Reproducible biomarkers: Leveraging nonlinear descriptors in the face of non-ergodicity

Any reliable biomarker has to be specific, generalizable, and reproducible across individuals and contexts. The exact values of such a biomarker must represent similar health states in different individuals and at different times within the same individual to result in the minimum possible false-positive and false-negative rates. The application of standard cut-off points and risk scores across populations hinges upon the assumption of such generalizability. Such generalizability, in turn, hinges upon this condition that the phenomenon investigated by current statistical methods is ergodic, i.e., its statistical measures converge over individuals and time within the finite limit of observations. However, emerging evidence indicates that biological processes abound with non-ergodicity, threatening this generalizability. Here, we present a solution for how to make generalizable inferences by deriving ergodic descriptions of non-ergodic phenomena. For this aim, we proposed capturing the origin of ergodicity-breaking in many biological processes: cascade dynamics. To assess our hypotheses, we embraced the challenge of identifying reliable biomarkers for heart disease and stroke, which, despite being the leading cause of death worldwide and decades of research, lacks reliable biomarkers and risk stratification tools. We showed that raw R-R interval data and its common descriptors based on mean and variance are non-ergodic and non-specific. On the other hand, the cascade-dynamical descriptors, the Hurst exponent encoding linear temporal correlations, and multifractal nonlinearity encoding nonlinear interactions across scales described the non-ergodic heart rate variability ergodically and were specific. This study inaugurates applying the critical concept of ergodicity in discovering and applying digital biomarkers of health and disease.