Discriminative Ability of LDL-Cholesterol to Identify Patients With Familial Hypercholesterolemia: A Cross-Sectional Study in 26 406 Individuals Tested for Genetic FH
BACKGROUND—Screening for familial hypercholesterolemia (FH) within affected families is often based on cutoff values for low-density lipoprotein cholesterol (LDL-C). However, the diagnostic accuracy of LDL-C levels is influenced by the magnitude of the LDL-C overlap between FH patients and unaffecte...
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| Veröffentlicht in: | Circulation. Cardiovascular genetics 2012-06, Vol.5 (3), p.354-359 |
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| container_title | Circulation. Cardiovascular genetics |
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| creator | Huijgen, Roeland Hutten, Barbara A Kindt, Iris Vissers, Maud N Kastelein, John J.P |
| description | BACKGROUND—Screening for familial hypercholesterolemia (FH) within affected families is often based on cutoff values for low-density lipoprotein cholesterol (LDL-C). However, the diagnostic accuracy of LDL-C levels is influenced by the magnitude of the LDL-C overlap between FH patients and unaffected relatives. The purpose of the current study was to assess to what extent this overlap is influenced by the severity of specific FH mutations.
METHODS AND RESULTS—Individuals were eligible if they underwent family screening for FH between 2003 and 2010. The entire cohort was then compared with those who were investigated for the presence of the most severe mutations (class 1). The area under the receiver operating characteristics curve and the sensitivity of the 90th percentile of LDL-C were calculated for both cohorts. We included 26 406 individuals, of whom 9169 (35%) carried an FH-causing mutation. In the entire cohort at baseline, mean LDL-C was 4.63±1.44 mmol/L for FH carriers (n=5372) and 2.96±0.96 mmol/L for unaffected relatives (n=15 148); P |
| doi_str_mv | 10.1161/CIRCGENETICS.111.962456 |
| format | Article |
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METHODS AND RESULTS—Individuals were eligible if they underwent family screening for FH between 2003 and 2010. The entire cohort was then compared with those who were investigated for the presence of the most severe mutations (class 1). The area under the receiver operating characteristics curve and the sensitivity of the 90th percentile of LDL-C were calculated for both cohorts. We included 26 406 individuals, of whom 9169 (35%) carried an FH-causing mutation. In the entire cohort at baseline, mean LDL-C was 4.63±1.44 mmol/L for FH carriers (n=5372) and 2.96±0.96 mmol/L for unaffected relatives (n=15 148); P<0.001. The corresponding operating characteristics curve (95% CI) was 86.6% (85.9%–87.2%), and the cutoff level of LDL-C above the 90th percentile showed a sensitivity of 68.5%. The operating characteristics curve and sensitivity significantly improved when the 5933 individuals tested for class 1 mutations were assessed separately; 96.2% (95.3%–97.1%) and 91.3%, respectively.
CONCLUSIONS—In summary, the overlap in terms of LDL-C levels between those with molecularly proven FH and unaffected relatives is to a large extent because of the high prevalence of modestly severe LDL-receptor mutations in the Netherlands.</description><identifier>ISSN: 1942-325X</identifier><identifier>EISSN: 1942-3268</identifier><identifier>DOI: 10.1161/CIRCGENETICS.111.962456</identifier><identifier>PMID: 22553281</identifier><language>eng</language><publisher>Hagerstown, MD: American Heart Association, Inc</publisher><subject>Adult ; Area Under Curve ; Biological and medical sciences ; Cholesterol, LDL - blood ; Cohort Studies ; Cross-Sectional Studies ; Discriminant Analysis ; Disorders of blood lipids. Hyperlipoproteinemia ; Female ; Genotype ; Humans ; Hyperlipoproteinemia Type II - epidemiology ; Hyperlipoproteinemia Type II - genetics ; Male ; Medical sciences ; Metabolic diseases ; Middle Aged ; Mutation ; Prevalence ; Receptors, LDL - genetics ; ROC Curve</subject><ispartof>Circulation. Cardiovascular genetics, 2012-06, Vol.5 (3), p.354-359</ispartof><rights>2012 American Heart Association, Inc.</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c2493-54f0521b1e60428946bb32425db5eeb3ac37412f4ac1dafc35566416a334fac23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,3688,27929,27930</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26051390$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22553281$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huijgen, Roeland</creatorcontrib><creatorcontrib>Hutten, Barbara A</creatorcontrib><creatorcontrib>Kindt, Iris</creatorcontrib><creatorcontrib>Vissers, Maud N</creatorcontrib><creatorcontrib>Kastelein, John J.P</creatorcontrib><title>Discriminative Ability of LDL-Cholesterol to Identify Patients With Familial Hypercholesterolemia: A Cross-Sectional Study in 26 406 Individuals Tested for Genetic FH</title><title>Circulation. Cardiovascular genetics</title><addtitle>Circ Cardiovasc Genet</addtitle><description>BACKGROUND—Screening for familial hypercholesterolemia (FH) within affected families is often based on cutoff values for low-density lipoprotein cholesterol (LDL-C). However, the diagnostic accuracy of LDL-C levels is influenced by the magnitude of the LDL-C overlap between FH patients and unaffected relatives. The purpose of the current study was to assess to what extent this overlap is influenced by the severity of specific FH mutations.
