An Adaptive Model Predictive Controller to Address the Biovariability in Blood Clotting Response During Therapy With Warfarin.

OBJECTIVE: Effective dosing of anticoagulants aims to prevent blood clot formation while avoiding hemorrhages. This complex task is challenged by several disturbing factors and drug-effect uncertainties, requesting frequent monitoring and adjustment. Biovariability in drug absorption and action further complicates titration and calls for individualized strategies. In this paper, we propose an adaptive closed-loop control algorithm to assist in warfarin therapy management. METHODS: The controller was designed and tested in silico using an established pharmacometrics model of warfarin, which accounts for inter-subject variability. The control algorithm is an adaptive Model Predictive Control (a-MPC) that leverages a simplified patient model, whose parameters are updated with a Bayesian strategy. Performance was quantitatively evaluated in simulations performed on a population of virtual subjects against an algorithm reproducing medical guidelines (MG) and an MPC controller available in the literature (l-MPC). RESULTS: The proposed a-MPC significantly (p 0.05) lowers rising time (2.8 vs. 4.4 and 11.2 days) and time out of range (3.3 vs. 7.2 and 12.9 days) with respect to both MG and l-MPC, respectively. Adaptivity grants a significantly (p 0.05) lower number of subjects reaching unsafe INR values compared to when this feature is not present (8.9% vs.15% of subjects presenting an overshoot outside the target range and 0.08% vs. 0.28% of subjects reaching dangerous INR values). CONCLUSION: The a-MPC algorithm improve warfarin therapy compared to the benchmark therapies. SIGNIFICANCE: This in-silico validation proves effectiveness of the a-MPC algorithm for anticoagulant administration, paving the way for clinical testing.

Neural correlates of user learning during long-term BCI training for the Cybathlon competition.

BACKGROUND: Brain-computer interfaces (BCIs) are systems capable of translating human brain patterns, measured through electroencephalography (EEG), into commands for an external device. Despite the great advances in machine learning solutions to enhance the performance of BCI decoders, the translational impact of this technology remains elusive. The reliability of BCIs is often unsatisfactory for end-users, limiting their application outside a laboratory environment. METHODS: We present the analysis on the data acquired from an end-user during the preparation for two Cybathlon competitions, where our pilot won the gold medal twice in a row. These data are of particular interest given the mutual learning approach adopted during the longitudinal training phase (8 months), the long training break in between the two events (1 year) and the demanding evaluation scenario. A multifaceted perspective on long-term user learning is proposed: we enriched the information gathered through conventional metrics (e.g., accuracy, application performances) by investigating novel neural correlates of learning in different neural domains. RESULTS: First, we showed that by focusing the training on user learning, the pilot was capable of significantly improving his performance over time even with infrequent decoder re-calibrations. Second, we revealed that the analysis of the within-class modifications of the pilot's neural patterns in the Riemannian domain is more effective in tracking the acquisition and the stabilization of BCI skills, especially after the 1-year break. These results further confirmed the key role of mutual learning in the acquisition of BCI skills, and particularly highlighted the importance of user learning as a key to enhance BCI reliability. CONCLUSION: We firmly believe that our work may open new perspectives and fuel discussions in the BCI field to shift the focus of future research: not only to the machine learning of the decoder, but also in investigating novel training procedures to boost the user learning and the stability of the BCI skills in the long-term. To this end, the analyses and the metrics proposed could be used to monitor the user learning during training and provide a marker guiding the decoder re-calibration to maximize the mutual adaptation of the user to the BCI system.