LDL-cholesterol differences predicted survival benefit in statin trials by the surrogate threshold effect (STE)
Abstract Objective We describe a new statistical method called the surrogate threshold effect (STE) that estimates the threshold level of a surrogate needed in a clinical trial to predict a benefit in the target clinical outcome. In this article, we apply this method to the LDL-cholesterol biomarker...
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Veröffentlicht in: | Journal of clinical epidemiology 2009-03, Vol.62 (3), p.328-336 |
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description | Abstract Objective We describe a new statistical method called the surrogate threshold effect (STE) that estimates the threshold level of a surrogate needed in a clinical trial to predict a benefit in the target clinical outcome. In this article, we apply this method to the LDL-cholesterol biomarker surrogate and survival benefit-target outcome in statin trials. Study Design and Setting We identified randomized trials comparing statin treatment to placebo treatment or no treatment and reporting all-cause and cardiovascular mortality. Trials with fewer than five all-cause deaths in at least one arm were excluded. Multiple regression modeled the reduction in all-cause and cardiovascular mortality as a function of LDL-cholesterol difference. The 95% confidence and 95% prediction bands were calculated and graphed to determine the minimum LDL-cholesterol difference (the surrogate threshold) below which there would be no predicted survival benefit. Results In 16 qualifying trials, regression analysis yielded an all-cause mortality model whose prediction bands demonstrated no overall survival gain with LDL-cholesterol difference values below 1.5 mmol/L. The cardiovascular mortality model yielded prediction bands that demonstrated no cardiovascular survival benefit with LDL-cholesterol difference values below 1.4 mmol/L. Conclusions In a multitrial setting, the STE approach is a promising yet straightforward statistical method for evaluating the surrogate validity of biomarkers. |
doi_str_mv | 10.1016/j.jclinepi.2008.06.004 |
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In this article, we apply this method to the LDL-cholesterol biomarker surrogate and survival benefit-target outcome in statin trials. Study Design and Setting We identified randomized trials comparing statin treatment to placebo treatment or no treatment and reporting all-cause and cardiovascular mortality. Trials with fewer than five all-cause deaths in at least one arm were excluded. Multiple regression modeled the reduction in all-cause and cardiovascular mortality as a function of LDL-cholesterol difference. The 95% confidence and 95% prediction bands were calculated and graphed to determine the minimum LDL-cholesterol difference (the surrogate threshold) below which there would be no predicted survival benefit. Results In 16 qualifying trials, regression analysis yielded an all-cause mortality model whose prediction bands demonstrated no overall survival gain with LDL-cholesterol difference values below 1.5 mmol/L. The cardiovascular mortality model yielded prediction bands that demonstrated no cardiovascular survival benefit with LDL-cholesterol difference values below 1.4 mmol/L. Conclusions In a multitrial setting, the STE approach is a promising yet straightforward statistical method for evaluating the surrogate validity of biomarkers.</description><identifier>ISSN: 0895-4356</identifier><identifier>EISSN: 1878-5921</identifier><identifier>DOI: 10.1016/j.jclinepi.2008.06.004</identifier><identifier>PMID: 18834708</identifier><language>eng</language><publisher>New York, NY: Elsevier Inc</publisher><subject>Biological and medical sciences ; Biomarker ; Biomarkers - blood ; Cardiovascular disease ; Cardiovascular Diseases - drug therapy ; Cardiovascular Diseases - mortality ; Cause of Death ; Cholesterol ; Cholesterol, LDL - blood ; Disorders of blood lipids. Hyperlipoproteinemia ; Epidemiology ; Female ; Forecasting ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use ; Internal Medicine ; LDL-cholesterol ; Levels of evidence ; Male ; Medical sciences ; Metabolic diseases ; Mortality ; Placebos ; Predictive Value of Tests ; Randomized Controlled Trials as Topic ; Regression analysis ; Risk Factors ; Statins ; Statistical methods ; Surrogate ; Survival ; Survival Analysis ; Treatment Outcome</subject><ispartof>Journal of clinical epidemiology, 2009-03, Vol.62 (3), p.328-336</ispartof><rights>Elsevier Inc.</rights><rights>2008 Elsevier Inc.</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c479t-16f8be43239d386a30e2ed9744d872ba88529488f2647a60189f18d556357bfc3</citedby><cites>FETCH-LOGICAL-c479t-16f8be43239d386a30e2ed9744d872ba88529488f2647a60189f18d556357bfc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/1033194058?