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sentence-level-ignorance-classifier

Text Classification
Transformers
Safetensors
English
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ignorance-classification
knowledge-gap
epilepsy
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Model card Files
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 Community
sentence-level-ignorance-classifier
File size: 88,152 Bytes
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<html><head><meta http-equiv="Content-Type" content="text/html; charset=utf-8"/><title>Annotation Guidelines</title><style>
/* cspell:disable-file */
/* webkit printing magic: print all background colors */
html {
	-webkit-print-color-adjust: exact;
}
* {
	box-sizing: border-box;
	-webkit-print-color-adjust: exact;
}

html,
body {
	margin: 0;
	padding: 0;
}
@media only screen {
	body {
		margin: 2em auto;
		max-width: 900px;
		color: rgb(55, 53, 47);
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}

body {
	line-height: 1.5;
	white-space: pre-wrap;
}

a,
a.visited {
	color: inherit;
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.pdf-relative-link-path {
	font-size: 80%;
	color: #444;
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h1,
h2,
h3 {
	letter-spacing: -0.01em;
	line-height: 1.2;
	font-weight: 600;
	margin-bottom: 0;
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/* Override strong tags inside headings to maintain consistent weight */
h1 strong,
h2 strong,
h3 strong {
	font-weight: 600;
}

.page-title {
	font-size: 2.5rem;
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h2 {
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h3 {
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.source {
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	font-weight: normal;
	padding: 0.25em 0.5em;
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ul.to-do-list {
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ul.to-do-list > li {
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ul.toggle > li {
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ul {
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ul > li {
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ol {
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ol.numbered-list.numbered-list-digits-2 {
	padding-inline-start: 2em;
}

ol.numbered-list.numbered-list-digits-3plus {
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}

ol > li {
	padding-left: 0.2em;
}

.mono ol {
	padding-inline-start: 2em;
}

.mono ol > li {
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.toggle {
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/* Indent toggle children */
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.toggle > li > details > summary {
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	padding: 0 0.5em;
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.collection-title {
	display: inline-block;
	margin-right: 1em;
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.page-description {
	margin-bottom: 2em;
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.simple-table {
	margin-top: 1em;
	font-size: 0.875rem;
	empty-cells: show;
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.simple-table td {
	height: 29px;
	min-width: 120px;
}

.simple-table th {
	height: 29px;
	min-width: 120px;
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.simple-table-header-color {
	background: rgb(247, 246, 243);
	color: black;
}
.simple-table-header {
	font-weight: 500;
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time {
	opacity: 0.5;
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.icon {
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	justify-content: center;
	max-width: 1.2em;
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	text-decoration: none;
	vertical-align: text-bottom;
	margin-right: 0.5em;
}

img.icon {
	border-radius: 3px;
}

.callout img.notion-static-icon {
	width: 1em;
	height: 1em;
}

.callout p {
	margin: 0;
}

.callout h1,
.callout h2,
.callout h3 {
	margin: 0 0 0.6rem;
}

.user-icon {
	width: 1.5em;
	height: 1.5em;
	border-radius: 100%;
	margin-right: 0.5rem;
}

.user-icon-inner {
	font-size: 0.8em;
}

.text-icon {
	border: 1px solid #000;
	text-align: center;
}

.page-cover-image {
	display: block;
	object-fit: cover;
	width: 100%;
	max-height: 30vh;
}

.page-header-icon {
	font-size: 3rem;
	margin-bottom: 1rem;
}

.page-header-icon-with-cover {
	margin-top: -0.72em;
	margin-left: 0.07em;
}

.page-header-icon img {
	border-radius: 3px;
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.link-to-page {
	margin: 1em 0;
	padding: 0;
	border: none;
	font-weight: 500;
}

p > .user {
	opacity: 0.5;
}

td > .user,
td > time {
	white-space: nowrap;
}

input[type="checkbox"] {
	transform: scale(1.5);
	margin-right: 0.6em;
	vertical-align: middle;
}

p {
	margin-top: 0.5em;
	margin-bottom: 0.5em;
}

.image {
	border: none;
	margin: 1.5em 0;
	padding: 0;
	border-radius: 0;
	text-align: center;
}

.code,
code {
	background: rgba(135, 131, 120, 0.15);
	border-radius: 3px;
	padding: 0.2em 0.4em;
	border-radius: 3px;
	font-size: 85%;
	tab-size: 2;
}

code {
	color: #eb5757;
}

.code {
	padding: 1.5em 1em;
}

.code-wrap {
	white-space: pre-wrap;
	word-break: break-all;
}

.code > code {
	background: none;
	padding: 0;
	font-size: 100%;
	color: inherit;
}

blockquote {
	font-size: 1em;
	margin: 1em 0;
	padding-left: 1em;
	border-left: 3px solid rgb(55, 53, 47);
}

blockquote.quote-large {
	font-size: 1.25em;
}

.bookmark {
	text-decoration: none;
	max-height: 8em;
	padding: 0;
	display: flex;
	width: 100%;
	align-items: stretch;
}

.bookmark-title {
	font-size: 0.85em;
	overflow: hidden;
	text-overflow: ellipsis;
	height: 1.75em;
	white-space: nowrap;
}

.bookmark-text {
	display: flex;
	flex-direction: column;
}

.bookmark-info {
	flex: 4 1 180px;
	padding: 12px 14px 14px;
	display: flex;
	flex-direction: column;
	justify-content: space-between;
}

.bookmark-image {
	width: 33%;
	flex: 1 1 180px;
	display: block;
	position: relative;
	object-fit: cover;
	border-radius: 1px;
}

.bookmark-description {
	color: rgba(55, 53, 47, 0.6);
	font-size: 0.75em;
	overflow: hidden;
	max-height: 4.5em;
	word-break: break-word;
}

