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<p><strong>Note:</strong> values on this page will change with every website update since they are based on randomly created values and the page was written in <ahref="https://rmarkdown.rstudio.com/">RMarkdown</a>. However, the methodology remains unchanged. This page was generated on 02 January 2019.</p>
<p>For this tutorial, we will create fake demonstration data to work with.</p>
<p>You can skip to <ahref="#cleaning-the-data">Cleaning the data</a> if you already have your own data ready. If you start your analysis, try to make the structure of your data generally look like this:</p>
<ahref="#needed-r-packages"class="anchor"></a>Needed R packages</h2>
<p>As with many uses in R, we need some additional packages for AMR analysis. The most important one is <ahref="https://dplyr.tidyverse.org/"><code>dplyr</code></a>, which tremendously improves the way we work with data - it allows for a very natural way of writing syntaxes in R. Another important dependency is <ahref="https://ggplot2.tidyverse.org/"><code>ggplot2</code></a>. This package can be used to create beautiful plots in R.</p>
<p>Our <code>AMR</code> package depends on these packages and even extends their use and functions.</p>
<divclass="sourceCode"id="cb1"><preclass="sourceCode r"><codeclass="sourceCode r"><aclass="sourceLine"id="cb1-1"data-line-number="1"><spanclass="kw"><ahref="https://www.rdocumentation.org/packages/base/topics/library">library</a></span>(dplyr) <spanclass="co"># the data science package</span></a>
<aclass="sourceLine"id="cb1-2"data-line-number="2"><spanclass="kw"><ahref="https://www.rdocumentation.org/packages/base/topics/library">library</a></span>(AMR) <spanclass="co"># this package, to simplify and automate AMR analysis</span></a>
<aclass="sourceLine"id="cb1-3"data-line-number="3"><spanclass="kw"><ahref="https://www.rdocumentation.org/packages/base/topics/library">library</a></span>(ggplot2) <spanclass="co"># for appealing plots</span></a></code></pre></div>
<p>We will create some fake example data to use for analysis. For antimicrobial resistance analysis, we need at least: a patient ID, name or code of a microorganism, a date and antimicrobial results (an antibiogram). It could also include a specimen type (e.g.to filter on blood or urine), the ward type (e.g.to filter on ICUs).</p>
<p>With additional columns (like a hospital name, the patients gender of even [well-defined] clinical properties) you can do a comparative analysis, as this tutorial will demonstrate too.</p>
<p>The <code>LETTERS</code> object is available in R - it’s a vector with 26 characters: <code>A</code> to <code>Z</code>. The <code>patients</code> object we just created is now a vector of length 260, with values (patient IDs) varying from <code>A1</code> to <code>Z10</code>. Now we we also set the gender of our patients, by putting the ID and the gender in a table:</p>
<p>For this tutorial, we will uses four different microorganisms: <em>Escherichia coli</em>, <em>Staphylococcus aureus</em>, <em>Streptococcus pneumoniae</em>, and <em>Klebsiella pneumoniae</em>:</p>
<p>For completeness, we can also add the hospital where the patients was admitted and we need to define valid antibmicrobial results for our randomisation:</p>
<p>Using the <code><ahref="https://www.rdocumentation.org/packages/dplyr/topics/sample">sample()</a></code> function, we can randomly select items from all objects we defined earlier. To let our fake data reflect reality a bit, we will also approximately define the probabilities of bacteria and the antibiotic results with the <code>prob</code> parameter.</p>
<p>Using the <code><ahref="https://www.rdocumentation.org/packages/dplyr/topics/join">left_join()</a></code> function from the <code>dplyr</code> package, we can ‘map’ the gender to the patient ID using the <code>patients_table</code> object we created earlier:</p>
