485 lines
No EOL
67 KiB
HTML
485 lines
No EOL
67 KiB
HTML
<?xml version="1.0" encoding="utf-8"?>
|
|
<!DOCTYPE html PUBLIC "-//W3C//DTD XHTML 1.0 Transitional//EN" "http://www.w3.org/TR/xhtml1/DTD/xhtml1-transitional.dtd">
|
|
<html xmlns="http://www.w3.org/1999/xhtml" xml:lang="en" lang="en">
|
|
|
|
<head><meta http-equiv="Content-Type" content="text/html; charset=utf-8" />
|
|
<!-- AppResources meta begin -->
|
|
<meta name="paf-app-resources" content="" />
|
|
<script type="text/javascript">var ncbi_startTime = new Date();</script>
|
|
|
|
<!-- AppResources meta end -->
|
|
|
|
<!-- TemplateResources meta begin -->
|
|
<meta name="paf_template" content="" />
|
|
|
|
<!-- TemplateResources meta end -->
|
|
|
|
<!-- Logger begin -->
|
|
<meta name="ncbi_db" content="books" /><meta name="ncbi_pdid" content="book-part" /><meta name="ncbi_acc" content="NBK548049" /><meta name="ncbi_domain" content="livertox" /><meta name="ncbi_report" content="record" /><meta name="ncbi_type" content="fulltext" /><meta name="ncbi_objectid" content="" /><meta name="ncbi_pcid" content="/NBK548049/" /><meta name="ncbi_pagename" content="Causality - LiverTox - NCBI Bookshelf" /><meta name="ncbi_bookparttype" content="chapter" /><meta name="ncbi_app" content="bookshelf" />
|
|
<!-- Logger end -->
|
|
|
|
<title>Causality - LiverTox - NCBI Bookshelf</title>
|
|
|
|
<!-- AppResources external_resources begin -->
|
|
<link rel="stylesheet" href="/core/jig/1.15.2/css/jig.min.css" /><script type="text/javascript" src="/core/jig/1.15.2/js/jig.min.js"></script>
|
|
|
|
<!-- AppResources external_resources end -->
|
|
|
|
<!-- Page meta begin -->
|
|
<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]" /><meta name="citation_title" content="Causality" /><meta name="citation_publisher" content="National Institute of Diabetes and Digestive and Kidney Diseases" /><meta name="citation_date" content="2019/11/20" /><meta name="citation_pmid" content="31643380" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK548049/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Causality" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="National Institute of Diabetes and Digestive and Kidney Diseases" /><meta name="DC.Date" content="2019/11/20" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK548049/" /><meta name="description" content="Drug induced liver injury is a diagnosis of exclusion that rests upon ruling out other common causes of liver disease, and knowledge of the pattern of injury associated with the specific drug. Unlike in hepatitis A or B, for instance, there are no specific diagnostic tests that establish causality for drug induced liver injury. The diagnosis can be very challenging, and even experts can disagree on the likelihood of the causality. For these reasons, attempts have been made to standardize causality assessment in drug induced adverse events. These methods generally rely upon careful delineation of the timing of onset of the adverse event in relation to starting the medication (challenge), and the timing of resolution in relation to stopping the medication (dechallenge). The causality is greatly strengthened if there is a recurrence on reexposure (rechallenge). Other helpful features are signs and symptoms of hypersensitivity, known drug allergies, the absence of competing diagnoses, and previous information on the occurrence of a similar adverse event with the medication. These factors are variously captured in the causality instruments and given various weights to achieve a rating score for the likelihood of the medication causing the injury. Commonly used instruments include the Naranjo Probability Scale, which is not specific to liver injury and can be used for any type of adverse drug reaction. In contrast, the Roussel Uclaf Causality Assessment Method (RUCAM) and its modification known as the Maria and Victorino (M & V) System, were developed specifically for drug induced liver injury. All three causality instruments have been used widely and perform reasonably well in comparison to the "gold standard" of expert opinion." /><meta name="og:title" content="Causality" /><meta name="og:type" content="book" /><meta name="og:description" content="Drug induced liver injury is a diagnosis of exclusion that rests upon ruling out other common causes of liver disease, and knowledge of the pattern of injury associated with the specific drug. Unlike in hepatitis A or B, for instance, there are no specific diagnostic tests that establish causality for drug induced liver injury. The diagnosis can be very challenging, and even experts can disagree on the likelihood of the causality. For these reasons, attempts have been made to standardize causality assessment in drug induced adverse events. These methods generally rely upon careful delineation of the timing of onset of the adverse event in relation to starting the medication (challenge), and the timing of resolution in relation to stopping the medication (dechallenge). The causality is greatly strengthened if there is a recurrence on reexposure (rechallenge). Other helpful features are signs and symptoms of hypersensitivity, known drug allergies, the absence of competing diagnoses, and previous information on the occurrence of a similar adverse event with the medication. These factors are variously captured in the causality instruments and given various weights to achieve a rating score for the likelihood of the medication causing the injury. Commonly used instruments include the Naranjo Probability Scale, which is not specific to liver injury and can be used for any type of adverse drug reaction. In contrast, the Roussel Uclaf Causality Assessment Method (RUCAM) and its modification known as the Maria and Victorino (M & V) System, were developed specifically for drug induced liver injury. All three causality instruments have been used widely and perform reasonably well in comparison to the "gold standard" of expert opinion." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK548049/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-livertox-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/livertox/Causality/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK548049/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><meta name="book-collection" content="NONE" />
|
|
|
|
<!-- Page meta end -->
|
|
<link rel="shortcut icon" href="//www.ncbi.nlm.nih.gov/favicon.ico" /><meta name="ncbi_phid" content="CE8DBB6E7C8D6DA10000000000B20098.m_13" />
|
|
<meta name='referrer' content='origin-when-cross-origin'/><link type="text/css" rel="stylesheet" href="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/css/3852956/3985586/3808861/4121862/3974050/3917732/251717/4216701/14534/45193/4113719/3849091/3984811/3751656/4033350/3840896/3577051/3852958/4008682/4207974/4206132/4062871/12930/3964959/3854974/36029/4128070/9685/3549676/3609192/3609193/3609213/3395586.css" /><link type="text/css" rel="stylesheet" href="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/css/3411343/3882866.css" media="print" /></head>
|
|
<body class="book-part">
|
|
<div class="grid">
|
|
<div class="col twelve_col nomargin shadow">
|
|
<!-- System messages like service outage or JS required; this is handled by the TemplateResources portlet -->
|
|
<div class="sysmessages">
|
|
<noscript>
|
|
<p class="nojs">
|
|
<strong>Warning:</strong>
|
|
The NCBI web site requires JavaScript to function.
