Oyomoare L Osazuwa-Peters1, Karen Schwander2, R J Waken2, Lisa de Las Fuentes2,3, Tuomas O Kilpeläinen4,5, Ruth J F Loos6,7, Susan B Racette8,9, Yun Ju Sung2, D C Rao2. 1. Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA, oosazuwa-peters@wustl.edu. 2. Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA. 3. Cardiovascular Division, Department of Medicine, Washington University, St. Louis, Missouri, USA. 4. Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 5. Department of Environmental Medicine and Public Health, The Icahn School of Medicine at Mount Sinai, New York, New York, USA. 6. Icahn School of Medicine at Mount Sinai, The Charles Bronfman Institute for Personalized Medicine, New York, New York, USA. 7. Icahn School of Medicine at Mount Sinai, The Mindich Child Health and Development Institute, New York, New York, USA. 8. Program in Physical Therapy, Washington University School of Medicine, St. Louis, Missouri, USA. 9. Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
Abstract
BACKGROUND: Dichotomization using the lower quartile as cutoff is commonly used for harmonizing heterogeneous physical activity (PA) measures across studies. However, this may create misclassification and hinder discovery of new loci. OBJECTIVES: This study aimed to evaluate the performance of selecting individuals from the extremes of the exposure (SIEE) as an alternative approach to reduce such misclassification. METHOD: For systolic and diastolic blood pressure in the Framingham Heart Study, we performed a genome-wide association study with gene-PA interaction analysis using three PA variables derived by SIEE and two other dichotomization approaches. We compared number of loci detected and overlap with loci found using a quantitative PA variable. In addition, we performed simulation studies to assess bias, false discovery rates (FDR), and power under synergistic/antagonistic genetic effects in exposure groups and in the presence/absence of measurement error. RESULTS: In the empirical analysis, SIEE's performance was neither the best nor the worst. In most simulation scenarios, SIEE was consistently outperformed in terms of FDR and power. Particularly, in a scenario characterized by antagonistic effects and measurement error, SIEE had the least bias and highest power. CONCLUSION: SIEE's promise appears limited to detecting loci with antagonistic effects. Further studies are needed to evaluate SIEE's full advantage.
BACKGROUND: Dichotomization using the lower quartile as cutoff is commonly used for harmonizing heterogeneous physical activity (PA) measures across studies. However, this may create misclassification and hinder discovery of new loci. OBJECTIVES: This study aimed to evaluate the performance of selecting individuals from the extremes of the exposure (SIEE) as an alternative approach to reduce such misclassification. METHOD: For systolic and diastolic blood pressure in the Framingham Heart Study, we performed a genome-wide association study with gene-PA interaction analysis using three PA variables derived by SIEE and two other dichotomization approaches. We compared number of loci detected and overlap with loci found using a quantitative PA variable. In addition, we performed simulation studies to assess bias, false discovery rates (FDR), and power under synergistic/antagonistic genetic effects in exposure groups and in the presence/absence of measurement error. RESULTS: In the empirical analysis, SIEE's performance was neither the best nor the worst. In most simulation scenarios, SIEE was consistently outperformed in terms of FDR and power. Particularly, in a scenario characterized by antagonistic effects and measurement error, SIEE had the least bias and highest power. CONCLUSION: SIEE's promise appears limited to detecting loci with antagonistic effects. Further studies are needed to evaluate SIEE's full advantage.
