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<!DOCTYPE html>
<html lang="en">
<head>
<meta charset="utf-8">
<meta name="viewport" content="width=device-width, initial-scale=1">
<title>NephroTDM</title>
<!-- Built single-file artifact: nephrotdm.html (build: __BUILD__) -->
<link rel="stylesheet" href="src/fonts.css">
<link rel="stylesheet" href="src/app.css">
</head>
<body>
<header class="app no-print">
<div class="brand">
<svg width="34" height="34" viewBox="0 0 34 34" aria-hidden="true"><rect width="34" height="34" rx="9" fill="#0b6e85"/><path d="M5 25 C 10 25, 11 9, 16 9 S 22 25, 29 25" fill="none" stroke="#ffffff" stroke-width="2.6" stroke-linecap="round"/><circle cx="16" cy="9" r="2.6" fill="#ffffff"/></svg>
<h1><span id="appName">NephroTDM</span> <span class="appver" id="titleVersion" title="Application version"></span></h1>
</div>
<nav class="nav" aria-label="Help">
<button type="button" id="btnGettingStarted" title="A short, step-by-step walkthrough for first-time use, opened in its own window">Getting started</button>
<button type="button" id="btnBackground" title="Why therapeutic drug monitoring, reference values, model-based estimation and sampling advice for the selected drug">Background</button>
<button type="button" id="btnAbout" title="Version, model documentation, contact and research-use disclaimer">About</button>
</nav>
<div class="actions">
<details class="menu">
<summary title="Save, restore or clear this session">Session</summary>
<div class="menu-pop">
<button type="button" id="btnExport" title="Download this session as a JSON file (pseudonym only, no identifiers required)">Export session</button>
<button type="button" id="btnImport" title="Restore a previously exported session">Import session</button>
<button type="button" id="btnClearSession" class="danger" title="Delete the autosaved copy kept in this browser and empty this page. Exported session files are not affected.">Clear session</button>
</div>
</details>
<button type="button" id="btnPrint" title="Generate an A4 report of this patient, dosing schedule, samples, AUC estimate and advice, with prepared-by and signature lines">Print report</button>
<input type="file" id="importFile" accept=".json" style="display:none">
</div>
<div class="sub" id="appSub">Model-informed therapeutic drug monitoring for kidney transplantation and nephrology. Choose a drug, enter the dosing and any measured concentrations, and the app estimates the patient’s exposure with its uncertainty and shows what a different dose would do. Everything runs locally in your browser: nothing you enter is sent or processed online. The only copy is an autosave in this browser.</div>
</header>
<main class="layout">
<div class="restore-bar no-print" id="restoreBar" role="status" hidden>
<span id="restoreText"></span>
<span class="restore-actions">
<button type="button" class="primary" id="restoreYes" title="Load the autosaved doses and measurements back into the form">Restore</button>
<button type="button" id="restoreNo" title="Discard the autosaved session and start empty">Discard</button>
</span>
</div>
<div class="stepper no-print" id="stepper">
<a class="step" href="#patientCard" data-step="wt"><i>1</i> Patient & covariates</a>
<a class="step" href="#chartCard" data-step="dose"><i>2</i> Dosing & samples</a>
<a class="step" href="#resultsCard" data-step="run"><i>3</i> Forecast</a>
<a class="step" href="#regimenCard" data-step="explore"><i>4</i> Explore dose (optional)</a>
<button type="button" class="linklike" id="stepperDismiss" title="Hide this guide">dismiss</button>
</div>
<div class="workspace">
<div class="col-in">
<!-- ============ 1 · PATIENT & COVARIATES ============ -->
<div class="card sessionbar" id="patientCard">
<h2><span class="stepnum">1</span> Patient & covariates</h2>
<div class="sess-row">
<div class="sess-field sess-drug">
<span class="f" id="drugLbl">Drug / PK model</span>
<div class="drug-cards" id="drugCards" role="group" aria-labelledby="drugLbl"></div>