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995,64385,64387,64389,72469</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21152242$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18834708$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Johnson, Kent R</creatorcontrib><creatorcontrib>Freemantle, Nick</creatorcontrib><creatorcontrib>Anthony, Danielle M</creatorcontrib><creatorcontrib>Lassere, Marissa N.D</creatorcontrib><title>LDL-cholesterol differences predicted survival benefit in statin trials by the surrogate threshold effect (STE)</title><title>Journal of clinical epidemiology</title><addtitle>J Clin Epidemiol</addtitle><description>Abstract Objective We describe a new statistical method called the surrogate threshold effect (STE) that estimates the threshold level of a surrogate needed in a clinical trial to predict a benefit in the target clinical outcome. In this article, we apply this method to the LDL-cholesterol biomarker surrogate and survival benefit-target outcome in statin trials. Study Design and Setting We identified randomized trials comparing statin treatment to placebo treatment or no treatment and reporting all-cause and cardiovascular mortality. Trials with fewer than five all-cause deaths in at least one arm were excluded. Multiple regression modeled the reduction in all-cause and cardiovascular mortality as a function of LDL-cholesterol difference. The 95% confidence and 95% prediction bands were calculated and graphed to determine the minimum LDL-cholesterol difference (the surrogate threshold) below which there would be no predicted survival benefit. Results In 16 qualifying trials, regression analysis yielded an all-cause mortality model whose prediction bands demonstrated no overall survival gain with LDL-cholesterol difference values below 1.5 mmol/L. The cardiovascular mortality model yielded prediction bands that demonstrated no cardiovascular survival benefit with LDL-cholesterol difference values below 1.4 mmol/L. Conclusions In a multitrial setting, the STE approach is a promising yet straightforward statistical method for evaluating the surrogate validity of biomarkers.</description><subject>Biological and medical sciences</subject><subject>Biomarker</subject><subject>Biomarkers - blood</subject><subject>Cardiovascular disease</subject><subject>Cardiovascular Diseases - drug therapy</subject><subject>Cardiovascular Diseases - mortality</subject><subject>Cause of Death</subject><subject>Cholesterol</subject><subject>Cholesterol, LDL - blood</subject><subject>Disorders of blood lipids. Hyperlipoproteinemia</subject><subject>Epidemiology</subject><subject>Female</subject><subject>Forecasting</subject><subject>Humans</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use</subject><subject>Internal Medicine</subject><subject>LDL-cholesterol</subject><subject>Levels of evidence</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metabolic diseases</subject><subject>Mortality</subject><subject>Placebos</subject><subject>Predictive Value of Tests</subject><subject>Randomized Controlled Trials as Topic</subject><subject>Regression analysis</subject><subject>Risk Factors</subject><subject>Statins</subject><subject>Statistical methods</subject><subject>Surrogate</subject><subject>Survival</subject><subject>Survival Analysis</subject><subject>Treatment Outcome</subject><issn>0895-4356</issn><issn>1878-5921</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFkk1v1DAQhiMEotvCX6gsIVA5JPgrzuSCQKV8SCtxaDlbjj2mDtlksbMr7b_H0S5U6oXTyNIzr2fmfYviktGKUabe9VVvhzDiNlScUqioqiiVT4oVgwbKuuXsabGi0NalFLU6K85T6illDW3q58UZAxCyobAqpvWndWnvpwHTjHEaiAveY8TRYiLbiC7YGR1Ju7gPezOQDkf0YSZhJGk2cy5zDGZIpDuQ-R4XME4_zYz5FTFlYUcwK9qZXN3e3bx9UTzzGceXp3pR_Ph8c3f9tVx___Lt-mOeRTbtXDLloUMpuGidAGUERY6ubaR00PDOANS8lQCeK9kYRRm0noGrayXqpvNWXBRvjrrbOP3e5eX0JiSLw2BGnHZJKwXAuaIZfPUI7KddHPNsmlEhWCtpDZlSR8rGKaWIXm9j2Jh4yJBeDNG9_muIXgzRVOlsSG68PMnvug26h7aTAxl4fQJMsmbw0Yw2pH8cZ6zmXPLMfThymK-2Dxh1smGxyYWYr6vdFP4_y_tHEgsV8q-_8IDpYW-duKb6donPkh4KOTmqBfEHMNjA4Q</recordid><startdate>20090301</startdate><enddate>20090301</enddate><creator>Johnson, Kent R</creator><creator>Freemantle, Nick</creator><creator>Anthony, Danielle M</creator><creator>Lassere, Marissa N.D</creator><general>Elsevier Inc</general><general>Elsevier</general><general>Elsevier Limited</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7RV</scope><scope>7T2</scope><scope>7T7</scope><scope>7TK</scope><scope>7U7</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88C</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M0T</scope><scope>M1P</scope><scope>M2O</scope><scope>M7N</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope></search><sort><creationdate>20090301</creationdate><title>LDL-cholesterol differences predicted survival benefit in statin trials by the surrogate threshold effect (STE)</title><author>Johnson, Kent R ; Freemantle, Nick ; Anthony, Danielle M ; Lassere, Marissa