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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="author" content="Nancy D Berkman, P Lina Santaguida, Meera Viswanathan, Sally C Morton" /><meta name="citation_title" content="The Empirical Evidence of Bias in Trials Measuring Treatment Differences" /><meta name="citation_publisher" content="Agency for Healthcare Research and Quality (US)" /><meta name="citation_date" content="2014/09" /><meta name="citation_author" content="Nancy D Berkman" /><meta name="citation_author" content="P Lina Santaguida" /><meta name="citation_author" content="Meera Viswanathan" /><meta name="citation_author" content="Sally C Morton" /><meta name="citation_pmid" content="25392898" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK253181/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="The Empirical Evidence of Bias in Trials Measuring Treatment Differences" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="Agency for Healthcare Research and Quality (US)" /><meta name="DC.Contributor" content="Nancy D Berkman" /><meta name="DC.Contributor" content="P Lina Santaguida" /><meta name="DC.Contributor" content="Meera Viswanathan" /><meta name="DC.Contributor" content="Sally C Morton" /><meta name="DC.Date" content="2014/09" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK253181/" /><meta name="DC.Language" content="en" /><meta name="description" content="To comprehensively and systematically review and compare empirical evaluations of specific types of bias on effect estimates in randomized controlled trials (RCTs) reported in systematic reviews." /><meta name="og:title" content="The Empirical Evidence of Bias in Trials Measuring Treatment Differences" /><meta name="og:type" content="book" /><meta name="og:description" content="To comprehensively and systematically review and compare empirical evaluations of specific types of bias on effect estimates in randomized controlled trials (RCTs) reported in systematic reviews." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK253181/" /><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-methreseeb-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/methreseeb/toc/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK253181/" /><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} </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="methodscollect" />
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<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></div><div class="pagination bk_noprnt"><span class="inactive page_link prev">< Prev</span><a class="active page_link next" href="/books/n/methreseeb/fm.s1/" title="Next page in this title">Next ></a></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/Book"><div class="meta-content fm-sec"><div class="iconblock whole_rhythm clearfix no_top_margin"><a href="http://www.ahrq.gov/" title="Agency for Healthcare Research and Quality (US)" class="img_link icnblk_img" ref="pagearea=logo&targetsite=external&targetcat=link&targettype=publisher"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-methreseeb-lrg.png" alt="Cover of The Empirical Evidence of Bias in Trials Measuring Treatment Differences" /></a><div class="icnblk_cntnt"><h1 id="_NBK253181_"><span itemprop="name">The Empirical Evidence of Bias in Trials Measuring Treatment Differences</span></h1><p><i>Methods Research Reports</i></p><p class="contrib-group">Investigators: <span itemprop="author">Nancy D Berkman</span>, PhD, MLIR, <span itemprop="author">P Lina Santaguida</span>, PhD, <span itemprop="author">Meera Viswanathan</span>, PhD, and <span itemprop="author">Sally C Morton</span>, PhD.</p><a data-jig="ncbitoggler" href="#__NBK253181_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK253181_ai__"><p class="contrib-group"><h4>Authors</h4>Investigators: <span itemprop="author">Nancy D Berkman</span>, PhD, MLIR, <span itemprop="author">P Lina Santaguida</span>, PhD, <span itemprop="author">Meera Viswanathan</span>, PhD, and <span itemprop="author">Sally C Morton</span>, PhD.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup> RTI-UNC Evidence-based Practice Center</div></div><div class="half_rhythm">Rockville (MD): <a href="http://www.ahrq.gov/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=publisher"><span itemprop="publisher">Agency for Healthcare Research and Quality (US)</span></a>; <span itemprop="datePublished">2014 Sep</span>.<div class="small">Report No.: 14-EHC050-EF</div></div><div class="half_rhythm"><ul class="inline_list"><li><span class="label"><a data-jig="ncbidialog" href="#_ncbi_dlg_cpyrght_NBK253181" data-jigconfig="modal:true">Copyright and
