From b9be19af5e3085216d0cd5af439332f631fa8b92 Mon Sep 17 00:00:00 2001
From: Johannes Ranke <jranke@uni-bremen.de>
Date: Mon, 15 Feb 2021 17:36:12 +0100
Subject: Fully rebuild docs, rerun tests and check

---
 docs/dev/articles/web_only/FOCUS_Z.html            |  35 ++--
 .../accessible-code-block-0.0.1/empty-anchor.js    |  15 ++
 .../figure-html/FOCUS_2006_Z_fits_1-1.png          | Bin 69227 -> 66640 bytes
 .../figure-html/FOCUS_2006_Z_fits_10-1.png         | Bin 109820 -> 106038 bytes
 .../figure-html/FOCUS_2006_Z_fits_11-1.png         | Bin 109050 -> 105042 bytes
 .../figure-html/FOCUS_2006_Z_fits_11a-1.png        | Bin 79154 -> 75626 bytes
 .../figure-html/FOCUS_2006_Z_fits_11b-1.png        | Bin 35734 -> 35744 bytes
 .../figure-html/FOCUS_2006_Z_fits_2-1.png          | Bin 69227 -> 66640 bytes
 .../figure-html/FOCUS_2006_Z_fits_3-1.png          | Bin 69006 -> 66424 bytes
 .../figure-html/FOCUS_2006_Z_fits_5-1.png          | Bin 83658 -> 80520 bytes
 .../figure-html/FOCUS_2006_Z_fits_6-1.png          | Bin 108890 -> 105149 bytes
 .../figure-html/FOCUS_2006_Z_fits_7-1.png          | Bin 108277 -> 104479 bytes
 .../figure-html/FOCUS_2006_Z_fits_9-1.png          | Bin 91586 -> 88890 bytes
 .../FOCUS_Z_files/header-attrs-2.6/header-attrs.js |  12 ++
 docs/dev/articles/web_only/NAFTA_examples.html     | 181 ++++++++++-----------
 .../accessible-code-block-0.0.1/empty-anchor.js    |  15 ++
 .../NAFTA_examples_files/figure-html/p10-1.png     | Bin 80950 -> 78793 bytes
 .../NAFTA_examples_files/figure-html/p11-1.png     | Bin 77737 -> 75470 bytes
 .../NAFTA_examples_files/figure-html/p12a-1.png    | Bin 83111 -> 80755 bytes
 .../NAFTA_examples_files/figure-html/p12b-1.png    | Bin 72088 -> 69885 bytes
 .../NAFTA_examples_files/figure-html/p13-1.png     | Bin 79355 -> 77126 bytes
 .../NAFTA_examples_files/figure-html/p14-1.png     | Bin 82078 -> 79693 bytes
 .../NAFTA_examples_files/figure-html/p15a-1.png    | Bin 78261 -> 75945 bytes
 .../NAFTA_examples_files/figure-html/p15b-1.png    | Bin 80090 -> 78004 bytes
 .../NAFTA_examples_files/figure-html/p16-1.png     | Bin 95466 -> 93075 bytes
 .../NAFTA_examples_files/figure-html/p5a-1.png     | Bin 84037 -> 81521 bytes
 .../NAFTA_examples_files/figure-html/p5b-1.png     | Bin 81732 -> 79783 bytes
 .../NAFTA_examples_files/figure-html/p6-1.png      | Bin 84055 -> 81974 bytes
 .../NAFTA_examples_files/figure-html/p7-1.png      | Bin 103771 -> 101606 bytes
 .../NAFTA_examples_files/figure-html/p8-1.png      | Bin 94196 -> 91429 bytes
 .../NAFTA_examples_files/figure-html/p9a-1.png     | Bin 80132 -> 77612 bytes
 .../NAFTA_examples_files/figure-html/p9b-1.png     | Bin 77691 -> 75129 bytes
 .../header-attrs-2.6/header-attrs.js               |  12 ++
 docs/dev/articles/web_only/benchmarks.html         |  65 ++++++--
 .../accessible-code-block-0.0.1/empty-anchor.js    |  15 ++
 .../header-attrs-2.6/header-attrs.js               |  12 ++
 docs/dev/articles/web_only/compiled_models.html    |  27 ++-
 .../accessible-code-block-0.0.1/empty-anchor.js    |  15 ++
 .../header-attrs-2.6/header-attrs.js               |  12 ++
 39 files changed, 277 insertions(+), 139 deletions(-)
 create mode 100644 docs/dev/articles/web_only/FOCUS_Z_files/accessible-code-block-0.0.1/empty-anchor.js
 create mode 100644 docs/dev/articles/web_only/FOCUS_Z_files/header-attrs-2.6/header-attrs.js
 create mode 100644 docs/dev/articles/web_only/NAFTA_examples_files/accessible-code-block-0.0.1/empty-anchor.js
 create mode 100644 docs/dev/articles/web_only/NAFTA_examples_files/header-attrs-2.6/header-attrs.js
 create mode 100644 docs/dev/articles/web_only/benchmarks_files/accessible-code-block-0.0.1/empty-anchor.js
 create mode 100644 docs/dev/articles/web_only/benchmarks_files/header-attrs-2.6/header-attrs.js
 create mode 100644 docs/dev/articles/web_only/compiled_models_files/accessible-code-block-0.0.1/empty-anchor.js
 create mode 100644 docs/dev/articles/web_only/compiled_models_files/header-attrs-2.6/header-attrs.js

(limited to 'docs/dev/articles/web_only')

diff --git a/docs/dev/articles/web_only/FOCUS_Z.html b/docs/dev/articles/web_only/FOCUS_Z.html
index 15c41eb7..694b33ca 100644
--- a/docs/dev/articles/web_only/FOCUS_Z.html
+++ b/docs/dev/articles/web_only/FOCUS_Z.html
@@ -32,7 +32,7 @@
       </button>
       <span class="navbar-brand">
         <a class="navbar-link" href="../../index.html">mkin</a>
-        <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">0.9.50.4</span>
+        <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.3.9000</span>
       </span>
     </div>
 
@@ -81,7 +81,7 @@
 <ul class="nav navbar-nav navbar-right">
 <li>
   <a href="https://github.com/jranke/mkin/">
-    <span class="fab fa fab fa-github fa-lg"></span>
+    <span class="fab fa-github fa-lg"></span>
      
   </a>
 </li>
@@ -95,14 +95,13 @@
 
       
 
-      </header><link href="FOCUS_Z_files/anchor-sections-1.0/anchor-sections.css" rel="stylesheet">
-<script src="FOCUS_Z_files/anchor-sections-1.0/anchor-sections.js"></script><div class="row">
+      </header><script src="FOCUS_Z_files/header-attrs-2.6/header-attrs.js"></script><script src="FOCUS_Z_files/accessible-code-block-0.0.1/empty-anchor.js"></script><div class="row">
   <div class="col-md-9 contents">
     <div class="page-header toc-ignore">
       <h1 data-toc-skip>Example evaluation of FOCUS dataset Z</h1>
                         <h4 class="author">Johannes Ranke</h4>
             
-            <h4 class="date">2020-11-30</h4>
+            <h4 class="date">Last change 16 January 2018 (rebuilt 2021-02-15)</h4>
       
       <small class="dont-index">Source: <a href="https://github.com/jranke/mkin/blob/master/vignettes/web_only/FOCUS_Z.rmd"><code>vignettes/web_only/FOCUS_Z.rmd</code></a></small>
       <div class="hidden name"><code>FOCUS_Z.rmd</code></div>
@@ -239,12 +238,12 @@
 <div class="sourceCode" id="cb34"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/summary-methods.html">summary</a></span><span class="op">(</span><span class="va">m.Z.FOCUS</span>, data <span class="op">=</span> <span class="cn">FALSE</span><span class="op">)</span><span class="op">$</span><span class="va">bpar</span></code></pre></div>
 <pre><code>##             Estimate se_notrans t value     Pr(&gt;t)     Lower      Upper
-## Z0_0       96.839001   1.994273 48.5585 4.0276e-42 92.827060 100.850943
-## k_Z0        2.215367   0.118456 18.7021 1.0410e-23  1.989432   2.466960
-## k_Z1        0.478310   0.028258 16.9265 6.2430e-22  0.424712   0.538673
-## k_Z2        0.451628   0.042139 10.7176 1.6313e-14  0.374337   0.544877
-## k_Z3        0.058692   0.015245  3.8498 1.7806e-04  0.034806   0.098972
-## f_Z2_to_Z3  0.471498   0.058350  8.0805 9.6614e-11  0.357741   0.588294
+## Z0_0       96.838822   1.994274 48.5584 4.0280e-42 92.826981 100.850664
+## k_Z0        2.215393   0.118458 18.7019 1.0413e-23  1.989456   2.466989
+## k_Z1        0.478305   0.028258 16.9266 6.2418e-22  0.424708   0.538666
+## k_Z2        0.451627   0.042139 10.7176 1.6314e-14  0.374339   0.544872
+## k_Z3        0.058692   0.015245  3.8499 1.7803e-04  0.034808   0.098965
+## f_Z2_to_Z3  0.471502   0.058351  8.0805 9.6608e-11  0.357769   0.588274
 ## sigma       3.984431   0.383402 10.3923 4.5575e-14  3.213126   4.755736</code></pre>
 <div class="sourceCode" id="cb36"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="../../reference/endpoints.html">endpoints</a></span><span class="op">(</span><span class="va">m.Z.FOCUS</span><span class="op">)</span></code></pre></div>
@@ -255,9 +254,9 @@
 ## $distimes
 ##        DT50    DT90
 ## Z0  0.31288  1.0394
-## Z1  1.44916  4.8140
+## Z1  1.44917  4.8141
 ## Z2  1.53478  5.0984
-## Z3 11.80983 39.2314</code></pre>
+## Z3 11.80986 39.2315</code></pre>
 <p>This fit corresponds to the final result chosen in Appendix 7 of the FOCUS report. Confidence intervals returned by mkin are based on internally transformed parameters, however.</p>
 </div>
 <div id="using-the-sforb-model" class="section level1">
@@ -353,13 +352,13 @@
 ## 
 ## $SFORB
 ##     Z0_b1     Z0_b2     Z3_b1     Z3_b2 
-## 2.4471371 0.0075126 0.0800070 0.0000000 
+## 2.4471322 0.0075125 0.0800069 0.0000000 
 ## 
 ## $distimes
 ##      DT50   DT90 DT50back DT50_Z0_b1 DT50_Z0_b2 DT50_Z3_b1 DT50_Z3_b2
-## Z0 0.3043 1.1848  0.35666    0.28325     92.265         NA         NA
+## Z0 0.3043 1.1848  0.35666    0.28325     92.266         NA         NA
 ## Z1 1.5148 5.0320       NA         NA         NA         NA         NA
-## Z2 1.6414 5.4525       NA         NA         NA         NA         NA
+## Z2 1.6414 5.4526       NA         NA         NA         NA         NA
 ## Z3     NA     NA       NA         NA         NA     8.6636        Inf</code></pre>
 <p>It is clear the degradation rate of Z3 towards the end of the experiment is very low as DT50_Z3_b2 (the second Eigenvalue of the system of two differential equations representing the SFORB system for Z3, corresponding to the slower rate constant of the DFOP model) is reported to be infinity. However, this appears to be a feature of the data.</p>
 </div>
@@ -367,9 +366,9 @@
 <h1 class="hasAnchor">
 <a href="#references" class="anchor"></a>References</h1>
 <!-- vim: set foldmethod=syntax: -->
-<div id="refs" class="references">
+<div id="refs" class="references hanging-indent">
 <div id="ref-FOCUSkinetics2014">
-<p>FOCUS Work Group on Degradation Kinetics. 2014. <em>Generic Guidance for Estimating Persistence and Degradation Kinetics from Environmental Fate Studies on Pesticides in Eu Registration</em>. 1.1 ed. <a href="http://esdac.jrc.ec.europa.eu/projects/degradation-kinetics" class="uri">http://esdac.jrc.ec.europa.eu/projects/degradation-kinetics</a>.</p>
+<p>FOCUS Work Group on Degradation Kinetics. 2014. <em>Generic Guidance for Estimating Persistence and Degradation Kinetics from Environmental Fate Studies on Pesticides in Eu Registration</em>. 1.1 ed. <a href="http://esdac.jrc.ec.europa.eu/projects/degradation-kinetics">http://esdac.jrc.ec.europa.eu/projects/degradation-kinetics</a>.</p>
 </div>
 </div>
 </div>
diff --git a/docs/dev/articles/web_only/FOCUS_Z_files/accessible-code-block-0.0.1/empty-anchor.js b/docs/dev/articles/web_only/FOCUS_Z_files/accessible-code-block-0.0.1/empty-anchor.js
new file mode 100644
index 00000000..ca349fd6
--- /dev/null
+++ b/docs/dev/articles/web_only/FOCUS_Z_files/accessible-code-block-0.0.1/empty-anchor.js
@@ -0,0 +1,15 @@
+// Hide empty <a> tag within highlighted CodeBlock for screen reader accessibility (see https://github.com/jgm/pandoc/issues/6352#issuecomment-626106786) -->
+// v0.0.1
+// Written by JooYoung Seo (jooyoung@psu.edu) and Atsushi Yasumoto on June 1st, 2020.
+
+document.addEventListener('DOMContentLoaded', function() {
+  const codeList = document.getElementsByClassName("sourceCode");
+  for (var i = 0; i < codeList.length; i++) {
+    var linkList = codeList[i].getElementsByTagName('a');
+    for (var j = 0; j < linkList.length; j++) {
+      if (linkList[j].innerHTML === "") {
+        linkList[j].setAttribute('aria-hidden', 'true');
+      }
+    }
+  }
+});
diff --git a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_1-1.png b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_1-1.png
index 575def46..2213c446 100644
Binary files a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_1-1.png and b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_1-1.png differ
diff --git a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_10-1.png b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_10-1.png
index 22305ab1..61b04d3a 100644
Binary files a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_10-1.png and b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_10-1.png differ
diff --git a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_11-1.png b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_11-1.png
index 2213f493..409f1203 100644
Binary files a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_11-1.png and b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_11-1.png differ
diff --git a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_11a-1.png b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_11a-1.png
index fc5e5556..4d6820cd 100644
Binary files a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_11a-1.png and b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_11a-1.png differ
diff --git a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_11b-1.png b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_11b-1.png
index 5c29341c..2e504961 100644
Binary files a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_11b-1.png and b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_11b-1.png differ
diff --git a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_2-1.png b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_2-1.png
index 575def46..2213c446 100644
Binary files a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_2-1.png and b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_2-1.png differ
diff --git a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_3-1.png b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_3-1.png
index 98ce34a7..7ab743af 100644
Binary files a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_3-1.png and b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_3-1.png differ
diff --git a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_5-1.png b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_5-1.png
index d04a411e..2e0dce77 100644
Binary files a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_5-1.png and b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_5-1.png differ
diff --git a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_6-1.png b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_6-1.png
index 29a74490..458299c1 100644
Binary files a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_6-1.png and b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_6-1.png differ
diff --git a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_7-1.png b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_7-1.png
index 0acfa2a4..eb833066 100644
Binary files a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_7-1.png and b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_7-1.png differ
diff --git a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_9-1.png b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_9-1.png
index ca191b00..e7501cbb 100644
Binary files a/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_9-1.png and b/docs/dev/articles/web_only/FOCUS_Z_files/figure-html/FOCUS_2006_Z_fits_9-1.png differ
diff --git a/docs/dev/articles/web_only/FOCUS_Z_files/header-attrs-2.6/header-attrs.js b/docs/dev/articles/web_only/FOCUS_Z_files/header-attrs-2.6/header-attrs.js
new file mode 100644
index 00000000..dd57d92e
--- /dev/null
+++ b/docs/dev/articles/web_only/FOCUS_Z_files/header-attrs-2.6/header-attrs.js
@@ -0,0 +1,12 @@
+// Pandoc 2.9 adds attributes on both header and div. We remove the former (to
+// be compatible with the behavior of Pandoc < 2.8).
+document.addEventListener('DOMContentLoaded', function(e) {
+  var hs = document.querySelectorAll("div.section[class*='level'] > :first-child");
+  var i, h, a;
+  for (i = 0; i < hs.length; i++) {
+    h = hs[i];
+    if (!/^h[1-6]$/i.test(h.tagName)) continue;  // it should be a header h1-h6
+    a = h.attributes;
+    while (a.length > 0) h.removeAttribute(a[0].name);
+  }
+});
diff --git a/docs/dev/articles/web_only/NAFTA_examples.html b/docs/dev/articles/web_only/NAFTA_examples.html
index fca15672..b9784415 100644
--- a/docs/dev/articles/web_only/NAFTA_examples.html
+++ b/docs/dev/articles/web_only/NAFTA_examples.html
@@ -32,7 +32,7 @@
       </button>
       <span class="navbar-brand">
         <a class="navbar-link" href="../../index.html">mkin</a>
-        <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">0.9.50.4</span>
+        <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.3.9000</span>
       </span>
     </div>
 
@@ -81,7 +81,7 @@
 <ul class="nav navbar-nav navbar-right">
 <li>
   <a href="https://github.com/jranke/mkin/">
-    <span class="fab fa fab fa-github fa-lg"></span>
+    <span class="fab fa-github fa-lg"></span>
      
   </a>
 </li>
@@ -95,14 +95,13 @@
 
       
 
-      </header><link href="NAFTA_examples_files/anchor-sections-1.0/anchor-sections.css" rel="stylesheet">
-<script src="NAFTA_examples_files/anchor-sections-1.0/anchor-sections.js"></script><div class="row">
+      </header><script src="NAFTA_examples_files/header-attrs-2.6/header-attrs.js"></script><script src="NAFTA_examples_files/accessible-code-block-0.0.1/empty-anchor.js"></script><div class="row">
   <div class="col-md-9 contents">
     <div class="page-header toc-ignore">
       <h1 data-toc-skip>Evaluation of example datasets from Attachment 1 to the US EPA SOP for the NAFTA guidance</h1>
                         <h4 class="author">Johannes Ranke</h4>
             
-            <h4 class="date">2020-11-30</h4>
+            <h4 class="date">26 February 2019 (rebuilt 2021-02-15)</h4>
       
