ALT We propose a novel method of understanding disease transformation from a healthy baseline with biomarker-level explainability. By modeling the biomarker covariance matrices of healthy controls and disease states, the perturbation can be individually characterized to accomplish mechanistic explanations of disease trajectories, both at a molecular level and for individual patients. Given a cohort of n patients each measured on p biomarkers, we define the biomarker "Hamiltonian" H = Xᵀ X / n ∈ Rᵖˣᵖ, where X ∈ Rⁿˣᵖ is the covariant biomarker matrix. The eigenvectors of H define a set of normal modes of biomarker coordination, and the eigenvalues quantify the energy carried by each mode. In the healthy state, the reference Hamiltonian H₀ governs this structure where disease perturbs H₀ by an additive operator ΔH, thus shifting eigenvalues and rotating eigenvectors in proportion to the severity of pathological disruption. We formalize this framework, derive the spectral change given a diseas

ALT Graphic abstract in Yu et al.