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Permissions</a></span></li></ul></div><div id="_ncbi_dlg_cpyrght_NBK253181" style="display:none" title="Copyright and Permissions"><div>This publication is in the public domain. For more information, see the <a href="/books/about/copyright/">Bookshelf Copyright Notice</a>.</div></div><div class="bk_noprnt"><form method="get" action="/books/n/methreseeb/" 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></div><div class="body-content whole_rhythm" itemprop="text"><div itemprop="description"><h2>Structured Abstract</h2><div id="objectives"><h4 class="inline">Objectives:</h4><p>To comprehensively and systematically review and compare empirical evaluations of specific types of bias on effect estimates in randomized controlled trials (RCTs) reported in systematic reviews.</p></div><div id="data_sources"><h4 class="inline">Data sources:</h4><p>MEDLINE<sup>®</sup>, the Cochrane Library, and the Evidence-based Practice Center methods library located at the Scientific Resource Center. Additional studies were identified from reference lists and technical experts. We included meta-epidemiological studies (studies drawing from multiple meta-analyses), meta-analyses, and simulation studies (in relation to reporting bias only) intended primarily to examine the influence of bias on treatment effects in RCTs.</p></div><div id="review_methods"><h4 class="inline">Review methods:</h4><p>Approaches to minimizing potential biases considered in the review included selection bias through randomization (sequence generation and allocation concealment); confounding through design or analysis; performance bias through fidelity to the protocol, avoidance of unintended interventions, patient or caregiver blinding and clinician or provider blinding; detection bias through outcome assessor and data analyst blinding and appropriate statistical methods; detection/performance bias through double blinding; attrition bias through intention-to-treat analysis or other approaches to accounting for dropouts; and reporting bias through complete reporting of all prespecified outcomes. Two people independently selected, extracted data from, and rated the quality of included studies. We did not pool the results quantitatively due to the heterogeneity of included studies.</p></div><div id="result"><h4 class="inline">Results:</h4><p>A total of 38 studies of trials (48 publications) met our inclusion criteria, from our review of 4,844 abstracts. Of these, 35 had usable evidence. Some studies concerned the effect of more than one type of bias on effect estimates. We reviewed 23 studies on allocation concealment, 14 studies on sequence generation, 2 studies on unspecified bias in randomization, 2 studies on confounding, 2 studies on fidelity to protocol and unintended interventions, 4 studies on patient and/or provider blinding, 8 studies on assessor blinding, 2 studies on appropriate statistical methods, 18 studies on double blinding, 15 studies on attrition bias, and 9 studies on selective outcome reporting.</p><p>Although a trend toward exaggeration of treatment effects was seen across bodies of evidence for most biases, the magnitude and precision of the effect varied widely across studies. We generally found evidence that was precise and consistent in direction of effect for assessor and double blinding, specifically in relation to subjective outcomes, and for selective outcome reporting. Evidence was generally consistent in direction of effect but with variable precision across studies for allocation concealment, sequence generation, and assessor blinding of objective or mixed outcomes. In contrast, evidence was generally inconsistent and imprecise in relation to confounding, adequate statistical methods, fidelity to the protocol, patient/provider blinding, and attrition bias.