.bookmark-href {
	font-size: 0.75em;
	margin-top: 0.25em;
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.sans { font-family: ui-sans-serif, -apple-system, BlinkMacSystemFont, "Segoe UI Variable Display", "Segoe UI", Helvetica, "Apple Color Emoji", "Noto Sans Arabic", "Noto Sans Hebrew", Arial, sans-serif, "Segoe UI Emoji", "Segoe UI Symbol"; }
.code { font-family: "SFMono-Regular", Menlo, Consolas, "PT Mono", "Liberation Mono", Courier, monospace; }
.serif { font-family: Lyon-Text, Georgia, ui-serif, serif; }
.mono { font-family: iawriter-mono, Nitti, Menlo, Courier, monospace; }
.pdf .sans { font-family: Inter, ui-sans-serif, -apple-system, BlinkMacSystemFont, "Segoe UI Variable Display", "Segoe UI", Helvetica, "Apple Color Emoji", "Noto Sans Arabic", "Noto Sans Hebrew", Arial, sans-serif, "Segoe UI Emoji", "Segoe UI Symbol", 'Twemoji', 'Noto Color Emoji', 'Noto Sans CJK JP'; }
.pdf:lang(zh-CN) .sans { font-family: Inter, ui-sans-serif, -apple-system, BlinkMacSystemFont, "Segoe UI Variable Display", "Segoe UI", Helvetica, "Apple Color Emoji", "Noto Sans Arabic", "Noto Sans Hebrew", Arial, sans-serif, "Segoe UI Emoji", "Segoe UI Symbol", 'Twemoji', 'Noto Color Emoji', 'Noto Sans CJK SC'; }
.pdf:lang(zh-TW) .sans { font-family: Inter, ui-sans-serif, -apple-system, BlinkMacSystemFont, "Segoe UI Variable Display", "Segoe UI", Helvetica, "Apple Color Emoji", "Noto Sans Arabic", "Noto Sans Hebrew", Arial, sans-serif, "Segoe UI Emoji", "Segoe UI Symbol", 'Twemoji', 'Noto Color Emoji', 'Noto Sans CJK TC'; }
.pdf:lang(ko-KR) .sans { font-family: Inter, ui-sans-serif, -apple-system, BlinkMacSystemFont, "Segoe UI Variable Display", "Segoe UI", Helvetica, "Apple Color Emoji", "Noto Sans Arabic", "Noto Sans Hebrew", Arial, sans-serif, "Segoe UI Emoji", "Segoe UI Symbol", 'Twemoji', 'Noto Color Emoji', 'Noto Sans CJK KR'; }
.pdf .code { font-family: Source Code Pro, "SFMono-Regular", Menlo, Consolas, "PT Mono", "Liberation Mono", Courier, monospace, 'Twemoji', 'Noto Color Emoji', 'Noto Sans Mono CJK JP'; }
.pdf:lang(zh-CN) .code { font-family: Source Code Pro, "SFMono-Regular", Menlo, Consolas, "PT Mono", "Liberation Mono", Courier, monospace, 'Twemoji', 'Noto Color Emoji', 'Noto Sans Mono CJK SC'; }
.pdf:lang(zh-TW) .code { font-family: Source Code Pro, "SFMono-Regular", Menlo, Consolas, "PT Mono", "Liberation Mono", Courier, monospace, 'Twemoji', 'Noto Color Emoji', 'Noto Sans Mono CJK TC'; }
.pdf:lang(ko-KR) .code { font-family: Source Code Pro, "SFMono-Regular", Menlo, Consolas, "PT Mono", "Liberation Mono", Courier, monospace, 'Twemoji', 'Noto Color Emoji', 'Noto Sans Mono CJK KR'; }
.pdf .serif { font-family: PT Serif, Lyon-Text, Georgia, ui-serif, serif, 'Twemoji', 'Noto Color Emoji', 'Noto Serif CJK JP'; }
.pdf:lang(zh-CN) .serif { font-family: PT Serif, Lyon-Text, Georgia, ui-serif, serif, 'Twemoji', 'Noto Color Emoji', 'Noto Serif CJK SC'; }
.pdf:lang(zh-TW) .serif { font-family: PT Serif, Lyon-Text, Georgia, ui-serif, serif, 'Twemoji', 'Noto Color Emoji', 'Noto Serif CJK TC'; }
.pdf:lang(ko-KR) .serif { font-family: PT Serif, Lyon-Text, Georgia, ui-serif, serif, 'Twemoji', 'Noto Color Emoji', 'Noto Serif CJK KR'; }
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</style></head><body><article id="33b6e642-b2f4-801f-b8ae-d29500de89cd" class="page sans"><header><h1 class="page-title" dir="auto">Annotation Guidelines</h1><p class="page-description" dir="auto"></p></header><div class="page-body"><div style="display:contents" dir="auto"><h2 id="33b6e642-b2f4-8160-80c5-dfd769186de6" class="">Definition of Epistemic Gap</h2></div><div style="display:contents" dir="auto"><blockquote id="33b6e642-b2f4-8161-bb5b-fecf44f7fe2c" class=""><strong>An Epistemic Gap (or Goal for Knowledge) </strong>statement<strong> </strong>identifies a missing or incomplete piece of knowledge requiring scientific investigation to resolve. As such, it provides a target for future research aimed at generating new knowledge.</blockquote></div><div style="display:contents" dir="auto"><h2 id="33b6e642-b2f4-8115-a56f-ceee9a72d5ae" class=""><strong>Types of Epistemic Gap Statements</strong></h2></div><div style="display:contents" dir="auto"><blockquote id="33b6e642-b2f4-8181-b0bf-c42b3c67ca35" class="">(i) <em>Gap-oriented</em>: acknowledge a research relevant gap in current scientific understanding by highlighting aspects that are unknown, poorly understood, or understudied.<br/><br/>(ii) <em>Goal-oriented</em>: forward-looking statements that identify scientific goals for future investigation with the aim to advance scientific understanding and generate new knowledge.</blockquote></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80b7-9ed1-edf419425afc" class="">
</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-802f-bcbe-dbb1218c447e" class=""><strong>Examples of </strong><em><strong>Gap-oriented</strong></em><strong> statements:</strong></p></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-81f3-88fe-cb145486d796" class="bulleted-list"><li style="list-style-type:disc"><em>“Disruptions in the MBD5 gene have been linked with an array of clinical features such as global developmental delay, intellectual disability, autistic-like symptoms, and seizures, through </em><em><mark class="highlight-orange">unclear mechanisms</mark></em><em>.”</em></li></ul></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-8048-be0a-e2889e45882f" class="bulleted-list"><li style="list-style-type:disc"><em>”Though this association is known, </em><em><mark class="highlight-orange">the exact mechanisms</mark></em><em> through which perturbed MBD5 expression leads to neurodevelopmental disorders </em><em><mark class="highlight-orange">remain highly underexplored</mark></em><em>.”</em></li></ul></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-8031-a82b-c19b70266cfd" class="bulleted-list"><li style="list-style-type:disc"><em>“It is </em><em><mark class="highlight-orange">not known how</mark></em><em> closely the transcriptomic changes in this animal model of Dravet syndrome recapitulate the transcriptomic changes in people with Dravet syndrome.”</em></li></ul></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-80ce-96e8-cfe62a1a0d5a" class="bulleted-list"><li style="list-style-type:disc"><em><mark class="highlight-default">“</mark></em><em><mark class="highlight-orange">Regarding behavioral disorders</mark></em><em><mark class="highlight-default">, </mark></em><em><mark class="highlight-orange">data from the literature may be misleading</mark></em><em><mark class="highlight-default">. </mark></em><em><mark class="highlight-orange">Few authors have properly analyzed these features</mark></em><em><mark class="highlight-default">, reported as aggressive or oppositional behaviors with psychiatric traits.” - (Highlights a poorly studied aspect)</mark></em></li></ul></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-805c-952e-ef41ef8427d5" class="bulleted-list"><li style="list-style-type:disc"><em>“Despite frequent use of mTOR inhibitors, </em><em><mark class="highlight-orange">there are only a few studies on their effect</mark></em><em> on epilepsy control in children under 2-years of age.” - (highlights an understudied area)</em></li></ul></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-8094-9c8b-cd205edaf000" class="bulleted-list"><li style="list-style-type:disc"><em>“Homomeric GIRK2 channels are predominant in some midbrain nuclei (L\u00fcscher and Slesinger, 2010; Luj\u00e1n and Aguado, 2015), but </em><em><mark class="highlight-orange">it is not clear how abundant they are</mark></em><em> in other brain structures: GIRK2 subunit is ubiquitously expressed throughout the brain, but it is usually co-localized with GIRK1 or GIRK3 subunits, and the proportion of GIRK2 homomers vs. GIRK1/2 or GIRK2/3 heterotetramers </em><em><mark class="highlight-orange">remains unknown.</mark></em><em>”</em></li></ul></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-80f1-9a74-e1348ac31937" class="bulleted-list"><li style="list-style-type:disc">“<em>Various ASMs were trialed in the literature, with different combinations, making it </em><em><mark class="highlight-orange">difficult to draw conclusions regarding which ASM is best for ST3GAL3-related DEE.</mark></em>”</li></ul></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-804b-ab3f-da86bbfd7d03" class="">
</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81bd-9b95-f2113918b379" class=""><strong>Examples of </strong><em><strong>Goal-oriented</strong></em><strong> statements:</strong></p></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-80c5-9cca-c449a48cbc55" class="bulleted-list"><li style="list-style-type:disc">“<em>Larger case series are </em><em><mark class="highlight-orange">needed, however, to determine which ASMs are most effective</mark></em><em> for ST3GAL3-related DEE.</em>”</li></ul></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-8030-95f4-e3c4800d35d6" class="bulleted-list"><li style="list-style-type:disc">”<em>The mechanism underlying the link between MBD5 and primary cilia </em><em><mark class="highlight-orange">requires further understanding</mark></em><em>.” </em></li></ul></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-8049-ad63-e628037dabef" class="bulleted-list"><li style="list-style-type:disc"><em>“Second, the</em><em><mark class="highlight-orange"> functional verification on the animal model should be subsequently conducted to ascertain whether</mark></em><em> the p.Asp920Glu variant influences the PCDH19 protein function and PCDH19-FE phenotype.”</em></li></ul></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-8020-99f1-fa9e1b6d944c" class="bulleted-list"><li style="list-style-type:disc"><em>“Therefore,</em><em><mark class="highlight-orange"> further elucidation of the role of miRNAs in EP</mark></em><em> may favor EP diagnosis and treatment.”</em></li></ul></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-80a1-9fbf-f88d15ae1fc4" class="bulleted-list"><li style="list-style-type:disc"><em>“Whether this was meaningful </em><em><mark class="highlight-orange">should be further explored</mark></em><em> by functional experiments.”</em></li></ul></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-809c-b0ff-e119307e49b6" class="bulleted-list"><li style="list-style-type:disc"><em>&quot;</em><em><mark class="highlight-orange">Further research is encouraged to confirm</mark></em><em> the discovered variants and other mutations as possible epilepsy pathogenic in the larger population.”</em></li></ul></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-80e1-9cbb-f84d989216c9" class="bulleted-list"><li style="list-style-type:disc">“<em>The significance of the brainstem changes </em><em><mark class="highlight-orange">is unclear and requires further investigation</mark></em><em>.”</em></li></ul></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8066-848b-fb0db60bbbab" class="">
