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Oct
4
Tue
ICM Distinguished Seminar Series presents “Taking (Small) Models to the Point of Care”
Oct 4 @ 11:00 am – 12:00 pm
ICM Distinguished Seminar Series presents "Taking (Small) Models to the Point of Care" @ 110 Clark Hall, VTC to 709 Traylor

Thomas Heldt, assistant professor of electrical and biomedical engineering at MIT, will present “Taking (Small) Models to the Point of Care.”

Abstract: Large volumes of heterogeneous data are now routinely collected and archived from patients in a variety of clinical environments, to support real-time decision-making, monitoring of disease progression, and titration of therapy. This rapid expansion of available physiological data has resulted in a data-rich – but often knowledge-poor – environment. Yet the abundance of clinical data also presents an opportunity to systematically fuse and analyze the available data streams, through appropriately chosen mathematical models, and to provide clinicians with insights that may not be readily extracted from visual review of the available data streams.

In this talk, I will highlight our work in model-based signal processing to derive additional and clinically useful information from routinely available data streams. In the first part of the talk, I will present our model-based approach to noninvasive, patient-specific and calibration free estimation of intracranial pressure, and will elaborate on the challenges of collecting high-quality clinical data for validation. In the second part of the talk, I will present our work on extracting clinically meaningful and actionable information from the shape of the capnogram, with applications to differentiating respiratory and cardiac causes of shortness of breath.

For those who cannot make it to the Homewood campus, the seminar will be video-conferenced to Traylor 709 on the School of Medicine campus.

For those who attend at Homewood, lunch will be provided at noon.

Nov
1
Tue
ICM Distinguished Seminar Series presents “Change Point Estimation of Brain Shape Data in Relation with Alzheimer’s Disease”
Nov 1 @ 11:00 am – 12:00 pm
ICM Distinguished Seminar Series presents "Change Point Estimation of Brain Shape Data in Relation with Alzheimer's Disease" @ Clark Hall 110, VTC to Traylor 709

Laurent Younes, professor and chair of the Department of Applied Mathematics and Statistics at Johns Hopkins University, will present “Change Point Estimation of Brain Shape Data in Relation with Alzheimer’s Disease.”

Abstract: The manifestation of an event, such as the onset of a disease, is not always immediate and often requires some time for its repercussions to become observable. Slowly progressing diseases, and in particular neuro-degenerative disorders such as Alzheimer’s disease (AD), fall into this category. The manifestation of such diseases is related to the onset of cognitive or functional impairment and, at the time when this occurs, the disease may have already had been affecting the brain anatomically and functionally for a considerable time. We consider a statistical two-phase regression model in which the change point of a disease biomarker is measured relative to another point in time, such as the manifestation of the disease, which is subject to right-censoring (i.e., possibly unobserved over the entire course of the study). We develop point estimation methods for this model, based on maximum likelihood, and bootstrap validation methods. The effectiveness of our approach is illustrated by numerical simulations, and by the estimation of a change point for atrophy in the context of Alzheimer’s disease, wherein it is related to the cognitive manifestation of the disease. This work is a collaboration with Marilyn Albert, Xiaoying Tang and Michael Miller, and was partially supported by the NIH.

For those who cannot make it to the Homewood campus, the seminar will be video-conferenced to Traylor 709 on the School of Medicine campus.

For those who attend at Homewood, lunch will be provided at noon.

Feb
6
Mon
ICM Distinguished Seminar Series presents “The Role of Quantitative Pharmacology in Drug Development”
Feb 6 @ 11:00 am – 12:00 pm

“The Role of Quantitative Clinical Pharmacology in Drug Development”

Don Stanski joined AstraZeneca in early 2014 as Global Head of Quantitative Clinical Pharmacology. He received his MD from the University of Calgary and his clinical anesthesiology residency at Massachusetts General Hospital, Boston, followed by research training in clinical pharmacology/ pharmacometrics from the late Lewis B. Sheiner at the University of California, San Francisco. He joined Stanford University in 1979 developing a clinical pharmacology and pharmacometric academic research program for anesthetic/analgesic drugs. In 1992 he became Chairman of the Department of Anesthesia. He retired emeritus from Stanford in 2005. He spent two years as a senior scientific advisor at the FDA then joined Novartis. He built an integrated Modeling and Simulation program at Novartis over the next eight years, prior to joining AstraZeneca. Don works out of AstraZeneca’s Gaithersburg, MD site.

