Abstracts - BCatS - Stanford University

Transcription

bcats
2005
biomedicalcomputationatstanford
abstractbook
bcats 2005 is brought to you by
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biomedical • computation • at • stanford
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october • fifteen • 2005
A Winning Formula
in Drug Discovery
At Roche Palo Alto, we are dedicated to discovering and developing new
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Roche is a proud sponsor of BCATS!
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Welcome
to the sixth annual symposium on
Biomedical Computation at Stanford (BCATS).
This student-run one-day symposium provides an interdisciplinary forum
for Stanford students and post-docs to share their research in widelyvarying fields involvoing biomedical computation. Since its inception
in 1999, BCATS has seen growth and change in the field of biomedical
computation. This year’s schedule features diverse, cutting-edge research
from the largest applicant pool ever.
We thank our keynote speakers, student presenters,
judges, sponsors, and all 2005 attendees.
The BCATS 2005 organizing committee
Maureen Hillenmeyer, Biomedical Informatics
Lior Ron, Graduate School of Business
Lucinda Southworth, Biomedical Informatics
Ryan Spilker, Biomechanical Engineering
Beverly Tang, Biomechanical Engineering
5
BCATS 2005 Schedule
8.00 am
Onsite Registration and Breakfast
Sequoia Plaza
8.45
Opening Remarks
Hewlett 200
Scientific Talks Session I
Hewlett 200
9.00
Eran A. Mukamel
Network structure and the biological representation of
time in cerebellar neural circuits
9.15
R. Dana Carpenter
Computer simulation of bone cross-sectional
morphogenesis
9.30
(page 17)
Omar David Perez
Derivation of causal protein signaling networks from
multiparameter single-cell data
9.45
(page 16)
(page 18)
Tianfang Li
Radiation dose reduction in 4D computed tomography
(page 19)
10.00
Poster Session I (even-numbered posters)
Packard Lobby
11.00
Keynote Address
Hewlett 200
Jeffrey Weiss, PhD
(pages 8–9, 29–87)
(page 12)
Verification, Validation, and Sensitivity Studies in
Computational Biomechanics
11.45
Lunch
Sequoia Plaza
12.30p
Poster Session II (odd-numbered posters)
Packard Lobby
1.30
Keynote Address
Hewlett 200
Leroy Hood, MD, PhD
Computational Challenges in Systems Biology
6
(pages 6–9, 29–77)
(page 13)
Scientific Talks Session II
2.15
Irene Elisabeth Vignon-Clementel
Impedance outflow boundary conditions for threedimensional patient specific modeling of blood flow
2.30
(page 20)
Serban Nacu
Foraging Regulation in Harvester Ants
2.45
Hewlett 200
(page 21)
Daniel Bruce Ennis
Visualization and Analysis of Diffusion Tensor Magnetic
(page 22)
Resonance Images using Orthogonal Tensor Invariants
3.00
Vishal Vaidyanathan
Modeling the aggregation of Alzheimers peptide Aβ21-43
(page 23)
using Molecular Dynamics and Distributed Computing
3.15
Break
Scientific Talks Session II
3.30
Pan-Chi Lee
(page 24)
Optimizing Dialysis
3.45
Rachel Weinstein
(page 25)
Pre-stabilization for Rigid Body Articulation with
Contact and Collision
4.00
Balaji Srinivasan
(page 26)
Integrated Protein Interaction Networks for 230
Microbes
4.15
David Rodriguez-Gomez
(page 27)
Efficient Free Energy Calculation of Peptide Insertion in
Membranes
4.30
Industry Keynote Address
Thomas Wu, MD, PhD
Hewlett 200
(page 14)
Bioinformatics at Genentech
5.00 pm
Awards and closing
Hewlett 200
7
BCATS 2005 Posters
poster
page
0
Abhay Sukumaran
Distributed cluster computing: a method for parallel simulation of large molecular
systems
30
1
Aditya Mandayam
tr0m
31
2
Andrew Holbrook
Segmentation of costal cartilage in lower abdomen CT data using watershed
markers
32
3
Alex Ten Eyck
Modeling biological tissue with nonconforming finite elements
33
4
Alain Laederach
Reconstructing RNA folding pathways from local probes of macromolecular
structure
34
5
Alex Pang
Prediction of venous obstruction following transvenous pacemaker placement: a
computer simulation approach
35
6
Alison L. Marsden
A computational study of energy efficiency and pressure losses in the total
cavopulmonary connection
36
7
Artit Wangperawong
Effects of size and hydrophobicity on single-walled carbon nanotubes
37
8
Andreas Sundquist
A strategy for whole-genome sequencing and assembly with high-throughput,
short-read technologies
38
9
Rebecca Maria Currano
Video-audio mapping of the physical environment for blind navigation
39
10
C. Alberto Figueroa
A new formulation to model blood flow and vessel motion in large, patient-specific
models of the cardiovascular system
40
11
Chase Garrett
Yarbrough
Application of a three dimensional image-based modeling technique to the circle of
41
Willis
12
Christopher B. Egner
SchemaTrans: automating the translation of arbitrarily formatted data to relational
databases
42
13
Christopher Enedah
Robotic perception of the skin’s mechanical properties - a validation study
43
14
Cesar A. Rodriguez
A theoretical model that complements an experimental system for quantitative
investigation of in vivo protein-protein interactions
44
15
Chuong B. Do
CONTRAlign: a discriminative framework for protein sequence alignment
45
16
Christopher Sewell
Metrics for a mastoidectomy simulator
46
17
Christopher D. Snow
Bringing the ribosome exit tunnel to life with distributed computing: a first look at
the thermodynamics of confined solvent and the nascent chain
47
18
Chand T. John
From biomedical images to geometric models
48
19
David Jing-Piao Lin
Algorithmic analysis of the quantitative distribution of neural stem cells in malignant
49
glioma
20
Diane Schroeder
Locating single-stranded regions of the human genome
50
21
Eduard Schreibmann
Image interpolation in 4D CT using a Bspline deformable registration model
51
22
Erich Konrad Elsen
GROMACS on the GPU
52
23
Tim A. Fonte
3-D simulations of hemodynamic factors in pulmonary hypertension
53
24
Gal Chechik
Filling missing components in yeast metabolic pathways using heterogeneous data
54
25
Gunnar F. Schroeder
Simulation of fluorescence anisotropy experiments: probing protein dynamics
55
26
Haidong Wang
Efficient prediction of protein-protein interactions using Markov networks
56
27
John Patrick Adams
Framework for identification of allosteric networks
57
8
poster
page
28
Jessica Ebert
Unsupervised Identification of Functionally Relevant Residues in Protein Families
58
29
Jessie Dale
Tenenbaum
A modified Bayesian approach to determination of causation in differential gene
expression
59
30
Jason A. Hackney
Use of a naive Bayesian classifier to identify gene regulatory networks in the
protozoan parasite, Enatmoaba histolytica
60
31
John F. LaDisa, Jr.
Patient-specific modeling of altered hemodynamics and arterial deformation induced
61
by coarctation of the aorta and subsequent stent implantation
32
Joseph Minhow Chan
Preferential coplanarity of RNA helices and its impact on RNA activity
62
33
Magda Anna Jonikas
Using coarse-grained simulations of RNA to explore intermediate folding pathways
63
34
Justus Roos
Quantitative and qualitative assessment of a new knowledge-based algorithm for
centerline restoration through femoro-popliteal artery occlusions in peripheral CT
angiography (CTA)
64
35
Jacob Michael Zahn
A common signature for human aging
65
36
Hyun Jin Kim
Chronic spinal cord injury modifies aortoiliac biomechanical forces and morphology
and increases abdominal aortic aneurysm disease risk
66
37
Jan Lipfert
Novel approaches to simulating amyloid formation: Reaction path annealing and
single molecule pulling
67
38
Michael Yu Zhang
Genomic instability signatures of colorectal carcinoma subtypes by hierarchical
clustering of gene copy data
68
39
Nina Singhal
Automatic state decomposition for constructing Markov models for macromolecular
dynamics
69
40
Padma Sundaram
Fold removal in CT colonography
70
41
Patrick Timothy
McGrath
Analysis of the transcriptional regulation of a bacterial cell cycle
71
42
Qiyu Peng
2D ultrasound image processing in identifying displacement history of urogenital
structures to pelvic floor muscle activity
72
43
Qiyu Peng
A novel palpation system to evaluate internal organs of genitourinary system
73
44
Rashmi Raghu
Viscoelastic arterial wall model for one-dimensional modeling of blood flow and
pressure
74
45
Rebecca Meredith
Loew
Differential gene expression between healthy and melanoma patients for T cells, B
cells and NK cells
75
46
Ron Y. Kwon
Mechanics of deformation of bone cells
76
47
Ryan J Tibshirani
A novel software for plotting multidimensional FACS data
77
48
Shaohua Sun
Registration of lung nodules using a semi-rigid model
78
49
Anthony Sherbondy
A Metropolis sampling framework for inferring neural connectivity in Diffusion Tensor
79
Images
50
Shirley Wu
Modeling of phosphorylation sites in protein structures using the FEATURE system
80
51
Su-In Lee
Identifying regulatory mechanisms associated with genetic variations among
individuals
81
52
Samuel S. Gross
CONTRAST: de novo gene prediction using a semi-Markov conditional random field
82
53
Brian Thorndyke
Removal of respiratory motion artifacts and the construction of 4D PET
83
54
Vincent Bangping Chu Ion size effects and the Poisson-Boltzmann equation
84
55
Jing Xu
85
Three-dimensional correlation analysis of the macromolecules on synaptic vesicles
9
10
The Stanford Center for Biomedical Computation
is pleased to sponsor BCATS.
Executive Committee:
Russ Altman — [email protected]
Scott Delp — [email protected]
David Paik — [email protected]
The Center for Bio-Medical Computation (CBMC) and its affiliated faculty group, Biomedical
Information Technology at Stanford (BITS), is an inter-connected, cross-disciplinary group of
researchers who develop, share, and utilize computer graphics, scientific computing, medical imaging, and biomechanical modeling applications in biology, bioengineering, and
medicine. Our mission is to establish a world-class biomedical computing and visualization center at Stanford that will support joint initiatives between the Schools of Engineering,
Medicine, and Humanities and Sciences.
Participating labs promote the efficient development of new courses, programs, computational models, and tools that can be used in classrooms, clinical practice, and the biomedical
research community. Our goal is to become be an international resource for partners in the
biotechnology, biomedical device, computing, medical imaging, and software industries.
The CMBC and BITS faculty support teaching and training in the biomedical computing sciences and the creation of interdisciplinary biocomputational courses at the undergraduate,
graduate, and post-graduate levels, both on-campus and at remote sites.
cbmc.stanford.edu
Genentech is a Proud Sponsor of the BCATS Symposium
Genentech
IN BUSINESS FOR LIFE
www.gene.com
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BCATS Keynote Speaker
Jeffrey Weiss, PhD
University of Utah
Departments of Bioengineering and Orthopedics,
Scientific Computing and Imaging Institute,
University of Utah
http://hodad.sci.utah.edu/~weiss/mrl
Jeff Weiss is an Associate Professor of Bioengineering, an Adjunct Associate Professor of Orthopedics and a Faculty Member in the Scientific Computing and Imaging (SCI) Institute at the
University of Utah. He grew up in Southern California and received the B.S. (1989) and M.S.
(1990) degrees in Bioengineering from the University of California, San Diego. He completed
his Ph.D. in Bioengineering at the University of Utah in 1994. Dr. Weiss received postdoctoral
training in computational biomechanics as a finite element analyst working with the Applied
Mechanics and Methods Development Groups at Lawrence Livermore National Laboratory.
Research in the Weiss Laboratories has historically focused on the biomechanics and healing
of musculoskeletal soft tissues, in particular the ligaments of the knee. Over the past five years,
the research focus has expanded considerably to include hard tissue as well as cardiovascular
tissues including the heart, coronary arteries and smaller vessels involved in angiogenesis.
A central theme of the approach to research is the use of multidisciplinary techniques. A
primary strength continues to be the combination of both experimental and computational
techniques, especially in the area of biomechanics, to address research questions that would
be impossible to investigate using approaches from a single technical discipline. Major areas
of research focus include subject-specific computational modeling of hip, knee and shoulder
biomechanics, structure-function relationships in connective tissues, mechanical aspects of
angiogenesis, and the direct integration of image data into biomechanical analyses.
Professor Weiss routinely serves on study section panels for the NIH and NSF and is currently an
Associate Editor for the Journal of Biomechanical Engineering, the Journal of Applied Biomechanics and Computer Methods in Biomechanics and Biomedical Engineering. He is a regular
reviewer for 15 additional international journals. Dr. Weiss has received a number of highly
coveted awards, including the Taylor & Francis prize for “outstanding innovation in computer
methods in biomechanics & biomedical engineering”, the ASME YC Fung Young Investigator
Award in May 2002, a NSF CAREER Award in February 2002 and a Whitaker Foundation Research Grant in March 1995.
12
BCATS Keynote Speaker
Leroy Hood, MD, PhD
Institute for Systems Biology
President, Institute for Systems Biology
M.D., Johns Hopkins School of Medicine, 1964
Ph.D., Biochemistry, California Institute of Technology, 1968
Dr. Hood’s research has focused on the study of molecular immunology, biotechnology, and
genomics. His professional career began at Caltech where he and his colleagues pioneered
four instruments—the DNA gene sequencer and synthesizer, and the protein synthesizer and
sequencer—which comprise the technological foundation for contemporary molecular biology. In particular, the DNA sequencer has revolutionized genomics by allowing the rapid automated sequencing of DNA, which played a crucial role in contributing to the successful mapping of the human genome during the 1990s. In 1992, Dr. Hood moved to the University of
Washington as founder and Chairman of the cross-disciplinary Department of Molecular Biotechnology. In 2000, he co-founded the Institute for Systems Biology in Seattle, Washington to
pioneer systems approaches to biology and medicine. Most recently, Dr. Hood’s lifelong contributions to biotechnology have earned him the prestigious 2004 Association for Molecular
Pathology (AMP) Award for Excellence in Molecular Diagnostics and the 2003 Lemelson–MIT
Prize for Innovation and Invention. He was also awarded the 2002 Kyoto Prize in Advanced
Technology and the 1987 Lasker Prize for his studies on the mechanism of immune diversity. He has published more than 600 peer-reviewed papers, received 14 patents, and has coauthored textbooks in biochemistry, immunology, molecular biology, and genetics, and is a
member of the National Academy of Sciences, the American Philosophical Society, the American Association of Arts and Sciences, and the Institute of Medicine. Dr. Hood has also played a
role in founding numerous biotechnology companies, including Amgen, Applied Biosystems,
Systemix, Darwin and Rosetta.
13
BCATS Industry Keynote Speaker
Thomas Wu, MD, PhD
Genentech
Dr. Wu is currently a Senior Scientist in the Department of Bioinformatics at Genentech, Inc.,
where he serves as group leader for microarray data analysis. His work also involves the development of bioinformatics tools for genomic sequence analysis, including the programs GMAP
and PMAP.
Prior to working at Genentech, he obtained his B.S. and M.S. degrees from Stanford University, M.D. from Harvard Medical School, and Ph.D. in computer science from the Massachusetts Institute of Technology. He completed his internship and residency in internal medicine
from Stanford University. He subsequently worked as a postdoctoral fellow in the Department
of Biochemistry at Stanford University, where he helped to develop the functional genomics
tools EMOTIF and EMATRIX, as well as methods for the superposition of multiple protein structures.
His awards include a Physician Postdoctoral Fellowship from the Howard Hughes Medical Institute; George M. Sprowls Award from M.I.T.; Martin Epstein Award from the American Medical Informatics Association, Frederick E. Terman Award from Stanford; Laureate Award from the
Tau Beta Pi engineering society; and election to Tau Beta Pi, Sigma Xi, and Phi Beta Kappa.
14
BCATS Talk
Abstracts
15
session I
9:00am
Eran A.
Mukamel
Network structure and the
biological representation of
time in cerebellar neural
circuits
Purpose
Behaviors from language perception and production to learning conditioned Pavlovian reflexes require neural circuits that encode and retain information about the timing of stimuli. The cerebellum is critical for learning
timed behaviors. Timing information is likely generated within the cerebellum,
and may be an emergent property of the large network of granule (GR) and Golgi (GO)
cells in the input layer. However, neural mechanisms for the generation of behaviorally relevant timing information are not known. Proposals to date included sparse representation and coherent oscillation, both
of which rely on individual GR cells to provide well-timed signals. Here we propose a model for distributed
encoding of timing information in cerebellar GR cell layer.
Mark J. Schnitzer
Methods
The cerebellar cortex is a crystal-like circuit of four or five neuronal cell-types. The GR axons extend several mm
along the cerebellar folia. This quasi-1D structure determines the dynamics of the recurrent net of excitatory
GRs and inhibitory GOs.
We studied the dynamics of a firing rate net with cerebellar structure, as well as a similar control net with randomly oriented GR axons. We used analytic theory and simulation to study the normal modes of each type of
net, and derived the distribution of oscillation frequencies from structural factors such as the orientation and
length of GR axons.
Results
Our main finding is that the number of distinct modes is limited by the population of the minority cell-type,
the GO. Due to the ratio of 10,000 GRs to each GO, this result implies that the vast number of GRs is not responsible for the fine temporal representation of sensory information.
A second result is that the proposed distributed mechanism for representing temporal information provides a
biologically plausible alternative to the single-cell based mechanisms of sparse encoding and coherent oscillation. Such a distributed scheme is a natural emergent property of the crystal-like network geometry.
Conclusion
Our results suggest that the organization of GR axons parallel to each other may be critical to create a broad
spectrum of oscillatory modes in the cerebellar input layer, and hence for representing a wide range of time intervals. We predict that manipulations that disrupt the geometrical structure of the cerebellar network would
narrow the range of stimulus frequencies represented by network dynamics. This could lead to behavioral
deficits, such as mistimed responses following training in classical conditioning experiments.
References
1. R.B. Ivry and R. M. Spencer, Curr Op Neurobio 14, 225 (2004)
2. M.D. Mauk and D. V. Buonomano, Ann Rev Neurosci 27, 307 (2004)
3. B. Ermentrout, Rep Prog Phys 61, 353 (1998)
16
Computer simulation of bone
cross-sectional morphogenesis
Purpose
Previous computational models of the development of bone cross-sections have used far-field loads such as joint reaction forces and muscle
forces as stimuli for bone growth [1,2]. However, numerous studies have
suggested that wrap-around tendons, adjacent musculature, and the fibrous layer of the periosteum can exert local bone surface pressures that
may also influence bone development [3-5]. In this study we incorporate
local periosteal surface pressures into a computational model of rat tibia morphogenesis.
session I
9:15am
R. Dana
Carpenter
Dennis R. Carter
Materials and Methods
The stimulus for new bone formation or bone resorption was calculated based on intracortical stresses
due to far-field bending and torsional loads, and the bone modeling response was modified based on
local periosteal surface loads imposed by adjacent muscles. Simulations began with a circular bone section representing the mid-shaft of the rat tibia at 17 days post-conception. Bending and torsional loads
were scaled with body mass data from growing rats [6]. Engineering beam theory was used to determine
bending stresses, and finite element software was used to determine shear stresses, principal moments
of inertia (properties proportional to bone bending stiffness), and the principal angle (θ1) corresponding
to the maximum moment of inertia (I1). A section with no surface loads and a section with surface loads
were grown to a simulated age of 17 months.
Results
The section that experienced no surface loading developed an elliptical geometry, and θ1 for this section
coincided with the direction of the applied bending moment. Application of periosteal surface pressures
resulted in a triangular geometry typical of the rat tibial diaphysis. The application of periosteal surface
pressures resulted in a 20% decrease in I1, and θ1 for this section did not coincide with the direction of
the applied bending moment.
Conclusions
The simulations performed in this study suggest that overall bone size is dictated by far-field loads and
that periosteal surface pressures can have large effects on bone cross-sectional morphology and the direction of a bone’s maximum bending stiffness. Including periosteal surface pressures imposed by adjacent muscles in simulations of bone morphogenesis presents a more realistic model of the in vivo loading
situation and subsequently produces a more realistic bone morphology.
References
[1] van der Meulen et al., 1993. Bone 14(4). [2] Levenston et al., 1998. Comput Methods Biomech Biomed
Engin 1(4). [3] Giori et al., 1993. J Orthop Res 11(4). [4] Teng and Herring, 1998. J Morphol 238(1). [5] Feik
et al., 1987. Br J Exp Pathol 68(6). [6] Donaldson, 1924. The Rat.
