Trajectories, bifurcations, and pseudo-time in large clinical datasets: applications to myocardial infarction and diabetes data

Background Large observational clinical datasets are becoming increasingly available for mining associations between various disease traits and administered therapy. These datasets can be considered as representations of the landscape of all possible disease conditions, in which a concrete disease state develops through stereotypical routes, characterized by “points of no return" and “final states" (such as lethal or recovery states). Extracting this information directly from the data remains challenging, especially in the case of synchronic (with a short-term follow-up) observations. Results Here we suggest a semi-supervised methodology for the analysis of large clinical datasets, characterized by mixed data types and missing values, through modeling the geometrical data structure as a bouquet of bifurcating clinical trajectories. The methodology is based on application of elastic principal graphs, which can address simultaneously the tasks of dimensionality reduction, data visualization, clustering, feature selection, and quantifying the geodesic distances (pseudo-time) in partially ordered sequences of observations. The methodology allows a patient to be positioned on a particular clinical trajectory (pathological scenario) and the degree of progression along it to be characterized with a qualitative estimate of the uncertainty of the prognosis. We developed a tool ClinTrajan for clinical trajectory analysis implemented in the Python programming language. We test the methodology in 2 large publicly available datasets: myocardial infarction complications and readmission of diabetic patients data. Conclusions Our pseudo-time quantification-based approach makes it possible to apply the methods developed for dynamical disease phenotyping and illness trajectory analysis (diachronic data analysis) to synchronic observational data.

The Mackey-Glass models, 40 years later

In 1977, Michael Mackey and Leon Glass published a short paper that presented and analyzed three delay-differential physiological models, one of which, now known as the Mackey-Glass equation, was shown to generate chaotic behavior. This paper also introduced the concept of a dynamical disease. In this perspective article, I attempt to place the Mackey-Glass paper and a 1979 followup in historical context, and thereby to gain some understanding of the very significant influence it has had across the sciences. This influence is mapped through a citation analysis, revealing both the timelessness of the themes broached in the Glass-Mackey papers, and of the broad influence of these papers, far transcending the specific scientific problems originally tackled.

Weighted and directed interactions in evolving large-scale epileptic brain networks

Epilepsy can be regarded as a network phenomenon with functionally and/or structurally aberrant connections in the brain. Over the past years, concepts and methods from network theory substantially contributed to improve the characterization of structure and function of these epileptic networks and thus to advance understanding of the dynamical disease epilepsy. We extend this promising line of research and assess—with high spatial and temporal resolution and using complementary analysis approaches that capture different characteristics of the complex dynamics—both strength and direction of interactions in evolving large-scale epileptic brain networks of 35 patients that suffered from drug-resistant focal seizures with different anatomical onset locations. Despite this heterogeneity, we find that even during the seizure-free interval the seizure onset zone is a brain region that, when averaged over time, exerts strongest directed influences over other brain regions being part of a large-scale network. This crucial role, however, manifested by averaging on the population-sample level only – in more than one third of patients, strongest directed interactions can be observed between brain regions far off the seizure onset zone. This may guide new developments for individualized diagnosis, treatment and control.

Mosquito breeding site water temperature observations and simulations towards improved vector-borne disease models for Africa

An energy budget model is developed to predict water temperature of typical mosquito larval developmental habitats. It assumes a homogeneous mixed water column driven by empirically derived fluxes. The model shows good agreement at both hourly and daily time scales with 10-min temporal resolution observed water temperatures, monitored between June and November 2013 within a peri-urban area of Kumasi, Ghana. There was a close match between larvae development times calculated using either the model-derived or observed water temperatures. The water temperature scheme represents a significant improvement over assuming the water temperature to be equal to air temperature. The energy budget model requires observed minimum and maximum temperatures, information that is generally available from weather stations. Our results show that hourly variations in water temperature are important for the simulation of aquatic-stage development times. By contrast, we found that larval development is insensitive to sub-hourly variations. Modelling suggests that in addition to water temperature, accurate estimation of degree-day development time is very important to correctly predict the larvae development times. The results highlight the potential of the model to predict water temperature of temporary bodies of surface water. Our study represents an important contribution towards the improvement of weatherdriven dynamical disease models, including those designed for malaria early forecasting systems.

Modeling Basal Ganglia for Understanding Parkinsonian Reaching Movements

We present a computational model that highlights the role of basal ganglia (BG) in generating simple reaching movements. The model is cast within the reinforcement learning (RL) framework with correspondence between RL components and neuroanatomy as follows: dopamine signal of substantia nigra pars compacta as the temporal difference error, striatum as the substrate for the critic, and the motor cortex as the actor. A key feature of this neurobiological interpretation is our hypothesis that the indirect pathway is the explorer. Chaotic activity, originating from the indirect pathway part of the model, drives the wandering, exploratory movements of the arm. Thus, the direct pathway subserves exploitation, while the indirect pathway subserves exploration. The motor cortex becomes more and more independent of the corrective influence of BG as training progresses. Reaching trajectories show diminishing variability with training. Reaching movements associated with Parkinson's disease (PD) are simulated by reducing dopamine and degrading the complexity of indirect pathway dynamics by switching it from chaotic to periodic behavior. Under the simulated PD conditions, the arm exhibits PD motor symptoms like tremor, bradykinesia and undershooting. The model echoes the notion that PD is a dynamical disease.

Voluntary performance

Will, purpose, and volition have long been viewed as either causes of behavior or of no direct consequence to behavior. In this essay, volition affects a flexible direct coupling of participant to task, modulating the degrees of freedom for kinematics in action, a point of view first introduced in theories of motor coordination. The consequence is an explanation consistent with present knowledge about involuntary and voluntary sources of control in human performance, and also the changes of the body expressed in aging and dynamical disease. Specifically, this view explains how tradeoffs between sources of overly regular versus overly random dynamics change the structure of variability in repeated measurements of voluntary performance.

Towards model-based control of Parkinson's disease

Modern model-based control theory has led to transformative improvements in our ability to track the nonlinear dynamics of systems that we observe, and to engineer control systems of unprecedented efficacy. In parallel with these developments, our ability to build computational models to embody our expanding knowledge of the biophysics of neurons and their networks is maturing at a rapid rate. In the treatment of human dynamical disease, our employment of deep brain stimulators for the treatment of Parkinson’s disease is gaining increasing acceptance. Thus, the confluence of these three developments—control theory, computational neuroscience and deep brain stimulation—offers a unique opportunity to create novel approaches to the treatment of this disease. This paper explores the relevant state of the art of science, medicine and engineering, and proposes a strategy for model-based control of Parkinson’s disease. We present a set of preliminary calculations employing basal ganglia computational models, structured within an unscented Kalman filter for tracking observations and prescribing control. Based upon these findings, we will offer suggestions for future research and development.