Background: We consider the problem of parameter estimation (model calibration) in nonlinear dynamic models of biological systems. Due to the frequent ill-conditioning and multi-modality of many of these problems, traditional local methods usually fail (unless initialized with very good guesses of the parameter vector). In order to surmount these difficulties, global optimization (GO) methods have been suggested as robust alternatives. Currently, deterministic GO methods can not solve problems of realistic size within this class in reasonable computation times. In contrast, certain types of stochastic GO methods have shown promising results, although the computational cost remains large. Rodriguez-Fernandez and coworkers have presented hybrid stochastic-deterministic GO methods which could reduce computation time by one order of magnitude while guaranteeing robustness. Our goal here was to further reduce the computational effort without loosing robustness. Results: We have developed a new procedure based on the scatter search methodology for nonlinear optimization of dynamic models of arbitrary (or even unknown) structure (i.e. black-box models). In this contribution, we describe and apply this novel metaheuristic, inspired by recent developments in the field of operations research, to a set of complex identification problems and we make a critical comparison with respect to the previous (above mentioned) successful methods. Conclusion: Robust and efficient methods for parameter estimation are of key importance in systems biology and related areas. The new metaheuristic presented in this paper aims to ensure the proper solution of these problems by adopting a global optimization approach, while keeping the computational effort under reasonable values. This new metaheuristic was applied to a set of three challenging parameter estimation problems of nonlinear dynamic biological systems, outperforming very significantly all the methods previously used for these benchmark problems.

Cortisol, secreted in the adrenal cortex in response to stress, is an informative biomarker that distinguishes anxiety disorders such as major depression and post-traumatic stress disorder (PTSD) from normal subjects. Yehuda et al. proposed a hypothesis that, in humans, the hypersensitive hypothalamus-pituitary-adrenal (HPA) axis is responsible for the occurrence of differing levels of cortisol in anxiety disorders. Specifically, PTSD subjects have lower cortisol levels during the late subjective night in comparison to normal subjects, and this was assumed to occur due to strong negative feedback loops in the HPA axis. In the present work, to address this hypothesis, we modeled the cortisol dynamics using nonlinear ordinary differential equations and estimated the kinetic parameters of the model to fit the experimental data of three categories, namely, normal, depressed, and PTSD human subjects. We concatenated the subjects (n = 3) in each category and created a model subject (n = 1) without considering the patient-to-patient variability in each case. The parameters of the model for the three categories were simultaneously obtained through global optimization. Bifurcation analysis carried out with the optimized parameters exhibited two supercritical Hopf points and, for the choice of parameters, the oscillations were found to be circadian in nature. The fitted kinetic parameters indicate that PTSD subjects have a strong negative feedback loop and, as a result, the predicted oscillating cortisol levels are extremely low at the nadir in contrast to normal subjects, albeit within the endocrinologic range. We also simulated the phenotypes for each of the categories and, as observed in the clinical data of PTSD patients, the simulated cortisol levels are consistently low at the nadir, and correspondingly the negative feedback was found to be extremely strong. These results from the model support the hypothesis that high stress intensity and strong negative feedback loop may cause hypersensitive neuro-endocrine axis that results in hypocortisolemia in PTSD. PTSD is an anxiety disorder that occurs among persons exposed to a traumatic event involving life threat and injury. This is a co-morbid psychiatric disorder that occurs along with depression. Cortisol is an informative endocrine biomarker that can distinguish PTSD from other co-morbid disorders. In comparison to normal subjects, hypocortisolemia was observed during the night in PTSD, while hypercortisolemia was observed in depressed subjects. From analyzing the clinical data, Yehuda et al. hypothesized that hypocortisolemia in PTSD was due to the strong negative feedback loop operating in the neuroendocrine axis under severe stress. We complemented this hypothesis by constructing a mathematical model for cortisol dynamics in HPA axis and estimated the kinetic parameters that fitted the cortisol time series obtained from the clinical data of normal, depressed and PTSD patients. The parameters obtained from the simulated phenotypes also strongly support the hypothesis that, due to disruptive negative feedback loops, cortisol levels are different in normal, PTSD and depressed subjects during the night. Importantly, the model predicted the transitions from normal to various diseased states, and these transitions were shown to occur due to changes in the strength of the negative feedback loop and the stress intensity in the neuro-endocrine axis.

Affect detection combined with a system that dynamically responds to a person’s emotional state allows an improved user experience with computers, systems, and environments and has a wide range of applications, including entertainment and health care. Previous studies on this topic have used a variety of machine learning algorithms and inputs such as audial, visual, or physiological signals. Recently, a lot of interest has been focused on the last, as speech or video recording is impractical for some applications. Therefore, there is a need to create Human–Computer Interface Systems capable of recognizing emotional states from noninvasive and nonintrusive physiological signals. Typically, the recognition task is carried out from electroencephalogram (EEG) signals, obtaining good accuracy. However, EEGs are difficult to register without interfering with daily activities, and recent studies have shown that it is possible to use electrocardiogram (ECG) signals for this purpose. This work improves the performance of emotion recognition from ECG signals using wavelet transform for signal analysis. Features of the ECG signal are extracted from the AMIGOS database using a wavelet scattering algorithm that allows obtaining features of the signal at different time scales, which are then used as inputs for different classifiers to evaluate their performance. The results show that the proposed algorithm for extracting features and classifying the signals obtains an accuracy of 88.8% in the valence dimension, 90.2% in arousal, and 95.3% in a two-dimensional classification, which is better than the performance reported in previous studies. This algorithm is expected to be useful for classifying emotions using wearable devices.