<select id="pt-drug" class="sr-only" aria-hidden="true" tabindex="-1" title="Which drug's population PK model to use for this patient">
<option value="mpa">Mycophenolic acid</option>
<option value="mpaped">MPA (pediatric kidney)</option>
<option value="tac">Tacrolimus (adult kidney)</option>
<option value="tacped">Tacrolimus (pediatric)</option>
<option value="evr">Everolimus (adult kidney)</option>
</select>
</div>
<div class="sess-field sf-num">
<div class="lbl-help">
<label class="f" for="pt-wt">Weight (kg)</label>
<button type="button" class="info" data-help="wt" aria-label="What is the weight field for?" aria-expanded="false" title="Body weight in kg">ⓘ</button>
</div>
<input type="number" inputmode="decimal" id="pt-wt" min="25" max="300" step="0.5" placeholder="e.g. 70" title="Body weight in kg">
</div>
<div class="sess-field sf-num" id="ageRow" style="display:none">
<div class="lbl-help">
<label class="f" for="pt-age">Age (years)</label>
<button type="button" class="info" data-help="age" aria-label="What is the age field for?" aria-expanded="false" title="Age in years">ⓘ</button>
</div>
<input type="number" inputmode="decimal" id="pt-age" min="1" max="100" step="1" placeholder="e.g. 45" title="Age in years">
</div>
<div class="sess-field" id="renalRow" style="display:none">
<div class="lbl-help">
<label class="f" for="pt-renal">Renal function</label>
<button type="button" class="info" data-help="renal" aria-label="What is the renal function field for?" aria-expanded="false" title="Renal function, if the model uses it">ⓘ</button>
</div>
<input type="text" id="pt-renal" placeholder="e.g. eGFR 70 mL/min" title="Renal function, if the model uses it">
</div>
<div class="sess-field" id="extraCovRow" style="display:none">
<div class="lbl-help">
<label class="f" for="pt-extracov">Other covariate</label>
<button type="button" class="info" data-help="extracov" aria-label="What is the other covariate field for?" aria-expanded="false" title="Other model covariates, if any">ⓘ</button>
</div>
<input type="text" id="pt-extracov" placeholder="e.g. as applicable" title="Other model covariates, if any">
</div>
<!-- Host for covariate rows generated from the model spec (model-driven UI) -->
<div id="generatedCovariates" style="display:contents"></div>
<div class="note warn no-print" id="scopeWarn" role="status" hidden style="flex:1 1 100%"></div>
<div class="sess-field sess-target">
<details class="sess-fold" id="windowFold">
<summary title="Therapeutic window used for probability-in-window. Fold open to change it.">
<span class="fold-lbl">Therapeutic window: AUC₀–12h</span>
<span class="fold-val" id="windowFoldVal">–</span>
<span class="fold-edit">change</span>
</summary>
<div class="legend-note">The target is the AUC over a <b>12-hour dosing interval at steady state</b> (AUC₀–12h). Regimens with another interval are compared as their 12-hour equivalent: AUC₁₂ = AUC₀–ₓ × 12/ₓ.</div>
<div class="lbl-help">
<label class="f" for="pt-winlo">Lower bound AUC₀–12h (mg·h/L)</label>
<button type="button" class="info" data-help="window" aria-label="What is the therapeutic window?" aria-expanded="false" title="Lower and upper bound for therapeutic AUC0–12h">ⓘ</button>
</div>
<input type="number" inputmode="decimal" id="pt-winlo" min="0.1" max="500" step="any" title="Lower bound of the therapeutic AUC0–12h window (mg·h/L)">
<label class="f" for="pt-winhi" style="margin-top:6px">Upper bound AUC₀–12h (mg·h/L)</label>
<input type="number" inputmode="decimal" id="pt-winhi" min="0.1" max="5000" step="any" title="Upper bound of the therapeutic AUC0–12h window (mg·h/L)">
<div class="legend-note" id="windowHint"></div>
</details>
</div>
<div class="sess-field sess-target" id="troughTargetRow" style="display:none">
<details class="sess-fold" id="troughFold">
<summary title="Therapeutic trough window used for probability-in-window. Fold open to change it.">
<span class="fold-lbl">Therapeutic window: trough</span>
