A Comparison of Case‐Control and Family‐Based Association Methods: The Example of Sickle‐Cell and Malaria
Summary There has been much debate about the relative merits of population‐ and family‐based strategies for testing genetic association, yet there is little empirical data that directly compare the two approaches. Here we compare case‐control and transmission/disequilibrium test (TDT) study designs...
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| Veröffentlicht in: | Annals of human genetics 2005-09, Vol.69 (5), p.559-565 |
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| container_title | Annals of human genetics |
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| creator | Ackerman, H. Usen, S. Jallow, M. Sisay‐Joof, F. Pinder, M. Kwiatkowski, D. P. |
| description | Summary
There has been much debate about the relative merits of population‐ and family‐based strategies for testing genetic association, yet there is little empirical data that directly compare the two approaches. Here we compare case‐control and transmission/disequilibrium test (TDT) study designs using a well‐established genetic association, the protective effect of the sickle‐cell trait against severe malaria. We find that the two methods give similar estimates of the level of protection (case‐control odds ratio = 0.10, 95% confidence interval 0.03–0.23; family‐based estimate of the odds ratio = 0.11, 95% confidence interval 0.04–0.25) and similar statistical significance of the result (case‐control: χ2= 41.26, p= 10−10, TDT: χ2= 39.06, p= 10−10) when 315 TDT cases are compared to 583 controls. We propose a family plus population control study design, which allows both case‐control and TDT analysis of the cases. This combination is robust against the respective weaknesses of the case‐control and TDT study designs, namely population structure and segregation distortion. The combined study design is especially cost‐effective when cases are difficult to ascertain and, when the case‐control and TDT results agree, offers greater confidence in the result. |
| doi_str_mv | 10.1111/j.1529-8817.2005.00180.x |
| format | Article |
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There has been much debate about the relative merits of population‐ and family‐based strategies for testing genetic association, yet there is little empirical data that directly compare the two approaches. Here we compare case‐control and transmission/disequilibrium test (TDT) study designs using a well‐established genetic association, the protective effect of the sickle‐cell trait against severe malaria. We find that the two methods give similar estimates of the level of protection (case‐control odds ratio = 0.10, 95% confidence interval 0.03–0.23; family‐based estimate of the odds ratio = 0.11, 95% confidence interval 0.04–0.25) and similar statistical significance of the result (case‐control: χ2= 41.26, p= 10−10, TDT: χ2= 39.06, p= 10−10) when 315 TDT cases are compared to 583 controls. We propose a family plus population control study design, which allows both case‐control and TDT analysis of the cases. This combination is robust against the respective weaknesses of the case‐control and TDT study designs, namely population structure and segregation distortion. The combined study design is especially cost‐effective when cases are difficult to ascertain and, when the case‐control and TDT results agree, offers greater confidence in the result.</description><identifier>ISSN: 0003-4800</identifier><identifier>EISSN: 1469-1809</identifier><identifier>DOI: 10.1111/j.1529-8817.2005.00180.x</identifier><identifier>PMID: 16138914</identifier><language>eng</language><publisher>350 Main Street , Malden , MA 02148 , USA , and 9600 Garsington Road , Oxford OX4 2DQ , UK: Blackwell Science Ltd</publisher><subject>Alleles ; Animals ; case control ; Case-Control Studies ; Confidence Intervals ; Disease association ; Female ; Fetal Blood - metabolism ; Gene Frequency ; Genetics, Population ; Genotype ; Globins - metabolism ; hemoglobin ; Hemoglobins - metabolism ; Humans ; Linkage Disequilibrium ; malaria ; Malaria - genetics ; Male ; Models, Statistical ; Odds Ratio ; plasmodium falciparum ; Plasmodium falciparum - metabolism ; Research Design ; segregation distortion ; sickle cell ; Sickle Cell Trait - genetics ; TDT ; transmission/disequilibrium test ; β‐globin</subject><ispartof>Annals of human genetics, 2005-09, Vol.69 (5), p.559-565</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4320-f7f07624c4a9bfb47824899bedae7d4b00160fc0479c4a6563f70dbaa3f4bdb93</citedby><cites>FETCH-LOGICAL-c4320-f7f07624c4a9bfb47824899bedae7d4b00160fc0479c4a6563f70dbaa3f4bdb93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1529-8817.2005.00180.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1529-8817.2005.00180.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1416,1432,27923,27924,45573,45574,46408,46832</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16138914$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ackerman, H.</creatorcontrib><creatorcontrib>Usen, S.</creatorcontrib><creatorcontrib>Jallow, M.</creatorcontrib><creatorcontrib>Sisay‐Joof, F.</creatorcontrib><creatorcontrib>Pinder, M.</creatorcontrib><creatorcontrib>Kwiatkowski, D. P.</creatorcontrib><title>A Comparison of Case‐Control and Family‐Based Association Methods: The Example of Sickle‐Cell and Malaria</title><title>Annals of human genetics</title><addtitle>Ann Hum Genet</addtitle><description>Summary
There has been much debate about the relative merits of population‐ and family‐based strategies for testing genetic association, yet there is little empirical data that directly compare the two approaches. Here we compare case‐control and transmission/disequilibrium test (TDT) study designs using a well‐established genetic association, the protective effect of the sickle‐cell trait against severe malaria. We find that the two methods give similar estimates of the level of protection (case‐control odds ratio = 0.10, 95% confidence interval 0.03–0.23; family‐based estimate of the odds ratio = 0.11, 95% confidence interval 0.04–0.25) and similar statistical significance of the result (case‐control: χ2= 41.26, p= 10−10, TDT: χ2= 39.06, p= 10−10) when 315 TDT cases are compared to 583 controls. We propose a family plus population control study design, which allows both case‐control and TDT analysis of the cases. This combination is robust against the respective weaknesses of the case‐control and TDT study designs, namely population structure and segregation distortion. The combined study design is especially cost‐effective when cases are difficult to ascertain and, when the case‐control and TDT results agree, offers greater confidence in the result.</description><subject>Alleles</subject><subject>Animals</subject><subject>case control</subject><subject>Case-Control Studies</subject><subject>Confidence Intervals</subject><subject>Disease association</subject><subject>Female</subject><subject>Fetal Blood - metabolism</subject><subject>Gene Frequency</subject><subject>Genetics, Population</subject><subject>Genotype</subject><subject>Globins - metabolism</subject><subject>hemoglobin</subject><subject>Hemoglobins - metabolism</subject><subject>Humans</subject><subject>Linkage Disequilibrium</subject><subject>malaria</subject><subject>Malaria - genetics</subject><subject>Male</subject><subject>Models, Statistical</subject><subject>Odds Ratio</subject><subject>plasmodium falciparum</subject><subject>Plasmodium falciparum - metabolism</subject><subject>Research Design</subject><subject>segregation distortion</subject><subject>sickle cell</subject><subject>Sickle Cell Trait - genetics</subject><subject>TDT</subject><subject>transmission/disequilibrium test</subject><subject>β‐globin</subject><issn>0003-4800</issn><issn>1469-1809</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkLtOwzAUhi0EoqXwCsgTW8Jx4iQ2YilRL0itGCiz5SS2mpLEJW5Fu_EIPCNPgtNWYsWLb9_5j_0hhAn4xI37lU-igHuMkcQPACIfgDDwd2eoT2jMPbfh56gPAKFHGUAPXVm7clDAaHiJeiQmIeOE9pEZ4tTUa9mW1jTYaJxKq36-vlPTbFpTYdkUeCzrstq7wyd3V-ChtSYv5aZ0BXO1WZrCPuDFUuHRTtbrSnUpr2X-Xh1yVHUMmcvKNZHX6ELLyqqb0zxAb-PRIp16s5fJczqceTkNA_B0oiGJA5pTyTOd0YQFlHGeqUKqpKCZ-0oMOgeacIfEURzqBIpMylDTrMh4OEB3x9x1az62ym5EXdrcPUY2ymytiFkUEUaZA9kRzFtjbau0WLdlLdu9ICA62WIlOtmiky062eIgW-xc6e2pxzarVfFXeLLrgMcj8FlWav_vYDGcTtwi_AWrlpAq</recordid><startdate>200509</startdate><enddate>200509</enddate><creator>Ackerman, H.