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YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

YCCI MISSION The mission of YCCI has not changed since its inception in 2006: To establish a home for the training of the next generation of clinical and translational scientists and to provide a robust infrastructure that promotes innovative and collaborative research directed at improving patient care.

KEY GOALS education  A key goal of YCCI is to attract highly talented pre- and post-doctoral students and junior faculty members across medicine, nursing, public health, biology, and biomedical engineering; imbue them with a spirit of discovery; train them in the use of state-of-the-art research tools; give them the skills to work within complex research teams; and support their professional development while at Yale and beyond.

clinical care  In parallel, YCCI fosters the translation of disease-related discoveries from the laboratory into the clinic and then into the community in a variety of ways: Bench to Bedside By stimulating the creation of interdisciplinary teams of translational researchers; by providing education and advice on the best approaches for addressing specific scientific questions; by making state-of-the-art core facilities and expanded biostatistical and bioinformatics resources available to these scientists; and by developing new methods and technological advances. Clinic to Community By establishing an organizational and regulatory infrastructure to support clinical studies; by catalyzing the formation of teams of research-oriented physicians, nurses, and epidemiologists; by integrating community clinics into the research effort; by creating new community outreach programs that bring together the School of Nursing, the School of Public Health, the School of Medicine, and the Robert Wood Johnson Program; and by supporting pilot grants and clinical scholars engaged in community-based outcomes research.

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March-May 2010

Contents FROM THE LEADERSHIP 2 Robert Sherwin, MD, Director, YCCI 4 Robert J. Alpern, MD, Dean, Yale School of Medicine 6 Marna Borgstrom, President and CEO, Yale-New Haven Hospital  8 Margaret Grey, DrPh, RN, FAAN, Dean, Yale School of Nursing 9 Paul Cleary, PhD, Dean, Yale School of Public Health

Clinical Research Review

24 CONTRACT DUE DILIGENCE

PHASE 1 Planning 8/23/2010–7/25/2010

3/2010–7/25/2010

TRANSLATIONAL SCIENCE 10 Moving Science Forward Combining basic science and cutting-edge approaches to cure diseases 14 Insights into Human Biology Yielding clinical breakthroughs

July 2010

Contract Signed

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Clinical science 16 Translating Science into Clinical Practice Moving discoveries from the laboratory to the patient quickly and efficiently Informatics 24 Building an Informatics Infrastructure A comprehensive informatics platform for patient care and clinical research

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BIOSTATISTICS 30 Integrating Biostatistics Expertise to Benefit Research YCAS is a hub for biostatistical support Windham At a Glance 34 Measurements and Milestones New London Highlights from the first four years of the CTSA

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Community 36 Broadening Community-Based Research  A transformed vision for moving medical advances from the bench to the bedside to the community

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NATIONAL COLLABORATIONS 46 Collaborating for Better Science Translation of science requires strategic partnerships Education 50 Training the Next Generation Establishing a home for the education and support of clinical and translational investigators

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INSTITUTIONAL COLLABORATIONS 42 One Is Better Than Two YCCI and YCC join forces to advance clinical research

