Jing Dong1, Matthew F Buas2, Puya Gharahkhani3, Bradley J Kendall4, Lynn Onstad5, Shanshan Zhao6, Lesley A Anderson7, Anna H Wu8, Weimin Ye9, Nigel C Bird10, Leslie Bernstein11, Wong-Ho Chow12, Marilie D Gammon13, Geoffrey Liu14, Carlos Caldas15, Paul D Pharoah16, Harvey A Risch17, Prasad G Iyer18, Brian J Reid5, Laura J Hardie19, Jesper Lagergren20, Nicholas J Shaheen21, Douglas A Corley22, Rebecca C Fitzgerald23, David C Whiteman24, Thomas L Vaughan5, Aaron P Thrift25. 1. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. 2. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York. 3. Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. 4. Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; School of Medicine, University of Queensland, Brisbane, Queensland, Australia; Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia. 5. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. 6. Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina. 7. Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland. 8. Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California. 9. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 10. Department of Oncology, Medical School, University of Sheffield, Sheffield, United Kingdom. 11. Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California. 12. Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas. 13. Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina. 14. Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Ontario, Canada. 15. Cancer Research UK, Cambridge Institute, Cambridge, United Kingdom. 16. Department of Oncology, University of Cambridge, Cambridge, United Kingdom; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. 17. Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut. 18. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. 19. Division of Epidemiology, Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds, United Kingdom. 20. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; School of Cancer Sciences, King's College London, London, United Kingdom. 21. Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina. 22. Division of Research, Kaiser Permanente Northern California, Oakland, California; San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, California. 23. Medical Research Council Cancer Unit, Hutchison-Medical Research Council Research Centre, University of Cambridge, Cambridge, United Kingdom. 24. Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. 25. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas. Electronic address: aaron.thrift@bcm.edu.
Abstract
BACKGROUND & AIMS: We developed comprehensive models to determine risk of Barrett's esophagus (BE) or esophageal adenocarcinoma (EAC) based on genetic and non-genetic factors. METHODS: We used pooled data from 3288 patients with BE, 2511 patients with EAC, and 2177 individuals without either (controls) from participants in the international Barrett's and EAC consortium as well as the United Kingdom's BE gene study and stomach and esophageal cancer study. We collected data on 23 genetic variants associated with risk for BE or EAC, and constructed a polygenic risk score (PRS) for cases and controls by summing the risk allele counts for the variants weighted by their natural log-transformed effect estimates (odds ratios) extracted from genome-wide association studies. We also collected data on demographic and lifestyle factors (age, sex, smoking, body mass index, use of nonsteroidal anti-inflammatory drugs) and symptoms of gastroesophageal reflux disease (GERD). Risk models with various combinations of non-genetic factors and the PRS were compared for their accuracy in identifying patients with BE or EAC using the area under the receiver operating characteristic curve (AUC) analysis. RESULTS: Individuals in the highest quartile of risk, based on genetic factors (PRS), had a 2-fold higher risk of BE (odds ratio, 2.22; 95% confidence interval, 1.89-2.60) or EAC (odds ratio, 2.46; 95% confidence interval, 2.07-2.92) than individual in the lowest quartile of risk based on PRS. Risk models developed based on only demographic or lifestyle factors or GERD symptoms identified patients with BE or EAC with AUC values ranging from 0.637 to 0.667. Combining data on demographic or lifestyle factors with data on GERD symptoms identified patients with BE with an AUC of 0.793 and patients with EAC with an AUC of 0.745. Including PRSs with these data only minimally increased the AUC values for BE (to 0.799) and EAC (to 0.754). Including the PRSs in the model developed based on non-genetic factors resulted in a net reclassification improvement for BE of 3.0% and for EAC of 5.6%. CONCLUSIONS: We used data from 3 large databases of patients from studies of BE or EAC to develop a risk prediction model based on genetic, clinical, and demographic/lifestyle factors. We identified a PRS that increases discrimination and net reclassification of individuals with vs without BE and EAC. However, the absolute magnitude of improvement is not sufficient to justify its clinical use.