       <small class="dont-index">Source: <a href="https://github.com/jranke/mkin/blob/master/vignettes/web_only/NAFTA_examples.rmd"><code>vignettes/web_only/NAFTA_examples.rmd</code></a></small>
       <div class="hidden name"><code>NAFTA_examples.rmd</code></div>
@@ -158,7 +157,7 @@
 ##          Estimate   Pr(&gt;t)   Lower    Upper
 ## parent_0 9.99e+01 1.41e-26 98.8116 101.0810
 ## k1       2.67e-02 5.05e-06  0.0243   0.0295
-## k2       2.42e-12 5.00e-01  0.0000      Inf
+## k2       2.26e-12 5.00e-01  0.0000      Inf
 ## g        6.47e-01 3.67e-06  0.6248   0.6677
 ## sigma    1.27e+00 8.91e-06  0.8395   1.6929
 ## 
@@ -167,7 +166,7 @@
 ##      DT50     DT90 DT50_rep
 ## SFO  67.7 2.25e+02 6.77e+01
 ## IORE 58.2 1.07e+03 3.22e+02
-## DFOP 55.5 5.22e+11 2.86e+11
+## DFOP 55.5 5.59e+11 3.07e+11
 ## 
 ## Representative half-life:
 ## [1] 321.51</code></pre>
@@ -209,7 +208,7 @@
 ##          Estimate   Pr(&gt;t)   Lower   Upper
 ## parent_0 9.84e+01 1.24e-27 97.8078 98.9187
 ## k1       1.55e-02 4.10e-04  0.0143  0.0167
-## k2       1.10e-11 5.00e-01  0.0000     Inf
+## k2       8.63e-12 5.00e-01  0.0000     Inf
 ## g        6.89e-01 2.92e-03  0.6626  0.7142
 ## sigma    6.48e-01 2.38e-05  0.4147  0.8813
 ## 
@@ -218,7 +217,7 @@
 ##      DT50     DT90 DT50_rep
 ## SFO  86.6 2.88e+02 8.66e+01
 ## IORE 85.5 7.17e+02 2.16e+02
-## DFOP 83.6 1.03e+11 6.29e+10
+## DFOP 83.6 1.32e+11 8.04e+10
 ## 
 ## Representative half-life:
 ## [1] 215.87</code></pre>
@@ -260,7 +259,7 @@
 ##          Estimate   Pr(&gt;t)   Lower   Upper
 ## parent_0 9.66e+01 1.57e-25 95.3476 97.8979
 ## k1       2.55e-02 7.33e-06  0.0233  0.0278
-## k2       3.60e-11 5.00e-01  0.0000     Inf
+## k2       3.22e-11 5.00e-01  0.0000     Inf
 ## g        8.61e-01 7.55e-06  0.8314  0.8867
 ## sigma    1.46e+00 6.93e-06  0.9661  1.9483
 ## 
@@ -269,7 +268,7 @@
 ##      DT50     DT90 DT50_rep
 ## SFO  38.6 1.28e+02 3.86e+01
 ## IORE 34.0 1.77e+02 5.32e+01
-## DFOP 34.1 9.07e+09 1.93e+10
+## DFOP 34.1 1.01e+10 2.15e+10
 ## 
 ## Representative half-life:
 ## [1] 53.17</code></pre>
@@ -311,7 +310,7 @@
 ##          Estimate   Pr(&gt;t)   Lower    Upper
 ## parent_0 9.89e+01 9.44e-49 95.4640 102.2573
 ## k1       1.81e-02 1.75e-01  0.0116   0.0281
-## k2       2.89e-10 5.00e-01  0.0000      Inf
+## k2       3.63e-10 5.00e-01  0.0000      Inf
 ## g        6.06e-01 2.19e-01  0.4826   0.7178
 ## sigma    7.40e+00 2.97e-15  6.0201   8.7754
 ## 
@@ -320,7 +319,7 @@
 ##      DT50     DT90 DT50_rep
 ## SFO  94.3 3.13e+02 9.43e+01
 ## IORE 96.7 1.51e+03 4.55e+02
-## DFOP 96.4 4.75e+09 2.40e+09
+## DFOP 96.4 3.77e+09 1.91e+09
 ## 
 ## Representative half-life:
 ## [1] 454.55</code></pre>
@@ -422,7 +421,7 @@
 ##          Estimate   Pr(&gt;t)  Lower  Upper
 ## parent_0 9.85e+01 2.54e-20 97.390 99.672
 ## k1       1.38e-01 3.52e-05  0.131  0.146
-## k2       9.03e-13 5.00e-01  0.000    Inf
+## k2       9.02e-13 5.00e-01  0.000    Inf
 ## g        6.52e-01 8.13e-06  0.642  0.661
 ## sigma    7.88e-01 6.13e-02  0.481  1.095
 ## 
@@ -431,7 +430,7 @@
 ##      DT50     DT90 DT50_rep
 ## SFO  16.9 5.63e+01 1.69e+01
 ## IORE 11.6 3.37e+02 1.01e+02
-## DFOP 10.5 1.38e+12 7.67e+11
+## DFOP 10.5 1.38e+12 7.69e+11
 ## 
 ## Representative half-life:
 ## [1] 101.43</code></pre>
@@ -443,15 +442,16 @@
 <div class="sourceCode" id="cb37"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">p9b</span> <span class="op">&lt;-</span> <span class="fu"><a href="../../reference/nafta.html">nafta</a></span><span class="op">(</span><span class="va">NAFTA_SOP_Attachment</span><span class="op">[[</span><span class="st">"p9b"</span><span class="op">]</span><span class="op">]</span><span class="op">)</span></code></pre></div>
 <pre><code>## Warning in sqrt(diag(covar)): NaNs produced</code></pre>
+<pre><code>## Warning in sqrt(diag(covar_notrans)): NaNs produced</code></pre>
 <pre><code>## Warning in sqrt(1/diag(V)): NaNs produced</code></pre>
 <pre><code>## Warning in cov2cor(ans$covar): diag(.) had 0 or NA entries; non-finite result is
 ## doubtful</code></pre>
 <pre><code>## The SFO model is rejected as S_SFO is equal or higher than the critical value S_c</code></pre>
 <pre><code>## The half-life obtained from the IORE model may be used</code></pre>
-<div class="sourceCode" id="cb43"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb44"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">p9b</span><span class="op">)</span></code></pre></div>
 <p><img src="NAFTA_examples_files/figure-html/p9b-1.png" width="700"></p>
-<div class="sourceCode" id="cb44"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb45"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/base/print.html">print</a></span><span class="op">(</span><span class="va">p9b</span><span class="op">)</span></code></pre></div>
 <pre><code>## Sums of squares:
 ##      SFO     IORE     DFOP 
@@ -475,12 +475,12 @@
 ## sigma             1.288 1.76e-04  0.7456  1.830
 ## 
 ## $DFOP
-##          Estimate Pr(&gt;t)   Lower   Upper
-## parent_0  94.7123     NA 93.1355 96.2891
-## k1         0.0389     NA  0.0266  0.0569
-## k2         0.0389     NA  0.0255  0.0592
-## g          0.5256     NA      NA      NA
-## sigma      1.5957     NA  0.9135  2.2779
+##          Estimate   Pr(&gt;t)   Lower   Upper
+## parent_0  94.7123 1.61e-16 93.1355 96.2891
+## k1         0.0389 1.08e-04  0.0266  0.0569
+## k2         0.0389 2.23e-04  0.0255  0.0592
+## g          0.5256      NaN      NA      NA
+## sigma      1.5957 2.50e-04  0.9135  2.2779
 ## 
 ## 
 ## DTx values:
@@ -496,15 +496,18 @@
 <div id="example-on-page-10" class="section level2">
 <h2 class="hasAnchor">
 <a href="#example-on-page-10" class="anchor"></a>Example on page 10</h2>
-<div class="sourceCode" id="cb46"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb47"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">p10</span> <span class="op">&lt;-</span> <span class="fu"><a href="../../reference/nafta.html">nafta</a></span><span class="op">(</span><span class="va">NAFTA_SOP_Attachment</span><span class="op">[[</span><span class="st">"p10"</span><span class="op">]</span><span class="op">]</span><span class="op">)</span></code></pre></div>
-<pre><code>## Warning in sqrt(diag(covar_notrans)): NaNs produced</code></pre>
+<pre><code>## Warning in sqrt(diag(covar)): NaNs produced</code></pre>
+<pre><code>## Warning in sqrt(1/diag(V)): NaNs produced</code></pre>
+<pre><code>## Warning in cov2cor(ans$covar): diag(.) had 0 or NA entries; non-finite result is
+## doubtful</code></pre>
 <pre><code>## The SFO model is rejected as S_SFO is equal or higher than the critical value S_c</code></pre>
 <pre><code>## The half-life obtained from the IORE model may be used</code></pre>
-<div class="sourceCode" id="cb50"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb53"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">p10</span><span class="op">)</span></code></pre></div>
 <p><img src="NAFTA_examples_files/figure-html/p10-1.png" width="700"></p>
-<div class="sourceCode" id="cb51"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb54"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/base/print.html">print</a></span><span class="op">(</span><span class="va">p10</span><span class="op">)</span></code></pre></div>
 <pre><code>## Sums of squares:
 ##      SFO     IORE     DFOP 
@@ -530,9 +533,9 @@
 ## $DFOP
 ##          Estimate   Pr(&gt;t)   Lower    Upper
 ## parent_0 101.7315 1.41e-09 91.6534 111.8097
-## k1         0.0495 5.63e-03  0.0240   0.1020
-## k2         0.0495 1.93e-03  0.0272   0.0903
-## g          0.4487      NaN  0.0000   1.0000
+## k1         0.0495 6.58e-03  0.0303   0.0809
+## k2         0.0495 2.60e-03  0.0410   0.0598
+## g          0.4487 5.00e-01      NA       NA
 ## sigma      8.0152 2.50e-04  4.5886  11.4418
 ## 
 ## 
@@ -553,14 +556,14 @@
 <div id="example-on-page-11" class="section level2">
 <h2 class="hasAnchor">
 <a href="#example-on-page-11" class="anchor"></a>Example on page 11</h2>
-<div class="sourceCode" id="cb53"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb56"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">p11</span> <span class="op">&lt;-</span> <span class="fu"><a href="../../reference/nafta.html">nafta</a></span><span class="op">(</span><span class="va">NAFTA_SOP_Attachment</span><span class="op">[[</span><span class="st">"p11"</span><span class="op">]</span><span class="op">]</span><span class="op">)</span></code></pre></div>
 <pre><code>## The SFO model is rejected as S_SFO is equal or higher than the critical value S_c</code></pre>
 <pre><code>## The half-life obtained from the IORE model may be used</code></pre>
-<div class="sourceCode" id="cb56"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb59"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">p11</span><span class="op">)</span></code></pre></div>
 <p><img src="NAFTA_examples_files/figure-html/p11-1.png" width="700"></p>
-<div class="sourceCode" id="cb57"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb60"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/base/print.html">print</a></span><span class="op">(</span><span class="va">p11</span><span class="op">)</span></code></pre></div>
 <pre><code>## Sums of squares:
 ##      SFO     IORE     DFOP 
@@ -596,10 +599,10 @@
 ##          DT50     DT90 DT50_rep
 ## SFO  2.16e+02 7.18e+02 2.16e+02
 ## IORE 9.73e+02 1.37e+08 4.11e+07
-## DFOP 3.07e+11 1.93e+12 6.97e+11
+## DFOP 3.07e+11 1.93e+12 6.98e+11
 ## 
 ## Representative half-life:
-## [1] 41148171</code></pre>
+## [1] 41148170</code></pre>
 <p>In this case, the DFOP fit reported for PestDF resulted in a negative value for the slower rate constant, which is not possible in mkin. The other results are in agreement.</p>
 </div>
 </div>
@@ -610,19 +613,21 @@
 <div id="example-on-page-12-upper-panel" class="section level2">
 <h2 class="hasAnchor">
 <a href="#example-on-page-12-upper-panel" class="anchor"></a>Example on page 12, upper panel</h2>
-<div class="sourceCode" id="cb59"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb62"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">p12a</span> <span class="op">&lt;-</span> <span class="fu"><a href="../../reference/nafta.html">nafta</a></span><span class="op">(</span><span class="va">NAFTA_SOP_Attachment</span><span class="op">[[</span><span class="st">"p12a"</span><span class="op">]</span><span class="op">]</span><span class="op">)</span></code></pre></div>
 <pre><code>## Warning in summary.mkinfit(x): Could not calculate correlation; no covariance
-## matrix
-
-## Warning in summary.mkinfit(x): Could not calculate correlation; no covariance
 ## matrix</code></pre>
+<pre><code>## Warning in sqrt(diag(covar)): NaNs produced</code></pre>
+<pre><code>## Warning in sqrt(diag(covar_notrans)): NaNs produced</code></pre>
+<pre><code>## Warning in sqrt(1/diag(V)): NaNs produced</code></pre>
+<pre><code>## Warning in cov2cor(ans$covar): diag(.) had 0 or NA entries; non-finite result is
+## doubtful</code></pre>
 <pre><code>## The SFO model is rejected as S_SFO is equal or higher than the critical value S_c</code></pre>
 <pre><code>## The half-life obtained from the IORE model may be used</code></pre>
-<div class="sourceCode" id="cb63"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb70"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">p12a</span><span class="op">)</span></code></pre></div>
 <p><img src="NAFTA_examples_files/figure-html/p12a-1.png" width="700"></p>
-<div class="sourceCode" id="cb64"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb71"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/base/print.html">print</a></span><span class="op">(</span><span class="va">p12a</span><span class="op">)</span></code></pre></div>
 <pre><code>## Sums of squares:
 ##      SFO     IORE     DFOP 
@@ -646,12 +651,12 @@
 ## sigma             3.965     NA    NA    NA
 ## 
 ## $DFOP
-##          Estimate   Pr(&gt;t) Lower Upper
-## parent_0  100.521 2.74e-10    NA    NA
-## k1          0.124 2.53e-05    NA    NA
-## k2          0.124 2.52e-02    NA    NA
-## g           0.793 5.00e-01    NA    NA
-## sigma       7.048 2.50e-04    NA    NA
+##          Estimate   Pr(&gt;t)   Lower   Upper
+## parent_0  100.521 2.74e-10 92.2366 108.805
+## k1          0.124 2.53e-05  0.0908   0.170
+## k2          0.124 2.52e-02  0.0456   0.339
+## g           0.793      NaN      NA      NA
+## sigma       7.048 2.50e-04  4.0349  10.061
 ## 
 ## 
 ## DTx values:
@@ -666,20 +671,18 @@
 <div id="example-on-page-12-lower-panel" class="section level2">
 <h2 class="hasAnchor">
 <a href="#example-on-page-12-lower-panel" class="anchor"></a>Example on page 12, lower panel</h2>
-<div class="sourceCode" id="cb66"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb73"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">p12b</span> <span class="op">&lt;-</span> <span class="fu"><a href="../../reference/nafta.html">nafta</a></span><span class="op">(</span><span class="va">NAFTA_SOP_Attachment</span><span class="op">[[</span><span class="st">"p12b"</span><span class="op">]</span><span class="op">]</span><span class="op">)</span></code></pre></div>
-<pre><code>## Warning in sqrt(diag(covar)): NaNs produced</code></pre>
 <pre><code>## Warning in qt(alpha/2, rdf): NaNs produced</code></pre>
 <pre><code>## Warning in qt(1 - alpha/2, rdf): NaNs produced</code></pre>
-<pre><code>## Warning in sqrt(1/diag(V)): NaNs produced</code></pre>
-<pre><code>## Warning in cov2cor(ans$covar): diag(.) had 0 or NA entries; non-finite result is
-## doubtful</code></pre>
+<pre><code>## Warning in sqrt(diag(covar_notrans)): NaNs produced</code></pre>
+<pre><code>## Warning in pt(abs(tval), rdf, lower.tail = FALSE): NaNs produced</code></pre>
 <pre><code>## The SFO model is rejected as S_SFO is equal or higher than the critical value S_c</code></pre>
 <pre><code>## The half-life obtained from the IORE model may be used</code></pre>
-<div class="sourceCode" id="cb74"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb80"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">p12b</span><span class="op">)</span></code></pre></div>
 <p><img src="NAFTA_examples_files/figure-html/p12b-1.png" width="700"></p>
-<div class="sourceCode" id="cb75"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb81"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/base/print.html">print</a></span><span class="op">(</span><span class="va">p12b</span><span class="op">)</span></code></pre></div>
 <pre><code>## Sums of squares:
 ##      SFO     IORE     DFOP 
@@ -704,11 +707,11 @@
 ## 
 ## $DFOP
 ##          Estimate Pr(&gt;t) Lower Upper
-## parent_0  97.6840     NA   NaN   NaN
-## k1         0.0589     NA    NA    NA
-## k2         0.0589     NA    NA    NA
-## g          0.6473     NA    NA    NA
-## sigma      3.4323     NA   NaN   NaN
+## parent_0  97.6840    NaN   NaN   NaN
+## k1         0.0589    NaN    NA    NA
+## k2         0.0589    NaN    NA    NA
+## g          0.6473    NaN    NA    NA
+## sigma      3.4323    NaN   NaN   NaN
 ## 
 ## 
 ## DTx values:
@@ -723,18 +726,14 @@
 <div id="example-on-page-13" class="section level2">
 <h2 class="hasAnchor">
 <a href="#example-on-page-13" class="anchor"></a>Example on page 13</h2>
-<div class="sourceCode" id="cb77"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb83"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">p13</span> <span class="op">&lt;-</span> <span class="fu"><a href="../../reference/nafta.html">nafta</a></span><span class="op">(</span><span class="va">NAFTA_SOP_Attachment</span><span class="op">[[</span><span class="st">"p13"</span><span class="op">]</span><span class="op">]</span><span class="op">)</span></code></pre></div>
-<pre><code>## Warning in sqrt(diag(covar)): NaNs produced</code></pre>
-<pre><code>## Warning in sqrt(1/diag(V)): NaNs produced</code></pre>
-<pre><code>## Warning in cov2cor(ans$covar): diag(.) had 0 or NA entries; non-finite result is
-## doubtful</code></pre>
 <pre><code>## The SFO model is rejected as S_SFO is equal or higher than the critical value S_c</code></pre>
 <pre><code>## The half-life obtained from the IORE model may be used</code></pre>
-<div class="sourceCode" id="cb83"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb86"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">p13</span><span class="op">)</span></code></pre></div>
 <p><img src="NAFTA_examples_files/figure-html/p13-1.png" width="700"></p>
-<div class="sourceCode" id="cb84"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb87"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/base/print.html">print</a></span><span class="op">(</span><span class="va">p13</span><span class="op">)</span></code></pre></div>
 <pre><code>## Sums of squares:
 ##      SFO     IORE     DFOP 
@@ -760,9 +759,9 @@
 ## $DFOP
 ##          Estimate Pr(&gt;t)    Lower    Upper
 ## parent_0 92.73500     NA 8.95e+01 95.92118
-## k1        0.00258     NA 4.25e-04  0.01569
-## k2        0.00258     NA 1.76e-03  0.00379
-## g         0.16452     NA       NA       NA
+## k1        0.00258     NA 4.14e-04  0.01611
+## k2        0.00258     NA 1.74e-03  0.00383
+## g         0.16452     NA 0.00e+00  1.00000
 ## sigma     3.41172     NA 2.02e+00  4.79960
 ## 
 ## 
@@ -779,7 +778,7 @@
 <div id="dt50-not-observed-in-the-study-and-dfop-problems-in-pestdf" class="section level1">
 <h1 class="hasAnchor">
 <a href="#dt50-not-observed-in-the-study-and-dfop-problems-in-pestdf" class="anchor"></a>DT50 not observed in the study and DFOP problems in PestDF</h1>
-<div class="sourceCode" id="cb86"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb89"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">p14</span> <span class="op">&lt;-</span> <span class="fu"><a href="../../reference/nafta.html">nafta</a></span><span class="op">(</span><span class="va">NAFTA_SOP_Attachment</span><span class="op">[[</span><span class="st">"p14"</span><span class="op">]</span><span class="op">]</span><span class="op">)</span></code></pre></div>
 <pre><code>## Warning in sqrt(diag(covar)): NaNs produced</code></pre>
 <pre><code>## Warning in sqrt(1/diag(V)): NaNs produced</code></pre>
@@ -787,10 +786,10 @@
 ## doubtful</code></pre>
 <pre><code>## The SFO model is rejected as S_SFO is equal or higher than the critical value S_c</code></pre>
 <pre><code>## The half-life obtained from the IORE model may be used</code></pre>
-<div class="sourceCode" id="cb92"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb95"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">p14</span><span class="op">)</span></code></pre></div>
 <p><img src="NAFTA_examples_files/figure-html/p14-1.png" width="700"></p>
-<div class="sourceCode" id="cb93"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb96"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/base/print.html">print</a></span><span class="op">(</span><span class="va">p14</span><span class="op">)</span></code></pre></div>
 <pre><code>## Sums of squares:
 ##      SFO     IORE     DFOP 
@@ -817,7 +816,7 @@
 ##          Estimate   Pr(&gt;t)    Lower    Upper
 ## parent_0 1.00e+02 2.96e-28 99.40280 101.2768
 ## k1       9.53e-03 1.20e-01  0.00638   0.0143
-## k2       5.33e-12 5.00e-01  0.00000      Inf
+## k2       6.08e-12 5.00e-01  0.00000      Inf
 ## g        3.98e-01 2.19e-01  0.30481   0.4998
 ## sigma    1.17e+00 7.68e-06  0.77406   1.5610
 ## 
@@ -826,7 +825,7 @@
 ##          DT50     DT90 DT50_rep
 ## SFO  2.48e+02 8.25e+02 2.48e+02
 ## IORE 4.34e+02 2.22e+04 6.70e+03
-## DFOP 3.48e+10 3.37e+11 1.30e+11
+## DFOP 3.05e+10 2.95e+11 1.14e+11
 ## 
 ## Representative half-life:
 ## [1] 6697.44</code></pre>
@@ -835,14 +834,14 @@
 <div id="n-is-less-than-1-and-dfop-fraction-parameter-is-below-zero" class="section level1">
 <h1 class="hasAnchor">
 <a href="#n-is-less-than-1-and-dfop-fraction-parameter-is-below-zero" class="anchor"></a>N is less than 1 and DFOP fraction parameter is below zero</h1>
-<div class="sourceCode" id="cb95"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb98"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">p15a</span> <span class="op">&lt;-</span> <span class="fu"><a href="../../reference/nafta.html">nafta</a></span><span class="op">(</span><span class="va">NAFTA_SOP_Attachment</span><span class="op">[[</span><span class="st">"p15a"</span><span class="op">]</span><span class="op">]</span><span class="op">)</span></code></pre></div>
 <pre><code>## The SFO model is rejected as S_SFO is equal or higher than the critical value S_c</code></pre>
 <pre><code>## The half-life obtained from the IORE model may be used</code></pre>
-<div class="sourceCode" id="cb98"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb101"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">p15a</span><span class="op">)</span></code></pre></div>
 <p><img src="NAFTA_examples_files/figure-html/p15a-1.png" width="700"></p>
-<div class="sourceCode" id="cb99"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb102"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/base/print.html">print</a></span><span class="op">(</span><span class="va">p15a</span><span class="op">)</span></code></pre></div>
 <pre><code>## Sums of squares:
 ##      SFO     IORE     DFOP 
@@ -866,12 +865,12 @@
 ## sigma             3.105 1.78e-04  1.795  4.416
 ## 
 ## $DFOP
-##          Estimate Pr(&gt;t)    Lower    Upper
-## parent_0 97.96751     NA 94.21913 101.7159
-## k1        0.00952     NA  0.00221   0.0411
-## k2        0.00952     NA  0.00626   0.0145
-## g         0.21241     NA  0.00000   1.0000
-## sigma     4.18778     NA  2.39747   5.9781
+##          Estimate   Pr(&gt;t)    Lower    Upper
+## parent_0 97.96751 2.85e-13 94.21913 101.7159
+## k1        0.00952 6.28e-02  0.00250   0.0363
+## k2        0.00952 1.27e-04  0.00646   0.0140
+## g         0.21241 5.00e-01  0.00000   1.0000
+## sigma     4.18778 2.50e-04  2.39747   5.9781
 ## 
 ## 
 ## DTx values:
@@ -882,7 +881,7 @@
 ## 
 ## Representative half-life:
 ## [1] 41.33</code></pre>
-<div class="sourceCode" id="cb101"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb104"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">p15b</span> <span class="op">&lt;-</span> <span class="fu"><a href="../../reference/nafta.html">nafta</a></span><span class="op">(</span><span class="va">NAFTA_SOP_Attachment</span><span class="op">[[</span><span class="st">"p15b"</span><span class="op">]</span><span class="op">]</span><span class="op">)</span></code></pre></div>
 <pre><code>## Warning in sqrt(diag(covar)): NaNs produced</code></pre>
 <pre><code>## Warning in sqrt(1/diag(V)): NaNs produced</code></pre>
@@ -890,10 +889,10 @@
 ## doubtful</code></pre>
 <pre><code>## The SFO model is rejected as S_SFO is equal or higher than the critical value S_c</code></pre>
 <pre><code>## The half-life obtained from the IORE model may be used</code></pre>
-<div class="sourceCode" id="cb107"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb110"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">p15b</span><span class="op">)</span></code></pre></div>
 <p><img src="NAFTA_examples_files/figure-html/p15b-1.png" width="700"></p>
-<div class="sourceCode" id="cb108"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb111"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/base/print.html">print</a></span><span class="op">(</span><span class="va">p15b</span><span class="op">)</span></code></pre></div>
 <pre><code>## Sums of squares:
 ##       SFO      IORE      DFOP 
@@ -911,7 +910,7 @@
 ## 
 ## $IORE
 ##                Estimate   Pr(&gt;t)    Lower  Upper
-## parent_0          99.83 1.81e-16 97.51348 102.14
+## parent_0          99.83 1.81e-16 97.51349 102.14
 ## k__iore_parent     0.38 3.22e-01  0.00352  41.05
 ## N_parent           0.00 5.00e-01 -1.07696   1.08
 ## sigma              2.21 2.57e-04  1.23245   3.19
@@ -938,16 +937,16 @@
 <div id="the-dfop-fraction-parameter-is-greater-than-1" class="section level1">
 <h1 class="hasAnchor">
 <a href="#the-dfop-fraction-parameter-is-greater-than-1" class="anchor"></a>The DFOP fraction parameter is greater than 1</h1>
-<div class="sourceCode" id="cb110"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb113"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">p16</span> <span class="op">&lt;-</span> <span class="fu"><a href="../../reference/nafta.html">nafta</a></span><span class="op">(</span><span class="va">NAFTA_SOP_Attachment</span><span class="op">[[</span><span class="st">"p16"</span><span class="op">]</span><span class="op">]</span><span class="op">)</span></code></pre></div>
 <pre><code>## The SFO model is rejected as S_SFO is equal or higher than the critical value S_c</code></pre>
 <pre><code>## The representative half-life of the IORE model is longer than the one corresponding</code></pre>
 <pre><code>## to the terminal degradation rate found with the DFOP model.</code></pre>
 <pre><code>## The representative half-life obtained from the DFOP model may be used</code></pre>
-<div class="sourceCode" id="cb115"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb118"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">p16</span><span class="op">)</span></code></pre></div>
 <p><img src="NAFTA_examples_files/figure-html/p16-1.png" width="700"></p>
-<div class="sourceCode" id="cb116"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb119"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/base/print.html">print</a></span><span class="op">(</span><span class="va">p16</span><span class="op">)</span></code></pre></div>
 <pre><code>## Sums of squares:
 ##      SFO     IORE     DFOP 
@@ -998,7 +997,7 @@
 <div id="references" class="section level1 unnumbered">
 <h1 class="hasAnchor">
 <a href="#references" class="anchor"></a>References</h1>
-<div id="refs" class="references">
+<div id="refs" class="references hanging-indent">
 <div id="ref-usepa2015">
 <p>US EPA. 2015. “Standard Operating Procedure for Using the NAFTA Guidance to Calculate Representative Half-Life Values and Characterizing Pesticide Degradation.”</p>
 </div>
diff --git a/docs/dev/articles/web_only/NAFTA_examples_files/accessible-code-block-0.0.1/empty-anchor.js b/docs/dev/articles/web_only/NAFTA_examples_files/accessible-code-block-0.0.1/empty-anchor.js
new file mode 100644
index 00000000..ca349fd6
--- /dev/null
+++ b/docs/dev/articles/web_only/NAFTA_examples_files/accessible-code-block-0.0.1/empty-anchor.js
@@ -0,0 +1,15 @@
+// Hide empty <a> tag within highlighted CodeBlock for screen reader accessibility (see https://github.com/jgm/pandoc/issues/6352#issuecomment-626106786) -->
+// v0.0.1
+// Written by JooYoung Seo (jooyoung@psu.edu) and Atsushi Yasumoto on June 1st, 2020.
+
+document.addEventListener('DOMContentLoaded', function() {
+  const codeList = document.getElementsByClassName("sourceCode");
+  for (var i = 0; i < codeList.length; i++) {
+    var linkList = codeList[i].getElementsByTagName('a');
+    for (var j = 0; j < linkList.length; j++) {
+      if (linkList[j].innerHTML === "") {
+        linkList[j].setAttribute('aria-hidden', 'true');
+      }
+    }
+  }
+});
diff --git a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p10-1.png b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p10-1.png
index 38b251ea..f5420ce8 100644
Binary files a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p10-1.png and b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p10-1.png differ
diff --git a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p11-1.png b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p11-1.png
index 77463495..0ae4bd9f 100644
Binary files a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p11-1.png and b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p11-1.png differ
diff --git a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p12a-1.png b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p12a-1.png
index ccf8f77a..57a48119 100644
Binary files a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p12a-1.png and b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p12a-1.png differ
diff --git a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p12b-1.png b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p12b-1.png
index 6b0dcaf2..c42d45f0 100644
Binary files a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p12b-1.png and b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p12b-1.png differ
diff --git a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p13-1.png b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p13-1.png
index ce177190..52dea51e 100644
Binary files a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p13-1.png and b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p13-1.png differ
diff --git a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p14-1.png b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p14-1.png
index f2f59ff7..ca1f29be 100644
Binary files a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p14-1.png and b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p14-1.png differ
diff --git a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p15a-1.png b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p15a-1.png
index c5759a5b..f69e6d3b 100644
Binary files a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p15a-1.png and b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p15a-1.png differ
diff --git a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p15b-1.png b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p15b-1.png
index 3640ea68..71fcd257 100644
Binary files a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p15b-1.png and b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p15b-1.png differ
diff --git a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p16-1.png b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p16-1.png
index b61f28e2..820501a3 100644
Binary files a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p16-1.png and b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p16-1.png differ
diff --git a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p5a-1.png b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p5a-1.png
index 8d38b89c..e264d2ea 100644
Binary files a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p5a-1.png and b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p5a-1.png differ
diff --git a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p5b-1.png b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p5b-1.png
index 3f2da285..e5b656a4 100644
Binary files a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p5b-1.png and b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p5b-1.png differ
diff --git a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p6-1.png b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p6-1.png
index 37274769..c9664c77 100644
Binary files a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p6-1.png and b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p6-1.png differ
diff --git a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p7-1.png b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p7-1.png
index 515e9095..a81f814c 100644
Binary files a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p7-1.png and b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p7-1.png differ
diff --git a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p8-1.png b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p8-1.png
index ebcc326c..75d72e7c 100644
Binary files a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p8-1.png and b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p8-1.png differ
diff --git a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p9a-1.png b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p9a-1.png
index a6f4e763..3ce13a97 100644
Binary files a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p9a-1.png and b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p9a-1.png differ
diff --git a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p9b-1.png b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p9b-1.png
index 2a8cf947..e2cf2f83 100644
Binary files a/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p9b-1.png and b/docs/dev/articles/web_only/NAFTA_examples_files/figure-html/p9b-1.png differ
diff --git a/docs/dev/articles/web_only/NAFTA_examples_files/header-attrs-2.6/header-attrs.js b/docs/dev/articles/web_only/NAFTA_examples_files/header-attrs-2.6/header-attrs.js
new file mode 100644
index 00000000..dd57d92e
--- /dev/null
+++ b/docs/dev/articles/web_only/NAFTA_examples_files/header-attrs-2.6/header-attrs.js
@@ -0,0 +1,12 @@
+// Pandoc 2.9 adds attributes on both header and div. We remove the former (to
+// be compatible with the behavior of Pandoc < 2.8).
+document.addEventListener('DOMContentLoaded', function(e) {
+  var hs = document.querySelectorAll("div.section[class*='level'] > :first-child");
+  var i, h, a;
+  for (i = 0; i < hs.length; i++) {
+    h = hs[i];
+    if (!/^h[1-6]$/i.test(h.tagName)) continue;  // it should be a header h1-h6
+    a = h.attributes;
+    while (a.length > 0) h.removeAttribute(a[0].name);
+  }
+});
diff --git a/docs/dev/articles/web_only/benchmarks.html b/docs/dev/articles/web_only/benchmarks.html
index 8e157c0f..a6d52649 100644
--- a/docs/dev/articles/web_only/benchmarks.html
+++ b/docs/dev/articles/web_only/benchmarks.html
@@ -32,7 +32,7 @@
       </button>
       <span class="navbar-brand">
         <a class="navbar-link" href="../../index.html">mkin</a>
-        <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">0.9.50.4</span>
+        <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.3.9000</span>
       </span>
     </div>
 
@@ -81,7 +81,7 @@
 <ul class="nav navbar-nav navbar-right">
 <li>
   <a href="https://github.com/jranke/mkin/">
-    <span class="fab fa fab fa-github fa-lg"></span>
+    <span class="fab fa-github fa-lg"></span>
      
   </a>
 </li>
@@ -95,14 +95,13 @@
 
       
 
-      </header><link href="benchmarks_files/anchor-sections-1.0/anchor-sections.css" rel="stylesheet">
-<script src="benchmarks_files/anchor-sections-1.0/anchor-sections.js"></script><div class="row">
+      </header><script src="benchmarks_files/header-attrs-2.6/header-attrs.js"></script><script src="benchmarks_files/accessible-code-block-0.0.1/empty-anchor.js"></script><div class="row">
   <div class="col-md-9 contents">
     <div class="page-header toc-ignore">
       <h1 data-toc-skip>Benchmark timings for mkin</h1>
                         <h4 class="author">Johannes Ranke</h4>
             
-            <h4 class="date">2020-11-30</h4>
+            <h4 class="date">Last change 13 May 2020 (rebuilt 2021-02-15)</h4>
       
       <small class="dont-index">Source: <a href="https://github.com/jranke/mkin/blob/master/vignettes/web_only/benchmarks.rmd"><code>vignettes/web_only/benchmarks.rmd</code></a></small>
       <div class="hidden name"><code>benchmarks.rmd</code></div>
@@ -137,17 +136,11 @@
   m1 <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFO"</span><span class="op">)</span><span class="op">)</span>
 <span class="va">t3</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/system.time.html">system.time</a></span><span class="op">(</span><span class="fu">mmkin_bench</span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">SFO_SFO</span>, <span class="va">FOMC_SFO</span>, <span class="va">DFOP_SFO</span><span class="op">)</span>, <span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">FOCUS_D</span><span class="op">)</span><span class="op">)</span><span class="op">)</span><span class="op">[[</span><span class="st">"elapsed"</span><span class="op">]</span><span class="op">]</span>
 <span class="va">t4</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/system.time.html">system.time</a></span><span class="op">(</span><span class="fu">mmkin_bench</span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">SFO_SFO</span>, <span class="va">FOMC_SFO</span>, <span class="va">DFOP_SFO</span><span class="op">)</span>, <span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">FOCUS_D</span><span class="op">)</span>,
-    error_model <span class="op">=</span> <span class="st">"tc"</span><span class="op">)</span><span class="op">)</span><span class="op">[[</span><span class="st">"elapsed"</span><span class="op">]</span><span class="op">]</span></code></pre></div>
-<pre><code>## Warning in mkinfit(models[[model_index]], datasets[[dataset_index]], ...): Optimisation did not converge:
-## iteration limit reached without convergence (10)
-
-## Warning in mkinfit(models[[model_index]], datasets[[dataset_index]], ...): Optimisation did not converge:
-## iteration limit reached without convergence (10)</code></pre>
-<div class="sourceCode" id="cb4"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="va">t5</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/system.time.html">system.time</a></span><span class="op">(</span><span class="fu">mmkin_bench</span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">SFO_SFO</span>, <span class="va">FOMC_SFO</span>, <span class="va">DFOP_SFO</span><span class="op">)</span>, <span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">FOCUS_D</span><span class="op">)</span>,
+    error_model <span class="op">=</span> <span class="st">"tc"</span><span class="op">)</span><span class="op">)</span><span class="op">[[</span><span class="st">"elapsed"</span><span class="op">]</span><span class="op">]</span>
+<span class="va">t5</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/system.time.html">system.time</a></span><span class="op">(</span><span class="fu">mmkin_bench</span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">SFO_SFO</span>, <span class="va">FOMC_SFO</span>, <span class="va">DFOP_SFO</span><span class="op">)</span>, <span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">FOCUS_D</span><span class="op">)</span>,
     error_model <span class="op">=</span> <span class="st">"obs"</span><span class="op">)</span><span class="op">)</span><span class="op">[[</span><span class="st">"elapsed"</span><span class="op">]</span><span class="op">]</span></code></pre></div>
 <p>Two metabolites, synthetic data:</p>
-<div class="sourceCode" id="cb5"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb3"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">m_synth_SFO_lin</span> <span class="op">&lt;-</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinmod</a></span><span class="op">(</span>parent <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFO"</span>, <span class="st">"M1"</span><span class="op">)</span>,
                            M1 <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFO"</span>, <span class="st">"M2"</span><span class="op">)</span>,
                            M2 <span class="op">=</span> <span class="fu"><a href="../../reference/mkinmod.html">mkinsub</a></span><span class="op">(</span><span class="st">"SFO"</span><span class="op">)</span>,
@@ -174,7 +167,7 @@
     error_model <span class="op">=</span> <span class="st">"obs"</span><span class="op">)</span><span class="op">)</span><span class="op">[[</span><span class="st">"elapsed"</span><span class="op">]</span><span class="op">]</span>
 <span class="va">t11</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/system.time.html">system.time</a></span><span class="op">(</span><span class="fu">mmkin_bench</span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">m_synth_DFOP_par</span><span class="op">)</span>, <span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">DFOP_par_c</span><span class="op">)</span>,
     error_model <span class="op">=</span> <span class="st">"obs"</span><span class="op">)</span><span class="op">)</span><span class="op">[[</span><span class="st">"elapsed"</span><span class="op">]</span><span class="op">]</span></code></pre></div>
-<div class="sourceCode" id="cb6"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb4"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">mkin_benchmarks</span><span class="op">[</span><span class="va">system_string</span>, <span class="fu"><a href="https://rdrr.io/r/base/paste.html">paste0</a></span><span class="op">(</span><span class="st">"t"</span>, <span class="fl">1</span><span class="op">:</span><span class="fl">11</span><span class="op">)</span><span class="op">]</span> <span class="op">&lt;-</span>
   <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="va">t1</span>, <span class="va">t2</span>, <span class="va">t3</span>, <span class="va">t4</span>, <span class="va">t5</span>, <span class="va">t6</span>, <span class="va">t7</span>, <span class="va">t8</span>, <span class="va">t9</span>, <span class="va">t10</span>, <span class="va">t11</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/r/base/save.html">save</a></span><span class="op">(</span><span class="va">mkin_benchmarks</span>, file <span class="op">=</span> <span class="st">"~/git/mkin/vignettes/web_only/mkin_benchmarks.rda"</span><span class="op">)</span></code></pre></div>
@@ -235,6 +228,16 @@
 <td align="right">1.786</td>
 <td align="right">3.729</td>
 </tr>
+<tr class="odd">
+<td align="left">1.0.3</td>
+<td align="right">1.722</td>
+<td align="right">3.419</td>
+</tr>
+<tr class="even">
+<td align="left">1.0.3.9000</td>
+<td align="right">2.770</td>
+<td align="right">3.458</td>
+</tr>
 </tbody>
 </table>
 </div>
@@ -298,13 +301,25 @@
 <td align="right">7.251</td>
 <td align="right">2.810</td>
 </tr>
+<tr class="odd">
+<td align="left">1.0.3</td>
+<td align="right">1.402</td>
+<td align="right">6.343</td>
+<td align="right">2.802</td>
+</tr>
+<tr class="even">
+<td align="left">1.0.3.9000</td>
+<td align="right">1.405</td>
+<td align="right">6.417</td>
+<td align="right">2.824</td>
+</tr>
 </tbody>
 </table>
 </div>
 <div id="two-metabolites" class="section level3">
 <h3 class="hasAnchor">
 <a href="#two-metabolites" class="anchor"></a>Two metabolites</h3>
-<p>Constant variance (t6 and t7), two-component error model (t8 and t9), and variance by variable (t10 and t11) for one model fitted to one dataset, i.e. one fit for each test.</p>
+<p>Constant variance (t6 and t7), two-component error model (t8 and t9), and variance by variable (t10 and t11) for one model fitted to one dataset, i.e. one fit for each test.</p>
 <table class="table">
 <thead><tr class="header">
 <th align="left">mkin version</th>
@@ -388,6 +403,24 @@
 <td align="right">1.958</td>
 <td align="right">3.105</td>
 </tr>
+<tr class="odd">
+<td align="left">1.0.3</td>
+<td align="right">0.771</td>
+<td align="right">1.251</td>
+<td align="right">1.464</td>
+<td align="right">3.074</td>
+<td align="right">1.940</td>
+<td align="right">2.831</td>
+</tr>
+<tr class="even">
+<td align="left">1.0.3.9000</td>
+<td align="right">0.772</td>
+<td align="right">1.263</td>
+<td align="right">1.483</td>
+<td align="right">3.101</td>
+<td align="right">1.958</td>
+<td align="right">2.843</td>
+</tr>
 </tbody>
 </table>
 </div>
diff --git a/docs/dev/articles/web_only/benchmarks_files/accessible-code-block-0.0.1/empty-anchor.js b/docs/dev/articles/web_only/benchmarks_files/accessible-code-block-0.0.1/empty-anchor.js
new file mode 100644
index 00000000..ca349fd6
--- /dev/null
+++ b/docs/dev/articles/web_only/benchmarks_files/accessible-code-block-0.0.1/empty-anchor.js
@@ -0,0 +1,15 @@
+// Hide empty <a> tag within highlighted CodeBlock for screen reader accessibility (see https://github.com/jgm/pandoc/issues/6352#issuecomment-626106786) -->
+// v0.0.1
+// Written by JooYoung Seo (jooyoung@psu.edu) and Atsushi Yasumoto on June 1st, 2020.
+
+document.addEventListener('DOMContentLoaded', function() {
+  const codeList = document.getElementsByClassName("sourceCode");
+  for (var i = 0; i < codeList.length; i++) {
+    var linkList = codeList[i].getElementsByTagName('a');
+    for (var j = 0; j < linkList.length; j++) {
+      if (linkList[j].innerHTML === "") {
+        linkList[j].setAttribute('aria-hidden', 'true');
+      }
+    }
+  }
+});
diff --git a/docs/dev/articles/web_only/benchmarks_files/header-attrs-2.6/header-attrs.js b/docs/dev/articles/web_only/benchmarks_files/header-attrs-2.6/header-attrs.js
new file mode 100644
index 00000000..dd57d92e
--- /dev/null
+++ b/docs/dev/articles/web_only/benchmarks_files/header-attrs-2.6/header-attrs.js
@@ -0,0 +1,12 @@
+// Pandoc 2.9 adds attributes on both header and div. We remove the former (to
+// be compatible with the behavior of Pandoc < 2.8).
+document.addEventListener('DOMContentLoaded', function(e) {
+  var hs = document.querySelectorAll("div.section[class*='level'] > :first-child");
+  var i, h, a;
+  for (i = 0; i < hs.length; i++) {
+    h = hs[i];
+    if (!/^h[1-6]$/i.test(h.tagName)) continue;  // it should be a header h1-h6
+    a = h.attributes;
+    while (a.length > 0) h.removeAttribute(a[0].name);
+  }
+});
diff --git a/docs/dev/articles/web_only/compiled_models.html b/docs/dev/articles/web_only/compiled_models.html
index a444f4bc..49a579fc 100644
--- a/docs/dev/articles/web_only/compiled_models.html
+++ b/docs/dev/articles/web_only/compiled_models.html
@@ -32,7 +32,7 @@
       </button>
       <span class="navbar-brand">
         <a class="navbar-link" href="../../index.html">mkin</a>
-        <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">0.9.50.4</span>
+        <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.3.9000</span>
       </span>
     </div>
 
