Reference equations for peak oxygen uptake for treadmill cardiopulmonary exercise tests based on the NHANES lean body mass equations, a FRIEND registry study

BACKGROUND: Cardiorespiratory fitness (CRF), measured by peak oxygen uptake (VO2peak), is a strong predictor of mortality. Despite its widespread clinical use, current reference equations for VO2peak show distorted calibration in obese individuals. Using data from the Fitness Registry and the Importance of Exercise National Database (FRIEND), we sought to develop novel reference equations for VO2peak better calibrated for overweight/obese individuals - in both males and females, by considering body composition metrics. METHODS AND RESULTS: Graded treadmill tests from 6,836 apparently healthy individuals were considered in data analysis. We used the National Health and Nutrition Examination Survey equations to estimate lean body mass (eLBM) and body fat percentage (eBF). Multivariable regression was used to determine sex-specific equations for predicting VO2peak considering age terms, eLBM and eBF. The resultant equations were expressed as VO2peak (male) = 2633.4 + 48.7✕eLBM (kg) - 63.6✕eBF (%) - 0.23✕Age2 (R2=0.44) and VO2peak (female) = 1174.9 + 49.4✕eLBM (kg) - 21.7✕eBF (%) - 0.158✕Age2 (R2=0.53). These equations were well-calibrated in subgroups based on sex, age and body mass index (BMI), in contrast to the Wasserman equation. In addition, residuals for the percent-predicted VO2peak (ppVO2) were stable over the predicted VO2peak range, with low CRF defined as < 70% ppVO2 and average CRF defined between 85-115%. CONCLUSIONS: The derived VO2peak reference equations provided physiologically explainable and were well-calibrated across the spectrum of age, sex and BMI. These equations will yield more accurate VO2peak evaluation, particularly in obese individuals. ### Competing Interest Statement M.T.W. reports research grant and in kind support from Bristol Myers Squibb, consulting for Leal Therapeutics, outside the submitted work. E.A.A. reports advisory board fees from Apple and Foresite Labs. E.A.A. has ownership interest in SVEXA, Nuevocor, DeepCell, and Personalis, outside the submitted work. E.A.A. is a board member of AstraZeneca. The remainder of authors report no potential conflicts of interest. ### Funding Statement Sources of funding: This work was supported by the Stanford Cardiovascular Institute seed fund and Wu-Tsai Human Performance Alliance. D.S.K. is supported by the Wu-Tsai Human Performance Alliance, the Stanford Center for Digital Health as a Digital Health Scholar, and NIH 1L30HL170306. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The analyses presented were derived from public data release of the FRIEND registry, dated 4/2021. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability: Data will be available to qualified investigators upon request to the FRIEND steering committee.