N.D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c479t-16f8be43239d386a30e2ed9744d872ba88529488f2647a60189f18d556357bfc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Biological and medical sciences</topic><topic>Biomarker</topic><topic>Biomarkers - blood</topic><topic>Cardiovascular disease</topic><topic>Cardiovascular Diseases - drug therapy</topic><topic>Cardiovascular Diseases - mortality</topic><topic>Cause of Death</topic><topic>Cholesterol</topic><topic>Cholesterol, LDL - blood</topic><topic>Disorders of blood lipids. Hyperlipoproteinemia</topic><topic>Epidemiology</topic><topic>Female</topic><topic>Forecasting</topic><topic>Humans</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use</topic><topic>Internal Medicine</topic><topic>LDL-cholesterol</topic><topic>Levels of evidence</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Metabolic diseases</topic><topic>Mortality</topic><topic>Placebos</topic><topic>Predictive Value of Tests</topic><topic>Randomized Controlled Trials as Topic</topic><topic>Regression analysis</topic><topic>Risk Factors</topic><topic>Statins</topic><topic>Statistical methods</topic><topic>Surrogate</topic><topic>Survival</topic><topic>Survival Analysis</topic><topic>Treatment Outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Johnson, Kent R</creatorcontrib><creatorcontrib>Freemantle, Nick</creatorcontrib><creatorcontrib>Anthony, Danielle M</creatorcontrib><creatorcontrib>Lassere, Marissa N.D</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Health and Safety Science Abstracts (Full archive)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Healthcare Administration Database (Alumni)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Healthcare Administration Database</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of clinical epidemiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Johnson, Kent R</au><au>Freemantle, Nick</au><au>Anthony, Danielle M</au><au>Lassere, Marissa N.D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>LDL-cholesterol differences predicted survival benefit in statin trials by the surrogate threshold effect (STE)</atitle><jtitle>Journal of clinical epidemiology</jtitle><addtitle>J Clin Epidemiol</addtitle><date>2009-03-01</date><risdate>2009</risdate><volume>62</volume><issue>3</issue><spage>328</spage><epage>336</epage><pages>328-336</pages><issn>0895-4356</issn><eissn>1878-5921</eissn><abstract>Abstract Objective We describe a new statistical method called the surrogate threshold effect (STE) that estimates the threshold level of a surrogate needed in a clinical trial to predict a benefit in the target clinical outcome. In this article, we apply this method to the LDL-cholesterol biomarker surrogate and survival benefit-target outcome in statin trials. Study Design and Setting We identified randomized trials comparing statin treatment to placebo treatment or no treatment and reporting all-cause and cardiovascular mortality. Trials with fewer than five all-cause deaths in at least one arm were excluded. Multiple regression modeled the reduction in all-cause and cardiovascular mortality as a function of LDL-cholesterol difference. The 95% confidence and 95% prediction bands were calculated and graphed to determine the minimum LDL-cholesterol difference (the surrogate threshold) below which there would be no predicted survival benefit. Results In 16 qualifying trials, regression analysis yielded an all-cause mortality model whose prediction bands demonstrated no overall survival gain with LDL-cholesterol difference values below 1.5 mmol/L. The cardiovascular mortality model yielded prediction bands that demonstrated no cardiovascular survival benefit with LDL-cholesterol difference values below 1.4 mmol/L. Conclusions In a multitrial setting, the STE approach is a promising yet straightforward statistical method for evaluating the surrogate validity of biomarkers.</abstract><cop>New York, NY</cop><pub>Elsevier Inc</pub><pmid>18834708</pmid><doi>10.1016/j.jclinepi.2008.06.004</doi><tpages>9</tpages></addata></record> |
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subjects | Biological and medical sciences Biomarker Biomarkers - blood Cardiovascular disease Cardiovascular Diseases - drug therapy Cardiovascular Diseases - mortality Cause of Death Cholesterol Cholesterol, LDL - blood Disorders of blood lipids. Hyperlipoproteinemia Epidemiology Female Forecasting Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use Internal Medicine LDL-cholesterol Levels of evidence Male Medical sciences Metabolic diseases Mortality Placebos Predictive Value of Tests Randomized Controlled Trials as Topic Regression analysis Risk Factors Statins Statistical methods Surrogate Survival Survival Analysis Treatment Outcome |
title | LDL-cholesterol differences predicted survival benefit in statin trials by the surrogate threshold effect (STE) |
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