</p><p>Studies differed markedly on a number of dimensions including measures/scales used to measure biases, the thoroughness of reporting of trial conduct that was required, approaches to statistical modeling and adjustment for potential confounding, types of outcomes and stratification by treatment or condition. Within many epidemiological studies, the included meta-analyses or trials varied along these dimensions as well.</p></div><div id="conclusions"><h4 class="inline">Conclusions:</h4><p>Theory suggests that bias in the conduct of studies would influence treatment effects. Our review found some evidence of this effect in relation to some aspects of RCT study conduct. When the bias was present, commonly the treatment effect was increased, but rarely were the estimates precise in the individual studies. However, because this evidence is limited and uncertain with respect to the magnitude of the impact, this does not necessarily imply that systematic reviewers can eliminate assessment of risk of bias. Due to the complexity of evaluating precision in meta-epidemiological studies developed from potentially heterogeneous meta-analyses or trials, we cannot be sure that studies were sufficiently powered. We suggest that systematic reviewers consider subgroup analyses, with and without studies with flaws in relation to specific biases of importance for review questions. Future studies evaluating the impact of biases on treatment effect should follow the lead of the BRANDO study and use modeling approaches that include careful construction of large datasets of trials (and eventually observational studies) designed to look at the effect of specific aspects of study conduct and the interrelationship between bias concerns.</p></div></div><div><h2>Contents</h2><div class="bktoc_all_cntnr top align_right" style="display:none"><ul class="inline_list_right"><li><a class="bktoc_all_exp" href="#">Expand All</a></li><li style="margin-left:.8em"><a class="bktoc_all_clps" href="#">Collapse All</a></li></ul></div><ul id="toc_tllNBK253181_fm_s1" class="simple-list toc toc-toggle"><li class="half_rhythm" id="toc_itm_NBK253181_fm_s1"><a href="/books/n/methreseeb/fm.s1/" class="toc-item">Preface</a></li><li class="half_rhythm" id="toc_itm_NBK253181_fm_ack"><a href="/books/n/methreseeb/fm.ack/" class="toc-item">Acknowledgments</a></li><li class="half_rhythm" id="toc_itm_NBK253181_fm_s2"><a href="/books/n/methreseeb/fm.s2/" class="toc-item">Technical Expert Panel</a></li><li class="half_rhythm" id="toc_itm_NBK253181_fm_s3"><a href="/books/n/methreseeb/fm.s3/" class="toc-item">Peer Reviewers</a></li><li class="half_rhythm" id="toc_itm_NBK253181_background"><a href="/books/n/methreseeb/background/" class="toc-item">Background</a><ul id="toc_lst_NBK253181_background_s1" class="simple-list toc bktoc_lst_exp"><li class="half_rhythm" id="toc_itm_NBK253181_background_s1"><a href="/books/n/methreseeb/background/#background.s1" class="toc-item">Key Questions</a></li></ul></li><li class="half_rhythm" id="toc_itm_NBK253181_methods"><a href="/books/n/methreseeb/methods/" class="toc-item">Methods</a><ul id="toc_lst_NBK253181_methods_s1" class="simple-list toc bktoc_lst_exp"><li class="half_rhythm" id="toc_itm_NBK253181_methods_s1"><a href="/books/n/methreseeb/methods/#methods.s1" class="toc-item">Literature Search Strategy</a></li><li class="half_rhythm" id="toc_itm_NBK253181_methods_s2"><a href="/books/n/methreseeb/methods/#methods.s2" class="toc-item">Inclusion and Exclusion Criteria</a></li><li class="half_rhythm" id="toc_itm_NBK253181_methods_s3"><a href="/books/n/methreseeb/methods/#methods.s3" class="toc-item">Study Selection</a></li><li class="half_rhythm" id="toc_itm_NBK253181_methods_s4"><a href="/books/n/methreseeb/methods/#methods.s4" class="toc-item">Data Extraction</a></li><li class="half_rhythm" id="toc_itm_NBK253181_methods_s5"><a