Integration of relational and hierarchical network information for protein function prediction

BACKGROUND:In the current climate of high-throughput computational biology, the inference of a protein's function from related measurements, such as protein-protein interaction relations, has become a canonical task. Most existing technologies pursue this task as a classification problem, on a term-by-term basis, for each term in a database, such as the Gene Ontology (GO) database, a popular rigorous vocabulary for biological functions. However, ontology structures are essentially hierarchies, with certain top to bottom annotation rules which protein function predictions should in principle follow. Currently, the most common approach to imposing these hierarchical constraints on network-based classifiers is through the use of transitive closure to predictions.RESULTS:We propose a probabilistic framework to integrate information in relational data, in the form of a protein-protein interaction network, and a hierarchically structured database of terms, in the form of the GO database, for the purpose of protein function prediction. At the heart of our framework is a factorization of local neighborhood information in the protein-protein interaction network across successive ancestral terms in the GO hierarchy. We introduce a classifier within this framework, with computationally efficient implementation, that produces GO-term predictions that naturally obey a hierarchical 'true-path' consistency from root to leaves, without the need for further post-processing.CONCLUSION:A cross-validation study, using data from the yeast Saccharomyces cerevisiae, shows our method offers substantial improvements over both standard 'guilt-by-association' (i.e., Nearest-Neighbor) and more refined Markov random field methods, whether in their original form or when post-processed to artificially impose 'true-path' consistency. Further analysis of the results indicates that these improvements are associated with increased predictive capabilities (i.e., increased positive predictive value), and that this increase is consistent uniformly with GO-term depth. Additional in silico validation on a collection of new annotations recently added to GO confirms the advantages suggested by the cross-validation study. Taken as a whole, our results show that a hierarchical approach to network-based protein function prediction, that exploits the ontological structure of protein annotation databases in a principled manner, can offer substantial advantages over the successive application of 'flat' network-based methods.

Exploiting Phonological Constraints for Handshape Inference in ASL Video

Handshape is a key articulatory parameter in sign language, and thus handshape recognition from signing video is essential for sign recognition and retrieval. Handshape transitions within monomorphemic lexical signs (the largest class of signs in signed languages) are governed by phonological rules. For example, such transitions normally involve either closing or opening of the hand (i.e., to exclusively use either folding or unfolding of the palm and one or more fingers). Furthermore, akin to allophonic variations in spoken languages, both inter- and intra- signer variations in the production of specific handshapes are observed. We propose a Bayesian network formulation to exploit handshape co-occurrence constraints, also utilizing information about allophonic variations to aid in handshape recognition. We propose a fast non-rigid image alignment method to gain improved robustness to handshape appearance variations during computation of observation likelihoods in the Bayesian network. We evaluate our handshape recognition approach on a large dataset of monomorphemic lexical signs. We demonstrate that leveraging linguistic constraints on handshapes results in improved handshape recognition accuracy. As part of the overall project, we are collecting and preparing for dissemination a large corpus (three thousand signs from three native signers) of American Sign Language (ASL) video. The video have been annotated using SignStream® [Neidle et al.] with labels for linguistic information such as glosses, morphological properties and variations, and start/end handshapes associated with each ASL sign.

Safe Compositional Network Sketches: NetSketch Tool Implementation

Numerous problems exist that can be modeled as traffic through a network in which constraints exist to regulate flow. Vehicular road travel, computer networks, and cloud based resource distribution, among others all have natural representations in this manner. As these networks grow in size and/or complexity, analysis and certification of the safety invariants becomes increasingly costly. The NetSketch formalism introduces a lightweight verification framework that allows for greater scalability than traditional analysis methods. The NetSketch tool was developed to provide the power of this formalism in an easy to use and intuitive user interface.