Authors: May E Montasser; Donfeng Gu; Jing Chen; Lawrence C Shimmin; Charles Gu; Tanika N Kelly; Cashell E Jaquish; Treva Rice; Dabeeru C Rao; Jie Cao; Jichun Chen; De-Pei Liu; Paul K Whelton; Jiang He; James E Hixson Journal: Am J Hypertens Date: 2011-06-09 Impact factor: 2.689
Authors: Yun J Sung; Thomas W Winkler; Lisa de Las Fuentes; Amy R Bentley; Michael R Brown; Aldi T Kraja; Karen Schwander; Ioanna Ntalla; Xiuqing Guo; Nora Franceschini; Yingchang Lu; Ching-Yu Cheng; Xueling Sim; Dina Vojinovic; Jonathan Marten; Solomon K Musani; Changwei Li; Mary F Feitosa; Tuomas O Kilpeläinen; Melissa A Richard; Raymond Noordam; Stella Aslibekyan; Hugues Aschard; Traci M Bartz; Rajkumar Dorajoo; Yongmei Liu; Alisa K Manning; Tuomo Rankinen; Albert Vernon Smith; Salman M Tajuddin; Bamidele O Tayo; Helen R Warren; Wei Zhao; Yanhua Zhou; Nana Matoba; Tamar Sofer; Maris Alver; Marzyeh Amini; Mathilde Boissel; Jin Fang Chai; Xu Chen; Jasmin Divers; Ilaria Gandin; Chuan Gao; Franco Giulianini; Anuj Goel; Sarah E Harris; Fernando Pires Hartwig; Andrea R V R Horimoto; Fang-Chi Hsu; Anne U Jackson; Mika Kähönen; Anuradhani Kasturiratne; Brigitte Kühnel; Karin Leander; Wen-Jane Lee; Keng-Hung Lin; Jian 'an Luan; Colin A McKenzie; He Meian; Christopher P Nelson; Rainer Rauramaa; Nicole Schupf; Robert A Scott; Wayne H H Sheu; Alena Stančáková; Fumihiko Takeuchi; Peter J van der Most; Tibor V Varga; Heming Wang; Yajuan Wang; Erin B Ware; Stefan Weiss; Wanqing Wen; Lisa R Yanek; Weihua Zhang; Jing Hua Zhao; Saima Afaq; Tamuno Alfred; Najaf Amin; Dan Arking; Tin Aung; R Graham Barr; Lawrence F Bielak; Eric Boerwinkle; Erwin P Bottinger; Peter S Braund; Jennifer A Brody; Ulrich Broeckel; Claudia P Cabrera; Brian Cade; Yu Caizheng; Archie Campbell; Mickaël Canouil; Aravinda Chakravarti; Ganesh Chauhan; Kaare Christensen; Massimiliano Cocca; Francis S Collins; John M Connell; Renée de Mutsert; H Janaka de Silva; Stephanie Debette; Marcus Dörr; Qing Duan; Charles B Eaton; Georg Ehret; Evangelos Evangelou; Jessica D Faul; Virginia A Fisher; Nita G Forouhi; Oscar H Franco; Yechiel Friedlander; He Gao; Bruna Gigante; Misa Graff; C Charles Gu; Dongfeng Gu; Preeti Gupta; Saskia P Hagenaars; Tamara B Harris; Jiang He; Sami Heikkinen; Chew-Kiat Heng; Makoto Hirata; Albert Hofman; Barbara V Howard; Steven Hunt; Marguerite R Irvin; Yucheng Jia; Roby Joehanes; Anne E Justice; Tomohiro Katsuya; Joel Kaufman; Nicola D Kerrison; Chiea Chuen Khor; Woon-Puay Koh; Heikki A Koistinen; Pirjo Komulainen; Charles Kooperberg; Jose E Krieger; Michiaki Kubo; Johanna Kuusisto; Carl D Langefeld; Claudia Langenberg; Lenore J Launer; Benjamin Lehne; Cora E Lewis; Yize Li; Sing Hui Lim; Shiow Lin; Ching-Ti Liu; Jianjun Liu; Jingmin Liu; Kiang Liu; Yeheng Liu; Marie Loh; Kurt K Lohman; Jirong Long; Tin Louie; Reedik Mägi; Anubha Mahajan; Thomas Meitinger; Andres Metspalu; Lili Milani; Yukihide Momozawa; Andrew P Morris; Thomas H Mosley; Peter Munson; Alison D Murray; Mike A Nalls; Ubaydah Nasri; Jill M Norris; Kari North; Adesola Ogunniyi; Sandosh Padmanabhan; Walter R Palmas; Nicholette D Palmer; James S Pankow; Nancy L Pedersen; Annette Peters; Patricia A Peyser; Ozren Polasek; Olli T Raitakari; Frida Renström; Treva K Rice; Paul M Ridker; Antonietta Robino; Jennifer G Robinson; Lynda M Rose; Igor Rudan; Charumathi Sabanayagam; Babatunde L Salako; Kevin Sandow; Carsten O Schmidt; Pamela J Schreiner; William R Scott; Sudha Seshadri; Peter Sever; Colleen M Sitlani; Jennifer A Smith; Harold Snieder; John M Starr; Konstantin Strauch; Hua Tang; Kent D Taylor; Yik Ying Teo; Yih Chung Tham; André G Uitterlinden; Melanie Waldenberger; Lihua Wang; Ya X Wang; Wen Bin Wei; Christine Williams; Gregory Wilson; Mary K Wojczynski; Jie Yao; Jian-Min Yuan; Alan B Zonderman; Diane M Becker; Michael Boehnke; Donald W Bowden; John C Chambers; Yii-Der Ida Chen; Ulf de Faire; Ian J Deary; Tõnu Esko; Martin Farrall; Terrence Forrester; Paul W Franks; Barry I Freedman; Philippe Froguel; Paolo Gasparini; Christian