b c a t s biomedicalcomputationatstanford 2 0 0 5

a b s t r a c t b o o k

bcats 2005 is brought to you by stanford center for bio-medical computation • nih/nibib • bio-x apple computer • genentech • alloy ventures • roche • agilent technologies life sciences society • wilson sonsini goodrich & rosati • bionexus stanford office of technology licensing • enterprise • stanford bookstore biomedical • computation • at • stanford

Bio-X is a Stanford University program supporting interdisciplinary work related to biology. The program is a joint project of the Schools of Humanities and Sciences, Engineering, Earth Sciences, and Medicine. Physics, chemistry, engineering, and computer science are combined in approaching important basic and applied problems in biology and medicine. Bio-X is designed to build community and communication.

The Program is facilitated by a new Center (The James H. Clark Center), which was completed in Summer of 2003 thanks to the enormous generosity of Jim Clark and Atlantic Philanthropies.

The Clark Center comprises the equipment, resources and utilities required to conduct breakthrough research at the cutting edge of engineering, science and medicine.

For more information on Bio-X, visit our website at: http://biox.stanford.edu

2 october • fifteen • 2005

AWinning Formula in Drug Discovery

At Roche Palo Alto, we are dedicated to discovering and developing new medicines that improve the lives of people affected with serious illnesses such as HIV/AIDS, Hepatitis C, Alzheimer’s disease and arthritis.

Our Global Research Informatics Group is enabling the search for new medicines by providing information- and technology-based solutions to researchers around the world. Our areas of expertise include Bioinformatics, Discovery IM, Information Science, Infrastructure, NCD IM, and Scientific Computing.

Our park-like campus offers a wide array of professional and personal amenities designed to promote a healthy work-life balance. Our employees enjoy all the benefits of the San Francisco Bay Area, from access to leading academic and research institutions to beautiful year-round weather and a diverse intellectual community. We are pleased to provide a competitive compensation program, with generous vacation and holiday schedules, a comprehensive relocation program, and retirement and pension plans. To learn more about career opportunities at Roche Palo Alto, please visit our website at http://paloalto.roche.com.

Roche is a proud sponsor of BCATS!

As an equal opportunity employer, we are committed to workforce diversity. 3 biomedical • computation • at • stanford

CHARTER Membership fees: ONLY US $60.00 (professionals, students, postdocs)

About the Life Sciences Society

The Life Sciences Society (LSS) was officially inaugurated on August 10, 2005 as an unaffiliated, non-profit society. World-renowned scientists support the LSS in its mission and goals.

MISSION To promote the integration of life sciences with computing, mathematics, and engineering and to encourage new benefits through interdisciplinary advances involving biological and medical applications.

GOALS The goal of the Life Sciences Society is to be the premier organization for scientists and engineers in the life sciences by providing the venue, tools and opportunity to expand the reach and focus of their individual disciplines into life sciences. The Life Sciences Society will provide tutorials, workshops, conferences, publications and community participation.

Get involved and make a difference ! Join LSS today and help to establish LSS as the premier organization for the life sciences.

Membership Benefits

• Discounts on all LSS activities and at the LSS BioShop • Complimentary mailbox at [email protected] • Complimentary subscriptions to The Scientist • Discounts on Morgan Kaufmann publications and Springer books (other discounts t.b.a.) • Discounts for LSS online tutorial streaming tapes and DVDs • LSS conference / workshop registration discounts • Free Life Sciences Review articles by leading scientists • Professional network, promoting your career, research and business goals

Join online: http://LifeSciencesSociety.org/ Visit our table at the BCATS 2005 Symposium

For more information contact: Vicky Markstein, LSS President ([email protected]) 4 october • fifteen • 2005

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 widely- varying 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 biomedical • computation • at • stanford 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 (page 16) time in cerebellar neural circuits 9.15 R. Dana Carpenter Computer simulation of bone cross-sectional (page 17) morphogenesis 9.30 Omar David Perez Derivation of causal protein signaling networks from (page 18) multiparameter single-cell data 9.45 Tianfang Li Radiation dose reduction in 4D computed tomography (page 19)

Packard Lobby 10.00 (even-numbered posters) Poster Session I (pages 8–9, 29–87)

11.00 Keynote Address Hewlett 200 Jeffrey Weiss, PhD (page 12) Verification, Validation, and Sensitivity Studies in Computational Biomechanics

11.45 Lunch Sequoia Plaza

Packard Lobby 12.30p (odd-numbered posters) Poster Session II (pages 6–9, 29–77)

1.30 Keynote Address Hewlett 200 Leroy Hood, MD, PhD (page 13) Computational Challenges in Systems Biology 6 october • fifteen • 2005

Scientific Talks Session II Hewlett 200 2.15 Irene Elisabeth Vignon-Clementel Impedance outflow boundary conditions for three- (page 20) dimensional patient specific modeling of blood flow 2.30 Serban Nacu Foraging Regulation in Harvester Ants (page 21) 2.45 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 Hewlett 200 Thomas Wu, MD, PhD (page 14) Bioinformatics at Genentech

5.00 pm Awards and closing Hewlett 200 7 biomedical • computation • at • stanford BCATS 2005 Posters poster page Distributed cluster computing: a method for parallel simulation of large molecular 0 Abhay Sukumaran 30 systems 1 Aditya Mandayam tr0m 31 Segmentation of costal cartilage in lower abdomen CT data using watershed 2 Andrew Holbrook 32 markers 3 Alex Ten Eyck Modeling biological tissue with nonconforming finite elements 33 Reconstructing RNA folding pathways from local probes of macromolecular 4 Alain Laederach 34 structure Prediction of venous obstruction following transvenous pacemaker placement: a 5 Alex Pang 35 computer simulation approach A computational study of energy efficiency and pressure losses in the total 6 Alison L. Marsden 36 cavopulmonary connection 7 Artit Wangperawong Effects of size and hydrophobicity on single-walled carbon nanotubes 37 A strategy for whole-genome sequencing and assembly with high-throughput, 8 Andreas Sundquist 38 short-read technologies 9 Rebecca Maria Currano Video-audio mapping of the physical environment for blind navigation 39 A new formulation to model blood flow and vessel motion in large, patient-specific 10 C. Alberto Figueroa 40 models of the cardiovascular system Chase Garrett Application of a three dimensional image-based modeling technique to the circle of 11 41 Yarbrough Willis SchemaTrans: automating the translation of arbitrarily formatted data to relational 12 Christopher B. Egner 42 databases 13 Christopher Enedah Robotic perception of the skin’s mechanical properties - a validation study 43 A theoretical model that complements an experimental system for quantitative 14 Cesar A. Rodriguez 44 investigation of in vivo protein-protein interactions 15 Chuong B. Do CONTRAlign: a discriminative framework for protein sequence alignment 45 16 Christopher Sewell Metrics for a mastoidectomy simulator 46 Bringing the ribosome exit tunnel to life with distributed computing: a first look at 17 Christopher D. Snow 47 the thermodynamics of confined solvent and the nascent chain 18 Chand T. John From biomedical images to geometric models 48 Algorithmic analysis of the quantitative distribution of neural stem cells in malignant 19 David Jing-Piao Lin 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 october • fifteen • 2005 poster page 28 Jessica Ebert Unsupervised Identification of Functionally Relevant Residues in Protein Families 58 Jessie Dale A modified Bayesian approach to determination of causation in differential gene 29 59 Tenenbaum expression Use of a naive Bayesian classifier to identify gene regulatory networks in the 30 Jason A. Hackney 60 protozoan parasite, Enatmoaba histolytica Patient-specific modeling of altered hemodynamics and arterial deformation induced 31 John F. LaDisa, Jr. 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 Quantitative and qualitative assessment of a new knowledge-based algorithm for 34 Justus Roos centerline restoration through femoro-popliteal artery occlusions in peripheral CT 64 angiography (CTA) 35 Jacob Michael Zahn A common signature for human aging 65 Chronic spinal cord injury modifies aortoiliac biomechanical forces and morphology 36 Hyun Jin Kim 66 and increases abdominal aortic aneurysm disease risk Novel approaches to simulating amyloid formation: Reaction path annealing and 37 Jan Lipfert 67 single molecule pulling Genomic instability signatures of colorectal carcinoma subtypes by hierarchical 38 Michael Yu Zhang 68 clustering of gene copy data Automatic state decomposition for constructing Markov models for macromolecular 39 Nina Singhal 69 dynamics 40 Padma Sundaram Fold removal in CT colonography 70 Patrick Timothy 41 Analysis of the transcriptional regulation of a bacterial cell cycle 71 McGrath 2D ultrasound image processing in identifying displacement history of urogenital 42 Qiyu Peng 72 structures to pelvic floor muscle activity 43 Qiyu Peng A novel palpation system to evaluate internal organs of genitourinary system 73 Viscoelastic arterial wall model for one-dimensional modeling of blood flow and 44 Rashmi Raghu 74 pressure Rebecca Meredith Differential gene expression between healthy and melanoma patients for T cells, B 45 75 Loew cells and NK cells 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 A Metropolis sampling framework for inferring neural connectivity in Diffusion Tensor 49 Anthony Sherbondy 79 Images 50 Shirley Wu Modeling of phosphorylation sites in protein structures using the FEATURE system 80 Identifying regulatory mechanisms associated with genetic variations among 51 Su-In Lee 81 individuals 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 Three-dimensional correlation analysis of the macromolecules on synaptic vesicles 85 9 biomedical • computation • at • stanford