<p>The resulting data set contains 5,000 blood culture isolates. With the <code><ahref="https://www.rdocumentation.org/packages/utils/topics/head">head()</a></code> function we can preview the first 6 values of this data set:</p>
<p>Use the frequency table function <code><ahref="../reference/freq.html">freq()</a></code> to look specifically for unique values in any variable. For example, for the <code>gender</code> variable:</p>
<divclass="sourceCode"id="cb10"><preclass="sourceCode r"><codeclass="sourceCode r"><aclass="sourceLine"id="cb10-1"data-line-number="1">data <spanclass="op">%>%</span><spanclass="st"></span><spanclass="kw"><ahref="../reference/freq.html">freq</a></span>(gender) <spanclass="co"># this would be the same: freq(data$gender)</span></a></code></pre></div>
<p>So, we can draw at least two conclusions immediately. From a data scientist perspective, the data looks clean: only values <code>M</code> and <code>F</code>. From a researcher perspective: there are slightly more men. Nothing we didn’t already know.</p>
<p>The data is already quite clean, but we still need to transform some variables. The <code>bacteria</code> column now consists of text, and we want to add more variables based on microbial IDs later on. So, we will transform this column to valid IDs. The <code><ahref="https://www.rdocumentation.org/packages/dplyr/topics/mutate">mutate()</a></code> function of the <code>dplyr</code> package makes this really easy:</p>
<p>We also want to transform the antibiotics, because in real life data we don’t know if they are really clean. The <code><ahref="../reference/as.rsi.html">as.rsi()</a></code> function ensures reliability and reproducibility in these kind of variables. The <code><ahref="https://www.rdocumentation.org/packages/dplyr/topics/summarise_all">mutate_at()</a></code> will run the <code><ahref="../reference/as.rsi.html">as.rsi()</a></code> function on defined variables:</p>
<p>Finally, we will apply <ahref="http://www.eucast.org/expert_rules_and_intrinsic_resistance/">EUCAST rules</a> on our antimicrobial results. In Europe, most medical microbiological laboratories already apply these rules. Our package features their latest insights on intrinsic resistance and exceptional phenotypes. Moreover, the <code><ahref="../reference/eucast_rules.html">eucast_rules()</a></code> function can also apply additional rules, like forcing <helptitle="ATC: J01CA01">ampicillin</help> = R when <helptitle="ATC: J01CR02">amoxicillin/clavulanic acid</help> = R.</p>
<p>Because the amoxicillin (column <code>amox</code>) and amoxicillin/clavulanic acid (column <code>amcl</code>) in our data were generated randomly, some rows will undoubtedly contain amox = S and amcl = R, which is technically impossible. The <code><ahref="../reference/eucast_rules.html">eucast_rules()</a></code> fixes this:</p>
<aclass="sourceLine"id="cb14-3"data-line-number="3"><spanclass="co"># Rules by the European Committee on Antimicrobial Susceptibility Testing (EUCAST)</span></a>
<aclass="sourceLine"id="cb14-22"data-line-number="22"><spanclass="co"># Table 1: Intrinsic resistance in Enterobacteriaceae (303 changes)</span></a>
<aclass="sourceLine"id="cb14-23"data-line-number="23"><spanclass="co"># Table 2: Intrinsic resistance in non-fermentative Gram-negative bacteria (no changes)</span></a>
<aclass="sourceLine"id="cb14-24"data-line-number="24"><spanclass="co"># Table 3: Intrinsic resistance in other Gram-negative bacteria (no changes)</span></a>
<aclass="sourceLine"id="cb14-25"data-line-number="25"><spanclass="co"># Table 4: Intrinsic resistance in Gram-positive bacteria (641 changes)</span></a>
<aclass="sourceLine"id="cb14-26"data-line-number="26"><spanclass="co"># Table 8: Interpretive rules for B-lactam agents and Gram-positive cocci (no changes)</span></a>
<aclass="sourceLine"id="cb14-27"data-line-number="27"><spanclass="co"># Table 9: Interpretive rules for B-lactam agents and Gram-negative rods (no changes)</span></a>
<aclass="sourceLine"id="cb14-28"data-line-number="28"><spanclass="co"># Table 10: Interpretive rules for B-lactam agents and other Gram-negative bacteria (no changes)</span></a>