|
|
<a href="/guide/browsers/#enablejs" title="Learn how to enable JavaScript" target="_blank">more...</a>
|
|
</p>
|
|
</noscript>
|
|
</div>
|
|
<!--/.sysmessage-->
|
|
<div class="wrap">
|
|
<div class="page">
|
|
<div class="top">
|
|
<div id="universal_header">
|
|
<section class="usa-banner">
|
|
<div class="usa-accordion">
|
|
<header class="usa-banner-header">
|
|
<div class="usa-grid usa-banner-inner">
|
|
<img src="https://www.ncbi.nlm.nih.gov/coreutils/uswds/img/favicons/favicon-57.png" alt="U.S. flag" />
|
|
<p>An official website of the United States government</p>
|
|
<button class="non-usa-accordion-button usa-banner-button" aria-expanded="false" aria-controls="gov-banner-top" type="button">
|
|
<span class="usa-banner-button-text">Here's how you know</span>
|
|
</button>
|
|
</div>
|
|
</header>
|
|
<div class="usa-banner-content usa-grid usa-accordion-content" id="gov-banner-top" aria-hidden="true">
|
|
<div class="usa-banner-guidance-gov usa-width-one-half">
|
|
<img class="usa-banner-icon usa-media_block-img" src="https://www.ncbi.nlm.nih.gov/coreutils/uswds/img/icon-dot-gov.svg" alt="Dot gov" />
|
|
<div class="usa-media_block-body">
|
|
<p>
|
|
<strong>The .gov means it's official.</strong>
|
|
<br />
|
|
Federal government websites often end in .gov or .mil. Before
|
|
sharing sensitive information, make sure you're on a federal
|
|
government site.
|
|
</p>
|
|
</div>
|
|
</div>
|
|
<div class="usa-banner-guidance-ssl usa-width-one-half">
|
|
<img class="usa-banner-icon usa-media_block-img" src="https://www.ncbi.nlm.nih.gov/coreutils/uswds/img/icon-https.svg" alt="Https" />
|
|
<div class="usa-media_block-body">
|
|
<p>
|
|
<strong>The site is secure.</strong>
|
|
<br />
|
|
The <strong>https://</strong> ensures that you are connecting to the
|
|
official website and that any information you provide is encrypted
|
|
and transmitted securely.
|
|
</p>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
</section>
|
|
<div class="usa-overlay"></div>
|
|
<header class="ncbi-header" role="banner" data-section="Header">
|
|
|
|
<div class="usa-grid">
|
|
<div class="usa-width-one-whole">
|
|
|
|
<div class="ncbi-header__logo">
|
|
<a href="/" class="logo" aria-label="NCBI Logo" data-ga-action="click_image" data-ga-label="NIH NLM Logo">
|
|
<img src="https://www.ncbi.nlm.nih.gov/coreutils/nwds/img/logos/AgencyLogo.svg" alt="NIH NLM Logo" />
|
|
</a>
|
|
</div>
|
|
|
|
<div class="ncbi-header__account">
|
|
<a id="account_login" href="https://account.ncbi.nlm.nih.gov" class="usa-button header-button" style="display:none" data-ga-action="open_menu" data-ga-label="account_menu">Log in</a>
|
|
<button id="account_info" class="header-button" style="display:none" aria-controls="account_popup" type="button">
|
|
<span class="fa fa-user" aria-hidden="true">
|
|
<svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 24 24" width="20px" height="20px">
|
|
<g style="fill: #fff">
|
|
<ellipse cx="12" cy="8" rx="5" ry="6"></ellipse>
|
|
<path d="M21.8,19.1c-0.9-1.8-2.6-3.3-4.8-4.2c-0.6-0.2-1.3-0.2-1.8,0.1c-1,0.6-2,0.9-3.2,0.9s-2.2-0.3-3.2-0.9 C8.3,14.8,7.6,14.7,7,15c-2.2,0.9-3.9,2.4-4.8,4.2C1.5,20.5,2.6,22,4.1,22h15.8C21.4,22,22.5,20.5,21.8,19.1z"></path>
|
|
</g>
|
|
</svg>
|
|
</span>
|
|
<span class="username desktop-only" aria-hidden="true" id="uname_short"></span>
|
|
<span class="sr-only">Show account info</span>
|
|
</button>
|
|
</div>
|
|
|
|
<div class="ncbi-popup-anchor">
|
|
<div class="ncbi-popup account-popup" id="account_popup" aria-hidden="true">
|
|
<div class="ncbi-popup-head">
|
|
<button class="ncbi-close-button" data-ga-action="close_menu" data-ga-label="account_menu" type="button">
|
|
<span class="fa fa-times">
|
|
<svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 48 48" width="24px" height="24px">
|
|
<path d="M38 12.83l-2.83-2.83-11.17 11.17-11.17-11.17-2.83 2.83 11.17 11.17-11.17 11.17 2.83 2.83 11.17-11.17 11.17 11.17 2.83-2.83-11.17-11.17z"></path>
|
|
</svg>
|
|
</span>
|
|
<span class="usa-sr-only">Close</span></button>
|
|
<h4>Account</h4>
|
|
</div>
|
|
<div class="account-user-info">
|
|
Logged in as:<br />
|
|
<b><span class="username" id="uname_long">username</span></b>
|
|
</div>
|
|
<div class="account-links">
|
|
<ul class="usa-unstyled-list">
|
|
<li><a id="account_myncbi" href="/myncbi/" class="set-base-url" data-ga-action="click_menu_item" data-ga-label="account_myncbi">Dashboard</a></li>
|
|
<li><a id="account_pubs" href="/myncbi/collections/bibliography/" class="set-base-url" data-ga-action="click_menu_item" data-ga-label="account_pubs">Publications</a></li>
|
|
<li><a id="account_settings" href="/account/settings/" class="set-base-url" data-ga-action="click_menu_item" data-ga-label="account_settings">Account settings</a></li>
|
|
<li><a id="account_logout" href="/account/signout/" class="set-base-url" data-ga-action="click_menu_item" data-ga-label="account_logout">Log out</a></li>
|
|
</ul>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
</div>
|
|
</header>
|
|
<div role="navigation" aria-label="access keys">
|
|
<a id="nws_header_accesskey_0" href="https://www.ncbi.nlm.nih.gov/guide/browsers/#ncbi_accesskeys" class="usa-sr-only" accesskey="0" tabindex="-1">Access keys</a>
|
|
<a id="nws_header_accesskey_1" href="https://www.ncbi.nlm.nih.gov" class="usa-sr-only" accesskey="1" tabindex="-1">NCBI Homepage</a>
|
|
<a id="nws_header_accesskey_2" href="/myncbi/" class="set-base-url usa-sr-only" accesskey="2" tabindex="-1">MyNCBI Homepage</a>
|
|
<a id="nws_header_accesskey_3" href="#maincontent" class="usa-sr-only" accesskey="3" tabindex="-1">Main Content</a>
|
|
<a id="nws_header_accesskey_4" href="#" class="usa-sr-only" accesskey="4" tabindex="-1">Main Navigation</a>
|
|
</div>
|
|
<section data-section="Alerts">
|
|
<div class="ncbi-alerts-placeholder"></div>
|
|
</section>
|
|
</div>
|
|
<div class="header">
|
|
<div class="res_logo"><h1 class="res_name"><a href="/books/" title="Bookshelf home">Bookshelf</a></h1><h2 class="res_tagline"></h2></div>
|
|