BACKGROUND & AIMS: We developed comprehensive models to determine risk of Barrett's esophagus (BE) or esophageal adenocarcinoma (EAC) based on genetic and non-genetic factors. METHODS: We used pooled data from 3288 patients with BE, 2511 patients with EAC, and 2177 individuals without either (controls) from participants in the international Barrett's and EAC consortium as well as the United Kingdom's BE gene study and stomach and esophageal cancer study. We collected data on 23 genetic variants associated with risk for BE or EAC, and constructed a polygenic risk score (PRS) for cases and controls by summing the risk allele counts for the variants weighted by their natural log-transformed effect estimates (odds ratios) extracted from genome-wide association studies. We also collected data on demographic and lifestyle factors (age, sex, smoking, body mass index, use of nonsteroidal anti-inflammatory drugs) and symptoms of gastroesophageal reflux disease (GERD). Risk models with various combinations of non-genetic factors and the PRS were compared for their accuracy in identifying patients with BE or EAC using the area under the receiver operating characteristic curve (AUC) analysis. RESULTS: Individuals in the highest quartile of risk, based on genetic factors (PRS), had a 2-fold higher risk of BE (odds ratio, 2.22; 95% confidence interval, 1.89-2.60) or EAC (odds ratio, 2.46; 95% confidence interval, 2.07-2.92) than individual in the lowest quartile of risk based on PRS. Risk models developed based on only demographic or lifestyle factors or GERD symptoms identified patients with BE or EAC with AUC values ranging from 0.637 to 0.667. Combining data on demographic or lifestyle factors with data on GERD symptoms identified patients with BE with an AUC of 0.793 and patients with EAC with an AUC of 0.745. Including PRSs with these data only minimally increased the AUC values for BE (to 0.799) and EAC (to 0.754). Including the PRSs in the model developed based on non-genetic factors resulted in a net reclassification improvement for BE of 3.0% and for EAC of 5.6%. CONCLUSIONS: We used data from 3 large databases of patients from studies of BE or EAC to develop a risk prediction model based on genetic, clinical, and demographic/lifestyle factors. We identified a PRS that increases discrimination and net reclassification of individuals with vs without BE and EAC. However, the absolute magnitude of improvement is not sufficient to justify its clinical use.
Authors: Maarten J G Leening; Moniek M Vedder; Jacqueline C M Witteman; Michael J Pencina; Ewout W Steyerberg Journal: Ann Intern Med Date: 2014-01-21 Impact factor: 25.391
Authors: Cathy C Laurie; Kimberly F Doheny; Daniel B Mirel; Elizabeth W Pugh; Laura J Bierut; Tushar Bhangale; Frederick Boehm; Neil E Caporaso; Marilyn C Cornelis; Howard J Edenberg; Stacy B Gabriel; Emily L Harris; Frank B Hu; Kevin B Jacobs; Peter Kraft; Maria Teresa Landi; Thomas Lumley; Teri A Manolio; Caitlin McHugh; Ian Painter; Justin Paschall; John P Rice; Kenneth M Rice; Xiuwen Zheng; Bruce S Weir Journal: Genet Epidemiol Date: 2010-09 Impact factor: 2.135