</p></div><div style="display:contents" dir="auto"><hr id="33b6e642-b2f4-809d-8f27-d092ce2fb9de"/></div><div style="display:contents" dir="auto"><h3 id="33b6e642-b2f4-81a3-baad-fd8bd7cc8467" class="">Exception #1</h3></div><div style="display:contents" dir="auto"><blockquote id="33b6e642-b2f4-81e4-97c9-dc1a6b282d8c" class=""><strong>Not all forward-looking statements qualify for annotation!</strong></blockquote></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8164-aa7b-c31a8ef5aa43" class="">Statements that provide future directions for action <strong>without</strong> identifying a scientific research goal should be annotated as <strong>practical recommendations</strong>, NOT as research directives. The intent is NOT to generate knowledge that advances scientific understanding, but rather apply existing knowledge (e.g., to support clinical practice, or methodological improvement, etc). </p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8098-ba22-efbcfdd671b5" class="">
</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81cd-9242-d61b57e847fa" class=""><strong>Examples of Practical Recommendations:</strong></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8187-a8f5-ea7263bcf1c1" class=""><em>❌ “For clinicians, patients with developmental regression accompanied with concurrent epilepsy and autism spectrum disorder should be advised that relevant </em><em><mark class="highlight-purple">genetic tests are necessary to clarify the diagnosis.</mark></em><em>”<br/>(Intent: recommends action for clinical practice, not research directive)</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81f3-add8-f773bb746af9" class=""><em>❌ &quot;Despite their caveats, when combined, these methods nevertheless provide a strong means for assessing the functionality of KCC2, albeit, in possible future studies on the functionality of the variant, </em><em><mark class="highlight-purple">additional complementary methods should be considered.</mark></em><em>&quot;</em><br/><em>(Intent: suggest to improve methodology for variant studies, not indicate the target for future research)</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8194-ae5c-f11d9a3b0031" class=""><em>❌ &quot;It becomes apparent that future in vitro studies on KCC2 variants </em><em><mark class="highlight-purple">should utilize isolated primary neurons or cortical neurons derived from induced pluripotent stem cells (iPSCs) as model systems</mark></em><em>.&quot;</em><br/><em>(Intent: suggest better experimental models, not indicate a specific research goal)</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8146-bc76-c3d20c18eade" class=""><em>❌ </em><em><mark class="highlight-purple">&quot;Future studies should include additional control cell lines</mark></em><em> to ensure that no off-target effects from gene editing are contributing to the phenotypes observed.&quot;</em><br/><em>(Intent: improve experimental rigor, not identify what we need to investigated)</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-814c-a42e-d5e60245f6d7" class=""><em>❌ &quot;</em><em><mark class="highlight-purple">Future endeavors should consider models more apt for matched datasets</mark></em><em>.&quot;</em><br/><em>(Intent: improve statistical approach, does not identify a scientific goal for knowledge)</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-814d-9b7e-f1b4516133d2" class=""><em>❌ According to this article&#x27;s findings and previous research, </em><em><mark class="highlight-purple">further diagnostic testing and management are needed to determine the severity and progression of the patient&#x27;s condition</mark></em><em>.&quot;<br/>(Intent: knowledge application to specific case management, not a research directive)</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81d1-ae61-ec46395adf55" class=""><em>❌ </em><em><mark class="highlight-gray">Among the remaining patients with neuroimaging abnormalities, FCD was the common presentation of NPRL3-related epilepsy (62.5%), which was consistent with the previous studies (6). However, for those with negative brain MRI results, small FCD may be overlooked.</mark></em><em> Thus, a </em><em><mark class="highlight-purple">PET scan is needed in the future to reveal the subtle metabolic or biochemical function changes</mark></em><em> in the brain of patients with NPRL3-related epilepsy.<br/>(This is a clinical/diagnostic action, not research directive. The intent is to suggest a practical next: step use PET scans to mprove detection/diagnosis in patients with negative MRI. This is about what clinicians should do, not what scientists should investigate)</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8165-861b-e1f74113de68" class=""><em>❌ </em><em><mark class="highlight-gray">Other conditions that implicate disease severity include Status Epilepticus [94], characterized by continuous or recurrent seizures lasting for an extended period or seizures occurring in rapid succession without the person regaining consciousness in between.</mark></em><em> Status epilepticus </em><em><mark class="highlight-purple">requires immediate medical attention</mark></em><em> as it can lead to significant complications and neurological damage. </em><em><mark class="highlight-gray">Epileptic Encephalopathy [95] refers to another group of severe epilepsy disorders that are associated with cognitive and developmental impairments.</mark></em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8006-9548-f79240b655e8" class="">
</p></div><div style="display:contents" dir="auto"><blockquote id="33b6e642-b2f4-813d-81a0-efd13976cb80" class="">Forward-looking statements with a clear scientific research goal should be annotated as Goal for Knowledge.</blockquote></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8075-bc01-fbc19610b6d4" class="">
</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8177-bec4-f2aad9666eee" class=""><strong>Examples:</strong></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81fc-a30d-cfedf157a87b" class="">✅ <em>We still need more detailed and accurate case reports, which will help in </em><em><mark class="highlight-orange">investigating the correlation between NUS1 variants and disease prognosis [</mark></em><em><mark class="highlight-orange"><strong>research goal</strong></mark></em><em><mark class="highlight-orange">]</mark></em><em>, and will also lay a solid foundation for the development of accurate and rapid genetic diagnosis and treatment in the future.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8167-b4e5-f4a459350af6" class="">✅ <em>Other scalable experimental approaches such as computational neuronal action potential modeling (Ben-Shalom et al., 2022) or dynamic action potential clamp recording (Berecki et al., 2018) may be valuable </em><em><mark class="highlight-orange">to determine the net effect of mixed dysfunctional properties on neuronal excitability [</mark></em><em><mark class="highlight-orange"><strong>research goal</strong></mark></em><em><mark class="highlight-orange">]</mark></em><em>.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-816e-bad2-ddc544c426d5" class="">✅ <em>Larger case series are needed, however, </em><em><mark class="highlight-orange">to determine which ASMs are most effective for ST3GAL3-related DEE [</mark></em><em><mark class="highlight-orange"><strong>research goal</strong></mark></em><em><mark class="highlight-orange">]</mark></em><em>.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8153-8ce1-f9f0382f2713" class="">✅ <em>Longitudinal follow-up is needed into adulthood however </em><em><mark class="highlight-orange">to determine how the epilepsy evolves [</mark></em><em><mark class="highlight-orange"><strong>research goal</strong></mark></em><em><mark class="highlight-orange">]</mark></em><em>.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8107-a7be-e5bb22a3c523" class="">
</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81ba-9f1c-f9d2459f2c64" class=""><strong>Decision Rule:</strong></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81f3-8a5f-cc040c4b7858" class="">Ask: Does the forward-looking statement identify a scientific research goal<strong>?</strong></p></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-812c-b2c9-eecad29701cb" class="bulleted-list"><li style="list-style-type:disc">Yes → Goal for Knowledge (research directive) ✅</li></ul></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-8174-92eb-efde4610cf3f" class="bulleted-list"><li style="list-style-type:disc">No → Probably a Practical recommendation <em>❌</em></li></ul></div><div style="display:contents" dir="auto"><div id="33b6e642-b2f4-80c4-bcee-d11923ec2053" class="column-list"><div style="display:contents" dir="auto"><div id="33b6e642-b2f4-80ca-b91e-d25cbc5daea8" style="width:50%" class="column"><div style="display:contents" dir="auto"><hr id="33b6e642-b2f4-81ee-a06d-e49c9342f283"/></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8089-9e12-c9c838528c2d" class="">
</p></div></div></div><div style="display:contents" dir="auto"><div id="33b6e642-b2f4-8016-88b9-eec77ea1c6d3" style="width:50%" class="column"><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-813e-8746-dc89c6ed9e86" class="">