@@ -81,7 +81,7 @@
 <ul class="nav navbar-nav navbar-right">
 <li>
   <a href="https://github.com/jranke/mkin/">
-    <span class="fab fa fab fa-github fa-lg"></span>
+    <span class="fab fa-github fa-lg"></span>
      
   </a>
 </li>
@@ -95,14 +95,13 @@
 
       
 
-      </header><link href="compiled_models_files/anchor-sections-1.0/anchor-sections.css" rel="stylesheet">
-<script src="compiled_models_files/anchor-sections-1.0/anchor-sections.js"></script><div class="row">
+      </header><script src="compiled_models_files/header-attrs-2.6/header-attrs.js"></script><script src="compiled_models_files/accessible-code-block-0.0.1/empty-anchor.js"></script><div class="row">
   <div class="col-md-9 contents">
     <div class="page-header toc-ignore">
       <h1 data-toc-skip>Performance benefit by using compiled model definitions in mkin</h1>
                         <h4 class="author">Johannes Ranke</h4>
             
-            <h4 class="date">2020-11-30</h4>
+            <h4 class="date">2021-02-15</h4>
       
       <small class="dont-index">Source: <a href="https://github.com/jranke/mkin/blob/master/vignettes/web_only/compiled_models.rmd"><code>vignettes/web_only/compiled_models.rmd</code></a></small>
       <div class="hidden name"><code>compiled_models.rmd</code></div>
@@ -160,10 +159,10 @@
   <span class="fu"><a href="https://rdrr.io/r/base/print.html">print</a></span><span class="op">(</span><span class="st">"R package rbenchmark is not available"</span><span class="op">)</span>
 <span class="op">}</span></code></pre></div>
 <pre><code>##                    test replications relative elapsed
-## 4            analytical            1    1.000   0.187
-## 3     deSolve, compiled            1    1.807   0.338
-## 2      Eigenvalue based            1    2.032   0.380
-## 1 deSolve, not compiled            1   43.048   8.050</code></pre>
+## 4            analytical            1    1.000   0.182
+## 3     deSolve, compiled            1    1.824   0.332
+## 2      Eigenvalue based            1    2.082   0.379
+## 1 deSolve, not compiled            1   46.181   8.405</code></pre>
 <p>We see that using the compiled model is by more than a factor of 10 faster than using deSolve without compiled code.</p>
 </div>
 <div id="model-without-analytical-solution" class="section level2">
@@ -190,13 +189,13 @@
 <span class="op">}</span></code></pre></div>
 <pre><code>## Temporary DLL for differentials generated and loaded</code></pre>
 <pre><code>##                    test replications relative elapsed
-## 2     deSolve, compiled            1    1.000   0.483
-## 1 deSolve, not compiled            1   29.969  14.475</code></pre>
-<p>Here we get a performance benefit of a factor of 30 using the version of the differential equation model compiled from C code!</p>
-<p>This vignette was built with mkin 0.9.50.4 on</p>
+## 2     deSolve, compiled            1    1.000   0.541
+## 1 deSolve, not compiled            1   29.091  15.738</code></pre>
+<p>Here we get a performance benefit of a factor of 29 using the version of the differential equation model compiled from C code!</p>
+<p>This vignette was built with mkin 1.0.3.9000 on</p>
 <pre><code>## R version 4.0.3 (2020-10-10)
 ## Platform: x86_64-pc-linux-gnu (64-bit)
-## Running under: Debian GNU/Linux 10 (buster)</code></pre>
+## Running under: Debian GNU/Linux bullseye/sid</code></pre>
 <pre><code>## CPU model: AMD Ryzen 7 1700 Eight-Core Processor</code></pre>
 </div>
   </div>
diff --git a/docs/dev/articles/web_only/compiled_models_files/accessible-code-block-0.0.1/empty-anchor.js b/docs/dev/articles/web_only/compiled_models_files/accessible-code-block-0.0.1/empty-anchor.js
new file mode 100644
index 00000000..ca349fd6
--- /dev/null
+++ b/docs/dev/articles/web_only/compiled_models_files/accessible-code-block-0.0.1/empty-anchor.js
@@ -0,0 +1,15 @@
+// Hide empty <a> tag within highlighted CodeBlock for screen reader accessibility (see https://github.com/jgm/pandoc/issues/6352#issuecomment-626106786) -->
+// v0.0.1
+// Written by JooYoung Seo (jooyoung@psu.edu) and Atsushi Yasumoto on June 1st, 2020.
+
+document.addEventListener('DOMContentLoaded', function() {
+  const codeList = document.getElementsByClassName("sourceCode");
+  for (var i = 0; i < codeList.length; i++) {
+    var linkList = codeList[i].getElementsByTagName('a');
+    for (var j = 0; j < linkList.length; j++) {
+      if (linkList[j].innerHTML === "") {
+        linkList[j].setAttribute('aria-hidden', 'true');
+      }
+    }
+  }
+});
diff --git a/docs/dev/articles/web_only/compiled_models_files/header-attrs-2.6/header-attrs.js b/docs/dev/articles/web_only/compiled_models_files/header-attrs-2.6/header-attrs.js
new file mode 100644
index 00000000..dd57d92e
--- /dev/null
+++ b/docs/dev/articles/web_only/compiled_models_files/header-attrs-2.6/header-attrs.js
@@ -0,0 +1,12 @@
+// Pandoc 2.9 adds attributes on both header and div. We remove the former (to
+// be compatible with the behavior of Pandoc < 2.8).
+document.addEventListener('DOMContentLoaded', function(e) {
+  var hs = document.querySelectorAll("div.section[class*='level'] > :first-child");
+  var i, h, a;
+  for (i = 0; i < hs.length; i++) {
+    h = hs[i];
+    if (!/^h[1-6]$/i.test(h.tagName)) continue;  // it should be a header h1-h6
+    a = h.attributes;
+    while (a.length > 0) h.removeAttribute(a[0].name);
+  }
+});
-- 
cgit v1.2.1


From 0b754ffa91b9496bdd2f892cf3ca2bd887028dea Mon Sep 17 00:00:00 2001
From: Johannes Ranke <jranke@uni-bremen.de>
Date: Tue, 27 Jul 2021 18:22:01 +0200
Subject: Fix dimethenamid vignette problems and update docs

---
 docs/dev/articles/web_only/dimethenamid_2018.html  | 420 +++++++++++++++++++++
 .../accessible-code-block-0.0.1/empty-anchor.js    |  15 +
 .../figure-html/f_parent_mkin_dfop_const-1.png     | Bin 0 -> 145534 bytes
 .../f_parent_mkin_dfop_const_test-1.png            | Bin 0 -> 146181 bytes
 .../figure-html/f_parent_mkin_dfop_tc_test-1.png   | Bin 0 -> 150274 bytes
 .../figure-html/f_parent_mkin_sfo_const-1.png      | Bin 0 -> 141499 bytes
 .../f_parent_nlmixr_saem_dfop_const-1.png          | Bin 0 -> 180061 bytes
 .../figure-html/f_parent_nlmixr_saem_dfop_tc-1.png | Bin 0 -> 151832 bytes
 .../f_parent_nlmixr_saem_sfo_const-1.png           | Bin 0 -> 124946 bytes
 .../figure-html/f_parent_nlmixr_saem_sfo_tc-1.png  | Bin 0 -> 140491 bytes
 .../figure-html/f_parent_saemix_dfop_const-1.png   | Bin 0 -> 58759 bytes
 .../f_parent_saemix_dfop_tc_moreiter-1.png         | Bin 0 -> 45420 bytes
 .../figure-html/f_parent_saemix_sfo_const-1.png    | Bin 0 -> 59913 bytes
 .../figure-html/f_parent_saemix_sfo_tc-1.png       | Bin 0 -> 53550 bytes
 .../figure-html/plot_parent_nlme-1.png             | Bin 0 -> 147409 bytes
 .../header-attrs-2.9/header-attrs.js               |  12 +
 16 files changed, 447 insertions(+)
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018.html
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/accessible-code-block-0.0.1/empty-anchor.js
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const-1.png
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const_test-1.png
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_tc_test-1.png
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_sfo_const-1.png
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_const-1.png
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_moreiter-1.png
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_const-1.png
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_tc-1.png
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/plot_parent_nlme-1.png
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/header-attrs-2.9/header-attrs.js

(limited to 'docs/dev/articles/web_only')

diff --git a/docs/dev/articles/web_only/dimethenamid_2018.html b/docs/dev/articles/web_only/dimethenamid_2018.html
new file mode 100644
index 00000000..7648f75a
--- /dev/null
+++ b/docs/dev/articles/web_only/dimethenamid_2018.html
@@ -0,0 +1,420 @@
+<!DOCTYPE html>
+<!-- Generated by pkgdown: do not edit by hand --><html lang="en">
+<head>
+<meta http-equiv="Content-Type" content="text/html; charset=UTF-8">
+<meta charset="utf-8">
+<meta http-equiv="X-UA-Compatible" content="IE=edge">
+<meta name="viewport" content="width=device-width, initial-scale=1.0">
+<title>Example evaluations of the dimethenamid data from 2018 • mkin</title>
+<!-- jquery --><script src="https://cdnjs.cloudflare.com/ajax/libs/jquery/3.4.1/jquery.min.js" integrity="sha256-CSXorXvZcTkaix6Yvo6HppcZGetbYMGWSFlBw8HfCJo=" crossorigin="anonymous"></script><!-- Bootstrap --><link rel="stylesheet" href="https://cdnjs.cloudflare.com/ajax/libs/twitter-bootstrap/3.4.1/css/bootstrap.min.css" integrity="sha256-bZLfwXAP04zRMK2BjiO8iu9pf4FbLqX6zitd+tIvLhE=" crossorigin="anonymous">
+<script src="https://cdnjs.cloudflare.com/ajax/libs/twitter-bootstrap/3.4.1/js/bootstrap.min.js" integrity="sha256-nuL8/2cJ5NDSSwnKD8VqreErSWHtnEP9E7AySL+1ev4=" crossorigin="anonymous"></script><!-- bootstrap-toc --><link rel="stylesheet" href="../../bootstrap-toc.css">
+<script src="../../bootstrap-toc.js"></script><!-- Font Awesome icons --><link rel="stylesheet" href="https://cdnjs.cloudflare.com/ajax/libs/font-awesome/5.12.1/css/all.min.css" integrity="sha256-mmgLkCYLUQbXn0B1SRqzHar6dCnv9oZFPEC1g1cwlkk=" crossorigin="anonymous">
+<link rel="stylesheet" href="https://cdnjs.cloudflare.com/ajax/libs/font-awesome/5.12.1/css/v4-shims.min.css" integrity="sha256-wZjR52fzng1pJHwx4aV2AO3yyTOXrcDW7jBpJtTwVxw=" crossorigin="anonymous">
+<!-- clipboard.js --><script src="https://cdnjs.cloudflare.com/ajax/libs/clipboard.js/2.0.6/clipboard.min.js" integrity="sha256-inc5kl9MA1hkeYUt+EC3BhlIgyp/2jDIyBLS6k3UxPI=" crossorigin="anonymous"></script><!-- headroom.js --><script src="https://cdnjs.cloudflare.com/ajax/libs/headroom/0.11.0/headroom.min.js" integrity="sha256-AsUX4SJE1+yuDu5+mAVzJbuYNPHj/WroHuZ8Ir/CkE0=" crossorigin="anonymous"></script><script src="https://cdnjs.cloudflare.com/ajax/libs/headroom/0.11.0/jQuery.headroom.min.js" integrity="sha256-ZX/yNShbjqsohH1k95liqY9Gd8uOiE1S4vZc+9KQ1K4=" crossorigin="anonymous"></script><!-- pkgdown --><link href="../../pkgdown.css" rel="stylesheet">
+<script src="../../pkgdown.js"></script><meta property="og:title" content="Example evaluations of the dimethenamid data from 2018">
+<meta property="og:description" content="mkin">
+<meta name="robots" content="noindex">
+<!-- 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>
+<![endif]-->
+</head>
+<body data-spy="scroll" data-target="#toc">
+    <div class="container template-article">
+      <header><div class="navbar navbar-default navbar-fixed-top" role="navigation">
+  <div class="container">
+    <div class="navbar-header">
+      <button type="button" class="navbar-toggle collapsed" data-toggle="collapse" data-target="#navbar" aria-expanded="false">
+        <span class="sr-only">Toggle navigation</span>
+        <span class="icon-bar"></span>
+        <span class="icon-bar"></span>
+        <span class="icon-bar"></span>
+      </button>
+      <span class="navbar-brand">
+        <a class="navbar-link" href="../../index.html">mkin</a>
+        <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</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>
+</li>
+<li class="dropdown">
+  <a href="#" class="dropdown-toggle" data-toggle="dropdown" role="button" aria-expanded="false">
+    Articles
+     
+    <span class="caret"></span>
+  </a>
+  <ul class="dropdown-menu" role="menu">
+<li>
+      <a href="../../articles/mkin.html">Introduction to mkin</a>
+    </li>
+    <li>
+      <a href="../../articles/FOCUS_D.html">Example evaluation of FOCUS Example Dataset D</a>
+    </li>
+    <li>
+      <a href="../../articles/FOCUS_L.html">Example evaluation of FOCUS Laboratory Data L1 to L3</a>
+    </li>
+    <li>
+      <a href="../../articles/web_only/FOCUS_Z.html">Example evaluation of FOCUS Example Dataset Z</a>
+    </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/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>
+    <li>
+      <a href="../../articles/web_only/benchmarks.html">Some benchmark timings</a>
+    </li>
+  </ul>
+</li>
+<li>
+  <a href="../../news/index.html">News</a>
+</li>
+      </ul>
+<ul class="nav navbar-nav navbar-right">
+<li>
+  <a href="https://github.com/jranke/mkin/">
+    <span class="fab fa-github fa-lg"></span>
+     
+  </a>
+</li>
+      </ul>
+</div>
+<!--/.nav-collapse -->
+  </div>
+<!--/.container -->
+</div>
+<!--/.navbar -->
+
+      
+
+      </header><script src="dimethenamid_2018_files/header-attrs-2.9/header-attrs.js"></script><script src="dimethenamid_2018_files/accessible-code-block-0.0.1/empty-anchor.js"></script><div class="row">
+  <div class="col-md-9 contents">
+    <div class="page-header toc-ignore">
+      <h1 data-toc-skip>Example evaluations of the dimethenamid data from 2018</h1>
+                        <h4 class="author">Johannes Ranke</h4>
+            
+            <h4 class="date">Last change 27 July 2021, built on 27 Jul 2021</h4>
+      
+      <small class="dont-index">Source: <a href="https://github.com/jranke/mkin/blob/master/vignettes/web_only/dimethenamid_2018.rmd"><code>vignettes/web_only/dimethenamid_2018.rmd</code></a></small>
+      <div class="hidden name"><code>dimethenamid_2018.rmd</code></div>
+
+    </div>
+
+    
+    
+<p><a href="http://www.jrwb.de">Wissenschaftlicher Berater, Kronacher Str. 12, 79639 Grenzach-Wyhlen, Germany</a><br><a href="http://chem.uft.uni-bremen.de/ranke">Privatdozent at the University of Bremen</a></p>
+<div id="introduction" class="section level1">
+<h1 class="hasAnchor">
+<a href="#introduction" class="anchor"></a>Introduction</h1>
+<p>During the preparation of the journal article on nonlinear mixed-effects models in degradation kinetics (submitted) and the analysis of the dimethenamid degradation data analysed therein, a need for a more detailed analysis using not only nlme and saemix, but also nlmixr for fitting the mixed-effects models was identified.</p>
+<p>This vignette is an attempt to satisfy this need.</p>
+</div>
+<div id="data" class="section level1">
+<h1 class="hasAnchor">
+<a href="#data" class="anchor"></a>Data</h1>
+<p>Residue data forming the basis for the endpoints derived in the conclusion on the peer review of the pesticide risk assessment of dimethenamid-P published by the European Food Safety Authority (EFSA) in 2018 <span class="citation">(EFSA 2018)</span> were transcribed from the risk assessment report <span class="citation">(Rapporteur Member State Germany, Co-Rapporteur Member State Bulgaria 2018)</span> which can be downloaded from the <a href="https://open.efsa.europa.eu/study-inventory/EFSA-Q-2014-00716">EFSA register of questions</a>.</p>
+<p>The data are <a href="https://pkgdown.jrwb.de/mkin/reference/dimethenamid_2018.html">available in the mkin package</a>. The following code (hidden by default, please use the button to the right to show it) treats the data available for the racemic mixture dimethenamid (DMTA) and its enantiomer dimethenamid-P (DMTAP) in the same way, as no difference between their degradation behaviour was identified in the EU risk assessment. The observation times of each dataset are multiplied with the corresponding normalisation factor also available in the dataset, in order to make it possible to describe all datasets with a single set of parameters.</p>
+<p>Also, datasets observed in the same soil are merged, resulting in dimethenamid (DMTA) data from six soils.</p>
+<div class="sourceCode" id="cb1"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va"><a href="https://pkgdown.jrwb.de/mkin/">mkin</a></span><span class="op">)</span>
+<span class="va">dmta_ds</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">lapply</a></span><span class="op">(</span><span class="fl">1</span><span class="op">:</span><span class="fl">8</span>, <span class="kw">function</span><span class="op">(</span><span class="va">i</span><span class="op">)</span> <span class="op">{</span>
+  <span class="va">ds_i</span> <span class="op">&lt;-</span> <span class="va">dimethenamid_2018</span><span class="op">$</span><span class="va">ds</span><span class="op">[[</span><span class="va">i</span><span class="op">]</span><span class="op">]</span><span class="op">$</span><span class="va">data</span>
+  <span class="va">ds_i</span><span class="op">[</span><span class="va">ds_i</span><span class="op">$</span><span class="va">name</span> <span class="op">==</span> <span class="st">"DMTAP"</span>, <span class="st">"name"</span><span class="op">]</span> <span class="op">&lt;-</span>  <span class="st">"DMTA"</span>
+  <span class="va">ds_i</span><span class="op">$</span><span class="va">time</span> <span class="op">&lt;-</span> <span class="va">ds_i</span><span class="op">$</span><span class="va">time</span> <span class="op">*</span> <span class="va">dimethenamid_2018</span><span class="op">$</span><span class="va">f_time_norm</span><span class="op">[</span><span class="va">i</span><span class="op">]</span>
+  <span class="va">ds_i</span>
+<span class="op">}</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/r/base/names.html">names</a></span><span class="op">(</span><span class="va">dmta_ds</span><span class="op">)</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">sapply</a></span><span class="op">(</span><span class="va">dimethenamid_2018</span><span class="op">$</span><span class="va">ds</span>, <span class="kw">function</span><span class="op">(</span><span class="va">ds</span><span class="op">)</span> <span class="va">ds</span><span class="op">$</span><span class="va">title</span><span class="op">)</span>
+<span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Borstel"</span><span class="op">]</span><span class="op">]</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/cbind.html">rbind</a></span><span class="op">(</span><span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Borstel 1"</span><span class="op">]</span><span class="op">]</span>, <span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Borstel 2"</span><span class="op">]</span><span class="op">]</span><span class="op">)</span>
+<span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Borstel 1"</span><span class="op">]</span><span class="op">]</span> <span class="op">&lt;-</span> <span class="cn">NULL</span>
+<span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Borstel 2"</span><span class="op">]</span><span class="op">]</span> <span class="op">&lt;-</span> <span class="cn">NULL</span>
+<span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Elliot"</span><span class="op">]</span><span class="op">]</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/cbind.html">rbind</a></span><span class="op">(</span><span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Elliot 1"</span><span class="op">]</span><span class="op">]</span>, <span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Elliot 2"</span><span class="op">]</span><span class="op">]</span><span class="op">)</span>
+<span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Elliot 1"</span><span class="op">]</span><span class="op">]</span> <span class="op">&lt;-</span> <span class="cn">NULL</span>
+<span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Elliot 2"</span><span class="op">]</span><span class="op">]</span> <span class="op">&lt;-</span> <span class="cn">NULL</span></code></pre></div>
+</div>
+<div id="parent-degradation" class="section level1">
+<h1 class="hasAnchor">
+<a href="#parent-degradation" class="anchor"></a>Parent degradation</h1>
+<p>We evaluate the observed degradation of the parent compound using simple exponential decline (SFO) and biexponential decline (DFOP), using constant variance (const) and a two-component variance (tc) as error models.</p>
+<div id="separate-evaluations" class="section level2">
+<h2 class="hasAnchor">
+<a href="#separate-evaluations" class="anchor"></a>Separate evaluations</h2>
+<p>As a first step, to get a visual impression of the fit of the different models, we do separate evaluations for each soil using the mmkin function from the mkin package:</p>
+<div class="sourceCode" id="cb2"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">f_parent_mkin_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="../../reference/mmkin.html">mmkin</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="st">"SFO"</span>, <span class="st">"DFOP"</span><span class="op">)</span>, <span class="va">dmta_ds</span>,
+  error_model <span class="op">=</span> <span class="st">"const"</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span>
+<span class="va">f_parent_mkin_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="../../reference/mmkin.html">mmkin</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="st">"SFO"</span>, <span class="st">"DFOP"</span><span class="op">)</span>, <span class="va">dmta_ds</span>,
+  error_model <span class="op">=</span> <span class="st">"tc"</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
+<p>The plot of the individual SFO fits shown below suggests that at least in some datasets the degradation slows down towards later time points, and that the scatter of the residuals error is smaller for smaller values (panel to the right):</p>
+<div class="sourceCode" id="cb3"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span><span class="op">)</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_sfo_const-1.png" width="700"></p>
+<p>Using biexponential decline (DFOP) results in a slightly more random scatter of the residuals:</p>
+<div class="sourceCode" id="cb4"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const-1.png" width="700"></p>
+<p>The population curve (bold line) in the above plot results from taking the mean of the individual transformed parameters, i.e. of log k1 and log k2, as well as of the logit of the g parameter of the DFOP model). Here, this procedure does not result in parameters that represent the degradation well, because in some datasets the fitted value for k2 is extremely close to zero, leading to a log k2 value that dominates the average. This is alleviated if only rate constants that pass the t-test for significant difference from zero (on the untransformed scale) are considered in the averaging:</p>
+<div class="sourceCode" id="cb5"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span>, test_log_parms <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const_test-1.png" width="700"></p>
+<p>While this is visually much more satisfactory, such an average procedure could introduce a bias, as not all results from the individual fits enter the population curve with the same weight. This is where nonlinear mixed-effects models can help out by treating all datasets with equally by fitting a parameter distribution model together with the degradation model and the error model (see below).</p>
+<p>The remaining trend of the residuals to be higher for higher predicted residues is reduced by using the two-component error model:</p>
+<div class="sourceCode" id="cb6"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span>, test_log_parms <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_tc_test-1.png" width="700"></p>
+</div>
+<div id="nonlinear-mixed-effects-models" class="section level2">
+<h2 class="hasAnchor">
+<a href="#nonlinear-mixed-effects-models" class="anchor"></a>Nonlinear mixed-effects models</h2>
+<p>Instead of taking a model selection decision for each of the individual fits, we fit nonlinear mixed-effects models (using different fitting algorithms as implemented in different packages) and do model selection using all available data at the same time. In order to make sure that these decisions are not unduly influenced by the type of algorithm used, by implementation details or by the use of wrong control parameters, we compare the model selection results obtained with different R packages, with different algorithms and checking control parameters.</p>
+<div id="nlme" class="section level3">
+<h3 class="hasAnchor">
+<a href="#nlme" class="anchor"></a>nlme</h3>
+<p>The nlme package was the first R extension providing facilities to fit nonlinear mixed-effects models. We use would like to do model selection from all four combinations of degradation models and error models based on the AIC. However, fitting the DFOP model with constant variance and using default control parameters results in an error, signalling that the maximum number of 50 iterations was reached, potentially indicating overparameterisation. However, the algorithm converges when the two-component error model is used in combination with the DFOP model. This can be explained by the fact that the smaller residues observed at later sampling times get more weight when using the two-component error model which will counteract the tendency of the algorithm to try parameter combinations unsuitable for fitting these data.</p>
+<div class="sourceCode" id="cb7"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va"><a href="https://svn.r-project.org/R-packages/trunk/nlme/">nlme</a></span><span class="op">)</span>
+<span class="va">f_parent_nlme_sfo_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/nlme.html">nlme</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span><span class="op">)</span>
+<span class="co">#f_parent_nlme_dfop_const &lt;- nlme(f_parent_mkin_const["DFOP", ])</span>
+<span class="co"># maxIter = 50 reached</span>
+<span class="va">f_parent_nlme_sfo_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/nlme.html">nlme</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span><span class="op">)</span>
+<span class="va">f_parent_nlme_dfop_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/nlme.html">nlme</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span></code></pre></div>
+<p>Note that overparameterisation is also indicated by warnings obtained when fitting SFO or DFOP with the two-component error model (‘false convergence’ in the ‘LME step’ in some iterations). In addition to these fits, attempts were also made to include correlations between random effects by using the log Cholesky parameterisation of the matrix specifying them. The code used for these attempts can be made visible below.</p>
+<div class="sourceCode" id="cb8"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">f_parent_nlme_sfo_const_logchol</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/nlme.html">nlme</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>,
+  random <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/pdLogChol.html">pdLogChol</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">DMTA_0</span> <span class="op">~</span> <span class="fl">1</span>, <span class="va">log_k_DMTA</span> <span class="op">~</span> <span class="fl">1</span><span class="op">)</span><span class="op">)</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/r/stats/anova.html">anova</a></span><span class="op">(</span><span class="va">f_parent_nlme_sfo_const</span>, <span class="va">f_parent_nlme_sfo_const_logchol</span><span class="op">)</span> <span class="co"># not better</span>
+<span class="co">#f_parent_nlme_dfop_tc_logchol &lt;- update(f_parent_nlme_dfop_tc,</span>
+<span class="co">#  random = pdLogChol(list(DMTA_0 ~ 1, log_k1 ~ 1, log_k2 ~ 1, g_qlogis ~ 1)))</span>
+<span class="co"># using log Cholesky parameterisation for random effects (nlme default) does</span>
+<span class="co"># not converge here and gives lots of warnings about the LME step not converging</span></code></pre></div>
+<p>The model comparison function of the nlme package can directly be applied to these fits showing a similar goodness-of-fit of the SFO model, but a much lower AIC for the DFOP model fitted with the two-component error model. Also, the likelihood ratio test indicates that this difference is significant. as the p-value is below 0.0001.</p>
+<div class="sourceCode" id="cb9"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/anova.html">anova</a></span><span class="op">(</span>
+  <span class="va">f_parent_nlme_sfo_const</span>, <span class="va">f_parent_nlme_sfo_tc</span>, <span class="va">f_parent_nlme_dfop_tc</span>
+<span class="op">)</span></code></pre></div>
+<pre><code>                        Model df    AIC    BIC  logLik   Test L.Ratio p-value
+f_parent_nlme_sfo_const     1  5 818.63 834.00 -404.31                       
+f_parent_nlme_sfo_tc        2  6 820.61 839.06 -404.31 1 vs 2   0.014  0.9049
+f_parent_nlme_dfop_tc       3 10 687.84 718.59 -333.92 2 vs 3 140.771  &lt;.0001</code></pre>
+<p>The selected model (DFOP with two-component error) fitted to the data assuming no correlations between random effects is shown below.</p>
+<div class="sourceCode" id="cb11"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="va">f_parent_nlme_dfop_tc</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/plot_parent_nlme-1.png" width="700"></p>
+</div>
+<div id="saemix" class="section level3">
+<h3 class="hasAnchor">
+<a href="#saemix" class="anchor"></a>saemix</h3>
+<p>The saemix package provided the first Open Source implementation of the Stochastic Approximation to the Expectation Maximisation (SAEM) algorithm. SAEM fits of degradation models can be performed using an interface to the saemix package available in current development versions of the mkin package.</p>
+<p>The corresponding SAEM fits of the four combinations of degradation and error models are fitted below. As there is no convergence criterion implemented in the saemix package, the convergence plots need to be manually checked for every fit.</p>
+<p>The convergence plot for the SFO model using constant variance is shown below.</p>
+<div class="sourceCode" id="cb12"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va">saemix</span><span class="op">)</span>
+<span class="va">f_parent_saemix_sfo_const</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
+  transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_sfo_const</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_const-1.png" width="700"></p>
+<p>Obviously the default number of iterations is sufficient to reach convergence. This can also be said for the SFO fit using the two-component error model.</p>
+<div class="sourceCode" id="cb13"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">f_parent_saemix_sfo_tc</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
+  transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_sfo_tc</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_tc-1.png" width="700"></p>
+<p>When fitting the DFOP model with constant variance, parameter convergence is not as unambiguous (see the failure of nlme with the default number of iterations above). Therefore, the number of iterations in the first phase of the algorithm was increased, leading to visually satisfying convergence.</p>
+<div class="sourceCode" id="cb14"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">f_parent_saemix_dfop_const</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
+  control <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/saemixControl.html">saemixControl</a></span><span class="op">(</span>nbiter.saemix <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="fl">800</span>, <span class="fl">200</span><span class="op">)</span>, print <span class="op">=</span> <span class="cn">FALSE</span>,
+    save <span class="op">=</span> <span class="cn">FALSE</span>, save.graphs <span class="op">=</span> <span class="cn">FALSE</span>, displayProgress <span class="op">=</span> <span class="cn">FALSE</span><span class="op">)</span>,
+  transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_const</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_const-1.png" width="700"></p>
+<p>The same applies to the case where the DFOP model is fitted with the two-component error model. Convergence of the variance of k2 is enhanced by using the two-component error, it remains more or less stable already after 200 iterations of the first phase.</p>
+<div class="sourceCode" id="cb15"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">f_parent_saemix_dfop_tc_moreiter</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
+  control <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/saemixControl.html">saemixControl</a></span><span class="op">(</span>nbiter.saemix <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="fl">800</span>, <span class="fl">200</span><span class="op">)</span>, print <span class="op">=</span> <span class="cn">FALSE</span>,
+    save <span class="op">=</span> <span class="cn">FALSE</span>, save.graphs <span class="op">=</span> <span class="cn">FALSE</span>, displayProgress <span class="op">=</span> <span class="cn">FALSE</span><span class="op">)</span>,
+  transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_moreiter-1.png" width="700"></p>
+<p>The four combinations can be compared using the model comparison function from the saemix package:</p>
+<div class="sourceCode" id="cb16"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/compare.saemix.html">compare.saemix</a></span><span class="op">(</span><span class="va">f_parent_saemix_sfo_const</span><span class="op">$</span><span class="va">so</span>, <span class="va">f_parent_saemix_sfo_tc</span><span class="op">$</span><span class="va">so</span>,
+  <span class="va">f_parent_saemix_dfop_const</span><span class="op">$</span><span class="va">so</span>, <span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span><span class="op">)</span></code></pre></div>
+<pre><code>Likelihoods calculated by importance sampling</code></pre>
+<pre><code>     AIC    BIC
+1 818.37 817.33
+2 820.38 819.14
+3 725.91 724.04
+4 683.64 681.55</code></pre>
+<p>As in the case of nlme fits, the DFOP model fitted with two-component error (number 4) gives the lowest AIC. The numeric values are reasonably close to the ones obtained using nlme, considering that the algorithms for fitting the model and for the likelihood calculation are quite different.</p>
+<p>In order to check the influence of the likelihood calculation algorithms implemented in saemix, the likelihood from Gaussian quadrature is added to the best fit, and the AIC values obtained from the three methods are compared.</p>
+<div class="sourceCode" id="cb19"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span> <span class="op">&lt;-</span>
+  <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/llgq.saemix.html">llgq.saemix</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span><span class="op">)</span></code></pre></div>
+<pre><code>[1] 683.64</code></pre>
+<div class="sourceCode" id="cb21"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span>, method <span class="op">=</span> <span class="st">"gq"</span><span class="op">)</span></code></pre></div>
+<pre><code>[1] 683.7</code></pre>
+<div class="sourceCode" id="cb23"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span>, method <span class="op">=</span> <span class="st">"lin"</span><span class="op">)</span></code></pre></div>
+<pre><code>[1] 683.17</code></pre>
+<p>The AIC values based on importance sampling and Gaussian quadrature are quite similar. Using linearisation is less accurate, but still gives a similar value.</p>
+</div>
+<div id="nlmixr" class="section level3">
+<h3 class="hasAnchor">
+<a href="#nlmixr" class="anchor"></a>nlmixr</h3>
+<p>In the last years, a lot of effort has been put into the nlmixr package which is designed for pharmacokinetics, where nonlinear mixed-effects models are routinely used, but which can also be used for related data like chemical degradation data. A current development branch of the mkin package provides an interface between mkin and nlmixr. Here, we check if we get equivalent results when using a refined version of the First Order Conditional Estimation (FOCE) algorithm used in nlme, namely First Order Conditional Estimation with Interaction (FOCEI), and the SAEM algorithm as implemented in nlmixr.</p>
+<p>First, the focei algorithm is used for the four model combinations and the goodness of fit of the results is compared.</p>
+<div class="sourceCode" id="cb25"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va"><a href="https://github.com/nlmixrdevelopment/nlmixr">nlmixr</a></span><span class="op">)</span>
+<span class="va">f_parent_nlmixr_focei_sfo_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"focei"</span><span class="op">)</span>
+<span class="va">f_parent_nlmixr_focei_sfo_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"focei"</span><span class="op">)</span>
+<span class="va">f_parent_nlmixr_focei_dfop_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"focei"</span><span class="op">)</span>
+<span class="va">f_parent_nlmixr_focei_dfop_tc</span><span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"focei"</span><span class="op">)</span></code></pre></div>
+<div class="sourceCode" id="cb26"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_focei_sfo_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_focei_sfo_tc</span><span class="op">$</span><span class="va">nm</span>,
+  <span class="va">f_parent_nlmixr_focei_dfop_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_focei_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
+<pre><code>                                    df    AIC
+f_parent_nlmixr_focei_sfo_const$nm   5 818.63
+f_parent_nlmixr_focei_sfo_tc$nm      6 820.61
+f_parent_nlmixr_focei_dfop_const$nm  9 728.11
+f_parent_nlmixr_focei_dfop_tc$nm    10 687.82</code></pre>
+<p>The AIC values are very close to the ones obtained with nlme which are repeated below for convenience.</p>
+<div class="sourceCode" id="cb28"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span>
+  <span class="va">f_parent_nlme_sfo_const</span>, <span class="va">f_parent_nlme_sfo_tc</span>, <span class="va">f_parent_nlme_dfop_tc</span>
+<span class="op">)</span></code></pre></div>
+<pre><code>                        df    AIC
+f_parent_nlme_sfo_const  5 818.63
+f_parent_nlme_sfo_tc     6 820.61
+f_parent_nlme_dfop_tc   10 687.84</code></pre>
+<p>Secondly, we use the SAEM estimation routine and check the convergence plots for SFO with constant variance</p>
+<div class="sourceCode" id="cb30"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_sfo_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
+  control <span class="op">=</span> <span class="fu">nlmixr</span><span class="fu">::</span><span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_const</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png" width="700"></p>
+<p>for SFO with two-component error</p>
+<div class="sourceCode" id="cb31"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_sfo_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
+  control <span class="op">=</span> <span class="fu">nlmixr</span><span class="fu">::</span><span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png" width="700"></p>
+<p>For DFOP with constant variance, the convergence plots show considerable instability of the fit, which can be alleviated by increasing the number of iterations and the number of parallel chains for the first phase of algorithm.</p>
+<div class="sourceCode" id="cb32"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_dfop_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
+  control <span class="op">=</span> <span class="fu">nlmixr</span><span class="fu">::</span><span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span>, nBurn <span class="op">=</span> <span class="fl">1000</span><span class="op">)</span>, nmc <span class="op">=</span> <span class="fl">15</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_dfop_const</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png" width="700"></p>
+<p>For DFOP with two-component error, the same increase in iterations and parallel chains was used, but using the two-component error appears to lead to a less erratic convergence, so this may not be necessary to this degree.</p>
+<div class="sourceCode" id="cb33"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_dfop_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
+  control <span class="op">=</span> <span class="fu">nlmixr</span><span class="fu">::</span><span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span>, nBurn <span class="op">=</span> <span class="fl">1000</span>, nmc <span class="op">=</span> <span class="fl">15</span><span class="op">)</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png" width="700"></p>
+<p>The AIC values are internally calculated using Gaussian quadrature. For an unknown reason, the AIC value obtained for the DFOP fit using the two-component error model is given as Infinity.</p>
+<div class="sourceCode" id="cb34"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_saem_sfo_tc</span><span class="op">$</span><span class="va">nm</span>,
+  <span class="va">f_parent_nlmixr_saem_dfop_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_saem_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
+<pre><code>                                   df    AIC
+f_parent_nlmixr_saem_sfo_const$nm   5 820.54
+f_parent_nlmixr_saem_sfo_tc$nm      6 835.26
+f_parent_nlmixr_saem_dfop_const$nm  9 842.84
+f_parent_nlmixr_saem_dfop_tc$nm    10 684.51</code></pre>
+<p>The following table gives the AIC values obtained with the three packages.</p>
+<div class="sourceCode" id="cb36"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">AIC_all</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/data.frame.html">data.frame</a></span><span class="op">(</span>
+  nlme <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlme_sfo_const</span><span class="op">)</span>, <span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlme_sfo_tc</span><span class="op">)</span>, <span class="cn">NA</span>, <span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlme_dfop_tc</span><span class="op">)</span><span class="op">)</span>,
+  nlmixr_focei <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">sapply</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_focei_sfo_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_focei_sfo_tc</span><span class="op">$</span><span class="va">nm</span>,
+  <span class="va">f_parent_nlmixr_focei_dfop_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_focei_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span>, <span class="va">AIC</span><span class="op">)</span>,
+  saemix <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">sapply</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">f_parent_saemix_sfo_const</span><span class="op">$</span><span class="va">so</span>, <span class="va">f_parent_saemix_sfo_tc</span><span class="op">$</span><span class="va">so</span>,
+    <span class="va">f_parent_saemix_dfop_const</span><span class="op">$</span><span class="va">so</span>, <span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span><span class="op">)</span>, <span class="va">AIC</span><span class="op">)</span>,
+  nlmixr_saem <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">sapply</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_saem_sfo_tc</span><span class="op">$</span><span class="va">nm</span>,
+  <span class="va">f_parent_nlmixr_saem_dfop_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_saem_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span>, <span class="va">AIC</span><span class="op">)</span>
+<span class="op">)</span>
+<span class="fu">kable</span><span class="op">(</span><span class="va">AIC_all</span><span class="op">)</span></code></pre></div>
+<table class="table">
+<thead><tr class="header">
+<th align="right">nlme</th>
+<th align="right">nlmixr_focei</th>
+<th align="right">saemix</th>
+<th align="right">nlmixr_saem</th>
+</tr></thead>
+<tbody>
+<tr class="odd">
+<td align="right">818.63</td>
+<td align="right">818.63</td>
+<td align="right">818.37</td>
+<td align="right">820.54</td>
+</tr>
+<tr class="even">
+<td align="right">820.61</td>
+<td align="right">820.61</td>
+<td align="right">820.38</td>
+<td align="right">835.26</td>
+</tr>
+<tr class="odd">
+<td align="right">NA</td>
+<td align="right">728.11</td>
+<td align="right">725.91</td>
+<td align="right">842.84</td>
+</tr>
+<tr class="even">
+<td align="right">687.84</td>
+<td align="right">687.82</td>
+<td align="right">683.64</td>
+<td align="right">684.51</td>
+</tr>
+</tbody>
+</table>
+</div>
+</div>
+</div>
+<div id="references" class="section level1">
+<h1 class="hasAnchor">
+<a href="#references" class="anchor"></a>References</h1>
+<!-- vim: set foldmethod=syntax: -->
+<div id="refs" class="references hanging-indent">
+<div id="ref-efsa_2018_dimethenamid">
+<p>EFSA. 2018. “Peer Review of the Pesticide Risk Assessment of the Active Substance Dimethenamid-P.” <em>EFSA Journal</em> 16 (4): 5211.</p>
+</div>
+<div id="ref-dimethenamid_rar_2018_b8">
+<p>Rapporteur Member State Germany, Co-Rapporteur Member State Bulgaria. 2018. “Renewal Assessment Report Dimethenamid-P Volume 3 - B.8 Environmental fate and behaviour, Rev. 2 - November 2017.” <a href="https://open.efsa.europa.eu/study-inventory/EFSA-Q-2014-00716">https://open.efsa.europa.eu/study-inventory/EFSA-Q-2014-00716</a>.</p>
+</div>
+</div>
+</div>
+  </div>
+
+  <div class="col-md-3 hidden-xs hidden-sm" id="pkgdown-sidebar">
+
+        <nav id="toc" data-toggle="toc"><h2 data-toc-skip>Contents</h2>
+    </nav>
+</div>
+
+</div>
+
+
+
+      <footer><div class="copyright">
+  <p>Developed by Johannes Ranke.</p>
+</div>
+
+<div class="pkgdown">
+  <p>Site built with <a href="https://pkgdown.r-lib.org/">pkgdown</a> 1.6.1.</p>
+</div>
+
+      </footer>
+</div>
+
+  
+
+
+  </body>
+</html>
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/accessible-code-block-0.0.1/empty-anchor.js b/docs/dev/articles/web_only/dimethenamid_2018_files/accessible-code-block-0.0.1/empty-anchor.js
new file mode 100644
index 00000000..ca349fd6
--- /dev/null
+++ b/docs/dev/articles/web_only/dimethenamid_2018_files/accessible-code-block-0.0.1/empty-anchor.js
@@ -0,0 +1,15 @@
+// Hide empty <a> tag within highlighted CodeBlock for screen reader accessibility (see https://github.com/jgm/pandoc/issues/6352#issuecomment-626106786) -->
+// v0.0.1
+// Written by JooYoung Seo (jooyoung@psu.edu) and Atsushi Yasumoto on June 1st, 2020.
+
+document.addEventListener('DOMContentLoaded', function() {
+  const codeList = document.getElementsByClassName("sourceCode");
+  for (var i = 0; i < codeList.length; i++) {
+    var linkList = codeList[i].getElementsByTagName('a');
+    for (var j = 0; j < linkList.length; j++) {
+      if (linkList[j].innerHTML === "") {
+        linkList[j].setAttribute('aria-hidden', 'true');
+      }
+    }
+  }
+});
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const-1.png
new file mode 100644
index 00000000..c51afe54
Binary files /dev/null and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const_test-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const_test-1.png
new file mode 100644
index 00000000..080f0dde
Binary files /dev/null and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const_test-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_tc_test-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_tc_test-1.png
new file mode 100644
index 00000000..a3933e54
Binary files /dev/null and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_tc_test-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_sfo_const-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_sfo_const-1.png
new file mode 100644
index 00000000..8dee2e3c
Binary files /dev/null and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_sfo_const-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png
new file mode 100644
index 00000000..54a8c1a6
Binary files /dev/null and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png
new file mode 100644
index 00000000..91f3d977
Binary files /dev/null and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png
new file mode 100644
index 00000000..c84f2926
Binary files /dev/null and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png
new file mode 100644
index 00000000..cfef9dfc
Binary files /dev/null and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_const-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_const-1.png
new file mode 100644
index 00000000..a4695eea
Binary files /dev/null and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_const-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_moreiter-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_moreiter-1.png
new file mode 100644
index 00000000..1c8fc837
Binary files /dev/null and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_moreiter-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_const-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_const-1.png
new file mode 100644
index 00000000..469ebafd
Binary files /dev/null and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_const-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_tc-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_tc-1.png
new file mode 100644
index 00000000..d26bcc09
Binary files /dev/null and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_tc-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/plot_parent_nlme-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/plot_parent_nlme-1.png
new file mode 100644
index 00000000..6edeb794
Binary files /dev/null and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/plot_parent_nlme-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/header-attrs-2.9/header-attrs.js b/docs/dev/articles/web_only/dimethenamid_2018_files/header-attrs-2.9/header-attrs.js
new file mode 100644
index 00000000..dd57d92e
--- /dev/null
+++ b/docs/dev/articles/web_only/dimethenamid_2018_files/header-attrs-2.9/header-attrs.js
@@ -0,0 +1,12 @@
+// Pandoc 2.9 adds attributes on both header and div. We remove the former (to
+// be compatible with the behavior of Pandoc < 2.8).
+document.addEventListener('DOMContentLoaded', function(e) {
+  var hs = document.querySelectorAll("div.section[class*='level'] > :first-child");
+  var i, h, a;
+  for (i = 0; i < hs.length; i++) {
+    h = hs[i];
+    if (!/^h[1-6]$/i.test(h.tagName)) continue;  // it should be a header h1-h6
+    a = h.attributes;
+    while (a.length > 0) h.removeAttribute(a[0].name);
+  }
+});
-- 
cgit v1.2.1


