2020/12/31 by Yoko Franchetti, Thomas D. Nolin, Franchetti, Yoko +3
Chemistry · Decision Sciences · Engineering · #Advanced Control Systems Optimization #Analytical Chemistry and Chromatography #FOS: Biological sciences #Quantitative Methods (q-bio.QM) #Scientific Measurement and Uncertainty Evaluation #thermodynamics and calorimetric analyses
paper · pdf · doi:10.48550/arxiv.2012.15647
openalex publication_date 2020/12/31 · openalex created_date 2022/07/25 · openalex updated_date 2026/07/28
We present an indirect signal processing-based measurement method for\nbiological quantities in humans that cannot be directly measured. We develop\nthe method by focusing on estimating hepatic enzyme and drug transporter\nactivity through breath-biopsy samples clinically obtained via the erythromycin\nbreath test (EBT): a small dose of radio-labeled drug is injected and the\nsubsequent content of radio-labeled CO2 is measured repeatedly in exhaled\nbreath; the resulting time series is analyzed. To model EBT we developed a\n14-variable non-linear reduced order dynamical model that describes the\nbehavior of the drug and its metabolites in the human body well enough to\ncapture all biological phenomena of interest. Based on this system of coupled\nnon-linear ordinary differential equations (ODEs) we treat the measurement\nproblem as inverse problem: we estimate the ODE parameters of individual\npatients from the measured EBT time series. These estimates then provide a\nmeasurement of the liver activity of interest. The parameters are hard to\nestimate as the ODEs are stiff and the problem needs to be regularized to\nensure stable convergence. We develop a formal operator framework to capture\nand treat the specific non-linearities present, and perform perturbation\nanalysis to establish properties of the estimation procedure and its solution.\nDevelopment of the method required 150,000 CPU hours at a supercomputing\ncenter, and a single production run takes CPU 24 hours. We introduce and\nanalyze the method in the context of future precision dosing of drugs for\nvulnerable patients (e.g., oncology, nephrology, or pediatrics) to eventually\nensure efficacy and avoid toxicity.\n