</p></div></div></div></div></div><div style="display:contents" dir="auto"><h3 id="33b6e642-b2f4-814c-a69c-fa68971038b1" class="">Exception #2</h3></div><div style="display:contents" dir="auto"><blockquote id="33b6e642-b2f4-815a-968c-d13f6a74d97b" class=""><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81fd-9cac-e84b9e6b1f8f" class=""><strong>Speculation alone is not sufficient to indicate a goal for knowledge!</strong></p></div></blockquote></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81b1-bc80-d12b3ec374dc" class=""><strong>Rationale:</strong> Scientific writing frequently contains <strong>tentative or hedged statements</strong> (e.g., <em>may</em>, <em>possibly</em>, <em>suggests</em>) due to disciplinary norms favoring cautious claims. However, <strong>not all uncertainty reflects a need for scientific investigation</strong>. Most speculative statements do not imply a need for further research. Annotating all such statements as epistemic gaps would lead to a high number of false positives, diluting truly meaningful goals for knowledge annotations.</p></div><div style="display:contents" dir="auto"><blockquote id="33b6e642-b2f4-8185-adb8-e91b5f0ff770" class="">A speculative statement should be annotated as a scientific goal for knowledge ONLY when it is commited to a testable hypothesis and explicitly framed as a target for future research.</blockquote></div><div style="display:contents" dir="auto"><h4 id="33b6e642-b2f4-8108-b1fc-efd55a7b2021" class="">Operational Assumption</h4></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-818a-afac-d65e360d7065" class="">When authors intend to propose a genuine research hypothesis for further investigation, they frame it as a future research target using explicit “research goal” markers, such as:</p></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-81fb-b451-c96ede83faf7" class="bulleted-list"><li style="list-style-type:disc">highlight inadequate scientific support (inadequate evidence base to support the claim)</li></ul></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-8178-b3a5-c9e049486a6b" class="bulleted-list"><li style="list-style-type:disc">calls for further investigation seaking confirmation</li></ul></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8009-931c-fdfe9f8a4605" class="">
</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-814b-8874-f1c000581a08" class=""><strong>Examples:</strong></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8025-a70d-dfcabfa662da" class="">✅ <em><mark class="highlight-default">These observations raise the possibility that D1050V disrupts NaV1.2 interactions with ankyrin and mimics a channel LoF. </mark></em><mark class="highlight-default">[Speculation] </mark><em><mark class="highlight-orange">Future investigations of the cell surface expression or localization of SCN2A variants in neurons can test this hypothesis</mark></em><em><mark class="highlight-default">. </mark></em><mark class="highlight-default">[EXPLICIT CALL FOR RESEARCH]</mark></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8062-ad57-ecd1ef506000" class=""><mark class="highlight-default">✅ </mark><em><mark class="highlight-default">Thus, loss of function of Bassoon was potentially the underlying mechanism of the pathogenicity of BSN variants, which is consistent with the pathogenesis of other genes encoding CAZ proteins, such as UNC13A\n27 and UNC13B.6 </mark></em><mark class="highlight-default">[Speculation]</mark><em><mark class="highlight-orange"> However, the functional effects of the BSN variants warrant further investigation.</mark></em><em><mark class="highlight-default"> </mark></em><mark class="highlight-default">[EXPLICIT CALL FOR RESEARCH]</mark></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8011-b3c3-fc94c108716b" class=""><mark class="highlight-default">✅ </mark><em><mark class="highlight-default">Altogether, this could suggest that haploinsufficiency of MBD5 could lead to decreased NMDAR expression, which would have similar effects to an antagonist and thus lead to primary cilia shortening. </mark></em><mark class="highlight-default">[Speculation]</mark><em><mark class="highlight-default"> </mark></em><em><mark class="highlight-orange">This should be further explored using high-resolution microscopy and advanced realistic models of human brain development, such as brain organoids.</mark></em><em><mark class="highlight-default"> </mark></em><mark class="highlight-default">[EXPLICIT CALL FOR RESEARCH]</mark></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80e9-8db2-eba6a4ec4c46" class=""><mark class="highlight-default">✅ </mark><em><mark class="highlight-default">Two possible hypotheses arise from our findings in this study. The first is that a loss of neuronal homeostasis is due to slowed or lack of production of neuronal proteins. Neurons have a large bias toward very long transcripts (27), so it is possible that the slowed elongation rate caused by the EEF1A2 mutations results in changes in expression of neuronal specific genes and alterations to development, while sparing the translation of shorter transcripts. </mark></em><mark class="highlight-default">[Speculation] </mark><em><mark class="highlight-default">[…] </mark></em><em><mark class="highlight-orange">Further studies using polysome and/or ribosome profiling should be able to rigorously test this hypothesis.</mark></em><em><mark class="highlight-default"> </mark></em><mark class="highlight-default">[EXPLICIT CALL FOR RESEARCH]</mark></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80f6-ad26-e5aaa72af198" class=""><mark class="highlight-default">✅ </mark><em><mark class="highlight-default">Clinical consequences of mammalian target of rapamycin complex 1 (mTORC1) upregulation may be amenable to tailored treatment with mTOR inhibitors. </mark></em><mark class="highlight-default">[Speculation]</mark><em><mark class="highlight-default"> </mark></em><em><mark class="highlight-orange">A clinical trial on an international scale would be needed to draw conclusions.</mark></em><em><mark class="highlight-default"> </mark></em><mark class="highlight-default">[EXPLICIT CALL FOR RESEARCH]</mark></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80ff-a5e6-c586d2057aa8" class=""><mark class="highlight-default">✅ </mark><em><mark class="highlight-default">Thus, loss of function of Bassoon was potentially the underlying mechanism of the pathogenicity of BSN variants, which is consistent with the pathogenesis of other genes encoding CAZ proteins, such as UNC13A\n27 and UNC13B.6 </mark></em><mark class="highlight-default">[HYPOTHESIS] </mark><em><mark class="highlight-orange">However, the functional effects of the BSN variants warrant further investigation.</mark></em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80ba-8083-e789ccf041be" class=""><mark class="highlight-default">✅ </mark><em><mark class="highlight-default">Existing medical research suggests that CUL3 mutations are closely related to neurodevelopmental disorder with or without autism or seizures (neurodevelopmental disorder with autism and seizures, OMIM: 619239). </mark></em><mark class="highlight-default">[Speculation]</mark><em><mark class="highlight-orange"> However, the number of published case reports of autism spectrum disorder due to CUL3 gene mutations is limited</mark></em><em><mark class="highlight-orange"><strong>.</strong></mark></em><em><mark class="highlight-default"> [Suggests inadequate scientific support in available evidence]</mark></em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80a7-9e6f-e31a169f6cf8" class=""><mark class="highlight-default">✅ </mark><em><mark class="highlight-default">KV channel blockers may thus be of therapeutic interest for individuals affected with KCNA6-related epilepsy with associated gain-of-function mechanisms. </mark></em><mark class="highlight-default">[Speculation]</mark><em><mark class="highlight-default"> </mark></em><em><mark class="highlight-orange">However, to date and to our knowledge, no KV1.6\u2010 specific small molecule inhibitors of KV1.6 have been reported.</mark></em><em><mark class="highlight-default"> [Indicates lack of supporting evidence]</mark></em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8172-91df-cfce7d8477ae" class=""><mark class="highlight-default">✅</mark><em><mark class="highlight-default"> Adjunctive treatment with sirolimus or everolimus in the youngest patients with drug-resistant seizures could improve their epilepsy control, as was reported by a few studies [9, 27]. </mark></em><em><mark class="highlight-orange">However, analyses were conducted only on a small number of patients. </mark></em><em><mark class="highlight-default">[Indicates lack of supporting evidence]</mark></em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8028-bf0d-ee0eb9247d23" class="">
</p></div><div style="display:contents" dir="auto"><blockquote id="33b6e642-b2f4-81f2-bb1d-fcacd9a69093" class="">In the absence of clear “reasearch goal” markers → annotate as NOT goal for knowledge.</blockquote></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80d3-ad8b-d77e83f24a7f" class="">