10 october • fifteen • 2005 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, medi- cal imaging, and biomechanical modeling applications in biology, bioengineering, and medicine. Our mission is to establish a world-class biomedical computing and visualiza- tion 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, computa- tional 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 sci- ences 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 11 biomedical • computation • at • stanford

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 Or- thopedics 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 Biome- chanics 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 Re- search Grant in March 1995. 12 october • fifteen • 2005

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 biolo- gy. In particular, the DNA sequencer has revolutionized genomics by allowing the rapid auto- mated sequencing of DNA, which played a crucial role in contributing to the successful map- ping 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 Bio- technology. 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 con- tributions 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 diver- sity. He has published more than 600 peer-reviewed papers, received 14 patents, and has co- authored textbooks in biochemistry, immunology, molecular biology, and genetics, and is a member of the National Academy of Sciences, the American Philosophical Society, the Ameri- can 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 biomedical • computation • at • stanford

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 devel- opment 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 Univer- sity, M.D. from Harvard Medical School, and Ph.D. in computer science from the Massachu- BCATS Talk setts 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 struc- tures. Abstracts His awards include a Physician Postdoctoral Fellowship from the Howard Hughes Medical In- stitute; George M. Sprowls Award from M.I.T.; Martin Epstein Award from the American Medi- cal 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 october • fifteen • 2005

BCATS Talk Abstracts

15 biomedical • computation • at • stanford session I Network structure and the 9:00am biological representation of time in cerebellar neural Eran A. circuits Purpose Mukamel Behaviors from language perception and production to learning condi- tioned Pavlovian reflexes require neural circuits that encode and retain in- Mark J. Schnitzer formation 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 in- formation 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.

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 ran- domly 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 respon- sible 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 oscil- lation. 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 in- tervals. 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 october • fifteen • 2005 Computer simulation of bone session I cross-sectional morphogenesis 9:15am

Purpose Previous computational models of the development of bone cross-sec- R. Dana tions have used far-field loads such as joint reaction forces and muscle forces as stimuli for bone growth [1,2]. However, numerous studies have Carpenter suggested that wrap-around tendons, adjacent musculature, and the fi- brous layer of the periosteum can exert local bone surface pressures that Dennis R. Carter may also influence bone development [3-5]. In this study we incorporate local periosteal surface pressures into a computational model of rat tibia mor- phogenesis.

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 sec- tion 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 di- rection of a bone’s maximum bending stiffness. Including periosteal surface pressures imposed by adja- cent 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 biomedical • computation • at • stanford session I Derivation of causal protein 9:30am signaling networks from multiparameter single-cell data Omar Purpose To demonstrate the use of Bayesian networks for automated elucidation of causal influences of protein signaling networks using simultaneous multi- David Perez variate measurements of phosphoproteins on single cells. To objectively Karen Sachs derive inter-molecular influence connections, we applied a probabilistic modeling algorithm to determine a graph of causal influences among Dana Pe’er phospho-signaling molecules in human primary CD4+ T cells.

Douglas Lauffen- Materials and Methods burger Simultaneosly measuring 11-phospho-epitopes by multiparameter flow cytometry. Critical to the derivation of causal inference, was the use of Garry P. Nolan multiple independent perturbation events that aided inferring the direc- tion of influence between the signaling components under study.

Results The approach identified a majority of classically reported signaling relation- ships, 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 impor- tant 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 Bio- technol. 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 october • fifteen • 2005 session I Radiation dose reduction in 4D 9:45am computed tomography Purpose Four-dimensional (4D) CT scans, acquired synchronously with a respiratory signal, provide Tianfang not only the 3D spatial information, but also temporal changes of the anatomy as a func- tion of the respiratory phase during the imaging, and can therefore be employed in 4D Li 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 Eduard Schreib- 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. mann Brian Thorndyke Method/Materials When 4D CT data are acquired with low tube current, the quality of each individual Gayle Tillman phase image is degraded because of the decrease in detected photon number. How- ever, the statistics can be dramatically improved if the time-resolved images of a pa- Arthur Boyer tient are properly registered to a specific phase and superposed together. In our ap- proach, the registration of the patient’s image at different phases is accomplished by Albert Koong 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 statisti- L. 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 posi- tion 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 biomedical • computation • at • stanford session II Impedance outflow boundary 2:15pm conditions for three-dimensional patient specific modeling of Irene E. blood flow Purpose Vignon- When modeling blood velocity and pressure fields, the assignment of appropri- ate boundary conditions is of critical importance. In three-dimensional problems, constant pressure is typically assigned to outlet boundaries resulting in unrealis- Clementel tic flow splits and inaccurate pressure waveforms. This problem is especially acute in fluid-solid interaction problems since the pressure pulse drives the vessel mo- C.A. Figueroa tion. To address this limitation, zero-dimensional, lumped parameter, models have been utilized in recent years. However, the parameters are difficult to relate to pa- K.E. Jansen tient specific data as they do not incorporate vasculature branching patterns or geo- metric data. Three-dimensional to one-dimensional iterative coupling methods have C.A. Taylor 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]).

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 con- sistent 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 en- ables 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 nonlin- ear 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 Structured- Tree 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 october • fifteen • 2005 session II Foraging regulation in 2:30pm harvester ants Serban Purpose An ant colony is an interesting example of a complex system. At the low level, a Nacu 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 Deborah Gordon of complex and robust behavior, achieved without central control. Information is transmitted across the colony by interactions among ants, and the behavior Susan Holmes 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.

Materials and Methods 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 adap- tive 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 biomedical • computation • at • stanford session II Visualization and analysis of 2:45pm diffusion tensor magnetic resonance images using Daniel orthogonal tensor invariants Purpose Bruce Diffusion tensor magnetic resonance imaging (DTMRI) is a technique that can map the three-dimensional orientation of tissue microstructure in the human brain. The richness of spatially varying tensor data, however, requires special- Ennis ized methods to visualize and quantify salient features. Diffusion tensors can be mathematically decomposed into orientation (eigenvectors) and shape (eigen- Gordon values) information. The purpose of our work was to analytically derive a new Kindlmann set of orthogonal tensor invariants (compact descriptors of tensor shape) and use them to improve the visualization and analysis of DTMRI data. Orthogonal- ity is a useful property of an invariant set, because it isolates the measurement of variation in one physiological property from variations in another.

Materials and Methods Theoretical extensions of the work by Criscione [1] in the field of strain energy functions resulted in the de- velopment 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 resolv- ing 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 anisot- ropy (highly ordered structure) can be visually resolved as being linear- or planar-anisotropic, thereby distin- guishing 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 di- rectionally 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 anisot- ropy 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 visualiza- tion and analysis of DTMRI data.

Reference Criscione JC, et al. J. Mech. Phys. Solids 2000;48(12).

22 october • fifteen • 2005 Modeling the aggregation of session II Alzheimers peptide Aβ21-43 3:00pm 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 Nicholas William 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 Kelley have proved to be extremely challenging to study experimentally and rela- tively little is known about their structure or aggregation mechanisms. In this Vijay Pande work we use computational methods to elucidate the mechanism of aggrega-

tion of Aβ21-43 and present insights from simulation on the possible structures of the oligomers.

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 ag- gregation 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 biomedical • computation • at • stanford session III 3:30pm Optimizing dialysis

Purpose Pan-Chi 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 Lee year). The population is also expected to grow six-fold over the next three de- Stefanos A. cades. 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 Zenios 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 progres- sion, 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 optimiza- tion 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 ap- proach to dialysis.