<aclass="sourceLine"id="cb14-29"data-line-number="29"><spanclass="co"># Table 11: Interpretive rules for macrolides, lincosamides, and streptogramins (no changes)</span></a>
<aclass="sourceLine"id="cb14-30"data-line-number="30"><spanclass="co"># Table 12: Interpretive rules for aminoglycosides (no changes)</span></a>
<aclass="sourceLine"id="cb14-31"data-line-number="31"><spanclass="co"># Table 13: Interpretive rules for quinolones (no changes)</span></a>
<aclass="sourceLine"id="cb14-33"data-line-number="33"><spanclass="co"># Other rules</span></a>
<aclass="sourceLine"id="cb14-34"data-line-number="34"><spanclass="co"># Non-EUCAST: ampicillin = R where amoxicillin/clav acid = R (403 changes)</span></a>
<aclass="sourceLine"id="cb14-35"data-line-number="35"><spanclass="co"># Non-EUCAST: piperacillin = R where piperacillin/tazobactam = R (no changes)</span></a>
<aclass="sourceLine"id="cb14-36"data-line-number="36"><spanclass="co"># Non-EUCAST: trimethoprim = R where trimethoprim/sulfa = R (no changes)</span></a>
<aclass="sourceLine"id="cb14-37"data-line-number="37"><spanclass="co"># Non-EUCAST: amoxicillin/clav acid = S where ampicillin = S (231 changes)</span></a>
<aclass="sourceLine"id="cb14-38"data-line-number="38"><spanclass="co"># Non-EUCAST: piperacillin/tazobactam = S where piperacillin = S (no changes)</span></a>
<aclass="sourceLine"id="cb14-39"data-line-number="39"><spanclass="co"># Non-EUCAST: trimethoprim/sulfa = S where trimethoprim = S (no changes)</span></a>
<aclass="sourceLine"id="cb14-41"data-line-number="41"><spanclass="co"># => EUCAST rules affected 4,588 out of 5,000 rows -> changed 1,942 test results.</span></a></code></pre></div>
<p>To conduct an analysis of antimicrobial resistance, you must <ahref="https://www.ncbi.nlm.nih.gov/pubmed/17304462">only include the first isolate of every patient per episode</a> (Hindler <em>et al.</em>, Clin Infect Dis. 2007). If you would not do this, you could easily get an overestimate or underestimate of the resistance of an antibiotic. Imagine that a patient was admitted with an MRSA and that it was found in 5 different blood cultures the following weeks (yes, some countries like the Netherlands have these blood drawing policies). The resistance percentage of oxacillin of all isolates would be overestimated, because you included this MRSA more than once. It would clearly be <ahref="https://en.wikipedia.org/wiki/Selection_bias">selection bias</a>.</p>
<p><em>(…) When preparing a cumulative antibiogram to guide clinical decisions about empirical antimicrobial therapy of initial infections, <strong>only the first isolate of a given species per patient, per analysis period (eg, one year) should be included, irrespective of body site, antimicrobial susceptibility profile, or other phenotypical characteristics (eg, biotype)</strong>. The first isolate is easily identified, and cumulative antimicrobial susceptibility test data prepared using the first isolate are generally comparable to cumulative antimicrobial susceptibility test data calculated by other methods, providing duplicate isolates are excluded.</em><br><ahref="https://clsi.org/standards/products/microbiology/documents/m39/">M39-A4 Analysis and Presentation of Cumulative Antimicrobial Susceptibility Test Data, 4th Edition. CLSI, 2014. Chapter 6.4</a></p>
<p>This <code>AMR</code> package includes this methodology with the <code><ahref="../reference/first_isolate.html">first_isolate()</a></code> function. It adopts the episode of a year (can be changed by user) and it starts counting days after every selected isolate. This new variable can easily be added to our data:</p>
<aclass="sourceLine"id="cb16-3"data-line-number="3"><spanclass="co"># </span><spanclass="al">NOTE</span><spanclass="co">: Using column `bacteria` as input for `col_mo`.</span></a>
<aclass="sourceLine"id="cb16-4"data-line-number="4"><spanclass="co"># </span><spanclass="al">NOTE</span><spanclass="co">: Using column `date` as input for `col_date`.</span></a>
