Development and Internal Validation of an Age Less-Dependent Frailty Score in the Cardiovascular Health Study

Aaron L. Troy^1,2Brendon Choy³Huaying Dong¹Julius M Gardin⁴Calvin Hirsch⁵Angela S Koh⁶William Kong⁷Kenneth J Mukamal³Anne B Newman⁸Michelle C Odden⁹Michael Shu¹⁰Yang Song¹Chenkai Wu¹¹Jordan Strom^1*

• ¹Beth Israel Deaconess Medical Center Richard A and Susan F Smith Center for Outcomes Research in Cardiology, Boston, United States
• ²Johns Hopkins University Department of Medicine, Baltimore, United States
• ³Harvard Medical School, Boston, United States
• ⁴Hackensack Meridian Hackensack University Medical Center, Hackensack, United States
• ⁵UC Davis Health, Sacramento, United States
• ⁶National Heart Centre Singapore, Singapore, Singapore
• ⁷National University Heart Centre, Singapore, Singapore
• ⁸University of Pittsburgh Department of Epidemiology, Pittsburgh, United States
• ⁹Stanford University Department of Epidemiology & Population Health, Stanford, United States
• ¹⁰University of Cincinnati College of Medicine, Cincinnati, United States
• ¹¹Duke Kunshan University Global Health Program, Suzhou, China

ABSTRACT Background: Frailty is a proxy for biologic aging that confers risk independently of chronologic age. Most frailty indices correlate strongly with chronologic age, making independent features of biologic aging challenging to identify. Methods: We aimed to create a novel Age Less-Dependent Frailty (AGELESS) Score less-associated with chronologic age than the Fried frailty phenotype. Among Cardiovascular Health Study participants with available echocardiographic data, we identified demographic, clinical, serologic, and echocardiographic variables more correlated with a continuous version of the Fried frailty phenotype than age, then used LASSO regression for variable selection. In a 25% leave-out sample, we internally validated the score's association with age-adjusted all-cause and cardiovascular mortality and compared model characteristics with the Fried frailty phenotype. Results: In 4,029 individuals (mean age 72 + 5.0 years, 59.6% female), serum cystatin C, depression, diabetes, educational attainment, forced expiratory volume in 1 second, and income were more associated with frailty than age and selected for inclusion in the AGELESS Score. Adjusted for age, individuals in the highest vs. lowest quartiles of the AGELESS Score had a higher risk of all-cause (HR 1.44, 95% CI 1.17-1.79, p<0.001) and CV death (HR 1.64, 95% CI 1.43-1.87, p=0.002). The AGELESS Score was less correlated with age (AGELESS r = 0.23, 95% CI 0.16-0.30; Fried r = 0.28, 95% CI 0.21-0.34; p-value for comparison of correlations < 0.001) and more closely associated with all-cause and CV mortality within each age quartile than the Fried frailty phenotype. Conclusions: We derived and internally validated a novel frailty score that is less associated with chronologic age than existing indices and predicts mortality within age strata better than the 3 existing reference standard for phenotypic frailty. This score could help identify high-risk patients with frailty across the age spectrum and may provide insights into mechanisms of biologic aging.