Systematic Verification of Safety Properties of Arbitrary Network Protocol Compositions Using CHAIN

Formal correctness of complex multi-party network protocols can be difficult to verify. While models of specific fixed compositions of agents can be checked against design constraints, protocols which lend themselves to arbitrarily many compositions of agents-such as the chaining of proxies or the peering of routers-are more difficult to verify because they represent potentially infinite state spaces and may exhibit emergent behaviors which may not materialize under particular fixed compositions. We address this challenge by developing an algebraic approach that enables us to reduce arbitrary compositions of network agents into a behaviorally-equivalent (with respect to some correctness property) compact, canonical representation, which is amenable to mechanical verification. Our approach consists of an algebra and a set of property-preserving rewrite rules for the Canonical Homomorphic Abstraction of Infinite Network protocol compositions (CHAIN). Using CHAIN, an expression over our algebra (i.e., a set of configurations of network protocol agents) can be reduced to another behaviorally-equivalent expression (i.e., a smaller set of configurations). Repeated applications of such rewrite rules produces a canonical expression which can be checked mechanically. We demonstrate our approach by characterizing deadlock-prone configurations of HTTP agents, as well as establishing useful properties of an overlay protocol for scheduling MPEG frames, and of a protocol for Web intra-cache consistency.

Generating Representative Web Workloads for Network and Server Performance Evaluation

One role for workload generation is as a means for understanding how servers and networks respond to variation in load. This enables management and capacity planning based on current and projected usage. This paper applies a number of observations of Web server usage to create a realistic Web workload generation tool which mimics a set of real users accessing a server. The tool, called Surge (Scalable URL Reference Generator) generates references matching empirical measurements of 1) server file size distribution; 2) request size distribution; 3) relative file popularity; 4) embedded file references; 5) temporal locality of reference; and 6) idle periods of individual users. This paper reviews the essential elements required in the generation of a representative Web workload. It also addresses the technical challenges to satisfying this large set of simultaneous constraints on the properties of the reference stream, the solutions we adopted, and their associated accuracy. Finally, we present evidence that Surge exercises servers in a manner significantly different from other Web server benchmarks.

Examples of Network Flow Verification Using TRAFFIC(X)

In our previous work, we developed TRAFFIC(X), a specification language for modeling bi-directional network flows featuring a type system with constrained polymorphism. In this paper, we present two ways to customize the constraint system: (1) when using linear inequality constraints for the constraint system, TRAFFIC(X) can describe flows with numeric properties such as MTU (maximum transmission unit), RTT (round trip time), traversal order, and bandwidth allocation over parallel paths; (2) when using Boolean predicate constraints for the constraint system, TRAFFIC(X) can describe routing policies of an IP network. These examples illustrate how to use the customized type system.

The Sensor Network Workbench: Towards Functional Specification, Verification and Deployment of Constrained Distributed Systems

As the commoditization of sensing, actuation and communication hardware increases, so does the potential for dynamically tasked sense and respond networked systems (i.e., Sensor Networks or SNs) to replace existing disjoint and inflexible special-purpose deployments (closed-circuit security video, anti-theft sensors, etc.). While various solutions have emerged to many individual SN-centric challenges (e.g., power management, communication protocols, role assignment), perhaps the largest remaining obstacle to widespread SN deployment is that those who wish to deploy, utilize, and maintain a programmable Sensor Network lack the programming and systems expertise to do so. The contributions of this thesis centers on the design, development and deployment of the SN Workbench (snBench). snBench embodies an accessible, modular programming platform coupled with a flexible and extensible run-time system that, together, support the entire life-cycle of distributed sensory services. As it is impossible to find a one-size-fits-all programming interface, this work advocates the use of tiered layers of abstraction that enable a variety of high-level, domain specific languages to be compiled to a common (thin-waist) tasking language; this common tasking language is statically verified and can be subsequently re-translated, if needed, for execution on a wide variety of hardware platforms. snBench provides: (1) a common sensory tasking language (Instruction Set Architecture) powerful enough to express complex SN services, yet simple enough to be executed by highly constrained resources with soft, real-time constraints, (2) a prototype high-level language (and corresponding compiler) to illustrate the utility of the common tasking language and the tiered programming approach in this domain, (3) an execution environment and a run-time support infrastructure that abstract a collection of heterogeneous resources into a single virtual Sensor Network, tasked via this common tasking language, and (4) novel formal methods (i.e., static analysis techniques) that verify safety properties and infer implicit resource constraints to facilitate resource allocation for new services. This thesis presents these components in detail, as well as two specific case-studies: the use of snBench to integrate physical and wireless network security, and the use of snBench as the foundation for semester-long student projects in a graduate-level Software Engineering course.

