OBJECTIVES: Report the development of the patient-centered myAURA application and suite of methods designed to aid epilepsy patients, caregivers, and clinicians in making decisions about self-management and care. MATERIALS AND METHODS: myAURA rests on an unprecedented collection of epilepsy-relevant heterogeneous data resources, such as biomedical databases, social media, and electronic health records (EHRs). We use a patient-centered biomedical dictionary to link the collected data in a multilayer knowledge graph (KG) computed with a generalizable, open-source methodology. RESULTS: Our approach is based on a novel network sparsification method that uses the metric backbone of weighted graphs to discover important edges for inference, recommendation, and visualization. We demonstrate by studying drug-drug interaction from EHRs, extracting epilepsy-focused digital cohorts from social media, and generating a multilayer KG visualization. We also present our patient-centered design and pilot-testing of myAURA, including its user interface. DISCUSSION: The ability to search and explore myAURA's heterogeneous data sources in a single, sparsified, multilayer KG is highly useful for a range of epilepsy studies and stakeholder support. CONCLUSION: Our stakeholder-driven, scalable approach to integrating traditional and nontraditional data sources enables both clinical discovery and data-powered patient self-management in epilepsy and can be generalized to other chronic conditions.

SUMMARY: The biomolecular networks underpinning cell function exhibit canalization, or the buffering of fluctuations required to function in a noisy environment. We present a new major release of CANA, v1.0.0, an open-source Python package for understanding canalization in automata network models, discrete dynamical systems in which activation of biomolecular entities (e.g. transcription of genes) is modeled as the activity of coupled automata. One understudied putative mechanism for canalization is the functional equivalence of biomolecular regulators (e.g. among the transcription factors for a gene). We study this mechanism using the theory of symmetry in discrete functions. We present a new exact method, schematodes, for finding maximal symmetry groups among the inputs to discrete functions, and integrate it into CANA. The schematodes method substantially outperforms the inexact method of previous CANA versions both in speed and accuracy. We apply CANA v1.0.0 to study symmetry in 74 experimentally supported automata network models from the Cell Collective (CC) repository. The symmetry distribution is significantly different in the CC than in random automata with the same in-degree (connectivity) and bias (average output) (Kolmogorov-Smirnov test, P ≪ .001). Its spread is much wider than in a null model (IQR 0.31 versus IQR 0.20 with equal medians), demonstrating that the CC is enriched in functions with extreme symmetry or asymmetry. AVAILABILITY AND IMPLEMENTATION: CANA source is on https://github.com/CASCI-lab/CANA and is installable via pip install cana. Source for schematodes is on https://github.com/CASCI-lab/schematodes. Analysis scripts are on https://github.com/CASCI-lab/symmetryInCellCollective.

MOTIVATION: Boolean networks are popular dynamical models of cellular processes in systems biology. Their attractors model phenotypes that arise from the interplay of key regulatory subcircuits. A succession diagram (SD) describes this interplay in a discrete analog of Waddington's epigenetic attractor landscape that allows for fast identification of attractors and attractor control strategies. Efficient computational tools for studying SDs are essential for the understanding of Boolean attractor landscapes and connecting them to their biological functions. RESULTS: We present a new approach to SD construction for asynchronously updated Boolean networks, implemented in the biologist's Boolean attractor landscape mapper, biobalm. We compare biobalm to similar tools and find a substantial performance increase in SD construction, attractor identification, and attractor control. We perform the most comprehensive comparative analysis to date of the SD structure in experimentally-validated Boolean models of cell processes and random ensembles. We find that random models (including critical Kauffman networks) have relatively small SDs, indicating simple decision structures. In contrast, nonrandom models from the literature are enriched in extremely large SDs, indicating an abundance of decision points and suggesting the presence of complex Waddington landscapes in nature. AVAILABILITY AND IMPLEMENTATION: The tool biobalm is available online at https://github.com/jcrozum/biobalm. Further data, scripts for testing, analysis, and figure generation are available online at https://github.com/jcrozum/biobalm-analysis and in the reproducibility artefact at https://doi.org/10.5281/zenodo.13854760.