</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81a7-b3cb-fb08b67369b6" class=""><strong>Examples:</strong></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8188-91e0-def0bebbf6c4" class=""><em>❌ </em><mark class="highlight-gray">Interestingly, caspase-3 expression in the cortex was significantly lower in children with DRE compared to adults with epilepsy, whereas in the white matter it was higher in children.</mark> This suggests age-related differences in caspase-3 expression within the DRE patient cohort. <mark class="highlight-gray">However, we did not find significant differences in protein expression based on gender. </mark>These findings indicate that the level of caspase-3 expression may independently contribute to the pathogenesis of epilepsy and can vary with age. </p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81a3-9aea-f28b00ec04cc" class=""><em>❌ </em><em><mark class="highlight-gray">Regression analysis revealed that while GFAP levels were significantly elevated in both the cortex and white matter of epilepsy patients across all age groups, there was no statistically significant difference in GFAP expression between children and adults. </mark></em><em>The lack of age dependence suggests that the reactive production of GFAP by astrocytes is not specific to a particular age group and supports our hypothesis of a common pathogenesis of FCD-associated temporal lobe DRE in both children and adults. </em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8190-b23e-f18867e63e5b" class=""><em>❌ </em><em><mark class="highlight-gray">We found a statistically significant negative correlation between GFAP expression and disease duration in the white matter, while there were no statistically significant changes in the cortex,</mark></em><em> suggesting a limitation of reparative processes within the nervous tissue. </em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8171-b30e-dfcc52425d54" class=""><em>❌ </em><em><mark class="highlight-gray">Additionally, we found a positive correlation between S100\u03b2 protein expression in the white matter and both disease duration and caspase-3 protein expression. </mark></em><mark class="highlight-gray">[FINDING] </mark><em>The increased presence of S100\u03b2 may potentially have proapoptotic effects, as it has been shown to upregulate nitric oxide (NO) expression, leading to neuronal and glial cell death and potentially participating in the pathogenesis of epilepsy [39]. </em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8162-9576-c33fc1894cec" class=""><em>❌ </em><em><mark class="highlight-gray">Notably, we found that all three disease-causing mutations increase the tRNA-binding capacity of eEF1A2.</mark></em> <em>We hypothesize that the mutation-induced increase in tRNA binding results in a broad sequestration of all tRNAs and reduces tRNA availability, thereby reducing the rate of elongation. </em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81ab-a470-db05d881b13d" class=""><em>❌ </em>The evidence from ClinGen Framework suggested an association between BSN variants and epilepsy. Conclusion: The BSN gene was potentially a novel candidate gene for epilepsy. <mark class="highlight-gray">The phenotypical severity was associated with the genotypes and the molecular subregional effects of the variants.</mark></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8142-8ed2-c115b0f81766" class=""><em>❌ Therefore, our results suggest that the position of the identified GABRA1 variants may potentially predict the intensity of one or more of these clinical features, reflecting the severity of the condition.  </em><em><mark class="highlight-gray">In this case, GABRA1 variants in the extracellular domain (L49H, P59L, W97R, D99G, G152S) will likely manifest with less severity, while variants in the transmembrane domain 1 (V270G), transmembrane domain 2 (T294R), and the linker between transmembrane domain 2 and 3 (P305L) may predict a more severe disease condition.</mark></em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80c8-9d1f-e7ca78c532ab" class="">
</p></div><div style="display:contents" dir="auto"><hr id="33b6e642-b2f4-8038-84d1-dbde8c14b47d"/></div><div style="display:contents" dir="auto"><h3 id="33b6e642-b2f4-8198-b1b2-cc5a01528fa2" class="">Exception #3</h3></div><div style="display:contents" dir="auto"><blockquote id="33b6e642-b2f4-81eb-97b7-fe5ced80e44a" class="">Statements that use ignorance terms such as <em>“unknown” or “uncertain” </em><strong>as labels for classification, grouping or description rather than to indicate a scientific research target </strong>should <strong>NOT</strong> be annotated as Epistemic Gaps.</blockquote></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80c4-bcfb-e78ea459e86f" class="">
</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81aa-8386-c4ae0af5b353" class="">Examples:</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8120-9291-e7fcbc6eebee" class=""><em>❌ </em>The aetiology of epilepsy is classified into genetic, structural, infectious, immunological, metabolic and <mark class="highlight-red">unknown</mark> aetiologies.</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81f2-9b94-c2cd1e868c08" class=""><em>❌ </em><em><mark class="highlight-gray">This study aims to explore the relationship between BSN variants and epilepsy. Methods: </mark></em><em>Whole-exome sequencing was performed in a cohort of 313 cases (trios) with epilepsies of </em><em><mark class="highlight-red">unknown</mark></em><em> causes. </em><em><mark class="highlight-gray">Additional cases with BSN variants were collected from China Epilepsy Gene V.1.0 Matching Platform.</mark></em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8172-9ad0-e255f41a6979" class=""><em>❌ </em>In light of the paramount importance of GABAAR \u03b11 subunit and its variants described so far, the present study focused on one hundred thirty-seven non-synonymous single-nucleotide polymorphisms (nsSNPs) within the coding region of the \u03b11 subunit, which were categorized as variants of <mark class="highlight-red">uncertain</mark> significance (VUS) in the ClinVar database.</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81fa-b3f5-cd42e30ec3a0" class=""><em>❌ </em>Addressing this, one hundred thirty-seven GABRA1 gene variants of <mark class="highlight-red">unknown</mark> clinical significance have been extracted from the ClinVar database and computationally analyzed for pathogenicity.</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8118-8420-d326de61b4bb" class=""><em>❌ </em>On the other hand, the number of variants with <mark class="highlight-red">unknown</mark> clinical significance continuously increases with the availability of next-generation sequencing (NGS), a trend that is also critical for personalized medicine and pharmacogenomics.</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81d9-99cb-e9fc9d9b854f" class=""><em>❌ </em>Thus, our data have important implications since predicting pathogenicity of specific genetic variants associated with epilepsy syndromes will contribute to variant interpretation for clinically <mark class="highlight-red">unknown</mark> genetic variants, which provides important insights into the underlying causes of the condition and guiding treatment decisions, such as selecting targeted therapies.</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81c3-aa5a-d711d0700526" class=""><em>❌ Thus, according to International League Against Epilepsy (ILAE), classification of the Epilepsies is a multi-level system including seizure types (focal onset, generalized onset and </em><em><mark class="highlight-red">unknown</mark></em><em> onset), epilepsy types (Generalized, Focal, Combined Generalized and Focal, </em><em><mark class="highlight-red">Unknown</mark></em><em>) and in the third level the epilepsy syndromes that are integrated with comorbidity and etiology which also includes genetic etiology.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81f1-9dba-d45e020a0d9c" class=""><em>❌ Combined with our study, a total of 88 patients with NPRL3-related epilepsy were found, of which 57 were boys and 30 were girls, respectively, while the gender of one case was </em><em><mark class="highlight-red">unknown</mark></em><em>.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81d0-ba3d-cd7cfd45a93f" class=""><em>❌ Indeed, genetic testing has already become an integral part of the diagnosis for epilepsy, especially for </em><em><mark class="highlight-red">unexplained</mark></em><em> epilepsy and pediatric epilepsy [41,42] and the phenotypic spectrum of GABRA1 gene such as infantile febrile seizures, bilateral\u2010tonic\u2010clonic seizures and atonic seizures has already been identified [32].</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8173-9550-d1898db2b602" class="">
</p></div><div style="display:contents" dir="auto"><hr id="33b6e642-b2f4-81da-bc80-cf4933ad9c20"/></div><div style="display:contents" dir="auto"><h2 id="33b6e642-b2f4-811e-befc-dfb88b411631" class="">Non-Epistemic Gap</h2></div><div style="display:contents" dir="auto"><blockquote id="33b6e642-b2f4-8189-872b-cd5e3a65c102" class=""><mark class="highlight-orange"><strong>Non-Epistemic Gap</strong></mark><mark class="highlight-orange"> </mark>identifies a gap or limitation in research or clinical practice with respect to available methods, technology, data, and therapeutic solutions. We identify four major categories of non-epistemic gap: methodological or technical gap, data gap, diagnostic gap and therapeutic gap.</blockquote></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80e3-a5b6-c543fea18ee1" class="">
</p></div><div style="display:contents" dir="auto"><h4 id="33b6e642-b2f4-8075-979d-fa9bff826494" class="">Types of Non-Epistemic Gap</h4></div><div style="display:contents" dir="auto"><blockquote id="33b6e642-b2f4-8097-b32a-cf56b7a6a37f" class=""><mark class="highlight-orange"><strong>Methodological/Technical Gap</strong></mark> refers to limitations in available methods or tools for research or clinical practice.</blockquote></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80e0-8798-e81e177b7384" class="">