Overlay Network Creation and Maintenance with Selfish Users

Overlay networks have been used for adding and enhancing functionality to the end-users without requiring modifications in the Internet core mechanisms. Overlay networks have been used for a variety of popular applications including routing, file sharing, content distribution, and server deployment. Previous work has focused on devising practical neighbor selection heuristics under the assumption that users conform to a specific wiring protocol. This is not a valid assumption in highly decentralized systems like overlay networks. Overlay users may act selfishly and deviate from the default wiring protocols by utilizing knowledge they have about the network when selecting neighbors to improve the performance they receive from the overlay. This thesis goes against the conventional thinking that overlay users conform to a specific protocol. The contributions of this thesis are threefold. It provides a systematic evaluation of the design space of selfish neighbor selection strategies in real overlays, evaluates the performance of overlay networks that consist of users that select their neighbors selfishly, and examines the implications of selfish neighbor and server selection to overlay protocol design and service provisioning respectively. This thesis develops a game-theoretic framework that provides a unified approach to modeling Selfish Neighbor Selection (SNS) wiring procedures on behalf of selfish users. The model is general, and takes into consideration costs reflecting network latency and user preference profiles, the inherent directionality in overlay maintenance protocols, and connectivity constraints imposed on the system designer. Within this framework the notion of user’s "best response" wiring strategy is formalized as a k-median problem on asymmetric distance and is used to obtain overlay structures in which no node can re-wire to improve the performance it receives from the overlay. Evaluation results presented in this thesis indicate that selfish users can reap substantial performance benefits when connecting to overlay networks composed of non-selfish users. In addition, in overlays that are dominated by selfish users, the resulting stable wirings are optimized to such great extent that even non-selfish newcomers can extract near-optimal performance through naïve wiring strategies. To capitalize on the performance advantages of optimal neighbor selection strategies and the emergent global wirings that result, this thesis presents EGOIST: an SNS-inspired overlay network creation and maintenance routing system. Through an extensive measurement study on the deployed prototype, results presented in this thesis show that EGOIST’s neighbor selection primitives outperform existing heuristics on a variety of performance metrics, including delay, available bandwidth, and node utilization. Moreover, these results demonstrate that EGOIST is competitive with an optimal but unscalable full-mesh approach, remains highly effective under significant churn, is robust to cheating, and incurs minimal overheads. This thesis also studies selfish neighbor selection strategies for swarming applications. The main focus is on n-way broadcast applications where each of n overlay user wants to push its own distinct file to all other destinations as well as download their respective data files. Results presented in this thesis demonstrate that the performance of our swarming protocol for n-way broadcast on top of overlays of selfish users is far superior than the performance on top of existing overlays. In the context of service provisioning, this thesis examines the use of distributed approaches that enable a provider to determine the number and location of servers for optimal delivery of content or services to its selfish end-users. To leverage recent advances in virtualization technologies, this thesis develops and evaluates a distributed protocol to migrate servers based on end-users demand and only on local topological knowledge. Results under a range of network topologies and workloads suggest that the performance of the distributed deployment is comparable to that of the optimal but unscalable centralized deployment.

Safe Compositional Specification of Network Systems With Polymorphic, Constrained Types

In the framework of iBench research project, our previous work created a domain specific language TRAFFIC [6] that facilitates specification, programming, and maintenance of distributed applications over a network. It allows safety property to be formalized in terms of types and subtyping relations. Extending upon our previous work, we add Hindley-Milner style polymorphism [8] with constraints [9] to the type system of TRAFFIC. This allows a programmer to use for-all quantifier to describe types of network components, escalating power and expressiveness of types to a new level that was not possible before with propositional subtyping relations. Furthermore, we design our type system with a pluggable constraint system, so it can adapt to different application needs while maintaining soundness. In this paper, we show the soundness of the type system, which is not syntax-directed but is easier to do typing derivation. We show that there is an equivalent syntax-directed type system, which is what a type checker program would implement to verify the safety of a network flow. This is followed by discussion on several constraint systems: polymorphism with subtyping constraints, Linear Programming, and Constraint Handling Rules (CHR) [3]. Finally, we provide some examples to illustrate workings of these constraint systems.

