2f:T1432,chart = { const height = 500; const margin = {top: 40, right: 30, bottom: 30, left: 50}; const xOccupancy = d3.scaleLinear() .domain([(startingOccupancy / 100), 0]) .range([margin.left, width - margin.right]); const xMax = xOccupancy(steps.at(-1).occupancyPct); const xStep = d3.scaleLinear() .domain(d3.extent(steps, (d) => d.step)) .range([margin.left, xMax]); const y = d3.scaleLinear() .domain([0, d3.max(steps, d => d.dose) + 5]) .range([height - margin.bottom, margin.top]); const svg = d3.create("svg") .attr("viewBox", [0, 0, width, height]) .attr("width", width) .attr("height", height) .attr("style", "max-width: 100%; height: auto; height: intrinsic; font: 10px sans-serif;") .style("-webkit-tap-highlight-color", "transparent") .style("overflow", "visible"); svg.append("g") .attr("transform", `translate(0,${margin.top})`) .call(d3.axisTop(xOccupancy).tickFormat(formatPct)) .call(g => g.append("text") .attr("x", width - margin.right) .attr("y", 16) .attr("text-anchor", "end") .attr("fill", "currentColor") .text("Target serotonin receptor occupancy") ); svg.append("g") .attr("transform", `translate(0,${height - margin.bottom})`) .call(d3.axisBottom(xStep).ticks(steps.length).tickFormat(d => d * form.stepInterval)) .call(g => g.select(".domain") .attr("d", function() { return d3.select(this).attr("d").replace(xMax, width - margin.right).replace(/V\d+$/, ""); }) ) .call(g => g.append("text") .attr("x", width - margin.right) .attr("y", -10) .attr("text-anchor", "end") .attr("fill", "currentColor") .text("Day") ); svg.append("g") .attr("transform", `translate(${margin.left},0)`) .call(d3.axisLeft(y).tickFormat(formatDose)) .call(g => g.append("text") .attr("x", -margin.left) .attr("y", 10) .attr("fill", "currentColor") .attr("text-anchor", "start") .text("Dose (mg)") ); const lineFactory = () => d3.line() .x(d => xOccupancy(d.occupancyPct)) .y(d => y(d.dose)); const stepPath = svg.append("path") .datum(steps) .attr("fill", "none") .attr("stroke", "#eee") .attr("stroke-width", 1.5) .attr("d", lineFactory().curve(d3.curveStepBefore)) .lower(); const path = svg.append("path") .datum(steps) .attr("fill", "none") .attr("stroke", "MediumPurple") .attr("stroke-width", 1.5) .attr("d", lineFactory()) const circles = svg.append("g") .attr("fill", "MediumPurple") .selectAll("circle") .data(steps) .join("circle") .attr("cx", d => xOccupancy(d.occupancyPct)) .attr("cy", d => y(d.dose)) .attr("r", 3); const pathOverlay = svg.append("path") .datum(steps) .attr("fill", "none") .attr("stroke", "transparent") .attr("stroke-width", 20) .attr("d", lineFactory()) .on("pointerenter pointermove", pointermoved) .on("pointerleave", pointerleft) .on("touchstart", event => event.preventDefault()); const tooltip = svg.append("g") .style("pointer-events", "none"); // Add the event listeners that show or hide the tooltip. const bisect = d3.bisector((d, x) => x - d.occupancyPct).center; function pointermoved(event) { const i = bisect(steps, xOccupancy.invert(d3.pointer(event)[0])); tooltip.style("display", null); const yPos = y(steps[i].dose); tooltip.attr("transform", `translate(${xOccupancy(steps[i].occupancyPct)},${yPos})`); const path = tooltip.selectAll("path") .data([,]) .join("path") .attr("fill", "white") .attr("stroke", "black") .attr("transform", ""); const text = tooltip.selectAll("text") .data([,]) .join("text") .call(text => text .selectAll("tspan") .data([ `Step ${steps[i].step}`, formatDose(formatDoseNumber(steps[i].dose)), formatPct(steps[i].occupancyPct) + ' occupancy', ]) .join("tspan") .attr("x", 0) .attr("y", (_, i) => `${i * 1.1}em`) .attr("font-weight", (_, i) => i ? null : "bold") .text(d => d) ); size(text, path); flip(text, path, yPos); } function pointerleft() { tooltip.style("display", "none"); } // Wraps the text with a callout path of the correct size, as measured in the page. function size(text, path) { const {x, y, width: w, height: h} = text.node().getBBox(); text.attr("transform", `translate(${-w / 2},${15 - y})`); path.attr("d", `M${-w / 2 - 10},5H-5l5,-5l5,5H${w / 2 + 10}v${h + 20}h-${w + 20}z`); } function flip(text, path, yPos) { const {width: w, height: h} = path.node().getBBox(); if (height - yPos - h <= 0) { path.attr("transform", "rotate(180)"); const transform = text.attr("transform"); const {y: yText} = text.node().getBBox(); text.attr("transform", transform.replace(/translate$([\d.