</creator><creator>Usen, S.</creator><creator>Jallow, M.</creator><creator>Sisay‐Joof, F.</creator><creator>Pinder, M.</creator><creator>Kwiatkowski, D. 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P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4320-f7f07624c4a9bfb47824899bedae7d4b00160fc0479c4a6563f70dbaa3f4bdb93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Alleles</topic><topic>Animals</topic><topic>case control</topic><topic>Case-Control Studies</topic><topic>Confidence Intervals</topic><topic>Disease association</topic><topic>Female</topic><topic>Fetal Blood - metabolism</topic><topic>Gene Frequency</topic><topic>Genetics, Population</topic><topic>Genotype</topic><topic>Globins - metabolism</topic><topic>hemoglobin</topic><topic>Hemoglobins - metabolism</topic><topic>Humans</topic><topic>Linkage Disequilibrium</topic><topic>malaria</topic><topic>Malaria - genetics</topic><topic>Male</topic><topic>Models, Statistical</topic><topic>Odds Ratio</topic><topic>plasmodium falciparum</topic><topic>Plasmodium falciparum - metabolism</topic><topic>Research Design</topic><topic>segregation distortion</topic><topic>sickle cell</topic><topic>Sickle Cell Trait - genetics</topic><topic>TDT</topic><topic>transmission/disequilibrium test</topic><topic>β‐globin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ackerman, H.</creatorcontrib><creatorcontrib>Usen, S.</creatorcontrib><creatorcontrib>Jallow, M.</creatorcontrib><creatorcontrib>Sisay‐Joof, F.</creatorcontrib><creatorcontrib>Pinder, M.</creatorcontrib><creatorcontrib>Kwiatkowski, D. 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There has been much debate about the relative merits of population‐ and family‐based strategies for testing genetic association, yet there is little empirical data that directly compare the two approaches. Here we compare case‐control and transmission/disequilibrium test (TDT) study designs using a well‐established genetic association, the protective effect of the sickle‐cell trait against severe malaria. We find that the two methods give similar estimates of the level of protection (case‐control odds ratio = 0.10, 95% confidence interval 0.03–0.23; family‐based estimate of the odds ratio = 0.11, 95% confidence interval 0.04–0.25) and similar statistical significance of the result (case‐control: χ2= 41.26, p= 10−10, TDT: χ2= 39.06, p= 10−10) when 315 TDT cases are compared to 583 controls. We propose a family plus population control study design, which allows both case‐control and TDT analysis of the cases. This combination is robust against the respective weaknesses of the case‐control and TDT study designs, namely population structure and segregation distortion. The combined study design is especially cost‐effective when cases are difficult to ascertain and, when the case‐control and TDT results agree, offers greater confidence in the result.</abstract><cop>350 Main Street , Malden , MA 02148 , USA , and 9600 Garsington Road , Oxford OX4 2DQ , UK</cop><pub>Blackwell Science Ltd</pub><pmid>16138914</pmid><doi>10.1111/j.1529-8817.2005.00180.x</doi><tpages>7</tpages></addata></record> |
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| subjects | Alleles Animals case control Case-Control Studies Confidence Intervals Disease association Female Fetal Blood - metabolism Gene Frequency Genetics, Population Genotype Globins - metabolism hemoglobin Hemoglobins - metabolism Humans Linkage Disequilibrium malaria Malaria - genetics Male Models, Statistical Odds Ratio plasmodium falciparum Plasmodium falciparum - metabolism Research Design segregation distortion sickle cell Sickle Cell Trait - genetics TDT transmission/disequilibrium test β‐globin |
| title | A Comparison of Case‐Control and Family‐Based Association Methods: The Example of Sickle‐Cell and Malaria |
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