Mary E. Meyerand - US grants

This application requests support to integrate physiologic magnetic resonance imaging (MRI) methods to better describe and delineate glioblastoma multiforme (GBM) brain tumors in preparation for radiation therapy treatment.We hypothesize that the use of these imaging methods will result in more precise radiotherapy treatment planning. The proposed research is based upon extensive preliminary data indicating chemical shift imaging (CSI), perfusion and diffusion imaging and MR-based hypoxia mapping add additional information about tumor physiology that can be incorporated into a treatment plan with the goal of decreasing the rate of tumor recurrence. Although regions of abnormality on T2 MRI are known to correlate with microscopic spread of tumor, some of this abnormality represents edema without malignant cells while other areas may contain a high concentration of malignant cells that should be incorporated into the treatment boost volume. While most malignant brain tumors recur within the radiation treatment fields, 20- 25% of recurrencesoccur outside of these fields. For this reason, we expect that in at least 25% of patients there will be a boost volume discrepancy >10%. We anticipate that at least some of these out-of-field recurrences could be predicted by the use of the imaging techniques. Thus, the imaging techniques will be used to identify "high-risk subvolumes" within each tumor, which may be at high risk of recurrence. After completing radiotherapy, patients will be followed with serial physiologic MRI scans;the study endpoint being the first recurrence.The SPECIFIC AIMS are: 1) Create maps of hypoxia within individual tumors using blood oxygen level dependent (BOLD) MRI combined with carbogen breathing. 2) Probe the proliferative potential of tumors using chemical-shift imaging (CSI). 3) Assess the angiogenic features of a tumor using contrast enhanced perfusion MRI. 4) Assess the cellularity of a tumor using diffusion-weighted MRI. 5) Compare the locations and areas of maps created in AIMS 1-4. 6) Generate clinical target volumes (CTV's) from the regions defined by AIM 5.

DESCRIPTION (provided by applicant): This project titled 'Validating resting state fMRI derived brain connectivity'represents a large scale effort to establish rigorously the reliability of brain connectivity measures derived from resting state fMRI (fcMRI). This method of studying the spatial pattern of connectivity between regions of the brain has recently seen an intensive period of growth. Recent publications indicate the method may be able to give insight into the large scale structure of interactions between brain regions that support the integrated functioning of the brain in human health. There is also a growing body of literature that indicates deviations from the normally observed pattern of connectivity may be a fundamental causative factor in many mental health disorders including schizophrenia, depression, and autism. In applying this method there are a large number of processing steps that must be applied to the data before the statistical measures of connectivity are calculated. There is currently a lack of knowledge as to the effects of different methods of preprocessing on the reliability of the results obtained using fcMRI. One type of processing required involves the removal of variations in the signal resulting from cardiac and respiratory induced pulsations in the brain. Currently simple digital filtering methods are usually used. Theoretical considerations indicate this type of processing may not give optimal results. This study will investigate the improvements that may be achieved by using more complex methods that involve utilizing recordings of the cardiac and respiratory cycle measured from the subject at the time of MRI scanning. Another factor that influences the accuracy and reliability of the results concerns processing that must be performed in order that comparisons between subjects may be made. In order that comparisons may be made between corresponding brain regions of different subjects the brain scans must be brought into alignment. It is well known in the neuroscience community that the different mathematical tools used to accomplish this are imperfect and that different methods introduce different errors. This study will investigate the differences in reliability that result from the application of the different methods to accomplish this alignment. In order that the results of the study will be sufficiently general to serve as a guide for investigators we will acquire fcMRI data from a large number of healthy individuals and use a study design known as a bootstrap design. Multiple MRI data sets will be acquired from each of approximately 100 volunteers. The data from all subjects will be processed with each of the different processing methods considered in the study. The methodology follows a procedure of choosing subsets of the subjects and calculating fcMRI measures. Next measures of the intra subject and intersubject reliability are calculated from the proceeding results. This basic procedure is repeated a large number of times building a large set of measurements from which reliable statistics may be calculated. The results derived from this study will serve to enable researchers in the field of fcMRI to conduct more informed study design and aid in the interpretation of the validity of results. This study represents an essential next step in the validation of fcMRI as a biomarker for the characterization of normal and pathological brain function. The research is intended to validate the results of an emerging method known as resting state fmri in understanding human and animal brain connectivity. It would serve to guide practitioners of the technical requirements for achieving optimal results utilizing this method. This proposed research contributes to both basic neuroscience and clinical neuroscience and will provide the foundation for future studies characterizing brain connectivity in normals and disruptions of connectivity in various patient populations.