<span class="fold-val" id="troughFoldVal">–</span>
<span class="fold-edit">change</span>
</summary>
<div class="legend-note">Both windows are clinical inputs from your protocol (see the background dialog for the IATDMCT consensus). Leave a window empty and the app reports intervals without probabilities.</div>
<label class="f" for="pt-tlo">Lower bound trough (µg/L)</label>
<input type="number" inputmode="decimal" id="pt-tlo" min="0" step="any" title="Lower bound of the therapeutic trough window (µg/L)">
<label class="f" for="pt-thi" style="margin-top:6px">Upper bound trough (µg/L)</label>
<input type="number" inputmode="decimal" id="pt-thi" min="0" step="any" title="Upper bound of the therapeutic trough window (µg/L)">
</details>
</div>
</div>
<div class="legend-note" id="drugHint" style="margin:6px 0 0"></div>
<div class="pending-notice" id="pendingNotice" hidden></div>
<div class="row2" style="margin-top:4px">
<div>
<label class="f" for="pt-code">Patient ID/name (optional)</label>
<input type="text" id="pt-code" placeholder="e.g. ID001" autocomplete="off">
</div>
<div>
<div class="sess-field" id="formRow">
<div class="lbl-help">
<label class="f" for="pt-form">Formulation</label>
<button type="button" class="info" data-help="form" aria-label="About the formulation covariate" aria-expanded="false" title="The model covariate: switches absorption and the dose conversion">ⓘ</button>
</div>
<select id="pt-form" title="The formulation is this model’s covariate: it switches the absorption rate, the lag-time structure and the dose conversion (×0.739 MMF, ×0.936 EC-MPS to MPA mg). Doses are entered as prescribed, in product mg.">
<option value="mmf">MMF (mycophenolate mofetil)</option>
<option value="ecmps">EC-MPS (enteric-coated)</option>
</select>
</div>
</div>
</div>
</div>
<!-- ============ 2 · DOSING & SAMPLES ============ -->
<div class="card" id="chartCard">
<h2><span class="stepnum">2</span> Dosing schedule & measured concentrations</h2>
<div class="seg no-print" id="modeSeg" role="radiogroup" aria-label="How the dosing schedule is entered" title="Choose how the dosing schedule is entered">
<label class="seg-opt" title="Enter each dose as a dated timeline">
<input type="radio" name="schedMode" value="full" checked> Full schedule (history)</label>
<label class="seg-opt" title="Patient at steady state on a fixed maintenance dose + interval">
<input type="radio" name="schedMode" value="ss"> Steady state (dose + interval)</label>
</div>
<div id="fullDoseUI">
<div class="tbl-wrap"><table class="data" id="doseTable"></table></div>
<form class="inline no-print" id="doseForm" novalidate>
<div class="row3" style="margin-top:8px">
<div class="f-dt"><label class="f" for="dose-dt">Date & time</label><input type="datetime-local" id="dose-dt" title="Scheduled date and time of the administration"></div>
<div><label class="f" for="dose-amt" id="doseAmtLbl">Dose (mg)</label><input type="number" inputmode="decimal" id="dose-amt" min="10" max="3000" step="any" placeholder="e.g. 1000" title="Dose in mg as prescribed"></div>
<div id="dosePredWrap" style="display:none"><label class="f" for="dose-pred">Prednisolone (mg/day), if changed</label><input type="number" inputmode="decimal" id="dose-pred" min="0" step="any" placeholder="patient value" title="Leave empty to use the prednisolone dose of the patient card. Enter a value only if the steroid dose was different on the day of this administration."></div>
<div id="doseFormWrap" style="display:none"><label class="f" for="dose-form">Formulation</label><select id="dose-form" title="The formulation of this administration. The suspension is absorbed faster and has lower bioavailability than the capsule; a switch is entered on the dose where it happened."></select></div>
<div style="align-self:end"><button class="secondary" type="submit" id="doseAdd" style="width:100%" title="Add this dose to the schedule">Add dose</button></div>
</div>
</form>
</div>