Authors: Merlise A Clyde; Rachel Palmieri Weber; Edwin S Iversen; Elizabeth M Poole; Jennifer A Doherty; Marc T Goodman; Roberta B Ness; Harvey A Risch; Mary Anne Rossing; Kathryn L Terry; Nicolas Wentzensen; Alice S Whittemore; Hoda Anton-Culver; Elisa V Bandera; Andrew Berchuck; Michael E Carney; Daniel W Cramer; Julie M Cunningham; Kara L Cushing-Haugen; Robert P Edwards; Brooke L Fridley; Ellen L Goode; Galina Lurie; Valerie McGuire; Francesmary Modugno; Kirsten B Moysich; Sara H Olson; Celeste Leigh Pearce; Malcolm C Pike; Joseph H Rothstein; Thomas A Sellers; Weiva Sieh; Daniel Stram; Pamela J Thompson; Robert A Vierkant; Kristine G Wicklund; Anna H Wu; Argyrios Ziogas; Shelley S Tworoger; Joellen M Schildkraut Journal: Am J Epidemiol Date: 2016-10-03 Impact factor: 4.897
Authors: Aaron P Thrift; Jennifer R Kramer; Zeeshan Qureshi; Peter A Richardson; Hashem B El-Serag Journal: Am J Gastroenterol Date: 2013-04-09 Impact factor: 10.864
Authors: David M Levine; Weronica E Ek; Rui Zhang; Xinxue Liu; Lynn Onstad; Cassandra Sather; Pierre Lao-Sirieix; Marilie D Gammon; Douglas A Corley; Nicholas J Shaheen; Nigel C Bird; Laura J Hardie; Liam J Murray; Brian J Reid; Wong-Ho Chow; Harvey A Risch; Olof Nyrén; Weimin Ye; Geoffrey Liu; Yvonne Romero; Leslie Bernstein; Anna H Wu; Alan G Casson; Stephen J Chanock; Patricia Harrington; Isabel Caldas; Irene Debiram-Beecham; Carlos Caldas; Nicholas K Hayward; Paul D Pharoah; Rebecca C Fitzgerald; Stuart Macgregor; David C Whiteman; Thomas L Vaughan Journal: Nat Genet Date: 2013-10-13 Impact factor: 38.330
Authors: Puya Gharahkhani; Rebecca C Fitzgerald; Thomas L Vaughan; Claire Palles; Ines Gockel; Ian Tomlinson; Matthew F Buas; Andrea May; Christian Gerges; Mario Anders; Jessica Becker; Nicole Kreuser; Tania Noder; Marino Venerito; Lothar Veits; Thomas Schmidt; Hendrik Manner; Claudia Schmidt; Timo Hess; Anne C Böhmer; Jakob R Izbicki; Arnulf H Hölscher; Hauke Lang; Dietmar Lorenz; Brigitte Schumacher; Andreas Hackelsberger; Rupert Mayershofer; Oliver Pech; Yogesh Vashist; Katja Ott; Michael Vieth; Josef Weismüller; Markus M Nöthen; Stephen Attwood; Hugh Barr; Laura Chegwidden; John de Caestecker; Rebecca Harrison; Sharon B Love; David MacDonald; Paul Moayyedi; Hans Prenen; R G Peter Watson; Prasad G Iyer; Lesley A Anderson; Leslie Bernstein; Wong-Ho Chow; Laura J Hardie; Jesper Lagergren; Geoffrey Liu; Harvey A Risch; Anna H Wu; Weimin Ye; Nigel C Bird; Nicholas J Shaheen; Marilie D Gammon; Douglas A Corley; Carlos Caldas; Susanne Moebus; Michael Knapp; Wilbert H M Peters; Horst Neuhaus; Thomas Rösch; Christian Ell; Stuart MacGregor; Paul Pharoah; David C Whiteman; Janusz Jankowski; Johannes Schumacher Journal: Lancet Oncol Date: 2016-08-12 Impact factor: 41.316
Authors: Nasim Mavaddat; Paul D P Pharoah; Kyriaki Michailidou; Jonathan Tyrer; Mark N Brook; Manjeet K Bolla; Qin Wang; Joe Dennis; Alison M Dunning; Mitul Shah; Robert Luben; Judith Brown; Stig E Bojesen; Børge G Nordestgaard; Sune F Nielsen; Henrik Flyger; Kamila Czene; Hatef Darabi; Mikael Eriksson; Julian Peto; Isabel Dos-Santos-Silva; Frank Dudbridge; Nichola Johnson; Marjanka K Schmidt; Annegien Broeks; Senno Verhoef; Emiel J Rutgers; Anthony Swerdlow; Alan Ashworth; Nick Orr; Minouk J Schoemaker; Jonine Figueroa; Stephen J Chanock; Louise Brinton; Jolanta Lissowska; Fergus J Couch; Janet E Olson; Celine Vachon; Vernon S Pankratz; Diether Lambrechts; Hans Wildiers; Chantal Van Ongeval; Erik van