Results This optimized approach to dialysis entails varying dosage depending on the characteristics of each indi- vidual 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 cur- rently 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 computational- ly-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 implemen- tation. This research develops such methodologies utilizing the tools of mathematical modeling and compu- tation.

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 october • fifteen • 2005 Pre-stabilization for rigid body session III articulation with contact 3:45pm and collision Purpose Modeling human motion accurately requires a robust method for dynamically Rachel simulating joints. We developed a method for dynamic simulation of articulated rigid bodies (ARBs) with unpredictable contact and collision. Many practitioners Weinstein solve these types of problems using reduced coordinate formulations. However, unpredictable contact and collision can pose serious difficulties, and closed loops, Joseph Teran such as those occurring between the legs and ground during human motion, of- ten require adding a nonlocal constraint to ensure loops remain closed. Further- Ron Fedkiw more, 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.

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 skel- etons 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, ef- fectively linear in the number of bodies and auxiliary constraints (comprising about 5% of the total computa- tion 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 biomedical • computation • at • stanford session III 4:00pm Integrated protein interaction networks for 230 microbes Purpose Balaji We sought to systematically combine diverse data types to create an in- Srinivasan tegrated picture of protein interaction in 230 microbes. Materials and Methods Antal F. Novak We calculated several different types of functional linkage between Jason A. Flannick proteins and assessed their ability to predict whether two proteins were likely to share the same COG, GO, or KEGG functional category. Serafim Batzoglou For example, protein pairs which are coinherited in multiple organ- isms are more likely to be functionally linked than pairs which show no Harley H. McAdams 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 clas- sify protein pairs as functionally linked or unlinked. We require no simplifying assumptions about statisti- cal 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 arbi- trarily scalable in terms of both the number of evidence types and the number of protein pairs consid- ered. 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 isola- tion. 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 scal- able 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 october • fifteen • 2005 Efficient free energy calculation of session III peptide insertion in membranes 4:15pm

Purpose As membrane-bound proteins are essential to cellular life, we are interested David in the possible roles of small peptides (in some sense the precursors of mod- ern proteins). We focus on the insertion of small alpha-helical peptides into Rodriguez- membranes, examining the stability of the inserted peptide relative to the interfacial configuration and its role in the association of individual pep- tides into larger multimeric structures, much like modern cellular channels. Gomez

Materials and Methods An ideal candidate for studies of peptide insertion is the synthetic peptide E. Darve

(LSLLLSL)3. At the water-membrane interface, this peptide folds into an am- phipathic alpha-helix. It was shown experimentally [1] that, in the presence A. Pohorille 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 mem- brane 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.

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 wa- ter-membrane interface. The transmembrane arrangement of a single peptide is only metastable, i.e. it corre- sponds 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 8" 7"

biomedical • computation • at • stanford

We’re not Thor We just make his hammer BCATS Poster

Developing a device that connects the world. Testing the water to make sure it stays clean. Discovering 10" a cure that keeps the world safe. They all require the 9.5" Abstracts 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 We’ll help make you stronger.

© Agilent Technologies, Inc. 2004

28

Job #: MENY AGIL 2M 40280 Ad #: 04-THOR-J rev Client/Product: Agilent Technologies Unit: page Ad Description: We’re not Thor Color: b/w Ad Description: Art Director: Stallings Safety (Live): 7" x 9-1/2" Copywriter: Trim Size: 8" x 10-1/2" Production: Hughes Bleed Size: non-bleed Line Screen: 133 Engraver: McGraphics

Publication(s) & Issue Date(s): BCATS booklet 2004

Saved: 9/28/04 8:26 AM Document Name: 04-thor-J Printed: 9/28/04 8:28 AM User Name: bill Graphics: Agilent_pos blk.eps october • fifteen • 2005

BCATS Poster Abstracts

29 biomedical • computation • at • stanford poster Distributed cluster computing: a method for parallel simulation 0 of large molecular systems Purpose Abhay Protein simulations on large timescales are very computationally ex- pensive. We describe a method of handling otherwise intractable Sukumaran problems using distributed clusters. Such clusters, with rapid internal communication, and together comprising a larger network, facilitate Guha Jayachandran a hybrid approach between supercomputers and traditional hetero- Vijay S. Pande geneous distributed systems. Materials and Methods MPI (message passing interface) is a specification for a library that sup- ports 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 serv- ers 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 ma- chines, 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 computation- al biology. Modern Methods in Computational Biology, Horizon Press (2003) 3. Message Passing Interface (MPI) specification http://www.mpi-forum.org/docs/ 30 october • fifteen • 2005 poster tr0m 1 tr0m, or the transcendentrecursiveobjectmodel, is an attempt to recreate linguistic patterns with transforms between existing, mutually disparate Aditya models of representation and behavior. Mandayam the hypothesis remains transcendence, or the emergence of patterns and properties invisible at the present. tr0m aims at creating bidirec- Amar Das tional transforms on non-collocated object models with an underlying set of base data. 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 man- aged 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 biomedical • computation • at • stanford poster Segmentation of costal cartilage in lower abdomen CT data using 2 watershed markers Purpose Andrew Focused ultrasound ablation is a promising non-invasive technique that heats a specific tumor region to fatal levels while minimizing cell death in nearby Holbrook healthy areas. Since high attenuation and reflection regions like bone and air can affect the focus (and thus effectiveness) of ultrasound, treatment plan- Kim Butts Pauly ning is necessary. With respect to the liver, the rib cage surrounds it, allow- ing 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 transi- tion 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 thresh- olding 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.

Materials and Methods An abdominal CT dataset was removed of its bright skin pixels through a distance based algorithm de- veloped by Zhou et al (1). A threshold, roughly removing fatty and muscular regions, segmented the re- maining 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 re- move 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 pack- age 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, soft- tissue, and skeleton from torso CT images,” Proceedings of SPIE, vol. 5370, 1634-1639, 2004.

32 october • fifteen • 2005 Modeling biological tissue with poster nonconforming finite elements 3

Purpose Alex Ten The ongoing pursuit in understanding the complex behavior of biological ma- terials such as muscles, blood vessels, and the cornea as well as the materials Eyck 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 Adrian Lew tools presently available are challenged by the large computational costs of modeling real three dimensional materials and complex kinematic con- straints such as incompressibility. Our goal is to develop a numerical method for the study of biological materials that exploits the advantages of noncon- forming finite elements, in an attempt to yield high accuracy with relatively low computational cost.

Methods Discontinuous Galerkin (DG) methods are a class of numerical methods that use nonconforming ele- ments 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 bet- ter 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 biomedical • computation • at • stanford poster Reconstructing RNA folding 4 pathways from local probes of Alain macromolecular structure Laederach 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 october • fifteen • 2005 Prediction of venous obstruction poster following transvenous pacemaker placement: a 5 computer simulation approach Alex Pang Purpose Alex Pang Venous obstruction is a major problem following transvenous pacemaker implantation in children with a prevalence of up to 26%. Obstruction is most Anne M. Dubin commonly observed at the lead-entry site and the junction of the subcla- vian (SC) and internal jugular (IJ) veins. Early studies have suggested that Nathan Wilson the ratio of lead to vessel size can act as a predictor of venous obstruction Jeffrey A. Feinstein though recent studies have disputed this finding. Understanding the effects of pacemaker lead implantation on blood flow characteristics may provide a Charles Taylor more accurate predictor of obstruction. We present a computational fluid dy- namics model which can predict areas of flow stagnation that may lead to vessel obstruction.

Materials and Methods We used custom software to create a computer model of the central veins based on angiographically-ob- tained 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 addi- tion 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 sig- nificantly alter vessel hemodynamics, inducing areas of stagnant flow specifically at the common sites of oc- clusion. Future methods that quantify stagnant flow to rank lead positions could yield an improved clinical strategy for lead placement.

35 biomedical • computation • at • stanford poster A computational study of energy efficiency and pressure losses 6 in the total cavopulmonary connection

Alison L. Purpose The total cavopulmonary connection (TCPC) is an operation per- Marsden formed to treat single ventricle congenital heart defects. The su- perior and inferior vena cavae are connected to the pulmonary Irene E. Vignon- arteries in a t-shaped junction, separating the systemic and pul- monary circulations. Previous studies of the total cavopulmonary Clementel connection (TCPC) have focused on rest conditions and simplified Jeffrey A. Feinstein geometry. In this work, we hypothesize that the effects of respira- tion and exercise cause significant hemodynamic disturbances and Charles A. Taylor 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 litera- ture). 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 catheter- ization (13 mmHg).