Social media data allows researchers to construct large digital cohorts - groups of users who post health-related content - to study the interplay between human behavior and medical treatment. Identifying the users most relevant to a specific health problem is, however, a challenge in that social media sites vary in the generality of their discourse. While X (formerly Twitter), Instagram, and Facebook cater to wide ranging topics, Reddit subgroups and dedicated patient advocacy forums trade in much more specific, biomedically-relevant discourse. To filter relevant users on any social media, we have developed a general method and tested it on epilepsy discourse. We analyzed the text from posts by users who mention epilepsy drugs at least once in the general-purpose social media sites X and Instagram, the epilepsy-focused Reddit subgroup (r/Epilepsy), and the Epilepsy Foundation of America (EFA) forums. We used a curated medical terminology dictionary to generate a knowledge graph (KG) from each social media site, whereby nodes represent terms, and edge weights denote the strength of association between pairs of terms in the collected text. Our method is based on computing the metric backbone of each KG, which yields the (sparsified) subgraph of edges that participate in shortest paths. By comparing the subset of users who contribute to the backbone to the subset who do not, we show that epilepsy-focused social media users contribute to the KG backbone in much higher proportion than do general-purpose social media users. Furthermore, using human annotation of Instagram posts, we demonstrate that users who do not contribute to the backbone are much more likely to use dictionary terms in a manner inconsistent with their biomedical meaning and are rightly excluded from the cohort of interest. Our metric backbone approach, thus, has several benefits: it yields focused user cohorts who engage in discourse relevant to a targeted biomedical problem; unlike engagement-based approaches, it can retain low-engagement users who nonetheless contribute meaningful biomedical insights and filter out very vocal users who contribute no relevant content, it is parameter-free, algebraically principled, does not require classifiers or human-curation, and is simple to compute with the open-source code we provide.

Genetic regulatory networks (GRNs) regulate the flow of genetic information from the genome to expressed messenger RNAs (mRNAs) and thus are critical to controlling the phenotypic characteristics of cells. Numerous methods exist for profiling mRNA transcript levels and identifying protein-DNA binding interactions at the genome-wide scale. These enable researchers to determine the structure and output of transcriptional regulatory networks, but uncovering the complete structure and regulatory logic of GRNs remains a challenge. The field of GRN inference aims to meet this challenge using computational modeling to derive the structure and logic of GRNs from experimental data and to encode this knowledge in Boolean networks, Bayesian networks, ordinary differential equation (ODE) models, or other modeling frameworks. However, most existing models do not incorporate dynamic transcriptional data since it has historically been less widely available in comparison to "static" transcriptional data. We report the development of an evolutionary algorithm-based ODE modeling approach (named EA) that integrates kinetic transcription data and the theory of attractor matching to infer GRN architecture and regulatory logic. Our method outperformed six leading GRN inference methods, none of which incorporate kinetic transcriptional data, in predicting regulatory connections among TFs when applied to a small-scale engineered synthetic GRN in Saccharomyces cerevisiae. Moreover, we demonstrate the potential of our method to predict unknown transcriptional profiles that would be produced upon genetic perturbation of the GRN governing a two-state cellular phenotypic switch in Candida albicans. We established an iterative refinement strategy to facilitate candidate selection for experimentation; the experimental results in turn provide validation or improvement for the model. In this way, our GRN inference approach can expedite the development of a sophisticated mathematical model that can accurately describe the structure and dynamics of the in vivo GRN.

SUMMARY: pystablemotifs is a Python 3 library for analyzing Boolean networks. Its non-heuristic and exhaustive attractor identification algorithm was previously presented in Rozum et al. (2021). Here, we illustrate its performance improvements over similar methods and discuss how it uses outputs of the attractor identification process to drive a system to one of its attractors from any initial state. We implement six attractor control algorithms, five of which are new in this work. By design, these algorithms can return different control strategies, allowing for synergistic use. We also give a brief overview of the other tools implemented in pystablemotifs. AVAILABILITY AND IMPLEMENTATION: The source code is on GitHub at https://github.com/jcrozum/pystablemotifs/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

We present a technique applicable in any dynamical framework to identify control-robust subsets of an interacting system. These robust subsystems, which we call stable modules, are characterized by constraints on the variables that make up the subsystem. They are robust in the sense that if the defining constraints are satisfied at a given time, they remain satisfied for all later times, regardless of what happens in the rest of the system, and can only be broken if the constrained variables are externally manipulated. We identify stable modules as graph structures in an expanded network, which represents causal links between variable constraints. A stable module represents a system "decision point", or trap subspace. Using the expanded network, small stable modules can be composed sequentially to form larger stable modules that describe dynamics on the system level. Collections of large, mutually exclusive stable modules describe the system's repertoire of long-term behaviors. We implement this technique in a broad class of dynamical systems and illustrate its practical utility via examples and algorithmic analysis of two published biological network models. In the segment polarity gene network of Drosophila melanogaster, we obtain a state-space visualization that reproduces by novel means the four possible cell fates and predicts the outcome of cell transplant experiments. In the T-cell signaling network, we identify six signaling elements that determine the high-signal response and show that control of an element connected to them cannot disrupt this response.