17
session I
9:30am
Derivation of causal protein
signaling networks from
multiparameter single-cell data
Purpose
Omar
To demonstrate the use of Bayesian networks for automated elucidation of
influences of protein signaling networks using simultaneous multiDavid Perez causal
variate measurements of phosphoproteins on single cells. To objectively
Karen Sachs
Dana Pe’er
Douglas Lauffenburger
Garry P. Nolan
derive inter-molecular influence connections, we applied a probabilistic
modeling algorithm to determine a graph of causal influences among
phospho-signaling molecules in human primary CD4+ T cells.
Simultaneosly measuring 11-phospho-epitopes by multiparameter flow
cytometry. Critical to the derivation of causal inference, was the use of
multiple independent perturbation events that aided inferring the direction of influence between the signaling components under study.
Results
The approach identified a majority of classically reported signaling relationships, and predicted several novel influence connections. A prediction of novel
inter-pathway crosstalk, causal influence of Erk on Akt, was confirmed experimentally.
Conclusion
The multivariate, simultaneous measures of biological states in cell populations allow for unprecedented
automatic construction of causal signaling network models in primary human cell subsets. Extension of
this concept will allow high throughput assembly of signaling network hierarchies in a variety of important biological systems.
References
Sachs K, Perez O, Pe’er D, Lauffenburger DA, Nolan GP. Causal protein-signaling networks derived from
multiparameter single-cell data.
Science. 2005 Apr 22;308(5721):523-9.
Perez OD, Nolan GP.
Simultaneous measurement of multiple active kinase states using polychromatic flow cytometry. Nat Biotechnol. 2002 Feb;20(2):155-62.
Perez OD, Krutzik PO, Nolan GP.
Flow cytometric analysis of kinase signaling cascades.
Methods Mol Biol. 2004;263:67-94.
18
session I
9:45am
Radiation dose reduction in 4D
computed tomography
Purpose
Tianfang
Li
Four-dimensional (4D) CT scans, acquired synchronously with a respiratory signal, provide
not only the 3D spatial information, but also temporal changes of the anatomy as a function of the respiratory phase during the imaging, and can therefore be employed in 4D
treatment planning to explicitly account for the respiratory motion. However, it usually
delivers 10~15 times more radiation dose to the patient as compared to the standard
3D CT, since multiple scans at each couch position are required to obtain the temporal
information. In this work we propose a statistic method to obtain high quality 4D CT
with low tube current, hence reducing the radiation exposure of patients.
Eduard Schreibmann
Brian Thorndyke
Method/Materials
Gayle Tillman
When 4D CT data are acquired with low tube current, the quality of each individual
phase image is degraded because of the decrease in detected photon number. HowArthur Boyer
ever, the statistics can be dramatically improved if the time-resolved images of a patient are properly registered to a specific phase and superposed together. In our apAlbert Koong
proach, the registration of the patient’s image at different phases is accomplished by
using a finite element-based deformable registration model, which is capable of regis- Karyn Goodman
tering two arbitrary phases to within a spatial accuracy of 2mm. The improvement of the
signal-to-noise ratio (SNR) of the CT image at a given phase was then achieved by statistiL. Xing
cally stacking the registered images. In order to find the optimal trade-off between noise
and resolution, we developed a novel 4D penalized weighted least square (4D-PWLS) method
to smooth the data spatially and temporally. The method was validated by motion-phantom and
patient studies using a GE Discovery-ST PET/CT scanner. A Varian RPM respiratory gating system was used
to track the motion and to facilitate the phase binning of the 4D CT data. In both studies, the CT data were acquired in
cine mode, at 120 kVp. The x-ray tube angular velocity was set to 2 rotations/sec. The cine duration at each couch position was set 1 sec longer than the “respiration” period to 6.1 sec, and the cine interval between images was 0.45 sec. The
total acquisition time for the motion phantom was about 30 sec covered 10 cm in axial direction with 8x2.5 mm slice
thickness; for the patient, the total acquisition time was about 1.5 min, with axial coverage of 25 cm using 4x2.5 mm
slice thickness. The 4D scans were acquired twice for the phantom at current 10 mA and 100 mA, respectively, with all
other parameters kept the same. The SNRs of the two sets of images were compared. The clinical 4D-CT patient study
was performed once at 80 mA. The dose to the patient was 80.2 mGy. The cine images were sorted on a GE Advantage
4D workstation to generate phased images.
Results
We calculated the SNRs for both studies. The average SNR of 10 mA phantom images increased by more than three-fold
from 0.051 to 0.165 after the proposed 4D-PWLS processing, without noticeable resolution loss. The patient images
acquired at 80mA showed an increase from 2.204 to 4.558 for the end-inspiration phase, and from 1.741 to 3.862 for
the end-expiration phase, respectively. By examining the subtraction images before and after processing, good edge
preservation was also observed in the patient study.
Conclusions
We have developed a low-dose 4D CT protocol. Through deformable registration and statistical smoothing, the method
incorporates information of different phases and allows us to obtain high quality 4D-CT images with low x-ray tube
current. The protocol greatly reduces the patient radiation dose during 4D CT scan and may have important practical
implications.
19
Impedance outflow boundary
2:15pm
conditions for three-dimensional
patient specific modeling of
blood flow
Irene E.
VignonClementel
session II
Purpose
When modeling blood velocity and pressure fields, the assignment of appropriate boundary conditions is of critical importance. In three-dimensional problems,
constant pressure is typically assigned to outlet boundaries resulting in unrealistic flow splits and inaccurate pressure waveforms. This problem is especially acute
in fluid-solid interaction problems since the pressure pulse drives the vessel motion. To address this limitation, zero-dimensional, lumped parameter, models have
been utilized in recent years. However, the parameters are difficult to relate to patient specific data as they do not incorporate vasculature branching patterns or geometric data. Three-dimensional to one-dimensional iterative coupling methods have
been derived and used for simple geometries but this staggered approach may lead to
convergence issues for problems with multiple outlets. A third type of boundary condition
based on the impedance derived from a one-dimensional model of vascular trees using linear
wave propagation theory has been developed and applied to patient data but only as a boundary condition for the
one-dimensional equations of blood flow (see for example [1-2]).
C.A. Figueroa
K.E. Jansen
C.A. Taylor
Material and Methods
We have developed a general method to couple a three-dimensional numerical domain with various analytic models
of the downstream domains [3]. Here we apply this method to assign impedance outflow boundary conditions for
three-dimensional simulations of blood flow based on a downstream model with one-dimensional wave propagation
theory in distributed vascular networks.
Results
Patient-specific examples are presented where realistic flow splits and pressure fields are computed. Time-varying
pressure and velocity fields were quantified for a normal subject and a diseased patient, showing characteristics consistent with clinical observations that could not be modeled with previously described boundary conditions.
Conclusion
The use of one-dimensional impedance outflow boundary conditions with three dimensional numerical models enables the simulation of blood flow at physiologic pressure. This methodology is applicable to predicting changes in
blood flow in the large arteries under varying physiologic conditions affecting the modeled domain and downstream
vasculature. The main limitation of the concept of impedance resides in the assumption of a periodic solution. For
problems where transient effects need to be modeled, coupling between a three-dimensional domain and a nonlinear one-dimensional model of blood flow is a necessary extension of the current methodology.
References
[1] M.S. Olufsen et al., Numerical Simulation and Experimental Validation of Blood Flow in Arteries with StructuredTree Outflow Conditions, ABME, 28, 1281-1299, 2000.
[2] B.N. Steele et al., Fractal Network Model for Simulating Abdominal and Lower Extremity Blood Flow During Resting
and Exercise Conditions. Submitted to Comp. Meth. Biomech. Biomed. Eng., 2005.
[3] I.E. Vignon-Clementel et al., Outflow Boundary Conditions for Three-Dimensional Finite Element Modeling of Blood
Flow and Pressure in Arteries, Accepted in Comp. Meth. in App. Mech. and Eng., 2005.
20
session II
Foraging regulation in
harvester ants
Purpose
An ant colony is an interesting example of a complex system. At the low level, a
colony consists of a large number of similar individuals, performing fairly simple
tasks, often with a random element. Yet at the high level, the colony is capable
of complex and robust behavior, achieved without central control. Information
is transmitted across the colony by interactions among ants, and the behavior
of individuals is strongly influenced by these interactions. Ants are also very
succesful creatures; it is estimated they make up at least 10% of the terrestrial
animal biomass. We have been studying a population of harvester ants living in
SE Arizona, focusing on trying to understand some of the laws that determine their
foraging behavior.
2:30pm
Serban
Nacu
Deborah Gordon
Susan Holmes
Harvester ants forage for seeds. On a typical morning there is a steady flow of foragers moving in and out of
the nest. We counted the number of ants in and out over ten second intervals. In one experiment, some of
the returning foragers were removed before reaching the nest. The colony was observed before and after the
removal, in order to estimate how it reacts to the removal. This was performed on multiple days and colonies.
Since some of the removed ants would have been otherwise seen again, the ant counts after the removal must
be adjusted upwards. The adjustment factors were computed from a related experiment, involving marking
individual ants in various colors and following them during the day. Computer simulations of the foraging
and the removal experiment were also performed.
Results
Foraging outflow decreased after the removal, even when adjusted for the removed foragers. There appears
to be a high level of randomness in the data: colony parameters do not seem to predict strongly how a colony
will react. One explanation for the flow decrease could be that ants base their decision to leave the nest on
encounters with returning ants. Preliminary results from computer simulations of this model appear to match
the results of the experiment.
Conclusion
Harvester ants respond to decreased forager inflow by sending fewer foragers outside. This may be an adaptive response to a potential external danger. In ongoing work, we are trying to understand in more detail the
low-level laws that cause this high-level behavior.
21
Visualization and analysis of
2:45pm
diffusion tensor magnetic
resonance images using
orthogonal tensor invariants
Daniel
Purpose
Diffusion tensor magnetic resonance imaging (DTMRI) is a technique that can
Bruce
map the three-dimensional orientation of tissue microstructure in the human
brain. The richness of spatially varying tensor data, however, requires specialEnnis
ized methods to visualize and quantify salient features. Diffusion tensors can be
session II
Gordon
Kindlmann
mathematically decomposed into orientation (eigenvectors) and shape (eigenvalues) information. The purpose of our work was to analytically derive a new
set of orthogonal tensor invariants (compact descriptors of tensor shape) and
use them to improve the visualization and analysis of DTMRI data. Orthogonality is a useful property of an invariant set, because it isolates the measurement of
variation in one physiological property from variations in another.
Theoretical extensions of the work by Criscione [1] in the field of strain energy functions resulted in the development of a spherical set of orthogonal tensor invariants. The invariant set is comprised of the tensor’s
isotropic norm, fractional anisotropy, and mode which respectively quantify the magnitude of isotropy, the
magnitude of anisotropy, and the mode of anisotropy. The inclusion of the tensor’s mode is useful for resolving an anisotropic region as linear-anisotropic, orthotropic, or planar-anisotropic.
Results
DTMRI data were obtained from a healthy volunteer who provided a signed statement of informed consent.
The theory was used to enhance the visualization of DTMRI data by implementing a colormap that encodes a
traditional fractional anisotropy map with the underlying tensor mode. Thus, areas of high fractional anisotropy (highly ordered structure) can be visually resolved as being linear- or planar-anisotropic, thereby distinguishing areas of purely fibrous structure from areas in which fibers cross or branch. Such maps also improve
the delineation of adjacent fiber tracks such as the corpus callosum and the cingulum bundle. Improved directionally encoded colormaps – maps that encode the direction of the primary eigenvector, often associated
with the local fiber direction – can also be generated. By incorporating tensor mode, areas of fibrous structure
are easily identified by enhanced color encoding of highly linear structures. Similarly, areas of planar anisotropy are de-emphasized as the primary eigenvector direction is indeterminant within a plane of rotation.
Supplemental material is available at www.stanford.edu/~dbe/BCATS_2005.
Conclusion
The theoretical development of orthogonal tensor invariant sets provides an improvement in the visualization and analysis of DTMRI data.
Reference
Criscione JC, et al. J. Mech. Phys. Solids 2000;48(12).
22
Modeling the aggregation of session II
3:00pm
Alzheimers peptide Aβ21-43
using molecular dynamics and
distributed computing
Vishal
Purpose
Alzheimer’s Disease(AD) has been associated with the formation of fibril- Vaidyanathan
lar aggregates of the 42 residue long beta amyloid peptide (Aβ) in the
brain[1]. Recent studies have shown that the active neurotoxic agents
are in fact low molecular weight oligomeric species rather than fibrillar
forms[2]. Knowledge of the structure of these oligomeric species and the
mechanism by which they form could prove to be vital in the search for
cures for AD. However, despite significant research focus, the Aβ peptides
have proved to be extremely challenging to study experimentally and relatively little is known about their structure or aggregation mechanisms. In this
work we use computational methods to elucidate the mechanism of aggregation of Aβ21-43 and present insights from simulation on the possible structures of the
oligomers.
Nicholas William
Kelley
Vijay Pande
Materials and Methods:
Since the process of aggregation takes secods to hours at experimental concentrations(~10µM) and one can
only simulate nanoseconds per day by traditional methods, simulating aggregation would require 10 billion
years to complete. Clearly new methods are needed and consequently, we have developed a means to use
Markov models to extend the information obtained from short simulations to experimentally relevant time
scales. We build this model by combining analytic theory and large-scale distributed computing of the aggregation starting from the encounter complex. The encounter complex aggregation of four chains of Aβ21-43
was studied by running molecular dynamics simulations in explicit water at a concentration of 14mM. The
Folding@Home distributed computing project[4] was used to obtain nearly 100µs of aggregate simulation
time. By the combination of these techniques, we can now create a kinetic model of this process.
Results and Conclusions
Using our methods, we have constructed a kinetic model of Aβ aggregation, predicting the long timescale
behavior of oligomerization. In agreement with experimental data, we find that Aβ21-43 forms heterogenous
oligomers with a hydrophobic core comprising of C-terminal residues of the chains and relatively unstructured
solvent exposed N-terminal chains[3]. However, our results allows us to go beyond experiment to predict a
more detailed structure of the oligomeric state. This is the first computational prediction of the structure and
mechanism of the Aβ oligomerization from a kinetic model corresponding to experimental conditions. We
conclude with a brief discussion of how our model could be used to test the impact of small molecule drugs
on the predicted oligomeric state.
References
[1] Annu. Rev. Neurosci. 24, 2001, pp 1121-1159.
[2] Proc. Natl. Acad. Sci. U.S.A. 100(18), 2003
[3] Biochemistry 42(44), 2003, pp 12749 - 12760;
[4] Science 290(5498), 2000, pp 1903-1904.
23
session III
3:30pm
Pan-Chi
Lee
Stefanos A.
Zenios
Optimizing dialysis
Purpose
The dialysis population in the US (currently 400,000 patients) has seen unusually
high mortality (>20% annually) and a rapidly rising cost of care ($23 billion per
year). The population is also expected to grow six-fold over the next three decades. Yet owing to a lack of thorough analysis, practitioners and policy-makers
continue to disagree over the best approach to dialysis. As a result, patients are
dialyzed ineffectively and poor outcomes are observed.
Methods
We constructed a richly-detailed simulation model that generates realistic dialysis
outcomes (i.e., patient demographics, co-existing medical conditions, disease progression, hospitalization, dialysis treatment, transplantation, quality-of-life, treatment expenses, etc.). The
model can simulate over 200,000 possible patient profiles from incidence of disease through death and was
calibrated to several databases, some of which were not available until recently. We then posed an optimization problem (a Markov decision process) with dynamics driven by the simulation model and then solved it
using Machine Learning. Through this elaborate setup, we were able to identify the most cost-effective approach to dialysis.
Results
This optimized approach to dialysis entails varying dosage depending on the characteristics of each individual patient. When we simulated the entire American dialysis population under this optimized approach,
we found that cost savings on the order of $400 millions per year are possible compared to guidelines currently recommended by the National Kidney Foundation. Furthermore, we identified several bottlenecks that
handicap the existing approach to dialysis. Sensitivity analysis revealed the findings are not adversely affected
by sampling error in the simulation parameters.
Conclusion
We have shown that it is possible to analyze dialysis in its full complexity using simulation and computationally-intensive methods. More generally, the problem investigated here is the optimal initiation of an expensive
therapy. This problem is systemic in health care and important for policy setting and clinic management. Yet
robust methodologies to develop such strategies are not widely available, inhibiting the practical implementation. This research develops such methodologies utilizing the tools of mathematical modeling and computation.
References
Pastan, Stephen, James Bailey. 1998. Dialysis therapy. The New England Journal of Medicine, Vol. 338 1428–
1437.
Sutton, Richard S., Andrew G. Barto. 1998. Reinforcement learning: An introduction. MIT Press, Cambridge,
MA.
24
Pre-stabilization for rigid body session III
articulation with contact 3:45pm
and collision
Purpose
Rachel
Modeling human motion accurately requires a robust method for dynamically
simulating joints. We developed a method for dynamic simulation of articulated
Weinstein
rigid bodies (ARBs) with unpredictable contact and collision. Many practitioners
solve these types of problems using reduced coordinate formulations. However,
unpredictable contact and collision can pose serious difficulties, and closed loops,
such as those occurring between the legs and ground during human motion, often require adding a nonlocal constraint to ensure loops remain closed. Furthermore, true dynamic simulation must be able to deal with unpredictable obstacles
requiring contact and collision handling. We found it easier to design algorithms that
treat closed loops and frequent contact and collision in maximal coordinates. Our approach
works with any method for specifying valid joint constraints, and requires no special considerations for closed
loops and/or branching.
Joseph Teran
Ron Fedkiw
Methods
Our pre-stabilization method relies on the ability to target any desired joint state. We temporarily evolve a
pair of rigid bodies forward in time to obtain a predicted joint state, and then use a black box joint model to
determine the closest allowable or desired joint state as input to our solver. This entails solving a 6n degree
of freedom nonlinear equation where n is the number of joints in the ARB. The situation is compounded by
contact and collision. We take an iterative approach and apply impulses one joint at a time. We iteratively
solve the 6 degree of freedom nonlinear system for each joint using Newton iteration on smaller systems of 3
equations by first finding and applying a linear impulse to satisfy the positional constraint, and then finding
and applying an angular impulse to satisfy the orientation constraint.
Results
Our method readily handles complicated contact, collision and articulation scenarios such as twenty skeletons dropping into a pile (over 20 million triangles) or a tank with gears driving treads. No special treatment
is required for branching, closed loops, contact, collision, friction, stacking, etc. The algorithm is efficient, effectively linear in the number of bodies and auxiliary constraints (comprising about 5% of the total computation time).
Conclusion
Currently, we are integrating control into our joint framework. Once that step is complete we will combine
this work with our existing muscle simulation and motion capture to develop an accurate model of dynamic
human motion allowing for contact and collision with an unpredictable environment.
References
Guendelman, E., Bridson, R., and Fedkiw, R. 2003. Nonconvex rigid bodies with stacking. ACM TOG (SIGGRAPH
Proc.) 22, 3, 871-878.
25
session III
4:00pm
Integrated protein interaction
networks for 230 microbes
Balaji
Srinivasan
Purpose
We sought to systematically combine diverse data types to create an integrated picture of protein interaction in 230 microbes.
Antal F. Novak
Jason A. Flannick
Serafim Batzoglou
Harley H. McAdams
We calculated several different types of functional linkage between
proteins and assessed their ability to predict whether two proteins
were likely to share the same COG, GO, or KEGG functional category.
For example, protein pairs which are coinherited in multiple organisms are more likely to be functionally linked than pairs which show no
such pattern, and pairs which are both coexpressed *and* coinherited
are even more likely to be functionally linked.
Given this intuition, we framed the problem of network integration as a high
dimensional binary classifier, where we use a vector of interaction predictors to classify protein pairs as functionally linked or unlinked. We require no simplifying assumptions about statistical dependence and no complicated parametric inference steps. Instead we directly compute the high
dimensional conditional posterior P(L|E), which gives the probability that two proteins are in the same
functional category given a vector of evidences. The evaluation of this posterior over millions of protein
pairs is made feasible by our use of the Gray-Moore dual tree algorithm, which makes our method arbitrarily scalable in terms of both the number of evidence types and the number of protein pairs considered. The output of our algorithm is the probability of functional linkage for every pair of proteins in a
given genome.
Results
We find that a plurality of the predictions in each integrated network hinge on moderate but consistent
evidence from multiple sources rather than strong evidence from a single source, yielding hidden biology
which would be missed if a single data source such as coexpression or coinheritance were used in isolation. We show that these subtle interactions have implications for fundamental cell biological processes
in several microbial species. For example, we find new proteins linked to cell division, DNA uptake, and
the cell cycle which would not have been found if our data sources had been used in isolation.
Conclusion
By systematically integrating several different data types across 230 species, we have constructed the
largest collection of probabilistic protein interaction networks compiled to date. Our methods are scalable and can be applied to any sequenced organism and any kind of experimental or computational
technique which produces pairwise measures of protein interaction.