</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80af-8a3f-deabc8bf95ab" class=""><strong>Examples:</strong></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80be-96ce-f79a1745e3f6" class=""><em>❌ </em><em><mark class="highlight-orange">Computational methods</mark></em><em> developed to predict drugs for polygenic diseases </em><em><mark class="highlight-orange">are unsuitable</mark></em><em> for monogenic diseases in general and monogenic epilepsies in particular.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-804a-acb5-d450fb449dd2" class=""><em>❌ Animal models of UBE3A overexpression have been used to study the syndrome, but with </em><em><mark class="highlight-orange">limited success in recapitulating the full range of Dup15q phenotypes</mark></em><em>.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8055-ac2e-d18f6df09a91" class=""><em>❌ However, </em><em><mark class="highlight-orange">ES has been less powerful in detecting structural variations</mark></em><em> (SVs) that involve intronic, GC-rich or repetitive regions than detecting single-nucleotide variants (SNVs).</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8050-88da-eb558a0de219" class=""><em>❌ </em><em><mark class="highlight-orange">Due to the limitation of WES</mark></em><em>, potentially disease-causing intron variants or copy number variants may not be detected, especially case 1 with only a heterozygous SZT2 variant.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8085-ba04-e4d44e9fa4ba" class=""><em>❌ The</em><em><mark class="highlight-orange"> generation of animal models for Dup15q has been difficult</mark></em><em>. […] However, </em><em><mark class="highlight-orange">this model has poor face validity</mark></em><em> as there were no behavioral phenotypes with maternal duplication, whereas paternal duplication resulted in subtle autism-like phenotypes (Nakatani et\u00a0al., 2009). […]<br/>Nevertheless, </em><em><mark class="highlight-orange">the construct validity of this model came into question</mark></em><em>, as the C terminal of Ube3a was tagged with a FLAG tag that affected the catalytic function of the protein. […] Although these models might be valid for studying the cellular and behavioral effects of Ube3a overexpression, </em><em><mark class="highlight-orange">they fail to encompass the full range of severe Dup15q phenotypes</mark></em><em> and replicate the complex genetics of the disease.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-808f-8135-d1aceaa63744" class=""><em>❌Due to a size limitation, minigene constructs only contain intronic regions and neighboring exons, which </em><em><mark class="highlight-orange">may not recapitulate all the necessary splicing components</mark></em><em>, so results from a minigene assay only serve as a proxy for in vivo splicing changes.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8080-a211-ffebf9702c93" class=""><em>❌ Furthermore, a causal relationship between c.791 + 6T&gt;G and the observed splicing change in NUS1 </em><em><mark class="highlight-orange">cannot be formally established based only on in vivo results</mark></em><em>, because contributions from other genetic differences between the patient and her parents could not be ruled out. </em><em><mark class="highlight-gray">Therefore, minigene assay can help establish this causal connection by comparing the transcript products of two expression constructs that differ only at the variant site, although it takes time and effort to set up this assay.</mark></em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80f8-af70-df73f3e7a3a0" class=""><em>❌ Last, </em><em><mark class="highlight-orange">mini mental and MOCA tests are limited tests</mark></em><em> to evaluate intellectual disability and are more reliable in patients older than 8 years and.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80b0-abbe-e33caf9149df" class=""><em>❌ Specifically, our results imply that the </em><em><mark class="highlight-orange">GoF versus LoF paradigm oversimplifies variant effect on channel function and does not fully capture</mark></em><em> the complete physiological impact of channel dysfunction.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80d5-89b0-f3b02a41ea9f" class=""><em>❌ Our findings illustrate a prevalence of complex biophysical effects for many variants suggesting that a </em><em><mark class="highlight-orange">simple binary scheme to classify variants as either GoF or LoF is insufficient</mark></em><em> to capture the full spectrum of variant channel dysfunction.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8009-8928-dedaa4f23b0d" class="">
</p></div><div style="display:contents" dir="auto"><blockquote id="33b6e642-b2f4-80c7-b0cf-ecd473685e76" class=""><mark class="highlight-orange"><strong>Diagnostic Gap</strong></mark><mark class="highlight-orange"> </mark>refers to limitations in available diagnostic solutions for clinical practice.</blockquote></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80a6-99ef-d020167bdc6c" class="">
</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-814d-a111-dc020affaf8f" class=""><strong>Examples:</strong></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8183-bcc6-f970f55f8855" class=""><em>❌ Due to overlapping phenotypes, among the patients, </em><em><mark class="highlight-orange">clinical subtyping was not possible</mark></em><em>. </em><em><mark class="highlight-gray">However, whole exome sequencing successfully pinpointed the molecular diagnosis which could be helpful for better management of these patients.</mark></em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-811f-b959-e7eaad94bb67" class=""><em>❌ </em><em><mark class="highlight-gray">Among the remaining patients with neuroimaging abnormalities, FCD was the common presentation of NPRL3-related epilepsy (62.5%), which was consistent with the previous studies (6).</mark></em><em> However, for those with negative brain MRI results, small </em><em><mark class="highlight-orange">FCD may be overlooked</mark></em><em>. </em><em><mark class="highlight-gray">Thus, a PET scan is needed in the future to reveal the subtle metabolic or biochemical function changes in the brain of patients with NPRL3-related epilepsy.</mark></em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81eb-8e44-f21f8644b5a7" class=""><em>❌ However, despite the tremendous progress that has been made in the development of both sequencing technology and bioinformatics in recent years, it should be noted that other </em><em><mark class="highlight-orange">diagnostic tests are still necessary to confirm or reject a diagnosis with certainty</mark></em><em><mark class="highlight-purple"> </mark></em><em>in cases where this approach results in the identification of genetic variants of uncertain clinical significance.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81d3-9efd-dac0a240e544" class=""><em>❌ However, since </em><em><mark class="highlight-orange">it usually takes months to obtain genetic testing results</mark></em><em>, this has also limited clinical utility when deciding on anti-seizure medications at the time of seizure onset.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8114-8b58-ccff004e0587" class="">
</p></div><div style="display:contents" dir="auto"><blockquote id="33b6e642-b2f4-8155-b3d9-cdf60ad56afd" class=""><mark class="highlight-orange"><strong>Therapeutic Gap</strong></mark> highlights challenges and limitations in available therapeutic solutions.</blockquote></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-809e-8a53-e2a1892511ae" class="">
</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81af-a740-fd0a93dfa966" class=""><strong>Examples:</strong></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81c0-a2c9-c1c29577ac60" class=""><em>❌ The current treatment of epilepsy with NPRL3 gene variants</em><em><mark class="highlight-purple"> </mark></em><em><mark class="highlight-orange">is lacking in specificity</mark></em><em>.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8161-9dfc-e91ee4455bc5" class=""><em>❌ Although current anti-EP drugs can reduce the frequency of convulsive episodes, the disorder </em><em><mark class="highlight-orange">remains incurable</mark></em><em> [4].</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8168-816f-cfb202bd96a6" class=""><em>❌ A drug that exerts a desirable effect in vitro, </em><em><mark class="highlight-orange">might not be able to penetrate</mark></em><em> the blood-brain barrier and </em><em><mark class="highlight-orange">produce a clinical antiseizure effect in vivo</mark></em><em>.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8178-b903-e025710f5820" class=""><em>❌ </em><em><mark class="highlight-orange">Few licensed or experimental antiseizure drugs are efficacious</mark></em><em> in people with or animal models of Dravet syndrome.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81cb-bdef-cd0bceb119f8" class=""><em>❌ We aimed to create a computational method to predict the efficacy of drugs for monogenic epilepsies, and to use the method to predict drugs for Dravet syndrome, as (1) it is the archetypal monogenic catastrophic epilepsy; (2) </em><em><mark class="highlight-orange">few antiseizure medications are efficacious</mark></em><em> in Dravet syndrome;</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81d9-9acb-e11a070be1f6" class=""><em>❌ </em><em><mark class="highlight-orange">Complete seizure control remains unattainable</mark></em><em> for most people with the condition, and the goal of current therapy is to reduce the frequency of seizures while minimizing the adverse effects of drugs.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81ae-840e-ca66873d1966" class=""><em>❌ With adequate serum concentration of antiepileptic drugs, the epilepsy symptoms in many patients </em><em><mark class="highlight-orange">still cannot be controlled well</mark></em><em>.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8177-96d9-f40543e9c472" class=""><em>❌ Because of the </em><em><mark class="highlight-orange">poor control of the epilepsy symptoms</mark></em><em> in the refractory epilepsy group, clinicians are more inclined to increase the dosage and use multiple drugs for treatment.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81fc-86c6-e2b809f5fea3" class=""><em>❌ Although multiple antiepileptic drugs (AEDs) may be used alone or in combination, approximately one-third of people with epilepsy </em><em><mark class="highlight-orange">are unable to fully control their epilepsy,</mark></em><em> a phenomenon termed drug resistance (L\u00f6scher et al., 2020).</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81b2-8386-ebdebca71741" class=""><em>❌ Nevertheless, about 20% of epileptic patients, as defined as refractory epilepsy, </em><em><mark class="highlight-orange">fail to respond to ASMs</mark></em><em> [6].</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8178-8002-e44a1c94227e" class=""><em>❌ Overall, evidence robust enough to guide antiseizure medication (ASM) choices in genetic epilepsies </em><em><mark class="highlight-orange">remains limited to the more frequent conditions</mark></em><em> for which controlled trials and observational studies have been possible.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81db-9820-efe4eca62412" class=""><em>❌ Precision medicine </em><em><mark class="highlight-orange">remains applicable to only a narrow number of patients</mark></em><em> with monogenic epilepsies and may target only part of the actual functional defects.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-812e-8496-d407a49969f3" class="">