<div class="search"><form method="get" action="/books/"><div class="search_form"><label for="database" class="offscreen_noflow">Search database</label><select id="database"><optgroup label="Recent"><option value="books" selected="selected" data-ac_dict="bookshelf-search">Books</option><option value="pubmed">PubMed</option><option value="clinvar">ClinVar</option><option value="gquery" class="last">All Databases</option></optgroup><optgroup label="All"><option value="gquery">All Databases</option><option value="assembly">Assembly</option><option value="biocollections">Biocollections</option><option value="bioproject">BioProject</option><option value="biosample">BioSample</option><option value="books" data-ac_dict="bookshelf-search">Books</option><option value="clinvar">ClinVar</option><option value="cdd">Conserved Domains</option><option value="gap">dbGaP</option><option value="dbvar">dbVar</option><option value="gene">Gene</option><option value="genome">Genome</option><option value="gds">GEO DataSets</option><option value="geoprofiles">GEO Profiles</option><option value="gtr">GTR</option><option value="ipg">Identical Protein Groups</option><option value="medgen">MedGen</option><option value="mesh">MeSH</option><option value="nlmcatalog">NLM Catalog</option><option value="nuccore">Nucleotide</option><option value="omim">OMIM</option><option value="pmc">PMC</option><option value="protein">Protein</option><option value="proteinclusters">Protein Clusters</option><option value="protfam">Protein Family Models</option><option value="pcassay">PubChem BioAssay</option><option value="pccompound">PubChem Compound</option><option value="pcsubstance">PubChem Substance</option><option value="pubmed">PubMed</option><option value="snp">SNP</option><option value="sra">SRA</option><option value="structure">Structure</option><option value="taxonomy">Taxonomy</option><option value="toolkit">ToolKit</option><option value="toolkitall">ToolKitAll</option><option value="toolkitbookgh">ToolKitBookgh</option></optgroup></select><div class="nowrap"><label for="term" class="offscreen_noflow" accesskey="/">Search term</label><div class="nowrap"><input type="text" name="term" id="term" title="Search Books. Use up and down arrows to choose an item from the autocomplete." value="" class="jig-ncbiclearbutton jig-ncbiautocomplete" data-jigconfig="dictionary:'bookshelf-search',disableUrl:'NcbiSearchBarAutoComplCtrl'" autocomplete="off" data-sbconfig="ds:'no',pjs:'no',afs:'no'" /></div><button id="search" type="submit" class="button_search nowrap" cmd="go">Search</button></div></div></form><ul class="searchlinks inline_list"><li>
|
|
<a href="/books/browse/">Browse Titles</a>
|
|
</li><li>
|
|
<a href="/books/advanced/">Advanced</a>
|
|
</li><li class="help">
|
|
<a href="/books/NBK3833/">Help</a>
|
|
</li><li class="disclaimer">
|
|
<a target="_blank" data-ga-category="literature_resources" data-ga-action="link_click" data-ga-label="disclaimer_link" href="https://www.ncbi.nlm.nih.gov/books/about/disclaimer/">Disclaimer</a>
|
|
</li></ul></div>
|
|
</div>
|
|
|
|
|
|
|
|
<!--<component id="Page" label="headcontent"/>-->
|
|
|
|
</div>
|
|
<div class="content">
|
|
<!-- site messages -->
|
|
<!-- Custom content 1 -->
|
|
<div class="col1">
|
|
|
|
</div>
|
|
|
|
<div class="container">
|
|
<div id="maincontent" class="content eight_col col">
|
|
<!-- Custom content in the left column above book nav -->
|
|
<div class="col2">
|
|
|
|
</div>
|
|
|
|
<!-- Book content -->
|
|
|
|
|
|
<!-- Custom content between navigation and content -->
|
|
<div class="col3">
|
|
|
|
</div>
|
|
|
|
<div class="document">
|
|
<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="All Drug Records" href="/books/n/livertox/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-livertox-lrg.png" alt="Cover of LiverTox" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK548049_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK548049_dtls__"><div>Bethesda (MD): <a href="https://www.niddk.nih.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Institute of Diabetes and Digestive and Kidney Diseases</a>; 2012-.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/livertox/">Drug Records</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/livertox/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/livertox/Zonisamide/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/livertox/causalityassess/" title="Next page in this title">Next ></a></div></div></div></div></div>
|
|
<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK548049_"><span class="title" itemprop="name">Causality</span></h1><p class="small">Last Update: <span itemprop="dateModified">November 20, 2019</span>.</p></div><div class="body-content whole_rhythm" itemprop="text"><p>Drug induced liver injury is a diagnosis of exclusion that rests upon ruling out other common causes of liver disease, and knowledge of the pattern of injury associated with the specific drug. Unlike in hepatitis A or B, for instance, there are no specific diagnostic tests that establish causality for drug induced liver injury. The diagnosis can be very challenging, and even experts can disagree on the likelihood of the causality. For these reasons, attempts have been made to standardize causality assessment in drug induced adverse events. These methods generally rely upon careful delineation of the timing of onset of the adverse event in relation to starting the medication (challenge), and the timing of resolution in relation to stopping the medication (dechallenge). The causality is greatly strengthened if there is a recurrence on reexposure (rechallenge). Other helpful features are signs and symptoms of hypersensitivity, known drug allergies, the absence of competing diagnoses, and previous information on the occurrence of a similar adverse event with the medication. These factors are variously captured in the causality instruments and given various weights to achieve a rating score for the likelihood of the medication causing the injury. Commonly used instruments include the Naranjo Probability Scale, which is not specific to liver injury and can be used for any type of adverse drug reaction. In contrast, the Roussel Uclaf Causality Assessment Method (<a class="def" href="/books/n/livertox/glossary/def-item/glossary.rucam/">RUCAM</a>) and its modification known as the Maria and Victorino (M & V) System, were developed specifically for drug induced liver injury. All three causality instruments have been used widely and perform reasonably well in comparison to the "gold standard" of expert opinion.</p><div id="Causality.RUCAM_Scale"><h2 id="_Causality_RUCAM_Scale_">RUCAM Scale</h2><p>The <b><a class="def" href="/books/n/livertox/glossary/def-item/glossary.rucam/">RUCAM</a> scale</b> was developed after an international meeting in Paris in 1989, under the auspices of the Council for International Organizations of Medical Scientists (CIOMS), directed at developing uniform diagnostic criteria for drug induced liver injury. The eight international experts invited to the meeting created a diagnostic instrument that came to be referred to as RUCAM (Roussel Uclaf Causality Assessment Method). Points are awarded for seven components:</p><ul><li class="half_rhythm"><div>Time to onset of the injury following start of the drug</div></li><li class="half_rhythm"><div>Subsequent course of the injury after stopping the drug</div></li><li class="half_rhythm"><div>Specific risk factors (age, alcohol use, pregnancy)</div></li><li class="half_rhythm"><div>Use of other medications with a potential for liver injury</div></li><li class="half_rhythm"><div>Exclusion of other causes of liver disease</div></li><li class="half_rhythm"><div>Known potential for hepatotoxicity of the implicated drug</div></li><li class="half_rhythm"><div>Response to rechallenge</div></li></ul><p>Total scores range from less than 0 to 14 with scores of 3 or below indicating unlikely, 4-5 possible, 6-8 probable, and >8 highly probable hepatotoxicity. Although available for almost three decades, <a class="def" href="/books/n/livertox/glossary/def-item/glossary.rucam/">RUCAM</a> is not commonly used in clinical practice and does not have full endorsement even by specialists in hepatotoxicity. One reason is that many of the factors included in the RUCAM score are not well described and open to variable interpretation. Another reason is that it is difficult to develop a single instrument that is accurate for all forms of drug induced liver injury. A more thorough discussion of the RUCAM including a printable copy of the RUCAM form and a manual of operation for its completion is given below.</p><ul><li class="half_rhythm"><div>