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50 ycci.yale.edu

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FROM THE LEADERSHIP

Robert Sherwin, MD Director, YCCI My vision was the fulfillment of two goals when YCCI received the Clinical and Translational Science Award (CTSA). The first goal—and the primary reason I wanted to be part of YCCI—was to establish a home for the training of the next generation of clinical and translational scientists. I am convinced that we must provide an environment that encourages the transition from clinician to clinician-scientist in order to have an impact on clinical research. The second goal was the provision of an infrastructure to foster the translation of disease-related discoveries from the laboratory to the clinic and then into the community. Today’s complex regulatory environment, coupled with the availability of sophisticated cutting-edge technology, renders such support invaluable for clinical and translational research. I am proud to say four years later that we’ve come a long way in reaching those goals. I’m especially gratified by the progress we’ve made in educating and training clinical and translational investigators working in a wide array of disciplines. Perhaps the best example of this advance is our YCCI Scholars program, which provides training and mentoring to junior faculty members from the Schools of Medicine, Nursing, Public Health, and Bioengineering. One indication of the program’s success is the track record of its 44 trainees. Collectively, this outstanding group has published 144 papers and received a total of nearly $50 million in independent funding. We’ve also made tremendous progress in establishing an infrastructure for researchers that supports their efforts to translate disease-related discoveries to benefit patients. YCCI’s Office of Research Services provides assistance with study design and protocol development, regulatory approval, biostatistics and bioinformatics, patient recruitment, access to inpatient and outpatient research facilities, financial support, and budgeting. This “onestop shopping” approach, which has markedly lowered the barriers that typically stand in the way of launching and conducting research studies, supported 357 projects and 225 investigators over the last year alone. Beyond the growth in these two areas, we’ve undertaken a number of initiatives to enhance clinical and translational research at Yale. Many of these have involved breaking down silos and bringing together experts from diverse backgrounds—a key factor in the success of clinical and translational research as we move forward. We embarked on an innovative partnership with the School of Public Health to greatly expand support in biostatistics and study design. We created new pilot grants supporting interdisciplinary research and state-of-the-art technologies. The development of integrated collaborations with such other facilities as the Yale 2

YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

Cancer Center has allowed us to share resources, eliminate redundancies, and increase the efficiency of conducting research. We’ve also developed research partnerships among the Schools of Medicine, Nursing, and Public Health directed at improving health in the local community and beyond. I’m pleased by the enthusiasm demonstrated by my colleagues across the medical campus as well as the level of financial and programmatic support we continue to receive from the University and Yale-New Haven Hospital. The School of Medicine has been exceptionally supportive, actively recruiting outstanding faculty members, expanding research facilities, developing new translational programs, and providing funding for our programs and core research resources. All these efforts are paying off; almost $200 million per year of NIH grant support is now directly connected to YCCI. Our collective hard work has positioned us to be the engine driving clinical and translational research at Yale. I fully expect the next five years to bring as many exciting changes as we’ve seen during the first grant cycle. We will build on the experience and lessons of the past four years, expanding the programs that have been successful and developing new ones to meet the growing demands of our clinical and translational research community. As part of our mission to break down the barriers between basic scientists and clinicians, we plan to expand our educational program to reach faculty members in basic science departments who are committed to translational research. We will also be integrating Robert Wood Johnson postdoctoral fellows, MD-PhD students, and PhD students from the “Med into Grad” program into our educational initiatives. The Office of Research Services will continue to spearhead an institution-wide improvement in the support of clinical trials. Our IT investments will include implementation of a newly purchased clinical trials management system to integrate all the elements of clinical trial activity as well as the development of a clinical research data repository. Our plans include developing a research recruitment campaign to increase subject participation in clinical trials; integrating and enhancing the quality of clinical research in additional areas of Yale-New Haven Hospital; and providing investigators with increased access to well-trained research support staff. We will continue to develop partnerships between Yale’s health sciences schools and community organizations and practitioners to expand community-based research and training. We will create new partnerships with other CTSAfunded institutions in the United States and the United Kingdom—University College London and Cambridge University are two examples—to open up new research

We believe that we are well on the way to becoming the bridge linking students, faculty, centers, departments, and schools across the divide separating basic science, clinical studies, and public health research.

opportunities. Support for the development of four new cores in high-throughput cell biology, genomics, smallmolecule screening, and mouse phenotyping on the West Campus will also be a high priority, along with disseminating information about these cores to users. We will also continue to seek opportunities to strengthen basic science and clinical science interactions—an effort that will be spearheaded by Kevan Herold, MD, who was appointed deputy director for translational research last year. It is our mission to be the catalyst for innovative clinical and translational research at Yale. We believe that we are well on the way to becoming the bridge joining students, faculty, centers, departments, and schools across the divide separating basic science, clinical studies, and public health research. ycci.yale.edu