From 137612045c23198f10d6e8612c32e266c2a6c00e Mon Sep 17 00:00:00 2001
From: Johannes Ranke <jranke@uni-bremen.de>
Date: Thu, 29 Jul 2021 12:17:56 +0200
Subject: Go back to 1.0.x version, update docs

---
 docs/dev/articles/web_only/dimethenamid_2018.html | 14 +++++++-------
 1 file changed, 7 insertions(+), 7 deletions(-)

(limited to 'docs/dev/articles/web_only')

diff --git a/docs/dev/articles/web_only/dimethenamid_2018.html b/docs/dev/articles/web_only/dimethenamid_2018.html
index 7648f75a..34d882a4 100644
--- a/docs/dev/articles/web_only/dimethenamid_2018.html
+++ b/docs/dev/articles/web_only/dimethenamid_2018.html
@@ -32,7 +32,7 @@
       </button>
       <span class="navbar-brand">
         <a class="navbar-link" href="../../index.html">mkin</a>
-        <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</span>
+        <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.5</span>
       </span>
     </div>
 
@@ -101,7 +101,7 @@
       <h1 data-toc-skip>Example evaluations of the dimethenamid data from 2018</h1>
                         <h4 class="author">Johannes Ranke</h4>
             
-            <h4 class="date">Last change 27 July 2021, built on 27 Jul 2021</h4>
+            <h4 class="date">Last change 27 July 2021, built on 29 Jul 2021</h4>
       
       <small class="dont-index">Source: <a href="https://github.com/jranke/mkin/blob/master/vignettes/web_only/dimethenamid_2018.rmd"><code>vignettes/web_only/dimethenamid_2018.rmd</code></a></small>
       <div class="hidden name"><code>dimethenamid_2018.rmd</code></div>
@@ -154,20 +154,20 @@
   error_model <span class="op">=</span> <span class="st">"tc"</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
 <p>The plot of the individual SFO fits shown below suggests that at least in some datasets the degradation slows down towards later time points, and that the scatter of the residuals error is smaller for smaller values (panel to the right):</p>
 <div class="sourceCode" id="cb3"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span><span class="op">)</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span><span class="op">)</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_sfo_const-1.png" width="700"></p>
 <p>Using biexponential decline (DFOP) results in a slightly more random scatter of the residuals:</p>
 <div class="sourceCode" id="cb4"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const-1.png" width="700"></p>
 <p>The population curve (bold line) in the above plot results from taking the mean of the individual transformed parameters, i.e. of log k1 and log k2, as well as of the logit of the g parameter of the DFOP model). Here, this procedure does not result in parameters that represent the degradation well, because in some datasets the fitted value for k2 is extremely close to zero, leading to a log k2 value that dominates the average. This is alleviated if only rate constants that pass the t-test for significant difference from zero (on the untransformed scale) are considered in the averaging:</p>
 <div class="sourceCode" id="cb5"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span>, test_log_parms <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span>, test_log_parms <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const_test-1.png" width="700"></p>
 <p>While this is visually much more satisfactory, such an average procedure could introduce a bias, as not all results from the individual fits enter the population curve with the same weight. This is where nonlinear mixed-effects models can help out by treating all datasets with equally by fitting a parameter distribution model together with the degradation model and the error model (see below).</p>
 <p>The remaining trend of the residuals to be higher for higher predicted residues is reduced by using the two-component error model:</p>
 <div class="sourceCode" id="cb6"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span>, test_log_parms <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span>, test_log_parms <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_tc_test-1.png" width="700"></p>
 </div>
 <div id="nonlinear-mixed-effects-models" class="section level2">
@@ -205,7 +205,7 @@ f_parent_nlme_sfo_tc        2  6 820.61 839.06 -404.31 1 vs 2   0.014  0.9049
 f_parent_nlme_dfop_tc       3 10 687.84 718.59 -333.92 2 vs 3 140.771  &lt;.0001</code></pre>
 <p>The selected model (DFOP with two-component error) fitted to the data assuming no correlations between random effects is shown below.</p>
 <div class="sourceCode" id="cb11"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="va">f_parent_nlme_dfop_tc</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_nlme_dfop_tc</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/plot_parent_nlme-1.png" width="700"></p>
 </div>
 <div id="saemix" class="section level3">
-- 
cgit v1.2.1


From 51fab94230e926cec690dc455964bd797a97b7c7 Mon Sep 17 00:00:00 2001
From: Johannes Ranke <jranke@uni-bremen.de>
Date: Wed, 4 Aug 2021 16:37:52 +0200
Subject: Improve AIC table in vignette

---
 docs/dev/articles/web_only/dimethenamid_2018.html | 14 +++++++++++++-
 1 file changed, 13 insertions(+), 1 deletion(-)

(limited to 'docs/dev/articles/web_only')

diff --git a/docs/dev/articles/web_only/dimethenamid_2018.html b/docs/dev/articles/web_only/dimethenamid_2018.html
index 34d882a4..9a6d8388 100644
--- a/docs/dev/articles/web_only/dimethenamid_2018.html
+++ b/docs/dev/articles/web_only/dimethenamid_2018.html
@@ -101,7 +101,7 @@
       <h1 data-toc-skip>Example evaluations of the dimethenamid data from 2018</h1>
                         <h4 class="author">Johannes Ranke</h4>
             
-            <h4 class="date">Last change 27 July 2021, built on 29 Jul 2021</h4>
+            <h4 class="date">Last change 4 August 2021, built on 04 Aug 2021</h4>
       
       <small class="dont-index">Source: <a href="https://github.com/jranke/mkin/blob/master/vignettes/web_only/dimethenamid_2018.rmd"><code>vignettes/web_only/dimethenamid_2018.rmd</code></a></small>
       <div class="hidden name"><code>dimethenamid_2018.rmd</code></div>
@@ -331,6 +331,8 @@ f_parent_nlmixr_saem_dfop_tc$nm    10 684.51</code></pre>
 <p>The following table gives the AIC values obtained with the three packages.</p>
 <div class="sourceCode" id="cb36"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">AIC_all</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/data.frame.html">data.frame</a></span><span class="op">(</span>
+  <span class="st">"Degradation model"</span> <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="st">"SFO"</span>, <span class="st">"SFO"</span>, <span class="st">"DFOP"</span>, <span class="st">"DFOP"</span><span class="op">)</span>,
+  <span class="st">"Error model"</span> <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="st">"const"</span>, <span class="st">"tc"</span>, <span class="st">"const"</span>, <span class="st">"tc"</span><span class="op">)</span>,
   nlme <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlme_sfo_const</span><span class="op">)</span>, <span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlme_sfo_tc</span><span class="op">)</span>, <span class="cn">NA</span>, <span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlme_dfop_tc</span><span class="op">)</span><span class="op">)</span>,
   nlmixr_focei <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">sapply</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_focei_sfo_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_focei_sfo_tc</span><span class="op">$</span><span class="va">nm</span>,
   <span class="va">f_parent_nlmixr_focei_dfop_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_focei_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span>, <span class="va">AIC</span><span class="op">)</span>,
@@ -342,6 +344,8 @@ f_parent_nlmixr_saem_dfop_tc$nm    10 684.51</code></pre>
 <span class="fu">kable</span><span class="op">(</span><span class="va">AIC_all</span><span class="op">)</span></code></pre></div>
 <table class="table">
 <thead><tr class="header">
+<th align="left">Degradation.model</th>
+<th align="left">Error.model</th>
 <th align="right">nlme</th>
 <th align="right">nlmixr_focei</th>
 <th align="right">saemix</th>
@@ -349,24 +353,32 @@ f_parent_nlmixr_saem_dfop_tc$nm    10 684.51</code></pre>
 </tr></thead>
 <tbody>
 <tr class="odd">
+<td align="left">SFO</td>
+<td align="left">const</td>
 <td align="right">818.63</td>
 <td align="right">818.63</td>
 <td align="right">818.37</td>
 <td align="right">820.54</td>
 </tr>
 <tr class="even">
+<td align="left">SFO</td>
+<td align="left">tc</td>
 <td align="right">820.61</td>
 <td align="right">820.61</td>
 <td align="right">820.38</td>
 <td align="right">835.26</td>
 </tr>
 <tr class="odd">
+<td align="left">DFOP</td>
+<td align="left">const</td>
 <td align="right">NA</td>
 <td align="right">728.11</td>
 <td align="right">725.91</td>
 <td align="right">842.84</td>
 </tr>
 <tr class="even">
+<td align="left">DFOP</td>
+<td align="left">tc</td>
 <td align="right">687.84</td>
 <td align="right">687.82</td>
 <td align="right">683.64</td>
-- 
cgit v1.2.1


From c41381a961263c28d60976e68923157916c78b15 Mon Sep 17 00:00:00 2001
From: Johannes Ranke <jranke@uni-bremen.de>
Date: Thu, 16 Sep 2021 15:31:13 +0200
Subject: Adapt and improve the dimethenamid vignette

Adapt to the corrected data and unify control parameters for saemix and
nlmixr with saem. Update docs
---
 docs/dev/articles/web_only/dimethenamid_2018.html  | 245 +++++++++++----------
 .../figure-html/f_parent_mkin_dfop_const-1.png     | Bin 145534 -> 141661 bytes
 .../f_parent_mkin_dfop_const_test-1.png            | Bin 146181 -> 141889 bytes
 .../figure-html/f_parent_mkin_dfop_tc_test-1.png   | Bin 150274 -> 144254 bytes
 .../figure-html/f_parent_mkin_sfo_const-1.png      | Bin 141499 -> 137650 bytes
 .../f_parent_nlmixr_saem_dfop_const-1.png          | Bin 180061 -> 174055 bytes
 .../figure-html/f_parent_nlmixr_saem_dfop_tc-1.png | Bin 151832 -> 162039 bytes
 .../f_parent_nlmixr_saem_sfo_const-1.png           | Bin 124946 -> 142453 bytes
 .../figure-html/f_parent_nlmixr_saem_sfo_tc-1.png  | Bin 140491 -> 144010 bytes
 .../figure-html/f_parent_saemix_dfop_const-1.png   | Bin 58759 -> 55927 bytes
 .../figure-html/f_parent_saemix_dfop_tc-1.png      | Bin 0 -> 43674 bytes
 .../figure-html/f_parent_saemix_sfo_const-1.png    | Bin 59913 -> 55667 bytes
 .../figure-html/f_parent_saemix_sfo_tc-1.png       | Bin 53550 -> 50848 bytes
 .../figure-html/plot_parent_nlme-1.png             | Bin 147409 -> 143978 bytes
 .../header-attrs-2.11/header-attrs.js              |  12 +
 15 files changed, 139 insertions(+), 118 deletions(-)
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc-1.png
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/header-attrs-2.11/header-attrs.js

(limited to 'docs/dev/articles/web_only')

diff --git a/docs/dev/articles/web_only/dimethenamid_2018.html b/docs/dev/articles/web_only/dimethenamid_2018.html
index 9a6d8388..b35d8210 100644
--- a/docs/dev/articles/web_only/dimethenamid_2018.html
+++ b/docs/dev/articles/web_only/dimethenamid_2018.html
@@ -32,7 +32,7 @@
       </button>
       <span class="navbar-brand">
         <a class="navbar-link" href="../../index.html">mkin</a>
-        <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.0.5</span>
+        <span class="version label label-info" data-toggle="tooltip" data-placement="bottom" title="In-development version">1.1.0</span>
       </span>
     </div>
 
@@ -95,13 +95,13 @@
 
       
 
-      </header><script src="dimethenamid_2018_files/header-attrs-2.9/header-attrs.js"></script><script src="dimethenamid_2018_files/accessible-code-block-0.0.1/empty-anchor.js"></script><div class="row">
+      </header><script src="dimethenamid_2018_files/header-attrs-2.11/header-attrs.js"></script><script src="dimethenamid_2018_files/accessible-code-block-0.0.1/empty-anchor.js"></script><div class="row">
   <div class="col-md-9 contents">
     <div class="page-header toc-ignore">
       <h1 data-toc-skip>Example evaluations of the dimethenamid data from 2018</h1>
                         <h4 class="author">Johannes Ranke</h4>
             
-            <h4 class="date">Last change 4 August 2021, built on 04 Aug 2021</h4>
+            <h4 class="date">Last change 16 September 2021, built on 16 Sep 2021</h4>
       
       <small class="dont-index">Source: <a href="https://github.com/jranke/mkin/blob/master/vignettes/web_only/dimethenamid_2018.rmd"><code>vignettes/web_only/dimethenamid_2018.rmd</code></a></small>
       <div class="hidden name"><code>dimethenamid_2018.rmd</code></div>
@@ -110,31 +110,28 @@
 
     
     