|
|
<a href="/books/n/livertox/rucam/">Roussel Uclaf Causality Assessment Method (RUCAM)</a>
|
|
</div></li></ul></div><div id="Causality.Maria__Victorino_M__V_Scale"><h2 id="_Causality_Maria__Victorino_M__V_Scale_">Maria & Victorino (M & V) Scale</h2><p>A second scale was developed by investigators from Portugal and referred to as the <b>M & V Clinical scale</b>. In this instrument, points are awarded for five components:</p><ul><li class="half_rhythm"><div>Time to onset of the injury following start of the drug</div></li><li class="half_rhythm"><div>Exclusion of other causes of liver disease</div></li><li class="half_rhythm"><div>Extrahepatic manifestations (rash, fever, eosinophilia, cytopenia)</div></li><li class="half_rhythm"><div>Known potential for hepatotoxicity of the implicated drug</div></li><li class="half_rhythm"><div>Response to rechallenge</div></li></ul><p>The value of this scale was later examined by investigators in the United Kingdom who concluded that it compared favorably to developed international consensus criteria for adverse drug reactions. A larger study from Spain, in contrast, directly compared the <a class="def" href="/books/n/livertox/glossary/def-item/glossary.rucam/">RUCAM</a> and the M & V scale on a large number of cases and concluded that RUCAM was the preferable instrument. A more complete discussion of the M & V scale as well as a printable copy of the scale and a manual of operations is given below.</p><ul><li class="half_rhythm"><div>
|
|
<a href="/books/n/livertox/MVcausality/">Maria & Victorino (M & V) System of Causality Assessment</a>
|
|
</div></li></ul></div><div id="Causality.Naranjo_Scale"><h2 id="_Causality_Naranjo_Scale_">Naranjo Scale</h2><p>The <b>Naranjo scale</b> was developed as a means of assessment of causality of any form of adverse drug reaction. Thus, the Naranjo scale is not specific for liver injury. Points are given for ten elements including time to onset, recovery, previous reports of similar injury, response to rechallenge and possibility of alternative causes. The Naranjo scale is easy to apply and is widely used in assessing adverse drug reactions, particularly in clinical trials. A more complete description of the Naranjo scale as well as a printable copy of the form and a manual of operations for its calculation is given below.</p><ul><li class="half_rhythm"><div>
|
|
<a href="/books/n/livertox/Narajo/">Adverse Drug Reaction Probability Scale (Naranjo)</a>
|
|
</div></li></ul></div><div id="Causality.Bayesian_Assessment"><h2 id="_Causality_Bayesian_Assessment_">Bayesian Assessment</h2><p>Another approach yet to be fully developed is Bayesian assessment for determining adverse drug reactions. This assessment, together with a scale developed by Naranjo, addresses the issue of adverse drug reactions of all types, not specifically that of drug induced liver injury. Bayesian assessment requires specific information on the frequency of the injury in exposed and unexposed persons and is a highly statistically based method not appropriate for use in clinical practice. More work is needed on these rather complicated approaches.</p></div><div id="Causality.Causality_Assessment_by_Expert"><h2 id="_Causality_Causality_Assessment_by_Expert_">Causality Assessment by Expert Opinion</h2><p>The most commonly used method to adjudicate causality, however, is “expert opinion.” In instances of official appraisal of a drug for potential hepatotoxicity, one or more experts with experience in evaluating drug induced liver injury render a personal opinion on the validity of the association after reviewing all existing data. This method is obviously restricted in applicability and dependent upon somewhat subjective judgment. While commonly used, it is unclear whether expert opinion is more accurate than the published scoring systems such as the <a class="def" href="/books/n/livertox/glossary/def-item/glossary.rucam/">RUCAM</a> and M & V scales.</p></div><div id="Causality.Causality_Assessment_in_the_Dr"><h2 id="_Causality_Causality_Assessment_in_the_Dr_">Causality Assessment in the Drug-Induced Liver Injury Network</h2><p>To help with consistency and uniformity in the process of expert opinion, the group of investigators participating in the Drug-Induced Liver Injury Network (DILIN) study worked to develop a standardized method of performing assessment of the likelihood that a medication is the cause of liver injury in individual cases of potential hepatotoxicity. For purposes of causality assessment, a narrative summary, summary of clinical findings, and sequential biochemical abnormalities are provided to three experts in hepatotoxicity. Causality assessment is made independently by the experts who grade the likelihood of a causal relationship between the drug and liver injury in one of five scores:</p><div id="Causality.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK548049/table/Causality.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__Causality.Tc_lrgtbl__"><table><tbody><tr><td scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Definite</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">…………………</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Greater than 95%</td></tr><tr><td scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very likely</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">…………………</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">75-95%</td></tr><tr><td scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Probable</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">…………………</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">50-75%</td></tr><tr><td scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Possible</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">…………………</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">25-50%</td></tr><tr><td scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Unlikely</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">…………………</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Less than 25%</td></tr></tbody></table></div></div><p>The five levels of causality are also defined in textual and legal terms.