<div id="ssDoseUI" style="display:none">
<div class="row3" style="margin-top:8px">
<div><label class="f" for="ss-dose" id="ssDoseLbl">Dose (mg)</label><input type="number" inputmode="decimal" id="ss-dose" min="10" max="3000" step="any" placeholder="e.g. 1000" title="Maintenance dose per administration, as prescribed"></div>
<div><label class="f" for="ss-interval">Interval (hours)</label><input type="number" inputmode="decimal" id="ss-interval" min="1" max="48" step="1" placeholder="e.g. 12" title="Dosing interval in hours"></div>
<div id="ssFormWrap" style="display:none"><label class="f" for="ss-form">Formulation</label><select id="ss-form" title="The formulation of the regimen (every dose of the stable regimen is given in this form)."></select></div>
<div class="f-dt"><label class="f" for="ss-anchor">Latest dose on</label><input type="datetime-local" id="ss-anchor" title="Date and time of the most recent administration; this anchors the forecast"></div>
</div>
<div class="legend-note" style="margin-top:6px">The app uses the exact periodic steady state of this regimen, ending with the latest dose. Time on the chart is in hours, with t = 0 h at the latest dose. To enter a dosing history that changed over time, switch to “Full schedule”. The regimen is taken to have run for a limited number of doses before the latest one (30 doses for mycophenolic acid and tacrolimus, 10 for everolimus), so a sample older than that is refused as “before the first dose”: use “Full schedule” for such samples.</div>
</div>
<h2 class="sub-h" style="display:flex;flex-wrap:wrap;align-items:baseline;gap:4px 12px"><span>Measured concentrations <span class="hint" id="sampleHint"></span></span><button type="button" class="linklike" id="tplClear" style="margin-left:auto" title="Remove all doses and measurements">clear all</button></h2>
<div class="note no-print" id="tacDoseNote" hidden>Immediate-release tacrolimus, twice daily (Prograf-type capsules). Prolonged-release products (once daily) are not covered by this model.</div>
<div class="note warn no-print" id="ecmpsSampleNote" hidden>EC-MPS: absorption is delayed and highly variable, the source model’s own conclusion is that sparse limited sampling is expected to be unreliable for EC-MPS. Prefer more samples spread across the dosing interval (e.g. 1.5, 2, 4, 6, 8 h), and treat trough-only results with particular caution.</div>
<div class="tbl-wrap"><table class="data" id="obsTable"></table></div>
<form class="inline no-print" id="obsForm" novalidate>
<div class="row3" style="margin-top:8px"> <div class="f-dt"><label class="f" for="obs-dt">Date & time</label><input type="datetime-local" id="obs-dt" title="Time the blood sample was drawn"></div>
<div class="f-sel"><label class="f" for="obs-offset">or hours after last dose</label>
<select id="obs-offset" title="Fill the sample time as an offset from the last dose">
<option value="">(none)</option>
<option value="0.33">+20 min</option>
<option value="1">+1 h</option>
<option value="1.5">+1.5 h</option>
<option value="2">+2 h</option>
<option value="3">+3 h</option>
<option value="4">+4 h</option>
<option value="6">+6 h</option>
<option value="12">+12 h (trough if q12h)</option>
</select>
</div>
<div><label class="f" for="obs-val" id="obsValLbl">Concentration (mg/L)</label><input type="number" inputmode="decimal" id="obs-val" min="0.001" max="1000" step="any" title="Measured serum concentration (mg/L). A result reported below the assay's limit of quantification cannot be used: omit it."></div>
<div id="obsHctWrap" style="display:none"><label class="f" for="obs-hct">Haematocrit (L/L)</label><input type="number" inputmode="decimal" id="obs-hct" min="0.1" max="0.65" step="any" placeholder="e.g. 0.33" title="Haematocrit measured with this sample, as a fraction (0.33, not 33 %). Empty = the patient-card value."></div>
<div style="align-self:end;display:flex;gap:8px;align-items:center">
<button class="secondary" type="submit" id="obsAdd" style="flex:1" title="Add this measurement to the fit">Add</button>
