OBJECTIVE: The differences between seronegative and seropositive rheumatoid arthritis (RA) have not been widely reported. We performed electronic health record (EHR)-based phenome-wide association studies (PheWAS) to identify disease associations in seropositive and seronegative RA. METHODS: A validated algorithm identified RA subjects from the de-identified version of the Vanderbilt University Medical Center EHR. Serotypes were determined by rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) values. We tested EHR-derived phenotypes using PheWAS comparing seropositive RA and seronegative RA, yielding disease associations. PheWAS was also performed in RF-positive versus RF-negative subjects and ACPA-positive versus ACPA-negative subjects. Following PheWAS, select phenotypes were then manually reviewed, and fibromyalgia was specifically evaluated using a validated algorithm. RESULTS: A total of 2,199 RA individuals with either RF or ACPA testing were identified. Of these, 1,382 patients (63%) were classified as seropositive. Seronegative RA was associated with myalgia and myositis (odds ratio [OR] 2.1, P = 3.7 × 10-10 ) and back pain. A manual review of the health record showed that among subjects coded for Myalgia and Myositis, ∼80% had fibromyalgia. Follow-up with a specific EHR algorithm for fibromyalgia confirmed that seronegative RA was associated with fibromyalgia (OR 1.8, P = 4.0 × 10-6 ). Seropositive RA was associated with chronic airway obstruction (OR 2.2, P = 1.4 × 10-4 ) and tobacco use (OR 2.2, P = 7.0 × 10-4 ). CONCLUSION: This PheWAS of RA patients identifies a strong association between seronegativity and fibromyalgia. It also affirms relationships between seropositivity and chronic airway obstruction and between seropositivity and tobacco use. These findings demonstrate the utility of the PheWAS approach to discover novel phenotype associations within different subgroups of a disease.
OBJECTIVE: The differences between seronegative and seropositive rheumatoid arthritis (RA) have not been widely reported. We performed electronic health record (EHR)-based phenome-wide association studies (PheWAS) to identify disease associations in seropositive and seronegative RA. METHODS: A validated algorithm identified RA subjects from the de-identified version of the Vanderbilt University Medical Center EHR. Serotypes were determined by rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) values. We tested EHR-derived phenotypes using PheWAS comparing seropositive RA and seronegative RA, yielding disease associations. PheWAS was also performed in RF-positive versus RF-negative subjects and ACPA-positive versus ACPA-negative subjects. Following PheWAS, select phenotypes were then manually reviewed, and fibromyalgia was specifically evaluated using a validated algorithm. RESULTS: A total of 2,199 RA individuals with either RF or ACPA testing were identified. Of these, 1,382 patients (63%) were classified as seropositive. Seronegative RA was associated with myalgia and myositis (odds ratio [OR] 2.1, P = 3.7 × 10-10 ) and back pain. A manual review of the health record showed that among subjects coded for Myalgia and Myositis, ∼80% had fibromyalgia. Follow-up with a specific EHR algorithm for fibromyalgia confirmed that seronegative RA was associated with fibromyalgia (OR 1.8, P = 4.0 × 10-6 ). Seropositive RA was associated with chronic airway obstruction (OR 2.2, P = 1.4 × 10-4 ) and tobacco use (OR 2.2, P = 7.0 × 10-4 ). CONCLUSION: This PheWAS of RA patients identifies a strong association between seronegativity and fibromyalgia. It also affirms relationships between seropositivity and chronic airway obstruction and between seropositivity and tobacco use. These findings demonstrate the utility of the PheWAS approach to discover novel phenotype associations within different subgroups of a disease.