References
Gray and Moore, Rapid Evaluation of Multiple Density Models, AI & Statistics 2003
26
Efficient free energy calculation of
peptide insertion in membranes
Purpose
As membrane-bound proteins are essential to cellular life, we are interested
in the possible roles of small peptides (in some sense the precursors of modern proteins). We focus on the insertion of small alpha-helical peptides into
membranes, examining the stability of the inserted peptide relative to the
interfacial configuration and its role in the association of individual peptides into larger multimeric structures, much like modern cellular channels.
session III
4:15pm
David
RodriguezGomez
An ideal candidate for studies of peptide insertion is the synthetic peptide
(LSLLLSL)3. At the water-membrane interface, this peptide folds into an amphipathic alpha-helix. It was shown experimentally [1] that, in the presence
of an electric field, the orientation changes from parallel to the membrane to
perpendicular and the location of the center-of-mass (COM) changes from the membrane surface to the center of the lipid bilayer. Furthermore, it associates into tetrameric ion
channels. Experimental results, however, provide no information about stability of individual helices in the
transmembrane orientation.
E. Darve
A. Pohorille
The so-called Adaptive Biasing Force (ABF) method for computation of free energy (FE) was developed in [2],
where it was shown that ABF is much more efficient than previous methods. This method allows for efficient
evaluation of the FE changes associated with the evolution of the system along a reaction coordinate. An
external force, opposite to the mean force, is added to the system and updated adaptively as the simulation
proceeds. Asymptotically, sampling becomes uniform along the reaction coordinate.
Results
We present the FE surface of insertion of (LSLLLSL)3 as a function of two coordinates: the distance of the COM
of the peptide to the center of the membrane (Z) and the orientation of the long axis of the protein relative to
the membrane surface (Φ). Also, we give information on the evolution of the peptide secondary structure. We
show how uniformity of sampling using ABF is accomplished. Finally, we give estimates of statistical errors.
Conclusion
The performed simulations point to a global minimum corresponding to the parallel orientation at the water-membrane interface. The transmembrane arrangement of a single peptide is only metastable, i.e. it corresponds to a local FE minimum. Our multidimensional version of ABF proves capable of sampling slow degrees
of freedom orthogonal to Z. In particular, no hysteresis is observed due to the penetration of water molecules
during insertion. Also, the helical structure of the backbone is preserved thanks to a careful definition of Φ
using solid-body mechanics.
References
[1] Lear et al, Science 240, 1177 (1988)
[2] Rodriguez-Gomez et al, J. Chem. Phys. 120, 3563 (2004).
27
We’re not Thor
We just make his hammer
Developing a device that connects the world. Testing
the water to make sure it stays clean. Discovering
a cure that keeps the world safe. They all require the
same thing: the right tools.
With Agilent we make sure you have them. Our
experience in the fields of electronics, communications,
life science and chemical analysis gives us a unique
perspective shared by no other company in the world.
And we build that expertise into every product
we make, from integrated test and measurement
solutions to advanced technologies and breakthrough
components.
So whether you’re a titan of industry or on the verge of
becoming one, trust the high-tech toolmakers at Agilent.
www.agilent.com
© Agilent Technologies, Inc. 2004
28
We’ll help make you stronger.
BCATS Poster
Abstracts
29
poster
0
Distributed cluster computing: a
method for parallel simulation
of large molecular systems
Abhay
Sukumaran
Purpose
Protein simulations on large timescales are very computationally expensive. We describe a method of handling otherwise intractable
problems using distributed clusters. Such clusters, with rapid internal
communication, and together comprising a larger network, facilitate
a hybrid approach between supercomputers and traditional heterogeneous distributed systems.
Guha Jayachandran
Vijay S. Pande
MPI (message passing interface) is a specification for a library that supports parallel computing in a portable and scalable manner. It is designed
to transparently support low-overhead communication within a collection
of heterogeneous processors. We use MPI-enabled software, a modified version
of GROMACS, to carry out molecular dynamics simulations on clusters. Each cluster has a master
node which supervises execution of the simulation on individual computers, and communicates with a
central server to receive simulation parameters and return results. The clusters might range from SMP
machines to heterogeneous distributed systems. Each cluster works independently, and the central servers coordinate distribution of work. Distribution of the MPI-enabled computational core and work units is
via the existing Folding@Home infrastructure, a project that enables individuals worldwide to contribute
processor time to protein simulations.
Results
The system enables new categories of applications to access the computing power afforded by clusters.
Cluster configurations vary widely, but on a standard benchmark DPCC membrane system on SMP machines, typical scaling factors approach 90% and 75% for 4 and 8 processors, respectively.
Conclusion
This system will make possible simulation of molecular systems larger than a single computer can handle
or to longer timescales. At the same time, it can generate large numbers of trajectories, more than can
be obtained with a traditional supercomputer. Such ensembles of trajectories are necessary for good
statistics. Immediate targets of interest for the system include simulation of the ribosome and of vesicle
fusion.
References
1. Charles Peck, Joshua Hursey, Joshua McCoy, and John Schaefer. Folding@Clusters. Super Computing
2004, Purdue University Exhibit
2. Stefan M. Larson, Christopher D. Snow, Michael Shirts, and Vijay S. Pande. Folding@Home and
Genome@Home: Using distributed computing to tackle previously intractable problems in computational biology. Modern Methods in Computational Biology, Horizon Press (2003)
3. Message Passing Interface (MPI) specification http://www.mpi-forum.org/docs/
30
tr0m poster
1
tr0m, or the transcendentrecursiveobjectmodel, is an attempt to recreate
linguistic patterns with transforms between existing, mutually disparate
models of representation and behavior.
the hypothesis remains transcendence, or the emergence of patterns
and properties invisible at the present. tr0m aims at creating bidirectional transforms on non-collocated object models with an underlying
set of base data.
Aditya
Mandayam
Amar Das
agilent laboratories’s alfa and cytoscape platforms serve as testbeds.
we attempt to create a set of interdependent models with the intention of a
single transform into the t-domain, eliminating the need for a conventional three
point conversion with dual transforms. with a focus solely on svo ordered languages, we have managed to categorise the behavior of a hundred kilobytes of raw text into one of twelve artificial bins.
these patterns, ‘grounds’, are modeled with units such as whitespace and punctuation.
isotropicity is added to by the introduction of models analogous to network topologies; the sentence
‘the network in a sentence’ suffices. raw textual data from scientific literature, experimental data, and
diagrammatic models define a common hierarchical hyper-graph data structure, based on agilent
cytoscape.
31
poster Segmentation of costal cartilage
2
in lower abdomen CT data using
watershed markers
Andrew
Holbrook
Purpose
Focused ultrasound ablation is a promising non-invasive technique that heats
a specific tumor region to fatal levels while minimizing cell death in nearby
healthy areas. Since high attenuation and reflection regions like bone and air
can affect the focus (and thus effectiveness) of ultrasound, treatment planning is necessary. With respect to the liver, the rib cage surrounds it, allowing ultrasonic transducer placement only in limited locations: the windows
between the ribs and the front and center abdominal region below the
sternum. Knowing the rib cage location with respect to the tumor is crucial.
However, the ribs are not solely comprised of bone; the ribs eventually transition to cartilage, which has a similar image intensity range in CT as organs like
the liver. This makes visualization difficult. In order to determine the available
treatment windows for a tumor, the ribs need to be fully extracted. Simple thresholding and a region-growing method (1) are inadequate, since neither address the problem
of similar intensity regions touching each other. We developed an algorithm to overcome this.
Kim Butts Pauly
An abdominal CT dataset was removed of its bright skin pixels through a distance based algorithm developed by Zhou et al (1). A threshold, roughly removing fatty and muscular regions, segmented the remaining region. Starting from the superior slice, rib regions were determined based on their size. Should a
region become larger than expected (i.e. a region was connected to the liver), a marker based watershed
transformation would separate the two and continue slice by slice. Finally, 3D labeling was used to remove any item smaller than a final threshold, and the remaining pixels were relabeled as bone. Algorithm
development was performed in MATLAB, and visualizations were performed in OsiriX.
Results
Preliminary results indicated that this segmentation method worked fairly well, successfully making the
ribs distinguishable from nearby organs. One small non-rib region seems to be misclassified: a lone vessel
below the sternum. Also, the ribs, compared with the original data may be slightly enlarged, but this is
often difficult to perceive and does not detract from the visualization of the dataset.
Conclusion
The algorithm does a good job segmenting the ribs from the surrounding tissues. In a 3D software package the data can be easily visualized and proper planning can now occur. The algorithm will be further
tested, accelerated, and automated with other datasets.
References
1. X. Zhou, T. Hara, H. Fujita, R. Yokoyama, T. Kiryu, and H. Hoshi, “Automated segmentations of skin, softtissue, and skeleton from torso CT images,” Proceedings of SPIE, vol. 5370, 1634-1639, 2004.
32
Modeling biological tissue with poster
nonconforming finite elements
3
Purpose
The ongoing pursuit in understanding the complex behavior of biological materials such as muscles, blood vessels, and the cornea as well as the materials
used in biomedical devices such as the shape memory alloys used in stents,
and the polymers used in intraocular lenses has lead us to take advantage
of the fast and robust tools of computational mechanics. Unfortunately, the
tools presently available are challenged by the large computational costs
of modeling real three dimensional materials and complex kinematic constraints such as incompressibility. Our goal is to develop a numerical method
for the study of biological materials that exploits the advantages of nonconforming finite elements, in an attempt to yield high accuracy with relatively low
computational cost.
Alex Ten
Eyck
Adrian Lew
Methods
Discontinuous Galerkin (DG) methods are a class of numerical methods that use nonconforming elements to model the behavior of physical phenomena. Nonconforming finite elements allow the property
of interest to be discontinuities across element faces. DG has long been used in the study of phenomena
where discontinuities are present such as shock waves. However, recent studies have shown that DG can
be equally successful in analyzing phenomena where the property of interest is inherently smooth across
the domain, such as the stresses in a blood vessel wall. Using the DG methodology, we developed and
implemented a class of numerical methods for quasistatic nonlinear elasticity. This method can be used
to model any material with a known strain energy density.
Results
The use of DG for nonlinear elasticity has shown tremendous advantages over traditional conforming
finite elements. In studies of neohookean materials (similar to isotropic biological tissues), DG can yield
better accuracy than conforming finite elements for the same computational cost. Unlike conforming
elements, DG does not lock with low order elements when modeling nearly incompressible materials.
Also, the spurious solutions caused by nonphysical kinematic constraints found in conforming elements
we not seen with DG.
Conclusions
The numerical evidence from 2D simulations and a 3D simulation of an idealized stent angioplasty shows
that DG is presently well suited for analyzing the behavior of biological materials. As this behavior is better understood, and multiscale models of tissue are developed, DG will become an even more attractive
candidate. The main advantages of using discontinuous finite element spaces have yet to be exploited
by researchers. The present method is hoped to be a preliminary agent in the development of robust and
parallel methods with the ability to completely model complex multiscale material behavior.
33
poster
4
Alain
Laederach
Reconstructing RNA folding
pathways from local probes of
macromolecular structure
A defining characteristic of most large RNA molecules is the presence
of multiple, long-lived intermediates along their folding pathway.
Inna Shcherbakova The ability to quantitatively identify and structurally characterize
these intermediates is at the heart of the RNA folding problem. Local
Mike Liang
probes of conformational change (e.g. the time-resolved changes in
Michael Brenowitz solvent accessibility of individual nucleotides reported by hydroxyl
radical (•OH) footprinting) can help define these intermediates and
Russ B. Altman
provide insight into their structures. However, reconstructing folding
pathways from a multitude of individual accessibility changes is daunting
because it creates a combinatorial explosion of possible kinetic models. We
show that clustering of time progress curves sufficiently reduces the dimensionality of
the data so as to make the problem of reconstructing the folding pathways computationally tractable.
Exhaustive enumeration of all possible kinetic models on a super-computer grid identifies the most
likely intermediates. A quantitative analysis of the flux through the best-fit kinetic model identifies
the major folding pathways of the intron. We used this combined experimental and computational
approach to reconstruct the folding pathways of the Tetrahymena thermophila group I intron under
two very different solution conditions. The flux during Mg2+-mediated folding is di-vided among
many parallel pathways. In contrast, the flux courses predominantly through three pathways during
the Na+-mediated reaction. These differences emphasize the critical role played by counterions and
highlight the unique role of Mg2+ in RNA folding. This work also establishes a general computational
framework for the kinetic analysis of local probes of macromolecular structure and illustrates the
potential of high performance computing as a tool for the analysis and interpretation of complex
processes like RNA folding.
34
Prediction of venous obstruction poster
following transvenous
pacemaker placement: a
computer simulation approach Alex Pang
5
Alex Pang
Anne M. Dubin
Nathan Wilson
Jeffrey A. Feinstein
Charles Taylor
Purpose
Venous obstruction is a major problem following transvenous pacemaker
implantation in children with a prevalence of up to 26%. Obstruction is most
commonly observed at the lead-entry site and the junction of the subclavian (SC) and internal jugular (IJ) veins. Early studies have suggested that
the ratio of lead to vessel size can act as a predictor of venous obstruction
though recent studies have disputed this finding. Understanding the effects
of pacemaker lead implantation on blood flow characteristics may provide a
more accurate predictor of obstruction. We present a computational fluid dynamics model which can predict areas of flow stagnation that may lead to vessel
obstruction.
We used custom software to create a computer model of the central veins based on angiographically-obtained patient data. Assuming resistance outlet boundary conditions, steady parabolic flow at the inlets, and
rigid vessel walls, steady-state flow simulations were performed. Two venous model sets, one patient-specific
and one idealized, were constructed. Each set included simulations before lead addition and after lead addition at several locations relative to the vessel lumen.
Results
Both model sets showed a three-fold increase in pressure differential [±10%] with lead addition regardless of
relative lead location. Velocity maps for both model sets show areas of stagnant flow in the innominate vein
and at the junction of the left SC and IJ veins induced by lead addition. Variations in placement significantly
altered blood flow characteristics in the innominate vein.
Conclusions
Consistent increases in pressure differential across all models imply that addition of leads cause a consistent
increase in vascular resistance regardless of position. Velocity maps confirm that placement of leads will significantly alter vessel hemodynamics, inducing areas of stagnant flow specifically at the common sites of occlusion. Future methods that quantify stagnant flow to rank lead positions could yield an improved clinical
strategy for lead placement.
35
poster
6
Alison L.
Marsden
A computational study of energy
efficiency and pressure losses
in the total cavopulmonary
connection
Irene E. VignonClementel
Charles A. Taylor
Purpose
The total cavopulmonary connection (TCPC) is an operation performed to treat single ventricle congenital heart defects. The superior and inferior vena cavae are connected to the pulmonary
arteries in a t-shaped junction, separating the systemic and pulmonary circulations. Previous studies of the total cavopulmonary
connection (TCPC) have focused on rest conditions and simplified
geometry. In this work, we hypothesize that the effects of respiration and exercise cause significant hemodynamic disturbances and
energy loss.
Methods
Time-dependent, 3-D blood flow simulations were performed using a
custom finite element solver. A patient specific TCPC model, including LPA
and RPA branching, was constructed from CT data. Blood flow features, pressure,
and energy losses were analyzed at rest and exercise, and with respiratory variation (based on MRI literature). Exercise IVC flow rates range between 2 and 5 times resting flow. Resistance boundary conditions
are enforced at the LPA and RPA outlets.
Results
Energy efficiency is high at rest but is found to drop substantially with maximal exercise. Flow vortices
increase in intensity with respiration and exercise, explaining higher energy dissipation when compared
to rest. Pressure drop and energy loss in the TCPC are small at rest but increase to significant levels, even
at moderate exercise. Simulation results at rest are well correlated with pressures obtained by catheterization (13 mmHg).
Conclusions
Pressure drop and energy loss in the TCPC are small at rest but increase to significant levels, even at moderate exercise. We conclude that the effects of respiration and exercise should be incorporated in models
to provide realistic evaluations of TCPC performance, and for future work in optimizing TCPC geometry.
36
Effects of size and
hydrophobicity on singlewalled carbon nanotubes
poster
7
Artit
Wangperawong
Purpose
Carbon nanotubes have recently gained much attention from various
bioscience societies due to their affinity with ion channels in biological entities. In addition to potential applications of these materials
as artificial ion channels, the physics behind the confinement effect
on water and ions is of fundamental interest. In order to understand
these phenomena, modern computational tools such as molecular
dynamics are more useful than physical experiments since they can
provide more detailed analyses. Previous studies showed the existence
of helical water structures inside nanotubes and seemingly abnormal
water transport phenomena through the nanotubes. The water transport
is especially indebted to the interplay of lost hydrogen bonds and hydrophobicity. Therefore, we hypothesize that different hydrophobicities would result in great changes in water transport. For computational simplicity we only used
carbon nanotubes, but we varied their hydrophobicities with water so that we can infer similar effects of other
nanotube types that actually exhibit the particular hydrophobicity with water.
Daejoong Kim
The physical model includes water and nanotubes of varying sizes and different hydrophobicities. We used a
GROMACS molecular dynamics package. The forcefield was Lennard-Jones 12-6 potentials (different C6 parameters results in different hydrophobicities) with electrostatic potentials.
Results
We analyzed the static and dynamic properties of water both inside and outside the nanotubes. Structural
analyses include visualization of water transport, density profiles in radial and axial directions and probability
density profiles of water dipole angles. Dynamic analyses include mean-squared displacement of water (selfdiffusion of water) and water occupancy within the nanotubes. Of special interest are angular distributions of
water as it is indicative of the network of hydrogen bonding. As the C6 value increases, the HOH plane vector
of the water within the tube tend to take positions such that the HOH plane vector is perpendicular to the
wall-normal vector. In other words, rotation in this dimension is more restrictive with a more hydrophilic tube.
In contrast, the HOH plane vector of the water within the tube remains perpendicular to the tube-axis vector
despite varying hydrophobicities.
Conclusion
Using molecular dynamics, we computed static and dynamic properties of water both inside and outside
nanotubes of varying sizes and different hydrophobicities.
References
(1) Hummer, G., Rasaiah, J. C., Noworyta, J. P. (2001) Nature, 414, 188-190.
(2) Koga, K., Gao, G. T., Tanaka, H., Zeng, X. C. (2001) Nature, 412, 802-805.
37
poster
A strategy for whole-genome
sequencing and assembly with
high-throughput, short-read
technologies
Andreas
Purpose
Sundquist
DNA sequencing is a central tool in the biological sciences that is now
8
Mostafa Ronaghi
Haixu Tang
Pavel Pevzner
Serafim Batzoglou
being used to obtain the entire genetic code of organisms. The predominant technology, Sanger sequencing, has improved tremendously and
can now read snippets of DNA up to 1000 bp long at a cost of 0.1 cents/
base, but it is still prohibitively expensive and time-consuming for large
genomes. New technologies, such as Pyrosequencing, will lower this cost
by orders of magnitude at the expense of shorter read lengths. In order to
obtain the full sequence of a genome, we randomly sample reads from the
genome to high coverage and then assemble the reads together based on
their overlaps. For complex genomes this process was traditionally infeasible
for short reads due to smaller and less unique overlaps. We have developed a sequencing protocol and an assembly program for sequencing large, mammalian genomes
with short reads.
Methods
Our strategy is a variant on a technique known as hierarchical sequencing that is more amenable to highthroughput methods. First, we take the genome and fragment it into BAC-sized pieces, randomly select fragments to high depth of coverage, and clone them individually. Then, we sample short reads from each clone
with relatively low coverage, keeping track of which clone each read came from.
Our assembly program uses the reads to determine which sets of clones overlap contiguously in the genome
and in which order, effectively breaking up and linearizing the assembly problem. Since each clone is only
sampled with low coverage, we pool reads from multiple, overlapping clones and assemble in three stages. In
the first stage we compute groups of reads that fall within small regions formed by the boundaries of clones
and merges reads within each group into larger, contiguous sequence (contigs). The next two stages combine
the contigs in successively larger regions for assembly into the final assembled sequence.
Results
We tested our methodology on S. cerevisiae, D. melanogaster, and human chromosomes 1, 11, and 21 by
simulating reads from their known sequence using different depths of coverage and read length. Our assembly program manages to deconvolute the random clones into contiguous, independent regions, allowing us
to scale linearly with genome size. The program assembles the reads into large contigs, which we compared
against the original genome for errors. We found that with short read lengths of 200 bp and only 11-fold coverage we were able to achieve contig sizes and misassembly rates comparable to those in draft mammalian
sequencing projects.
We conclude that our strategy will enable future high-throughput sequencing technologies to produce cheap,
high-quality assemblies of complex genomes.
