{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T03:22:00Z","timestamp":1722914520537},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"13","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Motivation: The question of how to best use information from known associated variants when conducting disease association studies has yet to be answered. Some studies compute a marginal P-value for each Several Nucleotide Polymorphisms independently, ignoring previously discovered variants. Other studies include known variants as covariates in logistic regression, but a weakness of this standard conditioning strategy is that it does not account for disease prevalence and non-random ascertainment, which can induce a correlation structure between candidate variants and known associated variants even if the variants lie on different chromosomes. Here, we propose a new conditioning approach, which is based in part on the classical technique of liability threshold modeling. Roughly, this method estimates model parameters for each known variant while accounting for the published disease prevalence from the epidemiological literature.<\/jats:p><jats:p>Results: We show via simulation and application to empirical datasets that our approach outperforms both the no conditioning strategy and the standard conditioning strategy, with a properly controlled false-positive rate. Furthermore, in multiple data sets involving diseases of low prevalence, standard conditioning produces a severe drop in test statistics whereas our approach generally performs as well or better than no conditioning. Our approach may substantially improve disease gene discovery for diseases with many known risk variants.<\/jats:p><jats:p>Availability: LTSOFT software is available online http:\/\/www.hsph.harvard.edu\/faculty\/alkes-price\/software\/<\/jats:p><jats:p>Contact: \u00a0nzaitlen@hsph.harvard.edu; aprice@hsph.harvard.edu<\/jats:p><jats:p>Supplementary information: Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/bts259","type":"journal-article","created":{"date-parts":[[2012,5,4]],"date-time":"2012-05-04T00:59:48Z","timestamp":1336093188000},"page":"1729-1737","source":"Crossref","is-referenced-by-count":33,"title":["Analysis of case\u2013control association studies with known risk variants"],"prefix":"10.1093","volume":"28","author":[{"given":"Noah","family":"Zaitlen","sequence":"first","affiliation":[{"name":"1 Department of Epidemiology, 2Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, 3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, 4Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, 5Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, 6Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, 7Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, 8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, 9Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, 10Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and 11Department of Genetic Medicine and Development, Univer"},{"name":"1 Department of Epidemiology, 2Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, 3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, 4Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, 5Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, 6Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, 7Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, 8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, 9Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, 10Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and 11Department of Genetic Medicine and Development, Univer"},{"name":"1 Department of Epidemiology, 2Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, 3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, 4Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, 5Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, 6Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, 7Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, 8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, 9Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, 10Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and 11Department of Genetic Medicine and Development, Univer"},{"name":"1 Department of Epidemiology, 2Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, 3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, 4Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, 5Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, 6Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, 7Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, 8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, 9Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, 10Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and 11Department of Genetic Medicine and Development, Univer"}]},{"given":"Bogdan","family":"Pa\u015faniuc","sequence":"additional","affiliation":[{"name":"1 Department of Epidemiology, 2Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, 3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, 4Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, 5Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, 6Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, 7Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, 8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, 9Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, 10Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and 11Department of Genetic Medicine and Development, Univer"},{"name":"1 Department of Epidemiology, 2Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, 3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, 4Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, 5Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, 6Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, 7Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, 8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, 9Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, 10Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and 11Department of Genetic Medicine and Development, Univer"},{"name":"1 Department of Epidemiology, 2Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, 3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, 4Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, 5Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, 6Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, 7Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, 8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, 9Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, 10Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and 11Department of Genetic Medicine and Development, Univer"},{"name":"1 Department of Epidemiology, 2Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, 3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, 4Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, 5Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, 6Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, 7Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, 8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, 9Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, 10Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and 11Department of Genetic Medicine and Development, Univer"}]},{"given":"Nick","family":"Patterson","sequence":"additional","affiliation":[{"name":"1 Department of Epidemiology, 2Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, 3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, 4Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, 5Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, 6Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, 7Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, 8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, 9Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, 10Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and 11Department of Genetic Medicine and Development, Univer"}]},{"given":"Samuela","family":"Pollack","sequence":"additional","affiliation":[{"name":"1 Department of Epidemiology, 2Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, 3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, 4Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, 5Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, 6Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, 7Department of Clinical 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Hospital, 6Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, 7Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, 8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, 9Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, 10Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and 11Department of Genetic Medicine and Development, Univer"},{"name":"1 Department of Epidemiology, 2Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, 3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, 4Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, 5Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, 6Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, 7Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, 8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, 9Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, 10Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and 11Department of Genetic Medicine and Development, Univer"},{"name":"1 Department of Epidemiology, 2Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, 3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, 4Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, 5Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, 6Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, 7Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, 8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, 9Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, 10Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and 11Department of Genetic Medicine and Development, Univer"}]},{"given":"Leif","family":"Groop","sequence":"additional","affiliation":[{"name":"1 Department of Epidemiology, 2Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, 3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, 4Program in Molecular and Genetic 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3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, 4Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, 5Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, 6Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, 7Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, 8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, 9Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, 10Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and 11Department of Genetic Medicine and Development, Univer"},{"name":"1 Department of Epidemiology, 2Department of Biostatistics, Harvard School 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2Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, 3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, 4Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, 5Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, 6Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, 7Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, 8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, 9Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, 10Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and 11Department of Genetic Medicine and Development, Univer"}]},{"given":"Brian E.","family":"Henderson","sequence":"additional","affiliation":[{"name":"1 Department of Epidemiology, 2Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, 3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, 4Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, 5Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, 6Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, 7Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, 8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, 9Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, 10Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and 11Department of Genetic Medicine and Development, Univer"}]},{"given":"Laurence N.","family":"Kolonel","sequence":"additional","affiliation":[{"name":"1 Department of Epidemiology, 2Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, 3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, 4Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, 5Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, 6Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, 7Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, 8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer 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8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, 9Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, 10Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 and 11Department of Genetic Medicine and Development, Univer"}]},{"given":"Kevin","family":"Waters","sequence":"additional","affiliation":[{"name":"1 Department of Epidemiology, 2Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, 3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, 4Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, 5Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, 6Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, 7Department of Clinical 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Univer"}]},{"given":"Peter","family":"Kraft","sequence":"additional","affiliation":[{"name":"1 Department of Epidemiology, 2Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, 3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, 4Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA, 5Center for Human Genetic Research, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, 6Departments of Genetics and of Medicine, Harvard Medical School, Boston, MA 02115, 7Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Scania University Hospital Lund University, Malm, Sweden SE-205, 8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, 9Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, 10Department of 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