</p><blockquote><p><b>Definite</b> (>95% assurance) implies that the association is “beyond a reasonable doubt”; that the agent is known to cause liver injury; the drug causes a specific clinical pattern of liver injury; and, that other possible competing diagnoses have been adequately and convincingly ruled out.</p><p><b>Very likely</b> (75% to 95% assurance) suggests that the association is “clear and convincing”; that the agent is known to cause liver injury; and, that most, but perhaps not all, competing diagnoses have been excluded or the pattern of injury is not completely typical.</p><p><b>Probable</b> (50% to 75% assurance) suggests that “the predominance of the evidence” supports the association. The agent may not have been previously linked to liver disease; and/or the pattern of injury may be atypical; and/or not all competing diagnoses have been completely excluded. Nevertheless, the reviewer believes that the weight of the evidence is in favor of the drug having caused the liver injury.</p><p><b>Possible</b> (25% to 50% assurance) suggests that the association is weak but cannot be ruled out completely. Perhaps the agent has not been clearly linked to liver injury; or, the pattern of injury is unusual for the medication; or, another cause of liver injury is present.</p><p><b>Unlikely</b> (<25% assurance) suggests that the liver injury is clearly due to another condition or its association with the medication is not at all convincing.</p></blockquote><p>While the five terms to grade causality are vague, attempts are made to provide an objective and critical evaluation of the likelihood that the liver injury is due to the suspected agent. Cases are not considered “probable” merely because there is no other explanation for the liver injury. Similarly, cases are not considered “definite” if another diagnosis is possible. If two or three drugs are implicated, only one can be considered probable, highly likely or definite and the others are assigned possible or unlikely scores so that the total percent assurance is not more than 100%.</p><p>The causality assessment is accepted as initially scored if there is complete agreement among the three expert reviewers. If there is disagreement, the reviewers meet to reconcile the differences and reach a final single score.</p></div><div id="Causality.Comparison_of_Probability_Scal"><h2 id="_Causality_Comparison_of_Probability_Scal_">Comparison of Probability Scales</h2><p>Scales for assessing causality in drug induced liver injury use four or five levels of likelihood and somewhat different terms, making direct comparisons of different scales difficult, as shown in the Table below. The World Health Organization has suggested that there be four levels of likelihood applied to adverse reaction causality assessment: certain, probable, possible, and unlikely. A comparison of the different scales in given in the Table. The differences in the scales are either at the top (mostly likely: separating “definite” from “highly likely” in the DILIN scale) or at the bottom (least likely: separating “not likely” from “excluded” in the <a class="def" href="/books/n/livertox/glossary/def-item/glossary.rucam/">RUCAM</a> and M & V scales).</p><div id="Causality.Td" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK548049/table/Causality.Td/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__Causality.Td_lrgtbl__"><table><thead><tr><th id="hd_h_Causality.Td_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">WHO<br />4 Levels</th><th id="hd_h_Causality.Td_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Naranjo<br />4 Levels</th><th id="hd_h_Causality.Td_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a class="def" href="/books/n/livertox/glossary/def-item/glossary.rucam/">RUCAM</a><br />5 Levels</th><th id="hd_h_Causality.Td_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">M & V<br />5 Levels</th><th id="hd_h_Causality.Td_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">DILIN<br />5 Levels</th></tr></thead><tbody><tr><td headers="hd_h_Causality.Td_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Level 1</b> [Certain]</td><td headers="hd_h_Causality.Td_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Definite</td><td headers="hd_h_Causality.Td_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Highly Probable</td><td headers="hd_h_Causality.Td_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Definite</td><td headers="hd_h_Causality.Td_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Definite and<br />Highly Likely</td></tr><tr><td headers="hd_h_Causality.Td_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Level 2</b> [Probable]</td><td headers="hd_h_Causality.Td_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Probable</td><td headers="hd_h_Causality.Td_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Probable</td><td headers="hd_h_Causality.Td_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Probable</td><td headers="hd_h_Causality.Td_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Probable</td></tr><tr><td headers="hd_h_Causality.Td_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Level 3</b> [Possible]</td><td headers="hd_h_Causality.Td_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Possible</td><td headers="hd_h_Causality.Td_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Possible</td><td headers="hd_h_Causality.Td_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Possible</td><td headers="hd_h_Causality.Td_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Possible</td></tr><tr><td headers="hd_h_Causality.Td_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Level 4</b> [Unlikely]</td><td headers="hd_h_Causality.Td_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Doubtful</td><td headers="hd_h_Causality.Td_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Not Likely and<br />Excluded</td><td headers="hd_h_Causality.Td_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Not Likely and<br />Excluded</td><td headers="hd_h_Causality.Td_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Unlikely</td></tr></tbody></table></div></div><p>
|
|
<a href="/books/n/livertox/causalityassess/">Causality Assessment Tools</a>
|
|
</p></div><div id="bk_toc_contnr"></div></div></div>
|
|
<div class="post-content"><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div><div class="small"><span class="label">Bookshelf ID: NBK548049</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/31643380" title="PubMed record of this page" ref="pagearea=meta&targetsite=entrez&targetcat=link&targettype=pubmed">31643380</a></span></div><div style="margin-top:2em" class="bk_noprnt"><a class="bk_cntns" href="/books/n/livertox/">Drug Records</a><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/livertox/Zonisamide/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/livertox/causalityassess/" title="Next page in this title">Next ></a></div></div></div></div>