38
Video-audio mapping of the
physical environment for blind
navigation
Purpose
The purpose of this research is to employ a new computer-based navigation
aid in developing a new methodology, focusing on perception and cognition, to govern the design of assistive technology for the blind.
Blindness or significant visual impairment eliminates or significantly decreases the effectiveness of a primary sensory channel. Detecting and
avoiding hazards is typically passed on to other primary or secondary
channels of lower bandwidth than vision. New devices are often designed
on this premise, with a high accompanying risk of sensory and cognitive
overload.
poster
9
Rebecca
Maria Currano
David Grossman
The research involves development and utilization of a portable interface that performs a
video-to-audio mapping of the physical environment to enable the blind and visually impaired to safely and independently navigate the world around them. It captures the environmental scene through 2 video cameras, and
applies geometrically and color-related artificial intelligence algorithms to decode the scene and assign names
and categories to objects within the scene. It then presents specific objects as sounds in 3D audio space.
We hypothesize that the likelihood of overloading the hearing channel and/or the cognitive process can be reduced through smart control of sound variables such as volume, repetition rate, accompanying tactile alerts, and
the classes of sounds chosen to represent objects. Cues should not unduly distract the user, or mask important
natural sounds such as speech, flow of traffic, or rear-approaching hazards.
Testing
Since cognitive load cannot be measured directly, tests must be created to measure other variables instead, such
as information retention from conversations, and rate of unintended encounters with objects and obstacles presented by the system, as well as those discernable by other natural environmental cues. Ear-tracking and gesture
study may also provide a means to study cognitive load through attention and discovery-related tasks.
Results
Currently the system recognizes red and green traffic lights and outputs a concatenated stereo audio stream that
identifies their presence, color, and azimuthal direction to the user.
Conclusion
The first stage of the project is complete. Next steps include further development of the object recognition capabilities and testing in various urban and campus settings.
Reference
Miele, JA, 9th International Conference on Audio Display, Boston, MA, July 2003.
Adcock, AB, Effects of Cognitive Load on Processing and Performance.
King, WJ, & Weghorst, SJ, Ear-Tracking: Visualizing Auditory Localization Strategies, CHI 95 proceedings, ACM.
Begley, S, Gestures Help Us Think, Wall Street Journal, Nov 14, 2003.
39
poster
A new formulation to model blood
flow and vessel motion in large,
patient-specific models of the
cardiovascular system
C. Alberto
Purpose
Figueroa
Blood velocity and pressure fields in large arteries are greatly influenced
10
by the deformability of the vessel. However, computational methods
for simulating blood flow in three-dimensional models of arteries have
either considered a rigid wall assumption for the vessel or significantly
simplified or reduced geometries. Computing blood flow in deformable
domains using standard techniques like the ALE method remains a formidable problem for large, realistic anatomic and physiologic models of the
cardiovascular system.
Irene E.
Vignon-Clementel
Kenneth E. Jansen
Thomas J.R. Hughes
Charles A. Taylor Materials and Methods
We have developed a new method to simulate blood flow in three-dimensional
deformable models of arteries called the Coupled Momentum Method for FluidSolid Interaction problems (CMM-FSI). This formulation starts from a conventional stabilized finite element formulation for the Navier-Stokes equations in a rigid domain and modifies it in such a way
that the deformability of the wall domain surrounding the fluid is taken into account. We consider a strong
coupling of the degrees-of-freedom of the fluid and the solid domains. The effect of the vessel wall boundary is
therefore added in a monolithic way to the fluid equations, resulting in a remarkably robust scheme.
Results
We present the application of the method to four different problems. The first problem considers an idealized
model of the common carotid artery and studies the impact of different outflow boundary conditions on the
simulation. The second example considers a subject-specific model of a healthy abdominal aorta, and compares
the solutions obtained with rigid and deformable wall theories. The third example illustrates an application to
disease research by comparing solutions obtained in an Abdominal Aortic Aneurysm model (AAA) under rest
and simulated exercise conditions. Lastly, the fourth geometry represents a subject-specific model of a severe
thoracic aortic coarctation and a modified post-operative model where the stenosis has been removed by placing a stent. This last problem exemplifies the applicability of the CMM-FSI to surgical planning.
Conclusion
We have derived, implemented and applied a new formulation to compute blood flow in deformable models of
arteries. The method has proven to be very robust and efficient, representing a minor increase in computational
effort beyond that of rigid wall simulations.
References
A Coupled Momentum Method for Modeling Blood Flow in Three-Dimensional Deformable Arteries. Alberto
Figueroa, Irene Vignon-Clementel, Kenneth E. Jansen, Thomas J.R. Hughes, Charles A. Taylor. Accepted for publication in Computer Methods in Applied Mechanics and Engineering, 2005.
40
Application of a three poster
dimensional image-based
modeling technique to the
circle of Willis
Chase Garrett
Purpose
Image-based modeling methods have been applied to quantify biomechanical factors in cardiovascular disease progression [1] and predict outcomes
Yarbrough
of medical interventions [2]. One approach that has been broadly applied
11
to create complex vascular models consists of creating several two dimensional segmentations along the center line of the blood vessel and lofting a
three dimensional NURB surface over these two dimensional segmentations
[3,4]. A boolean union operation applied to the collection of
2-D vessel segments is then used to create solid models. The principal shortcomings of this 2-D approach are that it is time-consuming and user-intensive
to create models and that the resulting models are inaccurate near bifurcations and
branches. Recently, Bekkers and Taylor introduced a new approach based on direct 3D
segmentation, a multiscale retriangulation and NURB surface fitting [5]. In the present study, we
implemented this approach into our image-based modeling framework and applied it to model the cerebral vascular system in a patient with a cerebral aneurysm.
Erik Bekkers
Nathan Wilson
Charles Taylor
Method
This technique uses the fast marching and level set methods for image segmentation and then a novel NURB surface fitting method for model representation. The only user interaction required is picking seed points and setting
parameters for the level set equations.
Results
Initial results indicate a 20-fold time reduction over two dimensional methods, and a more accurate representation
of the dataset, especially where vessel junctions or irregular shapes occur. One challenge in applying this direct-3D
approach has been in separating adjacent vessels.
Conclusions: The 3-D image-based modeling technique presents dramatic benefits in efficiency and noticeable increases in accuracy. However, since 2-D methods still have some advantages with data that is difficult to segment,
future work should include creating an environment in which it is possible to combine the two techniques.
References
[1] C.A. Taylor, T.J.R. Hughes, and C.K. Zarins, “Computational Investigations in Vascular Disease.” Computers in Physics, Vol. 10, No. 3, pp. 224-232, 1996.
[2] C.A. Taylor, M.T. Draney, J. P. Ku, D. Parker, B. N. Steele, K. Wang, and C.K. Zarins, “Predictive Medicine: Computational Techniques in Therapeutic Decision-Making.” Computer Aided Surgery. Vol. 4, No. 5, pp. 231-247, 1999.
[3] K.C. Wang, R.W. Dutton, C.A. Taylor, “Level Sets for Vascular Model Construction in Computational Hemodynamics.” IEEE Engineering in Medicine and Biology. Vol. 18, No. 6, pp. 33-39, 1999.
[4] N. Wilson, K. Wang, R. Dutton, C.A. Taylor, “A Software Framework for Creating Patient Specific Geometric Models
from Medical Imaging Data for Simulation Based Medical Planning of Vascular Surgery.” Lecture Notes in Computer
Science, Vol. 2208, pp. 449-456, 2001.
[5] E.J. Bekkers, C.A. Taylor, “Multi-scale Smooth Vascular Surface Model Generation from Medical Imaging Data using Hierarchical Features.” Submitted to IEEE Transactions on Medical Imaging”, 2005.
41
poster
SchemaTrans: automating the
translation of arbitrarily
formatted data to relational
databases
Christopher B. While quantity of data in the bioinformatics world is increasing at
a dramatic rate, the data remain relatively difficult to access proEgner
grammatically. Much of this difficulty is due to disparate data mod-
12
els expressed in different lexical formats not well suited to rapid,
random access. SchemaTrans is an attempt to mitigate these isJudith D. Cohn
sues by providing a pipeline to move data and format information
into a relational database in the most automated manner possible
while still providing the user with the ability to tailor the database to
his needs. Once the data are in the database, significant gains in application development and data access times can be realized. Under continuing development, SchemaTrans is a tool for creating the framework to hold data
in a relational database and then transcribing the data into that framework. Currently, SchemaTrans
can read XML, a standard format, as well as the HSSP and Homstrad custom, text-based formats, and
can write its output either to SQL scripts files or directly to an Oracle database. Input and output
mechanisms have been generalized and abstracted to facilitate the addition of new formats at each
end of the pipeline. A graphical user interface has been developed, in addition to the command line
batch mode, to allow the user to easily customize the input, schema translation, data transcription,
and output stages of the pipeline. The project binary is currently available from the Protein Function
Inference Group website at Los Alamos National Laboratory and the transition to open-source licensing is in progress.
42
Robotic perception of the skin’s poster
mechanical properties - a
validation study
Christopher
Current teledermatology consultations are limited to transmission of visual
images of the patient’s skin to the dermatologist via real-time video links
Enedah
or using the store-and-forward procedure. While visual information is
13
adequate in some cases, the absence of tactile information means the
dermatologist has to make a diagnosis without familiar tools. Studies
have found consultations relying only on visual images to be less accurate than face-to-face consultations1. Tactile images convey information
about the skin’s mechanical properties, such as skin roughness and tissue
stiffness, which are not conveyed visually. Such information is often relied
on by dermatologists and for good reason. For instance, cancerous tissue is
often stiffer and its surface typically feels rougher than normal skin.
Kenneth J. Waldron
Hayes B. Gladstone
The goal of the teledermatology project is to deliver in real time, tactile and visual images
of the human skin to a dermatologist at a remote location. This requires use of sensing devices such as the
texture and stiffness perception device described in [2]. Data from the sensors must be interpreted and used
to create a representation of the surface. This process is depicted below.
Sensing and Data Acquisition -> Data Analysis -> Digital Representation -> Transmission -> Tactile Display
(Phases in Teledermatology)
The sensing device used is the texture and stiffness perception device which is described in [2]. It consists of
an array of piezoelectric sensors and a pair of accelerometers. As the probe is dragged across the skin surface, the skin texture results in contact force variations, which are detected by the piezoelectric sensors, and
vibration of the probe body which is detected by the accelerometers. Data from both sensing mechanisms
is subsequently analyzed in time and frequency domains taking into account additional information such as
position and motion data of the probe. The end result is a digital representation of the skin surface. A digital
representation of the skin’s underlying tissue is generated from stress data which is acquired from the piezoelectric sensors when the probe is pushed a known distance into the tissue.
Experiments are being carried out to compare robotic results with the expert knowledge of dermatologists.
Preliminary clinical data comparing the robotic perception of skin pathologies with that of a dermatologist
would be presented.
References
1. Eedy DJ, Wootton R. Teledermatology: A Review. In The British Journal of Dermatology, 2001 Apr;144(4):696707.
2. Waldron KJ, Enedah C, Gladstone HB. Stiffness and Texture Perception for Teledermatology. In Studies in
Health Technology and Informatics, 2005;111:579-85
3. Howe RD, Cutkosky MR. Dynamic Tactile Sensing: Perception of Fine Surface Features with Stress Rate Sensing. In IEEE Transactions on Robotics and Automation, Vol. 9, No. 2, April 1993.
43
poster
A theoretical model that
complements an experimental
system for quantitative
investigation of in vivo proteinprotein interactions
Cesar A.
14
Rodriguez
Andrew Lipkin
Sanjiv S. Gambhir
Purpose
The goal of this project is to provide formal qualitative/quantitative models of the in
vivo interactions between the chaperone proteins hsp90, p23, and bioluminescent versions of the two proteins (hsp90-rluc, and p23-rluc). The models are the explicit expression of a theoretical framework for organizing and interpreting the data gathered using the protein reporter complementation assay which is an experimental system under
development for investigating in vivo protein-protein interactions. The theoretical and
experimental aspects of the overall project are intended to be complementary.
Methods
The following activities are required to construct the models; seed specie and component selection,
process selection, rule declaration, network generation, equation generation, analysis (overall behavior, steady
state, mass balance, parameter sensitivity), hypothesis generation, and iterative development.
Materials
The software tools used are BioNetGen 1.1.5, JDesigner 1.9, Visio 10, Cellerator 1.4.4, and Mathematica 5.1.
Results
Interactions between hsp90 and p23 generate a system with 6 species, 12 processes, and 6 rate constants (endogenous system). Interactions between hsp90, p23, hsp90-rluc, and p23-rluc generate a system with 29 species, 98 processes, and 6 rate
constants (experimental system).
The overall behavior as time elapses of the endogenous and experimental systems is composed of two phases; increase in the
concentration of complexes followed by a steady state.
In the endogenous and experimental systems, as the initial concentration of the monomers approaches 1000 µM or the ratio
ki/k-i approaches 1000, the percentage of monomers found in a complex at steady state approaches 100%.
In the endogenous system, as the ratio of k1/k-1 approaches 1000 (hsp90 homodimerization), the percentage of monomers
in the hsp90-p23 dimer configuration at steady state approaches 0.
In the endogenous and experimental systems, less p23 than hsp90 is present in the complexes at steady state.
In the endogenous system, as the initial concentration of the monomers approaches 1000 µM, the percentage of the monomers found in the tetramer configuration (hsp90-hsp90-p23-p23) at steady state approaches 100%.
As the initial concentration of the experimental monomers (hsp90-rluc, p23-rluc) approaches the concentration of the endogenous monomers (hsp90, p23), the steady state concentration of the endogenous complexes (X3-X6) decreases proportionally.
Conclusion
A set of quantitative and testable hypotheses can be formulated from the theoretical results reported above.
44
CONTRAlign: A discriminative poster
framework for protein sequence
alignment
Purpose
Chuong B.
In recent years, most alignment methods that have claimed significant improvements in alignment accuracy have done so not by proposing substanDo
tially new algorithms for alignment but rather by incorporating additional
15
sources of information, such as extending sequences via profiles or using
predicted secondary structures. While these methods have demonstrated
the utility of external information, the scoring models used are often ad
hoc, difficult to train, and prone to overfitting.
Sam S. Gross
Robert C. Edgar
Serafim Batzoglou
We present CONTRAlign (CONditionally TRained Alignment), an extensible and
fully automatic framework for robust parameter selection and protein pairwise
sequence alignment based on a probabilistic model known as a conditional random
field (CRF). In the CONTRAlign methodology, the user first defines an appropriate model topology
for pairwise alignment. Unlike ad hoc algorithms in which model complexity (and hence the risk of overfitting) corresponds roughly with the number of free parameters in the model, the effective complexity of a
CONTRAlign CRF-based model is controlled by a set of regularization parameters, “knobs” which determine
the balance between model expressivity and overfitting. Given a set of gold standard partially labelled alignments, CONTRAlign uses gradient-based optimization and holdout cross validation to automatically determine optimal regularization constants and a set of alignment parameters which will perform well on both the
training set and future alignment problems.
Results
We show that even under stringent cross-validation conditions, CONTRAlign can learn both substitution and
gap parameters which generalize well to previously unseen sequences using as few as 20 alignments; in contrast, traditional methods of substitution parameter estimation typically require large databases of thousands
of aligned blocks. Augmenting the aligner to account for known secondary structures and positional solvent
accessibilities is done seamlessly in the CONTRAlign model and yields accuracy improvements of 5-10% in
total correctly aligned positions. Finally, an extension of CONTRAlign to multiple alignment gives cross-validated accuracies matching or exceeding the current best methods.
Conclusion
As an aligner, CONTRAlign yields alignment accuracies which are equal or superior to current state-of-theart protein alignment models while requiring orders of magnitude smaller training sets. As a framework,
CONTRAlign frees aligner developers from issues of parameter estimation and model overfitting, allowing
designers to quickly try out a variety of model topologies and automatically identifying relevant features for
alignment without the need for manual parameter tuning.
45
poster
16
Metrics for a mastoidectomy
simulator
Christopher
Sewell
Dan Morris
Nikolas Blevins
Federico Barbagli
Kenneth Salisbury
Purpose
Simulation-based training can be a safe, cost-effective, and easily accessible tool for gaining experience in surgery. Another promising,
though not yet largely exploited, advantage of simulations is their
potential to objectively evaluate user performance and provide detailed constructive criticisms.
We have developed a simulator for ear surgery (specifically, a mastoidectomy). We are now creating an interface for this simulator that
allows instructors or the trainee to replay a run of the simulator, objectively score the performance according to various criteria, and visually
highlight problem areas. Two views are shown side-by-side, the left showing the procedure as originally seen by the user, and the right showing special
effects to highlight various metrics. As bone is drilled away in the left view, dots can appear in
the right view, green if the removed bone was within the line of sight and red if not, since drilling bone
that cannot be seen can cause visual cues identifying vulnerable underlying structures to be missed. Alternatively, dots can appear green or red depending on whether the bone voxel was also removed in a
model run of the simulator by an expert surgeon in order to highlight exactly where the trainee should be
drilling. Cut-away views allow the locations of these dots to be seen in relation to critical structures of the
ear. Interactive graphs can be selected to show plots of drill forces and velocities as functions of distances
from vulnerable structures and compared to force and velocity profiles obtained from expert surgeons.
Collision forces with anatomical structures can be shown graphically and with markers at the contact
points in the right-side view. The areas of these structures that have and have not been properly exposed
(by sufficiently thinning the surrounding bone so as to be able to establish their positions through visual
cues) can also be appropriately shaded in the right-side view. Quantitative measures, such as percent of
bone removed that was visible, percent of correct voxels removed, number and severity of collisions with
vulnerable structures, and percent of structures properly exposed, are also reported.
Results and Conclusions
Our metrics have been developed in consultation with experienced surgeons. We are planning a user
study in which our metrics will be evaluated by determining correlations between medical students’ simulator scores and experts’ assessments of their performance on real plastic temporal bone models.
46
Bringing the ribosome exit poster
tunnel to life with distributed
computing: a first look at the
thermodynamics of confined
solvent and the nascent chain
Christopher
Purpose
During translation the ribosome synthesizes proteins, extruding the new
D. Snow
polypeptides through a ~100 Å exit tunnel (1). To fully understand cotrans-
17
lational folding and the translation process, we must study the formative
environment of the nascent chain. The ribosome tunnel composition is heterogeneous, including multiple protein chains, rRNA, and attendant counterions. The tunnel varies in diameter between 10-20 Å. The diversity of protein sequence space translated by the ribosome is vast, and it is tempting to
imagine the exit tunnel playing a generic role as a passive container. However,
recent work on specific nascent chains has demonstrated that the ribosome is not a
universal translator (2). Certain nascent polypeptide chains (and the macrolide antibiotics) bind to
the exit tunnel and stall translation (3). Also, the tunnel may actively recognize and respond to an entire class
of nascent chain, namely transmembrane sequences (4). To date, no crystal structure has revealed the details
of nascent chain interactions with the ribosome, and no experiment has inventoried the complement of water
molecules and counterions associated with the exit tunnel. Thus, there is an opportunity for atomic simulation
to provide fresh insight.
Colin Aitken
Vijay S. Pande
We have built a large model of the solvated ribosome exit tunnel in atomic detail (~80,000 atoms). We relied
upon the Folding@Home distributed computing project to compute several thousand long molecular dynamics simulations. Essentially, we leveraged volunteer processors to focus an enormous amount of computational power (over 4,000 CPU years over the last 9 months). We then employed a novel array of algorithms
to analyze water structure, build Markovian models of long timescale kinetics, and visualize the interplay
between protein, solvent and rRNA.
Results and Conclusion
The scope of the computation allows us to simultaneously determine the relative free energy of water binding at all locations throughout the model with unprecedented precision. Surprisingly, we observed fine water
structure throughout the ribosome exit tunnel with implications for antibiotic binding affinity and interactions with nascent peptide chains. The organized hydration density provides a view of the exit tunnel that is
strikingly different from the prevailing notion of a passive, nonstick container. In this new view, water becomes
a dominant player for nascent chain thermodynamics.
References
1. Klein DJ, Moore PB, Steitz TA. J Mol Biol. 2004 Jun 25;340(1):141-77.
2. Nakatogawa H, Murakami A, Ito K. Curr Opin Microbiol. 2004 Apr;7(2):145-50.
3. Tu D, Blaha G, Moore PB, Steitz TA. Cell. 2005 Apr 22;121(2):257-70.
4. Johnson AE. FEBS Lett. 2005 Feb 7;579(4):916-20.
47
poster From biomedical images to
18
Chand T.