-<p><a href="http://www.jrwb.de">Wissenschaftlicher Berater, Kronacher Str. 12, 79639 Grenzach-Wyhlen, Germany</a><br><a href="http://chem.uft.uni-bremen.de/ranke">Privatdozent at the University of Bremen</a></p>
+<p><a href="http://www.jrwb.de">Wissenschaftlicher Berater, Kronacher Str. 12, 79639 Grenzach-Wyhlen, Germany</a></p>
 <div id="introduction" class="section level1">
 <h1 class="hasAnchor">
 <a href="#introduction" class="anchor"></a>Introduction</h1>
-<p>During the preparation of the journal article on nonlinear mixed-effects models in degradation kinetics (submitted) and the analysis of the dimethenamid degradation data analysed therein, a need for a more detailed analysis using not only nlme and saemix, but also nlmixr for fitting the mixed-effects models was identified.</p>
+<p>During the preparation of the journal article on nonlinear mixed-effects models in degradation kinetics <span class="citation">(Ranke et al. 2021)</span> and the analysis of the dimethenamid degradation data analysed therein, a need for a more detailed analysis using not only nlme and saemix, but also nlmixr for fitting the mixed-effects models was identified.</p>
 <p>This vignette is an attempt to satisfy this need.</p>
 </div>
 <div id="data" class="section level1">
 <h1 class="hasAnchor">
 <a href="#data" class="anchor"></a>Data</h1>
-<p>Residue data forming the basis for the endpoints derived in the conclusion on the peer review of the pesticide risk assessment of dimethenamid-P published by the European Food Safety Authority (EFSA) in 2018 <span class="citation">(EFSA 2018)</span> were transcribed from the risk assessment report <span class="citation">(Rapporteur Member State Germany, Co-Rapporteur Member State Bulgaria 2018)</span> which can be downloaded from the <a href="https://open.efsa.europa.eu/study-inventory/EFSA-Q-2014-00716">EFSA register of questions</a>.</p>
+<p>Residue data forming the basis for the endpoints derived in the conclusion on the peer review of the pesticide risk assessment of dimethenamid-P published by the European Food Safety Authority (EFSA) in 2018 <span class="citation">(EFSA 2018)</span> were transcribed from the risk assessment report <span class="citation">(Rapporteur Member State Germany, Co-Rapporteur Member State Bulgaria 2018)</span> which can be downloaded from the Open EFSA repository <a href="https://open.efsa.europa.eu">https://open.efsa.europa.eu/study-inventory/EFSA-Q-2014-00716</a>.</p>
 <p>The data are <a href="https://pkgdown.jrwb.de/mkin/reference/dimethenamid_2018.html">available in the mkin package</a>. The following code (hidden by default, please use the button to the right to show it) treats the data available for the racemic mixture dimethenamid (DMTA) and its enantiomer dimethenamid-P (DMTAP) in the same way, as no difference between their degradation behaviour was identified in the EU risk assessment. The observation times of each dataset are multiplied with the corresponding normalisation factor also available in the dataset, in order to make it possible to describe all datasets with a single set of parameters.</p>
 <p>Also, datasets observed in the same soil are merged, resulting in dimethenamid (DMTA) data from six soils.</p>
 <div class="sourceCode" id="cb1"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va"><a href="https://pkgdown.jrwb.de/mkin/">mkin</a></span><span class="op">)</span>
-<span class="va">dmta_ds</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">lapply</a></span><span class="op">(</span><span class="fl">1</span><span class="op">:</span><span class="fl">8</span>, <span class="kw">function</span><span class="op">(</span><span class="va">i</span><span class="op">)</span> <span class="op">{</span>
+<span class="va">dmta_ds</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">lapply</a></span><span class="op">(</span><span class="fl">1</span><span class="op">:</span><span class="fl">7</span>, <span class="kw">function</span><span class="op">(</span><span class="va">i</span><span class="op">)</span> <span class="op">{</span>
   <span class="va">ds_i</span> <span class="op">&lt;-</span> <span class="va">dimethenamid_2018</span><span class="op">$</span><span class="va">ds</span><span class="op">[[</span><span class="va">i</span><span class="op">]</span><span class="op">]</span><span class="op">$</span><span class="va">data</span>
   <span class="va">ds_i</span><span class="op">[</span><span class="va">ds_i</span><span class="op">$</span><span class="va">name</span> <span class="op">==</span> <span class="st">"DMTAP"</span>, <span class="st">"name"</span><span class="op">]</span> <span class="op">&lt;-</span>  <span class="st">"DMTA"</span>
   <span class="va">ds_i</span><span class="op">$</span><span class="va">time</span> <span class="op">&lt;-</span> <span class="va">ds_i</span><span class="op">$</span><span class="va">time</span> <span class="op">*</span> <span class="va">dimethenamid_2018</span><span class="op">$</span><span class="va">f_time_norm</span><span class="op">[</span><span class="va">i</span><span class="op">]</span>
   <span class="va">ds_i</span>
 <span class="op">}</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/r/base/names.html">names</a></span><span class="op">(</span><span class="va">dmta_ds</span><span class="op">)</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">sapply</a></span><span class="op">(</span><span class="va">dimethenamid_2018</span><span class="op">$</span><span class="va">ds</span>, <span class="kw">function</span><span class="op">(</span><span class="va">ds</span><span class="op">)</span> <span class="va">ds</span><span class="op">$</span><span class="va">title</span><span class="op">)</span>
-<span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Borstel"</span><span class="op">]</span><span class="op">]</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/cbind.html">rbind</a></span><span class="op">(</span><span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Borstel 1"</span><span class="op">]</span><span class="op">]</span>, <span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Borstel 2"</span><span class="op">]</span><span class="op">]</span><span class="op">)</span>
-<span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Borstel 1"</span><span class="op">]</span><span class="op">]</span> <span class="op">&lt;-</span> <span class="cn">NULL</span>
-<span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Borstel 2"</span><span class="op">]</span><span class="op">]</span> <span class="op">&lt;-</span> <span class="cn">NULL</span>
 <span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Elliot"</span><span class="op">]</span><span class="op">]</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/cbind.html">rbind</a></span><span class="op">(</span><span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Elliot 1"</span><span class="op">]</span><span class="op">]</span>, <span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Elliot 2"</span><span class="op">]</span><span class="op">]</span><span class="op">)</span>
 <span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Elliot 1"</span><span class="op">]</span><span class="op">]</span> <span class="op">&lt;-</span> <span class="cn">NULL</span>
 <span class="va">dmta_ds</span><span class="op">[[</span><span class="st">"Elliot 2"</span><span class="op">]</span><span class="op">]</span> <span class="op">&lt;-</span> <span class="cn">NULL</span></code></pre></div>
@@ -154,20 +151,20 @@
   error_model <span class="op">=</span> <span class="st">"tc"</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
 <p>The plot of the individual SFO fits shown below suggests that at least in some datasets the degradation slows down towards later time points, and that the scatter of the residuals error is smaller for smaller values (panel to the right):</p>
 <div class="sourceCode" id="cb3"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span><span class="op">)</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span><span class="op">)</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_sfo_const-1.png" width="700"></p>
 <p>Using biexponential decline (DFOP) results in a slightly more random scatter of the residuals:</p>
 <div class="sourceCode" id="cb4"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const-1.png" width="700"></p>
 <p>The population curve (bold line) in the above plot results from taking the mean of the individual transformed parameters, i.e. of log k1 and log k2, as well as of the logit of the g parameter of the DFOP model). Here, this procedure does not result in parameters that represent the degradation well, because in some datasets the fitted value for k2 is extremely close to zero, leading to a log k2 value that dominates the average. This is alleviated if only rate constants that pass the t-test for significant difference from zero (on the untransformed scale) are considered in the averaging:</p>
 <div class="sourceCode" id="cb5"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span>, test_log_parms <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span>, test_log_parms <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const_test-1.png" width="700"></p>
 <p>While this is visually much more satisfactory, such an average procedure could introduce a bias, as not all results from the individual fits enter the population curve with the same weight. This is where nonlinear mixed-effects models can help out by treating all datasets with equally by fitting a parameter distribution model together with the degradation model and the error model (see below).</p>
 <p>The remaining trend of the residuals to be higher for higher predicted residues is reduced by using the two-component error model:</p>
 <div class="sourceCode" id="cb6"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span>, test_log_parms <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span>, test_log_parms <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_tc_test-1.png" width="700"></p>
 </div>
 <div id="nonlinear-mixed-effects-models" class="section level2">
@@ -177,175 +174,184 @@
 <div id="nlme" class="section level3">
 <h3 class="hasAnchor">
 <a href="#nlme" class="anchor"></a>nlme</h3>
-<p>The nlme package was the first R extension providing facilities to fit nonlinear mixed-effects models. We use would like to do model selection from all four combinations of degradation models and error models based on the AIC. However, fitting the DFOP model with constant variance and using default control parameters results in an error, signalling that the maximum number of 50 iterations was reached, potentially indicating overparameterisation. However, the algorithm converges when the two-component error model is used in combination with the DFOP model. This can be explained by the fact that the smaller residues observed at later sampling times get more weight when using the two-component error model which will counteract the tendency of the algorithm to try parameter combinations unsuitable for fitting these data.</p>
+<p>The nlme package was the first R extension providing facilities to fit nonlinear mixed-effects models. We would like to do model selection from all four combinations of degradation models and error models based on the AIC. However, fitting the DFOP model with constant variance and using default control parameters results in an error, signalling that the maximum number of 50 iterations was reached, potentially indicating overparameterisation. However, the algorithm converges when the two-component error model is used in combination with the DFOP model. This can be explained by the fact that the smaller residues observed at later sampling times get more weight when using the two-component error model which will counteract the tendency of the algorithm to try parameter combinations unsuitable for fitting these data.</p>
 <div class="sourceCode" id="cb7"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va"><a href="https://svn.r-project.org/R-packages/trunk/nlme/">nlme</a></span><span class="op">)</span>
 <span class="va">f_parent_nlme_sfo_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/nlme.html">nlme</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span><span class="op">)</span>
-<span class="co">#f_parent_nlme_dfop_const &lt;- nlme(f_parent_mkin_const["DFOP", ])</span>
-<span class="co"># maxIter = 50 reached</span>
+<span class="co"># f_parent_nlme_dfop_const &lt;- nlme(f_parent_mkin_const["DFOP", ])</span>
 <span class="va">f_parent_nlme_sfo_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/nlme.html">nlme</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span><span class="op">)</span>
 <span class="va">f_parent_nlme_dfop_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/nlme.html">nlme</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span></code></pre></div>
-<p>Note that overparameterisation is also indicated by warnings obtained when fitting SFO or DFOP with the two-component error model (‘false convergence’ in the ‘LME step’ in some iterations). In addition to these fits, attempts were also made to include correlations between random effects by using the log Cholesky parameterisation of the matrix specifying them. The code used for these attempts can be made visible below.</p>
+<p>Note that a certain degree of overparameterisation is also indicated by a warning obtained when fitting DFOP with the two-component error model (‘false convergence’ in the ‘LME step’ in iteration 3). However, as this warning does not occur in later iterations, and specifically not in the last of the 6 iterations, we can ignore this warning.</p>
+<p>The model comparison function of the nlme package can directly be applied to these fits showing a much lower AIC for the DFOP model fitted with the two-component error model. Also, the likelihood ratio test indicates that this difference is significant. as the p-value is below 0.0001.</p>
 <div class="sourceCode" id="cb8"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="va">f_parent_nlme_sfo_const_logchol</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/nlme.html">nlme</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>,
-  random <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/pdLogChol.html">pdLogChol</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">DMTA_0</span> <span class="op">~</span> <span class="fl">1</span>, <span class="va">log_k_DMTA</span> <span class="op">~</span> <span class="fl">1</span><span class="op">)</span><span class="op">)</span><span class="op">)</span>
-<span class="fu"><a href="https://rdrr.io/r/stats/anova.html">anova</a></span><span class="op">(</span><span class="va">f_parent_nlme_sfo_const</span>, <span class="va">f_parent_nlme_sfo_const_logchol</span><span class="op">)</span> <span class="co"># not better</span>
-<span class="co">#f_parent_nlme_dfop_tc_logchol &lt;- update(f_parent_nlme_dfop_tc,</span>
-<span class="co">#  random = pdLogChol(list(DMTA_0 ~ 1, log_k1 ~ 1, log_k2 ~ 1, g_qlogis ~ 1)))</span>
-<span class="co"># using log Cholesky parameterisation for random effects (nlme default) does</span>
-<span class="co"># not converge here and gives lots of warnings about the LME step not converging</span></code></pre></div>
-<p>The model comparison function of the nlme package can directly be applied to these fits showing a similar goodness-of-fit of the SFO model, but a much lower AIC for the DFOP model fitted with the two-component error model. Also, the likelihood ratio test indicates that this difference is significant. as the p-value is below 0.0001.</p>
-<div class="sourceCode" id="cb9"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/anova.html">anova</a></span><span class="op">(</span>
   <span class="va">f_parent_nlme_sfo_const</span>, <span class="va">f_parent_nlme_sfo_tc</span>, <span class="va">f_parent_nlme_dfop_tc</span>
 <span class="op">)</span></code></pre></div>
 <pre><code>                        Model df    AIC    BIC  logLik   Test L.Ratio p-value
-f_parent_nlme_sfo_const     1  5 818.63 834.00 -404.31                       
-f_parent_nlme_sfo_tc        2  6 820.61 839.06 -404.31 1 vs 2   0.014  0.9049
-f_parent_nlme_dfop_tc       3 10 687.84 718.59 -333.92 2 vs 3 140.771  &lt;.0001</code></pre>
+f_parent_nlme_sfo_const     1  5 796.60 811.82 -393.30                       
+f_parent_nlme_sfo_tc        2  6 798.60 816.86 -393.30 1 vs 2    0.00   0.998
+f_parent_nlme_dfop_tc       3 10 671.91 702.34 -325.96 2 vs 3  134.69  &lt;.0001</code></pre>
+<p>In addition to these fits, attempts were also made to include correlations between random effects by using the log Cholesky parameterisation of the matrix specifying them. The code used for these attempts can be made visible below.</p>
+<div class="sourceCode" id="cb10"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">f_parent_nlme_sfo_const_logchol</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/nlme.html">nlme</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>,
+  random <span class="op">=</span> <span class="fu">nlme</span><span class="fu">::</span><span class="fu"><a href="https://rdrr.io/pkg/nlme/man/pdLogChol.html">pdLogChol</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">DMTA_0</span> <span class="op">~</span> <span class="fl">1</span>, <span class="va">log_k_DMTA</span> <span class="op">~</span> <span class="fl">1</span><span class="op">)</span><span class="op">)</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/r/stats/anova.html">anova</a></span><span class="op">(</span><span class="va">f_parent_nlme_sfo_const</span>, <span class="va">f_parent_nlme_sfo_const_logchol</span><span class="op">)</span>
+<span class="va">f_parent_nlme_sfo_tc_logchol</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/nlme.html">nlme</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>,
+  random <span class="op">=</span> <span class="fu">nlme</span><span class="fu">::</span><span class="fu"><a href="https://rdrr.io/pkg/nlme/man/pdLogChol.html">pdLogChol</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">DMTA_0</span> <span class="op">~</span> <span class="fl">1</span>, <span class="va">log_k_DMTA</span> <span class="op">~</span> <span class="fl">1</span><span class="op">)</span><span class="op">)</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/r/stats/anova.html">anova</a></span><span class="op">(</span><span class="va">f_parent_nlme_sfo_tc</span>, <span class="va">f_parent_nlme_sfo_tc_logchol</span><span class="op">)</span>
+<span class="va">f_parent_nlme_dfop_tc_logchol</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/nlme.html">nlme</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>,
+  random <span class="op">=</span> <span class="fu">nlme</span><span class="fu">::</span><span class="fu"><a href="https://rdrr.io/pkg/nlme/man/pdLogChol.html">pdLogChol</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">DMTA_0</span> <span class="op">~</span> <span class="fl">1</span>, <span class="va">log_k1</span> <span class="op">~</span> <span class="fl">1</span>, <span class="va">log_k2</span> <span class="op">~</span> <span class="fl">1</span>, <span class="va">g_qlogis</span> <span class="op">~</span> <span class="fl">1</span><span class="op">)</span><span class="op">)</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/r/stats/anova.html">anova</a></span><span class="op">(</span><span class="va">f_parent_nlme_dfop_tc</span>, <span class="va">f_parent_nlme_dfop_tc_logchol</span><span class="op">)</span></code></pre></div>
+<p>While the SFO variants converge fast, the additional parameters introduced by this lead to convergence warnings for the DFOP model. The model comparison clearly show that adding correlations between random effects does not improve the fits.</p>
 <p>The selected model (DFOP with two-component error) fitted to the data assuming no correlations between random effects is shown below.</p>
 <div class="sourceCode" id="cb11"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_nlme_dfop_tc</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="va">f_parent_nlme_dfop_tc</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/plot_parent_nlme-1.png" width="700"></p>
 </div>
 <div id="saemix" class="section level3">
 <h3 class="hasAnchor">
 <a href="#saemix" class="anchor"></a>saemix</h3>
-<p>The saemix package provided the first Open Source implementation of the Stochastic Approximation to the Expectation Maximisation (SAEM) algorithm. SAEM fits of degradation models can be performed using an interface to the saemix package available in current development versions of the mkin package.</p>
-<p>The corresponding SAEM fits of the four combinations of degradation and error models are fitted below. As there is no convergence criterion implemented in the saemix package, the convergence plots need to be manually checked for every fit.</p>
-<p>The convergence plot for the SFO model using constant variance is shown below.</p>
+<p>The saemix package provided the first Open Source implementation of the Stochastic Approximation to the Expectation Maximisation (SAEM) algorithm. SAEM fits of degradation models can be conveniently performed using an interface to the saemix package available in current development versions of the mkin package.</p>
+<p>The corresponding SAEM fits of the four combinations of degradation and error models are fitted below. As there is no convergence criterion implemented in the saemix package, the convergence plots need to be manually checked for every fit. As we will compare the SAEM implementation of saemix to the results obtained using the nlmixr package later, we define control settings that work well for all the parent data fits shown in this vignette.</p>
 <div class="sourceCode" id="cb12"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va">saemix</span><span class="op">)</span>
-<span class="va">f_parent_saemix_sfo_const</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
-  transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
+<span class="va">saemix_control</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/saemixControl.html">saemixControl</a></span><span class="op">(</span>nbiter.saemix <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="fl">800</span>, <span class="fl">300</span><span class="op">)</span>, nb.chains <span class="op">=</span> <span class="fl">15</span>,
+    print <span class="op">=</span> <span class="cn">FALSE</span>, save <span class="op">=</span> <span class="cn">FALSE</span>, save.graphs <span class="op">=</span> <span class="cn">FALSE</span>, displayProgress <span class="op">=</span> <span class="cn">FALSE</span><span class="op">)</span></code></pre></div>
+<p>The convergence plot for the SFO model using constant variance is shown below.</p>
+<div class="sourceCode" id="cb13"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">f_parent_saemix_sfo_const</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
+  control <span class="op">=</span> <span class="va">saemix_control</span>, transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_sfo_const</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_const-1.png" width="700"></p>
 <p>Obviously the default number of iterations is sufficient to reach convergence. This can also be said for the SFO fit using the two-component error model.</p>
-<div class="sourceCode" id="cb13"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb14"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_saemix_sfo_tc</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
-  transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
+  control <span class="op">=</span> <span class="va">saemix_control</span>, transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_sfo_tc</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_tc-1.png" width="700"></p>
 <p>When fitting the DFOP model with constant variance, parameter convergence is not as unambiguous (see the failure of nlme with the default number of iterations above). Therefore, the number of iterations in the first phase of the algorithm was increased, leading to visually satisfying convergence.</p>
-<div class="sourceCode" id="cb14"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb15"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_saemix_dfop_const</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
-  control <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/saemixControl.html">saemixControl</a></span><span class="op">(</span>nbiter.saemix <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="fl">800</span>, <span class="fl">200</span><span class="op">)</span>, print <span class="op">=</span> <span class="cn">FALSE</span>,
-    save <span class="op">=</span> <span class="cn">FALSE</span>, save.graphs <span class="op">=</span> <span class="cn">FALSE</span>, displayProgress <span class="op">=</span> <span class="cn">FALSE</span><span class="op">)</span>,
-  transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
+  control <span class="op">=</span> <span class="va">saemix_control</span>, transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_const</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_const-1.png" width="700"></p>
-<p>The same applies to the case where the DFOP model is fitted with the two-component error model. Convergence of the variance of k2 is enhanced by using the two-component error, it remains more or less stable already after 200 iterations of the first phase.</p>
-<div class="sourceCode" id="cb15"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="va">f_parent_saemix_dfop_tc_moreiter</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
-  control <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/saemixControl.html">saemixControl</a></span><span class="op">(</span>nbiter.saemix <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="fl">800</span>, <span class="fl">200</span><span class="op">)</span>, print <span class="op">=</span> <span class="cn">FALSE</span>,
-    save <span class="op">=</span> <span class="cn">FALSE</span>, save.graphs <span class="op">=</span> <span class="cn">FALSE</span>, displayProgress <span class="op">=</span> <span class="cn">FALSE</span><span class="op">)</span>,
-  transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
-<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
-<p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_moreiter-1.png" width="700"></p>
-<p>The four combinations can be compared using the model comparison function from the saemix package:</p>
+<p>The same applies in the case where the DFOP model is fitted with the two-component error model. Convergence of the variance of k2 is enhanced by using the two-component error, it remains more or less stable already after 200 iterations of the first phase.</p>
 <div class="sourceCode" id="cb16"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/compare.saemix.html">compare.saemix</a></span><span class="op">(</span><span class="va">f_parent_saemix_sfo_const</span><span class="op">$</span><span class="va">so</span>, <span class="va">f_parent_saemix_sfo_tc</span><span class="op">$</span><span class="va">so</span>,
-  <span class="va">f_parent_saemix_dfop_const</span><span class="op">$</span><span class="va">so</span>, <span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="va">f_parent_saemix_dfop_tc</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
+  control <span class="op">=</span> <span class="va">saemix_control</span>, transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc-1.png" width="700"> The four combinations and including the variations of the DFOP/tc combination can be compared using the model comparison function from the saemix package:</p>
+<div class="sourceCode" id="cb17"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/compare.saemix.html">compare.saemix</a></span><span class="op">(</span>
+  <span class="va">f_parent_saemix_sfo_const</span><span class="op">$</span><span class="va">so</span>,
+  <span class="va">f_parent_saemix_sfo_tc</span><span class="op">$</span><span class="va">so</span>,
+  <span class="va">f_parent_saemix_dfop_const</span><span class="op">$</span><span class="va">so</span>,
+  <span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span><span class="op">)</span></code></pre></div>
 <pre><code>Likelihoods calculated by importance sampling</code></pre>
 <pre><code>     AIC    BIC
-1 818.37 817.33
-2 820.38 819.14
-3 725.91 724.04
-4 683.64 681.55</code></pre>
-<p>As in the case of nlme fits, the DFOP model fitted with two-component error (number 4) gives the lowest AIC. The numeric values are reasonably close to the ones obtained using nlme, considering that the algorithms for fitting the model and for the likelihood calculation are quite different.</p>
+1 796.37 795.33
+2 798.37 797.13
+3 713.16 711.28
+4 666.10 664.01</code></pre>
+<p>As in the case of nlme fits, the DFOP model fitted with two-component error (number 4) gives the lowest AIC. Using more iterations and/or more chains does not have a large influence on the final AIC (not shown).</p>
 <p>In order to check the influence of the likelihood calculation algorithms implemented in saemix, the likelihood from Gaussian quadrature is added to the best fit, and the AIC values obtained from the three methods are compared.</p>
-<div class="sourceCode" id="cb19"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span> <span class="op">&lt;-</span>
-  <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/llgq.saemix.html">llgq.saemix</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span><span class="op">)</span>
-<span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span><span class="op">)</span></code></pre></div>
-<pre><code>[1] 683.64</code></pre>
-<div class="sourceCode" id="cb21"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span>, method <span class="op">=</span> <span class="st">"gq"</span><span class="op">)</span></code></pre></div>
-<pre><code>[1] 683.7</code></pre>
-<div class="sourceCode" id="cb23"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span>, method <span class="op">=</span> <span class="st">"lin"</span><span class="op">)</span></code></pre></div>
-<pre><code>[1] 683.17</code></pre>
-<p>The AIC values based on importance sampling and Gaussian quadrature are quite similar. Using linearisation is less accurate, but still gives a similar value.</p>
+<div class="sourceCode" id="cb20"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span> <span class="op">&lt;-</span>
+  <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/llgq.saemix.html">llgq.saemix</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span><span class="op">)</span></code></pre></div>
+<pre><code>[1] 666.1</code></pre>
+<div class="sourceCode" id="cb22"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span>, method <span class="op">=</span> <span class="st">"gq"</span><span class="op">)</span></code></pre></div>
+<pre><code>[1] 666.03</code></pre>
+<div class="sourceCode" id="cb24"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span>, method <span class="op">=</span> <span class="st">"lin"</span><span class="op">)</span></code></pre></div>
+<pre><code>[1] 665.48</code></pre>
+<p>The AIC values based on importance sampling and Gaussian quadrature are very similar. Using linearisation is known to be less accurate, but still gives a similar value.</p>
 </div>
 <div id="nlmixr" class="section level3">
 <h3 class="hasAnchor">
 <a href="#nlmixr" class="anchor"></a>nlmixr</h3>
-<p>In the last years, a lot of effort has been put into the nlmixr package which is designed for pharmacokinetics, where nonlinear mixed-effects models are routinely used, but which can also be used for related data like chemical degradation data. A current development branch of the mkin package provides an interface between mkin and nlmixr. Here, we check if we get equivalent results when using a refined version of the First Order Conditional Estimation (FOCE) algorithm used in nlme, namely First Order Conditional Estimation with Interaction (FOCEI), and the SAEM algorithm as implemented in nlmixr.</p>
-<p>First, the focei algorithm is used for the four model combinations and the goodness of fit of the results is compared.</p>
-<div class="sourceCode" id="cb25"><pre class="downlit sourceCode r">
+<p>In the last years, a lot of effort has been put into the nlmixr package which is designed for pharmacokinetics, where nonlinear mixed-effects models are routinely used, but which can also be used for related data like chemical degradation data. A current development branch of the mkin package provides an interface between mkin and nlmixr. Here, we check if we get equivalent results when using a refined version of the First Order Conditional Estimation (FOCE) algorithm used in nlme, namely the First Order Conditional Estimation with Interaction (FOCEI), and the SAEM algorithm as implemented in nlmixr.</p>
+<p>First, the focei algorithm is used for the four model combinations. A number of warnings are produced with unclear significance.</p>
+<div class="sourceCode" id="cb26"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va"><a href="https://github.com/nlmixrdevelopment/nlmixr">nlmixr</a></span><span class="op">)</span>
 <span class="va">f_parent_nlmixr_focei_sfo_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"focei"</span><span class="op">)</span>
 <span class="va">f_parent_nlmixr_focei_sfo_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"focei"</span><span class="op">)</span>
 <span class="va">f_parent_nlmixr_focei_dfop_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"focei"</span><span class="op">)</span>
 <span class="va">f_parent_nlmixr_focei_dfop_tc</span><span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"focei"</span><span class="op">)</span></code></pre></div>
-<div class="sourceCode" id="cb26"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_focei_sfo_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_focei_sfo_tc</span><span class="op">$</span><span class="va">nm</span>,
-  <span class="va">f_parent_nlmixr_focei_dfop_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_focei_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
-<pre><code>                                    df    AIC
-f_parent_nlmixr_focei_sfo_const$nm   5 818.63
-f_parent_nlmixr_focei_sfo_tc$nm      6 820.61
-f_parent_nlmixr_focei_dfop_const$nm  9 728.11
-f_parent_nlmixr_focei_dfop_tc$nm    10 687.82</code></pre>
+<div class="sourceCode" id="cb27"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">aic_nlmixr_focei</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">sapply</a></span><span class="op">(</span>
+  <span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_focei_sfo_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_focei_sfo_tc</span><span class="op">$</span><span class="va">nm</span>,
+    <span class="va">f_parent_nlmixr_focei_dfop_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_focei_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span>,
+  <span class="va">AIC</span><span class="op">)</span></code></pre></div>
 <p>The AIC values are very close to the ones obtained with nlme which are repeated below for convenience.</p>
 <div class="sourceCode" id="cb28"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span>
-  <span class="va">f_parent_nlme_sfo_const</span>, <span class="va">f_parent_nlme_sfo_tc</span>, <span class="va">f_parent_nlme_dfop_tc</span>
+<code class="sourceCode R"><span class="va">aic_nlme</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">sapply</a></span><span class="op">(</span>
+  <span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">f_parent_nlme_sfo_const</span>, <span class="cn">NA</span>, <span class="va">f_parent_nlme_sfo_tc</span>, <span class="va">f_parent_nlme_dfop_tc</span><span class="op">)</span>,
+  <span class="kw">function</span><span class="op">(</span><span class="va">x</span><span class="op">)</span> <span class="kw">if</span> <span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/NA.html">is.na</a></span><span class="op">(</span><span class="va">x</span><span class="op">[</span><span class="fl">1</span><span class="op">]</span><span class="op">)</span><span class="op">)</span> <span class="cn">NA</span> <span class="kw">else</span> <span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">x</span><span class="op">)</span><span class="op">)</span>
+<span class="va">aic_nlme_nlmixr_focei</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/data.frame.html">data.frame</a></span><span class="op">(</span>
+  <span class="st">"Degradation model"</span> <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="st">"SFO"</span>, <span class="st">"SFO"</span>, <span class="st">"DFOP"</span>, <span class="st">"DFOP"</span><span class="op">)</span>,
+  <span class="st">"Error model"</span> <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/rep.html">rep</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="st">"constant variance"</span>, <span class="st">"two-component"</span><span class="op">)</span>, <span class="fl">2</span><span class="op">)</span>,
+  <span class="st">"AIC (nlme)"</span> <span class="op">=</span> <span class="va">aic_nlme</span>,
+  <span class="st">"AIC (nlmixr with FOCEI)"</span> <span class="op">=</span> <span class="va">aic_nlmixr_focei</span>,
+  check.names <span class="op">=</span> <span class="cn">FALSE</span>
 <span class="op">)</span></code></pre></div>
-<pre><code>                        df    AIC
-f_parent_nlme_sfo_const  5 818.63
-f_parent_nlme_sfo_tc     6 820.61
-f_parent_nlme_dfop_tc   10 687.84</code></pre>
-<p>Secondly, we use the SAEM estimation routine and check the convergence plots for SFO with constant variance</p>
+<p>Secondly, we use the SAEM estimation routine and check the convergence plots. The control parameters also used for the saemix fits are defined beforehand.</p>
+<div class="sourceCode" id="cb29"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">nlmixr_saem_control</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span>,
+  nBurn <span class="op">=</span> <span class="fl">1000</span>, nEm <span class="op">=</span> <span class="fl">300</span>, nmc <span class="op">=</span> <span class="fl">15</span><span class="op">)</span></code></pre></div>
+<p>The we fit SFO with constant variance</p>
 <div class="sourceCode" id="cb30"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_sfo_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
-  control <span class="op">=</span> <span class="fu">nlmixr</span><span class="fu">::</span><span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span><span class="op">)</span>
+  control <span class="op">=</span> <span class="va">nlmixr_saem_control</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_const</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png" width="700"></p>
-<p>for SFO with two-component error</p>
+<p>and SFO with two-component error.</p>
 <div class="sourceCode" id="cb31"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_sfo_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
-  control <span class="op">=</span> <span class="fu">nlmixr</span><span class="fu">::</span><span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span><span class="op">)</span>
+  control <span class="op">=</span> <span class="va">nlmixr_saem_control</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png" width="700"></p>
-<p>For DFOP with constant variance, the convergence plots show considerable instability of the fit, which can be alleviated by increasing the number of iterations and the number of parallel chains for the first phase of algorithm.</p>
+<p>For DFOP with constant variance, the convergence plots show considerable instability of the fit, which indicates overparameterisation which was already observed earlier for this model combination.</p>
 <div class="sourceCode" id="cb32"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_dfop_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
-  control <span class="op">=</span> <span class="fu">nlmixr</span><span class="fu">::</span><span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span>, nBurn <span class="op">=</span> <span class="fl">1000</span><span class="op">)</span>, nmc <span class="op">=</span> <span class="fl">15</span><span class="op">)</span>
+  control <span class="op">=</span> <span class="va">nlmixr_saem_control</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_dfop_const</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png" width="700"></p>
-<p>For DFOP with two-component error, the same increase in iterations and parallel chains was used, but using the two-component error appears to lead to a less erratic convergence, so this may not be necessary to this degree.</p>
+<p>For DFOP with two-component error, a less erratic convergence is seen.</p>
 <div class="sourceCode" id="cb33"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_dfop_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
-  control <span class="op">=</span> <span class="fu">nlmixr</span><span class="fu">::</span><span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span>, nBurn <span class="op">=</span> <span class="fl">1000</span>, nmc <span class="op">=</span> <span class="fl">15</span><span class="op">)</span><span class="op">)</span>
+  control <span class="op">=</span> <span class="va">nlmixr_saem_control</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png" width="700"></p>
-<p>The AIC values are internally calculated using Gaussian quadrature. For an unknown reason, the AIC value obtained for the DFOP fit using the two-component error model is given as Infinity.</p>
+<p>The AIC values are internally calculated using Gaussian quadrature. For an unknown reason, the AIC value obtained for the DFOP fit using constant error is given as Infinity.</p>
 <div class="sourceCode" id="cb34"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_saem_sfo_tc</span><span class="op">$</span><span class="va">nm</span>,
   <span class="va">f_parent_nlmixr_saem_dfop_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_saem_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
 <pre><code>                                   df    AIC
-f_parent_nlmixr_saem_sfo_const$nm   5 820.54
-f_parent_nlmixr_saem_sfo_tc$nm      6 835.26
-f_parent_nlmixr_saem_dfop_const$nm  9 842.84
-f_parent_nlmixr_saem_dfop_tc$nm    10 684.51</code></pre>
+f_parent_nlmixr_saem_sfo_const$nm   5 798.68
+f_parent_nlmixr_saem_sfo_tc$nm      6 808.88
+f_parent_nlmixr_saem_dfop_const$nm  9 815.95
+f_parent_nlmixr_saem_dfop_tc$nm    10 669.57</code></pre>
 <p>The following table gives the AIC values obtained with the three packages.</p>
 <div class="sourceCode" id="cb36"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">AIC_all</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/data.frame.html">data.frame</a></span><span class="op">(</span>
+  check.names <span class="op">=</span> <span class="cn">FALSE</span>,
   <span class="st">"Degradation model"</span> <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="st">"SFO"</span>, <span class="st">"SFO"</span>, <span class="st">"DFOP"</span>, <span class="st">"DFOP"</span><span class="op">)</span>,
   <span class="st">"Error model"</span> <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="st">"const"</span>, <span class="st">"tc"</span>, <span class="st">"const"</span>, <span class="st">"tc"</span><span class="op">)</span>,
   nlme <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlme_sfo_const</span><span class="op">)</span>, <span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlme_sfo_tc</span><span class="op">)</span>, <span class="cn">NA</span>, <span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlme_dfop_tc</span><span class="op">)</span><span class="op">)</span>,
   nlmixr_focei <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">sapply</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_focei_sfo_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_focei_sfo_tc</span><span class="op">$</span><span class="va">nm</span>,
   <span class="va">f_parent_nlmixr_focei_dfop_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_focei_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span>, <span class="va">AIC</span><span class="op">)</span>,
   saemix <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">sapply</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">f_parent_saemix_sfo_const</span><span class="op">$</span><span class="va">so</span>, <span class="va">f_parent_saemix_sfo_tc</span><span class="op">$</span><span class="va">so</span>,
-    <span class="va">f_parent_saemix_dfop_const</span><span class="op">$</span><span class="va">so</span>, <span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span><span class="op">)</span>, <span class="va">AIC</span><span class="op">)</span>,
+    <span class="va">f_parent_saemix_dfop_const</span><span class="op">$</span><span class="va">so</span>, <span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span><span class="op">)</span>, <span class="va">AIC</span><span class="op">)</span>,
   nlmixr_saem <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">sapply</a></span><span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_saem_sfo_tc</span><span class="op">$</span><span class="va">nm</span>,
   <span class="va">f_parent_nlmixr_saem_dfop_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_saem_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span>, <span class="va">AIC</span><span class="op">)</span>
 <span class="op">)</span>
 <span class="fu">kable</span><span class="op">(</span><span class="va">AIC_all</span><span class="op">)</span></code></pre></div>
 <table class="table">
 <thead><tr class="header">
-<th align="left">Degradation.model</th>
-<th align="left">Error.model</th>
+<th align="left">Degradation model</th>
+<th align="left">Error model</th>
 <th align="right">nlme</th>
 <th align="right">nlmixr_focei</th>
 <th align="right">saemix</th>
@@ -355,34 +361,34 @@ f_parent_nlmixr_saem_dfop_tc$nm    10 684.51</code></pre>
 <tr class="odd">
 <td align="left">SFO</td>
 <td align="left">const</td>
-<td align="right">818.63</td>
-<td align="right">818.63</td>
-<td align="right">818.37</td>
-<td align="right">820.54</td>
+<td align="right">796.60</td>
+<td align="right">796.62</td>
+<td align="right">796.37</td>
+<td align="right">798.68</td>
 </tr>
 <tr class="even">
 <td align="left">SFO</td>
 <td align="left">tc</td>
-<td align="right">820.61</td>
-<td align="right">820.61</td>
-<td align="right">820.38</td>
-<td align="right">835.26</td>
+<td align="right">798.60</td>
+<td align="right">798.61</td>
+<td align="right">798.37</td>
+<td align="right">808.88</td>
 </tr>
 <tr class="odd">
 <td align="left">DFOP</td>
 <td align="left">const</td>
 <td align="right">NA</td>
-<td align="right">728.11</td>
-<td align="right">725.91</td>
-<td align="right">842.84</td>
+<td align="right">750.91</td>
+<td align="right">713.16</td>
+<td align="right">815.95</td>
 </tr>
 <tr class="even">
 <td align="left">DFOP</td>
 <td align="left">tc</td>
-<td align="right">687.84</td>
-<td align="right">687.82</td>
-<td align="right">683.64</td>
-<td align="right">684.51</td>
+<td align="right">671.91</td>
+<td align="right">666.60</td>
+<td align="right">666.10</td>
+<td align="right">669.57</td>
 </tr>
 </tbody>
 </table>
@@ -397,6 +403,9 @@ f_parent_nlmixr_saem_dfop_tc$nm    10 684.51</code></pre>
 <div id="ref-efsa_2018_dimethenamid">
 <p>EFSA. 2018. “Peer Review of the Pesticide Risk Assessment of the Active Substance Dimethenamid-P.” <em>EFSA Journal</em> 16 (4): 5211.</p>
 </div>
+<div id="ref-ranke2021">
+<p>Ranke, Johannes, Janina Wöltjen, Jana Schmidt, and Emmanuelle Comets. 2021. “Taking Kinetic Evaluations of Degradation Data to the Next Level with Nonlinear Mixed-Effects Models.” <em>Environments</em> 8 (8). <a href="https://doi.org/10.3390/environments8080071">https://doi.org/10.3390/environments8080071</a>.</p>
+</div>
 <div id="ref-dimethenamid_rar_2018_b8">
 <p>Rapporteur Member State Germany, Co-Rapporteur Member State Bulgaria. 2018. “Renewal Assessment Report Dimethenamid-P Volume 3 - B.8 Environmental fate and behaviour, Rev. 2 - November 2017.” <a href="https://open.efsa.europa.eu/study-inventory/EFSA-Q-2014-00716">https://open.efsa.europa.eu/study-inventory/EFSA-Q-2014-00716</a>.</p>
 </div>
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const-1.png
index c51afe54..8eb464d1 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const_test-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const_test-1.png
index 080f0dde..9e4b951a 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const_test-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const_test-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_tc_test-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_tc_test-1.png
index a3933e54..830fec65 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_tc_test-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_tc_test-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_sfo_const-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_sfo_const-1.png
index 8dee2e3c..133249a4 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_sfo_const-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_mkin_sfo_const-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png
index 54a8c1a6..db28e43d 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png
index 91f3d977..718524e7 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png
index c84f2926..9dde6124 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png
index cfef9dfc..e2368797 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_const-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_const-1.png
index a4695eea..7c79b56c 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_const-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_const-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc-1.png
new file mode 100644
index 00000000..8478adcf
Binary files /dev/null and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_const-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_const-1.png
index 469ebafd..18b546e9 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_const-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_const-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_tc-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_tc-1.png
index d26bcc09..6a0c05c5 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_tc-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_tc-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/plot_parent_nlme-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/plot_parent_nlme-1.png
index 6edeb794..ed978664 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/plot_parent_nlme-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/plot_parent_nlme-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/header-attrs-2.11/header-attrs.js b/docs/dev/articles/web_only/dimethenamid_2018_files/header-attrs-2.11/header-attrs.js
new file mode 100644
index 00000000..dd57d92e
--- /dev/null
+++ b/docs/dev/articles/web_only/dimethenamid_2018_files/header-attrs-2.11/header-attrs.js
@@ -0,0 +1,12 @@
+// Pandoc 2.9 adds attributes on both header and div. We remove the former (to
+// be compatible with the behavior of Pandoc < 2.8).
+document.addEventListener('DOMContentLoaded', function(e) {
+  var hs = document.querySelectorAll("div.section[class*='level'] > :first-child");
+  var i, h, a;
+  for (i = 0; i < hs.length; i++) {
+    h = hs[i];
+    if (!/^h[1-6]$/i.test(h.tagName)) continue;  // it should be a header h1-h6
+    a = h.attributes;
+    while (a.length > 0) h.removeAttribute(a[0].name);
+  }
+});
-- 
cgit v1.2.1


