Making Sense of Complexity

Summary of the Workshop on Dynamical Modeling of Complex Biomedical Systems

George Casella, Rongling Wu, and Sam S. Wu

University of Florida

Scott T. Weidman

National Research Council

Board on Mathematical Sciences and Their Applications

National Research Council

NATIONAL ACADEMY PRESS

Washington, D.C.



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Making Sense of Complexity: Summary of the Workshop on Dynamical Modeling of Complex Biomedical Systems Making Sense of Complexity Summary of the Workshop on Dynamical Modeling of Complex Biomedical Systems George Casella, Rongling Wu, and Sam S. Wu University of Florida Scott T. Weidman National Research Council Board on Mathematical Sciences and Their Applications National Research Council NATIONAL ACADEMY PRESS Washington, D.C.

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Making Sense of Complexity: Summary of the Workshop on Dynamical Modeling of Complex Biomedical Systems NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. This summary is based on work supported by the Burroughs Wellcome Fund, Department of Energy, Microsoft Corporation, National Science Foundation (under Grant No. DMS-0109132), and the Sloan Foundation. Any opinions, findings, conclusions, or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the sponsors. International Standard Book Number 0-309-08423-7 Additional copies of this report are available from: Board on Mathematical Sciences and Their Applications National Research Council 2101 Constitution Avenue, N.W. Washington, DC 20418 Copyright 2002 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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Making Sense of Complexity: Summary of the Workshop on Dynamical Modeling of Complex Biomedical Systems THE NATIONAL ACADEMIES National Academy of Sciences National Academy of Engineering Institute of Medicine National Research Council The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Bruce M. Alberts is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. William A. Wulf is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Bruce M. Alberts and Dr. William A. Wulf are chairman and vice chairman, respectively, of the National Research Council.

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Making Sense of Complexity: Summary of the Workshop on Dynamical Modeling of Complex Biomedical Systems BOARD ON MATHEMATICAL SCIENCES AND THEIR APPLICATIONS PETER J. BICKEL, University of California at Berkeley, Chair DIMITRIS BERTSIMAS, MIT Sloan School of Management GEORGE CASELLA, University of Florida JENNIFER CHAYES, Microsoft Corporation DAVID EISENBUD, Mathematical Sciences Research Institute CIPRIAN I. FOIAS, Indiana University RAYMOND L. JOHNSON, University of Maryland IAIN M. JOHNSTONE, Stanford University SALLIE KELLER-McNULTY, Los Alamos National Laboratory ARJEN K. LENSTRA, Citibank, N.A. ROBERT LIPSHUTZ, Affymetrix, Inc. GEORGE C. PAPANICOLAOU, Stanford University ALAN S. PERELSON, Los Alamos National Laboratory LINDA PETZOLD, University of California at Santa Barbara DOUGLAS RAVENEL, University of Rochester STEPHEN M. ROBINSON, University of Wisconsin-Madison S.R. SRINIVASA VARADHAN, New York University Staff SCOTT T. WEIDMAN, Director BARBARA W. WRIGHT, Administrative Assistant

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Making Sense of Complexity: Summary of the Workshop on Dynamical Modeling of Complex Biomedical Systems Preface On April 26-28, 2001, the Board on Mathematical Sciences and Their Applications (BMSA) and the Board on Life Sciences of the National Research Council cosponsored a workshop on the dynamical modeling of complex biomedical systems. The workshop’s goal was to identify some open research questions in the mathematical sciences whose solution would contribute to important unsolved problems in three general areas of the biomedical sciences: disease states, cellular processes, and neuroscience. The workshop drew a diverse group of over 80 researchers, who engaged in lively discussions. To convey the workshop’s excitement more broadly, and to help more mathematical scientists become familiar with these very fertile interface areas, the BMSA appointed one of its members, George Casella, of the University of Florida, as rapporteur. He developed this summary with the help of two colleagues from his university, Rongling Wu and Sam S. Wu, assisted by Scott Weidman, BMSA director. This summary represents the viewpoint of its authors only and should not be taken as a consensus report of the BMSA or of the National Research Council. We are grateful to the following individuals who reviewed this summary: Peter J. Bickel, University of California at Berkeley; Ronald Douglas, Texas A&M University; Nina Fedoroff, Pennsylvania State University; and Keith Worsley, McGill University. Funding for the workshop was provided by the Burroughs Wellcome Fund, the Department of Energy, Microsoft Corporation, the National Science Foundation, and the Sloan Foundation. The workshop organizers were Peter J. Bickel, University of California at Berkeley; David Galas, Keck Graduate Institute; David Hoel, Medical University of South Carolina; Iain Johnstone, Stanford University; Alan Perelson, Los Alamos National Laboratory; De Witt Sumners, Florida State University; and James Weiss, University of California at Los Angeles Videotapes of the workshop’s presentations are available online at <http://www.msri.org/publications/video/index6.html/> and also through a link at <http://www.nas.edu/bms>.

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Making Sense of Complexity: Summary of the Workshop on Dynamical Modeling of Complex Biomedical Systems Contents 1   INTRODUCTION   1 2   MODELING PROCESSES WITHIN THE CELL   4 3   PROBABILISTIC MODELS THAT REPRESENT BIOLOGICAL OBSERVATIONS   10 4   MODELING WITH COMPARTMENTS   15 5   FROM THE COMPARTMENT TO THE FLUID   18 6   GENE TRANSFER AS A BIOMEDICAL TOOL   23 7   THE DATA FLOOD: ANALYSIS OF MASSIVE AND COMPLEX GENOMIC DATA SETS   26 8   SUMMARY   30     REFERENCES   31     APPENDIX: WORKSHOP PROGRAM AND ATTENDEES   33

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