<aclass="sourceLine"id="cb16-5"data-line-number="5"><spanclass="co"># </span><spanclass="al">NOTE</span><spanclass="co">: Using column `patient_id` as input for `col_patient_id`.</span></a>
<aclass="sourceLine"id="cb16-6"data-line-number="6"><spanclass="co"># => Found 2,925 first isolates (58.5% of total)</span></a></code></pre></div>
<p>So only 58.5% is suitable for resistance analysis! We can now filter on is with the <code><ahref="https://www.rdocumentation.org/packages/dplyr/topics/filter">filter()</a></code> function, also from the <code>dplyr</code> package:</p>
<p>For future use, the above two syntaxes can be shortened with the <code><ahref="../reference/first_isolate.html">filter_first_isolate()</a></code> function:</p>
<p>Only 3 isolates are marked as ‘first’ according to CLSI guideline. But when reviewing the antibiogram, it is obvious that some isolates are absolutely different strains and show be included too. This is why we weigh isolates, based on their antibiogram. The <code><ahref="../reference/key_antibiotics.html">key_antibiotics()</a></code> function adds a vector with 18 key antibiotics: 6 broad spectrum ones, 6 small spectrum for Gram negatives and 6 small spectrum for Gram positives. These can be defined by the user.</p>
<p>If a column exists with a name like ‘key(…)ab’ the <code><ahref="../reference/first_isolate.html">first_isolate()</a></code> function will automatically use it and determine the first weighted isolates. Mind the NOTEs in below output:</p>
<aclass="sourceLine"id="cb19-4"data-line-number="4"><spanclass="co"># </span><spanclass="al">NOTE</span><spanclass="co">: Using column `bacteria` as input for `col_mo`.</span></a>
<aclass="sourceLine"id="cb19-5"data-line-number="5"><spanclass="co"># Warning: These columns do not exist and will be ignored: cfur, pita, trsu, vanc, teic, tetr, eryt, oxac, rifa, tobr, coli, cfot, cfta, mero.</span></a>
<aclass="sourceLine"id="cb19-6"data-line-number="6"><spanclass="co"># THIS MAY STRONGLY INFLUENCE THE OUTCOME.</span></a>
<aclass="sourceLine"id="cb19-7"data-line-number="7"><spanclass="co"># </span><spanclass="al">NOTE</span><spanclass="co">: Using column `bacteria` as input for `col_mo`.</span></a>
<aclass="sourceLine"id="cb19-8"data-line-number="8"><spanclass="co"># </span><spanclass="al">NOTE</span><spanclass="co">: Using column `date` as input for `col_date`.</span></a>
<aclass="sourceLine"id="cb19-9"data-line-number="9"><spanclass="co"># </span><spanclass="al">NOTE</span><spanclass="co">: Using column `patient_id` as input for `col_patient_id`.</span></a>
<aclass="sourceLine"id="cb19-10"data-line-number="10"><spanclass="co"># </span><spanclass="al">NOTE</span><spanclass="co">: Using column `keyab` as input for `col_keyantibiotics`. Use col_keyantibiotics = FALSE to prevent this.</span></a>
<aclass="sourceLine"id="cb19-11"data-line-number="11"><spanclass="co"># [Criterion] Inclusion based on key antibiotics, ignoring I.</span></a>
<aclass="sourceLine"id="cb19-12"data-line-number="12"><spanclass="co"># => Found 4,390 first weighted isolates (87.8% of total)</span></a></code></pre></div>
<p>Instead of 3, now 9 isolates are flagged. In total, 87.8% of all isolates are marked ‘first weighted’ - 146.3% more than when using the CLSI guideline. In real life, this novel algorithm will yield 5-10% more isolates than the classic CLSI guideline.</p>
<p>You might want to start by getting an idea of how the data is distributed. It’s an important start, because it also decides how you will continue your analysis. ## Dispersion of species To just get an idea how the species are distributed, create a frequency table with our <code><ahref="../reference/freq.html">freq()</a></code> function. We created the <code>genus</code> and <code>species</code> column earlier based on the microbial ID. With <code><ahref="https://www.rdocumentation.org/packages/base/topics/paste">paste()</a></code>, we can concatenate them together.</p>
