Rapid, high-resolution, non-destructive assessments of metabolic and morphological homogeneity uniquely identify high-grade cervical precancerous lesions.

Purpose: Two-photon microscopy (2PM) is an emerging clinical imaging modality with the potential to non-invasively assess tissue metabolism and morphology in high-resolution. This study aimed to assess the translational potential of 2PM for improved detection of high-grade cervical precancerous lesions. Experimental Design: 2P images attributed to reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) and oxidized flavoproteins (FP) were acquired from the full epithelial thickness of freshly excised human cervical tissue biopsies (N = 62). Fifteen biopsies harbored high-grade squamous intraepithelial lesions (HSILs), 14 biopsies harbored low-grade SILs (LSILs), and 33 biopsies were benign. Quadratic discriminant analysis (QDA) leveraged morphological and metabolic functional metrics extracted from these images to predict the presence of HSILs. We performed gene set enrichment analysis (GSEA) using datasets available on the Gene Expression Omnibus (GEO) to validate the presence of metabolic reprogramming in HSILs. Results: Integrating metabolic and morphological 2P-derived metrics from finely sampled, full-thickness epithelia achieved a high 90.8 ± 6.1% sensitivity and 72.3 ± 11.3% specificity of HSIL detection. Notably, sensitivity (91.4 ± 12.0%) and specificity (77.5 ± 12.6%) were maintained when utilizing metrics from only two images at 12- and 72-µm from the tissue surface. Upregulation of glycolysis, fatty acid metabolism, and oxidative phosphorylation in HSIL tissues validated the metabolic reprogramming captured by 2P biomarkers. Conclusion: Label-free 2P images from as few as two epithelial depths enable rapid and robust HSIL detection through the quantitative characterization of metabolic and morphological reprogramming, underscoring the potential of this tool for clinical evaluation of cervical precancers.

Identification of disease modules using higher-order network structure.

Motivation: Higher-order interaction patterns among proteins have the potential to reveal mechanisms behind molecular processes and diseases. While clustering methods are used to identify functional groups within molecular interaction networks, these methods largely focus on edge density and do not explicitly take into consideration higher-order interactions. Disease genes in these networks have been shown to exhibit rich higher-order structure in their vicinity, and considering these higher-order interaction patterns in network clustering have the potential to reveal new disease-associated modules. Results: We propose a higher-order community detection method which identifies community structure in networks with respect to specific higher-order connectivity patterns beyond edges. Higher-order community detection on four different protein-protein interaction networks identifies biologically significant modules and disease modules that conventional edge-based clustering methods fail to discover. Higher-order clusters also identify disease modules from genome-wide association study data, including new modules that were not discovered by top-performing approaches in a Disease Module DREAM Challenge. Our approach provides a more comprehensive view of community structure that enables us to predict new disease-gene associations. Availability and implementation: https://github.com/Reed-CompBio/graphlet-clustering.

Reconciling Signaling Pathway Databases with Network Topologies.

A major goal of molecular systems biology is to understand the coordinated function of genes or proteins in response to cellular signals and to understand these dynamics in the context of disease. Signaling pathway databases such as KEGG, NetPath, NCI-PID, and Panther describe the molecular interactions involved in different cellular responses. While the same pathway may be present in different databases, prior work has shown that the particular proteins and interactions differ across database annotations. However, to our knowledge no one has attempted to quantify their structural differences. It is important to characterize artifacts or other biases within pathway databases, which can provide a more informed interpretation for downstream analyses. In this work we consider signaling pathways as graphs and we use topological measures to study their structure. We find that topological characterization using graphlets (small, connected subgraphs) distinguishes signaling pathways from appropriate null models of interaction networks. Next, we quantify topological similarity across pathway databases. Our analysis reveals that the pathways harbor database-specific characteristics implying that even though these databases describe the same pathways, they tend to be systematically different from one another. We show that pathway-specific topology can be uncovered after accounting for database-specific structure. This work presents the first step towards elucidating common pathway structure beyond their specific database annotations.Data Availability: https://github.com/Reed-CompBio/pathway-reconciliation.

Graphery: interactive tutorials for biological network algorithms.

Networks have been an excellent framework for modeling complex biological information, but the methodological details of network-based tools are often described for a technical audience. We have developed Graphery, an interactive tutorial webserver that illustrates foundational graph concepts frequently used in network-based methods. Each tutorial describes a graph concept along with executable Python code that can be interactively run on a graph. Users navigate each tutorial using their choice of real-world biological networks that highlight the diverse applications of network algorithms. Graphery also allows users to modify the code within each tutorial or write new programs, which all can be executed without requiring an account. Graphery accepts ideas for new tutorials and datasets that will be shaped by both computational and biological researchers, growing into a community-contributed learning platform. Graphery is available at https://graphery.reedcompbio.org/.

Reduced network extremal ensemble learning (RenEEL) scheme for community detection in complex networks.

We introduce an ensemble learning scheme for community detection in complex networks. The scheme uses a Machine Learning algorithmic paradigm we call Extremal Ensemble Learning. It uses iterative extremal updating of an ensemble of network partitions, which can be found by a conventional base algorithm, to find a node partition that maximizes modularity. At each iteration, core groups of nodes that are in the same community in every ensemble partition are identified and used to form a reduced network. Partitions of the reduced network are then found and used to update the ensemble. The smaller size of the reduced network makes the scheme efficient. We use the scheme to analyze the community structure in a set of commonly studied benchmark networks and find that it outperforms all other known methods for finding the partition with maximum modularity.

Peer-to-peer lending and bias in crowd decision-making.

Peer-to-peer lending is hypothesized to help equalize economic opportunities for the world's poor. We empirically investigate the "flat-world" hypothesis, the idea that globalization eventually leads to economic equality, using crowdfinancing data for over 660,000 loans in 220 nations and territories made between 2005 and 2013. Contrary to the flat-world hypothesis, we find that peer-to-peer lending networks are moving away from flatness. Furthermore, decreasing flatness is strongly associated with multiple variables: relatively stable patterns in the difference in the per capita GDP between borrowing and lending nations, ongoing migration flows from borrowing to lending nations worldwide, and the existence of a tie as a historic colonial. Our regression analysis also indicates a spatial preference in lending for geographically proximal borrowers. To estimate the robustness for these patterns for future changes, we construct a network of borrower and lending nations based on the observed data. Then, to perturb the network, we stochastically simulate policy and event shocks (e.g., erecting walls) or regulatory shocks (e.g., Brexit). The simulations project a drift towards rather than away from flatness. However, levels of flatness persist only for randomly distributed shocks. By contrast, loss of the top borrowing nations produces more flatness, not less, indicating how the welfare of the overall system is tied to a few distinctive and critical country-pair relationships.