Control of complex networks requires both structure and dynamics

The study of network structure has uncovered signatures of the organization of complex systems. However, there is also a need to understand how to control them; for example, identifying strategies to revert a diseased cell to a healthy state, or a mature cell to a pluripotent state. Two recent methodologies suggest that the controllability of complex systems can be predicted solely from the graph of interactions between variables, without considering their dynamics: structural controllability and minimum dominating sets. We demonstrate that such structure-only methods fail to characterize controllability when dynamics are introduced. We study Boolean network ensembles of network motifs as well as three models of biochemical regulation: the segment polarity network in Drosophila melanogaster, the cell cycle of budding yeast Saccharomyces cerevisiae, and the floral organ arrangement in Arabidopsis thaliana. We demonstrate that structure-only methods both undershoot and overshoot the number and which sets of critical variables best control the dynamics of these models, highlighting the importance of the actual system dynamics in determining control. Our analysis further shows that the logic of automata transition functions, namely how canalizing they are, plays an important role in the extent to which structure predicts dynamics.Comment: 15 pages, 6 figure

Modularity and the spread of perturbations in complex dynamical systems

We propose a method to decompose dynamical systems based on the idea that modules constrain the spread of perturbations. We find partitions of system variables that maximize 'perturbation modularity', defined as the autocovariance of coarse-grained perturbed trajectories. The measure effectively separates the fast intramodular from the slow intermodular dynamics of perturbation spreading (in this respect, it is a generalization of the 'Markov stability' method of network community detection). Our approach captures variation of modular organization across different system states, time scales, and in response to different kinds of perturbations: aspects of modularity which are all relevant to real-world dynamical systems. It offers a principled alternative to detecting communities in networks of statistical dependencies between system variables (e.g., 'relevance networks' or 'functional networks'). Using coupled logistic maps, we demonstrate that the method uncovers hierarchical modular organization planted in a system's coupling matrix. Additionally, in homogeneously-coupled map lattices, it identifies the presence of self-organized modularity that depends on the initial state, dynamical parameters, and type of perturbations. Our approach offers a powerful tool for exploring the modular organization of complex dynamical systems

Evaluation of linear classifiers on articles containing pharmacokinetic evidence of drug-drug interactions

Background. Drug-drug interaction (DDI) is a major cause of morbidity and mortality. [...] Biomedical literature mining can aid DDI research by extracting relevant DDI signals from either the published literature or large clinical databases. However, though drug interaction is an ideal area for translational research, the inclusion of literature mining methodologies in DDI workflows is still very preliminary. One area that can benefit from literature mining is the automatic identification of a large number of potential DDIs, whose pharmacological mechanisms and clinical significance can then be studied via in vitro pharmacology and in populo pharmaco-epidemiology. Experiments. We implemented a set of classifiers for identifying published articles relevant to experimental pharmacokinetic DDI evidence. These documents are important for identifying causal mechanisms behind putative drug-drug interactions, an important step in the extraction of large numbers of potential DDIs. We evaluate performance of several linear classifiers on PubMed abstracts, under different feature transformation and dimensionality reduction methods. In addition, we investigate the performance benefits of including various publicly-available named entity recognition features, as well as a set of internally-developed pharmacokinetic dictionaries. Results. We found that several classifiers performed well in distinguishing relevant and irrelevant abstracts. We found that the combination of unigram and bigram textual features gave better performance than unigram features alone, and also that normalization transforms that adjusted for feature frequency and document length improved classification. For some classifiers, such as linear discriminant analysis (LDA), proper dimensionality reduction had a large impact on performance. Finally, the inclusion of NER features and dictionaries was found not to help classification.Comment: Pacific Symposium on Biocomputing, 201

Actionable models of control in complex systems for the biomedical domain

Modern artificial intelligence (AI) and machine learning (ML) techniques predict system behavior from previous observations. However, in biology, and in true complex systems in general, profound transformation in system behavior can occur from never before seen observations. Moreover, AI/ML techniques are often unable to provide an explanation for their predictions. I will argue that complex systems modeling, while using AI/ ML techniques to estimate parameters, needs to produce actionable, dynamical models that can predict and explain system behavior for rare or unseen control events. This is particularly true for understanding biochemical regulation under dynamical perturbations from environmental and evolutionary events. Towards that goal, I will present our recent work uncovering effective control pathways in the canalizing dynamics of biochemical regulation. Our methodology centers on removing redundancy from systems biology models of development, cell cycle, and cancer response, as well as in models of cortical networks cultured from mouse brains. Removing the large amounts of redundancy in these models, reveals preferred pathways for the spread of perturbations and the building blocks of dynamical response, leading to the prediction of actionable control interventions

City-wide Analysis of Electronic Health Records Reveals Gender and Age Biases in the Administration of Known Drug-Drug Interactions

The occurrence of drug-drug-interactions (DDI) from multiple drug dispensations is a serious problem, both for individuals and health-care systems, since patients with complications due to DDI are likely to reenter the system at a costlier level. We present a large-scale longitudinal study (18 months) of the DDI phenomenon at the primary- and secondary-care level using electronic health records (EHR) from the city of Blumenau in Southern Brazil (pop. $\approx 340,000$). We found that 181 distinct drug pairs known to interact were dispensed concomitantly to 12\% of the patients in the city's public health-care system. Further, 4\% of the patients were dispensed drug pairs that are likely to result in major adverse drug reactions (ADR)---with costs estimated to be much larger than previously reported in smaller studies. The large-scale analysis reveals that women have a 60\% increased risk of DDI as compared to men; the increase becomes 90\% when considering only DDI known to lead to major ADR. Furthermore, DDI risk increases substantially with age; patients aged 70-79 years have a 34\% risk of DDI when they are dispensed two or more drugs concomitantly. Interestingly, a statistical null model demonstrates that age- and female-specific risks from increased polypharmacy fail by far to explain the observed DDI risks in those populations, suggesting unknown social or biological causes. We also provide a network visualization of drugs and demographic factors that characterize the DDI phenomenon and demonstrate that accurate DDI prediction can be included in healthcare and public-health management, to reduce DDI-related ADR and costs