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FROM THE LEADERSHIP

Robert J. Alpern, MD Dean, Yale School of Medicine Promoting clinical and translational research has been and continues to be one of my top priorities and an important component of the School of Medicine’s strategic plan. In 2004, more than a year before the CTSA was announced, I initiated a strategic planning process to evaluate and strengthen the status of clinical and translational research at the Yale School of Medicine (YSM). This process set the stage for transforming the clinical research structure at the school, and was supported at the highest levels of Yale University and Yale-New Haven Hospital. Two major goals that emerged from the strategic planning process were first, to establish a home for training the next generation of clinical and translational scientists; and second, to provide a robust infrastructure that would promote innovative and collaborative research to improve patient care. With the Yale 4

YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

YCCI and the CTSA, working in

concert, have brought together our community of translational researchers, presenting wider opportunities throughout their career development and providing core support that ensures their success.

CTSA and the Yale Center for Clinical Investigation (YCCI)

now in their fifth year, our strategy to leverage and integrate institutional investments and commitments to clinical and translational research has clearly been highly successful. The School of Medicine has made a major commitment to building its research program, including investing in recruiting outstanding faculty; expanding the facilities available for research; and supporting and developing a broad array of research programs. These research areas include a number of such new translational programs as the Yale Stem Cell Center; the Program in Cellular Neuroscience, Neurodegeneration, and Repair; and the Human and Translational Immunology Program. The most recent initiatives include creating five new interdisciplinary research institutes and four new cores on the West Campus to carry out transformative science to advance knowledge of basic biology and human disease. Together with Yale-New Haven Hospital and the Yale Medical Group, we are moving to align medical science more closely with clinical care, building on a long tradition of excellence that began with the founding of the School of Medicine two centuries ago. The goal is to extend the scope of our research in close association with expanding programs of patient care. We are supporting several major initiatives with Yale-New Haven Hospital that will have a major impact on our translational research capabilities. These include joint purchase and implementation of IT systems to enhance clinical research; joint support of personnel and space for YCCI’s hospital research unit; and joint support of the clinical trials office and infrastructure needed to manage our robust research enterprise in an efficient, effective, and compliant manner. Bringing together faculty and programs at the School of Medicine, School of Nursing, School of Public Health, and Yale-New Haven Hospital has greatly strengthened YCCI’s training programs and stimulated interdisciplinary research. One measure of success is the Junior Scholars program, whose trainees have obtained approximately $47.5 million in funding since it began—a demonstration of YCCI’s successful mentorship program and a reflection of the improved infrastructural support for research. Because YCCI is critical to achieving our broader strategic goals, YSM has made a significant commitment to its development during the current grant cycle. Overall, we have contributed $70 million to support YCCI’s administration;

biomedical informatics; educational programs and trainees; communitybased research and engagement; the Office of Research Services and YCCI’s regulatory and clinical structure; biostatistics and study design support; and YCCI-related research cores. We plan to continue supporting these initiatives during the next funding period with a commitment of approximately $101 million. These figures do not include $100 million already committed to renovate additional clinical and translational research space. YCCI is involved in a planning process to evaluate the space requirements of the Yale Medical Group to better serve our patient population—a source we draw on to meet accrual requirements for clinical trials. Of note is YCCI’s inclusion in the capital campaigns of both YSM and the University; Yale is actively encouraging donors to support clinical and translational research, specifically citing the need to fund infrastructure and training for young investigators. I am convinced that our integrated approach has allowed Yale to advance clinical and translational research effectively, comprehensively, and expeditiously. The School of Medicine remains committed to this vision, designed to foster the translation of disease-related research from the laboratory into the clinic and on into the community. With the ongoing support of the CTSA and the commitment of additional institutional resources, Yale is well positioned to continue its high level of scientific achievement and to translate these discoveries into new therapeutic approaches that benefit patients.