John
Scott L. Delp
geometric models
Purpose
Algorithms for constructing 3D models of structures from biomedical images are
usually context-specific. Hence, software developed to facilitate general biomedical image analysis is usually limited in scope. The 3D Slicer, however, is a
freely available, open-source, extensible and customizable image analysis software package currently under development. The objective of this project was
to develop modeling tools within Slicer that can be applied broadly while still
allowing the context-specific flexibility that clinical researchers need.
Development for Slicer 2.6 was done using Tcl 8.4.5/Tk 8.4.5 and Microsoft Visual
C++ .NET 2003 in Windows XP. Many tools were developed to facilitate manual
segmentation, four of which required designing nontrivial algorithms:
1. Inserting intermediate points in user-defined polygons
2. Selecting and moving points by automatic proximity detection
3. Real-time cardinal spline interpolation of a user-defined polygon
4. Automatic sampling of points from a cardinal spline for model construction
Algorithms 1 and 2 were developed to automatically detect the proximity of the user’s mouse pointer location
to different parts of a control polygon being modified in real time. Algorithm 3 was developed to compute
derivatives at the ends of a control polygon based on limited information and to render a cardinal spline
through an arbitrary set of control points based on the de Casteljau algorithm. Algorithm 4 was developed
using simple affine interpolation of parameter values. Preliminary testing was done to debug these algorithms in Tcl and Visual C++. Further testing is currently underway.
Results
Algorithms 1 and 4 work well when user-defined polygons have only small changes in curvature between adjacent vertices. Algorithm 2 works well under normal circumstances. Algorithm 3 performs well overall, but
does have precision problems and curvature problems at spline endpoints that are common to many types
of parametric curves.
Conclusions
The manual segmentation tools and the four algorithms developed above have helped make Slicer into a
more practical tool for image analysis in the Neuromuscular Biomechanics Lab at Stanford and Brigham and
Women’s Hospital at Harvard.
References
A. S. Arnold, S. Salinas, D. J. Asakawa, S. L. Delp. Accuracy of Muscle Moment Arms Estimated from MRI-Based
Musculoskeletal Models of the Lower Extremity. Computer Aided Surgery, 5: 108-119, 2000.
G. Farin. Curves and Surfaces for CAGD, 5th ed., Academic Press, 2002.
http://slicer.org
48
Algorithmic analysis of the poster
quantitative distribution of
neural stem cells in malignant
glioma David JingPurpose
One of the largest obstacles in traditional brain tumor treatments such as surgery
Piao Lin
and radiation is the degree to which glioma cells migrate away from the main
19
tumor mass. As an emerging alternative therapy, neural stem cells (NSCs) hold
great promise for glioma therapy because of their inherent ability to migrate
toward the main tumor mass as well as target metastatic tumor sites. NSCs can
thus potentially be used as therapeutic delivery vehicles for targeting tumor
cells. Despite several studies supporting the ability of NSCs to track disseminating glioma, there have been limited studies characterizing the distribution of NSCs.
The purpose of our study was to quantitatively investigate the distribution
of human NSCs in human gliomas in a mouse model. Analyzing the quantitative distribution of NSCs is important for assessing the application of in
vitro chemoattractant studies to in vivo distribution and determining the
comprehensiveness of potential NSC drug therapy for gliomas.
Methods
We used confocal microscopy, medical imaging software, and mathematical
modeling to quantify the distribution of human NSCs in experimental human
glioma after caudal lateral implantation in adult nude mice.
Josip Najbauer
Paul Salvaterra
Adam Mamelak
Michael Barish
Elizabeth Garcia
Marianne Metz
Steven Kendall
Maggie Johnson
Karen Aboody
Results:
Our results confirm that injected human NSCs achieve a broad distribution throughout masses
of human glioma and target metastatic glioma islands. NSCs seemed to follow the tumor gradient, showing higher
density at the centroid of the tumor mass. We estimated that NSCs carrying a representative tumor therapeutic with
a “killing radius” of fifty microns would eliminate over 56% of the main tumor mass.
Conclusions:
We conclude that NSC-mediated delivery of therapeutic enzymes may likely be effective due to the broad area of
tumor covered by NSCs and their demonstrated ability to track metastatic islands of tumors. We have demonstrated
novel methods and algorithms for analyzing the distribution of neural stem cells within intracranial glioma. Our
study should serve as a quantitative model for future studies that seek to (1) understand the chemical and biological
factors involved in the stem-cell tumor tropism and (2) achieve the most efficient conditions that produce optimal
therapeutic effects with NSCs in glioma.
References
Aboody, K.S., et al. 2000. Neural stem cells display extensive tropism for pathology in adult brain: Evidence from intracranial gliomas. Proc. Natl. Acad. Sci. U.S.A. 97: 12846-12851.
Westphal M, Black P. Perspectives of cellular and molecular neurosurgery. Journ. of Neuro-Onc. 2004; 70: 255-269.
Weissleder R. Scaling down imaging: molecular mapping of cancer in mice. Nature Reviews Cancer. 2002; 2: 1-8.
49
poster Locating single-stranded regions of
20
the human genome
Diane
Schroeder
Richard Myers
50
DNA becomes single-stranded in a variety of important biological situations, including the transcription initiation bubble and DNA replication. In
addition, there is evidence that some genes, such as c-myc, might be regulated by nearby denaturation-prone DNA sequences and the proteins
that bind to those denatured sequences. I am developing a genomewide assay to find denatured DNA regions in vivo. I will use this data to
1) see how often DNA denaturation is involved in gene regulation and 2)
create an algorithm that predicts new genomic regions likely to regulate
genes via DNA denaturation.
Image interpolation in 4D CT
using a Bspline deformable
registration model
Purpose
To study organ deformation during respiratory motion and develop a
method for deriving the phase-binned 3D image sets through the interpolation of the images at some known phase points.
poster
21
Eduard
Schreibmann
Brian Thorndyke
Lei Xing
Methods and materials
4D CT datasets for 3 patients were acquired. For each patient, the correlation between inhale and exhale phases was studied and the deformation of the anatomy between the two phases was quantified using
a BSpline deformable model. In this method, the deformations field between the inhale and exhale phases was defined on a set of nodes overlaid on the image and the deformation coefficients were determined through
iteratively modifying the node displacements until the optimal transformation was
obtained. Once the deformation field between the two phases is determined, the images at an arbitrary
phase can be deduced by an interpolation of the transformation coefficients. The accuracy of the proposed scheme was assessed by comparing the interpolated images with the actual image sets acquired
at the corresponding phases. The difference between the two sets of images was quantified by (a) monitoring the positions of implanted surface fiducial markers (b) checkerboard display and (c) analysis of the
subtraction of the interpolated and the actual images.
Results
It is shown that the images at the intermediate phases could be derived by an interpolation of the deformation field. An analysis of movements of implanted and surface fiducial markers in the interpolated
and actual 4D CT images indicated that 3 mm accuracy is achievable by the interpolation. The geometric
accuracy was confirmed by the evaluations of the checkerboard and subtraction images of the interpolated and actual 4D CT images. The subtraction of the two images indicated a similar level of success. The
fractional voxels having a difference higher than 20 HU was only 0.1% in all the subtraction images. The
proposed technique was also used to automatically map the organ contours in a known phase to other
phases. The mapping provides an effective way for designing patient specific margins in the presence of
respiratory motion. Finally, the technique lead to a 90% reduction in the acquired data because in the
BSpline approach a lattice of only a few thousand values is sufficient to describe a CT dataset of 25 million
pixels.
Conclusions
This study suggests that the organ deformation during the breathing process can be well modeled by using a BSpline deformable algorithm and it is possible to obtain 4D images by interpolating the 3D images
acquired at some distinct phases. The proposed technique offers useful means for radiation dose reduction, binning artifacts removal, and disk storage improvement in 4D imaging.
51
poster
22
GROMACS on the GPU
Erich Konrad
Elsen
Purpose
The purpose of our project is to harness the computational power of
GPUs (commercial graphics cards) to speed up molecular dynamics
simulations and reduce the runtime of simulations.
Vishal Vaidyanathan
Materials and methods
Eric Darve
We are re-implementing parts of the GROMACS molecular dynamics package on the GPU using the BrookGPU language developed
Pat Hanrahan
here at Stanford. All major parts of the code except the neighbor
Vijay Pande
list search have been mapped to the streaming computing model
and ported to the GPU.
Ian Buck
Results
For the force calculations, ATI’s X800XT PE achieves almost 5x the GFLOPS of a
Pentium IV 3.0Ghz. NVIDIA achieves only 1.5x the number of GFLOPS of the CPU. On ATI, the overall
runtime is reduced to 70% of the original runtime.
Conclusion
As GPUs increase in power faster than CPUs the performance gap will only widen. For a wide variety
of applications streaming computing will be the future of scientific computing. The new Cell processor from IBM shows promise for being extremely useful and powerful (256 GFLOPS peak in single
precision) as a streaming processor for scientific computation.
References
Buck, I., Foley, T., Horn, D., Sugerman, J., Fatahalian, K., Houston, M., Hanrahan, P. “Brook for GPUs:
Stream Computing on Graphics Hardware.” In Proceedings of Supercomputing 2005. http://graphics.
stanford.edu/papers/brookgpu/brookgpu.pdf.
Lindhal, E., Hess, B., van der Spoel, D., “Gromacs 3.0: A package for molecular simulation and trajectory
analysis.” Journal of Molecular Modeling. 7:306-317, 2001.
Erez, M., Ahn, J., Garg, A., Dally, W., Darve, E. “Analysis and Performance Results of a Molecular Modeling Application on Merrimac,” Proceedings of the 2004 ACM/IEEE conference on Supercomputing, p.
42, 2004.
52
3-D simulations of hemodynamic poster
factors in pulmonary
hypertension
Tim A. Fonte
Purpose
23
Primary pulmonary hypertension is a deadly disease with undetermined
origins. Simulations of blood flow in healthy and hypertensive pulmonary
arteries (PAs) provide detailed information about flow characteristics and
forces on vessel walls, which can lead to a new understanding of how vessels remodel and the disease progresses.
Irene E.
Vignon-Clementel
C. Alberto Figueroa
Charles A. Taylor
Models of PAs for healthy and hypertensive subjects were created from
MRA [1] to the maximum detail of each data set (50-70 vessels per model). Blood flow was measured with PC-MRI at the main, left, and right PAs.
Arterial pressure was measured for the hypertension subjects. The models
were meshed with 3-4 million elements. A custom finite element method
was used to solve the incompressible Navier-Stokes equations over multiple
cardiac cycles. Resistance boundary conditions were set at the outlets to obtain
patient-specific flow split and pressure [2], and a Womersley velocity profile was set at
the inlet. Simulations were performed with both rigid walls and a deformable fluid-structure model [3].
Additional simulations utilized adaptive meshing based on local error [4].
Results
The mean wall shear stress (mwss) in the left and right PAs is 16.8 dynes/cm2 (healthy) and 3.5 dynes/cm2
(hypertension). Flow recirculation was observed in both healthy and hypertensive subjects; however there
is more complex flow in the healthy arteries. There are large regions of low, stagnant flow in the patient with
pulmonary hypertension. An adaptively refined anisotropic mesh of 1 million elements was used to obtain
comparable results to a 3 million element isotropic mesh (mwss difference of 6% in the left and right PAs).
Conclusions
There are dramatic differences in blood flow characteristics between healthy PAs and PAs with pulmonary
hypertension, especially the lower wall shear stress seen with pulmonary hypertension. Adaptive meshing
allowed for similar results at a fraction of the computational cost.
References
[1] N. Wilson et. al., A Software Framework for Creating Patient Specific Geometric Models from Medical Imaging Data for Simulation Based Medical Planning of Vascular Surgery. Lect. in Comp. Sci., 2001; 2208; 449-456.
[2] I. Vignon et. al., Outflow Boundary Conditions for Three-Dimensional Finite Element Modeling of Blood
Flow and Pressure in Arteries. Accepted in Comp. Meth. in App. Mech. and Eng., 2005.
[3] C.A. Figueroa et. al., A Coupled Momentum Method For Modeling Blood Flow In Three-Dimensional Deformable Arteries. Accepted in Comp. Meth. in App. Mech. and Eng., 2005.
[4] J. Müller et al., Anisotropic Adaptive Finite Element Method for Modeling Blood Flow, Accepted in Comp.
Meth. Biomech. Biomed. Engr., 2005.
53
poster
Filling missing components in
yeast metabolic pathways using
heterogeneous data
Gal Chechik The set of cellular metabolic reactions forms a complex network of
24
interactions, but even in well studied organisms the resulting pathways contain many unidentified enzymes. We study how ‘neighborAviv Regev
hood relations’ between enzymes in metabolic pathway are maniDaphne Koller
fested in functional properties of the corresponding genes and
their products, including mRNA expression, protein domain content and cellular localizations. We develop compact and interpretable probabilistic models for representing protein-domain co-occurrences and gene expression time courses. The former can provide
predictions of domains and genes functions and the later reveals the
relation between the activation time of yeast genes and the usage of their
protein products in the pathways. These models are then combined for completing the unidentified enzymes in the pathways, achieving accuracy that is significantly superior to
existing state-of-the-art approaches.
54
Simulation of fluorescence poster
anisotropy experiments: probing
protein dynamics
Purpose
Gunnar F.
Time-resolved fluorescence anisotropy decay experiments on a protein-attached dye can probe local protein dynamics and steric restrictions, but
Schroeder
are difficult to interpret at the structural level [1]. Aiming at an atomistic
25
description, we have carried out molecular dynamics simulations of such
experiments.
Ulrike Alexiev
Helmut Grubmuller
Results
Our simulations describe an Alexa488 fluorescent dye maleimide derivative covalently attached via a single cysteine to the AB-loop of bacteriorhodopsin. Fluorescence anisotropy decay curves obtained from the
simulations agree well with the measured ones. Three anisotropy decay components were resolved and assigned 1) to the fast dynamics of the attached dye
on the picosecond timescale, 2) to the slower dynamics of the loop at the one nanosecond timescale and 3) to the overall tumbling of the molecule. For the biologically relevant one nanosecond component we identified two processes from simulations, the motion of the flexible loop as well as
slow conformational dynamics of the dye. These two processes are not separable by experiment alone.
Furthermore, analysis of the correlation between the dye and the protein motion revealed which part
and which motion of the protein is actually probed by the experiment. Finally, our simulations allowed to
test the usual and inevitable assumption underlying these types of spectroscopic measurements that the
attached dye probe does not severely perturb the protein dynamics. For the case at hand, by comparison
with a simulation of the dye-free protein, the perturbation was quantified and found to be small.
References
[1] U. Alexiev, I. Rimke, and T. Pohlmann. Elucidation of the nature of the conformational changes of the
EF-interhelical loop in bacteriorhodopsin and of the helix VIII on the cytoplasmic surface of bovine rhodopsin: A time-resolved fluorescence depolarization study. J. Mol. Biol. 328:705-719 (2003)
[2] G. F. Schroeder, U. Alexiev, and H. Grubmuller. Simulation of fluorescence anisotropy experiments:
Probing protein dynamics. Biophys. J., accepted.
55
poster Efficient prediction of protein-
26
Haidong
Wang*
protein interactions using Markov
networks
* These authors contributed equally
Purpose
Mapping the network of protein-protein interactions is a key step towards
understanding many cellular processes. Current assays for measuring interactions are noisy and partial. Recent work [1] has shown that Markov
networks can effectively integrate heterogeneous data and deal with
noise to make better predictions. However, standard inference methods
in these models are slow and do not scale to large, dense networks. We
propose a new algorithm that speeds up the computation without reducing prediction accuracy, opening the door towards a genome-wide analysis,
and allowing the use of richer models involving multiple interaction types such
as regulatory interactions.
Matt Schefer*
Gal Elidan
Daphne Koller
Methods
Our model utilizes multiple interaction and cellular localization assays, treating them as noisy sensors
for the underlying truth. It encodes a preference for transitivity in the interaction graph, and the fact
that interacting proteins tend to be localized in the same compartment. Unlike previous work, we
restrict to models that satisfy certain regularity conditions. While these conditions do not necessarily
hold in biological systems, they allow the use of more efficient inference algorithms, using min-cut or
linear programming rather than iterative methods such as loopy belief propagation.
Results
We train our model on a set of 2000 reliable protein-protein interactions and 2000 non-interactions,
and compare our models with standard max-likelihood learning [1] using 4-fold cross-validation. In
weak models, which do not account for transitivity, our method is worse than [1], because the approximation forced by the regularity condition introduces significant error. In the richer models that
include transitivity, we are collectively classifying all of the interactions together, which helps correct
these errors. Here, we achieve improvements in both accuracy and running time. The true positive,
false positive rate, and running time are: our method – TP=85.6%, FP=1%, time=280 sec vs. Jaimovich
et al [1] – TP=84%, FP=2%, time=452 sec. When we further account for the possibility of noisy localization results, we obtain further improvements: TP=87.2%, FP=1.2%, time=680 sec vs. TP=85.5%, FP=2%,
time=788 sec. Our method also scales to data sets with many more interactions, where the existing
method fails. With 6000 (less reliable) interactions, we obtain an accuracy of TP=86.4%, FP=2.7%.
References
1. Jaimovich A, Elidan G, Margalit H, and Friedman N. Towards an Integrated Protein-Protein Interaction Network. RECOMB 2005
56
Framework for identification of
allosteric networks
Purpose
Allosteric regulation is a key feature of enzyme function. Lockless et al. proposed an algorithm that uses sequence data to search for potential allosteric
networks in proteins using statistical analysis of multiple sequence alignments. We have created user-friendly
software to perform this algorithm. We are applying the software to the
chaperonin proteins.
poster
27
John
Patrick
Adams
Erik J. Miller
Christoph Spiess
A protein of interest’s sequences are collected and aligned using the ClustalW algorithm and Blosum62 scoring matrix. We read the alignment into an
application that analyzes the alignment to identify statistically interesting pairs
of sites within the protein that appear to be evolutionarily coupled. The site-site coupling energies, a statistical measure of the strength with which the sites influence each other,
can then be clustered, mapped as a network, or colored on a three-dimensional PDB structure for analysis.
Identified coupled sites can be confirmed by assaying the protein containing designed point mutations at
those sites for loss of allosteric behavior.
Results
Chaperonins are large protein complexes that couple the energy of ATP hydrolysis to the folding of newly synthesized proteins. They are essential proteins composed of two rings of 7-9 subunits, each subunit consisting
of 3 domains. There are several modes of allostery within the chaperonins, providing an ideal family to test
our software. Cooperativity includes negative inter-ring and positive intra-ring cooperativity for ATP hydrolysis, and allosteric coupling of ATP hydrolysis within a subunit to substrate remodeling. We are undertaking
a statistical analysis of large-scale sequence alignments to generate hypotheses about the mechanisms of
chaperonin activity.
Conclusion
We have developed an extensible cross-platform java application that makes the analysis of protein alignments for site-site coupling simple for any user. We hope that this will promote the use of this new method
to understand communication within the domains of a protein. Compared to experimental approaches such
as mutagenesis, it drastically reduces the time needed for analysis and allows the study of proteins that are
difficult to manipulate experimentally. We hope that it will serve as a foundation for the development of more
advanced algorithms to be able to analyze more complex problems in protein science such as binding of receptors and ligands.
References
Lockless, S.W. et al., Evolutionarily conserved pathways of energetic connectivity in protein families. Science,
1999. 286(5438): p. 295-9.
Suel, G.M., et al., Evolutionarily conserved networks of residues mediate allosteric communication in proteins.
Nat Struct Biol, 2003: p. Advanced Online Publication.
57
poster
28
Jessica
Ebert
Unsupervised identification of
functionally relevant residues in
protein families
Purpose
Both the impending increase of solved structures for proteins of unknown function and the uncertainties involved in sequence based functional annotation methods point to the need for a greater understanding of the relationship between structure and function. Because global
structural similarity does not imply functional homology, methods are
required for the identification of functionally relevant regions of protein
structures upon which models can be built to recognize similar sites in
other proteins. Identification of examples of a functional site used in the
construction of such a model, however, often represents a bottleneck in functional annotation pipelines. Furthermore, a residue that is not directly involved in
a protein’s chemical activity may nonetheless contribute to an active site’s environment in a
manner that might make it an interesting target for protein engineering and drug design applications.
We propose to identify positions in a protein family that are directly or indirectly involved in the family’s
functional activity by locating residues whose physicochemical environments are both conserved and
unique. While core residues will likely yield models representing generic hydrophobic positions, the environments of functional residues may have unique characteristics that will give rise to highly sensitive and
specific models.
Russ Altman
Methods
We first build a multiple structure alignment in order to find residue correspondences across the family,
and then use FEATURE (Wei and Altman, 1998) to model the environment around each of the alignment’s
columns. FEATURE identifies attributes of the environments around a column’s residues that distinguish
them from negative training examples selected to match the column’s atom density and sequence composition. We build several models for a column, each of which excludes one residue.