|
|
|
|
</div>
|
|
|
|
<!-- Custom content below content -->
|
|
<div class="col4">
|
|
|
|
</div>
|
|
|
|
|
|
<!-- Book content -->
|
|
|
|
<!-- Custom contetnt below bottom nav -->
|
|
<div class="col5">
|
|
|
|
</div>
|
|
</div>
|
|
|
|
<div id="rightcolumn" class="four_col col last">
|
|
<!-- Custom content above discovery portlets -->
|
|
<div class="col6">
|
|
<div id="ncbi_share_book"><a href="#" class="ncbi_share" data-ncbi_share_config="popup:false,shorten:true" ref="id=NBK548049&db=books">Share</a></div>
|
|
|
|
</div>
|
|
<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK548049/?report=reader">PubReader</a></li><li><a href="/books/NBK548049/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK548049" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK548049" style="display:none" title="Cite this Page"><div class="bk_tt">LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Causality. [Updated 2019 Nov 20].<span class="bk_cite_avail"></span></div></div></li><li><a href="/books/NBK548049/pdf/Bookshelf_NBK548049.pdf">PDF version of this page</a> (86K)</li><li><a href="#" class="toggle-glossary-link" title="Enable/disable links to the glossary">Disable Glossary Links</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>New and Updated</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22LiverTox%22+AND+pmcbook&sort=date&size=200" ref="pagearea=source-links&targetsite=external&targetcat=link&targettype=uri">In PubMed</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Bulk Download</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="https://ftp.ncbi.nlm.nih.gov/pub/litarch/29/31/" ref="pagearea=source-links&targetsite=external&targetcat=link&targettype=uri">Bulk download LiverTox data from FTP</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Overviews</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/n/livertox/intro/">Introduction</a></li><li><a href="/books/n/livertox/ClinicalCourse/">Clinical Course</a></li><li><a href="/books/n/livertox/ClinicalOutcome/">Clinical Outcomes</a></li><li><a href="/books/n/livertox/ImmuneFeatures/">Immune Features</a></li><li><a href="/books/n/livertox/Phenotypes_intro/">Phenotypes</a></li><li><a href="/books/NBK548049/">Causality</a></li><li><a href="/books/n/livertox/DrugCategory/">Likelihood Scale</a></li><li><a href="/books/n/livertox/Severity/">Severity Grading</a></li><li><a href="/books/n/livertox/CaseReport/">Writing a Case Report</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Support Links</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/n/livertox/">LiverTox Homepage</a></li><li><a href="/books/n/livertox/masterlistintro/">Master List of LiverTox Drugs [with Metadata]</a></li><li><a href="/books/n/livertox/drugliverinjury/">LiverTox Drugs by Drug Class</a></li><li><a href="/books/n/livertox/aboutus/">About LiverTox</a></li><li><a href="/books/n/livertox/editorsandreviewers/">Editors and Review Committee</a></li><li><a href="/books/n/livertox/alert/">Meetings and News</a></li><li><a href="/books/n/livertox/abbreviation/">Abbreviations Used</a></li><li><a href="/books/n/livertox/glossary/">Glossary</a></li><li><a href="/books/n/livertox/resource/">Information Resources</a></li><li><a href="/books/n/livertox/disclaimer/">User/Medical Advice Disclaimer</a></li><li><a href="/books/n/livertox/Contactus/">Contact Us</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/30981720" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Causality in medicine.</a><span class="source">[C R Biol. 2019]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Causality in medicine.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Bach JF. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">C R Biol. 2019 Mar-May; 342(3-4):55-57. Epub 2019 Apr 10.</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/35426719" ref="ordinalpos=1&linkpos=2&log$=relatedarticles&logdbfrom=pubmed">Causality Constraints on Gravitational Effective Field Theories.</a><span class="source">[Phys Rev Lett. 2022]</span><div class="brieflinkpop offscreen_noflow">Causality Constraints on Gravitational Effective Field Theories.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">de Rham C, Tolley AJ, Zhang J. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Phys Rev Lett. 2022 Apr 1; 128(13):131102. </em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/30988445" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Quasi-experimental causality in neuroscience and behavioural research.</a><span class="source">[Nat Hum Behav. 2018]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Quasi-experimental causality in neuroscience and behavioural research.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Marinescu IE, Lawlor PN, Kording KP. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Nat Hum Behav. 2018 Dec; 2(12):891-898. Epub 2018 Nov 26.</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/29160439" ref="ordinalpos=1&linkpos=4&log$=relatedarticles&logdbfrom=pubmed">Causality in Pharmacoepidemiology and Pharmacovigilance: a theoretical excursion.</a><span class="source">[Rev Bras Epidemiol. 2017]</span><div class="brieflinkpop offscreen_noflow">Causality in Pharmacoepidemiology and Pharmacovigilance: a theoretical excursion.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Mota DM, Kuchenbecker RS. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Rev Bras Epidemiol. 2017 Jul-Sep; 20(3):475-486. </em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/25615064" ref="ordinalpos=1&linkpos=5&log$=relatedarticles&logdbfrom=pubmed">Effect of measurement noise on Granger causality.</a><span class="source">[Phys Rev E Stat Nonlin Soft Ma...]</span><div class="brieflinkpop offscreen_noflow">Effect of measurement noise on Granger causality.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Nalatore H, Sasikumar N, Rangarajan G. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Phys Rev E Stat Nonlin Soft Matter Phys. 2014 Dec; 90(6):062127. Epub 2014 Dec 18.