DESCRIPTION (provided by applicant): The goal of this Clinical Neuroengineering Training Program (CNTP) is to train a cohort of engineers and scientists with an interdisciplinary approach linking the traditional areas of biomedical engineering and physical science, neuroscience, and clinical practice. We have designed the CNTP around the premise that interdisciplinary research is a mode of research by teams or individuals that integrates information, data, techniques, tools, perspectives, concepts, and/or theories from two or more disciplines to advance fundamental understanding or to solve problems whose solutions are beyond the scope of a single discipline. Students conducting interdisciplinary research also benefit greatly from the guidance of mentors in the three disciplines represented on their dissertation committees. Co-mentoring allows students to have direct relationships with researchers in the different fields while synthesizing the training and advice to form their own skills and experiences for their future interdisciplinary research goals. One of our objectives in making the CNTP a successful training program is that the research conducted by CNTP trainees will have an impact on multiple fields or disciplines, and produce results that feed back into and enhance disciplinary research. It will also create students with an expanded research vocabulary and abilities in more than one discipline, and with an enhanced understanding of the interconnectedness inherent in complex problems. As the name, Clinical Neuroengineering implies, the foundation and driving force of our program is the Clinic. This emphasis on the Clinic is the common thread that ties together all aspects of our program: The research of our trainers is designed to answer clinical questions;the formal course plan for our trainees includes clinical rotations in the hospital, a course in medical ethics and another in public policy. This focus on clinical medicine is almost universally absent in graduate education. We believe this makes our Program distinctly different from any other department or training program in the country, and makes the educational experience for our trainees truly interdisciplinary. PUBLIC HEALTH RELEVANCE: The next decade will see unprecedented opportunities as well as challenges for medical science. Biological knowledge and understanding is increasing at an exponential rate particularly as to human disease. At the same time, there is growing dissatisfaction on the part of U.S. citizens for what is perceived as lack of translation to direct human benefit. Further, delivering new treatments is becoming increasingly problematic because of the remarkable changes in health-care delivery. Insurers and government regulators are insisting on new and very different means of demonstrating efficacy, particularly as it relates to quality of life and cost-effectiveness. Indeed, Evidence Based Medicine has become a mantra of health care administrators and one that biomedical engineers must not only understand but also master. Consequently, the context in which the scientist and engineer must operate has expanded greatly and into areas not typically addressed by traditional curricula. Rather, interdisciplinary teams of engineers, physicians, clinicians, and scientists will be critical to future medical successes. This means that the scientist or engineer of the future must have more than a passing acquaintance with many disciplines. The engineer or scientist must be able to problem solve in a multi-dimensional context. They must be able to orchestrate different disciplines;recognizing where and when each individual discipline is appropriate and needed. The goal of this Clinical Neuroengineering Training Program (CNTP) is to train a cohort of engineers and scientists with an interdisciplinary approach linking the traditional areas of biomedical engineering and physical science, neuroscience, and clinical practice.

? DESCRIPTION (provided by applicant): Epilepsy affects an estimated 2.5 million people in the United States and is associated with a high risk of progressive cognitive and psychosocial dysfunction, and enormous socioeconomic and health-care utilization costs. There is currently little understanding of why some patients respond well to anticonvulsant therapy whereas others develop uncontrolled seizures and progressive brain dysfunction. Powerful imaging tools are now available for quantitatively characterizing the structural and functional connections between brain regions that make up epileptic networks, providing a promising new approach for understanding, predicting, and treating refractory epilepsy. Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and the largest group among those with medically refractory seizures. The Epilepsy Connectome Project (ECP) will collect detailed connectivity measurements in 200 people with idiopathic TLE using diffusion-weighted magnetic resonance imaging of structural connections, functional magnetic resonance imaging of dynamic network interactions, and magnetoencephalography to measure these interactions with millisecond time resolution. The methods will closely mirror those currently used by the Human Connectome Project (HCP) to study network connectivity in healthy participants, and the HCP data will provide a critical baseline against which to compare the ECP connectome data. These comparisons, based on large cohorts studied with sensitive, state-of-the-art methods, will reveal for the first time the full extent of abnormal network structure and function in TLE. The data will be used to test four major hypotheses: 1) that recurring seizures over many years lead to connectivity abnormalities in TLE, 2) that connectivity abnormalities account for the cognitive and psychosocial dysfunction observed in people with TLE, 3) that the severity of connectivity abnormalities predicts the risk of subsequent decline in cognitive and psychosocial function, and 4) that the severity of connectivity abnormalities predicts the risk of developing medically refractory seizures. Evidence supporting these hypotheses would lead directly to novel clinical tools for diagnosis and individualized management of patients with epilepsy based on quantitative imaging of the connectome.