Conclusions Pressure drop and energy loss in the TCPC are small at rest but increase to significant levels, even at mod- erate 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 october • fifteen • 2005 Effects of size and poster hydrophobicity on single- walled carbon nanotubes 7

Purpose Artit Carbon nanotubes have recently gained much attention from various bioscience societies due to their affinity with ion channels in biologi- Wangpera- cal 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 wong these phenomena, modern computational tools such as molecular Daejoong Kim 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 hydro- phobicity. Therefore, we hypothesize that different hydrophobicities would re- sult 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.

Materials and Methods 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 pa- rameters 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 (self- diffusion 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 biomedical • computation • at • stanford poster A strategy for whole-genome sequencing and assembly with 8 high-throughput, short-read Andreas technologies Sundquist Purpose DNA sequencing is a central tool in the biological sciences that is now Mostafa Ronaghi being used to obtain the entire genetic code of organisms. The predomi- nant technology, Sanger sequencing, has improved tremendously and Haixu Tang 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 Pavel Pevzner genomes. New technologies, such as Pyrosequencing, will lower this cost Serafim Batzoglou 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 se- quencing 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 high- throughput methods. First, we take the genome and fragment it into BAC-sized pieces, randomly select frag- ments 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 assem- bly 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 cov- erage 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 october • fifteen • 2005 Video-audio mapping of the poster physical environment for blind navigation 9

Purpose The purpose of this research is to employ a new computer-based navigation aid in developing a new methodology, focusing on perception and cogni- Rebecca tion, to govern the design of assistive technology for the blind. Maria Currano Blindness or significant visual impairment eliminates or significantly de- creases the effectiveness of a primary sensory channel. Detecting and avoiding hazards is typically passed on to other primary or secondary David Grossman channels of lower bandwidth than vision. New devices are often designed on this premise, with a high accompanying risk of sensory and cognitive overload.

Materials and Methods 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 inde- pendently 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 re- duced 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 pre- sented 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 capa- bilities 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 biomedical • computation • at • stanford poster A new formulation to model blood flow and vessel motion in large, 10 patient-specific models of the C. Alberto cardiovascular system Purpose Figueroa Blood velocity and pressure fields in large arteries are greatly influenced by the deformability of the vessel. However, computational methods Irene E. for simulating blood flow in three-dimensional models of arteries have either considered a rigid wall assumption for the vessel or significantly Vignon-Clementel simplified or reduced geometries. Computing blood flow in deformable Kenneth E. Jansen domains using standard techniques like the ALE method remains a formi- dable problem for large, realistic anatomic and physiologic models of the Thomas J.R. Hughes cardiovascular system.

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 Fluid- Solid Interaction problems (CMM-FSI). This formulation starts from a conventional stabi- lized 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 plac- ing 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 pub- lication in Computer Methods in Applied Mechanics and Engineering, 2005.

40 october • fifteen • 2005 Application of a three poster dimensional image-based modeling technique to the 11 circle of Willis

Purpose Chase Garrett Image-based modeling methods have been applied to quantify biomechani- cal factors in cardiovascular disease progression [1] and predict outcomes Yarbrough of medical interventions [2]. One approach that has been broadly applied to create complex vascular models consists of creating several two dimen- sional segmentations along the center line of the blood vessel and lofting a three dimensional NURB surface over these two dimensional segmentations Erik Bekkers [3,4]. A boolean union operation applied to the collection of Nathan Wilson 2-D vessel segments is then used to create solid models. The principal short- comings of this 2-D approach are that it is time-consuming and user-intensive Charles Taylor 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 vas- cular system in a patient with a cerebral aneurysm.

Method This technique uses the fast marching and level set methods for image segmentation and then a novel NURB sur- face 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 in- creases 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 Phys- ics, 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: Computa- tional 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 Hemodynam- ics.” 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 us- ing Hierarchical Features.” Submitted to IEEE Transactions on Medical Imaging”, 2005.

41 biomedical • computation • at • stanford poster SchemaTrans: automating the translation of arbitrarily 12 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 pro- Egner grammatically. Much of this difficulty is due to disparate data mod- els expressed in different lexical formats not well suited to rapid, random access. SchemaTrans is an attempt to mitigate these is- Judith 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 ap- plication development and data access times can be realized. Under con- tinuing 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 licens- ing is in progress.

42 october • fifteen • 2005 Robotic perception of the skin’s poster mechanical properties - a validation study 13

Current teledermatology consultations are limited to transmission of visual Christopher images of the patient’s skin to the dermatologist via real-time video links or using the store-and-forward procedure. While visual information is Enedah adequate in some cases, the absence of tactile information means the dermatologist has to make a diagnosis without familiar tools. Studies Kenneth J. Waldron have found consultations relying only on visual images to be less accu- rate than face-to-face consultations1. Tactile images convey information Hayes B. Gladstone 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.

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 sur- face, 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 piezo- electric 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):696- 707. 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 Sens- ing. In IEEE Transactions on Robotics and Automation, Vol. 9, No. 2, April 1993.

43 biomedical • computation • at • stanford poster A theoretical model that complements an experimental 14 system for quantitative investigation of in vivo protein- Cesar A. protein interactions Purpose Rodriguez 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 ver- sions of the two proteins (hsp90-rluc, and p23-rluc). The models are the explicit expres- Andrew Lipkin sion of a theoretical framework for organizing and interpreting the data gathered us- ing the protein reporter complementation assay which is an experimental system under Sanjiv S. Gambhir 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 sys- tem). 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 mono- mers 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 endog- enous monomers (hsp90, p23), the steady state concentration of the endogenous complexes (X3-X6) decreases proportion- ally.

Conclusion A set of quantitative and testable hypotheses can be formulated from the theoretical results reported above.

44 october • fifteen • 2005 CONTRAlign: A discriminative poster framework for protein sequence alignment 15 Purpose Chuong B. In recent years, most alignment methods that have claimed significant im- provements in alignment accuracy have done so not by proposing substan- tially new algorithms for alignment but rather by incorporating additional Do sources of information, such as extending sequences via profiles or using predicted secondary structures. While these methods have demonstrated Sam S. Gross the utility of external information, the scoring models used are often ad Robert C. Edgar hoc, difficult to train, and prone to overfitting. Serafim Batzoglou Materials and Methods 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 overfit- ting) 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 align- ments, CONTRAlign uses gradient-based optimization and holdout cross validation to automatically deter- mine 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 con- trast, 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-vali- dated 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-the- art 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 biomedical • computation • at • stanford poster Metrics for a mastoidectomy 16 simulator Christopher Purpose Simulation-based training can be a safe, cost-effective, and easily ac- cessible tool for gaining experience in surgery. Another promising, Sewell though not yet largely exploited, advantage of simulations is their potential to objectively evaluate user performance and provide de- Dan Morris tailed constructive criticisms. Nikolas Blevins Materials and Methods Federico Barbagli We have developed a simulator for ear surgery (specifically, a mas- toidectomy). We are now creating an interface for this simulator that Kenneth Salisbury allows instructors or the trainee to replay a run of the simulator, objec- tively score the performance according to various criteria, and visually highlight problem areas. Two views are shown side-by-side, the left show- ing 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. Al- ternatively, 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’ sim- ulator scores and experts’ assessments of their performance on real plastic temporal bone models.

46 october • fifteen • 2005 Bringing the ribosome exit poster tunnel to life with distributed computing: a first look at the 17 thermodynamics of confined solvent and the nascent chain Purpose Christopher During translation the ribosome synthesizes proteins, extruding the new polypeptides through a ~100 Å exit tunnel (1). To fully understand cotrans- D. Snow lational folding and the translation process, we must study the formative environment of the nascent chain. The ribosome tunnel composition is het- Colin Aitken erogeneous, including multiple protein chains, rRNA, and attendant coun- terions. The tunnel varies in diameter between 10-20 Å. The diversity of pro- Vijay S. Pande tein 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.

Materials and Methods 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 dy- namics simulations. Essentially, we leveraged volunteer processors to focus an enormous amount of compu- tational 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 bind- ing 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 interac- tions 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 biomedical • computation • at • stanford poster From biomedical images to 18 geometric models Purpose Algorithms for constructing 3D models of structures from biomedical images are Chand T. usually context-specific. Hence, software developed to facilitate general bio- medical image analysis is usually limited in scope. The 3D Slicer, however, is a John freely available, open-source, extensible and customizable image analysis soft- ware package currently under development. The objective of this project was Scott L. Delp to develop modeling tools within Slicer that can be applied broadly while still allowing the context-specific flexibility that clinical researchers need.