To determine whether a column gives rise to a model that is both sensitive and specific, we scan each
residue in the family against the model for the column that was built without using information from the
protein to which the residue belongs. The area under the ROC curve for a column and the average score
separation between the column’s residues and other residues then reflect the ability of the column’s models to score residues from the column higher than residues from other columns.
Results
We have identified eight positions in a family of serine proteases whose environments are both conserved
and unique. The three positions of the catalytic triad are included in this set of residues, and the other five
residues are in close proximity to the family’s active site.
References
(1) Wei L, Altman RB. Pac Symp Biocomput. 1998: 497-508.
58
A modified Bayesian approach to poster
determination of causation in
differential gene expression
Purpose
Jessie Dale
DNA microarrays have given researchers vast amounts of new data
regarding differences in gene expression between normal and disTenenbaum
eased tissue types. Still missing, however, is the ability to use this
29
information about differential gene expression to gain insight into
upstream causal mechanisms of disease. We have developed a modified Bayesian approach to predict the most likely ligand responsible
for changes in gene expression given a list of genes observed to be
significantly up- or down-regulated and a set of possible ligands.
Paul J. Utz
Atul J. Butte
Our model was trained on a large DNA microarray data set made available by
the Alliance for Cell Signaling in conjunction with Nature Publishing Group. In this
data set, B cells were stimulated with 32 different ligands and gene expression data was observed at
four time points. We have applied multiple methods for representing this time course data representation (extreme value z-scores, area under the curve, q-value, etc.) to develop a probabilistic model
which allows us to make predictions regarding the relative likelihood of each ligand in our training
data given a set of genes observed to be significantly affected in an independent test data set.
Results
Using the various methods described above for representation of time course data and different algorithms for determination of significance, we tested our prediction method on independent test
data sets which we downloaded from the Gene Expression Omnibus. Different methods above gave
varying success rates in predicting the ligand that was actually used in the experiment that generated
the test data. Strikingly, in some cases our method was able to make a correct prediction even in cell
types that differ from the type used to train the model (macrophages vs. B cells).
Conclusions
While our method has some obvious limitations, for example the finite set of ligands in the training
data, as well as a sub-optimal true positive rate of 67%, we believe it shows promise for future use in
disease mechanism elucidation. We continue to refine the method to improve accuracy.
References
1.
http://www.signaling-gateway.org/
2.
http://www.ncbi.nlm.nih.gov/geo/
59
poster Use of a naive Bayesian classifier
30
Jason A.
Hackney
to identify gene regulatory
networks in the protozoan
parasite, Enatmoaba histolytica
Gretchen M.
Ehrenkaufer
Upinder Singh
Purpose
Entamoeba histolytica is a protozoan parasite responsible for amebic colitis, a disease that kills over 100,000 per year. Little is known about gene
regulation in protozoan parasites, in general, and E. histolytica in particular. We wished to identify gene regulatory networks within E. histoyltica
trophozoites, in order to better understand the biology of this important
parasite.
We hybridized RNA isolated from mid-log cultures of E. histolytica HM-1:
IMSS trophozoites to a short oligonucleotide array. This array contains probes
designed against 7,770 of the ~10,000 amebic genes. We identified genes with
either high or low signal on the microarray. The promoters for these genes were retrieved from a promoter database, and motif elucidation using the MEME program was carried out. We
identified thirty motifs in each set, and filtered for motifs that occurred in both sets. These motifs were
used to create a naive Bayesian classifier, in which motif presence and position in the promoter were used
as predictive variables for gene expression. Results from our microarray hybridization were randomly partitioned into a training set and cross-validation set.
Results
The Bayesian classifier was able to accurately predict the expression of 70% of amebic genes. By determining which promoter motifs are used to classify genes, we were able to find a set of three motifs that
are predictive of low gene expression in amebic trophozoites. While any single motif was unable to predict gene expression, genes with more than one motif were highly likely to have low expression. The
three motifs were found in a stereotypical spacing and distance from the transcription start site. A large
number of genes with this regulatory pattern belong to the same gene family. This family is known to
have median to low expression in trophozoites, with increased expression during stress response. We find
that genes of this family with two motifs show this expression pattern, while a family member with none
of these motifs was equally expressed in normal and stress response conditions.
Conclusions
We have been able to identify a regulatory module that affects gene expression of a large family of amebic genes. The network identified in this work is highly complex, and understanding this network and the
genes it regulates should lead to a better understanding of both genetic regulation in ameba, and evolutionary dynamics of regulatory networks. Importantly, this work can be extended easily to novel analyses,
including comparisons of amebic strains that differ in virulence, or the stress response pathways.
60
Patient-specific modeling of poster
altered hemodynamics and
arterial deformation induced
by coarctation of the aorta
John F.
and subsequent stent
implantation
LaDisa, Jr.
31
Purpose
Stents are playing an increasing role in the treatment of aortic coarctation
(CoA)(1). However, morbidity (hypertension, aneurysms, stroke) persists(2) and
may be attributed to abnormal hemodynamics in the aorta and its branches(3).
We hypothesized that computational fluid dynamics (CFD) modeling can be
used to quantify alterations in blood pressure (BP), flow and vascular deformation introduced by CoA, and stent implantation.
C. Alberto Figueroa
Irene E.
Vignon-Clementel
Frandics P. Chan
Charles A. Taylor
Magnetic resonance angiography was performed(4) before and after stent implantation in a 13 year old patient with severe CoA. Computational representations of the aorta and cervical arteries were created using custom software that facilitates vascular model construction(5). Time-resolved, 2D phase-contrast magnetic
resonance (PCMR) imaging was performed in the ascending and descending aorta and
cervical arteries. The ascending aorta PCMR waveform was mapped to the aortic inlet. Resistance boundary conditions were imposed at the descending aorta, innominate, left common
carotid (LCCA) and subclavian arteries (LSA) based on cuff BP and PCMR data. CFD simulations were performed using
a validated stabilized finite-element method(6). Systolic BP, diastolic BP and pulse pressure were quantified before and
after stenting and compared with clinical observations. Aortic deformation proximal and distal to the coarctation was
compared to that obtained from PCMR data of spatially equivalent regions.
Results
CoA caused hypertension (134-142 mmHg) and elevated pulse pressure (66-73 mmHg) in the cervical arteries consistent with BP measurements. Pronounced deformation (8%) occurred in the LCCA and LSA with concomitant increases
in blood flow through a collateral artery from the LSA to the descending aorta. SBP decreased after stenting (111-112
mmHg) in arteries proximal to the stenosis and collateral flow was attenuated by 56%. A 17 mmHg gradient across the
coarctation was also reduced to 4 mmHg after stenting, similar to clinical observations. Aortic displacement was consistent with the luminal behavior revealed by PCMR.
Conclusion
These findings demonstrate that CFD modeling can reproduce hemodynamic waveforms and clinical observations in
patients with CoA. The results may ultimately provide insight into sources of morbidity and offer quantitative assessment of treatment options such as stent implantation.
References
1.
Johnston, T. A. et al., Catheter Cardiovasc Interv 62, 499 (2004).
2.
Ou, P. et al., Eur Heart J 25, 1853 (2004).
3.
O’Rourke, M. F. et al., Circulation 44, 281 (1971).
4.
Alley, M. T. et al., Radiographics 18, 273–285 (1998).
5.
Ku, J. P. et al., Ann Biomed Eng 30, 743–752 (2002).
6.
Taylor, C. A. et al., Ann Biomed Eng 26, 1 (1998).
61
poster Preferential coplanarity of RNA helices
32
Joseph
Minhow
Chan
and its impact on RNA activity
Purpose
RNA molecules, which are transcribed from DNA and are used by the ribosome to synthesize proteins can also catalyze complex chemical reactions in the cell. As the structure of RNA dictates
function in the cell, it is essential to understand the basic principles that govern RNA structure.
The hypothesis to be tested is that RNA structure can be described through vector analysis. That
is, vectors normal to the RNA bases, and more specifically the RNA helices, are preferentially
oriented bipolarly in the same plane. Although this is a natural tendency for all helices, the
fact that multiple helices of many RNA molecules will often align in a plane despite turns and
loops is striking.
Methodology
Alain Laederach The
distribution of normal vectors to the bases of a given RNA molecule can be described by
using Principal Component Analysis (a statistical method of describing the spread of a given
Armin Schwartz- set of vectors) and fitting the Dimroth-Watson distribution, an antipodally symmetric probability density functions where f(x) = f(-x) [1]. This distribution can fit two general cases onto
man
a dataset: the girdle case (which has a minimum density along the third principal component
and describes a plane) and the bipolar case (which has a maximum density along the first principal
Russ Altman component
and describes a pole). One measurement of how well the model fits the data is dispersion
s of a dataset, the 3rd eigenvalue for the girdle case and the 1st eigenvalue for the bipolar case. The angle
dispersion, a more tangible measurement, can be calculated with the formula: arcsin(sqrt(s)). By fitting a density
function to RNA bases, several applications can be accomplished. First, RNA viewing can be optimized by orienting the viewer’s
vision along the third principal component of the normal vectors to the bases. Second, given the highly planar and bipolar orientation of helices, one can determine how significant helices are to overall molecular planarity and bipolarity, as well as to function. To
do this, one can perform a random helices test in which, for a given molecule, 100,000 random helical orientations of that molecule
are tested for higher planarity or bipolarity against the wild-type conformation. Finally, subdomains of RNA—important regions of
the RNA that, when cleaved from the rest of the molecule, maintain the same conformation—can be identified by local areas of
coplanarity or with specific, multiple bipolar orientations. Tests were performed on t-RNA (PDB ID 1EHZ), the P4-P6 RNA subdomain
of the protozoan Tetrahymena known for its catalytic capabilities (1GID), its supradomain (1GRZ), and rRNA (1FFK). This method
will later be performed on a whole database of RNA molecules. Other models for fitting datasets will be analyzed as well, such as
one that takes into account multiple bipolar concentrations. Such a model would use a k-means clustering approach with clusters
concentrated in distinct bipolar regions.
Results
The angle dispersions for 1EHZ, 1GID, 1GRZ, and 1FFK in the girdle case were respectively 16.63, 18.35, 25.10, and 30.90 degrees
with a maximum value of 35.26 degrees. In the bipolar case, the angle dispersions were respectively 45.66, 29.86, 42.03, and 51.36
degrees with a max value of 54.74 degrees. The results for the random helices test for planarity for these same RNA were as follows
respectively: 0.779%, 2.29%, 4.43%, and 34.7% of the random helical orientations scored a higher planarity than the wild-type. The
results for bipolarity were as follows: 97.9%, 0%, 6.58%, and 56.4% of random helical orientations scored higher bipolarity than the
wild-type. Locating the P4-P6 subdomain of 1GRZ was a success by finding the most planar group of 11 helices in 1GRZ.
Conclusion
The angle dispersions for the girdle case suggest that all the molecules are fairly planar except for 1FFK, the ribosomal subunit. Observation of this molecule confirms this measurement; 1FFK is a very nonplanar molecule. The angle dispersions for bipolarity were
poorer overall. Rather than fitting one bipolar concentration to the data, a more apt model would probably involve multiple bipolar
concentrations. This conclusion is most evident with the result of the random helices test for bipolarity for 1EHZ, which scored
97.9%, a very bad rating. However, a closer look of the t-RNA molecule reveals that it has two distinct, polar helical regions. Overall,
these results largely justify the Dimroth-Watson models as an accurate means of describing the planarity or bipolarity of any set of
vectors. Calculation of p-values is pending. An approach similar to the random helices test might be used to output a computational
p-value. The identification of RNA subdomains using these vector models is very promising, as the P4-P6 subdomain of 1GRZ was
a success.
Resources: 1. Geoffrey S. Watson. Equatorial distributions on a sphere. Biometrika, 52(1/2):193–201, 1965.
62
poster
Using coarse-grained simulations
of RNA to explore intermediate
folding pathways
Magda Anna
The structure of large catalytic RNAs (e.g. group I and II introns) is of
interest because of their auto-catalytic self-splicing activity, which
is contingent upon the formation of specific tertiary contacts. We
Jonikas
are exploring the folding of the Tetrahymena thermophila group
33
I intron by running coarse-grained simulations of RNA using the
Alain Laederach
molecular dynamics (MD) package NAST (Nucleic Acid SimulaRuss Altman
tion Tool). Results from time-resolved hydroxyl radical footprinting define specific three-dimensional constraints (in the form of
contact order formation) on the structures of the folding intermediates. By carrying out constrained MD simulations, it is possible to
determine the effect of these experimental constraints on the relative
mobility of the rest of the molecule. Multiple replica exchange MD is used
to improve sampling by regularly exchanging the structures of simulations run at different temperatures on a large super-computer grid. Exchanges are attempted randomly between
runs and accepted or rejected using a metropolis criterion in order to ensure the detailed balance
condition in this Monte Carlo process. Using this approach we make structural predictions for 3 folding intermediates along the folding pathways of the T. thermophila group I intron.
63
poster
34
Justus
Roos
Quantitative and qualitative
assessment of a new knowledgebased algorithm for centerline
restoration through femoropopliteal artery occlusions in
peripheral CT angiography
(CTA)
Tejas Rakshe
Matus Straka
Sandy Napel
Dominik
Fleischmann
Purpose
To assess the accuracy of a new knowledge-based algorithm for automated centerline tracking trough femoro-popliteal occlusions in
CTA, a currently unresolved and labor intensive problem.
CTA was performed in 20 patients (mean age 69y, range 44-88y) with a
total of 26 femoro-popliteal arterial occlusions (mean length132mm,
range 16-400mm),.Occlusions were categorized into <75mm (n=8), 75150mm (n=11), and >150mm (n=7). Two radiologists used a semi-automated centerline extraction technique and bridged occluded segments by manually setting subsequent control points in the center of the vessel. A new knowledge-based
centerline algorithm was used to track the same occluded segments. Accuracy of the algorithm was
quantified by calculating the maximum deviation from the average of the two manually derived centerlines. Diagnostic image quality was compared between curved planar reformations (CPR) generated with both methods.
Results
The knowledge-based algorithm successfully interpolated all femoro-popliteal occlusions in 20 patients. The average of the maximum deviation (in mm [for occlusion length] between the expert
driven and the automated centerline interpolation was 0.1mm [for <75mm], 3.7mm [for 75-150mm],
and 16.7mm [for >150mm]. CPRs based on automated centerlines were indistinguishable from those
based on manual vessel tracking for occlusions shorter than 75mm.
Conclusion
The proposed knowledge-based algorithm allows an accurate automated interpolation of femoropopliteal occlusions up to a length of 75 mm. This may substantially accelerate the creation of CPRs in
patients with peripheral arterial occlusive disease
64
A common signature for poster
human aging
35
Purpose
Aging is marked by the gradual decline of a multitude of physiological functions
leading to an increasing probability of death. At the molecular level, we are just
beginning to assemble protein and gene expression changes that can be used
as biomarkers for aging. Rather than search for molecular biomarkers by focusing on only one gene, an attractive approach is to screen all genetic pathways
in parallel for age-related changes by using DNA microarrays to search for
gene expression changes in the elderly.
To profile transcriptional changes with age, we used Affymetrix Hu133 2.0
Plus DNA chips, which consist of approximately 55,000 probe sets corresponding to 25,000 unique genes. To determine age-regulated genes, we
implemented a multiple regression model including terms for age, sex, and
tissue type. We chose genes which were significant to a p-value threshold
of 0.001 or better. In our treatment of genetic pathways, we used a modified
Gene Set Enrichment Analysis(GSEA)(Mootha et al. 2003) consisting of a Van
der Waerden non-parametric test to choose genetic pathways that are regulated with age.
Jacob
Michael
Zahn
Rebecca Sonu
Emily Crane
Ralph Rabkin
Ronald W. Davis
Kevin G. Becker
Art B. Owen
Hannes Vogel
Stuart K. Kim
Results
We have identified a molecular profile for aging consisting of 250 age-regulated
genes in human muscle. Of these 250 genes, 92 genes can be shown to be physiological biomarkers of aging in the muscle. We compared the transcriptional profile of muscle aging to previous transcriptional profiles of aging in kidney and brain, and found a common signature for aging
in these diverse human tissues. The common aging signature consists of three genetic pathways: genes in
the extracellular matrix increase expression with age, genes encoding components of the cytosolic ribosome
increase expression with age, and genes encoding subunits of the mitochondrial electron transport chain decrease with age. We also compared transcriptional profiles of aging in human to that of the mouse, and found
that the electron transport chain pathway decreases expression with age in both mammals.
Conclusions
In this study, we have generated a high-resolution profile of aging in the human muscle. Our results provide
the first evidence for a common signature of changes of gene expression in different human tissues. We have
also found the first evidence for a public mammalian signature for aging in the decreased expression of the
electron transport chain.
References
1.) Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S et al. (2003) PGC-1alpha-responsive genes
involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34(3):
267-273.
65
poster
Chronic spinal cord injury modifies
aortoiliac biomechanical forces
and morphology and increases
abdominal aortic aneurysm
Hyun Jin Kim disease risk
36
Purpose
Spinal cord injury (SCI) patients have a greater risk of abdominal aortic aneurysms (AAA) compared to age and risk-factor matched ambulatory control
subjects1. We propose that reduced lower-limb blood flow and resistive hemodynamic conditions observed in SCI patients upregulate pro-inflammatory infrarenal aortic gene expression, potentially promoting AAA disease.
We used magnetic resonance (MR) imaging and computational flow modeling to determine the relationship between hemodynamic conditions in SCI
subjects and AAA risk.
Janice J. Yeung
C. Alberto Figueroa
Irene E.
Vignon-Clementel
Mary T. Draney
Robert J. Herfkens We constructed 3-D computational models from the MRI data of five SCI subjects and six age and risk-factor matched control subjects using custom softRonald L. Dalman ware2.
We solved the 3-D equations of blood flow in deformable models of arteries using a novel finite element method3. Inflow boundary conditions at the
Charles A. Taylor supraceliac
level were specified using PC-MRI data, and impedance boundary conditions were specified at the outlets4. The impedance waveforms were generated using
Womersley’s elastic tube theory and an asymmetric binary fractal tree model of the distal vessels,
using vascular branching laws from the size of the outlet branch to that of the capillaries5.
Results
MRA of the abdominal aorta in all SCI subjects revealed bumpy, ectatic infrarenal aortas and very narrow iliac arteries. PC-MRI data at the level of the infrarenal aortas showed biphasic flow waveforms with little oscillatory flow in
the SCI subjects in comparison to triphasic flow waveforms in control subjects. Computed pressure waveforms of
SCI subjects showed slower decay in diastole. The computed daily averaged wall shear stress of the infrarenal aortic
regions was lower in SCI subjects as compared to control subjects.
Conclusion
Computational methods were used to identify the unique biomechanical forces acting in the abdominal aorta of patients with SCI that may contribute to aortic degeneration, enlargement and increased prevalence of AAA disease.
References
1. Gordon, I.L. et al. Am Surg. 1996;62(3):249-52.
2. Wilson, N.M. et al. Lecture Notes in Computer Science. 2001;2208:449-56.
3. Figueroa, C.A. et al., A coupled momentum method for modeling blood flow in three-dimensional deformable
arteries. Comp. Meth. Appl. Mech. Engng. Accepted for publication in 2005.
4. Vignon-Clementel, I.E. et al., Outflow boundary conditions for three-dimensional finite element modeling of blood
flow and pressure in arteries. Comp. Meth. Appl. Mech. Engng. Accepted for publication in 2005.
5. Steele, B.N. et al., Fractal network model for simulating abdominal and lower extremity blood flow during resting
and exercise conditions. Comput Methods Biomech Biomed Engin. Submitted in 2005.
66
Novel approaches to simulating poster
amyloid formation: reaction path
annealing and single molecule
pulling
Jan Lipfert
Purpose
37
Insoluble, misfolded protein aggregates termed amyloid are involved in several
neurodegenerative diseases, including Alzheimer’s and Parkinson’s, and the prion protein’s transition from the native protein fold to amyloid fibrils is believed
to be the underlying mechanism of prion diseases, such as BSE in cattle and CJD
in humans. We employ two completely different computational strategies to investigate the structure, energetics and dynamics of amyloid formation in atomic
detail: “Reaction path annealing”[1] and “single molecule pulling”[2] simulations.
The simulations allow us to compute free energies of binding and asses the energetic barriers for the elementary step in amyloid formation and to highlight the molecular details that contribute to amyloid stability.
Sebastian
Doniach
Methods
We employ the heptapeptide GNNQQNY from yeast prion protein Sup35 as our model system. Eisenberg and
coworkers showed that GNNQQNY has amyloid properties similar to full length Sup35 (as judged by cooperative kinetics of aggregation, fibril formation and cross-beta structure) [3].
