided t-test for significant difference from zero is shown based on estimators for the untransformed parameters.</li> <li>Summary and plotting functions. The <code>summary</code> of an <code>mkinfit</code> object is in fact a full report that should give enough information to be able to approximately reproduce the fit with other tools.</li> <li>The chi-squared error level as defined in the FOCUS kinetics guidance (see below) is calculated for each observed variable.</li> <li>The ‘variance by variable’ error model which is often fitted using Iteratively Reweighted Least Squares (IRLS) can be specified as <code>error_model = "obs"</code>.</li> @@ -168,8 +190,8 @@ <li>Model comparisons using the Akaike Information Criterion (AIC) are supported which can also be used for non-constant variance. In such cases the FOCUS chi-squared error level is not meaningful.</li> <li>By default, kinetic rate constants and kinetic formation fractions are transformed internally using <a href="https://pkgdown.jrwb.de/mkin/reference/transform_odeparms.html"><code>transform_odeparms</code></a> so their estimators can more reasonably be expected to follow a normal distribution.</li> <li>When parameter estimates are backtransformed to match the model definition, confidence intervals calculated from standard errors are also backtransformed to the correct scale, and will not include meaningless values like negative rate constants or formation fractions adding up to more than 1, which cannot occur in a single experiment with a single defined radiolabel position.</li> -<li>When a metabolite decline phase is not described well by SFO kinetics, SFORB kinetics can be used for the metabolite. Mathematically, the SFORB model is equivalent to the DFOP model used by other tools for biphasic metabolite curves. However, the SFORB model has the advantage that there is a mechanistic interpretation of the model parameters.</li> -<li>Nonlinear mixed-effects models can be created from fits of the same degradation model to different datasets for the same compound by using the <a href="https://pkgdown.jrwb.de/mkin/reference/nlme.mmkin.html">nlme.mmkin</a> and <a href="https://pkgdown.jrwb.de/mkin/reference/saem.html">saem.mmkin</a> and methods. Note that the convergence of the nlme fits depends on the quality of the data. Convergence is better for simple models and data for many groups (e.g. soils). The saem method uses the <code>saemix</code> package as a backend. Analytical solutions suitable for use with this package have been implemented for parent only models and the most important models including one metabolite (SFO-SFO and DFOP-SFO). Fitting other models with <code>saem.mmkin</code>, while it makes use of the compiled ODE models that mkin provides, has longer run times (at least six minutes on my system).</li> +<li>When a metabolite decline phase is not described well by SFO kinetics, SFORB kinetics can be used for the metabolite. Mathematically, the SFORB model is equivalent to the DFOP model. However, the SFORB model has the advantage that there is a mechanistic interpretation of the model parameters.</li> +<li>Nonlinear mixed-effects models (hierarchical models) can be created from fits of the same degradation model to different datasets for the same compound by using the <a href="https://pkgdown.jrwb.de/mkin/reference/nlme.mmkin.html">nlme.mmkin</a> and <a href="https://pkgdown.jrwb.de/mkin/reference/saem.html">saem.mmkin</a> methods. Note that the convergence of the nlme fits depends on the quality of the data. Convergence is better for simple models and data for many groups (e.g. soils). The saem method uses the <code>saemix</code> package as a backend. Analytical solutions suitable for use with this package have been implemented for parent only models and the most important models including one metabolite (SFO-SFO and DFOP-SFO). Fitting other models with <code>saem.mmkin</code>, while it makes use of the compiled ODE models that mkin provides, has longer run times (from a couple of minutes to more than an hour).</li> </ul> </div> <div class="section level3"> @@ -185,7 +207,7 @@ <div class="section level2"> <h2 id="gui">GUI<a class="anchor" aria-label="anchor" href="#gui"></a> </h2> -<p>There is a graphical user interface that may be useful. Please refer to its <a href="https://pkgdown.jrwb.de/gmkin/" class="external-link">documentation page</a> for installation instructions and a manual.</p> +<p>There is a graphical user interface that may be useful. Please refer to its <a href="https://pkgdown.jrwb.de/gmkin/" class="external-link">documentation page</a> for installation instructions and a manual. It only supports evaluations using (generalised) nonlinear regression, but not simultaneous fits using nonlinear mixed-effects models.</p> </div> <div class="section level2"> <h2 id="news">News<a class="anchor" aria-label="anchor" href="#news"></a> @@ -202,8 +224,8 @@ <p>The first <code>mkin</code> code was <a href="https://r-forge.r-project.org/scm/viewvc.php?view=rev&root=kinfit&revision=8" class="external-link">published on 11 May 2010</a> and the <a href="https://cran.r-project.org/src/contrib/Archive/mkin/" class="external-link">first CRAN version</a> on 18 May 2010.</p> <p>In 2011, Bayer Crop Science started to distribute an R based successor to KinGUI named KinGUII whose R code is based on <code>mkin</code>, but which added, among other refinements, a closed source graphical user interface (GUI), iteratively reweighted least squares (IRLS) optimisation of the variance for each of the observed variables, and Markov Chain Monte Carlo (MCMC) simulation functionality, similar to what is available e.g. in the <code>FME</code> package.