From 047d048b89e167fb354b45cd7c6b719b9f4cdd28 Mon Sep 17 00:00:00 2001
From: Johannes Ranke <jranke@uni-bremen.de>
Date: Fri, 17 Sep 2021 08:47:09 +0200
Subject: Put the AIC comparison in a subsubsection

---
 docs/dev/articles/web_only/dimethenamid_2018.html | 46 ++++++++++++-----------
 1 file changed, 25 insertions(+), 21 deletions(-)

(limited to 'docs/dev/articles/web_only')

diff --git a/docs/dev/articles/web_only/dimethenamid_2018.html b/docs/dev/articles/web_only/dimethenamid_2018.html
index b35d8210..26b352e1 100644
--- a/docs/dev/articles/web_only/dimethenamid_2018.html
+++ b/docs/dev/articles/web_only/dimethenamid_2018.html
@@ -101,7 +101,7 @@
       <h1 data-toc-skip>Example evaluations of the dimethenamid data from 2018</h1>
                         <h4 class="author">Johannes Ranke</h4>
             
-            <h4 class="date">Last change 16 September 2021, built on 16 Sep 2021</h4>
+            <h4 class="date">Last change 17 September 2021, built on 17 Sep 2021</h4>
       
       <small class="dont-index">Source: <a href="https://github.com/jranke/mkin/blob/master/vignettes/web_only/dimethenamid_2018.rmd"><code>vignettes/web_only/dimethenamid_2018.rmd</code></a></small>
       <div class="hidden name"><code>dimethenamid_2018.rmd</code></div>
@@ -114,7 +114,7 @@
 <div id="introduction" class="section level1">
 <h1 class="hasAnchor">
 <a href="#introduction" class="anchor"></a>Introduction</h1>
-<p>During the preparation of the journal article on nonlinear mixed-effects models in degradation kinetics <span class="citation">(Ranke et al. 2021)</span> and the analysis of the dimethenamid degradation data analysed therein, a need for a more detailed analysis using not only nlme and saemix, but also nlmixr for fitting the mixed-effects models was identified.</p>
+<p>During the preparation of the journal article on nonlinear mixed-effects models in degradation kinetics <span class="citation">(Ranke et al. 2021)</span> and the analysis of the dimethenamid degradation data analysed therein, a need for a more detailed analysis using not only nlme and saemix, but also nlmixr for fitting the mixed-effects models was identified, as many model variants do not converge when fitted with nlme, and not all relevant error models can be fitted with saemix.</p>
 <p>This vignette is an attempt to satisfy this need.</p>
 </div>
 <div id="data" class="section level1">
@@ -124,7 +124,7 @@
 <p>The data are <a href="https://pkgdown.jrwb.de/mkin/reference/dimethenamid_2018.html">available in the mkin package</a>. The following code (hidden by default, please use the button to the right to show it) treats the data available for the racemic mixture dimethenamid (DMTA) and its enantiomer dimethenamid-P (DMTAP) in the same way, as no difference between their degradation behaviour was identified in the EU risk assessment. The observation times of each dataset are multiplied with the corresponding normalisation factor also available in the dataset, in order to make it possible to describe all datasets with a single set of parameters.</p>
 <p>Also, datasets observed in the same soil are merged, resulting in dimethenamid (DMTA) data from six soils.</p>
 <div class="sourceCode" id="cb1"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va"><a href="https://pkgdown.jrwb.de/mkin/">mkin</a></span><span class="op">)</span>
+<code class="sourceCode R"><span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va"><a href="https://pkgdown.jrwb.de/mkin/">mkin</a></span>, quietly <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span>
 <span class="va">dmta_ds</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">lapply</a></span><span class="op">(</span><span class="fl">1</span><span class="op">:</span><span class="fl">7</span>, <span class="kw">function</span><span class="op">(</span><span class="va">i</span><span class="op">)</span> <span class="op">{</span>
   <span class="va">ds_i</span> <span class="op">&lt;-</span> <span class="va">dimethenamid_2018</span><span class="op">$</span><span class="va">ds</span><span class="op">[[</span><span class="va">i</span><span class="op">]</span><span class="op">]</span><span class="op">$</span><span class="va">data</span>
   <span class="va">ds_i</span><span class="op">[</span><span class="va">ds_i</span><span class="op">$</span><span class="va">name</span> <span class="op">==</span> <span class="st">"DMTAP"</span>, <span class="st">"name"</span><span class="op">]</span> <span class="op">&lt;-</span>  <span class="st">"DMTA"</span>
@@ -258,14 +258,14 @@ f_parent_nlme_dfop_tc       3 10 671.91 702.34 -325.96 2 vs 3  134.69  &lt;.0001
 <div class="sourceCode" id="cb20"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span> <span class="op">&lt;-</span>
   <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/llgq.saemix.html">llgq.saemix</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span><span class="op">)</span>
-<span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span><span class="op">)</span></code></pre></div>
-<pre><code>[1] 666.1</code></pre>
-<div class="sourceCode" id="cb22"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span>, method <span class="op">=</span> <span class="st">"gq"</span><span class="op">)</span></code></pre></div>
-<pre><code>[1] 666.03</code></pre>
-<div class="sourceCode" id="cb24"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span>, method <span class="op">=</span> <span class="st">"lin"</span><span class="op">)</span></code></pre></div>
-<pre><code>[1] 665.48</code></pre>
+<span class="va">AIC_parent_saemix_methods</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span>
+  is <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span>, method <span class="op">=</span> <span class="st">"is"</span><span class="op">)</span>,
+  gq <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span>, method <span class="op">=</span> <span class="st">"gq"</span><span class="op">)</span>,
+  lin <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span>, method <span class="op">=</span> <span class="st">"lin"</span><span class="op">)</span>
+<span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/r/base/print.html">print</a></span><span class="op">(</span><span class="va">AIC_parent_saemix_methods</span><span class="op">)</span></code></pre></div>
+<pre><code>    is     gq    lin 
+666.10 666.03 665.48 </code></pre>
 <p>The AIC values based on importance sampling and Gaussian quadrature are very similar. Using linearisation is known to be less accurate, but still gives a similar value.</p>
 </div>
 <div id="nlmixr" class="section level3">
@@ -273,19 +273,19 @@ f_parent_nlme_dfop_tc       3 10 671.91 702.34 -325.96 2 vs 3  134.69  &lt;.0001
 <a href="#nlmixr" class="anchor"></a>nlmixr</h3>
 <p>In the last years, a lot of effort has been put into the nlmixr package which is designed for pharmacokinetics, where nonlinear mixed-effects models are routinely used, but which can also be used for related data like chemical degradation data. A current development branch of the mkin package provides an interface between mkin and nlmixr. Here, we check if we get equivalent results when using a refined version of the First Order Conditional Estimation (FOCE) algorithm used in nlme, namely the First Order Conditional Estimation with Interaction (FOCEI), and the SAEM algorithm as implemented in nlmixr.</p>
 <p>First, the focei algorithm is used for the four model combinations. A number of warnings are produced with unclear significance.</p>
-<div class="sourceCode" id="cb26"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb22"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va"><a href="https://github.com/nlmixrdevelopment/nlmixr">nlmixr</a></span><span class="op">)</span>
 <span class="va">f_parent_nlmixr_focei_sfo_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"focei"</span><span class="op">)</span>
 <span class="va">f_parent_nlmixr_focei_sfo_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"focei"</span><span class="op">)</span>
 <span class="va">f_parent_nlmixr_focei_dfop_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"focei"</span><span class="op">)</span>
 <span class="va">f_parent_nlmixr_focei_dfop_tc</span><span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"focei"</span><span class="op">)</span></code></pre></div>
-<div class="sourceCode" id="cb27"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb23"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">aic_nlmixr_focei</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">sapply</a></span><span class="op">(</span>
   <span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_focei_sfo_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_focei_sfo_tc</span><span class="op">$</span><span class="va">nm</span>,
     <span class="va">f_parent_nlmixr_focei_dfop_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_focei_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span>,
   <span class="va">AIC</span><span class="op">)</span></code></pre></div>
 <p>The AIC values are very close to the ones obtained with nlme which are repeated below for convenience.</p>
-<div class="sourceCode" id="cb28"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb24"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">aic_nlme</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">sapply</a></span><span class="op">(</span>
   <span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">f_parent_nlme_sfo_const</span>, <span class="cn">NA</span>, <span class="va">f_parent_nlme_sfo_tc</span>, <span class="va">f_parent_nlme_dfop_tc</span><span class="op">)</span>,
   <span class="kw">function</span><span class="op">(</span><span class="va">x</span><span class="op">)</span> <span class="kw">if</span> <span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/NA.html">is.na</a></span><span class="op">(</span><span class="va">x</span><span class="op">[</span><span class="fl">1</span><span class="op">]</span><span class="op">)</span><span class="op">)</span> <span class="cn">NA</span> <span class="kw">else</span> <span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">x</span><span class="op">)</span><span class="op">)</span>
@@ -297,35 +297,35 @@ f_parent_nlme_dfop_tc       3 10 671.91 702.34 -325.96 2 vs 3  134.69  &lt;.0001
   check.names <span class="op">=</span> <span class="cn">FALSE</span>
 <span class="op">)</span></code></pre></div>
 <p>Secondly, we use the SAEM estimation routine and check the convergence plots. The control parameters also used for the saemix fits are defined beforehand.</p>
-<div class="sourceCode" id="cb29"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb25"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">nlmixr_saem_control</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span>,
   nBurn <span class="op">=</span> <span class="fl">1000</span>, nEm <span class="op">=</span> <span class="fl">300</span>, nmc <span class="op">=</span> <span class="fl">15</span><span class="op">)</span></code></pre></div>
 <p>The we fit SFO with constant variance</p>
-<div class="sourceCode" id="cb30"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb26"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_sfo_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
   control <span class="op">=</span> <span class="va">nlmixr_saem_control</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_const</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png" width="700"></p>
 <p>and SFO with two-component error.</p>
-<div class="sourceCode" id="cb31"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb27"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_sfo_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
   control <span class="op">=</span> <span class="va">nlmixr_saem_control</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png" width="700"></p>
 <p>For DFOP with constant variance, the convergence plots show considerable instability of the fit, which indicates overparameterisation which was already observed earlier for this model combination.</p>
-<div class="sourceCode" id="cb32"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb28"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_dfop_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
   control <span class="op">=</span> <span class="va">nlmixr_saem_control</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_dfop_const</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png" width="700"></p>
 <p>For DFOP with two-component error, a less erratic convergence is seen.</p>
-<div class="sourceCode" id="cb33"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb29"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_dfop_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
   control <span class="op">=</span> <span class="va">nlmixr_saem_control</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png" width="700"></p>
 <p>The AIC values are internally calculated using Gaussian quadrature. For an unknown reason, the AIC value obtained for the DFOP fit using constant error is given as Infinity.</p>
-<div class="sourceCode" id="cb34"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb30"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_saem_sfo_tc</span><span class="op">$</span><span class="va">nm</span>,
   <span class="va">f_parent_nlmixr_saem_dfop_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_saem_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
 <pre><code>                                   df    AIC
@@ -333,8 +333,12 @@ f_parent_nlmixr_saem_sfo_const$nm   5 798.68
 f_parent_nlmixr_saem_sfo_tc$nm      6 808.88
 f_parent_nlmixr_saem_dfop_const$nm  9 815.95
 f_parent_nlmixr_saem_dfop_tc$nm    10 669.57</code></pre>
+</div>
+<div id="comparison" class="section level3">
+<h3 class="hasAnchor">
+<a href="#comparison" class="anchor"></a>Comparison</h3>
 <p>The following table gives the AIC values obtained with the three packages.</p>
-<div class="sourceCode" id="cb36"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb32"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">AIC_all</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/data.frame.html">data.frame</a></span><span class="op">(</span>
   check.names <span class="op">=</span> <span class="cn">FALSE</span>,
   <span class="st">"Degradation model"</span> <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="st">"SFO"</span>, <span class="st">"SFO"</span>, <span class="st">"DFOP"</span>, <span class="st">"DFOP"</span><span class="op">)</span>,
-- 
cgit v1.2.1


From 5c15ef747568b3a9a9c094b6aa546dc80e3aa87a Mon Sep 17 00:00:00 2001
From: Johannes Ranke <jranke@uni-bremen.de>
Date: Mon, 27 Sep 2021 20:10:01 +0200
Subject: intervals() methods, more DFOP/tc variants

---
 docs/dev/articles/web_only/dimethenamid_2018.html  | 274 +++++++++++++++++----
 .../f_parent_nlmixr_saem_dfop_const-1.png          | Bin 174055 -> 195559 bytes
 .../figure-html/f_parent_nlmixr_saem_dfop_tc-1.png | Bin 162039 -> 167023 bytes
 .../f_parent_nlmixr_saem_dfop_tc_10k-1.png         | Bin 0 -> 156319 bytes
 .../f_parent_nlmixr_saem_dfop_tc_1k-1.png          | Bin 0 -> 162039 bytes
 .../f_parent_nlmixr_saem_sfo_const-1.png           | Bin 142453 -> 145173 bytes
 .../figure-html/f_parent_nlmixr_saem_sfo_tc-1.png  | Bin 144010 -> 150391 bytes
 .../figure-html/f_parent_saemix_dfop_tc_10k-1.png  | Bin 0 -> 39487 bytes
 .../figure-html/f_parent_saemix_dfop_tc_mkin-1.png | Bin 0 -> 44861 bytes
 .../f_parent_saemix_dfop_tc_mkin_10k-1.png         | Bin 0 -> 38868 bytes
 10 files changed, 230 insertions(+), 44 deletions(-)
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc_10k-1.png
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc_1k-1.png
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_10k-1.png
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin-1.png
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin_10k-1.png

(limited to 'docs/dev/articles/web_only')

diff --git a/docs/dev/articles/web_only/dimethenamid_2018.html b/docs/dev/articles/web_only/dimethenamid_2018.html
index 26b352e1..aa84435d 100644
--- a/docs/dev/articles/web_only/dimethenamid_2018.html
+++ b/docs/dev/articles/web_only/dimethenamid_2018.html
@@ -101,7 +101,7 @@
       <h1 data-toc-skip>Example evaluations of the dimethenamid data from 2018</h1>
                         <h4 class="author">Johannes Ranke</h4>
             
-            <h4 class="date">Last change 17 September 2021, built on 17 Sep 2021</h4>
+            <h4 class="date">Last change 27 September 2021, built on 27 Sep 2021</h4>
       