Materials and Methods 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 algo- rithms 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 ad- jacent 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 october • fifteen • 2005 Algorithmic analysis of the poster quantitative distribution of neural stem cells in malignant 19 glioma David Jing- Purpose One of the largest obstacles in traditional brain tumor treatments such as surgery and radiation is the degree to which glioma cells migrate away from the main Piao Lin 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 Josip Najbauer thus potentially be used as therapeutic delivery vehicles for targeting tumor cells. Despite several studies supporting the ability of NSCs to track dissemi- Paul Salvaterra nating glioma, there have been limited studies characterizing the distribu- tion of NSCs. Adam Mamelak Michael Barish The purpose of our study was to quantitatively investigate the distribution of human NSCs in human gliomas in a mouse model. Analyzing the quan- Elizabeth Garcia titative distribution of NSCs is important for assessing the application of in vitro chemoattractant studies to in vivo distribution and determining the Marianne Metz comprehensiveness of potential NSC drug therapy for gliomas. Steven Kendall Methods Maggie Johnson We used confocal microscopy, medical imaging software, and mathematical modeling to quantify the distribution of human NSCs in experimental human Karen Aboody glioma after caudal lateral implantation in adult nude mice.

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 in- tracranial 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 biomedical • computation • at • stanford poster Locating single-stranded regions of 20 the human genome

Diane DNA becomes single-stranded in a variety of important biological situa- tions, including the transcription initiation bubble and DNA replication. In Schroeder addition, there is evidence that some genes, such as c-myc, might be reg- ulated by nearby denaturation-prone DNA sequences and the proteins that bind to those denatured sequences. I am developing a genome- Richard Myers wide 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.

50 october • fifteen • 2005 Image interpolation in 4D CT poster using a Bspline deformable registration model 21 Purpose Eduard To study organ deformation during respiratory motion and develop a method for deriving the phase-binned 3D image sets through the in- terpolation of the images at some known phase points. Schreibmann

Methods and materials Brian Thorndyke 4D CT datasets for 3 patients were acquired. For each patient, the cor- Lei Xing relation between inhale and exhale phases was studied and the defor- mation of the anatomy between the two phases was quantified using a BSpline deformable model. In this method, the deformations field be- tween the inhale and exhale phases was defined on a set of nodes over- laid 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 pro- posed 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) moni- toring 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 de- formation 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 interpo- lated 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 us- ing 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 reduc- tion, binning artifacts removal, and disk storage improvement in 4D imaging.

51 biomedical • computation • at • stanford poster 22 GROMACS on the GPU Erich Konrad Purpose The purpose of our project is to harness the computational power of Elsen 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 dynam- Pat Hanrahan ics package on the GPU using the BrookGPU language developed here at Stanford. All major parts of the code except the neighbor Vijay Pande list search have been mapped to the streaming computing model Ian Buck and ported to the GPU. 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 proces- sor 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 Model- ing Application on Merrimac,” Proceedings of the 2004 ACM/IEEE conference on Supercomputing, p. 42, 2004.

52 october • fifteen • 2005 3-D simulations of hemodynamic poster factors in pulmonary hypertension 23

Purpose Tim A. Fonte 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 Irene E. forces on vessel walls, which can lead to a new understanding of how ves- sels remodel and the disease progresses. Vignon-Clementel

Materials and Methods C. Alberto Figueroa Models of PAs for healthy and hypertensive subjects were created from Jeffrey A. Feinstein MRA [1] to the maximum detail of each data set (50-70 vessels per mod- el). Blood flow was measured with PC-MRI at the main, left, and right PAs. Charles A. Taylor 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 Imag- ing 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 De- formable 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 biomedical • computation • at • stanford poster Filling missing components in yeast metabolic pathways using 24 heterogeneous data

Gal Chechik The set of cellular metabolic reactions forms a complex network of interactions, but even in well studied organisms the resulting path- Aviv Regev ways contain many unidentified enzymes. We study how ‘neighbor- hood relations’ between enzymes in metabolic pathway are mani- Daphne Koller fested in functional properties of the corresponding genes and their products, including mRNA expression, protein domain con- tent and cellular localizations. We develop compact and interpre- table probabilistic models for representing protein-domain co-oc- currences 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 com- pleting the unidentified enzymes in the pathways, achieving accuracy that is significantly superior to existing state-of-the-art approaches.

54 october • fifteen • 2005 Simulation of fluorescence poster anisotropy experiments: probing protein dynamics 25 Purpose Gunnar F. Time-resolved fluorescence anisotropy decay experiments on a protein-at- tached dye can probe local protein dynamics and steric restrictions, but are difficult to interpret at the structural level [1]. Aiming at an atomistic Schroeder description, we have carried out molecular dynamics simulations of such experiments. Ulrike Alexiev

Results Helmut Grubmuller Our simulations describe an Alexa488 fluorescent dye maleimide de- rivative covalently attached via a single cysteine to the AB-loop of bac- teriorhodopsin. Fluorescence anisotropy decay curves obtained from the simulations agree well with the measured ones. Three anisotropy decay com- ponents 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 nanosec- ond timescale and 3) to the overall tumbling of the molecule. For the biologically relevant one nanosec- ond 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 rho- dopsin: 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 biomedical • computation • at • stanford poster Efficient prediction of protein- protein interactions using Markov 26 networks Haidong * These authors contributed equally Purpose Wang* Mapping the network of protein-protein interactions is a key step towards understanding many cellular processes. Current assays for measuring in- Matt Schefer* teractions are noisy and partial. Recent work [1] has shown that Markov Gal Elidan networks can effectively integrate heterogeneous data and deal with noise to make better predictions. However, standard inference methods Daphne Koller in these models are slow and do not scale to large, dense networks. We propose a new algorithm that speeds up the computation without reduc- ing 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.

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 ap- proximation 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 localiza- tion 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 Interac- tion Network. RECOMB 2005

56 october • fifteen • 2005 Framework for identification of poster allosteric networks 27

Purpose Allosteric regulation is a key feature of enzyme function. Lockless et al. pro- John posed an algorithm that uses sequence data to search for potential allosteric networks in proteins using statistical analysis of multiple sequence align- Patrick ments. We have created user-friendly software to perform this algorithm. We are applying the software to the Adams chaperonin proteins.

Materials and Methods Erik J. Miller A protein of interest’s sequences are collected and aligned using the Clust- Christoph Spiess alW 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 cou- pling 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 syn- thesized 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 hydro- lysis, 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 align- ments 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 re- ceptors 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 biomedical • computation • at • stanford poster Unsupervised identification of functionally relevant residues in 28 protein families Jessica Purpose Both the impending increase of solved structures for proteins of un- known function and the uncertainties involved in sequence based func- Ebert tional annotation methods point to the need for a greater understand- ing of the relationship between structure and function. Because global Russ Altman 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 func- tional 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 envi- ronments of functional residues may have unique characteristics that will give rise to highly sensitive and specific models.

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 com- position. 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 mod- els 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 october • fifteen • 2005 A modified Bayesian approach to poster determination of causation in differential gene expression 29 Purpose DNA microarrays have given researchers vast amounts of new data Jessie Dale regarding differences in gene expression between normal and dis- eased tissue types. Still missing, however, is the ability to use this Tenenbaum information about differential gene expression to gain insight into upstream causal mechanisms of disease. We have developed a modi- Paul J. Utz fied Bayesian approach to predict the most likely ligand responsible Atul J. Butte for changes in gene expression given a list of genes observed to be significantly up- or down-regulated and a set of possible ligands.

Materials and Methods 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 represen- tation (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 al- gorithms 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 biomedical • computation • at • stanford poster Use of a naive Bayesian classifier to identify gene regulatory 30 networks in the protozoan parasite, Enatmoaba histolytica Jason A. Purpose Hackney Entamoeba histolytica is a protozoan parasite responsible for amebic coli- Gretchen M. tis, a disease that kills over 100,000 per year. Little is known about gene regulation in protozoan parasites, in general, and E. histolytica in particu- Ehrenkaufer lar. We wished to identify gene regulatory networks within E. histoyltica trophozoites, in order to better understand the biology of this important Upinder Singh parasite.