</em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=31643380" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=31643380" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="recent_activity" id="Shutter"></a></div><div class="portlet_content"><div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" id="HTDisplay" class=""><div class="action"><a href="javascript:historyDisplayState('ClearHT')">Clear</a><a href="javascript:historyDisplayState('HTOff')" class="HTOn">Turn Off</a><a href="javascript:historyDisplayState('HTOn')" class="HTOff">Turn On</a></div><ul id="activity"><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=1" href="/portal/utils/pageresolver.fcgi?recordid=67c8e277f4a390645e3b1956">Causality - LiverTox</a><div class="ralinkpop offscreen_noflow">Causality - LiverTox<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=2" href="/portal/utils/pageresolver.fcgi?recordid=67c8e276b15b832ebc191d31">Phenotypes Of Drug Induced Liver Injury - LiverTox</a><div class="ralinkpop offscreen_noflow">Phenotypes Of Drug Induced Liver Injury - LiverTox<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=3" href="/portal/utils/pageresolver.fcgi?recordid=67c8e275a68b6b5afc7d9200">Immunological Features - LiverTox</a><div class="ralinkpop offscreen_noflow">Immunological Features - LiverTox<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=4" href="/portal/utils/pageresolver.fcgi?recordid=67c8e274a68b6b5afc7d8cca">Clinical Outcomes - LiverTox</a><div class="ralinkpop offscreen_noflow">Clinical Outcomes - LiverTox<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=5" href="/portal/utils/pageresolver.fcgi?recordid=67c8e273b15b832ebc191259">Clinical Course and Diagnosis of Drug Induced Liver Disease - LiverTox</a><div class="ralinkpop offscreen_noflow">Clinical Course and Diagnosis of Drug Induced Liver Disease - LiverTox<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li></ul><p class="HTOn">Your browsing activity is empty.</p><p class="HTOff">Activity recording is turned off.</p><p id="turnOn" class="HTOff"><a href="javascript:historyDisplayState('HTOn')">Turn recording back on</a></p><a class="seemore" href="/sites/myncbi/recentactivity">See more...</a></div></div></div>
|
|
|
|
<!-- Custom content below discovery portlets -->
|
|
<div class="col7">
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
<!-- Custom content after all -->
|
|
<div class="col8">
|
|
|
|
</div>
|
|
<div class="col9">
|
|
|
|
</div>
|
|
|
|
<script type="text/javascript" src="/corehtml/pmc/js/jquery.scrollTo-1.4.2.js"></script>
|
|
<script type="text/javascript">
|
|
(function($){
|
|
$('.skiplink').each(function(i, item){
|
|
var href = $($(item).attr('href'));
|
|
href.attr('tabindex', '-1').addClass('skiptarget'); // ensure the target can receive focus
|
|
$(item).on('click', function(event){
|
|
event.preventDefault();
|
|
$.scrollTo(href, 0, {
|
|
onAfter: function(){
|
|
href.focus();
|
|
}
|
|
});
|
|
});
|
|
});
|
|
})(jQuery);
|
|
</script>
|
|
</div>
|
|
<div class="bottom">
|
|
|
|
<div id="NCBIFooter_dynamic">
|
|
<!--<component id="Breadcrumbs" label="breadcrumbs"/>
|
|
<component id="Breadcrumbs" label="helpdesk"/>-->
|
|
|
|
</div>
|
|
|
|
<div class="footer" id="footer">
|
|
<section class="icon-section">
|
|
<div id="icon-section-header" class="icon-section_header">Follow NCBI</div>
|
|
<div class="grid-container container">
|
|
<div class="icon-section_container">
|
|
<a class="footer-icon" id="footer_twitter" href="https://twitter.com/ncbi" aria-label="Twitter"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
|
<defs>
|
|
<style>
|
|
.cls-11 {
|
|
fill: #737373;
|
|
}
|
|
</style>
|
|
</defs>
|
|
<title>Twitter</title>
|
|
<path class="cls-11" d="M250.11,105.48c-7,3.14-13,3.25-19.27.14,8.12-4.86,8.49-8.27,11.43-17.46a78.8,78.8,0,0,1-25,9.55,39.35,39.35,0,0,0-67,35.85,111.6,111.6,0,0,1-81-41.08A39.37,39.37,0,0,0,81.47,145a39.08,39.08,0,0,1-17.8-4.92c0,.17,0,.33,0,.5a39.32,39.32,0,0,0,31.53,38.54,39.26,39.26,0,0,1-17.75.68,39.37,39.37,0,0,0,36.72,27.3A79.07,79.07,0,0,1,56,223.34,111.31,111.31,0,0,0,116.22,241c72.3,0,111.83-59.9,111.83-111.84,0-1.71,0-3.4-.1-5.09C235.62,118.54,244.84,113.37,250.11,105.48Z">
|
|
</path>
|
|
</svg></a>
|
|
<a class="footer-icon" id="footer_facebook" href="https://www.facebook.com/ncbi.nlm" aria-label="Facebook"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
|
<title>Facebook</title>
|
|
<path class="cls-11" d="M210.5,115.12H171.74V97.82c0-8.14,5.39-10,9.19-10h27.14V52l-39.32-.12c-35.66,0-42.42,26.68-42.42,43.77v19.48H99.09v36.32h27.24v109h45.41v-109h35Z">
|
|
</path>
|
|
</svg></a>
|
|
<a class="footer-icon" id="footer_linkedin" href="https://www.linkedin.com/company/ncbinlm" aria-label="LinkedIn"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
|
<title>LinkedIn</title>
|
|
<path class="cls-11" d="M101.64,243.37H57.79v-114h43.85Zm-22-131.54h-.26c-13.25,0-21.82-10.36-21.82-21.76,0-11.65,8.84-21.15,22.33-21.15S101.7,78.72,102,90.38C102,101.77,93.4,111.83,79.63,111.83Zm100.93,52.61A17.54,17.54,0,0,0,163,182v61.39H119.18s.51-105.23,0-114H163v13a54.33,54.33,0,0,1,34.54-12.66c26,0,44.39,18.8,44.39,55.29v58.35H198.1V182A17.54,17.54,0,0,0,180.56,164.44Z">
|
|
</path>
|
|
</svg></a>
|
|
<a class="footer-icon" id="footer_github" href="https://github.com/ncbi" aria-label="GitHub"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
|
<defs>
|
|
<style>
|
|
.cls-11,
|
|
.cls-12 {
|
|
fill: #737373;
|
|
}
|
|
|
|
.cls-11 {
|
|
fill-rule: evenodd;
|
|
}
|
|
</style>
|
|
</defs>
|
|
<title>GitHub</title>
|
|
<path class="cls-11" d="M151.36,47.28a105.76,105.76,0,0,0-33.43,206.1c5.28,1,7.22-2.3,7.22-5.09,0-2.52-.09-10.85-.14-19.69-29.42,6.4-35.63-12.48-35.63-12.48-4.81-12.22-11.74-15.47-11.74-15.47-9.59-6.56.73-6.43.73-6.43,10.61.75,16.21,10.9,16.21,10.9,9.43,16.17,24.73,11.49,30.77,8.79,1-6.83,3.69-11.5,6.71-14.14C108.57,197.1,83.88,188,83.88,147.51a40.92,40.92,0,0,1,10.9-28.39c-1.1-2.66-4.72-13.42,1-28,0,0,8.88-2.84,29.09,10.84a100.26,100.26,0,0,1,53,0C198,88.3,206.9,91.14,206.9,91.14c5.76,14.56,2.14,25.32,1,28a40.87,40.87,0,0,1,10.89,28.39c0,40.62-24.74,49.56-48.29,52.18,3.79,3.28,7.17,9.71,7.17,19.58,0,14.15-.12,25.54-.12,29,0,2.82,1.9,6.11,7.26,5.07A105.76,105.76,0,0,0,151.36,47.28Z">
|
|
</path>
|
|
<path class="cls-12" d="M85.66,199.12c-.23.52-1.06.68-1.81.32s-1.2-1.06-.95-1.59,1.06-.69,1.82-.33,1.21,1.07.94,1.6Zm-1.3-1">
|
|
</path>
|
|
<path class="cls-12" d="M90,203.89c-.51.47-1.49.25-2.16-.49a1.61,1.61,0,0,1-.31-2.19c.52-.47,1.47-.25,2.17.49s.82,1.72.3,2.19Zm-1-1.08">
|
|
</path>
|
|
<path class="cls-12" d="M94.12,210c-.65.46-1.71,0-2.37-.91s-.64-2.07,0-2.52,1.7,0,2.36.89.65,2.08,0,2.54Zm0,0"></path>
|
|
<path class="cls-12" d="M99.83,215.87c-.58.64-1.82.47-2.72-.41s-1.18-2.06-.6-2.7,1.83-.46,2.74.41,1.2,2.07.58,2.7Zm0,0">
|
|
</path>
|
|
<path class="cls-12" d="M107.71,219.29c-.26.82-1.45,1.2-2.64.85s-2-1.34-1.74-2.17,1.44-1.23,2.65-.85,2,1.32,1.73,2.17Zm0,0">
|
|
</path>
|
|
<path class="cls-12" d="M116.36,219.92c0,.87-1,1.59-2.24,1.61s-2.29-.68-2.3-1.54,1-1.59,2.26-1.61,2.28.67,2.28,1.54Zm0,0">
|
|
</path>
|
|
<path class="cls-12" d="M124.42,218.55c.15.85-.73,1.72-2,1.95s-2.37-.3-2.52-1.14.73-1.75,2-2,2.37.29,2.53,1.16Zm0,0"></path>
|
|
</svg></a>
|
|
<a class="footer-icon" id="footer_blog" href="https://ncbiinsights.ncbi.nlm.nih.gov/" aria-label="Blog">
|
|
<svg xmlns="http://www.w3.org/2000/svg" id="Layer_1" data-name="Layer 1" viewBox="0 0 40 40">