Gieger; Bernardo Lessa Horta; Yi-Jen Hung; Jost B Jonas; Norihiro Kato; Jaspal S Kooner; Markku Laakso; Terho Lehtimäki; Kae-Woei Liang; Patrik K E Magnusson; Anne B Newman; Albertine J Oldehinkel; Alexandre C Pereira; Susan Redline; Rainer Rettig; Nilesh J Samani; James Scott; Xiao-Ou Shu; Pim van der Harst; Lynne E Wagenknecht; Nicholas J Wareham; Hugh Watkins; David R Weir; Ananda R Wickremasinghe; Tangchun Wu; Wei Zheng; Yoichiro Kamatani; Cathy C Laurie; Claude Bouchard; Richard S Cooper; Michele K Evans; Vilmundur Gudnason; Sharon L R Kardia; Stephen B Kritchevsky; Daniel Levy; Jeff R O'Connell; Bruce M Psaty; Rob M van Dam; Mario Sims; Donna K Arnett; Dennis O Mook-Kanamori; Tanika N Kelly; Ervin R Fox; Caroline Hayward; Myriam Fornage; Charles N Rotimi; Michael A Province; Cornelia M van Duijn; E Shyong Tai; Tien Yin Wong; Ruth J F Loos; Alex P Reiner; Jerome I Rotter; Xiaofeng Zhu; Laura J Bierut; W James Gauderman; Mark J Caulfield; Paul Elliott; Kenneth Rice; Patricia B Munroe; Alanna C Morrison; L Adrienne Cupples; Dabeeru C Rao; Daniel I Chasman Journal: Am J Hum Genet Date: 2018-02-15 Impact factor: 11.025
Authors: Tuomas O Kilpeläinen; Lu Qi; Soren Brage; Stephen J Sharp; Emily Sonestedt; Ellen Demerath; Tariq Ahmad; Samia Mora; Marika Kaakinen; Camilla Helene Sandholt; Christina Holzapfel; Christine S Autenrieth; Elina Hyppönen; Stéphane Cauchi; Meian He; Zoltan Kutalik; Meena Kumari; Alena Stančáková; Karina Meidtner; Beverley Balkau; Jonathan T Tan; Massimo Mangino; Nicholas J Timpson; Yiqing Song; M Carola Zillikens; Kathleen A Jablonski; Melissa E Garcia; Stefan Johansson; Jennifer L Bragg-Gresham; Ying Wu; Jana V van Vliet-Ostaptchouk; N Charlotte Onland-Moret; Esther Zimmermann; Natalia V Rivera; Toshiko Tanaka; Heather M Stringham; Günther Silbernagel; Stavroula Kanoni; Mary F Feitosa; Soren Snitker; Jonatan R Ruiz; Jeffery Metter; Maria Teresa Martinez Larrad; Mustafa Atalay; Maarit Hakanen; Najaf Amin; Christine Cavalcanti-Proença; Anders Grøntved; Göran Hallmans; John-Olov Jansson; Johanna Kuusisto; Mika Kähönen; Pamela L Lutsey; John J Nolan; Luigi Palla; Oluf Pedersen; Louis Pérusse; Frida Renström; Robert A Scott; Dmitry Shungin; Ulla Sovio; Tuija H Tammelin; Tapani Rönnemaa; Timo A Lakka; Matti Uusitupa; Manuel Serrano Rios; Luigi Ferrucci; Claude Bouchard; Aline Meirhaeghe; Mao Fu; Mark Walker; Ingrid B Borecki; George V Dedoussis; Andreas Fritsche; Claes Ohlsson; Michael Boehnke; Stefania Bandinelli; Cornelia M van Duijn; Shah Ebrahim; Debbie A Lawlor; Vilmundur Gudnason; Tamara B Harris; Thorkild I A Sørensen; Karen L Mohlke; Albert Hofman; André G Uitterlinden; Jaakko Tuomilehto; Terho Lehtimäki; Olli Raitakari; Bo Isomaa; Pål R Njølstad; Jose C Florez; Simin Liu; Andy Ness; Timothy D Spector; E Shyong Tai; Philippe Froguel; Heiner Boeing; Markku Laakso; Michael Marmot; Sven Bergmann; Chris Power; Kay-Tee Khaw; Daniel Chasman; Paul Ridker; Torben Hansen; Keri L Monda; Thomas Illig; Marjo-Riitta Järvelin; Nicholas J Wareham; Frank B Hu; Leif C Groop; Marju Orho-Melander; Ulf Ekelund; Paul W Franks; Ruth J F Loos Journal: PLoS Med Date: 2011-11-01 Impact factor: 11.069
Authors: Shafqat Ahmad; Gull Rukh; Tibor V Varga; Ashfaq Ali; Azra Kurbasic; Dmitry Shungin; Ulrika Ericson; Robert W Koivula; Audrey Y Chu; Lynda M Rose; Andrea Ganna; Qibin Qi; Alena Stančáková; Camilla H Sandholt; Cathy E Elks; Gary Curhan; Majken K Jensen; Rulla M Tamimi; Kristine H Allin; Torben Jørgensen; Soren Brage; Claudia Langenberg; Mette Aadahl; Niels Grarup; Allan Linneberg; Guillaume Paré; Patrik K E Magnusson; Nancy L Pedersen; Michael Boehnke; Anders Hamsten; Karen L Mohlke; Louis T Pasquale; Oluf Pedersen; Robert A Scott; Paul M Ridker; Erik Ingelsson; Markku Laakso; Torben Hansen; Lu Qi; Nicholas J Wareham; Daniel I Chasman; Göran Hallmans; Frank B Hu; Frida Renström; Marju Orho-Melander; Paul W Franks Journal: PLoS Genet Date: 2013-07-25 Impact factor: 5.917