Everton Jose Santana ^1,2,3* Nicholas Cauwenberghs ³ Bettia E. Celestin ⁴ Tatiana Kuznetsova ³ Christopher Gardner ⁵ Ross Arena ⁶ Leonard Kaminsky ⁷ Matthew Harber ⁸ Euan Ashley ¹ Jeffrey Wilcox Christle ¹ Jonathan Myers ⁹ Francois Haddad ^1,2*

• ¹ Division of Cardiovascular Medicine, Department of Medicine, School of Medicine, Stanford University, Stanford, California, United States
• ² Stanford Cardiovascular Institute, School of Medicine, Stanford University, Stanfordd, California, United States
• ³ Research Unit Hypertension and Cardiovascular Epidemiology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
• ⁴ Pathology Stem Cell Institute, School of Medicine, Stanford University, Stanford, California, United States
• ⁵ Stanford Prevention Research Center, Department of Medicine, School of Medicine, Stanford University, Stanford, California, United States
• ⁶ Department of Physical Therapy, College of Applied Health Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
• ⁷ Fisher Institute for Health and Well-Being, Ball State University, Muncie, Indiana, United States
• ⁸ Ball State University, Muncie, Indiana, United States
• ⁹ VA Palo Alto Health Care System, Veterans Health Administration, United States Department of Veterans Affairs, Palo Alto, California, United States

Background: Indexing peak oxygen uptake (VO₂peak) to total body mass can underestimate cardiorespiratory fitness (CRF) in women, older adults, and individuals with obesity. The primary objective of this multicenter study was to derive and validate a body size-independent scaling metric for VO₂peak. This metric was termed Exercise Body Mass (EBM).In a cohort of apparently healthy individuals from the Fitness Registry and the Importance of Exercise National Database (FRIEND), we derived EBM using multivariable log-normal regression analysis. Subsequently, we developed a novel workload (WL) equation based on speed (Sp), fractional grade (fGr), and heart rate reserve (HRR). The generalized equation for VO₂peak can be expressed as: VO₂peak = Cst * EBM * WL, where Cst is a constant representing the VO₂peak equivalent of one metabolic equivalent of task. This generalized equation was, then, externally validated using the Stanford Exercise Testing (SET) dataset.Results: A total of 5,618 apparently healthy individuals with a respiratory exchange ratio >1.0 (57% male, mean age 44±13 years) were included. The EBM was expressed as: Mass(kg) 0.63 * Height(m) 0.53 * 1.16 (if male) * exp (-0.39 *10 -4 *Age 2 ) which was also approximated using simple sex-specific additive equations. Unlike total body mass, EBM provided body size-independent scaling across both sexes and WL categories. The generalized VO₂peak equation was expressed as: 11 * EBM * [2 + Sp (in mph) * (1.06 + 5.22* fGr) + 0.019*HRR] and had an R 2 of 0.83, P< 0.001. This generalized equation mitigated bias in VO₂peak estimations across age, sex, and body mass index subgroups and was validated in SET registry, achieving an R 2 of 0.84 (P < 0.001).We derived a generalized equation for VO₂peak in treadmill exercise testing using a novel body size-independent scaling metric. This approach significantly reduced biases in CRF estimates across age, sex, and body composition.