</div>
</div>
</form>
</div>
</div>
<div class="col-out">
<!-- ============ 3 · FORECAST & RESULTS ============ -->
<div class="card" id="resultsCard">
<h2><span class="stepnum">3</span> Forecast</h2>
<div class="stale-banner" id="staleBanner">Inputs changed. Press “Run forecast” to update.</div>
<div class="actions-inline no-print" id="runBar">
<button type="button" class="primary" id="btnRun" style="flex:1" title="Run the Bayesian individualization and refresh the plot, AUC estimate, trough and advisories">Run forecast</button>
<button type="button" class="secondary" id="btnDiag" disabled title="Inspect how well the fitted model explains this patient’s samples: observed vs individual prediction, residuals, parameter ranges, shrinkage and MCMC quality. Available after a forecast has run.">Fit diagnostics</button>
</div>
<div class="run-hint" id="runHint" role="alert" aria-live="assertive"></div>
<div class="progress-wrap" id="progress">
<div class="bar"><div id="progressBar"></div></div>
<div class="msg" id="progressMsg"></div>
<button type="button" class="linklike no-print" id="btnCancelRun" title="Stop this forecast; no result is produced">Cancel</button>
</div>
<div id="fitStatus"></div>
<div id="paramBlock"></div>
<div class="tiles"><div id="aucBlock"></div><div id="troughBlock"></div></div>
<div id="advisoryBlock"></div>
<div id="chartBox">
<div class="chart-head no-print">
<label class="check chart-log" title="Show the concentration axis on a logarithmic scale">
<input type="checkbox" id="logY"> Log scale (y-axis)
</label>
</div>
<div id="chart"></div>
</div>
<div class="legend-note" id="chartNote"></div>
<details class="help advanced no-print" id="advancedForecast">
<summary>Advanced fitting options</summary>
<div>
<div class="lbl-help">
<label class="f" for="pt-recency">Down-weight older samples</label>
<button type="button" class="info" data-help="recency" aria-label="What does weighting of older samples do?" aria-expanded="false" title="Optional: give older measurements a larger residual error, so they influence the individual fit less than recent ones. Off by default.">ⓘ</button>
</div>
<select id="pt-recency" title="Optional: give older measurements a larger residual error, so they influence the individual fit less than recent ones. Off by default.">
<option value="off">Off (all samples equal)</option>
<option value="low">Low (up to ×1.5)</option>
<option value="medium">Medium (up to ×2)</option>
<option value="high">High (up to ×3)</option>
</select>
<div class="legend-note" id="recencyHint"></div>
</div>
</details>
<details class="help no-print" id="howto">
<summary>How to read these results</summary>
<ul id="howtoList"></ul>
</details>
</div>
<!-- ============ 4 · DOSE EXPLORER ============ -->
<div class="card" id="regimenCard">
<h2><span class="stepnum">4</span> Explore dose
<button type="button" class="info" data-help="ivexplore" aria-label="About the dose explorer" aria-expanded="false">ⓘ</button>
</h2>
<div class="iv-controls no-print">
<label class="f" for="iv-amt" id="ivAmtLbl">Dose (mg)</label>
<input type="number" inputmode="decimal" id="iv-amt" step="any" title="Dose per administration to evaluate, prefilled with the last dose entered">
<label class="f" for="iv-interval">Interval</label>
<select id="iv-interval" title="Dosing interval to simulate. AUCs are normalized to a 12-hour equivalent (AUC12 = AUC0-x × 12/x) so they stay comparable with the AUC0-12h therapeutic window.">
<option value="12" selected>12 h (twice daily)</option>
<option value="24">24 h (once daily)</option>
</select>
<button type="button" class="secondary" id="iv-run" title="Evaluate candidate doses using this patient's fitted parameters" disabled>Explore</button>
<span class="hint" id="iv-status"></span>
</div>
<div id="iv-out"><div class="note">Run a forecast in card 3 first. This explorer reuses that fit's own parameters.</div></div>
</div>