NETEMBED: A Network Resource Mapping Service for Distributed Applications

Emerging configurable infrastructures such as large-scale overlays and grids, distributed testbeds, and sensor networks comprise diverse sets of available computing resources (e.g., CPU and OS capabilities and memory constraints) and network conditions (e.g., link delay, bandwidth, loss rate, and jitter) whose characteristics are both complex and time-varying. At the same time, distributed applications to be deployed on these infrastructures exhibit increasingly complex constraints and requirements on resources they wish to utilize. Examples include selecting nodes and links to schedule an overlay multicast file transfer across the Grid, or embedding a network experiment with specific resource constraints in a distributed testbed such as PlanetLab. Thus, a common problem facing the efficient deployment of distributed applications on these infrastructures is that of "mapping" application-level requirements onto the network in such a manner that the requirements of the application are realized, assuming that the underlying characteristics of the network are known. We refer to this problem as the network embedding problem. In this paper, we propose a new approach to tackle this combinatorially-hard problem. Thanks to a number of heuristics, our approach greatly improves performance and scalability over previously existing techniques. It does so by pruning large portions of the search space without overlooking any valid embedding. We present a construction that allows a compact representation of candidate embeddings, which is maintained by carefully controlling the order via which candidate mappings are inserted and invalid mappings are removed. We present an implementation of our proposed technique, which we call NETEMBED – a service that identify feasible mappings of a virtual network configuration (the query network) to an existing real infrastructure or testbed (the hosting network). We present results of extensive performance evaluation experiments of NETEMBED using several combinations of real and synthetic network topologies. Our results show that our NETEMBED service is quite effective in identifying one (or all) possible embeddings for quite sizable queries and hosting networks – much larger than what any of the existing techniques or services are able to handle.

A Neural Network Model of Speech Acquisition and Motor Equivalent Speech Production

This article describes a neural network model that addresses the acquisition of speaking skills by infants and subsequent motor equivalent production of speech sounds. The model learns two mappings during a babbling phase. A phonetic-to-orosensory mapping specifies a vocal tract target for each speech sound; these targets take the form of convex regions in orosensory coordinates defining the shape of the vocal tract. The babbling process wherein these convex region targets are formed explains how an infant can learn phoneme-specific and language-specific limits on acceptable variability of articulator movements. The model also learns an orosensory-to-articulatory mapping wherein cells coding desired movement directions in orosensory space learn articulator movements that achieve these orosensory movement directions. The resulting mapping provides a natural explanation for the formation of coordinative structures. This mapping also makes efficient use of redundancy in the articulator system, thereby providing the model with motor equivalent capabilities. Simulations verify the model's ability to compensate for constraints or perturbations applied to the articulators automatically and without new learning and to explain contextual variability seen in human speech production.

Emergence of Tri-Phasic Muscle Activation from the Non-linear Interactions of Central and Spinal Neural Network Circuits

The origin of the tri-phasic burst pattern, observed in the EMGs of opponent muscles during rapid self-terminated movements, has been controversial. Here we show by computer simulation that the pattern emerges from interactions between a central neural trajectory controller (VITE circuit) and a peripheral neuromuscularforce controller (FLETE circuit). Both neural models have been derived from simple functional constraints that have led to principled explanations of a wide variety of behavioral and neurobiological data, including, as shown here, the generation of tri-phasic bursts.

A Neural Network Model for the Spatial and Temporal Response of Retinal Ganglion Cells

This article introduces a quantitative model of early visual system function. The model is formulated to unify analyses of spatial and temporal information processing by the nervous system. Functional constraints of the model suggest mechanisms analogous to photoreceptors, bipolar cells, and retinal ganglion cells, which can be formally represented with first order differential equations. Preliminary numerical simulations and analytical results show that the same formal mechanisms can explain the behavior of both X (linear) and Y (nonlinear) retinal ganglion cell classes by simple changes in the relative width of the receptive field (RF) center and surround mechanisms. Specifically, an increase in the width of the RF center results in a change from X-like to Y-like response, in agreement with anatomical data on the relationship between α- and