       <small class="dont-index">Source: <a href="https://github.com/jranke/mkin/blob/master/vignettes/web_only/dimethenamid_2018.rmd"><code>vignettes/web_only/dimethenamid_2018.rmd</code></a></small>
       <div class="hidden name"><code>dimethenamid_2018.rmd</code></div>
@@ -174,7 +174,7 @@
 <div id="nlme" class="section level3">
 <h3 class="hasAnchor">
 <a href="#nlme" class="anchor"></a>nlme</h3>
-<p>The nlme package was the first R extension providing facilities to fit nonlinear mixed-effects models. We would like to do model selection from all four combinations of degradation models and error models based on the AIC. However, fitting the DFOP model with constant variance and using default control parameters results in an error, signalling that the maximum number of 50 iterations was reached, potentially indicating overparameterisation. However, the algorithm converges when the two-component error model is used in combination with the DFOP model. This can be explained by the fact that the smaller residues observed at later sampling times get more weight when using the two-component error model which will counteract the tendency of the algorithm to try parameter combinations unsuitable for fitting these data.</p>
+<p>The nlme package was the first R extension providing facilities to fit nonlinear mixed-effects models. We would like to do model selection from all four combinations of degradation models and error models based on the AIC. However, fitting the DFOP model with constant variance and using default control parameters results in an error, signalling that the maximum number of 50 iterations was reached, potentially indicating overparameterisation. Nevertheless, the algorithm converges when the two-component error model is used in combination with the DFOP model. This can be explained by the fact that the smaller residues observed at later sampling times get more weight when using the two-component error model which will counteract the tendency of the algorithm to try parameter combinations unsuitable for fitting these data.</p>
 <div class="sourceCode" id="cb7"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va"><a href="https://svn.r-project.org/R-packages/trunk/nlme/">nlme</a></span><span class="op">)</span>
 <span class="va">f_parent_nlme_sfo_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/nlme.html">nlme</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span><span class="op">)</span>
@@ -182,7 +182,7 @@
 <span class="va">f_parent_nlme_sfo_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/nlme.html">nlme</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span><span class="op">)</span>
 <span class="va">f_parent_nlme_dfop_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlme/man/nlme.html">nlme</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span></code></pre></div>
 <p>Note that a certain degree of overparameterisation is also indicated by a warning obtained when fitting DFOP with the two-component error model (‘false convergence’ in the ‘LME step’ in iteration 3). However, as this warning does not occur in later iterations, and specifically not in the last of the 6 iterations, we can ignore this warning.</p>
-<p>The model comparison function of the nlme package can directly be applied to these fits showing a much lower AIC for the DFOP model fitted with the two-component error model. Also, the likelihood ratio test indicates that this difference is significant. as the p-value is below 0.0001.</p>
+<p>The model comparison function of the nlme package can directly be applied to these fits showing a much lower AIC for the DFOP model fitted with the two-component error model. Also, the likelihood ratio test indicates that this difference is significant as the p-value is below 0.0001.</p>
 <div class="sourceCode" id="cb8"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/anova.html">anova</a></span><span class="op">(</span>
   <span class="va">f_parent_nlme_sfo_const</span>, <span class="va">f_parent_nlme_sfo_tc</span>, <span class="va">f_parent_nlme_dfop_tc</span>
@@ -216,6 +216,8 @@ f_parent_nlme_dfop_tc       3 10 671.91 702.34 -325.96 2 vs 3  134.69  &lt;.0001
 <div class="sourceCode" id="cb12"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va">saemix</span><span class="op">)</span>
 <span class="va">saemix_control</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/saemixControl.html">saemixControl</a></span><span class="op">(</span>nbiter.saemix <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="fl">800</span>, <span class="fl">300</span><span class="op">)</span>, nb.chains <span class="op">=</span> <span class="fl">15</span>,
+    print <span class="op">=</span> <span class="cn">FALSE</span>, save <span class="op">=</span> <span class="cn">FALSE</span>, save.graphs <span class="op">=</span> <span class="cn">FALSE</span>, displayProgress <span class="op">=</span> <span class="cn">FALSE</span><span class="op">)</span>
+<span class="va">saemix_control_10k</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/saemixControl.html">saemixControl</a></span><span class="op">(</span>nbiter.saemix <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="fl">10000</span>, <span class="fl">1000</span><span class="op">)</span>, nb.chains <span class="op">=</span> <span class="fl">15</span>,
     print <span class="op">=</span> <span class="cn">FALSE</span>, save <span class="op">=</span> <span class="cn">FALSE</span>, save.graphs <span class="op">=</span> <span class="cn">FALSE</span>, displayProgress <span class="op">=</span> <span class="cn">FALSE</span><span class="op">)</span></code></pre></div>
 <p>The convergence plot for the SFO model using constant variance is shown below.</p>
 <div class="sourceCode" id="cb13"><pre class="downlit sourceCode r">
@@ -229,35 +231,65 @@ f_parent_nlme_dfop_tc       3 10 671.91 702.34 -325.96 2 vs 3  134.69  &lt;.0001
   control <span class="op">=</span> <span class="va">saemix_control</span>, transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_sfo_tc</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_tc-1.png" width="700"></p>
-<p>When fitting the DFOP model with constant variance, parameter convergence is not as unambiguous (see the failure of nlme with the default number of iterations above). Therefore, the number of iterations in the first phase of the algorithm was increased, leading to visually satisfying convergence.</p>
+<p>When fitting the DFOP model with constant variance (see below), parameter convergence is not as unambiguous.</p>
 <div class="sourceCode" id="cb15"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_saemix_dfop_const</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
   control <span class="op">=</span> <span class="va">saemix_control</span>, transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_const</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_const-1.png" width="700"></p>
-<p>The same applies in the case where the DFOP model is fitted with the two-component error model. Convergence of the variance of k2 is enhanced by using the two-component error, it remains more or less stable already after 200 iterations of the first phase.</p>
+<p>This is improved when the DFOP model is fitted with the two-component error model. Convergence of the variance of k2 is enhanced, it remains more or less stable already after 200 iterations of the first phase.</p>
 <div class="sourceCode" id="cb16"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_saemix_dfop_tc</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
   control <span class="op">=</span> <span class="va">saemix_control</span>, transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
-<p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc-1.png" width="700"> The four combinations and including the variations of the DFOP/tc combination can be compared using the model comparison function from the saemix package:</p>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc-1.png" width="700"></p>
+<p>We also check if using many more iterations (10 000 for the first and 1000 for the second phase) improve the result in a significant way. The AIC values obtained are compared further below.</p>
 <div class="sourceCode" id="cb17"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/compare.saemix.html">compare.saemix</a></span><span class="op">(</span>
+<code class="sourceCode R"><span class="va">f_parent_saemix_dfop_tc_10k</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
+  control <span class="op">=</span> <span class="va">saemix_control_10k</span>, transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_10k</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_10k-1.png" width="700"></p>
+<p>An alternative way to fit DFOP in combination with the two-component error model is to use the model formulation with transformed parameters as used per default in mkin.</p>
+<div class="sourceCode" id="cb18"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">f_parent_saemix_dfop_tc_mkin</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
+  control <span class="op">=</span> <span class="va">saemix_control</span>, transformations <span class="op">=</span> <span class="st">"mkin"</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_mkin</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin-1.png" width="700"></p>
+<p>As the convergence plots do not clearly indicate that the algorithm has converged, we again use a much larger number of iterations, which leads to satisfactory convergence (see below).</p>
+<div class="sourceCode" id="cb19"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">f_parent_saemix_dfop_tc_mkin_10k</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
+  control <span class="op">=</span> <span class="va">saemix_control_10k</span>, transformations <span class="op">=</span> <span class="st">"mkin"</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_mkin_10k</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin_10k-1.png" width="700"></p>
+<p>The four combinations (SFO/const, SFO/tc, DFOP/const and DFOP/tc), including the variations of the DFOP/tc combination can be compared using the model comparison function of the saemix package:</p>
+<div class="sourceCode" id="cb20"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">AIC_parent_saemix</span> <span class="op">&lt;-</span> <span class="fu">saemix</span><span class="fu">::</span><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/compare.saemix.html">compare.saemix</a></span><span class="op">(</span>
   <span class="va">f_parent_saemix_sfo_const</span><span class="op">$</span><span class="va">so</span>,
   <span class="va">f_parent_saemix_sfo_tc</span><span class="op">$</span><span class="va">so</span>,
   <span class="va">f_parent_saemix_dfop_const</span><span class="op">$</span><span class="va">so</span>,
-  <span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span><span class="op">)</span></code></pre></div>
+  <span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span>,
+  <span class="va">f_parent_saemix_dfop_tc_10k</span><span class="op">$</span><span class="va">so</span>,
+  <span class="va">f_parent_saemix_dfop_tc_mkin</span><span class="op">$</span><span class="va">so</span>,
+  <span class="va">f_parent_saemix_dfop_tc_mkin_10k</span><span class="op">$</span><span class="va">so</span><span class="op">)</span></code></pre></div>
 <pre><code>Likelihoods calculated by importance sampling</code></pre>
-<pre><code>     AIC    BIC
-1 796.37 795.33
-2 798.37 797.13
-3 713.16 711.28
-4 666.10 664.01</code></pre>
-<p>As in the case of nlme fits, the DFOP model fitted with two-component error (number 4) gives the lowest AIC. Using more iterations and/or more chains does not have a large influence on the final AIC (not shown).</p>
+<div class="sourceCode" id="cb22"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/base/colnames.html">rownames</a></span><span class="op">(</span><span class="va">AIC_parent_saemix</span><span class="op">)</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span>
+  <span class="st">"SFO const"</span>, <span class="st">"SFO tc"</span>, <span class="st">"DFOP const"</span>, <span class="st">"DFOP tc"</span>, <span class="st">"DFOP tc more iterations"</span>,
+  <span class="st">"DFOP tc mkintrans"</span>, <span class="st">"DFOP tc mkintrans more iterations"</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/r/base/print.html">print</a></span><span class="op">(</span><span class="va">AIC_parent_saemix</span><span class="op">)</span></code></pre></div>
+<pre><code>                                     AIC    BIC
+SFO const                         796.37 795.33
+SFO tc                            798.37 797.13
+DFOP const                        713.16 711.28
+DFOP tc                           666.10 664.01
+DFOP tc more iterations           666.15 664.06
+DFOP tc mkintrans                 682.26 680.17
+DFOP tc mkintrans more iterations 666.12 664.04</code></pre>
+<p>As in the case of nlme fits, the DFOP model fitted with two-component error (number 4) gives the lowest AIC. Using a much larger number of iterations does not improve the fit a lot. When the mkin transformations are used instead of the saemix transformations, this large number of iterations leads to a goodness of fit that is comparable to the result obtained with saemix transformations.</p>
 <p>In order to check the influence of the likelihood calculation algorithms implemented in saemix, the likelihood from Gaussian quadrature is added to the best fit, and the AIC values obtained from the three methods are compared.</p>
-<div class="sourceCode" id="cb20"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb24"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span> <span class="op">&lt;-</span>
-  <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/llgq.saemix.html">llgq.saemix</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span><span class="op">)</span>
+  <span class="fu">saemix</span><span class="fu">::</span><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/llgq.saemix.html">llgq.saemix</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span><span class="op">)</span>
 <span class="va">AIC_parent_saemix_methods</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span>
   is <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span>, method <span class="op">=</span> <span class="st">"is"</span><span class="op">)</span>,
   gq <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span>, method <span class="op">=</span> <span class="st">"gq"</span><span class="op">)</span>,
@@ -273,19 +305,19 @@ f_parent_nlme_dfop_tc       3 10 671.91 702.34 -325.96 2 vs 3  134.69  &lt;.0001
 <a href="#nlmixr" class="anchor"></a>nlmixr</h3>
 <p>In the last years, a lot of effort has been put into the nlmixr package which is designed for pharmacokinetics, where nonlinear mixed-effects models are routinely used, but which can also be used for related data like chemical degradation data. A current development branch of the mkin package provides an interface between mkin and nlmixr. Here, we check if we get equivalent results when using a refined version of the First Order Conditional Estimation (FOCE) algorithm used in nlme, namely the First Order Conditional Estimation with Interaction (FOCEI), and the SAEM algorithm as implemented in nlmixr.</p>
 <p>First, the focei algorithm is used for the four model combinations. A number of warnings are produced with unclear significance.</p>
-<div class="sourceCode" id="cb22"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb26"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va"><a href="https://github.com/nlmixrdevelopment/nlmixr">nlmixr</a></span><span class="op">)</span>
 <span class="va">f_parent_nlmixr_focei_sfo_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"focei"</span><span class="op">)</span>
 <span class="va">f_parent_nlmixr_focei_sfo_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"focei"</span><span class="op">)</span>
 <span class="va">f_parent_nlmixr_focei_dfop_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"focei"</span><span class="op">)</span>
 <span class="va">f_parent_nlmixr_focei_dfop_tc</span><span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"focei"</span><span class="op">)</span></code></pre></div>
-<div class="sourceCode" id="cb23"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb27"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">aic_nlmixr_focei</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">sapply</a></span><span class="op">(</span>
   <span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_focei_sfo_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_focei_sfo_tc</span><span class="op">$</span><span class="va">nm</span>,
     <span class="va">f_parent_nlmixr_focei_dfop_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_focei_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span>,
   <span class="va">AIC</span><span class="op">)</span></code></pre></div>
 <p>The AIC values are very close to the ones obtained with nlme which are repeated below for convenience.</p>
-<div class="sourceCode" id="cb24"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb28"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">aic_nlme</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/lapply.html">sapply</a></span><span class="op">(</span>
   <span class="fu"><a href="https://rdrr.io/r/base/list.html">list</a></span><span class="op">(</span><span class="va">f_parent_nlme_sfo_const</span>, <span class="cn">NA</span>, <span class="va">f_parent_nlme_sfo_tc</span>, <span class="va">f_parent_nlme_dfop_tc</span><span class="op">)</span>,
   <span class="kw">function</span><span class="op">(</span><span class="va">x</span><span class="op">)</span> <span class="kw">if</span> <span class="op">(</span><span class="fu"><a href="https://rdrr.io/r/base/NA.html">is.na</a></span><span class="op">(</span><span class="va">x</span><span class="op">[</span><span class="fl">1</span><span class="op">]</span><span class="op">)</span><span class="op">)</span> <span class="cn">NA</span> <span class="kw">else</span> <span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">x</span><span class="op">)</span><span class="op">)</span>
@@ -297,48 +329,70 @@ f_parent_nlme_dfop_tc       3 10 671.91 702.34 -325.96 2 vs 3  134.69  &lt;.0001
   check.names <span class="op">=</span> <span class="cn">FALSE</span>
 <span class="op">)</span></code></pre></div>
 <p>Secondly, we use the SAEM estimation routine and check the convergence plots. The control parameters also used for the saemix fits are defined beforehand.</p>
-<div class="sourceCode" id="cb25"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="va">nlmixr_saem_control</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span>,
-  nBurn <span class="op">=</span> <span class="fl">1000</span>, nEm <span class="op">=</span> <span class="fl">300</span>, nmc <span class="op">=</span> <span class="fl">15</span><span class="op">)</span></code></pre></div>
+<div class="sourceCode" id="cb29"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">nlmixr_saem_control_800</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span>,
+  nBurn <span class="op">=</span> <span class="fl">800</span>, nEm <span class="op">=</span> <span class="fl">300</span>, nmc <span class="op">=</span> <span class="fl">15</span><span class="op">)</span>
+<span class="va">nlmixr_saem_control_1000</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span>,
+  nBurn <span class="op">=</span> <span class="fl">1000</span>, nEm <span class="op">=</span> <span class="fl">300</span>, nmc <span class="op">=</span> <span class="fl">15</span><span class="op">)</span>
+<span class="va">nlmixr_saem_control_10k</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span>,
+  nBurn <span class="op">=</span> <span class="fl">10000</span>, nEm <span class="op">=</span> <span class="fl">1000</span>, nmc <span class="op">=</span> <span class="fl">15</span><span class="op">)</span></code></pre></div>
 <p>The we fit SFO with constant variance</p>
-<div class="sourceCode" id="cb26"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb30"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_sfo_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
-  control <span class="op">=</span> <span class="va">nlmixr_saem_control</span><span class="op">)</span>
+  control <span class="op">=</span> <span class="va">nlmixr_saem_control_800</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_const</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png" width="700"></p>
 <p>and SFO with two-component error.</p>
-<div class="sourceCode" id="cb27"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb31"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_sfo_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
-  control <span class="op">=</span> <span class="va">nlmixr_saem_control</span><span class="op">)</span>
+  control <span class="op">=</span> <span class="va">nlmixr_saem_control_800</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png" width="700"></p>
 <p>For DFOP with constant variance, the convergence plots show considerable instability of the fit, which indicates overparameterisation which was already observed earlier for this model combination.</p>
-<div class="sourceCode" id="cb28"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb32"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_dfop_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
-  control <span class="op">=</span> <span class="va">nlmixr_saem_control</span><span class="op">)</span>
+  control <span class="op">=</span> <span class="va">nlmixr_saem_control_800</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_dfop_const</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png" width="700"></p>
 <p>For DFOP with two-component error, a less erratic convergence is seen.</p>
-<div class="sourceCode" id="cb29"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb33"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_dfop_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
-  control <span class="op">=</span> <span class="va">nlmixr_saem_control</span><span class="op">)</span>
+  control <span class="op">=</span> <span class="va">nlmixr_saem_control_800</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png" width="700"></p>
-<p>The AIC values are internally calculated using Gaussian quadrature. For an unknown reason, the AIC value obtained for the DFOP fit using constant error is given as Infinity.</p>
-<div class="sourceCode" id="cb30"><pre class="downlit sourceCode r">
+<p>To check if an increase in the number of iterations improves the fit, we repeat the fit with 1000 iterations for the burn in phase and 300 iterations for the second phase.</p>
+<div class="sourceCode" id="cb34"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_dfop_tc_1000</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
+  control <span class="op">=</span> <span class="va">nlmixr_saem_control_1000</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_dfop_tc_1000</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc_1k-1.png" width="700"></p>
+<p>Here the fit looks very similar, but we will see below that it shows a higher AIC than the fit with 800 iterations in the burn in phase. Next we choose 10 000 iterations for the burn in phase and 1000 iterations for the second phase for comparison with saemix.</p>
+<div class="sourceCode" id="cb35"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_dfop_tc_10k</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
+  control <span class="op">=</span> <span class="va">nlmixr_saem_control_10k</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_dfop_tc_10k</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc_10k-1.png" width="700"></p>
+<p>In the above convergence plot, the time course of ‘eta.DMTA_0’ and ‘log_k2’ indicate a false convergence.</p>
+<p>The AIC values are internally calculated using Gaussian quadrature.</p>
+<div class="sourceCode" id="cb36"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_saem_sfo_tc</span><span class="op">$</span><span class="va">nm</span>,
-  <span class="va">f_parent_nlmixr_saem_dfop_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_saem_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
-<pre><code>                                   df    AIC
-f_parent_nlmixr_saem_sfo_const$nm   5 798.68
-f_parent_nlmixr_saem_sfo_tc$nm      6 808.88
-f_parent_nlmixr_saem_dfop_const$nm  9 815.95
-f_parent_nlmixr_saem_dfop_tc$nm    10 669.57</code></pre>
+  <span class="va">f_parent_nlmixr_saem_dfop_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_saem_dfop_tc</span><span class="op">$</span><span class="va">nm</span>,
+  <span class="va">f_parent_nlmixr_saem_dfop_tc_1000</span><span class="op">$</span><span class="va">nm</span>,
+  <span class="va">f_parent_nlmixr_saem_dfop_tc_10k</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
+<pre><code>                                     df    AIC
+f_parent_nlmixr_saem_sfo_const$nm     5 798.69
+f_parent_nlmixr_saem_sfo_tc$nm        6 810.33
+f_parent_nlmixr_saem_dfop_const$nm    9 736.00
+f_parent_nlmixr_saem_dfop_tc$nm      10 664.85
+f_parent_nlmixr_saem_dfop_tc_1000$nm 10 669.57
+f_parent_nlmixr_saem_dfop_tc_10k$nm  10    Inf</code></pre>
+<p>We can see that again, the DFOP/tc model shows the best goodness of fit. However, increasing the number of burn-in iterations from 800 to 1000 results in a higher AIC. If we further increase the number of iterations to 10 000 (burn-in) and 1000 (second phase), the AIC cannot be calculated for the nlmixr/saem fit, supporting that the fit did not converge properly.</p>
 </div>
 <div id="comparison" class="section level3">
 <h3 class="hasAnchor">
 <a href="#comparison" class="anchor"></a>Comparison</h3>
-<p>The following table gives the AIC values obtained with the three packages.</p>
-<div class="sourceCode" id="cb32"><pre class="downlit sourceCode r">
+<p>The following table gives the AIC values obtained with the three packages using the same control parameters (800 iterations burn-in, 300 iterations second phase, 15 chains).</p>
+<div class="sourceCode" id="cb38"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">AIC_all</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/data.frame.html">data.frame</a></span><span class="op">(</span>
   check.names <span class="op">=</span> <span class="cn">FALSE</span>,
   <span class="st">"Degradation model"</span> <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="st">"SFO"</span>, <span class="st">"SFO"</span>, <span class="st">"DFOP"</span>, <span class="st">"DFOP"</span><span class="op">)</span>,
@@ -368,7 +422,7 @@ f_parent_nlmixr_saem_dfop_tc$nm    10 669.57</code></pre>
 <td align="right">796.60</td>
 <td align="right">796.62</td>
 <td align="right">796.37</td>
-<td align="right">798.68</td>
+<td align="right">798.69</td>
 </tr>
 <tr class="even">
 <td align="left">SFO</td>
@@ -376,7 +430,7 @@ f_parent_nlmixr_saem_dfop_tc$nm    10 669.57</code></pre>
 <td align="right">798.60</td>
 <td align="right">798.61</td>
 <td align="right">798.37</td>
-<td align="right">808.88</td>
+<td align="right">810.33</td>
 </tr>
 <tr class="odd">
 <td align="left">DFOP</td>
@@ -384,7 +438,7 @@ f_parent_nlmixr_saem_dfop_tc$nm    10 669.57</code></pre>
 <td align="right">NA</td>
 <td align="right">750.91</td>
 <td align="right">713.16</td>
-<td align="right">815.95</td>
+<td align="right">736.00</td>
 </tr>
 <tr class="even">
 <td align="left">DFOP</td>
@@ -392,10 +446,142 @@ f_parent_nlmixr_saem_dfop_tc$nm    10 669.57</code></pre>
 <td align="right">671.91</td>
 <td align="right">666.60</td>
 <td align="right">666.10</td>
-<td align="right">669.57</td>
+<td align="right">664.85</td>
 </tr>
 </tbody>
 </table>
+<div class="sourceCode" id="cb39"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/nlme/man/intervals.html">intervals</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">)</span></code></pre></div>
+<pre><code>Approximate 95% confidence intervals
+
+ Fixed effects:
+            lower       est.      upper
+DMTA_0 96.2802274 98.2761977 100.272168
+k1      0.0339753  0.0645487   0.095122
+k2      0.0058977  0.0088887   0.011880
+g       0.9064373  0.9514417   0.996446
+
+ Random effects:
+              lower     est.   upper
+sd(DMTA_0)  0.44404 2.102366 3.76069
+sd(k1)      0.25433 0.589731 0.92514
+sd(k2)     -0.33139 0.099797 0.53099
+sd(g)       0.39606 1.092234 1.78841
+
+ 
+       lower     est.    upper
+a.1 0.863644 1.063021 1.262398
+b.1 0.022555 0.029599 0.036643</code></pre>
+<div class="sourceCode" id="cb41"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/nlme/man/intervals.html">intervals</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">)</span></code></pre></div>
+<pre><code>Approximate 95% confidence intervals
+
+ Fixed effects:
+            lower       est.      upper
+DMTA_0 96.2802274 98.2761977 100.272168
+k1      0.0339753  0.0645487   0.095122
+k2      0.0058977  0.0088887   0.011880
+g       0.9064373  0.9514417   0.996446
+
+ Random effects:
+              lower     est.   upper
+sd(DMTA_0)  0.44404 2.102366 3.76069
+sd(k1)      0.25433 0.589731 0.92514
+sd(k2)     -0.33139 0.099797 0.53099
+sd(g)       0.39606 1.092234 1.78841
+
+ 
+       lower     est.    upper
+a.1 0.863644 1.063021 1.262398
+b.1 0.022555 0.029599 0.036643</code></pre>
+<div class="sourceCode" id="cb43"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/nlme/man/intervals.html">intervals</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_10k</span><span class="op">)</span></code></pre></div>
+<pre><code>Approximate 95% confidence intervals
+
+ Fixed effects:
+            lower       est.      upper
+DMTA_0 96.3027896 98.2641150 100.225440
+k1      0.0338214  0.0644055   0.094990
+k2      0.0058857  0.0087896   0.011693
+g       0.9086138  0.9521421   0.995670
+
+ Random effects:
+              lower    est.   upper
+sd(DMTA_0)  0.41448 2.05327 3.69206
+sd(k1)      0.25507 0.59132 0.92758
+sd(k2)     -0.36781 0.09016 0.54813
+sd(g)       0.38585 1.06994 1.75402
+
+ 
+       lower     est.    upper
+a.1 0.866273 1.066115 1.265957
+b.1 0.022501 0.029541 0.036581</code></pre>
+<div class="sourceCode" id="cb45"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/nlme/man/intervals.html">intervals</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_mkin_10k</span><span class="op">)</span></code></pre></div>
+<pre><code>Approximate 95% confidence intervals
+
+ Fixed effects:
+            lower       est.      upper
+DMTA_0 96.3021306 98.2736091 100.245088
+k1      0.0401701  0.0645140   0.103611
+k2      0.0064706  0.0089398   0.012351
+g       0.8817692  0.9511605   0.980716
+
+ Random effects:
+                lower     est.   upper
+sd(DMTA_0)    0.42392 2.068018 3.71212
+sd(log_k1)    0.25440 0.589877 0.92536
+sd(log_k2)   -0.38431 0.084334 0.55298
+sd(g_qlogis)  0.39107 1.077303 1.76353
+
+ 
+       lower     est.    upper
+a.1 0.865291 1.064897 1.264504
+b.1 0.022491 0.029526 0.036561</code></pre>
+<div class="sourceCode" id="cb47"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/nlme/man/intervals.html">intervals</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_dfop_tc</span><span class="op">)</span></code></pre></div>
+<pre><code>Approximate 95% confidence intervals
+
+ Fixed effects:
+            lower       est.      upper
+DMTA_0 96.3059406 98.2990616 100.292183
+k1      0.0402306  0.0648255   0.104456
+k2      0.0067864  0.0093097   0.012771
+g       0.8769017  0.9505258   0.981067
+
+ Random effects:
+             lower     est. upper
+sd(DMTA_0)      NA 1.724654    NA
+sd(log_k1)      NA 0.592808    NA
+sd(log_k2)      NA 0.010741    NA
+sd(g_qlogis)    NA 1.087349    NA
+
+ 
+          lower     est. upper
+sigma_low    NA 1.081809    NA
+rsd_high     NA 0.032051    NA</code></pre>
+<div class="sourceCode" id="cb49"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/nlme/man/intervals.html">intervals</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_dfop_tc_10k</span><span class="op">)</span></code></pre></div>
+<pre><code>Approximate 95% confidence intervals
+
+ Fixed effects:
+           lower       est.     upper
+DMTA_0 96.426510 97.8987836 99.371057
+k1      0.040006  0.0644407  0.103799
+k2      0.006748  0.0092476  0.012673
+g       0.879251  0.9511399  0.981147
+
+ Random effects:
+             lower       est. upper
+sd(DMTA_0)      NA 3.7049e-04    NA
+sd(log_k1)      NA 5.9221e-01    NA
+sd(log_k2)      NA 3.8628e-07    NA
+sd(g_qlogis)    NA 1.0694e+00    NA
+
+ 
+          lower     est. upper
+sigma_low    NA 1.082343    NA
+rsd_high     NA 0.034895    NA</code></pre>
 </div>
 </div>
 </div>
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png
index db28e43d..af70163c 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png
index 718524e7..5e4ce944 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc_10k-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc_10k-1.png
new file mode 100644
index 00000000..6f72ee69
Binary files /dev/null and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc_10k-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc_1k-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc_1k-1.png
new file mode 100644
index 00000000..718524e7
Binary files /dev/null and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc_1k-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png
index 9dde6124..8e49bde4 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png
index e2368797..015f2d0b 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_10k-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_10k-1.png
new file mode 100644
index 00000000..0975126f
Binary files /dev/null and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_10k-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin-1.png
new file mode 100644
index 00000000..957d13af
Binary files /dev/null and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin_10k-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin_10k-1.png
new file mode 100644
index 00000000..ae8c1555
Binary files /dev/null and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin_10k-1.png differ
-- 
cgit v1.2.1


From ff83d8b2ba623513d92ac90fac4a1b0ec98c2cb5 Mon Sep 17 00:00:00 2001
From: Johannes Ranke <jranke@uni-bremen.de>
Date: Tue, 5 Oct 2021 17:33:52 +0200
Subject: Update docs

---
 docs/dev/articles/web_only/dimethenamid_2018.html | 12 ++++++------
 1 file changed, 6 insertions(+), 6 deletions(-)

(limited to 'docs/dev/articles/web_only')

diff --git a/docs/dev/articles/web_only/dimethenamid_2018.html b/docs/dev/articles/web_only/dimethenamid_2018.html
index aa84435d..13b0f98e 100644
--- a/docs/dev/articles/web_only/dimethenamid_2018.html
+++ b/docs/dev/articles/web_only/dimethenamid_2018.html
@@ -101,7 +101,7 @@
       <h1 data-toc-skip>Example evaluations of the dimethenamid data from 2018</h1>
                         <h4 class="author">Johannes Ranke</h4>
             
-            <h4 class="date">Last change 27 September 2021, built on 27 Sep 2021</h4>
+            <h4 class="date">Last change 27 September 2021, built on 05 Okt 2021</h4>
       
       <small class="dont-index">Source: <a href="https://github.com/jranke/mkin/blob/master/vignettes/web_only/dimethenamid_2018.rmd"><code>vignettes/web_only/dimethenamid_2018.rmd</code></a></small>
       <div class="hidden name"><code>dimethenamid_2018.rmd</code></div>
@@ -151,20 +151,20 @@
   error_model <span class="op">=</span> <span class="st">"tc"</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
 <p>The plot of the individual SFO fits shown below suggests that at least in some datasets the degradation slows down towards later time points, and that the scatter of the residuals error is smaller for smaller values (panel to the right):</p>
 <div class="sourceCode" id="cb3"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span><span class="op">)</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span><span class="op">)</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_sfo_const-1.png" width="700"></p>
 <p>Using biexponential decline (DFOP) results in a slightly more random scatter of the residuals:</p>
 <div class="sourceCode" id="cb4"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const-1.png" width="700"></p>
 <p>The population curve (bold line) in the above plot results from taking the mean of the individual transformed parameters, i.e. of log k1 and log k2, as well as of the logit of the g parameter of the DFOP model). Here, this procedure does not result in parameters that represent the degradation well, because in some datasets the fitted value for k2 is extremely close to zero, leading to a log k2 value that dominates the average. This is alleviated if only rate constants that pass the t-test for significant difference from zero (on the untransformed scale) are considered in the averaging:</p>
 <div class="sourceCode" id="cb5"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span>, test_log_parms <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span>, test_log_parms <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const_test-1.png" width="700"></p>
 <p>While this is visually much more satisfactory, such an average procedure could introduce a bias, as not all results from the individual fits enter the population curve with the same weight. This is where nonlinear mixed-effects models can help out by treating all datasets with equally by fitting a parameter distribution model together with the degradation model and the error model (see below).</p>
 <p>The remaining trend of the residuals to be higher for higher predicted residues is reduced by using the two-component error model:</p>
 <div class="sourceCode" id="cb6"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span>, test_log_parms <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span>, test_log_parms <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_tc_test-1.png" width="700"></p>
 </div>
 <div id="nonlinear-mixed-effects-models" class="section level2">
@@ -205,7 +205,7 @@ f_parent_nlme_dfop_tc       3 10 671.91 702.34 -325.96 2 vs 3  134.69  &lt;.0001
 <p>While the SFO variants converge fast, the additional parameters introduced by this lead to convergence warnings for the DFOP model. The model comparison clearly show that adding correlations between random effects does not improve the fits.</p>
 <p>The selected model (DFOP with two-component error) fitted to the data assuming no correlations between random effects is shown below.</p>
 <div class="sourceCode" id="cb11"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="va">f_parent_nlme_dfop_tc</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_nlme_dfop_tc</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/plot_parent_nlme-1.png" width="700"></p>
 </div>
 <div id="saemix" class="section level3">
-- 
cgit v1.2.1


From c0638c84568d475b3b059e2c6e593e6f03b846bc Mon Sep 17 00:00:00 2001
From: Johannes Ranke <jranke@uni-bremen.de>
Date: Tue, 11 Jan 2022 19:57:58 +0100
Subject: Update static docs

---
 docs/dev/articles/web_only/dimethenamid_2018.html  | 286 ++++++++++-----------
 .../f_parent_nlmixr_saem_dfop_const-1.png          | Bin 195559 -> 183868 bytes
 .../figure-html/f_parent_nlmixr_saem_dfop_tc-1.png | Bin 167023 -> 165931 bytes
 .../f_parent_nlmixr_saem_dfop_tc_10k-1.png         | Bin 156319 -> 153748 bytes
 .../f_parent_nlmixr_saem_dfop_tc_1k-1.png          | Bin 162039 -> 154763 bytes
 .../f_parent_nlmixr_saem_sfo_const-1.png           | Bin 145173 -> 142217 bytes
 .../figure-html/f_parent_nlmixr_saem_sfo_tc-1.png  | Bin 150391 -> 151002 bytes
 .../figure-html/f_parent_saemix_dfop_const-1.png   | Bin 55927 -> 52351 bytes
 .../figure-html/f_parent_saemix_dfop_tc-1.png      | Bin 43674 -> 42286 bytes
 .../figure-html/f_parent_saemix_dfop_tc_mkin-1.png | Bin 44861 -> 45118 bytes
 .../f_parent_saemix_dfop_tc_mkin_moreiter-1.png    | Bin 0 -> 43391 bytes
 .../figure-html/f_parent_saemix_sfo_const-1.png    | Bin 55667 -> 54513 bytes
 .../figure-html/f_parent_saemix_sfo_tc-1.png       | Bin 50848 -> 50300 bytes
 13 files changed, 137 insertions(+), 149 deletions(-)
 create mode 100644 docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin_moreiter-1.png

(limited to 'docs/dev/articles/web_only')

diff --git a/docs/dev/articles/web_only/dimethenamid_2018.html b/docs/dev/articles/web_only/dimethenamid_2018.html
index 13b0f98e..a2ea5c8d 100644
--- a/docs/dev/articles/web_only/dimethenamid_2018.html
+++ b/docs/dev/articles/web_only/dimethenamid_2018.html
@@ -101,7 +101,7 @@
       <h1 data-toc-skip>Example evaluations of the dimethenamid data from 2018</h1>
                         <h4 class="author">Johannes Ranke</h4>
             
-            <h4 class="date">Last change 27 September 2021, built on 05 Okt 2021</h4>
+            <h4 class="date">Last change 11 January 2022, built on 11 Jan 2022</h4>
       
