title: B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies.
abstract: OBJECTIVE
  B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information.
  
  
  RESULTS
  We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56-1.76], P < 0.0001 and 1.18 (95% CI, 1.11-1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ(2) = 17.0; CRP, χ(2) = 10.5; BNP and CRP, χ(2) = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022-0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322-0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS.
  
  
  CONCLUSIONS
  B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.
authors.affiliation: Department of Medicine I, University Hospital Munich, Ludwig-Maximilians University, 81377 Munich, Germany.
authors.forename: Moritz F
authors.initials: MF
authors.lastname: Sinner
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Stepas
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
authors.forename: Carlee B
authors.initials: CB
authors.lastname: Moser
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands Netherlands Consortium for Healthy Aging (NCHA), 2300 RC Leiden, The Netherlands.
authors.forename: Bouwe P
authors.initials: BP
authors.lastname: Krijthe
authors.affiliation: Icelandic Heart Association, Research Institute, IS-201 Kopavogur, Iceland The University of Iceland, IS-101 Reykjavik, Iceland.
authors.forename: Thor
authors.initials: T
authors.lastname: Aspelund
authors.affiliation: Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA 98195, USA Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
authors.forename: Nona
authors.initials: N
authors.lastname: Sotoodehnia
authors.affiliation: National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01702, USA.
authors.forename: João D
authors.initials: JD
authors.lastname: Fontes
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands Netherlands Consortium for Healthy Aging (NCHA), 2300 RC Leiden, The Netherlands.
authors.forename: A Cecile J W
authors.initials: AC
authors.lastname: Janssens
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kronmal
authors.affiliation: National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01702, USA Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Jared W
authors.initials: JW
authors.lastname: Magnani
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands Netherlands Consortium for Healthy Aging (NCHA), 2300 RC Leiden, The Netherlands.
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Witteman
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Alanna M
authors.initials: AM
authors.lastname: Chamberlain
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Lubitz
authors.affiliation: Department of General and Interventional Cardiology, University Heart Center, 20246 Hamburg-Eppendorf, Germany.
authors.forename: Renate B
authors.initials: RB
authors.lastname: Schnabel
authors.affiliation: National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01702, USA Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118, USA.
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.affiliation: National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01702, USA Cardiology Division, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wang
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Agarwal
authors.affiliation: National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01702, USA Departments of Medicine and Quantitative Health Sciences, University of Massachusetts, Worcester, MA 01605, USA Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA 01609, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: McManus
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
authors.forename: Oscar H
authors.initials: OH
authors.lastname: Franco
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01702, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yin
authors.affiliation: National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01702, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Larson
authors.affiliation: Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Burke
authors.affiliation: Laboratory of Epidemiology, Demography, and Biometry, National Institute of Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lenore J
authors.initials: LJ
authors.lastname: Launer
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands Netherlands Consortium for Healthy Aging (NCHA), 2300 RC Leiden, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01702, USA Center for Population Studies, NHLBI, Framingham, MA 01702, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.affiliation: Division of Cardiology, University of Maryland Medical Center, Baltimore, MD 21201, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Gottdiener
authors.affiliation: Department of Medicine I, University Hospital Munich, Ludwig-Maximilians University, 81377 Munich, Germany Deutsches Zentrum für Herz-Kreislauferkrankungen (DZHK), partner site Munich Heart Alliance, 80802 Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kääb
authors.affiliation: Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: David
authors.initials: D
authors.lastname: Couper
authors.affiliation: Laboratory of Epidemiology, Demography, and Biometry, National Institute of Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.affiliation: University of Wisconsin, School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Brad C
authors.initials: BC
authors.lastname: Astor
authors.affiliation: Baylor College of Medicine, Houston, TX 77030, USA Methodist DeBakey Heart and Vascular Center, Houston, TX 77030, USA.
authors.forename: Christie M
authors.initials: CM
authors.lastname: Ballantyne
authors.affiliation: Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ron C
authors.initials: RC
authors.lastname: Hoogeveen
authors.affiliation: Cardiovascular and Pulmonary Branch, NHLBI, Bethesda, MD 20892, USA.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Arai
authors.affiliation: Epidemiological Cardiology Research Center (EPICARE), Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Elsayed Z
authors.initials: EZ
authors.lastname: Soliman
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Ellinor
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands Netherlands Consortium for Healthy Aging (NCHA), 2300 RC Leiden, The Netherlands Department of Internal Medicine, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands Inspectorate for Health Care, 3500 GR The Hague, The Netherlands Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Bruno H C
authors.initials: BH
authors.lastname: Stricker
authors.affiliation: Icelandic Heart Association, Research Institute, IS-201 Kopavogur, Iceland The University of Iceland, IS-101 Reykjavik, Iceland.
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.affiliation: Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Heckbert
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pencina
authors.affiliation: National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01702, USA Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118, USA alonso@umn.edu emelia@bu.edu.
authors.forename: Emelia J
authors.initials: EJ
authors.lastname: Benjamin
authors.affiliation: Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA alonso@umn.edu emelia@bu.edu.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Alonso
mesh_terms: D000368:Aged; D001281:Atrial Fibrillation / Q000097:blood* / Q000453:epidemiology*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism*; D005060:Europe / Q000453:epidemiology; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D020097:Natriuretic Peptide, Brain / Q000097:blood*; D010446:Peptide Fragments / Q000097:blood*; D011237:Predictive Value of Tests; D018570:Risk Assessment; D012307:Risk Factors; D014481:United States / Q000453:epidemiology
chemical_list: D015415:Biomarkers; D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D002097:C-Reactive Protein
keywords: Atrial fibrillation; B-type natriuretic peptide; Biomarker; C-reactive protein; Epidemiology; Risk prediction