</div>
</div>
</main>
<!-- Fit diagnostics dialog -->
<div class="modal-backdrop" id="diagModal" hidden>
<div class="modal modal-wide" role="dialog" aria-modal="true" aria-labelledby="diagTitle">
<button type="button" class="modal-close" id="diagClose" title="Close">×</button>
<h2 id="diagTitle">Fit diagnostics</h2>
<div id="diagModalBody"></div>
</div>
</div>
<footer class="app">
<div class="credit">NephroTDM v<span id="footerVersion"></span> · model-informed therapeutic drug monitoring, for research use only.<br>
Not for independent clinical decision-making without verification.</div>
</footer>
<div class="modal-backdrop" id="gettingStartedModal" hidden>
<div class="modal" role="dialog" aria-modal="true" aria-labelledby="gettingStartedTitle">
<button type="button" class="modal-close" id="gettingStartedClose" title="Close">×</button>
<h2 id="gettingStartedTitle">Getting started</h2>
<div id="gettingStartedBody"></div>
</div>
</div>
<div class="modal-backdrop" id="backgroundModal" hidden>
<div class="modal" role="dialog" aria-modal="true" aria-labelledby="backgroundTitle">
<button type="button" class="modal-close" id="backgroundClose" title="Close">×</button>
<h2 id="backgroundTitle">Background</h2>
<div id="backgroundBody"></div>
</div>
</div>
<div class="modal-backdrop" id="aboutModal" hidden>
<div class="modal" role="dialog" aria-modal="true" aria-labelledby="aboutTitle">
<button type="button" class="modal-close" id="aboutClose" title="Close">×</button>
<h2 id="aboutTitle">About this app</h2>
<div id="aboutBody"></div>
</div>
</div>
<div class="modal-backdrop" id="reportModal" hidden>
<div class="modal" role="dialog" aria-modal="true" aria-labelledby="reportTitle">
<button type="button" class="modal-close" id="reportClose" title="Close">×</button>
<h2 id="reportTitle">Generate report</h2>
<p class="src">The report prints the current patient data, the last <b>run</b> forecast, model findings and the fields below. Both fields are optional and are kept in the session (and in exported session files) until you change them.</p>
<label class="f" for="rp-prepared">Prepared by (name, role)</label>
<input type="text" id="rp-prepared" placeholder="e.g. J. Researcher, pharmacologist" autocomplete="off"
title="Who performed the calculations, printed in the report header and on the signature line">
<label class="f" for="rp-advice" style="margin-top:10px">Advice (free text, printed verbatim in the Advice section)</label>
<textarea id="rp-advice" rows="5" placeholder="e.g. Repeat the AUC after a change."
title="Your advice for the treating clinician. The model findings are printed separately above it. The advice itself is yours."></textarea>
<div class="actions-inline" style="margin-top:14px;display:flex;gap:8px">
<button type="button" class="primary" id="rp-generate" style="flex:1" title="Build the report sheet and open the print dialog">Generate report</button>
<button type="button" class="secondary" id="rp-cancel" title="Close without printing">Cancel</button>
</div>
</div>
</div>
<div id="reportSheet" hidden></div>
<div class="help-pop" id="helpPop" hidden role="tooltip"></div>
<div class="toast" id="toast" role="status" aria-live="polite"></div>
<script src="src/version.js"></script>
<script src="src/model.js"></script>
<script src="src/tacrolimus.js"></script>
<script src="src/everolimus.js"></script>
<script src="src/tacped.js"></script>
<script src="src/mpaped.js"></script>
<script src="src/bayes.js"></script>
<script src="src/parallel.js"></script>
<script src="src/chart.js"></script>
<script src="src/diagnostics.js"></script>
<script src="src/texts_tac.js"></script>
<script src="src/texts_evr.js"></script>
<script src="src/texts_tacped.js"></script>
<script src="src/texts_mpaped.js"></script>
<script src="src/author_photo.js"></script>
<script src="src/report.js"></script>
<script src="src/visits.js"></script>
<script src="src/ui.js"></script>
</body>
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