 

 

 

Dave Boulton joined AstraZeneca in early 2015. He is the Late-Phase Metabolics Franchise Lead for Quantitative Clinical Pharmacology where he is accountable for anti-diabetic and anti-hyperkalemic medicines. He received his BPharm and PhD from the University of Otago, New Zealand, with an internship between his degrees qualifying him as a licensed Pharmacist. This was followed by 4 years of postdoctoral training at the Medical University of South Carolina, Charleston, SC. Dave then joined Bristol-Myers Squibb where for 14 years he worked as an individual contributor and later in leadership roles as a Clinical Pharmacologist in a number of therapeutic areas and in all phases of drug development. Dave works out of AstraZeneca’s Gaithersburg, MD site.

Click here to view webcast.

 

“The Role of Quantitative Clinical Pharmacology in Drug Development”

Dr. Stanski will discuss the integration and quantitative modelling of data and disease information over the research and development spectrum to generate knowledge that informs clinical drug development and underpins business decisions which is the core mission of the Quantitative Clinical Pharmacology (QCP) Department at AstraZeneca (AZ). This framework ensures the right patient gets the right dose at the right time with optimized trial designs and clearly identified proof of mechanisms. The organizational structure and role of the QCP in the drug development process at AstraZeneca will be outlined. The role of Clinical Pharmacology and Pharmacology scientists in the R&D process will be discussed. Dr. Boulton will provide an example of integrated model-based approaches to answering key clinical questions for AZ’s sodium-glucose linked co-transporter-2 (SGLT-2) inhibitor, dapagliflozin, which is approved for type 2 diabetes mellitus but is now being proposed as a new treatment for heart failure and chronic kidney disease. The QCP-driven modeling approach uses quantitative systems pharmacology, longitudinal pharmacometric, pharmacokinetic/pharmacodynamic, and model-based meta-analysis approaches to provide the organization with a scientific basis on which to invest in these potential new indications without having to conduct expensive and time-consuming Phase 2b studies.

Click here to view webcast.

Apr
4
Tue
ICM Distinguished Seminar Series presents “Steering Cancer Evolution: Harnessing Phenotypic Heterogeneity to Design Better Therapies”
Apr 4 @ 11:00 am – 12:00 pm
ICM Distinguished Seminar Series presents "Steering Cancer Evolution: Harnessing Phenotypic Heterogeneity to Design Better Therapies" @ 110 Clark Hall, Johns Hopkins Homewood campus

Alexander, R.A. Anderson, the co-director of Integrated Mathematical Oncology and senior member of the Moffitt Cancer Center, will present on April 4, 2017, as part of the Institute for Computational Medicine’s Distinguished Seminar Series. The title of his presentation is “Steering Cancer Evolution: Harnessing Phenotypic Heterogeneity to Design Better Therapies.”

The seminar begins at 11 a.m. in Clark Hall 110 on the Homewood campus, and it will be video-teleconferenced to Traylor 709 on the Johns Hopkins School of Medicine campus. Click here to view webcast. Lunch will provided to those in attendance on the Homewood campus.

 

Abstract: Heterogeneity in cancer is an observed fact, both genetically and phenotypically. Cell-to-cell variation is seen in all aspects of cancer, from early development to invasion and subsequent metastasis. This heterogeneity is also at the heart of why many cancer treatments fail, as it facilitates the emergence of drug resistance. The complex spatial and temporal process by which tumors initiate, grow and evolve is a major focus of the oncology community and one that requires the integration of multiple disciplines. Tumor heterogeneity at the tissue scale is largely due to ecological variations in 
terms of the tumor habitat driven by spatially heterogeneous vascularity, which is
readily observed on cross sectional imaging. Molecular techniques have 
historically averaged genomic signals from large numbers of cells obtained in a 
single biopsy site, thus smoothing and potentially hiding underlying spatial 
variations. The complex dialogue between tumor cells and
 environment that produces intra- and inter-tumoral heterogeneity is
fundamentally governed by Darwinian dynamics. That is, local micro-
environmental conditions select phenotypic clones that are best adapted to
 survive and proliferate and, conversely, the phenotypic properties of the cells affect the 
environmental properties. While these complex interactions have enormous 
clinical implications because they promote resistance to therapy, the dynamics 
are impossible to fully capture via experimentation alone.