Project Summary: The University of Wisconsin (UW) Graduate Program in Clinical Investigation (GPCI) was developed by the UW Institute for Clinical and Translational Research (ICTR) and continues to be administered by the ICTR Workforce Development group. GPCI houses multiple educational options for trainees in the translational research continuum, but all are based on a common didactic foundation encompassing biostatistics, epidemiology, clinical study design, clinical trials conduct, and the ethical and responsible conduct of research. These essential curriculum elements are shared by the Certificate in the Fundamentals of Clinical Research, the MS in Clinical Investigation, and two PhD programs. The PhD in Clinical Investigation is an applied degree in which trainees focus on the creation of novel methodologies and tools for translational science within the context of a specific biomedical discipline. The PhD in Clinical and Translational Science leverages the core curriculum to give trainees the skills and tools necessary to move their biomedical research along the translational pathway. Since its inception in 2008, GPCI has created a robust infrastructure for training future members of the translational workforce that has allowed students in the program to accumulate an impressive record of publications and research awards. For this NRSA application, new leadership has been appointed distinct from the parental UL1. David DeMets, PhD, and Elizabeth Meyerand, PhD, both have outstanding training records with mentees at all levels and are exemplary investigators in translational sciences. Specific aims include maintaining both existing, high-performing PhD programs; applying an integrated evaluation approach for continuous program improvement and longitudinal outcomes tracking; and developing recruitment strategies to foster trainee diversity and success. In addition, a new postdoctoral training program will be created for individuals with professional degrees (MD, DVM, PharmD, Nursing) to enhance the translational potential of their prior research and provide a bridge to future independent careers in translational sciences. All trainees will benefit from the existing comprehensive mentoring approach, development of individualized career development plans (ICDP), and integrated program activities including federally-mandated training (HIPAA, CITI, GCP, RCR, etc.) and additional training in team science, scientific leadership, mentor-mentee relationships, and writing manuscripts and grants. GPCI also provides career development seminars and workshops in innovation and entrepreneurship. The expanded program will support 15 two-year appointments combined in all pre and postdoctoral categories.

The Planning Grants for Engineering Research Centers competition was run as a pilot solicitation within the ERC program. Planning grants are not required as part of the full ERC competition, but intended to build capacity among teams to plan for convergent, center-scale engineering research.

Between 2016 and 2050, the number of older adults (age>65) in the US will grow from 49 million to 84 million. The combination of the growing aging population with increasingly complex care needs presents a major societal challenge to deliver safe, effective and efficient health care. While older adults prefer to stay in their home or a familiar environment, they also require health services, but are at high risk for patient safety issues and healthcare-associated harm when interacting with the healthcare delivery system. We need to develop technologies that can help older adults stay healthy and safe longer: this includes supporting safe interactions of older adults with the healthcare system (e.g. emergency room, hospital). We plan to develop an ERC for Healthy and Safe Aging (ERC-HSA) that will engage multiple disciplines (engineering, health sciences) and older adults and their caregivers to develop older-care-application-specific smart sensing technologies and integrate them into the overall coordinated older adult care system. The proposed ERC-HSA will be integrated in the newly created Wisconsin Institute for Healthcare Systems Engineering at UW-Madison and will benefit from complementary expertise of researchers at other Universities. During the ERC planning stage, we will work with various universities and local groups to develop strategies and programs aimed at enhancing diversity of our future students and addressing ageism, i.e. biases targeted at older adults. We will also build stronger ties with the health technology industry in the Greater Madison area as well as along the ?Health Highway?, a 600-mile Midwestern stretch that spans four states and represents a growing healthcare ecosystem.