Authors: Fina Kurreeman; Katherine Liao; Lori Chibnik; Brendan Hickey; Eli Stahl; Vivian Gainer; Gang Li; Lynn Bry; Scott Mahan; Kristin Ardlie; Brian Thomson; Peter Szolovits; Susanne Churchill; Shawn N Murphy; Tianxi Cai; Soumya Raychaudhuri; Isaac Kohane; Elizabeth Karlson; Robert M Plenge Journal: Am J Hum Genet Date: 2011-01-07 Impact factor: 11.025
Authors: Joshua C Denny; Marylyn D Ritchie; Melissa A Basford; Jill M Pulley; Lisa Bastarache; Kristin Brown-Gentry; Deede Wang; Dan R Masys; Dan M Roden; Dana C Crawford Journal: Bioinformatics Date: 2010-03-24 Impact factor: 6.937
Authors: Yvonne C Lee; Bing Lu; Gilles Boire; Boulos Paul Haraoui; Carol A Hitchon; Janet E Pope; J Carter Thorne; Edward Clark Keystone; Daniel H Solomon; Vivian P Bykerk Journal: Ann Rheum Dis Date: 2012-07-11 Impact factor: 19.103
Authors: Omri Gottesman; Helena Kuivaniemi; Gerard Tromp; W Andrew Faucett; Rongling Li; Teri A Manolio; Saskia C Sanderson; Joseph Kannry; Randi Zinberg; Melissa A Basford; Murray Brilliant; David J Carey; Rex L Chisholm; Christopher G Chute; John J Connolly; David Crosslin; Joshua C Denny; Carlos J Gallego; Jonathan L Haines; Hakon Hakonarson; John Harley; Gail P Jarvik; Isaac Kohane; Iftikhar J Kullo; Eric B Larson; Catherine McCarty; Marylyn D Ritchie; Dan M Roden; Maureen E Smith; Erwin P Böttinger; Marc S Williams Journal: Genet Med Date: 2013-06-06 Impact factor: 8.822
Authors: Lindsey C McKernan; Matthew C Lenert; Leslie J Crofford; Colin G Walsh Journal: Arthritis Care Res (Hoboken) Date: 2019-07-23 Impact factor: 4.794
Authors: Anurag Verma; Anastasia Lucas; Shefali S Verma; Yu Zhang; Navya Josyula; Anqa Khan; Dustin N Hartzel; Daniel R Lavage; Joseph Leader; Marylyn D Ritchie; Sarah A Pendergrass Journal: Am J Hum Genet Date: 2018-03-29 Impact factor: 11.025
Authors: Jeffrey A Sparks; Tzu-Chieh Lin; Carlos A Camargo; Medha Barbhaiya; Sara K Tedeschi; Karen H Costenbader; Benjamin A Raby; Hyon K Choi; Elizabeth W Karlson Journal: Semin Arthritis Rheum Date: 2017-09-18 Impact factor: 5.532
Authors: Hassan S Dashti; Brian E Cade; Gerda Stutaite; Richa Saxena; Susan Redline; Elizabeth W Karlson Journal: Sleep Date: 2021-03-12 Impact factor: 5.849
Authors: April Barnado; Robert J Carroll; Carolyn Casey; Lee Wheless; Joshua C Denny; Leslie J Crofford Journal: Arthritis Care Res (Hoboken) Date: 2018-11 Impact factor: 4.794
Authors: Yichi Zhang; Tianrun Cai; Sheng Yu; Kelly Cho; Chuan Hong; Jiehuan Sun; Jie Huang; Yuk-Lam Ho; Ashwin N Ananthakrishnan; Zongqi Xia; Stanley Y Shaw; Vivian Gainer; Victor Castro; Nicholas Link; Jacqueline Honerlaw; Sicong Huang; David Gagnon; Elizabeth W Karlson; Robert M Plenge; Peter Szolovits; Guergana Savova; Susanne Churchill; Christopher O'Donnell; Shawn N Murphy; J Michael Gaziano; Isaac Kohane; Tianxi Cai; Katherine P Liao Journal: Nat Protoc Date: 2019-11-20 Impact factor: 13.491
Authors: Alessandra Zaccardelli; Xinyi Liu; Julia A Ford; Jing Cui; Bing Lu; Su H Chu; Peter H Schur; Cameron B Speyer; Karen H Costenbader; William H Robinson; Jeremy Sokolove; Elizabeth W Karlson; Carlos A Camargo; Jeffrey A Sparks Journal: Arthritis Care Res (Hoboken) Date: 2021-04 Impact factor: 4.794