Here we present an integrated theoretical/experimental approach to develop dynamical models of the complex multiscale interactions that manifest as temporal and spatial heterogeneity in cancers and ultimately govern tumor response and resistance to therapy. Specifically, we examine the impact of micro-environmental modulation on cancer evolution both in silico, using a hybrid multiscale mathematical model, and in vivo, using three different spontaneous murine cancers. These models allow the tumor to be steered into a less invasive pathway through the application of small but selective biological force. Our long term goal is explicitly translational as we focus our integrated approach on an emerging cancer treatment paradigm that actively harnesses evolutionary dynamics to improve patient outcomes.

Apr
6
Thu
ICM Distinguished Seminar Series presents “Using Modeling to Inform Critical Decisions: Three Stories of Preclinical Molecules”
Apr 6 @ 3:30 pm – 4:30 pm
ICM Distinguished Seminar Series presents "Using Modeling to Inform Critical Decisions: Three Stories of Preclinical Molecules" @ 107 Latrobe Hall

Yasmin Hashambhoy-Ramsay will present “Using Modeling to Inform Critical Decisions: Three Stories of Preclinical Molecules” on April 6 in a presentation hosted by the Institute for Computational Medicine.

Bio: Yasmin Hashambhoy-Ramsay is a computational biologist working in the biotech industry in Cambridge, Massachusetts. She was born and raised in Toronto and obtained her undergraduate degree in Applied Mathematics and Engineering at Queen’s University. A strong desire to help patients drew her to Johns Hopkins, and she is a proud alumna of the BME PhD program. She graduated from Rai Winslow’s lab and worked as a postdoctoral fellow with Feilim Mac Gabhann. As a Principal Scientist at Merrimack Pharmaceuticals, she used modeling to help advance drug development on various antibody and nanotherapeutic preclinical teams. She looks forward to starting a new position at Jounce Therapeutics in April as a Senior Bioinformatics Scientist.

Abstract: When I was a graduate student and postdoc at Johns Hopkins, I loved doing biomedical research. The thought of taking rational, engineering approaches to understand biological mechanisms really appealed to me; however, I wasn’t sure if folks in industry appreciated these approaches too. It turns out that they do, and lots of pharmaceutical companies use computational biology to inform critical decisions. Over the past five years, I have worked on a number of preclinical teams at Merrimack Pharmaceuticals. In this talk, I will share three stories describing how I used different modeling approaches to answer critical questions that helped advance the development of early stage oncology drugs.

Oct
3
Tue
ICM Distinguished Seminar Series: “Studies of Brain and Behavior in Epilepsy”
Oct 3 @ 11:00 am – 12:00 pm

“Studies of Brain and Behavior in Epilepsy”

 

Dr. Nathan Crone is a neurologist at Johns Hopkins with expertise in epileptology, clinical neurophysiology, and cognitive neurology.  Dr. Crone’s research program uses computational analysis of intracranial EEG recordings for studies in functional mapping, cognitive neuroscience, and brain-machine interfacing.  Dr. Crone’s lab has developed advanced methods for online and offline functional mapping cortical networks responsible for motor, speech and language function, and for real-time mapping and decoding of the human cortical networks controlling upper limb movements and speech.  This research has supported a variety of multi-disciplinary scientific collaborations across departments, campuses, and institutions.  More recently, Dr. Crone has contributed to the development of an app for the Apple Watch that detects seizures.

Click here to view webcast.

“Studies of Brain and Behavior in Epilepsy”

 

Recent advances in the management of epilepsy highlight the importance of continuing innovations in computational medicine. For example, computational advances in the analysis of EEG signals have allowed clinicians to map the brain networks responsible for both normal and abnormal (seizure) behavior with unprecedented spatial and temporal resolution.  These tools can visualize the human brain at work as its different functional-anatomic components are recruited in real time during different behaviors.  Moreover, functional interactions between different brain areas can be studied to understand how individual brain regions contribute to the overall activity and function of brain networks.  Meanwhile, advances in consumer mobile electronics, including wearable computing devices such as the Apple Watch, have the potential to transform the management of epilepsy by providing automatic seizure detection and alerting, data driven healthcare analytics, and tools that empower patients to take a more active role in their own management.

 

References

Lachaux JP, Axmacher N, Mormann F, Halgren E, Crone NE. High-frequency neural activity and human cognition: Past, present and possible future of intracranial EEG research. Progress in Neurobiology, 2012.

http://www.hopkinsmedicine.org/epiwatch/

 

Click here to view webcast.