The proposed ERC-HSA will develop a convergent research agenda organized around expertise in sensor technologies, data analytics and system design that will be combined with deep knowledge about aging care to develop technologies that effectively address the societal problem of healthy and safe aging. With advice of experts in strategic planning, team science, diversity and aging, we will coordinate various activities, including webinar on team science and team research, targeted roundtables and a workshop with industry. We will organize roundtables to develop the innovative convergent research program and create opportunities for conversations among researchers from various backgrounds. Older adults and their caregivers and healthcare professionals will actively participate in these activities as we propose to do research not on older adults, but with and for older adults. We will blend expertise in three thrust areas: (1) human-centered modeling, simulation and design of patient work and clinical workflow, (2) health/healthcare data analytics, and (3) sensors and sensing technologies. Our goal is to go beyond designing siloed and fragmented technologies and promote innovative convergent research that will design the next generation of technologies for healthy and safe aging.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

PROJECT SUMMARY/ABSTRACT This proposal requests establishment of a new NIGMS T32 Biotechnology Training Program at UW-Madison. BTP has an aim of increasing mentoring skills through provision of WISCIENCE- and NRMN-inspired workshops to our mentors deepen skills and impacts in the promotion of excellence in science. For our trainees, our aim is to improve their ability to clearly communicate the basics of science and also to understand the constraints and solutions to carrying out rigorous, reproducible and responsible research across the breadth of topics relevant to a successful career in biotechnology. Our training plan focuses on supporting a diversity of trainees and helping them to learn to speak clearly and interact effectively with a breadth of colleagues. This is the basis for our cross-disciplinary career development efforts. Each year, BTP receives up to 100 applications from new TGE students that join our mentor?s labs. This high level of interest reflects the visible, innovative and successful training that BTP provides at UW-Madison. BTP requests support for 11 new trainees each year from this large group of enthusiastic applicants and continued support for a 2nd year, accounting for our request for a total of 22 NIGMS-funded trainees each year. BTP trainees will receive NIGMS support during the 2nd and 3rd years of graduate school and participate in BTP program activities during all years they are in graduate school. BTP trainees (with mentor guidance) will have leading roles in organizing, teaching and presenting in a completely revamped BTP Seminar, which provides the framework for our cross-disciplinary approach to integrative training in rigorous, reproducible and responsible conduct of research. Trainees also complete courses in responsible conduct of research in the 1st and 4th years, a required course in rigorous and reproducible methods of research, and an innovative class in entrepreneurship that sets the stage for internships. BTP trainees will complete internships and other career advancement opportunities through a newly formed innovative connection to the biotechnology trade advocacy group BioForward Wisconsin, its ~150 industry members and other sponsors. BTP is committed to tracking and analyzing the outcomes of its programs, trainees, mentors and internship sponsors. We will use professionally designed and distributed anonymous surveys, personal interviews, institutional data and social media to continue this effort and enlist professionals from the UW-Madison Survey Center and LEAD to carry out independent assessment and analysis to continually improve the impacts and outcomes of the BTP.

PROJECT SUMMARY/ABSTRACT Consistently a high priority, interdisciplinary women?s health research thrives at the University of Wisconsin- Madison (UW) because of the overall climate of excellence, stellar research career development programs, and dedication to collaboration between diverse disciplines. This exceptional tradition provides an outstanding environment to foster the next generation of leaders in women?s health research. The UW BIRCWH will provide novel, competency-based training and career development opportunities for these future leaders. The vision of the UW BIRCWH program is to improve women?s health by developing a scientific workforce capable of leading independently-funded biomedical, behavioral, and clinical research. The Multiple PIs bring extensive knowledge, experience, and skills in women?s health research, didactic training, mentoring, and research leadership. The program assembles 40 NIH-funded senior faculty mentors from 21 Departments in 11 Schools/Centers across UW to represent the entire translational spectrum. The UW BIRCWH program aims to: a) identify/prepare committed and capable scholars; b) expand scholar knowledge of women?s health and sex/gender research; c) enhance fundamental research skills; and d) foster independent research careers. The UW BIRCWH program will support three early career scholars (assistant professor), for two to three years pending attainment of scientific independence. The UW BIRCWH program will prioritize the goal of gender, racial, ethnic, and sexual orientation equity and diversity in the program, the scientific workforce, and all scientific pursuits. Core competencies will provide the foundation for the UW BIRCWH career development program ensuring that scholars master the concepts that underpin women?s health research, sex/gender differences research, and the intersection of women leaders and the advancement of women?s health. The program will provide scholars with a competency-based curriculum, new courses focused on women?s health, individualized experiential opportunities, and novel team science training. The program will align each scholar with three established faculty mentors, each with designated and complementary roles, to provide interdisciplinary team mentoring with an innovative component that emphasizes career coaching. The program will systematically gather actionable feedback from scholars, faculty mentors, and senior advisors to evaluate both process and outcome measures designed for continuous improvement, for programmatic evolution, and to ultimately meet program goals. The UW BIRCWH program will leverage a highly interdisciplinary environment, committed leadership, and ambitious early career faculty to fuel discoveries and translational activities that will drive the future of women?s health and sex/gender differences research.