Materials and Methods 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 re- trieved 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 par- titioned 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 deter- mining 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 pre- dict 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 ame- bic 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 evolu- tionary 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 october • fifteen • 2005 Patient-specific modeling of poster altered hemodynamics and arterial deformation induced 31 by coarctation of the aorta and subsequent stent John F. implantation Purpose LaDisa, Jr. Stents are playing an increasing role in the treatment of aortic coarctation (CoA)(1). However, morbidity (hypertension, aneurysms, stroke) persists(2) and C. Alberto Figueroa may be attributed to abnormal hemodynamics in the aorta and its branches(3). We hypothesized that computational fluid dynamics (CFD) modeling can be Irene E. used to quantify alterations in blood pressure (BP), flow and vascular deforma- tion introduced by CoA, and stent implantation. Vignon-Clementel Frandics P. Chan Materials and Methods Magnetic resonance angiography was performed(4) before and after stent im- Charles A. Taylor plantation in a 13 year old patient with severe CoA. Computational representa- tions of the aorta and cervical arteries were created using custom software that fa- Jeffrey A. Feinstein cilitates 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. Re- sistance 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 consis- tent 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 con- sistent 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 assess- ment 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 biomedical • computation • at • stanford poster Preferential coplanarity of RNA helices and its impact on RNA activity 32 Purpose RNA molecules, which are transcribed from DNA and are used by the ribosome to synthesize pro- teins can also catalyze complex chemical reactions in the cell. As the structure of RNA dictates Joseph 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 Minhow 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 Chan 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 prob- ability 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 orienta- tion 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. Ob- servation 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 october • fifteen • 2005 Using coarse-grained simulations poster of RNA to explore intermediate folding pathways 33 The structure of large catalytic RNAs (e.g. group I and II introns) is of Magda Anna 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 I intron by running coarse-grained simulations of RNA using the Alain Laederach molecular dynamics (MD) package NAST (Nucleic Acid Simula- tion Tool). Results from time-resolved hydroxyl radical footprint- Russ Altman ing define specific three-dimensional constraints (in the form of contact order formation) on the structures of the folding interme- diates. 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 dif- ferent 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 fold- ing intermediates along the folding pathways of the T. thermophila group I intron.

63 biomedical • computation • at • stanford poster Quantitative and qualitative assessment of a new knowledge- 34 based algorithm for centerline restoration through femoro- Justus popliteal artery occlusions in peripheral CT angiography Roos (CTA) Tejas Rakshe Purpose To assess the accuracy of a new knowledge-based algorithm for au- Matus Straka tomated centerline tracking trough femoro-popliteal occlusions in Sandy Napel CTA, a currently unresolved and labor intensive problem. Dominik Material and Methods CTA was performed in 20 patients (mean age 69y, range 44-88y) with a Fleischmann total of 26 femoro-popliteal arterial occlusions (mean length132mm, range 16-400mm),.Occlusions were categorized into <75mm (n=8), 75- 150mm (n=11), and >150mm (n=7). Two radiologists used a semi-automat- ed centerline extraction technique and bridged occluded segments by manu- ally 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 cen- terlines. Diagnostic image quality was compared between curved planar reformations (CPR) gener- ated with both methods.

Results The knowledge-based algorithm successfully interpolated all femoro-popliteal occlusions in 20 pa- tients. 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 femoro- popliteal occlusions up to a length of 75 mm. This may substantially accelerate the creation of CPRs in patients with peripheral arterial occlusive disease

64 october • fifteen • 2005 A common signature for poster human aging 35 Purpose Jacob 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 Michael as biomarkers for aging. Rather than search for molecular biomarkers by focus- ing on only one gene, an attractive approach is to screen all genetic pathways Zahn in parallel for age-related changes by using DNA microarrays to search for gene expression changes in the elderly. Rebecca Sonu Materials and Methods Emily Crane To profile transcriptional changes with age, we used Affymetrix Hu133 2.0 Plus DNA chips, which consist of approximately 55,000 probe sets corre- Ralph Rabkin sponding to 25,000 unique genes. To determine age-regulated genes, we implemented a multiple regression model including terms for age, sex, and Ronald W. Davis tissue type. We chose genes which were significant to a p-value threshold Kevin G. Becker 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 Art B. Owen der Waerden non-parametric test to choose genetic pathways that are regu- lated with age. 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 physiologi- cal biomarkers of aging in the muscle. We compared the transcriptional profile of muscle ag- ing 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 de- crease 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 biomedical • computation • at • stanford poster Chronic spinal cord injury modifies aortoiliac biomechanical forces 36 and morphology and increases abdominal aortic aneurysm Hyun Jin Kim disease risk Purpose Spinal cord injury (SCI) patients have a greater risk of abdominal aortic aneu- Janice J. Yeung rysms (AAA) compared to age and risk-factor matched ambulatory control subjects1. We propose that reduced lower-limb blood flow and resistive he- C. Alberto Figueroa modynamic conditions observed in SCI patients upregulate pro-inflamma- tory infrarenal aortic gene expression, potentially promoting AAA disease. Irene E. We used magnetic resonance (MR) imaging and computational flow model- Vignon-Clementel ing to determine the relationship between hemodynamic conditions in SCI subjects and AAA risk. Mary T. Draney Material and Methods Robert J. Herfkens We constructed 3-D computational models from the MRI data of five SCI sub- jects and six age and risk-factor matched control subjects using custom soft- Ronald L. Dalman ware2. We solved the 3-D equations of blood flow in deformable models of ar- Charles A. Taylor teries using a novel finite element method3. Inflow boundary conditions at the supraceliac level were specified using PC-MRI data, and impedance boundary con- ditions 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 arter- ies. 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 pa- tients 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 october • fifteen • 2005 Novel approaches to simulating poster amyloid formation: reaction path annealing and single molecule 37 pulling Jan Lipfert Purpose Insoluble, misfolded protein aggregates termed amyloid are involved in several Sebastian neurodegenerative diseases, including Alzheimer’s and Parkinson’s, and the pri- on protein’s transition from the native protein fold to amyloid fibrils is believed Doniach 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 in- vestigate 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 ener- getic barriers for the elementary step in amyloid formation and to highlight the mo- lecular details that contribute to amyloid stability.

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 coopera- tive 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 experi- ments, 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 el- ementary 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 biomedical • computation • at • stanford poster Genomic instability signatures of colorectal carcinoma subtypes 38 by hierarchical clustering of Michael Yu gene copy data Purpose Zhang Colorectal carcinoma (CRC) is the second most commonly diagnosed can- cer in the United States. The most widely-used indicator of CRC prognosis, clinical staging, is unfortunately a poor predictor of tumor recurrence. We Keyan Salari developed a novel genomic technology that sheds light on the genomic Kyle Farnam instability underlying neoplasia in CRC by looking at gene copy number alterations to discover clinically relevant biomarkers. These biomarkers Jochen Kumm can be used to form signatures which identify subtypes of CRC, providing James Ford a more accurate and complete prognosis. Ron Davis Materials and Methods We used the high-resolution, barcode array-based molecular inversion probe Hanlee Ji (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 cal- culated 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 de- lineated 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 october • fifteen • 2005 Automatic state decomposition poster for constructing Markov models for macromolecular dynamics 39 Purpose Nina Singhal Understanding the kinetics of protein folding is an important biologi- 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 John D. Chodera states and calculated the transition probabilities between the states, assuming Markovian, or history independent, transitions. In this work, Vijay S. Pande we develop algorithms for the automatic decomposition of the protein William C. Swope or other macromolecular conformation space into regions which are ki- netically related and transitions between them Markovian.

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 decom- position 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 mo- lecular systems in the future.

69 biomedical • computation • at • stanford poster 40 Fold removal in CT colonography

Purpose Padma Normal haustral folds complicate both, the visual and computer-aided detection (CAD) of polyps in CTC data. We present a method to straight- Sundaram en and flatten the colon by simulating stretching of the colonic surface using a quasistatic Finite Element Model (FEM). The output of our algo- Eftychios Sifakis rithm is a 3D fold-free surface that can be displayed as a single image David Paik and/or subjected to a CAD algorithm. Christopher Materials and methods We created several mathematical phantoms using MATLAB 7.0.1, with Beaulieu folds and polyps modeled as half sine functions and hemispheres, re- Sandy Napel spectively. 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, contain- ing 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 in- variant 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 assump- tion 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 ef- ficiency of interpretation by reducing visual clutter and sources of false positive detections by CAD. Continued development is warranted.