</p></div><div style="display:contents" dir="auto"><blockquote id="33b6e642-b2f4-811e-a5e7-f1cae74271f0" class=""><mark class="highlight-orange"><strong>Data Gap</strong></mark> refers to unavailability of data to support scientific discovery.</blockquote></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80a5-81b8-d673f6b13deb" class="">
</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8105-8096-d92b04b505d3" class=""><strong>Examples:</strong></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-810e-ac43-ecd653119669" class=""><em>❌ For some drugs, the intermediate transcriptome score </em><em><mark class="highlight-orange">is not currently available</mark></em><em>, as their transcriptomic effects are </em><em><mark class="highlight-orange">still to be assayed</mark></em><mark class="highlight-purple">.</mark></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-810f-969e-f66ad5602db3" class=""><em>❌ </em><em><mark class="highlight-orange">Brain tissue</mark></em><em> from people with monogenic epilepsies </em><em><mark class="highlight-orange">is scarce/unavailable</mark></em><em>.</em><br/>(Focus is on scarcity of experimental material for clinical practice, no epistemic consequence discussed or need for research)</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-811d-9fd0-c43d22c4c033" class=""><em>❌ Familial focal epilepsy with variable foci (FFEVF) is a rare type of focal epilepsy syndrome; it is associated with NPRL3 variant. However, </em><em><mark class="highlight-orange">relevant reports are rare</mark></em><em> in China.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81cc-89c4-c788ec1b9bfc" class=""><em>❌ However, this is a rare condition, with</em><em><mark class="highlight-purple"> </mark></em><em><mark class="highlight-orange">limited reports in the literature</mark></em><em>.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-818a-be16-c9d7b9623104" class=""><em>❌ The VUS are so rare that </em><em><mark class="highlight-orange">there are no previous reports</mark></em><em>.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81d5-bd38-c9b6a077b3ea" class=""><em>❌ </em><em><mark class="highlight-orange">Only twenty-four individuals </mark></em><em>with ST3GAL3-related congenital disorder of glycosylation (CDG) have been </em><em><mark class="highlight-orange">described in the literature</mark></em><em>.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-819e-85f1-d92982550a3a" class=""><em>❌ The MRI findings in our case were still present at the age of 5\u2009years, although follow-up imaging was </em><em><mark class="highlight-orange">not available for the two siblings in the literature</mark></em><em>.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8162-9b0c-f2aacd0dd344" class=""><em>❌ There were some </em><em><mark class="highlight-orange">missing data</mark></em><em> from literature review, and </em><em><mark class="highlight-orange">not all cases had all the reported variables of interest available.</mark></em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8136-b535-e110ecc91394" class=""><em>❌ Nevertheless, for many variants, </em><em><mark class="highlight-orange">the functional testing in respective in vitro or in vivo systems is not available.</mark></em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81c0-83ce-c23f5e60014e" class=""><em>❌ Satterstrom et al. have reported six protein truncating variants (PTVs), four missense variants and two synonymous (15), whereas </em><em><mark class="highlight-orange">further phenotypic data were not specified.</mark></em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8115-b374-d0d171254a7d" class=""><em>❌ </em><em><mark class="highlight-orange">Few cases of patients with NEXMIF variants had been reported</mark></em><em>, and to date, no deaths have been reported to our knowledge.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8147-9aeb-f42f249f8374" class=""><em>❌ Other large cohorts of disease natural history </em><em><mark class="highlight-orange">didn’t present data</mark></em><em> on brain involvement [20].</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-817b-b923-cba4437b6e55" class=""><em>❌ </em><em><mark class="highlight-orange">Other phenotypes</mark></em><em>, particularly those of mild/modDEE and self-limited familial infantile epilepsy, </em><em><mark class="highlight-orange">are relatively underrepresented</mark></em><em>.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81a3-a949-cc7db1b3a7c8" class=""><em>❌ </em><em><mark class="highlight-orange">Loss-of-function variants have been less reported</mark></em><em>, and primarily cause neurodevelopmental delays with generalized epilepsy, neurodevelopmental disorder without epilepsy, intellectual disability, autism spectrum disorder, and mobility disorders.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81bb-9826-c14a49e6cea2" class="">
</p></div><div style="display:contents" dir="auto"><blockquote id="33b6e642-b2f4-8175-9ac7-e2f3205967d8" class="">Statements discussing non-epistemic limitations should be annotated as Goal for Knowledge only when the limitation is framed as a target for future research.</blockquote></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-808b-8d1c-d67ecd164675" class="">
</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8147-b7ec-c1fde6982b96" class=""><strong>Examples:</strong></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81ed-9b35-c49806b3a769" class="">✅ <em><mark class="highlight-orange">There is a need for dedicated enhanced computational methods</mark></em><em> to predict drugs for monogenic diseases, in general and monogenic epilepsies in particular.</em><br/><em>(Acknowledges the need for technological innovation; Implied: is meant to be accomplished via scientific investigation)</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81c7-a98e-da9879e210d0" class="">✅ <em>Our finding of mixed functional properties </em><em><mark class="highlight-orange">suggests </mark></em><em><mark class="highlight-orange"><mark class="highlight-default_background">a need for a more nuanced classification </mark></mark></em><em><mark class="highlight-default_background">of SCN2A variant dysfunction.</mark></em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-814c-b850-fe15f1c98d1d" class="">✅ <em><mark class="highlight-default"><mark class="highlight-default_background">Our findings</mark></mark></em><em><mark class="highlight-orange"><mark class="highlight-default_background"> indicate that a more nuanced framework </mark></mark></em><em><mark class="highlight-default"><mark class="highlight-default_background">for describing and reporting the function effects of ion channel variants </mark></mark></em><em><mark class="highlight-orange"><mark class="highlight-default_background">will be valuable</mark></mark></em><em><mark class="highlight-default_background">.</mark></em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-810a-824d-c5e17701bc55" class="">✅ <em>However, the explosion in genetic data makes the functional evaluation of individual variants using traditional whole-cell patch clamp techniques insufficient, and </em><em><mark class="highlight-orange">techniques with more scalable throughput are required to meet demand.</mark></em><em> </em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-810a-8e1a-ef298aa449e4" class="">✅ As such, <mark class="highlight-orange">it is desirable to identify additional drugs that can be used to treat Dravet syndrome</mark>, so that any individual with the condition has more treatment options available and, hence, better chances of finding an efficacious and well-tolerated treatment.</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-809c-a5c1-dca73cd9a4b7" class="">
</p></div><div style="display:contents" dir="auto"><h4 id="33b6e642-b2f4-80f4-926c-df4570889c3c" class="">Additional instructions for Therapeutic Gap annotation</h4></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-817f-851a-e8540d158b65" class="">A therapeutic gap statement qualifies as Epistemic Gap if it does at least one of the following:</p></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-81f3-b93d-c2149e353806" class="bulleted-list"><li style="list-style-type:disc"><em>Questions the effectiveness</em> of therapeutic solutions implying the need for scientific confirmation</li></ul></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-8193-8239-d2170c197f0b" class="bulleted-list"><li style="list-style-type:disc"><em>Expresses a lack of</em> (knowledge about) effective therapeutic solutions</li></ul></div><div style="display:contents" dir="auto"><ul id="33b6e642-b2f4-816d-9175-e1e6dc388aa6" class="bulleted-list"><li style="list-style-type:disc"><em>Calls for research</em> to address a therapeutic gap (e.g., indicates the need for development and discovery of new drugs)</li></ul></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80e1-a729-f2863fb388e2" class="">
</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-814f-b9f5-ddc18a60717d" class=""><strong>Examples:</strong></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8182-aecc-e5a5edaaab00" class="">✅ Specific Cav2.3 inhibitors would be required to <mark class="highlight-purple">test if inhibition of Cav2.3 could ameliorate CDKL5 deficiency phenotypes</mark> in mouse and human models.</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8142-99f9-ec9c5cee5746" class="">✅<em> At present, </em><em><mark class="highlight-purple">no effective drugs have been found</mark></em><em> for this disease.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81a7-b86d-f1006d40b21f" class="">✅<em> There is </em><em><mark class="highlight-purple">no specific medicine</mark></em><em> for the NEXMIF variant, and it can only be treated according to the symptoms.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8169-bc67-de67a2bf5347" class="">✅ As such, <mark class="highlight-purple">it is desirable to identify additional drugs that can be used to treat Dravet syndrome</mark>, so that any individual with the condition has more treatment options available and, hence, better chances of finding an efficacious and well-tolerated treatment.</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-810a-a8bc-e21353a853d9" class="">