-]+),\s?[\d.-]+$/, `translate($1,${10 - h - yText})`)); } } return svg.node(); }30:[{"id":"3c4027a5ce2d54d968aa812a63a9e52ebfa1cc042fb9d06cf93b62fd78a1f2e675a5f0e273432e5c93c02e488024fbe69a42d009a28712ffff6472e0d8dee240","href":"https://static.observableusercontent.com/files/3c4027a5ce2d54d968aa812a63a9e52ebfa1cc042fb9d06cf93b62fd78a1f2e675a5f0e273432e5c93c02e488024fbe69a42d009a28712ffff6472e0d8dee240","name":"dose_sert_systemic_review_supplemental_2.csv","type":"text/csv","lastModified":1748239041790.098,"size":552}] 2d:{"title":"Hyperbolic tapering calculator","cells":[{"id":0,"value":"# Hyperbolic tapering calculator","pinned":false,"hidden":false,"mode":"md"},{"id":104,"value":"viewof medicationName = Inputs.select([...new Set(dose_sert_systemic_review_supplemental_2.map(m => m.Antidepressant))], {label: 'Medication', value: 'Venlafaxine XR', disabled: true, ...inputOptions})","pinned":false,"hidden":false,"mode":"ojs"},{"id":139,"value":"medication = dose_sert_systemic_review_supplemental_2.find(m => m.Antidepressant === medicationName)","pinned":false,"hidden":false,"mode":"ojs"},{"id":14,"value":"viewof form = {\n const taperSpeeds = [\n {label: \"Faster\", value: 10}, // value is % of occupancy to reduce each step\n {label: \"Moderate\", value: 5},\n {label: \"Slower\", value: 2.5},\n ];\n return Inputs.form({\n startingDose: Inputs.number([0, Infinity], {label: \"Starting dose (mg)\", value: 75, ...inputOptions}),\n // taperLength: Inputs.range([2, 52], {step: 1, label: \"Tapering length (weeks)\", value: 16, ...inputOptions}),\n stepInterval: Inputs.range([2, 28], {step: 1, label: \"Tapering step interval (days)\", value: 14, ...inputOptions}),\n taperSpeed: Inputs.select(taperSpeeds, {label: \"Tapering speed\", format: x => x.label, value: taperSpeeds[1]})\n \n });\n}","pinned":false,"hidden":false,"mode":"ojs"},{"id":56,"value":"steps[0].dose - steps[1].dose > 37.5 ? md`⚠️` : md` ` // TODO","pinned":false,"hidden":false,"mode":"ojs"},{"id":313,"value":"$2f","pinned":true,"hidden":false,"mode":"ojs"},{"id":662,"value":"viewof showCompounding = Inputs.toggle({label: \"Compounding?\", value: true})","pinned":false,"hidden":false,"mode":"ojs"},{"id":667,"value":"viewof compoundOptions = showCompounding ? Inputs.form({\n concentration: Inputs.number([0, Infinity], {label: \"Concentration (mg/mL)\", value: 7.5}),\n perDay: Inputs.number([1, Infinity], {label: \"Doses per day\", value: 2, step: 1})\n}) : hiddenInput({concentration: 1, perDay: 1})","pinned":false,"hidden":false,"mode":"ojs"},{"id":664,"value":"\n\n \n \n \n \n \n \n \n \n \n \n ${steps.map(({step, occupancy, occupancyPct, dose, volume}) => (\n htl.html`\n \n \n \n \n \n `))}\n \n

step	day	dose (daily)	volume (${compoundOptions.perDay}x daily)	receptor occupancy
${step}	${step * form.stepInterval}	${formatDose(formatDoseNumber(dose))}	${formatVolume(formatVoumeNumber(volume))}	${formatPct(occupancyPct)}

\n","pinned":false,"hidden":false,"mode":"html"},{"id":570,"value":"formatPct = d3.format(\".0%\")","pinned":false,"hidden":false,"mode":"ojs"},{"id":574,"value":"formatDoseNumber = d3.format(\".1f\")","pinned":false,"hidden":false,"mode":"ojs"},{"id":806,"value":"formatVoumeNumber = d3.format(\".2f\")","pinned":false,"hidden":false,"mode":"ojs"},{"id":576,"value":"formatDose = d => `${d}mg`","pinned":false,"hidden":false,"mode":"ojs"},{"id":797,"value":"formatVolume = d => `${d}mL`","pinned":true,"hidden":false,"mode":"ojs"},{"id":268,"value":"startingOccupancy = occupancyAtDose(form.startingDose, medication.K, medication.Vm)","pinned":false,"hidden":false,"mode":"ojs"},{"id":21,"value":"steps = {\n const volumeFactor = compoundOptions.concentration * compoundOptions.perDay;\n \n let lowestDose = form.startingDose;\n let lowestOccupancy = startingOccupancy;\n const steps = [\n {\n step: 0, \n occupancy: startingOccupancy, \n occupancyPct: startingOccupancy / 100, \n dose: form.startingDose, \n volume: form.startingDose / volumeFactor\n },\n ];\n\n while ((lowestOccupancy - form.taperSpeed.value) > 0) {\n const prevStep = steps.at(-1);\n const targetOccupancy = prevStep.occupancy - form.taperSpeed.value;\n const dose = doseAtOccupancy(targetOccupancy, medication.K, medication.Vm);\n steps.push({\n step: prevStep.step + 1, \n occupancy: targetOccupancy, \n occupancyPct: targetOccupancy / 100,\n dose: dose,\n volume: dose / volumeFactor\n });\n lowestOccupancy = targetOccupancy;\n lowestDose = dose;\n }\n \n return steps;\n}","pinned":true,"hidden":false,"mode":"ojs"},{"id":265,"value":"function doseAtOccupancy(occupancy, K, Vm) {\n return (occupancy * K) / (Vm - occupancy);\n}","pinned":true,"hidden":false,"mode":"ojs"},{"id":253,"value":"function occupancyAtDose(dose, K, Vm) {\n return (dose * Vm) / (K + dose);\n}","pinned":true,"hidden":false,"mode":"ojs"},{"id":144,"value":"From [Figure 1](https://www.nature.com/articles/s41380-021-01285-w/figures/1) of Sørensen et al. (2022):\n> The dose-occupancy relationship for antidepressants that were administered at four or more different doses (citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, paroxetine, venlafaxine, and vortioxetine), fitted according to a 2-parameter Michaelis–Menten model as ${tex`${formulaTex}`}, where V_m is the horizontal asymptote (expressing maximum occupancy), x is the drug dose and the parameter K is the dose where the occupancy is halfway between 0 and V_m. The parameter estimates V_m and K for each model are provided in Supplementary Table 2.\n\nFrom Supplementary Table 2 (`dose_sert_systemic_review_supplemental_2.csv`):\n> RoI: brain region of interest; Vm: the horizontal asymptote (expressing maximum occupancy); K: the dose where the occupancy is halfway between 0 and Vm.","pinned":false,"hidden":false,"mode":"md"},{"id":125,"value":"dose_sert_systemic_review_supplemental_2 = await FileAttachment(\"dose_sert_systemic_review_supplemental_2.csv\").csv({typed: \"auto\"})","pinned":true,"hidden":false,"mode":"ojs"},{"id":120,"value":"1. Horowitz M, Taylor DM. 2024. The Maudsley Deprescribing Guidelines: Antidepressants, Benzodiazepines, Gabapentinoids and Z-drugs. United Kingdom: Wiley.\n2. Sørensen, A., Ruhé, H.G. & Munkholm, K. The relationship between dose and serotonin transporter occupancy of antidepressants—a systematic review. Mol Psychiatry 27, 192–201 (2022). https://doi.org/10.1038/s41380-021-01285-w","pinned":false,"hidden":false,"mode":"md"},{"id":4,"value":"### Appendix","pinned":false,"hidden":false,"mode":"md"},{"id":6,"value":"import {tanh} from \"@fil/math\"","pinned":true,"hidden":false,"mode":"ojs"},{"id":9,"value":"function coth(x) {\n return 1 / tanh(x);\n}","pinned":false,"hidden":false,"mode":"ojs"},{"id":81,"value":"function csch(x) { \n return 1 / Math.sinh(x);\n}","pinned":false,"hidden":false,"mode":"ojs"},{"id":47,"value":"inputOptions = ({width: 320})","pinned":true,"hidden":false,"mode":"ojs"},{"id":32,"value":"(viewof form).querySelectorAll('label').forEach(label => label.style.setProperty('--label-width', '200px')),\n(viewof medicationName).querySelectorAll('label').forEach(label => label.style.setProperty('--label-width', '200px'))","pinned":true,"hidden":false,"mode":"ojs"},{"id":554,"value":"tex.block`${formulaTex}`","pinned":true,"hidden":false,"mode":"ojs"},{"id":218,"value":"formulaTex = String.raw`f\\left({x,K,V_m} \\right) = \\frac{{V_mx}}{{K + x}}`","pinned":true,"hidden":false,"mode":"ojs"},{"id":189,"value":"sorensen_et_al_figures.classList.add(\"fix-line-height\")","pinned":true,"hidden":false,"mode":"ojs"},{"id":786,"value":"function hiddenInput(v) {\n let value = v;\n const node = html``;\n\n Object.defineProperty(node, \"value\", {\n get() {\n return value;\n },\n set(v) {\n value = v;\n }\n });\n \n return node;\n}","pinned":true,"hidden":false,"mode":"ojs"},{"id":176,"value":"","pinned":true,"hidden":false,"mode":"html"}],"files":"$W30","stdlib":"1","titling":"auto"}