Recommendation of a Strategy

Computational Bio-Discovery

Wolfgang Kraske PhD EE

A scientific paradigm

Bio-Information Networking

Community Tool Services

Model Characterization

Wolfgang F. Kraske, PhD

PhD Electrical Engineering University of Southern California, December 1995Advisor- Irving S. Reed, PhD, Charles E. Powell Professor Emeritus of E.E./C.S.Research- Geometric Algebra for Topological Information RepresentationMS Electrical Engineering University of Southern California, December 1986Research- Microwave Imaging and Signal ProcessingBS Physics/Mathematics-University of Maryland, UMCP, 1982

Computational Bio-Discovery
An Awkward Situation

Cellsin Vivo?

BioinformaticResearchSystem

Computational Bio-Discovery
Overview

Emerging Environment for Bio-Discovery

Community Enterprise and Tools

Model Characterization

Vector/Small Molecule

Sequence

Structure

Pathway

Computational Bio-Discovery
Goal

Establish a breakthrough network environment to promote significant drug discoveries

Integrate tools over network to promote community analysis and discoveryIntegration of Research communities

Integration of internal with external scientific communities

Integration with external patient and lay communities

Computational Bio-Discovery
Network Communities

ClinicalApplications& Research

Internal Biological Informatics Laboratory Algorithmic Definition of Structural Model Characteristics

Wet Laboratory Sequencing and Molecular Data Acquisition

PharmaceuticalResearch &Development

Mathematics andComputer ScienceResearch & Development

External ApplicationComputing Resources

CommunityBio-InformationNetwork Sources

PCR

Mass Spectrometry

Magnetic ResonanceSpectroscopy

Micro-Array

Gel Electrophoresis

Protein RapidTranslation

Southern Blot

X-ray crystallography

Computational Bio-Discovery
Challenge: Tool Integration

Tool Software Accelrys/illumina

MOLMOL/WPDB

UNIO/APSY

DBToolKit

BLAST/ZDOCK

Sequencher/Velvet

Mathlab/Octave/R

HMMER

Enterprise Software O3D/Flash/Flex/JS

Quick-time/MPlayer

Ajax/REST Service

MVC:php/ruby/perl/C#

mySQL/Oracle/MSSQL

Linux/Windows

Sybase/EMC

Centrifugation

Titration

Electron Microscopy

Light Microscopy

IVC Emulsion

Phage Display

Computational Bio-Discovery
Service Architecture Solution

Legend

Mass StorageDatabase ServerEntity ServerTool ServerWeb Content ServerHTTP ServerSocial ServerEthernet/ 100/1000 Base TNetwork SwitchLoad Balance ServerFirewall ServerFiber ChannelRest Server/

CampusLaboratoriesFirewall

REST Server

CampusSwitch

Load Balancing

Internet

Load BalancingFirewall

EntityServersDatabaseServers

MassStorage

NetworkSwitchWeb SegmentData SegmentApplicationSegmentExternalServicesWeb/Session/ToolServers

Scalable Algorithm Solutions

Parallel Language & Algorithm Library

Research Application of Parallel Algorithms

Parallel Algorithm & OS Development

Parallel Algorithm& OS Layer

MPP Clusterw/Algorithm & OS Layer

SMP w/Algorithm

MassStorage

Cloud:

App Engine

EC2/3

Oracle Metro

MS Azure

Web Services

WF Kraske, Voxar-All ATM Distributed Biomedical Visualization:T3D MPP, 8th IEEE Symposium on Computer Based Med Systems, 249, 1995

Dell Xeon Cluster, Message Passing Innterface

MVC Architecture

Fibers

REST-Representation State Transfer

Zend Framework

Ajax XMLHttpRequest

Iterated Software Lifecycle

Requirements

Design

Development

Test

Implementation

Analysis

Deployment

Upgrade orNew Iteration

CoreF1ProtoFn...