       <small class="dont-index">Source: <a href="https://github.com/jranke/mkin/blob/master/vignettes/web_only/dimethenamid_2018.rmd"><code>vignettes/web_only/dimethenamid_2018.rmd</code></a></small>
       <div class="hidden name"><code>dimethenamid_2018.rmd</code></div>
@@ -151,20 +151,20 @@
   error_model <span class="op">=</span> <span class="st">"tc"</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
 <p>The plot of the individual SFO fits shown below suggests that at least in some datasets the degradation slows down towards later time points, and that the scatter of the residuals error is smaller for smaller values (panel to the right):</p>
 <div class="sourceCode" id="cb3"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span><span class="op">)</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span><span class="op">)</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_sfo_const-1.png" width="700"></p>
 <p>Using biexponential decline (DFOP) results in a slightly more random scatter of the residuals:</p>
 <div class="sourceCode" id="cb4"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const-1.png" width="700"></p>
 <p>The population curve (bold line) in the above plot results from taking the mean of the individual transformed parameters, i.e. of log k1 and log k2, as well as of the logit of the g parameter of the DFOP model). Here, this procedure does not result in parameters that represent the degradation well, because in some datasets the fitted value for k2 is extremely close to zero, leading to a log k2 value that dominates the average. This is alleviated if only rate constants that pass the t-test for significant difference from zero (on the untransformed scale) are considered in the averaging:</p>
 <div class="sourceCode" id="cb5"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span>, test_log_parms <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span>, test_log_parms <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_const_test-1.png" width="700"></p>
 <p>While this is visually much more satisfactory, such an average procedure could introduce a bias, as not all results from the individual fits enter the population curve with the same weight. This is where nonlinear mixed-effects models can help out by treating all datasets with equally by fitting a parameter distribution model together with the degradation model and the error model (see below).</p>
 <p>The remaining trend of the residuals to be higher for higher predicted residues is reduced by using the two-component error model:</p>
 <div class="sourceCode" id="cb6"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span>, test_log_parms <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="fu"><a href="../../reference/mixed.html">mixed</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span><span class="op">)</span>, test_log_parms <span class="op">=</span> <span class="cn">TRUE</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_mkin_dfop_tc_test-1.png" width="700"></p>
 </div>
 <div id="nonlinear-mixed-effects-models" class="section level2">
@@ -205,7 +205,7 @@ f_parent_nlme_dfop_tc       3 10 671.91 702.34 -325.96 2 vs 3  134.69  &lt;.0001
 <p>While the SFO variants converge fast, the additional parameters introduced by this lead to convergence warnings for the DFOP model. The model comparison clearly show that adding correlations between random effects does not improve the fits.</p>
 <p>The selected model (DFOP with two-component error) fitted to the data assuming no correlations between random effects is shown below.</p>
 <div class="sourceCode" id="cb11"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_nlme_dfop_tc</span><span class="op">)</span></code></pre></div>
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/graphics/plot.default.html">plot</a></span><span class="op">(</span><span class="va">f_parent_nlme_dfop_tc</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/plot_parent_nlme-1.png" width="700"></p>
 </div>
 <div id="saemix" class="section level3">
@@ -217,50 +217,54 @@ f_parent_nlme_dfop_tc       3 10 671.91 702.34 -325.96 2 vs 3  134.69  &lt;.0001
 <code class="sourceCode R"><span class="kw"><a href="https://rdrr.io/r/base/library.html">library</a></span><span class="op">(</span><span class="va">saemix</span><span class="op">)</span>
 <span class="va">saemix_control</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/saemixControl.html">saemixControl</a></span><span class="op">(</span>nbiter.saemix <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="fl">800</span>, <span class="fl">300</span><span class="op">)</span>, nb.chains <span class="op">=</span> <span class="fl">15</span>,
     print <span class="op">=</span> <span class="cn">FALSE</span>, save <span class="op">=</span> <span class="cn">FALSE</span>, save.graphs <span class="op">=</span> <span class="cn">FALSE</span>, displayProgress <span class="op">=</span> <span class="cn">FALSE</span><span class="op">)</span>
-<span class="va">saemix_control_10k</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/saemixControl.html">saemixControl</a></span><span class="op">(</span>nbiter.saemix <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="fl">10000</span>, <span class="fl">1000</span><span class="op">)</span>, nb.chains <span class="op">=</span> <span class="fl">15</span>,
+<span class="va">saemix_control_moreiter</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/saemixControl.html">saemixControl</a></span><span class="op">(</span>nbiter.saemix <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="fl">1600</span>, <span class="fl">300</span><span class="op">)</span>, nb.chains <span class="op">=</span> <span class="fl">15</span>,
     print <span class="op">=</span> <span class="cn">FALSE</span>, save <span class="op">=</span> <span class="cn">FALSE</span>, save.graphs <span class="op">=</span> <span class="cn">FALSE</span>, displayProgress <span class="op">=</span> <span class="cn">FALSE</span><span class="op">)</span></code></pre></div>
 <p>The convergence plot for the SFO model using constant variance is shown below.</p>
 <div class="sourceCode" id="cb13"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_saemix_sfo_const</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
   control <span class="op">=</span> <span class="va">saemix_control</span>, transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
-<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_sfo_const</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
+<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-ANY-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_sfo_const</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_const-1.png" width="700"></p>
 <p>Obviously the default number of iterations is sufficient to reach convergence. This can also be said for the SFO fit using the two-component error model.</p>
 <div class="sourceCode" id="cb14"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_saemix_sfo_tc</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
   control <span class="op">=</span> <span class="va">saemix_control</span>, transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
-<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_sfo_tc</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
+<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-ANY-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_sfo_tc</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_tc-1.png" width="700"></p>
 <p>When fitting the DFOP model with constant variance (see below), parameter convergence is not as unambiguous.</p>
 <div class="sourceCode" id="cb15"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_saemix_dfop_const</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
   control <span class="op">=</span> <span class="va">saemix_control</span>, transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
-<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_const</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
+<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-ANY-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_const</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_const-1.png" width="700"></p>
 <p>This is improved when the DFOP model is fitted with the two-component error model. Convergence of the variance of k2 is enhanced, it remains more or less stable already after 200 iterations of the first phase.</p>
 <div class="sourceCode" id="cb16"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_saemix_dfop_tc</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
   control <span class="op">=</span> <span class="va">saemix_control</span>, transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
-<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
+<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-ANY-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc-1.png" width="700"></p>
-<p>We also check if using many more iterations (10 000 for the first and 1000 for the second phase) improve the result in a significant way. The AIC values obtained are compared further below.</p>
 <div class="sourceCode" id="cb17"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="va">f_parent_saemix_dfop_tc_10k</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
-  control <span class="op">=</span> <span class="va">saemix_control_10k</span>, transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
-<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_10k</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
-<p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_10k-1.png" width="700"></p>
+<code class="sourceCode R"><span class="co"># The last time I tried (2022-01-11) this gives an error in solve.default(omega.eta)</span>
+<span class="co"># system is computationally singular: reciprocal condition number = 5e-17</span>
+<span class="co">#f_parent_saemix_dfop_tc_10k &lt;- mkin::saem(f_parent_mkin_tc["DFOP", ], quiet = TRUE,</span>
+<span class="co">#  control = saemix_control_10k, transformations = "saemix")</span>
+<span class="co"># Now we do not get a significant improvement by using twice the number of iterations</span>
+<span class="va">f_parent_saemix_dfop_tc_moreiter</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
+  control <span class="op">=</span> <span class="va">saemix_control_moreiter</span>, transformations <span class="op">=</span> <span class="st">"saemix"</span><span class="op">)</span>
+<span class="co">#plot(f_parent_saemix_dfop_tc_moreiter$so, plot.type = "convergence")</span></code></pre></div>
 <p>An alternative way to fit DFOP in combination with the two-component error model is to use the model formulation with transformed parameters as used per default in mkin.</p>
 <div class="sourceCode" id="cb18"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_saemix_dfop_tc_mkin</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
   control <span class="op">=</span> <span class="va">saemix_control</span>, transformations <span class="op">=</span> <span class="st">"mkin"</span><span class="op">)</span>
-<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_mkin</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
-<p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin-1.png" width="700"></p>
-<p>As the convergence plots do not clearly indicate that the algorithm has converged, we again use a much larger number of iterations, which leads to satisfactory convergence (see below).</p>
+<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-ANY-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_mkin</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin-1.png" width="700"> As the convergence plots do not clearly indicate that the algorithm has converged, we again use four times the number of iterations, which leads to almost satisfactory convergence (see below).</p>
 <div class="sourceCode" id="cb19"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="va">f_parent_saemix_dfop_tc_mkin_10k</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
-  control <span class="op">=</span> <span class="va">saemix_control_10k</span>, transformations <span class="op">=</span> <span class="st">"mkin"</span><span class="op">)</span>
-<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_mkin_10k</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
-<p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin_10k-1.png" width="700"></p>
+<code class="sourceCode R"><span class="va">saemix_control_muchmoreiter</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/saemix/man/saemixControl.html">saemixControl</a></span><span class="op">(</span>nbiter.saemix <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="fl">3200</span>, <span class="fl">300</span><span class="op">)</span>, nb.chains <span class="op">=</span> <span class="fl">15</span>,
+    print <span class="op">=</span> <span class="cn">FALSE</span>, save <span class="op">=</span> <span class="cn">FALSE</span>, save.graphs <span class="op">=</span> <span class="cn">FALSE</span>, displayProgress <span class="op">=</span> <span class="cn">FALSE</span><span class="op">)</span>
+<span class="va">f_parent_saemix_dfop_tc_mkin_muchmoreiter</span> <span class="op">&lt;-</span> <span class="fu">mkin</span><span class="fu">::</span><span class="fu"><a href="../../reference/saem.html">saem</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, quiet <span class="op">=</span> <span class="cn">TRUE</span>,
+  control <span class="op">=</span> <span class="va">saemix_control_muchmoreiter</span>, transformations <span class="op">=</span> <span class="st">"mkin"</span><span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/pkg/saemix/man/plot-SaemixObject-ANY-method.html">plot</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_mkin_muchmoreiter</span><span class="op">$</span><span class="va">so</span>, plot.type <span class="op">=</span> <span class="st">"convergence"</span><span class="op">)</span></code></pre></div>
+<p><img src="dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin_moreiter-1.png" width="700"></p>
 <p>The four combinations (SFO/const, SFO/tc, DFOP/const and DFOP/tc), including the variations of the DFOP/tc combination can be compared using the model comparison function of the saemix package:</p>
 <div class="sourceCode" id="cb20"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">AIC_parent_saemix</span> <span class="op">&lt;-</span> <span class="fu">saemix</span><span class="fu">::</span><span class="fu"><a href="https://rdrr.io/pkg/saemix/man/compare.saemix.html">compare.saemix</a></span><span class="op">(</span>
@@ -268,9 +272,9 @@ f_parent_nlme_dfop_tc       3 10 671.91 702.34 -325.96 2 vs 3  134.69  &lt;.0001
   <span class="va">f_parent_saemix_sfo_tc</span><span class="op">$</span><span class="va">so</span>,
   <span class="va">f_parent_saemix_dfop_const</span><span class="op">$</span><span class="va">so</span>,
   <span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span>,
-  <span class="va">f_parent_saemix_dfop_tc_10k</span><span class="op">$</span><span class="va">so</span>,
+  <span class="va">f_parent_saemix_dfop_tc_moreiter</span><span class="op">$</span><span class="va">so</span>,
   <span class="va">f_parent_saemix_dfop_tc_mkin</span><span class="op">$</span><span class="va">so</span>,
-  <span class="va">f_parent_saemix_dfop_tc_mkin_10k</span><span class="op">$</span><span class="va">so</span><span class="op">)</span></code></pre></div>
+  <span class="va">f_parent_saemix_dfop_tc_mkin_muchmoreiter</span><span class="op">$</span><span class="va">so</span><span class="op">)</span></code></pre></div>
 <pre><code>Likelihoods calculated by importance sampling</code></pre>
 <div class="sourceCode" id="cb22"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/base/colnames.html">rownames</a></span><span class="op">(</span><span class="va">AIC_parent_saemix</span><span class="op">)</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span>
@@ -278,14 +282,14 @@ f_parent_nlme_dfop_tc       3 10 671.91 702.34 -325.96 2 vs 3  134.69  &lt;.0001
   <span class="st">"DFOP tc mkintrans"</span>, <span class="st">"DFOP tc mkintrans more iterations"</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/r/base/print.html">print</a></span><span class="op">(</span><span class="va">AIC_parent_saemix</span><span class="op">)</span></code></pre></div>
 <pre><code>                                     AIC    BIC
-SFO const                         796.37 795.33
-SFO tc                            798.37 797.13
-DFOP const                        713.16 711.28
-DFOP tc                           666.10 664.01
-DFOP tc more iterations           666.15 664.06
-DFOP tc mkintrans                 682.26 680.17
-DFOP tc mkintrans more iterations 666.12 664.04</code></pre>
-<p>As in the case of nlme fits, the DFOP model fitted with two-component error (number 4) gives the lowest AIC. Using a much larger number of iterations does not improve the fit a lot. When the mkin transformations are used instead of the saemix transformations, this large number of iterations leads to a goodness of fit that is comparable to the result obtained with saemix transformations.</p>
+SFO const                         796.38 795.34
+SFO tc                            798.38 797.13
+DFOP const                        705.75 703.88
+DFOP tc                           665.65 663.57
+DFOP tc more iterations           665.88 663.80
+DFOP tc mkintrans                 674.02 671.94
+DFOP tc mkintrans more iterations 667.94 665.86</code></pre>
+<p>As in the case of nlme fits, the DFOP model fitted with two-component error (number 4) gives the lowest AIC. Using a much larger number of iterations does not significantly change the AIC. When the mkin transformations are used instead of the saemix transformations, we need four times the number of iterations to obtain a goodness of fit that almost as good as the result obtained with saemix transformations.</p>
 <p>In order to check the influence of the likelihood calculation algorithms implemented in saemix, the likelihood from Gaussian quadrature is added to the best fit, and the AIC values obtained from the three methods are compared.</p>
 <div class="sourceCode" id="cb24"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_saemix_dfop_tc</span><span class="op">$</span><span class="va">so</span> <span class="op">&lt;-</span>
@@ -297,7 +301,7 @@ DFOP tc mkintrans more iterations 666.12 664.04</code></pre>
 <span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/r/base/print.html">print</a></span><span class="op">(</span><span class="va">AIC_parent_saemix_methods</span><span class="op">)</span></code></pre></div>
 <pre><code>    is     gq    lin 
-666.10 666.03 665.48 </code></pre>
+665.65 665.68 665.11 </code></pre>
 <p>The AIC values based on importance sampling and Gaussian quadrature are very similar. Using linearisation is known to be less accurate, but still gives a similar value.</p>
 </div>
 <div id="nlmixr" class="section level3">
@@ -327,72 +331,78 @@ DFOP tc mkintrans more iterations 666.12 664.04</code></pre>
   <span class="st">"AIC (nlme)"</span> <span class="op">=</span> <span class="va">aic_nlme</span>,
   <span class="st">"AIC (nlmixr with FOCEI)"</span> <span class="op">=</span> <span class="va">aic_nlmixr_focei</span>,
   check.names <span class="op">=</span> <span class="cn">FALSE</span>
-<span class="op">)</span></code></pre></div>
+<span class="op">)</span>
+<span class="fu"><a href="https://rdrr.io/r/base/print.html">print</a></span><span class="op">(</span><span class="va">aic_nlme_nlmixr_focei</span><span class="op">)</span></code></pre></div>
+<pre><code>  Degradation model       Error model AIC (nlme) AIC (nlmixr with FOCEI)
+1               SFO constant variance     796.60                  796.60
+2               SFO     two-component         NA                  798.64
+3              DFOP constant variance     798.60                  745.87
+4              DFOP     two-component     671.91                  740.42</code></pre>
 <p>Secondly, we use the SAEM estimation routine and check the convergence plots. The control parameters also used for the saemix fits are defined beforehand.</p>
-<div class="sourceCode" id="cb29"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb30"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">nlmixr_saem_control_800</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span>,
   nBurn <span class="op">=</span> <span class="fl">800</span>, nEm <span class="op">=</span> <span class="fl">300</span>, nmc <span class="op">=</span> <span class="fl">15</span><span class="op">)</span>
 <span class="va">nlmixr_saem_control_1000</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span>,
   nBurn <span class="op">=</span> <span class="fl">1000</span>, nEm <span class="op">=</span> <span class="fl">300</span>, nmc <span class="op">=</span> <span class="fl">15</span><span class="op">)</span>
 <span class="va">nlmixr_saem_control_10k</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/saemControl.html">saemControl</a></span><span class="op">(</span>logLik <span class="op">=</span> <span class="cn">TRUE</span>,
   nBurn <span class="op">=</span> <span class="fl">10000</span>, nEm <span class="op">=</span> <span class="fl">1000</span>, nmc <span class="op">=</span> <span class="fl">15</span><span class="op">)</span></code></pre></div>
-<p>The we fit SFO with constant variance</p>
-<div class="sourceCode" id="cb30"><pre class="downlit sourceCode r">
+<p>Then we fit SFO with constant variance</p>
+<div class="sourceCode" id="cb31"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_sfo_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
   control <span class="op">=</span> <span class="va">nlmixr_saem_control_800</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_const</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png" width="700"></p>
 <p>and SFO with two-component error.</p>
-<div class="sourceCode" id="cb31"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb32"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_sfo_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"SFO"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
   control <span class="op">=</span> <span class="va">nlmixr_saem_control_800</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png" width="700"></p>
-<p>For DFOP with constant variance, the convergence plots show considerable instability of the fit, which indicates overparameterisation which was already observed earlier for this model combination.</p>
-<div class="sourceCode" id="cb32"><pre class="downlit sourceCode r">
+<p>For DFOP with constant variance, the convergence plots show considerable instability of the fit, which indicates overparameterisation which was already observed above for this model combination.</p>
+<div class="sourceCode" id="cb33"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_dfop_const</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_const</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
   control <span class="op">=</span> <span class="va">nlmixr_saem_control_800</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_dfop_const</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png" width="700"></p>
 <p>For DFOP with two-component error, a less erratic convergence is seen.</p>
-<div class="sourceCode" id="cb33"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb34"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_dfop_tc</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
   control <span class="op">=</span> <span class="va">nlmixr_saem_control_800</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_dfop_tc</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png" width="700"></p>
 <p>To check if an increase in the number of iterations improves the fit, we repeat the fit with 1000 iterations for the burn in phase and 300 iterations for the second phase.</p>
-<div class="sourceCode" id="cb34"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb35"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_dfop_tc_1000</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
   control <span class="op">=</span> <span class="va">nlmixr_saem_control_1000</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_dfop_tc_1000</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc_1k-1.png" width="700"></p>
 <p>Here the fit looks very similar, but we will see below that it shows a higher AIC than the fit with 800 iterations in the burn in phase. Next we choose 10 000 iterations for the burn in phase and 1000 iterations for the second phase for comparison with saemix.</p>
-<div class="sourceCode" id="cb35"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb36"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">f_parent_nlmixr_saem_dfop_tc_10k</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/nlmixr.html">nlmixr</a></span><span class="op">(</span><span class="va">f_parent_mkin_tc</span><span class="op">[</span><span class="st">"DFOP"</span>, <span class="op">]</span>, est <span class="op">=</span> <span class="st">"saem"</span>,
   control <span class="op">=</span> <span class="va">nlmixr_saem_control_10k</span><span class="op">)</span>
 <span class="fu"><a href="https://rdrr.io/pkg/nlmixr/man/traceplot.html">traceplot</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_dfop_tc_10k</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
 <p><img src="dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc_10k-1.png" width="700"></p>
 <p>In the above convergence plot, the time course of ‘eta.DMTA_0’ and ‘log_k2’ indicate a false convergence.</p>
 <p>The AIC values are internally calculated using Gaussian quadrature.</p>
-<div class="sourceCode" id="cb36"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb37"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/r/stats/AIC.html">AIC</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_sfo_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_saem_sfo_tc</span><span class="op">$</span><span class="va">nm</span>,
   <span class="va">f_parent_nlmixr_saem_dfop_const</span><span class="op">$</span><span class="va">nm</span>, <span class="va">f_parent_nlmixr_saem_dfop_tc</span><span class="op">$</span><span class="va">nm</span>,
   <span class="va">f_parent_nlmixr_saem_dfop_tc_1000</span><span class="op">$</span><span class="va">nm</span>,
   <span class="va">f_parent_nlmixr_saem_dfop_tc_10k</span><span class="op">$</span><span class="va">nm</span><span class="op">)</span></code></pre></div>
-<pre><code>                                     df    AIC
-f_parent_nlmixr_saem_sfo_const$nm     5 798.69
-f_parent_nlmixr_saem_sfo_tc$nm        6 810.33
-f_parent_nlmixr_saem_dfop_const$nm    9 736.00
-f_parent_nlmixr_saem_dfop_tc$nm      10 664.85
-f_parent_nlmixr_saem_dfop_tc_1000$nm 10 669.57
-f_parent_nlmixr_saem_dfop_tc_10k$nm  10    Inf</code></pre>
+<pre><code>                                     df     AIC
+f_parent_nlmixr_saem_sfo_const$nm     5  798.71
+f_parent_nlmixr_saem_sfo_tc$nm        6  808.64
+f_parent_nlmixr_saem_dfop_const$nm    9 1995.96
+f_parent_nlmixr_saem_dfop_tc$nm      10  664.96
+f_parent_nlmixr_saem_dfop_tc_1000$nm 10  667.39
+f_parent_nlmixr_saem_dfop_tc_10k$nm  10     Inf</code></pre>
 <p>We can see that again, the DFOP/tc model shows the best goodness of fit. However, increasing the number of burn-in iterations from 800 to 1000 results in a higher AIC. If we further increase the number of iterations to 10 000 (burn-in) and 1000 (second phase), the AIC cannot be calculated for the nlmixr/saem fit, supporting that the fit did not converge properly.</p>
 </div>
 <div id="comparison" class="section level3">
 <h3 class="hasAnchor">
 <a href="#comparison" class="anchor"></a>Comparison</h3>
 <p>The following table gives the AIC values obtained with the three packages using the same control parameters (800 iterations burn-in, 300 iterations second phase, 15 chains).</p>
-<div class="sourceCode" id="cb38"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb39"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="va">AIC_all</span> <span class="op">&lt;-</span> <span class="fu"><a href="https://rdrr.io/r/base/data.frame.html">data.frame</a></span><span class="op">(</span>
   check.names <span class="op">=</span> <span class="cn">FALSE</span>,
   <span class="st">"Degradation model"</span> <span class="op">=</span> <span class="fu"><a href="https://rdrr.io/r/base/c.html">c</a></span><span class="op">(</span><span class="st">"SFO"</span>, <span class="st">"SFO"</span>, <span class="st">"DFOP"</span>, <span class="st">"DFOP"</span><span class="op">)</span>,
@@ -420,168 +430,146 @@ f_parent_nlmixr_saem_dfop_tc_10k$nm  10    Inf</code></pre>
 <td align="left">SFO</td>
 <td align="left">const</td>
 <td align="right">796.60</td>
-<td align="right">796.62</td>
-<td align="right">796.37</td>
-<td align="right">798.69</td>
+<td align="right">796.60</td>
+<td align="right">796.38</td>
+<td align="right">798.71</td>
 </tr>
 <tr class="even">
 <td align="left">SFO</td>
 <td align="left">tc</td>
 <td align="right">798.60</td>
-<td align="right">798.61</td>
-<td align="right">798.37</td>
-<td align="right">810.33</td>
+<td align="right">798.64</td>
+<td align="right">798.38</td>
+<td align="right">808.64</td>
 </tr>
 <tr class="odd">
 <td align="left">DFOP</td>
 <td align="left">const</td>
 <td align="right">NA</td>
-<td align="right">750.91</td>
-<td align="right">713.16</td>
-<td align="right">736.00</td>
+<td align="right">745.87</td>
+<td align="right">705.75</td>
+<td align="right">1995.96</td>
 </tr>
 <tr class="even">
 <td align="left">DFOP</td>
 <td align="left">tc</td>
 <td align="right">671.91</td>
-<td align="right">666.60</td>
-<td align="right">666.10</td>
-<td align="right">664.85</td>
+<td align="right">740.42</td>
+<td align="right">665.65</td>
+<td align="right">664.96</td>
 </tr>
 </tbody>
 </table>
-<div class="sourceCode" id="cb39"><pre class="downlit sourceCode r">
+<div class="sourceCode" id="cb40"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/nlme/man/intervals.html">intervals</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">)</span></code></pre></div>
 <pre><code>Approximate 95% confidence intervals
 
  Fixed effects:
             lower       est.      upper
-DMTA_0 96.2802274 98.2761977 100.272168
-k1      0.0339753  0.0645487   0.095122
-k2      0.0058977  0.0088887   0.011880
-g       0.9064373  0.9514417   0.996446
+DMTA_0 96.3087887 98.2761715 100.243554
+k1      0.0336893  0.0643651   0.095041
+k2      0.0062993  0.0088001   0.011301
+g       0.9100426  0.9524920   0.994941
 
  Random effects:
-              lower     est.   upper
-sd(DMTA_0)  0.44404 2.102366 3.76069
-sd(k1)      0.25433 0.589731 0.92514
-sd(k2)     -0.33139 0.099797 0.53099
-sd(g)       0.39606 1.092234 1.78841
+               lower      est.    upper
+sd(DMTA_0)   0.41868 2.0607469  3.70281
+sd(k1)       0.25611 0.5935653  0.93102
+sd(k2)     -10.29603 0.0029188 10.30187
+sd(g)        0.38083 1.0572543  1.73368
 
  
-       lower     est.    upper
-a.1 0.863644 1.063021 1.262398
-b.1 0.022555 0.029599 0.036643</code></pre>
-<div class="sourceCode" id="cb41"><pre class="downlit sourceCode r">
+      lower     est.    upper
+a.1 0.86253 1.061610 1.260690
+b.1 0.02262 0.029666 0.036712</code></pre>
+<div class="sourceCode" id="cb42"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/nlme/man/intervals.html">intervals</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc</span><span class="op">)</span></code></pre></div>
 <pre><code>Approximate 95% confidence intervals
 
  Fixed effects:
             lower       est.      upper
-DMTA_0 96.2802274 98.2761977 100.272168
-k1      0.0339753  0.0645487   0.095122
-k2      0.0058977  0.0088887   0.011880
-g       0.9064373  0.9514417   0.996446
-
- Random effects:
-              lower     est.   upper
-sd(DMTA_0)  0.44404 2.102366 3.76069
-sd(k1)      0.25433 0.589731 0.92514
-sd(k2)     -0.33139 0.099797 0.53099
-sd(g)       0.39606 1.092234 1.78841
-
- 
-       lower     est.    upper
-a.1 0.863644 1.063021 1.262398
-b.1 0.022555 0.029599 0.036643</code></pre>
-<div class="sourceCode" id="cb43"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/nlme/man/intervals.html">intervals</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_10k</span><span class="op">)</span></code></pre></div>
-<pre><code>Approximate 95% confidence intervals
-
- Fixed effects:
-            lower       est.      upper
-DMTA_0 96.3027896 98.2641150 100.225440
-k1      0.0338214  0.0644055   0.094990
-k2      0.0058857  0.0087896   0.011693
-g       0.9086138  0.9521421   0.995670
+DMTA_0 96.3087887 98.2761715 100.243554
+k1      0.0336893  0.0643651   0.095041
+k2      0.0062993  0.0088001   0.011301
+g       0.9100426  0.9524920   0.994941
 
  Random effects:
-              lower    est.   upper
-sd(DMTA_0)  0.41448 2.05327 3.69206
-sd(k1)      0.25507 0.59132 0.92758
-sd(k2)     -0.36781 0.09016 0.54813
-sd(g)       0.38585 1.06994 1.75402
+               lower      est.    upper
+sd(DMTA_0)   0.41868 2.0607469  3.70281
+sd(k1)       0.25611 0.5935653  0.93102
+sd(k2)     -10.29603 0.0029188 10.30187
+sd(g)        0.38083 1.0572543  1.73368
 
  
-       lower     est.    upper
-a.1 0.866273 1.066115 1.265957
-b.1 0.022501 0.029541 0.036581</code></pre>
-<div class="sourceCode" id="cb45"><pre class="downlit sourceCode r">
-<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/nlme/man/intervals.html">intervals</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_mkin_10k</span><span class="op">)</span></code></pre></div>
+      lower     est.    upper
+a.1 0.86253 1.061610 1.260690
+b.1 0.02262 0.029666 0.036712</code></pre>
+<div class="sourceCode" id="cb44"><pre class="downlit sourceCode r">
+<code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/nlme/man/intervals.html">intervals</a></span><span class="op">(</span><span class="va">f_parent_saemix_dfop_tc_mkin_muchmoreiter</span><span class="op">)</span></code></pre></div>
 <pre><code>Approximate 95% confidence intervals
 
  Fixed effects:
             lower       est.      upper
-DMTA_0 96.3021306 98.2736091 100.245088
-k1      0.0401701  0.0645140   0.103611
-k2      0.0064706  0.0089398   0.012351
-g       0.8817692  0.9511605   0.980716
+DMTA_0 96.3402070 98.2789378 100.217669
+k1      0.0397896  0.0641976   0.103578
+k2      0.0041987  0.0084427   0.016977
+g       0.8656257  0.9521509   0.983992
 
  Random effects:
-                lower     est.   upper
-sd(DMTA_0)    0.42392 2.068018 3.71212
-sd(log_k1)    0.25440 0.589877 0.92536
-sd(log_k2)   -0.38431 0.084334 0.55298
-sd(g_qlogis)  0.39107 1.077303 1.76353
+                lower    est.   upper
+sd(DMTA_0)    0.38907 2.01821 3.64735
+sd(log_k1)    0.25653 0.59512 0.93371
+sd(log_k2)   -0.20501 0.37610 0.95721
+sd(g_qlogis)  0.39712 1.18296 1.96879
 
  
        lower     est.    upper
-a.1 0.865291 1.064897 1.264504
-b.1 0.022491 0.029526 0.036561</code></pre>
-<div class="sourceCode" id="cb47"><pre class="downlit sourceCode r">
+a.1 0.868558 1.070260 1.271963
+b.1 0.022461 0.029505 0.036548</code></pre>
+<div class="sourceCode" id="cb46"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/nlme/man/intervals.html">intervals</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_dfop_tc</span><span class="op">)</span></code></pre></div>
 <pre><code>Approximate 95% confidence intervals
 
  Fixed effects:
             lower       est.      upper
-DMTA_0 96.3059406 98.2990616 100.292183
-k1      0.0402306  0.0648255   0.104456
-k2      0.0067864  0.0093097   0.012771
-g       0.8769017  0.9505258   0.981067
+DMTA_0 96.3224806 98.2941093 100.265738
+k1      0.0402270  0.0648200   0.104448
+k2      0.0068547  0.0093928   0.012871
+g       0.8764066  0.9501419   0.980848
 
  Random effects:
              lower     est. upper
-sd(DMTA_0)      NA 1.724654    NA
-sd(log_k1)      NA 0.592808    NA
-sd(log_k2)      NA 0.010741    NA
-sd(g_qlogis)    NA 1.087349    NA
+sd(DMTA_0)      NA 1.686509    NA
+sd(log_k1)      NA 0.592805    NA
+sd(log_k2)      NA 0.009766    NA
+sd(g_qlogis)    NA 1.082616    NA
 
  
           lower     est. upper
-sigma_low    NA 1.081809    NA
-rsd_high     NA 0.032051    NA</code></pre>
-<div class="sourceCode" id="cb49"><pre class="downlit sourceCode r">
+sigma_low    NA 1.081677    NA
+rsd_high     NA 0.032073    NA</code></pre>
+<div class="sourceCode" id="cb48"><pre class="downlit sourceCode r">
 <code class="sourceCode R"><span class="fu"><a href="https://rdrr.io/pkg/nlme/man/intervals.html">intervals</a></span><span class="op">(</span><span class="va">f_parent_nlmixr_saem_dfop_tc_10k</span><span class="op">)</span></code></pre></div>
 <pre><code>Approximate 95% confidence intervals
 
  Fixed effects:
-           lower       est.     upper
-DMTA_0 96.426510 97.8987836 99.371057
-k1      0.040006  0.0644407  0.103799
-k2      0.006748  0.0092476  0.012673
-g       0.879251  0.9511399  0.981147
+            lower       est.      upper
+DMTA_0 96.2302085 98.1641090 100.098010
+k1      0.0398514  0.0643909   0.104041
+k2      0.0066292  0.0090784   0.012432
+g       0.8831478  0.9527284   0.981734
 
  Random effects:
              lower       est. upper
-sd(DMTA_0)      NA 3.7049e-04    NA
-sd(log_k1)      NA 5.9221e-01    NA
-sd(log_k2)      NA 3.8628e-07    NA
-sd(g_qlogis)    NA 1.0694e+00    NA
+sd(DMTA_0)      NA 1.6257e+00    NA
+sd(log_k1)      NA 5.9627e-01    NA
+sd(log_k2)      NA 5.8400e-07    NA
+sd(g_qlogis)    NA 1.0676e+00    NA
 
  
           lower     est. upper
-sigma_low    NA 1.082343    NA
-rsd_high     NA 0.034895    NA</code></pre>
+sigma_low    NA 1.087722    NA
+rsd_high     NA 0.031883    NA</code></pre>
 </div>
 </div>
 </div>
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png
index af70163c..27546d8d 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_const-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png
index 5e4ce944..dcb8a2f0 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc_10k-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc_10k-1.png
index 6f72ee69..7871ef69 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc_10k-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc_10k-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc_1k-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc_1k-1.png
index 718524e7..69aaae8e 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc_1k-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_dfop_tc_1k-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png
index 8e49bde4..4316ed0b 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_const-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png
index 015f2d0b..fb6dd51c 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_nlmixr_saem_sfo_tc-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_const-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_const-1.png
index 7c79b56c..fd4a686d 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_const-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_const-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc-1.png
index 8478adcf..25a82cbe 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin-1.png
index 957d13af..9a6547a2 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin_moreiter-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin_moreiter-1.png
new file mode 100644
index 00000000..30ee4ea0
Binary files /dev/null and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_dfop_tc_mkin_moreiter-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_const-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_const-1.png
index 18b546e9..c406f3f2 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_const-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_const-1.png differ
diff --git a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_tc-1.png b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_tc-1.png
index 6a0c05c5..aaf2e0c8 100644
Binary files a/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_tc-1.png and b/docs/dev/articles/web_only/dimethenamid_2018_files/figure-html/f_parent_saemix_sfo_tc-1.png differ
-- 
cgit v1.2.1