70 october • fifteen • 2005 poster Analysis of the transcriptional regulation of a bacterial cell 41

We have created an Affymetrix chip for Caulobacter crescentus that is Patrick both an expression array and an intergenic tiling array. This array can be used for analysis of gene expression, for high-resolution chromatin Timothy immunoprecipitation experiments, for identification of expression in intergenic regions such as non-coding RNAs (ncRNAs), and for identi- McGrath fication 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 pairs upstream of the predicted start codon and the stop codon of Antonio Iniesta each gene. We have identified transcriptional start sites of ~600 op- erons to an accuracy of 5 base pairs. Motif searching of the DNA se- Alison Hottes quence 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 biomedical • computation • at • stanford poster 2D ultrasound image processing in identifying displacement 42 history of urogenital Qiyu Peng structures to pelvic floor muscle activity Ruth C. Jones Purpose The measurement of the PFM’ ability to contract voluntarily is of value in the assess- Kirk Robert McConnell ment of women with urinary or fecal incontinence. Ultrasound imaging provides a considerable amount of dynamic data that cannot be visually assimilated by the Chris E. Constantinou 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, espe- cially 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 lin- ear 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, con- traction 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 dur- ing 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 pos- terior 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 dys- function: 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 move- ment. Am J Obst Gynecol. 2001; 65-70.

72 october • fifteen • 2005 A novel palpation system to poster evaluate internal organs of genitourinary system 43

Introduction Qiyu Peng Palpation provides information relating the mechanical properties of the tis- sue such as its stiffness. In clinics, palpation is used to evaluate in accessible Ruth C. Jones internal organs of the genitourinary system such as the prostate, vagina and uterus. We developed a novel palpation system suitable for the evaluation Kirk Robert of the static and dynamic properties of internal organs. McConnell Prototype of the System The prototype of the system is made of a probe with four force and displace- Sadao Omata ment sensors and a six degrees-of-freedom measuring device that can track Chris E. the position (x, y, z) and orientation (azimuth, elevation and roll angles) of the probe (Flock of Birds, FOB) (Fig. 1). Constantinou 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 orien- tation 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 as- sumed 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 reconstruc- tion 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 Genitouri- nary system.

Acknowledgments NIH-NIBIB grant 1 R21 EB001654 Biodesign, Clark center, Stanford University

73 biomedical • computation • at • stanford poster Viscoelastic arterial wall model for one-dimensional modeling of 44 blood flow and pressure Rashmi Purpose The one-dimensional equations of blood flow consist of conservation of mass, conservation of momentum and a constitutive relationship that de- Raghu scribes 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 non- Irene E. linear elastic constitutive models have been used in these types of simu- Vignon-Clementel lations. However, arterial tissue is known to have viscoelastic properties. The purpose of this work is to derive and incorporate a viscoelastic con- C. Alberto Figueroa stitutive model for the arterial wall in the existing one-dimensional equa- tions of blood flow and to implement it in the corresponding finite element Charles A. Taylor simulation environment.

Materials and Methods 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 visco- elastic 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 implementa- tion 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 mod- els 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 october • fifteen • 2005 Differential gene expression poster between healthy and melanoma patients for T cells, B cells and 45 NK cells Purpose Rebecca 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 Materials and Methods Agilent’s feature extraction software scanned the microarrays and produced Loew 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 Rebecca Critchley- and green frequencies for each probe and its background. From this, the con- trol spot data and data for 172 genes frequently suffering from dye saturation Thorne were removed using the flags provided by Agilent. A correlation matrix revealed a strong correlation between the pooled samples and the averages of the pa- Peter Lee tients represented. It also showed a good negative correlation between the dye swap arrays. Next, the loess and variance stabilizing normalization methods were Susan Holmes 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.

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 Mela- noma Patients and Healthy Donors. Cancer Res. 2004 64: 3661-3667.

75 biomedical • computation • at • stanford poster Mechanics of deformation of 46 bone cells

Ron Y. Kwon Purpose Fluid flow can be a potent loading mechanism for eliciting biochemi- Sheyi A. Ayeni cal responses in bone cells. However, understanding the mechanism by which fluid flow-induced mechanical loads are transduced into Christopher R. chemical signals is difficult since the mechanics of flow-induced bone cell deformation are not well understood. The objectives of this study Jacobs were to (1) develop a methodology for determining fluid flow-in- duced cellular deformations in vitro, and (2) use the methodology to investigate the mechanics of osteoblastic cells exposed to steady and oscillatory fluid flow.

Materials and Methods 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 cal- culated 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 oscilla- tory 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 in- vestigate 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 october • fifteen • 2005 poster A novel software for plotting multidimensional FACS data 47 Purpose Ryan J. 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 Tibshirani basic science and clinical research. The power of FACS stems from its abil- ity to simultaneously measure the levels of many proteins (currently up to twelve) on a single cell. However, current software for FACS analysis is lim- ited 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.

Materials and Methods 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 polygo- nal 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 plot- ting 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 biomedical • computation • at • stanford poster Registration of lung nodules 48 using a semi-rigid model Shaohua Purpose The tracking of lung nodules in sequential CT scans for the same patient is help- Sun ful 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 Material and Methods 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 cen- tered on a nodule in the source scan, followed by 3D connected component analysis. We retain the component containing the nodule and the 7 largest re- maining 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 pa- rameter 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; nod- ules 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 transforma- tion 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 october • fifteen • 2005 A metropolis sampling framework poster for inferring neural connectivity in diffusion tensor images 49 Purpose Diffusion Tensor Imaging (DTI) is a magnetic resonance (MR) imaging method that Anthony can be used to measure the local information about the structure of the white mat- ter within the human brain. Combining DTI data with the computational methods Sherbondy of MR Tractography, neuroscientists can estimate the locations and sizes of nerve bundles (white matter pathways) that course through the human brain. David Akers Current deterministic tractography algorithms have become quite good at recon- Pat Hanrahan structing certain white matter structures such as the corona radiata and the su- perior and inferior longitudinal fasciculi, but these algorithms have also met with consistent reproducible failure when attempting to reconstruct some sets of neural pathways.

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 be- tween 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 unsuccess- ful 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 tractogra- phy 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 connectiv- ity 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 sam- pling 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 biomedical • computation • at • stanford poster Modeling of phosphorylation sites in protein structures using the 50 FEATURE system Shirley Wu Purpose Phosphorylation of proteins regulates a large number of biological process- es in organisms. The ability to predict phosphorylation sites in new and Megan Y. So existing protein structures would contribute greatly to our understanding Russ B. Altman and manipulation of these pathways. We use an existing method, FEA- TURE, to characterize the 3-D environment around these sites and to il- luminate areas in which we can improve the modeling of variable, low density data sets.

Materials and Methods 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 phosphoryla- tion sites. Negative training sites were randomly chosen from a non-redundant subset of the PDB. Se- quence alignment to eliminate homology was done using ClustalW.

Results Separation between positive and negative sites using positive sites derived from annotated phospho- residues 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 environ- ments. 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 Pro- tein 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 october • fifteen • 2005 Identifying regulatory mechanisms poster associated with genetic variations among individuals 51 Motivation Genomic sequence polymorphisms create variations in the expression of Su-In Lee genes by perturbing the complex network of regulatory interactions. Much work has focused on identifying quantitative trait loci (QTLs) that affect the Aimee Dudley expression of genes1-3. However, there has been little work on identifying the regulatory mechanisms associated with such sequence polymorphisms, Dana Pe’er a task that can play an important role in understanding genetic diseases, Daphne Koller and suggesting targets for drug design.

Methods We present a method based on probabilistic models4 that can provide a fine- grained understanding of the regulatory mechanisms caused by genetic sequence polymorphisms. Given the genomic expression and the marker-based genotype pro- file of many individuals, our method provides a mechanistic explanation for the association be- tween 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 regu- lator 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 regula- tory interactions, and (3) associating regulatory models with modules of genes, providing higher statisti- cal 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 expla- nations with polymorphisms. We experimentally verified one of these hypotheses in the wet-lab, validat- ing 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 biomedical • computation • at • stanford poster CONTRAST: de novo gene prediction using a semi-Markov 52 conditional random field Purpose Samuel S. De novo gene prediction, defined as the identification of the location and structure of protein coding genes using genomic sequences alone, re- Gross mains an important problem. Although full-length experimentally verified transcripts exist for approximately 60-85% of all human genes, traditional Chuong B. Do experimental methods for identifying genes based on 5’ EST sampling and cDNA clone sequencing are now reaching the point of diminishing returns. Serafim Batzoglou As a result, efforts to identify new genes by RT-PCR from computational- ly 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 semi- Markov conditional random field (sCRF).