Iterated Weekly Functional Roll out

Agile and eXtreme programming processes

I Jacobson, G Booch, J Rumbaugh, Unified Software Development Process, Addison Wesley 1999

Use Case Management

SoftwareDevelopment

Programmer

Program

Test &Validation

Evaluator

Use Case

Project Manager

ResourceManagement

Report

Report

Planning

Stakeholder

Control

Conceptual Model

Sequence: Linear

Small Molecule: Node

Structure: Spatial

Pathway: Time & Space

Allometric Scaling

The 4th dimension of life (Evolution/Temporal Development)

Evolution maximizes external surface area versus internal efficiency to yield a one quarter scaling of fractal dimension(size invariant property)ie Protein folding, capillary & mitochondria formation

Conventional EuclideanBiological (Fractal)

LengthLA1/2V1/3M1/3la1/3v1/4M1/4

AreaL2AV2/3M2/3l3aV3/4M3/4

VolumeL3A3/2VMl4a3/2vM

GB west, RH Brown, BJ Enquist, The Forth Dimension of Life, Science 1677, 284, 1999

WF Kraske, Analysis & Segmentation of Higher Dimensional Data Sets, SPIE Press 264, IS12, 1995

Computational Bio-Discovery
Scale Free Versus Random

Random Network

Scale-Free Network

Scale Free Interaction characterizes the natural (Organic) behavior of : Metabolic signaling pathways

Internet links

Bioinformatic Analysis Algorithms

Protein Interactome

Knockout of Proteins Eliminates Temporal Communicationbetween Processes

Knockout of Scaffold Proteins Eliminate Structure

NATURE | doi:10.1038/nature02555 |www.nature.com/nature

NATURE | doi:10.1038/nature02555 |www.nature.com/nature2004, pp 1-6

Iterative Construction of
Deterministic Scale-Free Networks

Peripheral Nodes with 4 Links

Hub Nodes with 6 Links

A. Barbasi, Linked, Penquin Books, pp. 232-237, 2003

Level 0

Level 1

Level 2

Hub Nodes with 15 Links

Model Based Algorithms

Algorithms are easily programmed and distributed on parallel computing architecturesTrivially distributed on an SMP architecture

Optimally distributed on an MPP architecture

Use fractional dimension models to analyze biomedical data setsMarkov field analysis

Cluster measures to establish hierarchical structure

Regular statistical characterization

MEJ Neuman, SH Strogatz, DJ Watt, Random Graphs with arbitrary degree distributions & applications, Physical Review E, 64, 026118-1, 2003

Kinase Pathway Analysis

Receptor Tyrosine Kinases EGFR(ErbB1/HER1-4)Inhibited by Irressa/Tarceva

Internalized by Herceptin

VEGFR (Tumor)

FGFR

Insulin Receptor (CD220)

Nonreceptor Tyrosine Kinases Bcr-Abl

Inhibited by GleevacSerine Threonine Kinases

P38- MAPK

Cyclin dependent Kinases

Flavopinridol HIV Treatment

Indirubin Chinese Herbal

Transcription & Translation

Hox Algorithm VarietiesHox Clock

Protein Micro-Array Analysis

Pathway Studio Interpret gene expression and other high throughput data

Build, expand and analyze pathways

Find relationships among genes, proteins, cell processes and diseases

Draw publication-quality pathway diagrams

BioConductor- analysis of single channel Affymetrix and two or more channel cDNA/Oligo micro-arrays based on theR statistical package

Pathway analysis for model organisms BIND: Bio-molecular Interaction Network

Database KEGG

Science Signaling

Prolexys HyNet protein-protein

Interaction database

Probe-target hybridization

Development up to present

Multidimensional Markov field analysis is a standard algorithm for sequence analysis, signal processing and multidimensional image processing

I have programmed a variety of multi-scale and multi-dimensional algorithms on Cloud and MPP architecture with great success

A Gelman,J Hill, Data Analysis Using Regression & Multilevel/Hierarchical Models, Cambridge University Press, 2008

Further Topics for Algorithms

Incorporation of RNAi Regulation of Transcription/ Translation, Epigenic Activation and Translational Coding Cycles

Agent Based Organization and Processing to Develop and Execute Processing SystemsNeural Networks

Genetic Algorithms

Swarm Algorithms

Applications in Phylogeny, Developmental Biology, Social Psychology

CD Manning,P Ragahavan, H Shutze, Introduction to Information Retrieval, Cambridge University Press, 2008

J Augen, Bioinformatics in the Post Genomic Era, Addison-Wesley, 2005

P Baldi, S Brunak, Bioinformatics The Machine Learning Approach, MIT, 2001

Translation Codon

Human Kinome

Montage Pictures

Montage Pictures

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