Physical inactivity is a major contributor to chronic illnesses and mortality globally. However, most interventions to address it rely on static, aggregate models that overlook idiographic (i.e., individual-level) dynamics, limiting intervention effectiveness. Leveraging mobile technology and control systems engineering principles, this dissertation provides a novel, comprehensive framework for personalized behavioral interventions that have been tested experimentally under the Control Optimization Trial (COT) paradigm. Through careful design of experiments, elaborate signal processing and model estimation, and judicious formulation of behavior intervention optimization as a control system problem, this dissertation develops tools to overcome challenges faced in the large-scale dissemination of mobile health (mHealth) interventions. A novel Three-Degrees-of-Freedom Kalman Filter-based Hybrid Model Predictive Control (3DoF-KF HMPC) controller is formulated for physical activity interventions and evaluated in a clinical trial, demonstrating its effectiveness. Furthermore, this dissertation expands on understanding the underlying dynamics influencing behavior change. Engineering principles are applied to develop a conceptual approach to generate dynamic hypotheses and translate these into first-principle dynamic models. The generated models are used in concert with system identification principles to enhance the design of experiments that yield dynamically informative data sets for behavioral medicine applications. Additionally, sophisticated search, filtering, and model estimation algorithms are applied to optimize and personalize model structures and estimate dynamic models that account for nonlinearities and “Just-in-Time” (JIT; moments of need, receptivity, and opportunity) context in behavior change systems. In addition, the pervasive issue of data missingness in interventions is addressed by integrating system identification principles with a Bayesian inference model-based technique for data imputation. The findings in this dissertation extend beyond physical activity, offering insights for promoting healthy behaviors in other applications, such as smoking cessation and weight management. The integration of control systems engineering in behavioral medicine research, as demonstrated in this dissertation, offers broad impacts by advancing the field's understanding of behavior change dynamics, enhancing accessibility to personalized behavioral health interventions, and improving patient outcomes. This research has the potential to radically improve behavioral interventions, increase affordability and accessibility, inspire interdisciplinary collaboration, and provide behavioral scientists with tools capable of addressing societal challenges in mHealth and preventive medicine.

Excessive weight gain during pregnancy is a significant public health concern and has been the recent focus of novel, control systems-based interventions. Healthy Mom Zone (HMZ) is an intervention study that aims to develop and validate an individually tailored and intensively adaptive intervention to manage weight gain for overweight or obese pregnant women using control engineering approaches. Motivated by the needs of the HMZ, this dissertation presents how to use system identification and state estimation techniques to assist in dynamical systems modeling and further enhance the performance of the closed-loop control system for interventions.

Underreporting of energy intake (EI) has been found to be an important consideration that interferes with accurate weight control assessment and the effective use of energy balance (EB) models in an intervention setting. To better understand underreporting, a variety of estimation approaches are developed; these include back-calculating energy intake from a closed-form of the EB model, a Kalman-filter based algorithm for recursive estimation from randomly intermittent measurements in real time, and two semi-physical identification approaches that can parameterize the extent of systematic underreporting with global/local modeling techniques. Each approach is analyzed with intervention participant data and demonstrates potential of promoting the success of weight control.

In addition, substantial efforts have been devoted to develop participant-validated models and incorporate into the Hybrid Model Predictive Control (HMPC) framework for closed-loop interventions. System identification analyses from Phase I led to modifications of the measurement protocols for Phase II, from which longer and more informative data sets were collected. Participant-validated models obtained from Phase II data significantly increase predictive ability for individual behaviors and provide reliable open-loop dynamic information for HMPC implementation. The HMPC algorithm that assigns optimized dosages in response to participant real time intervention outcomes relies on a Mixed Logical Dynamical framework which can address the categorical nature of dosage components, and translates sequential decision rules and other clinical considerations into mixed-integer linear constraints. The performance of the HMPC decision algorithm was tested with participant-validated models, with the results indicating that HMPC is superior to "IF-THEN" decision rules.

Increasing interest in individualized treatment strategies for prevention and treatment of health disorders has created a new application domain for dynamic modeling and control. Standard population-level clinical trials, while useful, are not the most suitable vehicle for understanding the dynamics of dosage changes to patient response. A secondary analysis of intensive longitudinal data from a naltrexone intervention for fibromyalgia examined in this dissertation shows the promise of system identification and control. This includes datacentric identification methods such as Model-on-Demand, which are attractive techniques for estimating nonlinear dynamical systems from noisy data. These methods rely on generating a local function approximation using a database of regressors at the current operating point, with this process repeated at every new operating condition. This dissertation examines generating input signals for data-centric system identification by developing a novel framework of geometric distribution of regressors and time-indexed output points, in the finite dimensional space, to generate sufficient support for the estimator. The input signals are generated while imposing “patient-friendly” constraints on the design as a means to operationalize single-subject clinical trials. These optimization-based problem formulations are examined for linear time-invariant systems and block-structured Hammerstein systems, and the results are contrasted with alternative designs based on Weyl's criterion. Numerical solution to the resulting nonconvex optimization problems is proposed through semidefinite programming approaches for polynomial optimization and nonlinear programming methods. It is shown that useful bounds on the objective function can be calculated through relaxation procedures, and that the data-centric formulations are amenable to sparse polynomial optimization. In addition, input design formulations are formulated for achieving a desired output and specified input spectrum. Numerical examples illustrate the benefits of the input signal design formulations including an example of a hypothetical clinical trial using the drug gabapentin. In the final part of the dissertation, the mixed logical dynamical framework for hybrid model predictive control is extended to incorporate a switching time strategy, where decisions are made at some integer multiple of the sample time, and manipulation of only one input at a given sample time among multiple inputs. These are considerations important for clinical use of the algorithm.

There is increasing interest in the medical and behavioral health communities towards developing effective strategies for the treatment of chronic diseases. Among these lie adaptive interventions, which consider adjusting treatment dosages over time based on participant response. Control engineering offers a broad-based solution framework for optimizing the effectiveness of such interventions. In this thesis, an approach is proposed to develop dynamical models and subsequently, hybrid model predictive control schemes for assigning optimal dosages of naltrexone, an opioid antagonist, as treatment for a chronic pain condition known as fibromyalgia. System identification techniques are employed to model the dynamics from the daily diary reports completed by participants of a blind naltrexone intervention trial. These self-reports include assessments of outcomes of interest (e.g., general pain symptoms, sleep quality) and additional external variables (disturbances) that affect these outcomes (e.g., stress, anxiety, and mood). Using prediction-error methods, a multi-input model describing the effect of drug, placebo and other disturbances on outcomes of interest is developed. This discrete time model is approximated by a continuous second order model with zero, which was found to be adequate to capture the dynamics of this intervention. Data from 40 participants in two clinical trials were analyzed and participants were classified as responders and non-responders based on the models obtained from system identification. The dynamical models can be used by a model predictive controller for automated dosage selection of naltrexone using feedback/feedforward control actions in the presence of external disturbances. The clinical requirement for categorical (i.e., discrete-valued) drug dosage levels creates a need for hybrid model predictive control (HMPC). The controller features a multiple degree-of-freedom formulation that enables the user to adjust the speed of setpoint tracking, measured disturbance rejection and unmeasured disturbance rejection independently in the closed loop system. The nominal and robust performance of the proposed control scheme is examined via simulation using system identification models from a representative participant in the naltrexone intervention trial. The controller evaluation described in this thesis gives credibility to the promise and applicability of control engineering principles for optimizing adaptive interventions.