href="/books/n/methreseeb/methods/#methods.s5" class="toc-item">Quality Assessment</a></li></ul></li><li class="half_rhythm" id="toc_itm_NBK253181_results"><a href="/books/n/methreseeb/results/" class="toc-item">Results</a><ul id="toc_lst_NBK253181_results_s1" class="simple-list toc bktoc_lst_exp"><li class="half_rhythm" id="toc_itm_NBK253181_results_s1"><a href="/books/n/methreseeb/results/#results.s1" class="toc-item">Results of Literature Searches</a></li><li class="half_rhythm" id="toc_itm_NBK253181_results_s2"><a href="/books/n/methreseeb/results/#results.s2" class="toc-item">Overview of Included Studies</a></li><li class="half_rhythm" id="toc_itm_NBK253181_results_s3"><a href="/books/n/methreseeb/results/#results.s3" class="toc-item">Selection Bias: Allocation Concealment</a></li><li class="half_rhythm" id="toc_itm_NBK253181_results_s10"><a href="/books/n/methreseeb/results/#results.s10" class="toc-item">Selection Bias: Sequence Generation (Randomization)</a></li><li class="half_rhythm" id="toc_itm_NBK253181_results_s17"><a href="/books/n/methreseeb/results/#results.s17" class="toc-item">Confounding</a></li><li class="half_rhythm" id="toc_itm_NBK253181_results_s23"><a href="/books/n/methreseeb/results/#results.s23" class="toc-item">Performance Bias: Fidelity to Protocol, Unintended Interventions, or Cointerventions</a></li><li class="half_rhythm" id="toc_itm_NBK253181_results_s29"><a href="/books/n/methreseeb/results/#results.s29" class="toc-item">Performance Bias: Patient/Caregiver or Provider Blinding</a></li><li class="half_rhythm" id="toc_itm_NBK253181_results_s34"><a href="/books/n/methreseeb/results/#results.s34" class="toc-item">Detection Bias: Assessor Blinding</a></li><li class="half_rhythm" id="toc_itm_NBK253181_results_s39"><a href="/books/n/methreseeb/results/#results.s39" class="toc-item">Detection Bias: Valid Statistical Methods</a></li><li class="half_rhythm" id="toc_itm_NBK253181_results_s41"><a href="/books/n/methreseeb/results/#results.s41" class="toc-item">Detection/Performance Bias: Double Blinding</a></li><li class="half_rhythm" id="toc_itm_NBK253181_results_s47"><a href="/books/n/methreseeb/results/#results.s47" class="toc-item">Attrition Bias</a></li><li class="half_rhythm" id="toc_itm_NBK253181_results_s53"><a href="/books/n/methreseeb/results/#results.s53" class="toc-item">Reporting Bias: Selective Outcome Reporting</a></li></ul></li><li class="half_rhythm" id="toc_itm_NBK253181_discussion"><a href="/books/n/methreseeb/discussion/" class="toc-item">Discussion</a><ul id="toc_lst_NBK253181_discussion_s1" class="simple-list toc bktoc_lst_exp"><li class="half_rhythm" id="toc_itm_NBK253181_discussion_s1"><a href="/books/n/methreseeb/discussion/#discussion.s1" class="toc-item">Key Considerations Across Studies</a></li><li class="half_rhythm" id="toc_itm_NBK253181_discussion_s2"><a href="/books/n/methreseeb/discussion/#discussion.s2" class="toc-item">Specific Biases: Key Considerations</a></li><li class="half_rhythm" id="toc_itm_NBK253181_discussion_s5"><a href="/books/n/methreseeb/discussion/#discussion.s5" class="toc-item">Performance Bias: Fidelity to Protocol, Unintended Interventions or Cointerventions</a></li><li class="half_rhythm" id="toc_itm_NBK253181_discussion_s9"><a href="/books/n/methreseeb/discussion/#discussion.s9" class="toc-item">Performance/Detection Bias: Double Blinding</a></li><li class="half_rhythm" id="toc_itm_NBK253181_discussion_s12"><a href="/books/n/methreseeb/discussion/#discussion.s12" class="toc-item">Limitations of the Review Process</a></li><li class="half_rhythm" id="toc_itm_NBK253181_discussion_s13"><a href="/books/n/methreseeb/discussion/#discussion.s13" class="toc-item">Research Gaps and Implications for Future Research</a></li><li class="half_rhythm" id="toc_itm_NBK253181_discussion_s14"><a href="/books/n/methreseeb/discussion/#discussion.s14" class="toc-item">Implications for Reviewers</a></li></ul></li><li class="half_rhythm" id="toc_itm_NBK253181_references_rl1"><a href="/books/n/methreseeb/references.rl1/" class="toc-item">References</a></li><li