The “reaction path annealing” algorithm is developed by our group and uses a
massively parallel implementation to study trajectories connecting the native and amyloid conformations based
on the Onsager-Machlup action. Our “pulling” simulations mimic AFM or optical tweezer single molecule experiments, studying the stability of an amyloid fibril under external mechanical force.
Results
Our two simulation methods allow us to study the transition of a single GNNQQNY strand into the amyloid
conformation and the unbinding of a single strand from an amyloid fibril under external force, respectively. The
computed free energy of binding of ~14 kcal/mol for both methods are in good agreement.
The simulated trajectories highlight the importance of side chain hydrogen bonding for amyloid stability, in
agreement with Max Perutz’ “polar zipper” hypothesis and recent findings by Eisenberg and coworkers [4]. Our
results are consistent with an autocatalytic mechanism of prion formation, whereby the presence of misfolded
protein triggers the conversion from the native to a misfolded state.
Conclusion
Reaction path annealing and single molecule pulling simulations were successfully applied to the problem of
amyloid formation. The results are in agreement with existing experimental findings and allow to study the elementary process of amyloid formation at a level of detail unavailable to experiments.
References
[1] J. Lipfert, J. Franklin, F. Wu and S. Doniach, JMB (2005) 349:648-658
[2] J. Lipfert and S. Doniach, Biophys. J. (2005) 88:401A-401A
[3] M. Balbirnie, R. Grothe and D. S. Eisenberg PNAS (2001) 98:2375-2380
[4] R. Nelson, et. al. Nature (2005) 435:773-778
67
poster
Genomic instability signatures of
colorectal carcinoma subtypes
by hierarchical clustering of
Michael Yu gene copy data
Purpose
Zhang
Colorectal carcinoma (CRC) is the second most commonly diagnosed can-
38
Keyan Salari
Kyle Farnam
Jochen Kumm
James Ford
Ron Davis
Hanlee Ji
cer in the United States. The most widely-used indicator of CRC prognosis,
clinical staging, is unfortunately a poor predictor of tumor recurrence. We
developed a novel genomic technology that sheds light on the genomic
instability underlying neoplasia in CRC by looking at gene copy number
alterations to discover clinically relevant biomarkers. These biomarkers
can be used to form signatures which identify subtypes of CRC, providing
a more accurate and complete prognosis.
We used the high-resolution, barcode array-based molecular inversion probe
(MIP) [1] technology as a quantitative assay to detect genome-wide gene copy
number alterations. Our probe set targets a large number of candidate cancer
genes throughout the human genome along with a high density of markers along
chromosome 18q, a region containing established CRC prognostic indicators. We analyzed
a panel of 20 CRC cell lines with known genomic instability events, chromosomal (CIN) or microsatellite (MSI),
and a cohort of 33 clinical CRC samples with known staging, stage II or III. Log2 ratios for this data set were calculated against scale normalized control data from a set of 32 normal cell lines. We implemented the statistical
method clustering along chromosomes (CLAC) [2] to make amplification/deletion significance calls with a false
discovery rate of 0.01. Probes called significant received a score based on their log2 ratios. Scores of zero were
assigned to all other probes. Finally, we performed agglomerative hierarchical clustering analyses on the CRC
cell lines and clinical samples using their CLAC significance scores.
Results
Hierarchical clustering of the CRC cell lines yielded two distinct clusters corresponding to the two types of
genomic instability. CIN was characterized by concentrated deletions along chromosome 18q, while MSI was
characterized by sparser, more heterogeneous gene copy alterations. The type of genomic instability was a
statistically significant predictor of cluster group (p=0.0093). Clustering of the clinical CRC samples yielded two
major clusters; however, they did not correspond significantly to staging category (p=0.22).
Conclusion
The stark distinction of the two clusters within the clinical samples and their non-correspondence to tissue
stage affirms the insufficiency of staging for prognosis and reveals potential subtypes of colon cancer as delineated by genomic instability signatures. The ability to differentiate between these subtypes hold promise in
next generation clinical prognostics.
References
1. Hardenbol, P. et al. (2003). Nat Biotechnol 21(6): 673-8.
2. Wang, P. et al. (2005). Biostatistics 6(1): 45-58.
68
Automatic state decomposition poster
for constructing Markov models
for macromolecular dynamics
Purpose
Nina Singhal
Understanding the kinetics of protein folding is an important biologi-
39
cal problem. Supercomputing, such as the Folding@Home project, can
generate large amounts of molecular dynamics simulation data. In
previous studies, we developed efficient models for analyzing these
large data sets that divided the conformation space into discrete
states and calculated the transition probabilities between the states,
assuming Markovian, or history independent, transitions. In this work,
we develop algorithms for the automatic decomposition of the protein
or other macromolecular conformation space into regions which are kinetically related and transitions between them Markovian.
John D. Chodera
Vijay S. Pande
William C. Swope
Methods
We first split conformations which are significantly dissimilar by some distance metric. In this work,
we examined torsion angle space and root mean square deviations. Following this initial decomposition,
we build a transition matrix and examine the eigenvalues and eigenvectors of this matrix to group similar
states. These states are iteratively refined by repeating this procedure.
Results
We apply these techniques to alanine dipeptide and compare the resulting states with a manual decomposition of the state space. We find our results in good agreement with the manual decomposition over
our distance metrics.
Conclusion
We have successfully implemented a new algorithm for finding kinetically relevant states from molecular
dynamics simulation data. This is an important first step in building a model of the folding process which
can describe the long timescale behavior. We plan to apply these algorithms to more complicated molecular systems in the future.
69
poster
40
Fold removal in CT colonography
Padma
Sundaram
Eftychios Sifakis
David Paik
Christopher
Beaulieu
Sandy Napel
Purpose
Normal haustral folds complicate both, the visual and computer-aided
detection (CAD) of polyps in CTC data. We present a method to straighten and flatten the colon by simulating stretching of the colonic surface
using a quasistatic Finite Element Model (FEM). The output of our algorithm is a 3D fold-free surface that can be displayed as a single image
and/or subjected to a CAD algorithm.
Materials and methods
We created several mathematical phantoms using MATLAB 7.0.1, with
folds and polyps modeled as half sine functions and hemispheres, respectively. The phantoms had folds, polyps on flat regions and polyps on
folds. We also tested our algorithm on a subvolume of actual patient data,
acquired under our IRB during a research CTC scan at our institution, containing a 6.9 mm polyp. Our algorithm stretches the surface in a direction normal to the
direction of the folds, resulting in flattening the folds, with minimal distortion to polyps. A spatially invariant response to pulling from both ends is essential, otherwise structures closer to the edges being
pulled will be more distorted than those farther away. Thus, we implemented a quasistatic assumption in our FEM so as to neglect inertial effects. To evaluate our methods we measured the curvature
and size of the polyps (diameters) and folds (heights) before and after simulated stretching.
Results
On phantom and patient data, our method shows reductions in fold height and curvature ranging
from 54.4% to 70.3%, and 36.3% to 86.1% respectively. Polyp size and curvature were reduced by
only 0% to 16%, and 0% to 20%, respectively. The output of our algorithm is a 3d surface that can be
viewed as a single image.
Conclusions
Our physics-based method to flatten the colonic surface using a quasistatic finite element model
suppresses folds while leaving polyps relatively undistorted, and has the potential to improve the efficiency of interpretation by reducing visual clutter and sources of false positive detections by CAD.
Continued development is warranted.
70
Analysis of the transcriptional
regulation of a bacterial cell
poster
41
Patrick
Timothy
McGrath
We have created an Affymetrix chip for Caulobacter crescentus that is
both an expression array and an intergenic tiling array. This array can
be used for analysis of gene expression, for high-resolution chromatin
immunoprecipitation experiments, for identification of expression in
intergenic regions such as non-coding RNAs (ncRNAs), and for identification of transcriptional start sites. We report here the creation of a
a novel algorithm to identify transcriptional start sites by analyzing
Hong-Lok Lee
the cross-correlation between all probes found between 200 base
Antonio Iniesta
pairs upstream of the predicted start codon and the stop codon of
each gene. We have identified transcriptional start sites of ~600 opAlison Hottes
erons to an accuracy of 5 base pairs. Motif searching of the DNA sequence upstream of the predicted +1 sites revealed the existence of
Lucy Shapiro
several novel motifs. We have also extended this approach to identify
genes with multiple plus one sites. This approach has identified over Harley McAdams
half (4 of 7) of previously identified genes known to have multiple plus
one sites. We further predict 50 new genes to be transcribed from multiple
plus one sites.
71
poster
2D ultrasound image processing
in identifying displacement
history of urogenital
structures to pelvic floor
Qiyu Peng
muscle activity
42
Ruth C. Jones
Kirk Robert McConnell
Chris E. Constantinou
Purpose
The measurement of the PFM’ ability to contract voluntarily is of value in the assessment of women with urinary or fecal incontinence. Ultrasound imaging provides
a considerable amount of dynamic data that cannot be visually assimilated by the
observer, particularly during fast events such as coughing. The purpose of this study
is to gain greater understanding of the biomechanical parameters of the PFM, especially during fast, stress events by using 2-D ultrasound imaging.
Methods
1. Experimental protocols
Consenting healthy and SUI female volunteers, age range 21-54 were examined in the supine
lithotomy position by ultrasound using a ultrasound scanner with a 3.5 MHz high definition curved linear array probe with a footprint of 10cm. With the probe in place, volunteers were asked to perform 3 maneuvers: a slow maximum
effort of voluntary PFM contraction with a 5 second hold then release; a cough; and a Valsalva maneuver.
2. Image processing
The procedures of image processing and segmentation are shown in Fig. 1.
3. Establishment of the coordinate system
After the segmentation, a coordinate system fixed on the posterior inferior margin of the symphysis pubis, assumed to be ellipse
in shape, was established (Fig. 2).
4. Measurement of the movement
Three typical positions (P1, P2 and P3 in Fig. 2 were chosen to quantitatively describe the movement of each structure.
Results
1. Movement of the edges during activities
Fig. 3 shows the movement history of the anterior and posterior edges of the UVJ and the ano-rectal junction during cough, contraction and Valsalva.
2. Direction of the movement of tissues
The directions of the movement of the three positions during cough, contraction and Valsalva were derived by linear regression
and shown in Fig. 4.
3. Trajectories of the movement of tissues
Fig. 5 shows trajectories of the three positions on the anterior and posterior edges of the UVJ and on the ano-rectal junction during cough, contraction and Valsalva.
4. Kinematics analysis of the movement
Fig.6-8 shows displacement, velocity and acceleration during cough, contraction and Valsalva. The positions on anterior and posterior edges of UVJ and ano-rectal junction are shown in solid, dotted and dash lines respectively.
Conclusion
The movement of anterior vaginal wall during cough was also measured by a novel palpation probe designed to evaluate function
of pelvic floor muscle. Fig. 9 compares the displacements measured by ultrasound on anterior UVJ and by the probe on anterior
vaginal wall.
The presented methods are able to visualize, quantitatively measure, analyze and describe the outlines of the urethra, bladder and
rectal interfaces and
define new parameters of PFM function.
References
1.
Tunn R, Petri E. Introital and trans-vaginal ultrasound as the main tool in the assessment of urogenital and pelvic floor dysfunction: an imaging panel and practical approach. Ultrasound Obstet Gynecol. 2003; 22(2):205-13.
2.
Reddy A, Delancey JOL, Zwica LM, Ashton-Miller J. On screen-vector based ultrasound assessment of vesical neck movement. Am J Obst Gynecol. 2001; 65-70.
72
A novel palpation system to
evaluate internal organs of
genitourinary system
Introduction
Palpation provides information relating the mechanical properties of the tissue such as its stiffness. In clinics, palpation is used to evaluate in accessible
internal organs of the genitourinary system such as the prostate, vagina and
uterus. We developed a novel palpation system suitable for the evaluation
of the static and dynamic properties of internal organs.
poster
43
Qiyu Peng
Ruth C. Jones
Kirk Robert
McConnell
Sadao Omata
Chris E.
Constantinou
Prototype of the System
The prototype of the system is made of a probe with four force and displacement sensors and a six degrees-of-freedom measuring device that can track
the position (x, y, z) and orientation (azimuth, elevation and roll angles) of the
probe (Flock of Birds, FOB) (Fig. 1).
The probe is made of an applicator with retractable low inertia cantilevered force and
displacement transducers in four directions (anterior, posterior, left and right). The transducers
are closed until they are inserted into the internal organ and touch the organ wall (Fig.2).
The sensor of FOB is fixed tightly on the handle of the probe. The coordinate of the point O’ (x0, y0, z0 ) and the orientation of the axes x’-y’-z’ (θa, θe, θr; namely, azimuth, elevation and roll angles) on the global coordinate system (Fig. 1)
were measured in real time by FOB.
Phantom Experiments
1. Static measurement
Phantom experiments were performed to test the probe. The internal cross sections of the phantoms, which are assumed to be elliptic, were derived from the displacements measured by the displacement sensors and the position and
orientation of the probe measured by FOB (Fig. 3).
Three phantoms (Fig. 4 a, b, c), which simulate three typical geometric and mechanical situations of the internal organ
of the genitourinary system, are designed to evaluate the static performances of the palpation system. 3D reconstruction of the phantoms are shown in Fig. 4 (d), (e), (f ). In (e) and (f ), the force signals in four directions are color-coded.
2. Dynamic measurements
A mechanical vibrator was used to simulate the activities of organ by perturbing the sensors on the applicator. The
results show the probe has ideal frequency response to low-frequency activities of organs.
Clinical Experiments
The palpation system was used to evaluate the functions of Pelvic Floor Muscles (PFM). Thirteen healthy volunteers and
six patients with Urinary Incontinence were tested. The typical force and displacement signals recorded during the static
measurements (profile of vaginal wall) and dynamic (cough) measurements are shown in Fig. 5. Detailed analysis of the
pilot data is ongoing.
Conclusions
The novel palpation system can be used to evaluate the static and dynamic properties of internal organ of Genitourinary system.
Acknowledgments
NIH-NIBIB grant 1 R21 EB001654
Biodesign, Clark center, Stanford University
73
poster
44
Rashmi
Raghu
Viscoelastic arterial wall model for
one-dimensional modeling of
blood flow and pressure
Purpose
Irene E.
Vignon-Clementel
C. Alberto Figueroa
Charles A. Taylor
The one-dimensional equations of blood flow consist of conservation of
mass, conservation of momentum and a constitutive relationship that describes the wall properties. The variables at a given point in the system are
the arterial flow rate, cross-sectional area and pressure. To date, only nonlinear elastic constitutive models have been used in these types of simulations. However, arterial tissue is known to have viscoelastic properties.
The purpose of this work is to derive and incorporate a viscoelastic constitutive model for the arterial wall in the existing one-dimensional equations of blood flow and to implement it in the corresponding finite element
simulation environment.
The viscoelastic arterial model used in the current work is based on Holenstein et al (1980).
The relevant viscoelastic relationship was derived from that work along with Fung (1993) and used to relate
pressure and cross-sectional area. This relationship consists of two parts: the instantaneous elastic response
of pressure and the convolution of the viscoelastic relaxation function with the history of instantaneous elastic
responses. The appropriate relaxation function was derived from a creep function based on Holenstein et al
(1980). The Olufsen (1999) non-linear elastic model is used as the instantaneous elastic response in the viscoelastic model.
Results
Preliminary results show that viscoelasticity has an impact on flow and pressure waves – viscoelasticity causes
internal energy dissipation. In a carotid model, with prescribed inlet flow and a resistance boundary condition
at the outlet, peak pressure and flow at the outlet were lower in the viscoelastic case than in the elastic case.
Plotting pressure against cross-sectional area also shows some hysteresis in the viscoelastic case unlike the
elastic case.
Conclusion
A viscoelastic arterial wall model has been derived for one-dimensional blood flow problems. The implementation of the model in a finite element code has allowed the investigation of differences between the non-linear
elastic and viscoelastic models. Further comparison studies of the elastic and viscoelastic constitutive models will be conducted with networks of vessels for a more thorough analysis of the effects of the viscoelastic
model.
References
Fung, Y.C. (1993) Biomechanics: Mechanical Properties of Living Tissues, 2nd edition, Springer-Verlag, New
York.
Holenstein, R., Niederer, P. and Anliker, M. (1980) “A Viscoelastic Model for Use in Predicting Arterial Pulse Waves”,
Journal of Biomechanical Engineering, 102, 318-325.
Olufsen, M. (1999) “Structured Tree Outflow Condition for Blood Flow in Larger Systemic Arteries”, American
Journal of Physiology, 276, 257-268.
74
Differential gene expression poster
between healthy and melanoma
patients for T cells, B cells and
NK cells
Rebecca
Purpose
The purpose was to determine whether any genes were significantly under or
over expressed in the B, CD4, CD8, or NK cells of melanoma patients.
Meredith
Loew
Agilent’s feature extraction software scanned the microarrays and produced
45
txt files. R was then used to analyze the data. The limma package in R read in
the txt files and created RG objects, which stored information such as the red
and green frequencies for each probe and its background. From this, the control spot data and data for 172 genes frequently suffering from dye saturation
were removed using the flags provided by Agilent. A correlation matrix revealed
a strong correlation between the pooled samples and the averages of the patients represented. It also showed a good negative correlation between the dye
swap arrays. Next, the loess and variance stabilizing normalization methods were
compared by plotting the normalized data for genes known to be expressed. Since
vsn produced tighter clusters, it was selected. The multtest package from Bioconductor
was used for multiple testing, and Westfall and Young’s step-down permutation method was
used to correct for the multiple testing bias. In order to increase the power of the study, CD4, CD8, and B cells were
combined.
Rebecca CritchleyThorne
Peter Lee
Susan Holmes
Results
From the combined CD4, CD8, and B cells, 29 genes emerged significant. Hierarchical clustering and heatmaps
were created using this list of genes. Lists of upstream nucleotides were also compiled for significant genes for
the purpose of motif discovery.
Conclusion
The high number of significant genes is encouraging. Hopefully, network analysis will related these genes with
known pathways.
References
Holmes, S., He, M., Xu, T., Lee, P. (2005) Memory T cells have gene expression patterns intermediate between naive
and effector PNAS, Vol. 102, no. 15, 5519-5523. http://www.pnas.org/cgi/reprint/102/15/5519
Kent, W. J., Sugnet, C. W., Furey, T. S., Roskin, K. M., Pringle, T. H., Zahler, A. M., and Haussler, D. (2002) The Human
Genome Browser at UCSC . http://www.genome.ucsc.edu
R Development Core Team. (2005) R: A Language and environment for statistical computing. R Foundation for
Statistical Computing, Vienna, Austria. ISBN 3-900051- 07-0. http://www.R-project.org
Tong Xu, Chen-Tsen Shu, Elizabeth Purdom, Demi Dang, Diane Ilsley, Yaqian Guo, Jeffrey Weber, Susan P. Holmes,
and Peter P. Lee Microarray Analysis Reveals Differences in Gene Expression of Circulating CD8+ T Cells in Melanoma Patients and Healthy Donors. Cancer Res. 2004 64: 3661-3667.
75
poster
46
Mechanics of deformation of
bone cells
Ron Y. Kwon Purpose
Sheyi A. Ayeni
Christopher R.
Jacobs
Fluid flow can be a potent loading mechanism for eliciting biochemical responses in bone cells. However, understanding the mechanism
by which fluid flow-induced mechanical loads are transduced into
chemical signals is difficult since the mechanics of flow-induced bone
cell deformation are not well understood. The objectives of this study
were to (1) develop a methodology for determining fluid flow-induced cellular deformations in vitro, and (2) use the methodology to
investigate the mechanics of osteoblastic cells exposed to steady and
oscillatory fluid flow.
1.0 micron diameter fluorescent beads were added to MC3T3-E1 cells. For each cell,
its beads were imaged during no flow, oscillatory flow (1.0 Pa peak sinusoidal shear stress at 1 Hz) and
steady flow (10s at 1.0Pa shear stress). Cross-correlation fields were calculated by constructing kernels
from bead intensity fields, and convolving the kernels with the bead images. Bead coordinates were calculated from the cross-correlation fields, allowing displacement curves to be generated. For steady flow,
bead displacement curves of each cell were fit to the creep response of a Kelvin body (standard linear
solid) using a nonlinear least squares method. The 2D Green Lagrange strain tensor Eij was determined
by creating bead triads using Delaunay triangulation, interpolating the displacements within each triad,
and differentiating the resulting displacement fields. From Eij, the principal strain and orientation were
determined.