</p></div><div style="display:contents" dir="auto"><h3 id="33b6e642-b2f4-81a7-ab00-e022c9c4161b" class="">Study Limitations</h3></div><div style="display:contents" dir="auto"><blockquote id="33b6e642-b2f4-81fe-8abb-e07c32cba7ae" class=""><mark class="highlight-orange"><strong>Study Limitation</strong></mark> statements qualify the validity of the current results, acknowledging sources of uncertainty or weaknesses in the design, methods, or analysis of the study that could affect the reliability, generalizability and interpretation of its findings (e.g., sample size, evaluation biases/inaccuracies, missing/unavailable data, etc.).</blockquote></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8044-90a1-c4f1ee6074f8" class="">
</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81ce-a62e-db45758f437f" class="">The following are examples of quality-oriented statements highlighting study-specific limitations:</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80b6-acac-f10b51ddedc4" class=""><em>❌ Here we should highlight that </em><em><mark class="highlight-orange">one of the limitations of our study is the brief period of follow-up</mark></em><em> of our patient, who is only at the age of 2 years at the time of writing. </em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8071-bca7-f54ac3bf6c00" class=""><em>❌ However, this study had several limitations. First, the</em><em><mark class="highlight-orange"> sample size was small and we only investigated</mark></em><em> the roles of miR-30b-5p and GRIN2A in vitro and in vivo.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80a7-a9e8-ff0e4a17d466" class=""><em>❌ The </em><em><mark class="highlight-orange">main limitation of this study is its retrospective character</mark></em><em>, which may </em><em><mark class="highlight-orange">hinder the objectivity and availability of all data</mark></em><em>. […] The seizure types and epileptiform discharge types </em><em><mark class="highlight-orange">could not be determined for some patients</mark></em><em> in the treatment and control groups </em><em><mark class="highlight-orange">because of missing data</mark></em><em> in the medical records. […] Secondly, </em><em><mark class="highlight-orange">the small cohort size,</mark></em><em> divided into smaller subgroups, </em><em><mark class="highlight-orange">could impede the statistical significance of the analysis</mark></em><em>.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8040-bd29-cd60477ba9ba" class=""><em>❌ The Clinical Effect score </em><em><mark class="highlight-orange">might be biased</mark></em><em> against less commonly used and newer drugs, as there is less chance for their adverse effects to be reported and less time for the reports to accumulate.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80f6-9b2f-f25dbdbc7096" class=""><em>❌ However, although </em><em><mark class="highlight-orange">differences are not significant due to insufficient patient numbers</mark></em><em>, epilepsy was present in 100% of patients (vs. 62% for other variants), unsupported walking was never achieved for 100% of patients (vs. 66%) and patients are non\u2010verbal (Table\u00a01).</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-803d-93b9-c01aef5dee26" class=""><em>❌ Moreover, other members of the family refused to provide blood samples due to privacy concerns. Therefore, only one unaffected family member was included in the genetic analysis. Consequently, it was </em><em><mark class="highlight-orange">difficult to calculate the penetrance accurately</mark></em><em>.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80d6-8291-da9b6723fc26" class=""><em>❌ Our work has limitations, including that this is a retrospective case series with few newly described cases. However, this is a rare condition, with limited reports in the literature. There were some </em><em><mark class="highlight-orange">missing data the from literature review</mark></em><em>, and not all cases had all the reported variables of interest available. [Data unavailability]</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8040-8c16-f3c4297d90b3" class=""><em>❌ </em><em><mark class="highlight-gray">Patients were likely to be misdiagnosed with sporadic epilepsy or other familial focal epilepsy forms until new affected members were identified, especially in smaller families.</mark></em><em> As the </em><em><mark class="highlight-orange">pedigrees were too small</mark></em><em> to demonstrate clear autosomal dominant inheritance, </em><em><mark class="highlight-orange">the prevalence of FFEVF was underestimated</mark></em><em>.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8055-bec0-e05c4eca0089" class="">
</p></div><div style="display:contents" dir="auto"><blockquote id="33b6e642-b2f4-8152-af7f-cb0249c631ca" class="">Annotate study limitation statements as Goals for Knowledge only when they highlight epistemic implications or indicate unfinished work, implying the need for additional work to address an unresolved research question.</blockquote></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-802f-91c4-e5ea83a765cd" class="">
</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8124-9d7e-d0a73302e2db" class="">Examples:</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8189-9a70-fcb106d2810a" class="">✅  <em><mark class="highlight-gray">“Our study has expanded the phenotype spectrum of FFEVF and found a new NPRL3 variant that had not been reported. Compared with unrelated healthy controls, we found that the NPRL3 variant was associated with the relative expression level of mRNA and abnormal splicing in vitro.</mark></em><em> However, the </em><em><mark class="highlight-purple">case-control design of the study</mark></em><em> involving unrelated healthy controls </em><em><mark class="highlight-purple">is highly underpowered for evaluating the pathogenicity of the variant</mark></em><em>.”</em> </p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-802a-8a91-f73034067354" class=""><mark class="highlight-default"><strong>Epistemic Gap</strong></mark>: variant pathogenicity is yet to be determined</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-814c-9344-f4d444a9c7d6" class="">✅  <em>A </em><em><mark class="highlight-purple">detailed analysis of the relationship</mark></em><em> between gene variants and clinical phenotypes </em><em><mark class="highlight-purple">has not been conducted yet. </mark></em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-801a-a5e2-c186cd2ef254" class=""><em><mark class="highlight-purple"> </mark></em><strong>Epistemic Gap:</strong> missing genotype–phenotype analysis</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81e4-902d-de486d7f21ef" class="">✅  <em><mark class="highlight-gray">Epilepsy control after sirolimus and everolimus discontinuation </mark></em><em><mark class="highlight-purple">has not been determined yet</mark></em><em><mark class="highlight-gray">.</mark></em><em> Most patients in this study continued the treatment at the end of data collection, so seizure recurrence assessment in a long-term follow-up after mTORi cessation was impossible. </em><em><mark class="highlight-gray">The long-term effect of mTORi on epilepsy control after their discontinuation should be addressed in future studies.</mark></em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-805f-bc97-f4f58f244e91" class=""><strong>Epistemic Gap</strong>: long-term effect of mTORi on epilepsy control is yet to be established</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8183-ac6c-c1d9c1b0473c" class="">✅  <em>This study has several limitations. The pathogenicity of the variants identified in this study was </em><em><mark class="highlight-purple">only supported by in silico analysis; the detailed functional alteration needs to be experimentally examined.</mark></em><em> </em><em><mark class="highlight-gray">Due to the limitation of WES, potentially disease-causing intron variants or copy number variants may not be detected, especially case 1 with only a heterozygous SZT2 variant. [Technical gap] </mark></em><em>The genotype-phenotype correlation needs more cases to further elucidate in the future. →</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-8024-a585-c4a5cc5db069" class=""><strong>Epistemic Gap</strong>: functional validation of variants pathogenicity is missing</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81d0-be3b-dca4d1bda7da" class="">✅ <em>Unfortunately, </em><em><mark class="highlight-purple">we could not explain</mark></em><em> </em><em><mark class="highlight-purple">the beneficial effect of VPA</mark></em><em> in several described patients by an effect of the drug on the KV3.2 channel. </em><em><mark class="highlight-gray">Again, more complex model systems such as iPSC-derived neurons from affected patients with appropriate expression of different ion channels may be needed to elucidate the underlying mechanism</mark></em><em>.</em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-807b-97d7-cadfab81d8ab" class=""><strong>Epistemic Gap</strong>: explanation of the mechanism is missing</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80ca-8a39-feee88888e80" class="">✅ <em>One limitation of this study was the small number of patients in the ambulantory group, what could provide additional </em><em><mark class="highlight-purple">information about the gravity spectrum of the brain manifestations in LAMA2-RD [Goal for Knowledge]</mark></em><em>. </em><em><mark class="highlight-gray">Another limitation was the lack of neuropsychological evaluation and quality-of-life tests for a better clinical characterization of the patients. [Study Limitation] Last, mini mental and MOCA tests are limited tests to evaluate intellectual disability and are more reliable in patients older than 8 years. </mark></em></p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-80a4-9ad4-f9161dee4051" class=""><strong>Goal for Knowledge Gap</strong>:  gravity spectrum of the brain manifestation in LAMA2-RD</p></div><div style="display:contents" dir="auto"><p id="33b6e642-b2f4-81e6-a437-efb436ce1d96" class="">
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