Exploring the incremental utility of circulating biomarkers for robust risk prediction of incident atrial fibrillation in European cohorts using regressions and modern machine learning methods.

Aims: To identify robust circulating predictors for incident atrial fibrillation (AF) using classical regressions and machine learning (ML) techniques within a broad spectrum of candidate variables.
Methods and Results: In pooled European community cohorts (n = 42 280 individuals), 14 routinely available biomarkers mirroring distinct pathophysiological pathways including lipids, inflammation, renal, and myocardium-specific markers (N-terminal pro B-type natriuretic peptide [NT-proBNP], high-sensitivity troponin I [hsTnI]) were examined in relation to incident AF using Cox regressions and distinct ML methods. Of 42 280 individuals (21 843 women [51.7%]; median [interquartile range, IQR] age, 52.2 [42.7, 62.0] years), 1496 (3.5%) developed AF during a median follow-up time of 5.7 years. In multivariable-adjusted Cox-regression analysis, NT-proBNP was the strongest circulating predictor of incident AF [hazard ratio (HR) per standard deviation (SD), 1.93 (95% CI, 1.82-2.04); P < 0.001]. Further, hsTnI [HR per SD, 1.18 (95% CI, 1.13-1.22); P < 0.001], cystatin C [HR per SD, 1.16 (95% CI, 1.10-1.23); P < 0.001], and C-reactive protein [HR per SD, 1.08 (95% CI, 1.02-1.14); P = 0.012] correlated positively with incident AF. Applying various ML techniques, a high inter-method consistency of selected candidate variables was observed. NT-proBNP was identified as the blood-based marker with the highest predictive value for incident AF. Relevant clinical predictors were age, the use of antihypertensive medication, and body mass index.
Conclusion: Using different variable selection procedures including ML methods, NT-proBNP consistently remained the strongest blood-based predictor of incident AF and ranked before classical cardiovascular risk factors. The clinical benefit of these findings for identifying at-risk individuals for targeted AF screening needs to be elucidated and tested prospectively.
Competing Interests: Conflict of interest: R.B.S. has received lecture fees and advisory board fees from BMS/Pfizer outside the submitted work. B.T. receives project-related funding by the German Heart Foundation and Ernst und Berta Grimmke-Stiftung unrelated to the submitted work. V.S. reports an honorarium for consulting from Sanofi. He also has research collaboration with Bayer Ltd (all unrelated to the present study). T.N. reports speaker honoraria from Servier outside the submitted work. S.S. received honoraria from Actelion (now Janssen) outside the submitted work. Furthermore, S.S. is a member of the advisory board of Actelion (now Janssen) and of Novartis. I.K. has received research grants by the Heart Foundation in Northern Sweden and Arnerska Research Foundation, both unrelated to the present study. S.B. reports honoraria to his institution from Abbott, Bayer, Siemens, Singulex, and Roche, outside the submitted work. S.B. also reports personal fees from Abbott, Bayer, Siemens, Novartis, Thermo Fisher, Astra Zeneca, AMGEN, Medtronic, and Pfizer. S.Co. has received honoraria for lecturing from The Dutch Beer Institute foundation—The Brewers of Europe, outside the submitted work. S.Co. and A.D.C. are the PI and Co-PI, respectively, of a research grant from ERAB (the European Foundation for Alcohol Research, EA 1767, completed in January 2020), which is unrelated to the present study. G.d.G. is a member of the International Scientific Forum on Alcohol Research. The members of the Forum receive no financial support. The Forum itself receives no support from any other organization or company in the alcoholic beverage industry. G.d.G. was also a consultant to the Web Newsletter of Assobirra, the Italian Association of the Beer and Malt Industries and is a corresponding member of the non-profit Accademia Italiana della Vite e del Vino. G.d.G. reports personal fees for given lectures at the 8th European Beer and Health Symposium (2017), Beer and Health Initiative (The Dutch Beer Institute Foundation—The Brewers of Europe), outside the submitted work. All remaining authors have declared no conflicts of interest.
(© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)