METHODS AND RESULTS—Individuals were eligible if they underwent family screening for FH between 2003 and 2010. The entire cohort was then compared with those who were investigated for the presence of the most severe mutations (class 1). The area under the receiver operating characteristics curve and the sensitivity of the 90th percentile of LDL-C were calculated for both cohorts. We included 26 406 individuals, of whom 9169 (35%) carried an FH-causing mutation. In the entire cohort at baseline, mean LDL-C was 4.63±1.44 mmol/L for FH carriers (n=5372) and 2.96±0.96 mmol/L for unaffected relatives (n=15 148); P<0.001. The corresponding operating characteristics curve (95% CI) was 86.6% (85.9%–87.2%), and the cutoff level of LDL-C above the 90th percentile showed a sensitivity of 68.5%. The operating characteristics curve and sensitivity significantly improved when the 5933 individuals tested for class 1 mutations were assessed separately; 96.2% (95.3%–97.1%) and 91.3%, respectively.
CONCLUSIONS—In summary, the overlap in terms of LDL-C levels between those with molecularly proven FH and unaffected relatives is to a large extent because of the high prevalence of modestly severe LDL-receptor mutations in the Netherlands.</description><subject>Adult</subject><subject>Area Under Curve</subject><subject>Biological and medical sciences</subject><subject>Cholesterol, LDL - blood</subject><subject>Cohort Studies</subject><subject>Cross-Sectional Studies</subject><subject>Discriminant Analysis</subject><subject>Disorders of blood lipids. Hyperlipoproteinemia</subject><subject>Female</subject><subject>Genotype</subject><subject>Humans</subject><subject>Hyperlipoproteinemia Type II - epidemiology</subject><subject>Hyperlipoproteinemia Type II - genetics</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metabolic diseases</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Prevalence</subject><subject>Receptors, LDL - genetics</subject><subject>ROC Curve</subject><issn>1942-325X</issn><issn>1942-3268</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkV1v0zAUhiMEYmPwF8A3SNxk83cb7qqsH5EqQLQI7iLHsVWDG3d2sil_iN_JqdptXNg-On7eY5_zZtkHgq8JkeSmrL6Xy_mX-bYqN5Ah14WkXMgX2SUpOM0ZldOXT7H4dZG9Sek3xpIzJl9nF5QKweiUXGZ_b13S0e1dp3p3b9Cscd71IwoWrW_XebkL3qTexOBRH1DVmq53dkTfgIYwoZ-u36GF2oNKebQaDybqZ43ZO_UZzVAZQ0r5xujehQ64TT-0I3IdohJxLFHVte7etYPyCW2P2hbZENHSdKZ3Gi1Wb7NXFi7Nu_N5lf1YzLflKl9_XVblbJ1ryguWC26xoKQhRmJOpwWXTcMop6JthDENU5pNOKGWK01aZTUTQkpOpGKMW6Upu8o-neoeYrgb4Cf1HuZjvFedCUOqCaaECww7oJMTqo_NRWPrA8xRxRGg-mhS_b9JkCH1ySRQvj8_MjR70z7pHl0B4OMZUEkrb6PqtEvPnMSCsAIDx0_cQ_Aw7_THDw8m1jujfL-rMWHQbTHJKSYUS4xxDguS_wAUdKvH</recordid><startdate>201206</startdate><enddate>201206</enddate><creator>Huijgen, Roeland</creator><creator>Hutten, Barbara A</creator><creator>Kindt, Iris</creator><creator>Vissers, Maud N</creator><creator>Kastelein, John J.P</creator><general>American Heart Association, Inc</general><general>Lippincott Williams & Wilkins</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>7X8</scope></search><sort><creationdate>201206</creationdate><title>Discriminative Ability of LDL-Cholesterol to Identify Patients With Familial Hypercholesterolemia: A Cross-Sectional Study in 26 406 Individuals Tested for Genetic FH</title><author>Huijgen, Roeland ; Hutten, Barbara A ; Kindt, Iris ; Vissers, Maud N ; Kastelein, John J.P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2493-54f0521b1e60428946bb32425db5eeb3ac37412f4ac1dafc35566416a334fac23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adult</topic><topic>Area Under Curve</topic><topic>Biological and medical sciences</topic><topic>Cholesterol, LDL - blood</topic><topic>Cohort Studies</topic><topic>Cross-Sectional Studies</topic><topic>Discriminant Analysis</topic><topic>Disorders of blood lipids. Hyperlipoproteinemia</topic><topic>Female</topic><topic>Genotype</topic><topic>Humans</topic><topic>Hyperlipoproteinemia Type II - epidemiology</topic><topic>Hyperlipoproteinemia Type II - genetics</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Metabolic diseases</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Prevalence</topic><topic>Receptors, LDL - genetics</topic><topic>ROC Curve</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huijgen, Roeland</creatorcontrib><creatorcontrib>Hutten, Barbara A</creatorcontrib><creatorcontrib>Kindt, Iris</creatorcontrib><creatorcontrib>Vissers, Maud N</creatorcontrib><creatorcontrib>Kastelein, John J.P</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>MEDLINE - Academic</collection><jtitle>Circulation. Cardiovascular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huijgen, Roeland</au><au>Hutten, Barbara A</au><au>Kindt, Iris</au><au>Vissers, Maud N</au><au>Kastelein, John J.P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discriminative Ability of LDL-Cholesterol to Identify Patients With Familial Hypercholesterolemia: A Cross-Sectional Study in 26 406 Individuals Tested for Genetic FH</atitle><jtitle>Circulation. Cardiovascular genetics</jtitle><addtitle>Circ Cardiovasc Genet</addtitle><date>2012-06</date><risdate>2012</risdate><volume>5</volume><issue>3</issue><spage>354</spage><epage>359</epage><pages>354-359</pages><issn>1942-325X</issn><eissn>1942-3268</eissn><abstract>BACKGROUND—Screening for familial hypercholesterolemia (FH) within affected families is often based on cutoff values for low-density lipoprotein cholesterol (LDL-C). However, the diagnostic accuracy of LDL-C levels is influenced by the magnitude of the LDL-C overlap between FH patients and unaffected relatives. The purpose of the current study was to assess to what extent this overlap is influenced by the severity of specific FH mutations.
METHODS AND RESULTS—Individuals were eligible if they underwent family screening for FH between 2003 and 2010. The entire cohort was then compared with those who were investigated for the presence of the most severe mutations (class 1). The area under the receiver operating characteristics curve and the sensitivity of the 90th percentile of LDL-C were calculated for both cohorts. We included 26 406 individuals, of whom 9169 (35%) carried an FH-causing mutation. In the entire cohort at baseline, mean LDL-C was 4.63±1.44 mmol/L for FH carriers (n=5372) and 2.96±0.96 mmol/L for unaffected relatives (n=15 148); P<0.001. The corresponding operating characteristics curve (95% CI) was 86.6% (85.9%–87.2%), and the cutoff level of LDL-C above the 90th percentile showed a sensitivity of 68.5%. The operating characteristics curve and sensitivity significantly improved when the 5933 individuals tested for class 1 mutations were assessed separately; 96.2% (95.3%–97.1%) and 91.3%, respectively.
CONCLUSIONS—In summary, the overlap in terms of LDL-C levels between those with molecularly proven FH and unaffected relatives is to a large extent because of the high prevalence of modestly severe LDL-receptor mutations in the Netherlands.</abstract><cop>Hagerstown, MD</cop><pub>American Heart Association, Inc</pub><pmid>22553281</pmid><doi>10.1161/CIRCGENETICS.111.962456</doi><tpages>6</tpages></addata></record> |
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| ispartof | Circulation. Cardiovascular genetics, 2012-06, Vol.5 (3), p.354-359 |
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| source | MEDLINE; American Heart Association Journals |
| subjects | Adult Area Under Curve Biological and medical sciences Cholesterol, LDL - blood Cohort Studies Cross-Sectional Studies Discriminant Analysis Disorders of blood lipids. Hyperlipoproteinemia Female Genotype Humans Hyperlipoproteinemia Type II - epidemiology Hyperlipoproteinemia Type II - genetics Male Medical sciences Metabolic diseases Middle Aged Mutation Prevalence Receptors, LDL - genetics ROC Curve |
| title | Discriminative Ability of LDL-Cholesterol to Identify Patients With Familial Hypercholesterolemia: A Cross-Sectional Study in 26 406 Individuals Tested for Genetic FH |
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