class="half_rhythm" id="toc_itm_NBK253181_appa"><a href="/books/n/methreseeb/appa/" class="toc-item">Appendix A Empirical Evidence of Bias Search Strategies</a></li><li class="half_rhythm" id="toc_itm_NBK253181_appb"><a href="/books/n/methreseeb/appb/" class="toc-item">Appendix B Screening and Abstraction Forms</a></li><li class="half_rhythm" id="toc_itm_NBK253181_appc"><a href="/books/n/methreseeb/appc/" class="toc-item">Appendix C Excluded Full-Text Article List</a></li><li class="half_rhythm" id="toc_itm_NBK253181_appd"><a href="/books/n/methreseeb/appd/" class="toc-item">Appendix D Detailed Study Characteristics</a></li><li class="half_rhythm" id="toc_itm_NBK253181_appe"><a href="/books/n/methreseeb/appe/" class="toc-item">Appendix E Study Quality Assessment</a></li></ul><div class="bktoc_all_cntnr align_right" style="display:none"><ul class="inline_list_right"><li><a class="bktoc_all_exp" href="#">Expand All</a></li><li style="margin-left:.8em"><a class="bktoc_all_clps" href="#">Collapse All</a></li></ul></div></div><div><p><b>Prepared for:</b>
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Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services<a class="bk_pop" href="#address1"><sup>1</sup></a>,
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<b>Contract No.</b>
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290-2007-10056-I. <b>Prepared by:</b>
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RTI-UNC Evidence-based Practice Center, Research Triangle Park, NC</p></div><div><h4 class="inline">Suggested citation:</h4><p>Berkman ND, Santaguida PL, Viswanathan M, Morton SC. The Empirical Evidence of Bias in Trials Measuring Treatment Differences. Methods Research Report. (Prepared by the RTI-UNC Evidence-based Practice Center under Contract No. 290-2007-10056-I.) AHRQ Publication No. 14-EHC050-EF. Rockville, MD: Agency for Healthcare Research and Quality; September 2014. <a href="http://www.effectivehealthcare.ahrq.gov/reports/final.cfm" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.effectivehealthcare.ahrq.gov/reports/final.cfm</a>.</p></div><div><p>This report is based on research conducted by the RTI International-University of North Carolina Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2007-10056-I). The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services.</p><p>The information in this report is intended to help health care decisionmakers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information (i.e., in the context of available resources and circumstances presented by individual patients).</p><p>This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.</p><p>None of the investigators have any affiliations or financial involvement that conflicts with the material presented in this report.</p></div><div><dl class="temp-labeled-list small"><dt>1</dt><dd><div id="address1"><p class="no_top_margin">540 Gaither Road, Rockville, MD 20850; <a href="http://www.ahrq.gov" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www<wbr style="display:inline-block"></wbr>.ahrq.gov</a></p></div></dd></dl></div></div></div>
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<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/NBK253181/?report=reader">PubReader</a></li><li><a href="/books/NBK253181/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK253181" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK253181" style="display:none" title="Cite this Page"><div class="bk_tt">Berkman ND, Santaguida PL, Viswanathan M, et al. The Empirical Evidence of Bias in Trials Measuring Treatment Differences [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2014 Sep. <span class="bk_cite_avail"></span></div></div></li><li><a href="/books/n/methreseeb/pdf/">PDF version of this title</a> (1.0M)</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Other titles in these collections</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/methodscollect/">AHRQ Methods for Effective Health Care</a></li><li><a href="/books/n/hstatcollect/">Health Services/Technology Assessment Texts
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