|
|
<defs><style>.cls-1{fill:#737373;}</style></defs>
|
|
<title>NCBI Insights Blog</title>
|
|
<path class="cls-1" d="M14,30a4,4,0,1,1-4-4,4,4,0,0,1,4,4Zm11,3A19,19,0,0,0,7.05,15a1,1,0,0,0-1,1v3a1,1,0,0,0,.93,1A14,14,0,0,1,20,33.07,1,1,0,0,0,21,34h3a1,1,0,0,0,1-1Zm9,0A28,28,0,0,0,7,6,1,1,0,0,0,6,7v3a1,1,0,0,0,1,1A23,23,0,0,1,29,33a1,1,0,0,0,1,1h3A1,1,0,0,0,34,33Z"></path>
|
|
</svg>
|
|
</a>
|
|
</div>
|
|
</div>
|
|
</section>
|
|
|
|
<section class="container-fluid bg-primary">
|
|
<div class="container pt-5">
|
|
<div class="row mt-3">
|
|
<div class="col-lg-3 col-12">
|
|
<p><a class="text-white" href="https://www.nlm.nih.gov/socialmedia/index.html">Connect with NLM</a></p>
|
|
<ul class="list-inline social_media">
|
|
<li class="list-inline-item"><a href="https://twitter.com/NLM_NIH" aria-label="Twitter" target="_blank" rel="noopener noreferrer"><svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" version="1.1" x="0px" y="0px" viewBox="0 0 249 249" style="enable-background:new 0 0 249 249;" xml:space="preserve">
|
|
<style type="text/css">
|
|
.st20 {
|
|
fill: #FFFFFF;
|
|
}
|
|
|
|
.st30 {
|
|
fill: none;
|
|
stroke: #FFFFFF;
|
|
stroke-width: 8;
|
|
stroke-miterlimit: 10;
|
|
}
|
|
</style>
|
|
<title>Twitter</title>
|
|
<g>
|
|
<g>
|
|
<g>
|
|
<path class="st20" d="M192.9,88.1c-5,2.2-9.2,2.3-13.6,0.1c5.7-3.4,6-5.8,8.1-12.3c-5.4,3.2-11.4,5.5-17.6,6.7 c-10.5-11.2-28.1-11.7-39.2-1.2c-7.2,6.8-10.2,16.9-8,26.5c-22.3-1.1-43.1-11.7-57.2-29C58,91.6,61.8,107.9,74,116 c-4.4-0.1-8.7-1.3-12.6-3.4c0,0.1,0,0.2,0,0.4c0,13.2,9.3,24.6,22.3,27.2c-4.1,1.1-8.4,1.3-12.5,0.5c3.6,11.3,14,19,25.9,19.3 c-11.6,9.1-26.4,13.2-41.1,11.5c12.7,8.1,27.4,12.5,42.5,12.5c51,0,78.9-42.2,78.9-78.9c0-1.2,0-2.4-0.1-3.6 C182.7,97.4,189.2,93.7,192.9,88.1z"></path>
|
|
</g>
|
|
</g>
|
|
<circle class="st30" cx="124.4" cy="128.8" r="108.2"></circle>
|
|
</g>
|
|
</svg></a></li>
|
|
<li class="list-inline-item"><a href="https://www.facebook.com/nationallibraryofmedicine" aria-label="Facebook" rel="noopener noreferrer" target="_blank">
|
|
<svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" version="1.1" x="0px" y="0px" viewBox="0 0 249 249" style="enable-background:new 0 0 249 249;" xml:space="preserve">
|
|
<style type="text/css">
|
|
.st10 {
|
|
fill: #FFFFFF;
|
|
}
|
|
|
|
.st110 {
|
|
fill: none;
|
|
stroke: #FFFFFF;
|
|
stroke-width: 8;
|
|
stroke-miterlimit: 10;
|
|
}
|
|
</style>
|
|
<title>Facebook</title>
|
|
<g>
|
|
<g>
|
|
<path class="st10" d="M159,99.1h-24V88.4c0-5,3.3-6.2,5.7-6.2h16.8V60l-24.4-0.1c-22.1,0-26.2,16.5-26.2,27.1v12.1H90v22.5h16.9 v67.5H135v-67.5h21.7L159,99.1z"></path>
|
|
</g>
|
|
</g>
|
|
<circle class="st110" cx="123.6" cy="123.2" r="108.2"></circle>
|
|
</svg>
|
|
</a></li>
|
|
<li class="list-inline-item"><a href="https://www.youtube.com/user/NLMNIH" aria-label="Youtube" target="_blank" rel="noopener noreferrer"><svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" version="1.1" x="0px" y="0px" viewBox="0 0 249 249" style="enable-background:new 0 0 249 249;" xml:space="preserve">
|
|
<title>Youtube</title>
|
|
<style type="text/css">
|
|
.st4 {
|
|
fill: none;
|
|
stroke: #FFFFFF;
|
|
stroke-width: 8;
|
|
stroke-miterlimit: 10;
|
|
}
|
|
|
|
.st5 {
|
|
fill: #FFFFFF;
|
|
}
|
|
</style>
|
|
<circle class="st4" cx="124.2" cy="123.4" r="108.2"></circle>
|
|
<g transform="translate(0,-952.36218)">
|
|
<path class="st5" d="M88.4,1037.4c-10.4,0-18.7,8.3-18.7,18.7v40.1c0,10.4,8.3,18.7,18.7,18.7h72.1c10.4,0,18.7-8.3,18.7-18.7 v-40.1c0-10.4-8.3-18.7-18.7-18.7H88.4z M115.2,1058.8l29.4,17.4l-29.4,17.4V1058.8z"></path>
|
|
</g>
|
|
</svg></a></li>
|
|
</ul>
|
|
</div>
|
|
<div class="col-lg-3 col-12">
|
|
<p class="address_footer text-white">National Library of Medicine<br />
|
|
<a href="https://www.google.com/maps/place/8600+Rockville+Pike,+Bethesda,+MD+20894/@38.9959508,-77.101021,17z/data=!3m1!4b1!4m5!3m4!1s0x89b7c95e25765ddb:0x19156f88b27635b8!8m2!3d38.9959508!4d-77.0988323" class="text-white" target="_blank" rel="noopener noreferrer">8600 Rockville Pike<br />
|
|
Bethesda, MD 20894</a></p>
|
|
</div>
|
|
<div class="col-lg-3 col-12 centered-lg">
|
|
<p><a href="https://www.nlm.nih.gov/web_policies.html" class="text-white">Web Policies</a><br />
|
|
<a href="https://www.nih.gov/institutes-nih/nih-office-director/office-communications-public-liaison/freedom-information-act-office" class="text-white">FOIA</a><br />
|
|
<a href="https://www.hhs.gov/vulnerability-disclosure-policy/index.html" class="text-white" id="vdp">HHS Vulnerability Disclosure</a></p>
|
|
</div>
|
|
<div class="col-lg-3 col-12 centered-lg">
|
|
<p><a class="supportLink text-white" href="https://support.nlm.nih.gov/">Help</a><br />
|
|
<a href="https://www.nlm.nih.gov/accessibility.html" class="text-white">Accessibility</a><br />
|
|
<a href="https://www.nlm.nih.gov/careers/careers.html" class="text-white">Careers</a></p>
|
|
</div>
|
|
</div>
|
|
<div class="row">
|
|
<div class="col-lg-12 centered-lg">
|
|
<nav class="bottom-links">
|
|
<ul class="mt-3">
|
|
<li>
|
|
<a class="text-white" href="//www.nlm.nih.gov/">NLM</a>
|
|
</li>
|
|
<li>
|
|
<a class="text-white" href="https://www.nih.gov/">NIH</a>
|
|
</li>
|
|
<li>
|
|
<a class="text-white" href="https://www.hhs.gov/">HHS</a>
|
|
</li>
|
|
<li>
|
|
<a class="text-white" href="https://www.usa.gov/">USA.gov</a>
|
|
</li>
|
|
</ul>
|
|
</nav>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
</section>
|
|
<script type="text/javascript" src="/portal/portal3rc.fcgi/rlib/js/InstrumentOmnitureBaseJS/InstrumentNCBIConfigJS/InstrumentNCBIBaseJS/InstrumentPageStarterJS.js?v=1"> </script>
|
|
<script type="text/javascript" src="/portal/portal3rc.fcgi/static/js/hfjs2.js"> </script>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<!--/.page-->
|
|
</div>
|
|
<!--/.wrap-->
|
|
</div><!-- /.twelve_col -->
|
|
</div>
|
|
<!-- /.grid -->
|
|
|
|
<span class="PAFAppResources"></span>
|
|
|
|
<!-- BESelector tab -->
|
|
|
|
|
|
|
|
<noscript><img alt="statistics" src="/stat?jsdisabled=true&ncbi_db=books&ncbi_pdid=book-part&ncbi_acc=NBK548049&ncbi_domain=livertox&ncbi_report=record&ncbi_type=fulltext&ncbi_objectid=&ncbi_pcid=/NBK548049/&ncbi_pagename=Causality - LiverTox - NCBI Bookshelf&ncbi_bookparttype=chapter&ncbi_app=bookshelf" /></noscript>
|
|
|
|
|
|
<!-- usually for JS scripts at page bottom -->
|
|
<!--<component id="PageFixtures" label="styles"></component>-->
|
|
|
|
|
|
<!-- CE8B5AF87C7FFCB1_0191SID /projects/books/PBooks@9.11 portal106 v4.1.r689238 Tue, Oct 22 2024 16:10:51 -->
|
|
<span id="portal-csrf-token" style="display:none" data-token="CE8B5AF87C7FFCB1_0191SID"></span>
|
|
|
|
<script type="text/javascript" src="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/js/3879255/4121861/3501987/4008961/3893018/3821238/4062932/4209313/4212053/4076480/3921943/3400083/3426610.js" snapshot="books"></script></body>
|
|
</html> |