Oct
4
Wed
ICM and CIS Joint Seminar: “Uncovering the Physical and Mathematical Principles of the Heart and the Brain With Diffusion MRI”
Oct 4 @ 3:00 pm – 4:00 pm

“Uncovering the Physical and Mathematical Principles of the Heart and the Brain With Diffusion MRI “

Van Wedeen is an Associate Professor of Radiology at the Harvard Medical School and the first Thomas J. Brady Endowed Chair in Radiology. Raised in New York City, Dr. Wedeen attended Harvard College with a Westinghouse Scholarship, concentrating in math, earned his MD at Albert Einstein, a residency in internal medicine at Columbia, and then joined Harvard-MGH in 1983 as one of their first fellows in NMR imaging. His work on imaging of motion and flow with tagging and phase contrast led in 1985 to the first MRA, published in Science1, and later, to the first tensor MRI, of cardiac strain, in 1989, and the imaging of myocardial fiber architecture and fiber function2. Building on this approach, Dr Wedeen’s lab for the past 20 years has focused on the mapping brain architecture and connectivity, among their firsts, they presented MRI tractography3 in 1995, developed high angular resolution diffusion MRI4 in 1999-2000, and innovations including DENSE, SMS, and balanced gradients. This program laid foundations for the Connectome Scanner and the Human Connectome Project5, in which Dr. Wedeen was a PI. Recently, this research, using a new analysis of diffusion MRI of the brain, has led Dr. Wedeen’s lab to a new hypothesis about brain architecture. Cerebral axons, they suggest, follow three axes of smooth Cartesian coordinate systems by means of parallel curved sheets – basic mathematical structures called foliations6. If correct, this architecture could provide coordination and authentication of brain structure and connectivity on microscopic and macroscopic scales, leading to new tools of for brain imaging, and potentially clues to brain function, particularly that of the human telencephalon. A focus of Dr. Wedeen’s current research is to further investigate this conjecture, its accuracy and implications, in collaborations of imaging, physics and neuroscience. Holding several patents, Dr. Wedeen is a Fellow of the International Society of Magnetic Resonance in Medicine and Director of Connectomics at the Martinos Imaging Center. Eight of Dr. Wedeen’s students have become professors in radiology and three department chairs.

 

Click here to view webcast.

“Uncovering the Physical and Mathematical Principles of the Heart and the Brain With Diffusion MRI ”

 

This year, 2017, honors the centenary of D’Arcy Thompson’s “On Growth and Form”. In it he inaugurates a program to understand living systems using the ideas that revolutionized physics: symmetry and conservation, non-Euclidean geometry, and anticipates broken symmetry, scaling, and emergence, and presumably other ideas yet to be recognized. In this talk, we discuss geometric symmetries in heart and the brain that had been gleaned only with difficulty or in part by classical methods, but which the new methods of diffusion MRI can uncover or make clear.

As an example of symmetry in biological structure, consider the eye and its sphericity. The early development of the eye yields a shape that is fairly round, but the finishing touches are provided by the movement of the eye in its socket, a dynamical system whose function drives structure to greater symmetry. In the heart, morphogenetic programs guide the ventricle to become a cylinder of helical fibers. However, once established, architecture is refined by dynamics. Whereas myocardial deformations vary by 2-3x across the thickness of the wall, cardiocytes converge upon an orientation field given by a toroidal helix, resembling the famed Hopf fibration of SU(2), uniquely to afford almost constant fiber shortenings, of 13±2%. Thus in the heart, universal structure emerges from dynamics.

Recently, fiber architecture of the brain has been noted to show a striking symmetry. Centralized nervous systems arise in bilateral species, and typically have the form of orthogonal grids or ladders coherent with the body axis. The vertebrate is no exception, its nervous system being patterned as an axial checkerboard of regions and connections. Diffusion MRI now suggests this pattern is expressed more extensively and precisely than previously suspected, by an ingenious mechanism. Fiber orientations adhere to coordinate systems by as parallel sheets of crossing fibers, a structure of notable symmetry, called a foliation. We discuss major predictions of this model, and some possible implications for brain mapping and for theories of function. Because we can measure this architecture with dMRI, we may ask how it is distributed among brain systems, and in this way, possibly gain insight into brain function.

 

 

 

Click here to view webcast.

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