<p>The <code><ahref="../reference/freq.html">freq()</a></code> function can be used like the base R language was intended:</p>
<p>The functions <code>portion_R</code>, <code>portion_RI</code>, <code>portion_I</code>, <code>portion_IS</code> and <code>portion_S</code> can be used to determine the portion of a specific antimicrobial outcome. They can be used on their own:</p>
<p>Or can be used in conjuction with <code><ahref="https://www.rdocumentation.org/packages/dplyr/topics/group_by">group_by()</a></code> and <code><ahref="https://www.rdocumentation.org/packages/dplyr/topics/summarise">summarise()</a></code>, both from the <code>dplyr</code> package:</p>
<p>Of course it would be very convenient to know the number of isolates responsible for the percentages. For that purpose the <code><ahref="../reference/count.html">n_rsi()</a></code> can be used, which works exactly like <code><ahref="https://www.rdocumentation.org/packages/dplyr/topics/n_distinct">n_distinct()</a></code> from the <code>dplyr</code> package. It counts all isolates available for every group (i.e.values S, I or R):</p>
<p>To show results in plots, most R users would nowadays use the <code>ggplot2</code> package. This package lets you create plots in layers. You can read more about it <ahref="https://ggplot2.tidyverse.org/">on their website</a>. A quick example would look like these syntaxes:</p>
<p>The <code>AMR</code> package contains functions to extend this <code>ggplot2</code> package, for example <code><ahref="../reference/ggplot_rsi.html">geom_rsi()</a></code>. It automatically transforms data with <code><ahref="../reference/count.html">count_df()</a></code> or <code><ahref="../reference/portion.html">portion_df()</a></code> and show results in stacked bars. Its simplest and shortest example:</p>
<p>Omit the <code>translate_ab = FALSE</code> to have the antibiotic codes (amox, amcl, cipr, gent) translated to official WHO names (amoxicillin, amoxicillin and betalactamase inhibitor, ciprofloxacin, gentamicin).</p>
<p>If we group on e.g.the <code>genus</code> column and add some additional functions from our package, we can create this:</p>
<divclass="sourceCode"id="cb32"><preclass="sourceCode r"><codeclass="sourceCode r"><aclass="sourceLine"id="cb32-1"data-line-number="1"><spanclass="co"># group the data on `genus`</span></a>
<aclass="sourceLine"id="cb32-3"data-line-number="3"><spanclass="st"></span><spanclass="co"># create bars with genus on x axis</span></a>
<aclass="sourceLine"id="cb32-4"data-line-number="4"><spanclass="st"></span><spanclass="co"># it looks for variables with class `rsi`,</span></a>
<aclass="sourceLine"id="cb32-5"data-line-number="5"><spanclass="st"></span><spanclass="co"># of which we have 4 (earlier created with `as.rsi`)</span></a>
<aclass="sourceLine"id="cb32-13"data-line-number="13"><spanclass="st"></span><spanclass="co"># turn 90 degrees, make it bars instead of columns</span></a>
<aclass="sourceLine"id="cb32-16"data-line-number="16"><spanclass="st"></span><spanclass="kw"><ahref="https://www.rdocumentation.org/packages/ggplot2/topics/labs">labs</a></span>(<spanclass="dt">title =</span><spanclass="st">"Resistance per genus and antibiotic"</span>, </a>
<aclass="sourceLine"id="cb32-17"data-line-number="17"><spanclass="dt">subtitle =</span><spanclass="st">"(this is fake data)"</span>) <spanclass="op">+</span></a>
<aclass="sourceLine"id="cb32-18"data-line-number="18"><spanclass="st"></span><spanclass="co"># and print genus in italic to follow our convention</span></a>
<aclass="sourceLine"id="cb32-19"data-line-number="19"><spanclass="st"></span><spanclass="co"># (is now y axis because we turned the plot)</span></a>
<p>To simplify this, we also created the <code><ahref="../reference/ggplot_rsi.html">ggplot_rsi()</a></code> function, which combines almost all above functions:</p>
<ahref="#using-an-independence-test-to-compare-resistance"class="anchor"></a>Using an independence test to compare resistance</h3>