Limbergen; Vessela Kristensen; Grethe Grenaker Alnæs; Silje Nord; Anne-Lise Borresen-Dale; Heli Nevanlinna; Taru A Muranen; Kristiina Aittomäki; Carl Blomqvist; Jenny Chang-Claude; Anja Rudolph; Petra Seibold; Dieter Flesch-Janys; Peter A Fasching; Lothar Haeberle; Arif B Ekici; Matthias W Beckmann; Barbara Burwinkel; Frederik Marme; Andreas Schneeweiss; Christof Sohn; Amy Trentham-Dietz; Polly Newcomb; Linda Titus; Kathleen M Egan; David J Hunter; Sara Lindstrom; Rulla M Tamimi; Peter Kraft; Nazneen Rahman; Clare Turnbull; Anthony Renwick; Sheila Seal; Jingmei Li; Jianjun Liu; Keith Humphreys; Javier Benitez; M Pilar Zamora; Jose Ignacio Arias Perez; Primitiva Menéndez; Anna Jakubowska; Jan Lubinski; Katarzyna Jaworska-Bieniek; Katarzyna Durda; Natalia V Bogdanova; Natalia N Antonenkova; Thilo Dörk; Hoda Anton-Culver; Susan L Neuhausen; Argyrios Ziogas; Leslie Bernstein; Peter Devilee; Robert A E M Tollenaar; Caroline Seynaeve; Christi J van Asperen; Angela Cox; Simon S Cross; Malcolm W R Reed; Elza Khusnutdinova; Marina Bermisheva; Darya Prokofyeva; Zalina Takhirova; Alfons Meindl; Rita K Schmutzler; Christian Sutter; Rongxi Yang; Peter Schürmann; Michael Bremer; Hans Christiansen; Tjoung-Won Park-Simon; Peter Hillemanns; Pascal Guénel; Thérèse Truong; Florence Menegaux; Marie Sanchez; Paolo Radice; Paolo Peterlongo; Siranoush Manoukian; Valeria Pensotti; John L Hopper; Helen Tsimiklis; Carmel Apicella; Melissa C Southey; Hiltrud Brauch; Thomas Brüning; Yon-Dschun Ko; Alice J Sigurdson; Michele M Doody; Ute Hamann; Diana Torres; Hans-Ulrich Ulmer; Asta Försti; Elinor J Sawyer; Ian Tomlinson; Michael J Kerin; Nicola Miller; Irene L Andrulis; Julia A Knight; Gord Glendon; Anna Marie Mulligan; Georgia Chenevix-Trench; Rosemary Balleine; Graham G Giles; Roger L Milne; Catriona McLean; Annika Lindblom; Sara Margolin; Christopher A Haiman; Brian E Henderson; Fredrick Schumacher; Loic Le Marchand; Ursula Eilber; Shan Wang-Gohrke; Maartje J Hooning; Antoinette Hollestelle; Ans M W van den Ouweland; Linetta B Koppert; Jane Carpenter; Christine Clarke; Rodney Scott; Arto Mannermaa; Vesa Kataja; Veli-Matti Kosma; Jaana M Hartikainen; Hermann Brenner; Volker Arndt; Christa Stegmaier; Aida Karina Dieffenbach; Robert Winqvist; Katri Pylkäs; Arja Jukkola-Vuorinen; Mervi Grip; Kenneth Offit; Joseph Vijai; Mark Robson; Rohini Rau-Murthy; Miriam Dwek; Ruth Swann; Katherine Annie Perkins; Mark S Goldberg; France Labrèche; Martine Dumont; Diana M Eccles; William J Tapper; Sajjad Rafiq; Esther M John; Alice S Whittemore; Susan Slager; Drakoulis Yannoukakos; Amanda E Toland; Song Yao; Wei Zheng; Sandra L Halverson; Anna González-Neira; Guillermo Pita; M Rosario Alonso; Nuria Álvarez; Daniel Herrero; Daniel C Tessier; Daniel Vincent; Francois Bacot; Craig Luccarini; Caroline Baynes; Shahana Ahmed; Mel Maranian; Catherine S Healey; Jacques Simard; Per Hall; Douglas F Easton; Montserrat Garcia-Closas Journal: J Natl Cancer Inst Date: 2015-04-08 Impact factor: 13.506
Authors: Gad Abraham; Aki S Havulinna; Oneil G Bhalala; Sean G Byars; Alysha M De Livera; Laxman Yetukuri; Emmi Tikkanen; Markus Perola; Heribert Schunkert; Eric J Sijbrands; Aarno Palotie; Nilesh J Samani; Veikko Salomaa; Samuli Ripatti; Michael Inouye Journal: Eur Heart J Date: 2016-09-21 Impact factor: 29.983