</p> <p>Somewhat in parallel, Syngenta has sponsored the development of an <code>mkin</code> and KinGUII based GUI application called CAKE, which also adds IRLS and MCMC, is more limited in the model formulation, but puts more weight on usability. CAKE is available for download from the <a href="https://cake-kinetics.org" class="external-link">CAKE website</a>, where you can also find a zip archive of the R scripts derived from <code>mkin</code>, published under the GPL license.</p> -<p>Finally, there is <a href="https://github.com/zhenglei-gao/KineticEval" class="external-link">KineticEval</a>, which contains a further development of the scripts used for KinGUII, so the different tools will hopefully be able to learn from each other in the future as well.</p> -<p>Thanks to René Lehmann, formerly working at the Umweltbundesamt, for the nice cooperation cooperation on parameter transformations, especially the isometric log-ratio transformation that is now used for formation fractions in case there are more than two transformation targets.</p> +<p>Finally, there is <a href="https://github.com/zhenglei-gao/KineticEval" class="external-link">KineticEval</a>, which contains some further development of the scripts used for KinGUII.</p> +<p>Thanks to René Lehmann, formerly working at the Umweltbundesamt, for the nice cooperation on parameter transformations, especially the isometric log-ratio transformation that is now used for formation fractions in case there are more than two transformation targets.</p> <p>Many inspirations for improvements of mkin resulted from doing kinetic evaluations of degradation data for my clients while working at Harlan Laboratories and at Eurofins Regulatory AG, and now as an independent consultant.</p> <p>Funding was received from the Umweltbundesamt in the course of the projects</p> <ul> @@ -213,19 +235,30 @@ <li>Project Number 112407 (Testing the feasibility of using an error model according to Rocke and Lorenzato for more realistic parameter estimates in the kinetic evaluation of degradation data, 2018-2019)</li> <li>Project Number 120667 (Development of objective criteria for the evaluation of the visual fit in the kinetic evaluation of degradation data, 2019-2020)</li> <li>Project Number 146839 (Checking the feasibility of using mixed-effects models for the derivation of kinetic modelling parameters from degradation studies, 2020-2021)</li> +<li>Project Number 173340 (Application of nonlinear hierarchical models to the kinetic evaluation of chemical degradation data)</li> </ul> -<p>Thanks are due also to Emmanuelle Comets, maintainer of the saemix package, for the nice collaboration on using the SAEM algorithm and its implementation in saemix for the evaluation of chemical degradation data.</p> +<p>Thanks to everyone involved for collaboration and support!</p> +<p>Thanks are due also to Emmanuelle Comets, maintainer of the saemix package, for her interest and support for using the SAEM algorithm and its implementation in saemix for the evaluation of chemical degradation data.</p> </div> <div class="section level2"> <h2 id="references">References<a class="anchor" aria-label="anchor" href="#references"></a> </h2> <table class="table"> -<tr><td>Ranke J, Wöltjen J, Schmidt J, and Comets E (2021) Taking kinetic evaluations of degradation data to the next level with nonlinear mixed-effects models. <i>Environments</i> <b>8</b> (8) 71 <a href="https://doi.org/10.3390/environments8080071" class="external-link">doi:10.3390/environments8080071</a> -</td></tr> -<tr><td>Ranke J, Meinecke S (2019) Error Models for the Kinetic Evaluation of Chemical Degradation Data <i>Environments</i> <b>6</b> (12) 124 <a href="https://doi.org/10.3390/environments6120124" class="external-link">doi:10.3390/environments6120124</a> -</td></tr> -<tr><td>Ranke J, Wöltjen J, Meinecke S (2018) Comparison of software tools for kinetic evaluation of chemical degradation data <i>Environmental Sciences Europe</i> <b>30</b> 17 <a href="https://doi.org/10.1186/s12302-018-0145-1" class="external-link">doi:10.1186/s12302-018-0145-1</a> -</td></tr> +<tr> +<td> +Ranke J, Wöltjen J, Schmidt J, and Comets E (2021) Taking kinetic evaluations of degradation data to the next level with nonlinear mixed-effects models. <i>Environments</i> <b>8</b> (8) 71 <a href="https://doi.org/10.3390/environments8080071" class="external-link">doi:10.3390/environments8080071</a> +</td> +</tr> +<tr> +<td> +Ranke J, Meinecke S (2019) Error Models for the Kinetic Evaluation of Chemical Degradation Data <i>Environments</i> <b>6</b> (12) 124 <a href="https://doi.org/10.3390/environments6120124" class="external-link">doi:10.3390/environments6120124</a> +</td> +</tr> +<tr> +<td> +Ranke J, Wöltjen J, Meinecke S (2018) Comparison of software tools for kinetic evaluation of chemical degradation data <i>Environmental Sciences Europe</i> <b>30</b> 17 <a href="https://doi.org/10.1186/s12302-018-0145-1" class="external-link">doi:10.1186/s12302-018-0145-1</a> +</td> +</tr> </table> </div> <div class="section level2"> @@ -282,7 +315,7 @@ <div class="pkgdown"> <p></p> -<p>Site built with <a href="https://pkgdown.r-lib.org/" class="external-link">pkgdown</a> 2.0.6.</p> +<p>Site built with <a 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