<p>The next example uses the included <code>septic_patients</code>, which is an anonymised data set containing 2,000 microbial blood culture isolates with their full antibiograms found in septic patients in 4 different hospitals in the Netherlands, between 2001 and 2017. It is true, genuine data. This <code>data.frame</code> can be used to practice AMR analysis.</p>
<p>We will compare the resistance to fosfomycin (column <code>fosf</code>) in hospital A and D. The input for the final <code><ahref="https://www.rdocumentation.org/packages/stats/topics/fisher.test">fisher.test()</a></code> will be this:</p>
<tableclass="table">
<thead><trclass="header">
<th></th>
<thalign="left">A</th>
<thalign="left">D</th>
</tr></thead>
<tbody>
<trclass="odd">
<td>IR</td>
<tdalign="left">24</td>
<tdalign="left">33</td>
</tr>
<trclass="even">
<td>S</td>
<tdalign="left">25</td>
<tdalign="left">77</td>
</tr>
</tbody>
</table>
<p>We can transform the data and apply the test in only a couple of lines:</p>
<aclass="sourceLine"id="cb34-2"data-line-number="2"><spanclass="st"></span><spanclass="kw"><ahref="https://www.rdocumentation.org/packages/dplyr/topics/filter">filter</a></span>(hospital_id <spanclass="op">%in%</span><spanclass="st"></span><spanclass="kw"><ahref="https://www.rdocumentation.org/packages/base/topics/c">c</a></span>(<spanclass="st">"A"</span>, <spanclass="st">"D"</span>)) <spanclass="op">%>%</span><spanclass="st"></span><spanclass="co"># filter on only hospitals A and D</span></a>
<aclass="sourceLine"id="cb34-3"data-line-number="3"><spanclass="st"></span><spanclass="kw"><ahref="https://www.rdocumentation.org/packages/dplyr/topics/select">select</a></span>(hospital_id, fosf) <spanclass="op">%>%</span><spanclass="st"></span><spanclass="co"># select the hospitals and fosfomycin</span></a>
<aclass="sourceLine"id="cb34-4"data-line-number="4"><spanclass="st"></span><spanclass="kw"><ahref="https://www.rdocumentation.org/packages/dplyr/topics/group_by">group_by</a></span>(hospital_id) <spanclass="op">%>%</span><spanclass="st"></span><spanclass="co"># group on the hospitals</span></a>
<aclass="sourceLine"id="cb34-5"data-line-number="5"><spanclass="st"></span><spanclass="kw"><ahref="../reference/count.html">count_df</a></span>(<spanclass="dt">combine_IR =</span><spanclass="ot">TRUE</span>) <spanclass="op">%>%</span><spanclass="st"></span><spanclass="co"># count all isolates per group (hospital_id)</span></a>
<aclass="sourceLine"id="cb34-6"data-line-number="6"><spanclass="st"></span>tidyr<spanclass="op">::</span><spanclass="kw"><ahref="https://www.rdocumentation.org/packages/tidyr/topics/spread">spread</a></span>(hospital_id, Value) <spanclass="op">%>%</span><spanclass="st"></span><spanclass="co"># transform output so A and D are columns</span></a>
<aclass="sourceLine"id="cb34-7"data-line-number="7"><spanclass="st"></span><spanclass="kw"><ahref="https://www.rdocumentation.org/packages/dplyr/topics/select">select</a></span>(A, D) <spanclass="op">%>%</span><spanclass="st"></span><spanclass="co"># and select these only</span></a>
<aclass="sourceLine"id="cb34-8"data-line-number="8"><spanclass="st"></span><spanclass="kw"><ahref="https://www.rdocumentation.org/packages/base/topics/matrix">as.matrix</a></span>() <spanclass="op">%>%</span><spanclass="st"></span><spanclass="co"># transform to good old matrix for fisher.test()</span></a>
<aclass="sourceLine"id="cb34-9"data-line-number="9"><spanclass="st"></span><spanclass="kw"><ahref="https://www.rdocumentation.org/packages/stats/topics/fisher.test">fisher.test</a></span>() <spanclass="co"># do Fisher's Exact Test</span></a>
<p>Developed by <ahref="https://www.rug.nl/staff/m.s.berends/">Matthijs S. Berends</a>, <ahref="https://www.rug.nl/staff/c.f.luz/">Christian F. Luz</a>, <ahref="https://www.rug.nl/staff/c.glasner/">Corinna Glasner</a>, <ahref="https://www.rug.nl/staff/a.w.friedrich/">Alex W. Friedrich</a>, <ahref="https://www.rug.nl/staff/b.sinha/">Bhanu N. M. Sinha</a>.</p>
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