Estimating the effect of a treatment on a given outcome, conditioned on a vector of covariates, is central in many applications. However, learning the impact of a treatment on a continuous temporal response, when the covariates suffer extensively from measurement error and even the timing of the treatments is uncertain, has not been addressed. We introduce a novel data-driven method that can estimate treatment-response trajectories in this challenging scenario. We model personalized treatment-response curves as a combination of parametric response functions, hierarchically sharing information across individuals, and a sparse Gaussian process for the baseline trend. Importantly, our model considers measurement error not only in treatment covariates, but also in treatment times, a problem which arises in practice for example when treatment information is based on self-reporting. In a challenging and timely problem of estimating the impact of diet on continuous blood glucose measurements, our model leads to significant improvements in estimation accuracy and prediction.
: In contrast to the data-driven approaches used in machine learning, mechanistic models use substantial knowledge of a specific problem to characterize the system with differential equations, and inference is done for example using filtering algorithms. Similar to our application, @cite_4 and @cite_41 study blood glucose dynamics, affected by nutrition and other factors. Another example is a computational model of the physiological mechanisms for type-2 diabetes, aiming to quantify factors useful for prevention of the disease @cite_39 .
@cite_41 @cite_4 @cite_39
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Type 2 diabetes leads to premature death and reduced quality of life for 8 of Americans. Nutrition management is critical to maintaining glycemic control, yet it is difficult to achieve due to the high individual differences in glycemic response to nutrition. Anticipating glycemic impact of different meals can be challenging not only for individuals with diabetes, but also for expert diabetes educators. Personalized computational models that can accurately forecast an impact of a given meal on an individual’s blood glucose levels can serve as the engine for a new generation of decision support tools for individuals with diabetes. However, to be useful in practice, these computational engines need to generate accurate forecasts based on limited datasets consistent with typical self-monitoring practices of individuals with type 2 diabetes. This paper uses three forecasting machines: (i) data assimilation, a technique borrowed from atmospheric physics and engineering that uses Bayesian modeling to infuse data with human knowledge represented in a mechanistic model, to generate real-time, personalized, adaptable glucose forecasts; (ii) model averaging of data assimilation output; and (iii) dynamical Gaussian process model regression. The proposed data assimilation machine, the primary focus of the paper, uses a modified dual unscented Kalman filter to estimate states and parameters, personalizing the mechanistic models. Model selection is used to make a personalized model selection for the individual and their measurement characteristics. The data assimilation forecasts are empirically evaluated against actual postprandial glucose measurements captured by individuals with type 2 diabetes, and against predictions generated by experienced diabetes educators after reviewing a set of historical nutritional records and glucose measurements for the same individual. The evaluation suggests that the data assimilation forecasts compare well with specific glucose measurements and match or exceed in accuracy expert forecasts. We conclude by examining ways to present predictions as forecast-derived range quantities and evaluate the comparative advantages of these ranges. A computational model of the physiological mechanisms driving an individual's health towards onset of type 2 diabetes (T2D) is described, calibrated and validated using data from the Diabetes Prevention Program (DPP). The objective of this model is to quantify the factors that can be used for prevention of T2D. The model is energy and mass balanced and continuously simulates trajectories of variables including body weight components, fasting plasma glucose, insulin, and glycosylated hemoglobin among others on the time-scale of years. Modeled mechanisms include dynamic representations of intracellular insulin resistance, pancreatic beta-cell insulin production, oxidation of macronutrients, ketogenesis, effects of inflammation and reactive oxygen species, and conversion between stored and activated metabolic species, with body-weight connected to mass and energy balance. The model was calibrated to 331 placebo and 315 lifestyle-intervention DPP subjects, and one year forecasts of all individuals were generated. Predicted population mean errors were less than or of the same magnitude as clinical measurement error; mean forecast errors for weight and HbA1c were 5 , supporting predictive capabilities of the model. Validation of lifestyle-intervention prediction is demonstrated by synthetically imposing diet and physical activity changes on DPP placebo subjects. Using subject level parameters, comparisons were made between exogenous and endogenous characteristics of subjects who progressed toward T2D (HbA1c > 6.5) over the course of the DPP study to those who did not. The comparison revealed significant differences in diets and pancreatic sensitivity to hyperglycemia but not in propensity to develop insulin resistance. A computational experiment was performed to explore relative contributions of exogenous versus endogenous factors between these groups. Translational uses to applications in public health and personalized healthcare are discussed. Computational systems biology unifies the mechanistic approach of systems biology with the data-driven approach of computational biology. Computational systems biology aims to develop algorithms that uncover the structure and parameterization of the underlying mechanistic model--in other words, to answer specific questions about the underlying mechanisms of a biological system--in a process that can be thought of as learning or inference. This volume offers state-of-the-art perspectives from computational biology, statistics, modeling, and machine learning on new methodologies for learning and inference in biological networks.The chapters offer practical approaches to biological inference problems ranging from genome-wide inference of genetic regulation to pathway-specific studies. Both deterministic models (based on ordinary differential equations) and stochastic models (which anticipate the increasing availability of data from small populations of cells) are considered. Several chapters emphasize Bayesian inference, so the editors have included an introduction to the philosophy of the Bayesian approach and an overview of current work on Bayesian inference. Taken together, the methods discussed by the experts in Learning and Inference in Computational Systems Biology provide a foundation upon which the next decade of research in systems biology can be built. Florence d'Alch e-Buc, John Angus, Matthew J. Beal, Nicholas Brunel, Ben Calderhead, Pei Gao, Mark Girolami, Andrew Golightly, Dirk Husmeier, Johannes Jaeger, Neil D. Lawrence, Juan Li, Kuang Lin, Pedro Mendes, Nicholas A. M. Monk, Eric Mjolsness, Manfred Opper, Claudia Rangel, Magnus Rattray, Andreas Ruttor, Guido Sanguinetti, Michalis Titsias, Vladislav Vyshemirsky, David L. Wild, Darren Wilkinson, Guy Yosiphon Graphical models (e.g., Bayesian and constraint networks, influence diagrams, and Markov decision processes) have become a central paradigm for knowledge representation and reasoning in both artificial intelligence and computer science in general. These models are used to perform many reasoning tasks, such as scheduling, planning and learning, diagnosis and prediction, design, hardware and software verification, and bioinformatics. These problems can be stated as the formal tasks of constraint satisfaction and satisfiability, combinatorial optimization, and probabilistic inference. It is well known that the tasks are computationally hard, but research during the past three decades has yielded a variety of principles and techniques that significantly advanced the state of the art. In this book we provide comprehensive coverage of the primary exact algorithms for reasoning with such models. The main feature exploited by the algorithms is the model's graph. We present inference-based, message-passing schemes (e.g., variable-elimination) and search-based, conditioning schemes (e.g., cycle-cutset conditioning and AND OR search). Each class possesses distinguished characteristics and in particular has different time vs. space behavior. We emphasize the dependence of both schemes on few graph parameters such as the treewidth, cycle-cutset, and (the pseudo-tree) height. We believe the principles outlined here would serve well in moving forward to approximation and anytime-based schemes. The target audience of this book is researchers and students in the artificial intelligence and machine learning area, and beyond. Table of Contents: Preface Introduction What are Graphical Models Inference: Bucket Elimination for Deterministic Networks Inference: Bucket Elimination for Probabilistic Networks Tree-Clustering Schemes AND OR Search Spaces and Algorithms for Graphical Models Combining Search and Inference: Trading Space for Time Conclusion Bibliography Author's Biography