Results
Fitting of the creep response during steady flow to the Kelvin model resulted in relaxation times of 1.7 ±
0.8 (± S.E., n=3) (Fig 1), the first such values reported for osteoblastic cells. The similarity of the relaxation
times (~1.7s) to the period of oscillations (1s), as well as the larger displacements observed during steady
flow as opposed to oscillatory flow, suggests that differences in the response of MC3T3-E1 cells to oscillatory flow (1 Hz) and steady flow are due to the inability of the cells to undergo large deformations during
oscillatory flow. The average strains of 1.0~3.5% (Fig 2) are of the same magnitude as those reported to
elicit osteogenic responses in osteoblasts subjected to substrate stretch.
Conclusion
The methodology presented allows in vitro quantification of cellular deformation. Future studies will investigate the correlation between deformation and mechanosensitive responses such as kinase activity
or protein localization, with the overall goal of relating of fluid-flow induced deformation and subsequent
chemical signaling.
76
poster
A novel software for plotting
multidimensional FACS data
Purpose
Flow cytometry (FACS) is a method for counting, examining, and sorting cells
that are suspended in a stream of fluid. Its applications are numerous in both
basic science and clinical research. The power of FACS stems from its ability to simultaneously measure the levels of many proteins (currently up to
twelve) on a single cell. However, current software for FACS analysis is limited to 2D visualizations, usually scatter or contour plots. Even in FlowJo, the
field’s most advanced software, a multidimensional interpretation of FACS
data requires considerable effort. We present a novel software “FACSwizard”
that is able to produce dynamic 3D and 4D representations of FACS data.
47
Ryan J.
Tibshirani
We have developed three techniques for data visualization.
(1) 3D setting: We have created scatter and contour plots that the user can freely rotate using the mouse.
Here, the main implementation challenge is to produce an accurate and fast contouring of the data; our
method is an application of the marching cubes algorithm, a technique used to render 3D visualizations
of human anatomy from CT and MR imaging.
(2) 4D setting, trellis plot: Data are incrementally stratified on two parameters, and correspondingly a
number of 2D plots displaying the other two parameters are laid out in a grid.
(3) 4D setting, dynamically-gated plot: The user performs custom stratification by drawing with a polygonal gating tool on a 2D plot. A second 2D plot displays the gated population along two other dimensions.
By using the mouse to drag the gate in the first plot, the user is able to simultaneously examine the newly
stratified population in the second plot.
Results
Our dynamic 3D plots provide a highly intuitive interpretation of 3D FACS data. As such, a single 3D plot
created by FACSwizard may provide more insight than three 2D plots produced by FlowJo. Our trellis plot
offers an immediate and global perspective of 4D data, which would be especially useful in a research
paper. Finally, our dynamically-gated plot is a novel idea that may be a very powerful tool for certain data.
In the case of data consisting of two cell surface markers and two phosphoproteins, for example, this
technique provides a rapid and flexible way of examining the phospho-responses of specific cell subsets.
We refer the reader to our website http://www.stanford.edu/~ryantibs/bcats05 for examples illustrating
these results.
Conclusion
Our software offers all of the standard 2D plotting utilities for FACS data, as well as novel 3D and 4D plotting techniques. These techniques allow fluid and intuitive manipulations of multidimensional plots, and
this can potentially yield new biological insights from the analysis of multiparametric FACS data.
77
poster
48
Shaohua
Sun
Registration of lung nodules
using a semi-rigid model
Purpose
The tracking of lung nodules in sequential CT scans for the same patient is helpful for determination of malignancy [1, 2]. We propose an automatic semi-rigid
registration scheme for tracking lung nodules over time that is robust to size/
shape changes.
Geoffrey D. Rubin
Sandy Napel
Following the lung segmentation, registration is performed for each nodule,
considering only large structures surrounding the nodule. We first delete all
voxels whose gray levels are less than 200 in a 60mmx60mmx60mm cube centered on a nodule in the source scan, followed by 3D connected component
analysis. We retain the component containing the nodule and the 7 largest remaining components, and allow each of these to undergo an affine transformation
independently. In the target scan, corresponding structures are found by transforming
the source structures. The nodule location in the target scan is determined by finding the transformation parameter set that maximizes an energy function of the 8 structure pairs in the source and target volumes. This
function consists of normalized correlation coefficient measuring structural similarity and the variance of the
parameter sets measuring relative movement amongst the structures. The proposed maximization scheme is
a two-layered optimization method, employing a Simulated Annealing [3] framework.
Results
We tested our method with 10 nodule pairs by simulating nodules resolve, grow and shrink uniformly by a
factor of 2, and grow non-uniformly. A target scan was simulated by transforming a source lung CT scan; nodules were simulated using a CT simulator and embedded in the source and at the transformed location in the
target. The transformation from source to target consisted of translation, rotation, and non-rigid transformation based on inspiration and cardiac models. The mean absolute distance errors for the four cases were 1.13
mm+/-1.08 mm(s.d.), 0.97 mm+/-1.10 mm(s.d.), 0.72 mm+/-0.73 mm(s.d.), and 1.09 mm+/-1.36 mm(s.d.). We
also matched 92 nodules in 12 pairs of patient scans and compared our registration to a radiologist’s visual
determination. The mean absolute distance error was 1.16 mm+/-0.79 mm(s.d.).
Conclusion
The proposed semi-rigid model shows promise for matching nodules in a series of CT scans and is robust to
size/shape change over time.
References
[1] C.I. Henschke, D.F. Yankelevitz, D. Libby and M. Kimmel, “CT screening for lung cancer: the first ten years,”
Cancer J., vol. 8 Suppl 1, pp. S47-54, May-Jun. 2002.
[2] J.P.W. Pluim and J.M. Fitzpatrick, “Image registration,” IEEE Trans.Med. Imaging, vol. 22, pp. 1341-1343,
2003.
[3] L. Ingber, “Very fast simulated re-annealing,” Mathematical and Computer Modelling, vol. 12, pp. 967-973,
1989.
78
A metropolis sampling framework poster
for inferring neural connectivity
in diffusion tensor images
Purpose
Anthony
Diffusion Tensor Imaging (DTI) is a magnetic resonance (MR) imaging method that
can be used to measure the local information about the structure of the white matter within the human brain. Combining DTI data with the computational methods Sherbondy
49
of MR Tractography, neuroscientists can estimate the locations and sizes of nerve
bundles (white matter pathways) that course through the human brain.
Current deterministic tractography algorithms have become quite good at reconstructing certain white matter structures such as the corona radiata and the superior and inferior longitudinal fasciculi, but these algorithms have also met with
consistent reproducible failure when attempting to reconstruct some sets of neural
pathways.
David Akers
Pat Hanrahan
One major set of challenging pathways include those that course temporally between the corpus
callosum and the cortical surface. There is strong evidence of the existence of these temporal connections between the left and right hemispheres. The evidence has been gathered from other measuring modalities, such as
functional MRI (fMRI), cadaver and primate studies, yet current tractography algorithms are invariably unsuccessful at recovering these pathways. Our work contributes a new Bayesian computational framework for performing
tractography through the sections of DTI data that have been a well recognized problem for previous tractography algorithms.
Materials and Methods:
Our tractography algorithm is designed to efficiently sample possible paths that connect user-defined regions of
the brain together. This approach allows a neuroscientist to use our algorithm in order to reason about connectivity in regions of DTI images that simply are not even possible with previous tractography algorithms.
We first show how to formulate our connectivity problem in terms suited for application of Bayesian inference
techniques. A defined posterior distribution on pathways encapsulates the neuroscientists’ prior knowledge of
pathway existence as well as beliefs of what would make a pathway more or less likely given some DTI information
along the pathway.
While it is true that Bayesian algorithms have been proposed by other researchers in this field, our algorithm offers
computational advantages over previous approaches when considering the problem of sampling pathways that
must connect two defined regions in the data. Specifically, we present a Markov Chain Monte Carlo path sampling algorithm to address the computational issues of sampling only pathways that connect the two regions.
Results
This work is illustrated by results from mathematically constructed DTI phantoms as well as real DTI data from a
normal human subject.
79
poster
Modeling of phosphorylation sites
in protein structures using the
FEATURE system
Shirley Wu Purpose
50
Megan Y. So
Russ B. Altman
Phosphorylation of proteins regulates a large number of biological processes in organisms. The ability to predict phosphorylation sites in new and
existing protein structures would contribute greatly to our understanding
and manipulation of these pathways. We use an existing method, FEATURE, to characterize the 3-D environment around these sites and to illuminate areas in which we can improve the modeling of variable, low
density data sets.
FEATURE is a supervised learning algorithm that uses a naive Bayes method
for distinguishing between provided positive and negative training sets of sites
in protein structures. The 3-D space around each data point is divided into radial shells,
and the physicochemical properties present in each shell are input into a vector. The significance of each
property in each shell given the two training sets is calculated and goes into a model that describes the
site. All protein structures used are derived from the Protein Data Bank (PDB). Phosphorylation site data
are derived from the PDB and from the Phospho.ELM database of experimentally verified phosphorylation sites. Negative training sites were randomly chosen from a non-redundant subset of the PDB. Sequence alignment to eliminate homology was done using ClustalW.
Results
Separation between positive and negative sites using positive sites derived from annotated phosphoresidues in the PDB was fair, with the Threonine model showing the best separation. Using positive sites
derived from Phospho.ELM, separation in the models was much worse. Model fingerprints showed very
few properties that differed significantly between positive and negative sites.
Conclusion
Reliable data on phosphorylation sites is still difficult to obtain. Although FEATURE was unable to build
high-quality models with this data using default settings, there may still be some retrievable signal within
the noise. More investigation into the selection of training sets and the target granularity of models may
greatly improve the performance of a structural model of phosphorylation sites.
References
Wei L, Altman RB. Recognizing protein binding sites using statistical descriptions of their 3D environments. Pac Symp Biocomput. 1998;:497-508.
H.M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T.N. Bhat, H. Weissig, I.N. Shindyalov, P.E. Bourne: The Protein Data Bank. Nucleic Acids Research, 28 pp. 235-242 (2000).
Diella F et al. Phospho.ELM: A database of experimentally verified phosphorylation sites in eukaryotic
proteins. BMC Bioinformatics 2004, 5:79.
80
Identifying regulatory mechanisms poster
associated with genetic variations
among individuals
Motivation
Su-In Lee
Genomic sequence polymorphisms create variations in the expression of
51
genes by perturbing the complex network of regulatory interactions. Much
work has focused on identifying quantitative trait loci (QTLs) that affect the
expression of genes1-3. However, there has been little work on identifying
the regulatory mechanisms associated with such sequence polymorphisms,
a task that can play an important role in understanding genetic diseases,
and suggesting targets for drug design.
Aimee Dudley
Dana Pe’er
Daphne Koller
Methods
We present a method based on probabilistic models4 that can provide a finegrained understanding of the regulatory mechanisms caused by genetic sequence
polymorphisms. Given the genomic expression and the marker-based genotype profile of many individuals, our method provides a mechanistic explanation for the association between gene expression and genetic variation. In our model, the expression of a gene is affected by three
kinds of factors: the sequence polymorphisms of the gene itself, the sequence polymorphisms of a regulator and the expression level of a regulator. The expression profile of a module of co-regulated genes is
induced by combinatorial relationships among these factors.
Our approach extends the previous genetic linkage analysis methods1-3 in three ways: (1) incorporating
the expression level of regulators as a factor in expression variation, (2) identifying combinatorial regulatory interactions, and (3) associating regulatory models with modules of genes, providing higher statistical significance for detecting the cause of the expression variation.
Results
We applied our method to a data set of recombinants generated by a cross between two strains of S.
cerevisiae1, resulting in fine-grained hypotheses about regulatory interactions associated with genetic
variations in yeast. We show that it outperforms the classical method1, both in statistical measures such
as the proportion of genetic variance explained, and in recovering biological relationships known in the
literature. Our method provided several well-supported novel hypotheses associating mechanistic explanations with polymorphisms. We experimentally verified one of these hypotheses in the wet-lab, validating the ability of our approach to detect indirect effects of a QTL on its target genes.
References
1.
Brem, R.B. & Kruglyak, L. PNAS 102, 1572-7 (2005).
2.
Morley, M. et al. Nature 430, 743-7 (2004).
3.
Schadt, E.E. et al. Nature 422, 297-302 (2003).
4.
Pearl, J. Probabilistic Reasoning in Intelligent Systems (1998).
81
poster
CONTRAST: de novo gene
prediction using a semi-Markov
conditional random field
Samuel S. Purpose
De novo gene prediction, defined as the identification of the location
and structure of protein coding genes using genomic sequences alone, reGross
mains an important problem. Although full-length experimentally verified
52
transcripts exist for approximately 60-85% of all human genes, traditional
experimental methods for identifying genes based on 5’ EST sampling and
cDNA clone sequencing are now reaching the point of diminishing returns.
As a result, efforts to identify new genes by RT-PCR from computationally predicted gene structures are taking on greater importance. De novo
gene predictors are particularly well-suited to this task as they do not rely on
cDNA or EST evidence, which is unlikely to exist for currently unknown human
genes. We present CONTRAST (CONditionally TRAined Search for Transcripts),
the first de novo gene predictor based on a probabilistic model known as a semiMarkov conditional random field (sCRF).
Chuong B. Do
Serafim Batzoglou
Almost every successful modern gene predictor is based on a generative probabilistic model known as a hidden Markov model (HMM). Although HMMs are easy to train, they have the disadvantage that they do not
directly model model the conditional probability P(Y|X) of a gene prediction Y given a sequence X. Instead,
normal HMM training optimizes the joint probability P(X,Y) = P(Y|X) P(X), which means a set of parameters
that leads to worse predictions may be prefered if it leads to a better value of P(X), a quantity irrelevant to the
problem of gene prediction. sCRFs avoid this problem by directly
modeling the conditional probability distribution while at the same time relaxing many of the strict independence assumptions required by HMMs. This allows for much more expressive models using a far richer set of
possible sequence features. We implemented a sCRF-based gene predictor, CONTRAST, and tested it on the
Drosophila melanogaster genome.
Results
In our tests on the D. melanogaster genome, CONTRAST performs significantly better than GENSCAN, one of
the most accurate single genome gene predictors. In particular, CONTRAST is able to avoid GENSCAN’s wellknown tendancy toward the prediction of many false positive genes.
Conclusion
We have shown that gene predictors based on sCRFs can be significantly more accurate than those based on
HMMs. There are many promising avenues of future research to be pursued in sCRF-based gene prediction. In
particular, we plan to extend CONTRAST’s relatively simple gene model, add 5’ and 3’ UTR prediction capabilities, and add the ability to use multiple alignments to increase predictive accuracy.
82
Removal of respiratory motion
artifacts and the construction of
4D PET
poster
53
Brian
Thorndyke
Purpose
Respiratory motion remains a challenging problem in positron emission tomography (PET) imaging of thoracic and abdominal cancer.
While PET has proven to be a valuable adjunct in the detection,
delineation and characterization of metabolically hyperactive tissue, the radionuclide signal may be significantly degraded by the
motion of the abdominothoracic organs. The most common solution is to “gate” the scan, effectively limiting image acquisition to
short-time interval snapshots corresponding to a particular point in
the respiratory cycle. One major drawback to gated PET is reduced
signal-to-noise ratio owing to the decimation of coincidence events. A
second problem is the limitation to a single gated interval, precluding the
possibility of following the PET image over time. We describe a method, coined
“restrospective stacking”, which both restores image quality and enables the generation of a timeresolved (4D) PET image from end-inhale to end-exhale.
Eduard Schreibmann
Lei Xing
Retrospective stacking uses b-spline deformable image registration to combine amplitude-binned
PET data along the entire respiratory cycle into a single respiratory end-point. The motion maps derived from the b-spline registration process can subsequently be used to generate a PET image at any
arbitrary point in the cycle. The technique was applied to F-18 FDG PET images of a pancreatic cancer
patient with a liver metastasis, whose lesion was poorly visible through gated PET. A restrospectively stacked image was generated at end-inhale, and this image was then interpolated at several
points from end-inhale to end-exhale. Cross section visualizations and contrast-to-noise ratios (CNRs)
at each respiratory point provided the basis of comparison between ungated, gated and retrospectively stacked PET.
Results
Both retrospective stacking and gated acquisition removed lesion motion artifacts. Retrospective
stacking, however, greatly enhanced the visibility of the tumor by increasing the CNR of the malignant to surrounding tissue by over 3-fold. The lesion and PET-visible organ motion was followed from
end-inhale to end-exhale using b-spline interpolation, and the image enhancement was maintained
throughout.
Conclusion
Patient data have demonstrated that retrospective stacking can correct for respiratory motion artifacts, significantly improving tumor visibility while providing a view of the tumor and surrounding
PET-visible tissue at any point in the respiratory cycle.
83
poster
54
Ion size effects and the PoissonBoltzmann equation
Vincent
Bangping
Chu
The ion atmospheres around nucleic acids play a significant role in their
structure and function. Due to their charged backbones, formation of tertiary structure in nucleic acids occurs upon the addition of counterions in
solution which screen the phosphate charges. Greater understanding of
the role of electrostatics in nucleic acid structure formation may yield insight into many outstanding problems in biology, such as the ribozyme
folding and gene regulation, and may lead to new drug designs and advanced molecular sensor development.
Jan Lipfert
Yu Bai
Poisson-Boltzmann (PB) theory has historically been the most widely
used framework in modeling electrostatics around biological moleRhiju Das
cules. Unfortunately, because it does not consider the finite sizes of ions
Sebastian Doniach in solution it is inaccurate, especially near the highly charged nucleic acid
surfaces. We present an extension based on earlier work that allows us to
Daniel Herschlag capture
these finite size effects in a lattice gas framework.
We have successfully prototyped the new model in Matlab for simple systems.
We are currently implementing and testing the new model in an existing PB Solver,
APBS, making extensive use of computing facilities in our group and the Bio-X cluster in order to
tackle even larger, biologically relevant systems.
References
Bai, Y., Das, R., Millett, I., Herschlag, D., and Doniach, S. Probing Counterion Modulated
Repulsion and Attraction Between Nucleic Acid Duplexes in Solution. Proc. Natl. Acad.
Sci. USA, 102(4):1035{1040, 2005.
Baker NA, Sept D, Joseph S, Holst MJ, McCammon JA. Electrostatics of nanosystems: application to microtubules and the ribosome. Proc. Natl. Acad. Sci. USA 98, 10037-10041 2001.
I. Borukhov, D. Andelman, and H. Orland, Physical Review Letters 79 (3), 435-438 (1997).
84
Three-dimensional correlation poster
analysis of the macromolecules
on synaptic vesicles
Purpose
Jing Xu
We studied the protein associations of the 50-nm-large synaptic vesicles (SVs)
55
in a model system, frog neuromuscular junctions (NMJ) from the structural
perspective, aiming to provide insights into the clustering, mobilization,
docking and fusion of these smallest functional organelles that carry neurotransmitters.
Mark L. Harlow
David Ress
David Yip
Sample preparation: Frog neuromuscular junctions were prepared with the
Mira Raman
conventional procedures for TEM.
Electron Microscope Tomography (EMT): This is a technology that gener- Robert M. Marshall
ates 3D volume data from stained biological tissue sections, enables studies
Uel J. McMahan
of the structures and localizations of cell organelles or protein aggregates. A
software package called EM3D was used to reconstruct and analyze the volume data.
Correlation analysis and probability map generation: Contact points from any two
vesicles were aligned based on a cross-correlation function given three dimensions of
rotational freedom as rigid body. And a large number of vesicles were aligned until the best mutual correlation was reached, the algorithm of which was adapted from [2].
Results
Each SV in the frog NMJ terminal is linked to other SVs by filamentous structures that are 3-30 nm long and
4-10 nm in diameter, and each SV contains scaffolding luminal filaments. The pattern of the position of contacts of these filaments to the vesicles was found by generating a probability map of the contacts from a large
number of vesicles. The high degree of clustering of the probability map indicates a constancy of the distribution. Most of the contacts are confined to five domains. The two maps found for the contacts of filaments from
outside and that from inside the vesicle are strikingly similar, which provides strong evidence that both types
of filaments contain the tails of proteins in the membrane and such membrane proteins are stereotypically organized. Furthermore, this distribution of vesicle proteins was used to determine the “orientations” of the SVs
within the nerve terminal, and it was found that the portion of membrane in the vesicles that are going to be
docked at the cell membrane are becoming oriented facing the membrane as the vesicles are within 125nm
distance from the membrane.
Conclusions
The SVs have similar macromolecular assembly and the SVs must be oriented in a specific way in order to be
docked at the active zone where there are fused with the cell membrane and release the neurotransmitters.
Reference
[1] Ress et al, Structure, 12 (10):1763-1774, 2004
[2] Penczek P et al, Ultramicroscopy, 40: 33-53, 1992
[3] Harlow et al, Nature 409:479-484, 2001
85
Notes
86
Notes
87
Notes
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