Understanding Subsystems in Biology through Dimensionality Reduction, Graph Partitioning and Analytical Modeling

Biological systems exhibit rich and complex behavior through the orchestrated interplay of a large array of components. It is hypothesized that separable subsystems with some degree of functional autonomy exist; deciphering their independent behavior and functionality would greatly facilitate understanding the system as a whole. Discovering and analyzing such subsystems are hence pivotal problems in the quest to gain a quantitative understanding of complex biological systems. In this work, using approaches from machine learning, physics and graph theory, methods for the identification and analysis of such subsystems were developed. A novel methodology, based on a recent machine learning algorithm known as non-negative matrix factorization (NMF), was developed to discover such subsystems in a set of large-scale gene expression data. This set of subsystems was then used to predict functional relationships between genes, and this approach was shown to score significantly higher than conventional methods when benchmarking them against existing databases. Moreover, a mathematical treatment was developed to treat simple network subsystems based only on their topology (independent of particular parameter values). Application to a problem of experimental interest demonstrated the need for extentions to the conventional model to fully explain the experimental data. Finally, the notion of a subsystem was evaluated from a topological perspective. A number of different protein networks were examined to analyze their topological properties with respect to separability, seeking to find separable subsystems. These networks were shown to exhibit separability in a nonintuitive fashion, while the separable subsystems were of strong biological significance. It was demonstrated that the separability property found was not due to incomplete or biased data, but is likely to reflect biological structure.

Sequence-Seeking and Counter Streams: A Model for Information Processing in the Cortex

This paper presents a model for the general flow in the neocortex. The basic process, called "sequence-seeking," is a search for a sequence of mappings or transformations, linking source and target representations. The search is bi-directional, "bottom-up" as well as "top-down," and it explores in parallel a large numbe rof alternative sequences. This operation is implemented in a structure termed "counter streams," in which multiple sequences are explored along two separate, complementary pathways which seeking to meet. The first part of the paper discusses the general sequence-seeking scheme and a number of related processes, such as the learning of successful sequences, context effects, and the use of "express lines" and partial matches. The second part discusses biological implications of the model in terms of connections within and between cortical areas. The model is compared with existing data, and a number of new predictions are proposed.

Output from the 1998 Product Development Value Stream Workshop: A Framework for Understanding Information Flow in the Product Development Process

The descriptions below and the attached diagrams are outputs of the 1998 LAI Product Development Focus Team workshop on the Value Chain in Product Development. A working group at that workshop was asked to model the product development process: in terms of the phases of product development and their interfaces, boundaries and outputs. Their work has proven to be generally useful to LAI researchers and industry members, and so is formalized here.

Extensions of a Theory of Networks for Approximation and Learning: Outliers and Negative Examples

Learning an input-output mapping from a set of examples can be regarded as synthesizing an approximation of a multi-dimensional function. From this point of view, this form of learning is closely related to regularization theory. In this note, we extend the theory by introducing ways of dealing with two aspects of learning: learning in the presence of unreliable examples and learning from positive and negative examples. The first extension corresponds to dealing with outliers among the sparse data. The second one corresponds to exploiting information about points or regions in the range of the function that are forbidden.

A Unified Statistical and Information Theoretic Framework for Multi-modal Image Registration

We formulate and interpret several multi-modal registration methods in the context of a unified statistical and information theoretic framework. A unified interpretation clarifies the implicit assumptions of each method yielding a better understanding of their relative strengths and weaknesses. Additionally, we discuss a generative statistical model from which we derive a novel analysis tool, the "auto-information function", as a means of assessing and exploiting the common spatial dependencies inherent in multi-modal imagery. We analytically derive useful properties of the "auto-information" as well as verify them empirically on multi-modal imagery. Among the useful aspects of the "auto-information function" is that it can be computed from imaging modalities independently and it allows one to decompose the search space of registration problems.

Information Processing and Transmission in Cellular Automata

A cellular automaton is an iterative array of very simple identical information processing machines called cells. Each cell can communicate with neighboring cells. At discrete moments of time the cells can change from one state to another as a function of the states of the cell and its neighbors. Thus on a global basis, the collection of cells is characterized by some type of behavior. The goal of this investigation was to determine just how simple the individual cells could be while the global behavior achieved some specified criterion of complexity ??ually the ability to perform a computation or to reproduce some pattern. The chief result described in this thesis is that an array of identical square cells (in two dimensions), each cell of which communicates directly with only its four nearest edge neighbors and each of which can exist in only two states, can perform any computation. This computation proceeds in a straight forward way. A configuration is a specification of the states of all the cells in some area of the iterative array. Another result described in this thesis is the existence of a self-reproducing configuration in an array of four-state cells, a reduction of four states from the previously known eight-state case. The technique of information processing in cellular arrays involves the synthesis of some basic components. Then the desired behaviors are obtained by the interconnection of these components. A chapter on components describes some sets of basic components. Possible applications of the results of this investigation, descriptions of some interesting phenomena (for vanishingly small cells), and suggestions for further study are given later.