Materials and Methods Almost every successful modern gene predictor is based on a generative probabilistic model known as a hid- den 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 indepen- dence 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 well- known 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 capabili- ties, and add the ability to use multiple alignments to increase predictive accuracy.

82 october • fifteen • 2005 Removal of respiratory motion poster artifacts and the construction of 4D PET 53 Purpose Brian Respiratory motion remains a challenging problem in positron emis- sion tomography (PET) imaging of thoracic and abdominal cancer. While PET has proven to be a valuable adjunct in the detection, Thorndyke delineation and characterization of metabolically hyperactive tis- sue, the radionuclide signal may be significantly degraded by the Eduard Schreibmann motion of the abdominothoracic organs. The most common solu- tion is to “gate” the scan, effectively limiting image acquisition to Lei Xing 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 time- resolved (4D) PET image from end-inhale to end-exhale.

Materials and Methods 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 de- rived 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 restrospec- tively 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 retrospec- tively 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 malig- nant 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 arti- facts, significantly improving tumor visibility while providing a view of the tumor and surrounding PET-visible tissue at any point in the respiratory cycle.

83 biomedical • computation • at • stanford poster Ion size effects and the Poisson- 54 Boltzmann equation

The ion atmospheres around nucleic acids play a significant role in their Vincent structure and function. Due to their charged backbones, formation of ter- tiary structure in nucleic acids occurs upon the addition of counterions in Bangping solution which screen the phosphate charges. Greater understanding of the role of electrostatics in nucleic acid structure formation may yield in- Chu sight into many outstanding problems in biology, such as the ribozyme folding and gene regulation, and may lead to new drug designs and ad- Jan Lipfert vanced molecular sensor development. Yu Bai Poisson-Boltzmann (PB) theory has historically been the most widely Rhiju Das used framework in modeling electrostatics around biological mole- 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 micro- tubules 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 october • fifteen • 2005 Three-dimensional correlation poster analysis of the macromolecules on synaptic vesicles 55 Purpose We studied the protein associations of the 50-nm-large synaptic vesicles (SVs) Jing Xu in a model system, frog neuromuscular junctions (NMJ) from the structural perspective, aiming to provide insights into the clustering, mobilization, Mark L. Harlow docking and fusion of these smallest functional organelles that carry neu- rotransmitters. David Ress

Materials and Methods 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 of the structures and localizations of cell organelles or protein aggregates. A Uel J. McMahan software package called EM3D was used to reconstruct and analyze the vol- ume 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 mu- tual 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 con- tacts 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 distribu- tion. 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 or- ganized. 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 biomedical • computation • at • stanford

Notes

86 october • fifteen • 2005

Notes

87 biomedical • computation • at • stanford

Notes

88 october • fifteen • 2005 BioNe us A grassroots approach to Bio- X

BioNexus is a newly-formed Stanford student/post-doc organization seeking to promot e and facilitate a community of interdisciplinary research and recreation within Bio-X.

We are planning social and academic activities to bring Bio-X together, from the bottom up .

Join the Nexus! http://bione us.stanford.edu 051165 9/29/04 10:03 AM Page 1 Weekend Road Trip Specials.

Giving you a terrific package is what Enterprise does best - especially on the weekends. We even have great rates designed to fit your college budget. So wherever your weekend plans take you, call Enterprise for great cars, low rates and free pick-up!

*As with all our renters, those in the 18/20 age group must meet certain qualifications to rent. Ask for details.

Pick-up is subject to geographic and other restrictions. Just dial (650) 833-8060. 89

Size: 6” X 5” BW non-bleed Output at 100% biomedical • computation • at • stanford

Combining Experience, Connections, and Capital to Create Winning Companies in both Information and Life Sciences

acquired by ArQule

Capital commitments since 1982 in excess of $1 Billion

General Partners Venture Partners Tony Di Bona David J. Ezequelle Ammar H. Hanafi Peter N. Loukianoff Michael W. Hunkapiller David W. Pidwell Douglas E. Kelly, M.D. W. Ferrell Sanders J. Leighton Read, M.D. Daniel I. Rubin John F. Shoch Craig C. Taylor www.alloyventures.com

90 october • fifteen • 2005 Why Choose a Mac? Count the ways you’ll love your new Apple Computer.

Simply take a Mac out of its box, plug it in and start surfing, working or Believe your ears. rocking. And when you want to add something new – such as a digital camera or iPod – you just plug it in and start using it. Too good to be true? No, the Mac is exactly that good. Welcome the impossibly small It just works. As easy as iPod. iPod nano Want a crash course on the Your iPod has a history. And it to the family. Mac? Lesson 1: It doesn’t starts with the Mac. Intuitive crash. Built by the same folks interface, elegant design, apple.com/ipodnano who designed its rock-solid operating seamless integration with Apple system and its award-winning software and a hearty dose of just applications, the Mac always starts up plain cool. If you love your iPod, you’ll and never lets you down. love a Mac.

Picture-perfect photos. It’s a musical instrument. If every picture tells a story, More than a place to turn up Got Questions? you’ll live happily ever after iTunes, the Mac lets you make with your new Mac. Plug in yoourur music, too. Whether you’re Got questions about your purchase or camera and the Mac does the rest, recording your next big hit, burning anything Apple related? Just drop an helping you import, edit, share and a mix CD or podcasting your e-mail to the friendly Stanford University organize your photos faster than you passion, you’ll be doing it all on the Apple Campus Reps at can say “cheese.” same computer countless pros trust. [email protected], [email protected], or [email protected] and they will be Home movies in HD. Online streamlined. sure to help you out! With a Mac, you get an editing With a Mac in your corner, suite, a special effects house you can get online in and a state-of-the-art cinema minutes. And once you’re all in one package. From recording there you might as well try all the built in Where can I purchase? your HD masterpiece to burning it to goodies — Mail, Safari, .Mac, iChat AV, AirPort DVD, a Mac grants you auteur status. and more — the Mac has to offer. Don’t forget to use your education discount! Join the party. It loves roadtrips. Buy a Mac and you become Mobility means more on Stanford Bookstore part of the solution. The Apple a Mac. Besides powering White Plaza experience includes top-rated the two most appealing 519 Lasuen Mall service online, in our retail stores and notebooks on the planet, (650) 725-6136 ext 456 via telephone. Plus, you join a iBook and PowerBook, Mac OS X www.stanfordbookstore.com worldwide network of Mac users, Tiger gives you easy connectivity happy to share their stories. from anywhere you dare to roam.

It does Windows. It’s beautiful. Your Mac may soon seem like To learn what separates your digital oasis, but that an Apple computer from doesn’t make you an island. every other machine on You’ll be able to connect to tthehe the market, just open office network, share Office files with your eyes. The Mac’s colleagues, and even use many of your design fold function into form, so Want to read more? PC hardware devices. the perfect computer looks the part. http://www.apple.com/switch 91 b c a t s 2 0 0 5 t h a n k y o u Administrative Help Previous Organizers Symposium Sponsors and Guidance Founding Sponsors Zhen LIn Stanford University Center for Carol Maxwell (Stanford) Zachary Pincus Bio-Medical Computation Ted Hopper (Stanford) Brian Naughton NIH – NIBIB Tiffany Murray (Stanford) Jessica Tenenbaum Bio-X Rosalind Ravasio (Stanford) David Buckeridge Fiona Sincock (Stanford) Gold Sponsors Heideh Fattaey (Stanford) Symposium Volunteers Apple Jill Sakata (Stanford) Genentech (William Wood) Jonathan Dugan (Stanford) Timothy McBride Alloy Ventures (Leighton Reed) Yue Lu (Stanford) Yael Garten Xinlei Qiu (Stanford) David Gobaud Vincent Foecke (Stanford) Silver Sponsors Greg Goldgorf Marcy Rivera (Roche) Roche (John Shon) Yang Huang Collyne Rusin (Roche) Agilent Nikesh Kotecha Annette Adler Life Sciences Society Christina Lu (Agilent Technologies) Wilson Sonsini Goodrich Cesar Rodriguez Jane Weber (Alloy Ventures) & Rosati Kahye Song Silvia Herrero (Apple) (Benjamin Glenn) Valentin Spitkovsky Justin Chang (Apple) Jessica Tenenbaum Vicky Markstein (Life Sciences Li Zhang Other Sponsors Society) Enterprise Stefan Zappe (Life Sciences Stanford Bookstore Society) Stanford OTL Julie Rubinstein (Enterprise) Jennifer Kesler (Genentech) John Brown (WSGR)

biomedicalcomputationatstanford