FROM THE LEADERSHIP

Marna Borgstrom President and CEO, Yale-New Haven Hospital The goals of Yale-New Haven Hospital (YNHH) have much in common with those of YCCI. YNHH provides high-quality patient care while YCCI aims to improve patient care by reducing the time required to translate laboratory discoveries into clinical treatments. YNHH prides itself on being a topnotch teaching hospital and offering training opportunities for nurses and other health care professionals while one of YCCI’s main missions is training the next generation of clinical and translational researchers. YNHH provides a setting for ongoing clinical research that brings medical care from the laboratory to the patient’s bedside while YCCI provides infrastructure to investigators and works with other ctsa sites to improve the conduct of biomedical research. Both organizations are dedicated to serving the community: YNHH as a public health advocate and responding to the community’s health care needs, and YCCI by engaging the community in clinical research efforts. Our partnership has reached a new level since the ctsa was awarded in 2006, and YNHH has demonstrated its support in a variety of ways. Teaching hospitals like YaleNew Haven Hospital attract the best and brightest minds in medicine. Experienced medical practitioners guide the next generation of researchers and health care providers to the discovery of new cures and treatments. One of our highest priorities is collaborating with the School of Medicine to recruit outstanding clinician-investigators to join our already renowned team. We have also provided seed funding for clinical research nurses and data analysts to assist newly recruited faculty. YNHH senior executives and its chief medical officer have served on YCCI’s executive committee and participated in annual strategic planning retreats, as well as attending meetings of the external scientific advisory board and sharing in the overall governance of YCCI. We provide space, ancillary, and financial support for the YCCI hospital research unit, which conducts high-quality nih-funded patient-based research; and we offer reduced clinical research fees for ancillary hospital services. We have also joined the School of Medicine in supporting the expansion of the clinical trials office as well as substantially contributing to the infrastructure costs of YCCI in conjunction with the Yale Cancer Center. 6

YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

We have partnered most recently with the School of Medicine and YCCI to enhance our IT infrastructure and find a solution to satisfy the medical school’s investigative needs along with the hospital’s clinical requirements. These efforts have included extensive evaluation of our joint requirements, leading to the selection of Epic Systems as a software vendor. We recently signed a multiyear contract with Epic to implement an electronic health record (EHR), and jointly recruited a new chief medical information officer to oversee the process. Our vision of the ehr is that it will be more than a technology to assist health care delivery; it will also provide an opportunity to capture information about our patients and combine it with the vast amount of research information available from the School of Medicine. To that end, we are jointly supporting the newly purchased clinical trial management system to integrate all components of clinical trial activity. We are also involved in planning a clinical research data repository that will allow us to extract information from research and return it to patients with the goal of improving their health care.

Our partnership with the School of Medicine and YCCI is an unparalleled opportunity to unite state-of-the-art clinical care, training, and scientific advancement in the development of new treatment approaches that benefit patients.

YCCI has helped YNHH by facilitating nursing research support and providing training and educational opportunities that we hope will lead to attaining hospital magnet status. This accomplishment will signify that we have met stringent quantitative and qualitative standards defining the highest quality of nursing practice and patient care. In the coming years, we will continue to work with YSM and YCCI to explore new ways of supporting hospital-based research and to maintain an environment that fosters cutting-edge clinical care, training, and scientific advancement.

FROM THE LEADERSHIP

I believe that multidisciplinary and translational research is critical to solving serious health problems.

Margaret Grey, DrPh, RN, FAAN Dean, Yale School of Nursing

The School of Nursing has been an active participant in the development and efforts of YCCI over the past four years, and I’m delighted by our accomplishments so far. Partnering with YCCI has helped ensure that the biobehavioral, behavioral, and community-based research that has long been our strength is cutting-edge and translated to improve the health of our communities. We have worked with YCCI to enhance communitybased research efforts, particularly NetHaven—a practicebased research network originally developed by the School of Nursing and expanded with the support of YCCI. NetHaven’s mission is the promotion of a practice-based interdisciplinary network of health care providers that conducts research relevant to clinical practice in diverse settings; develops culturally competent, evidence-based models of care; and 8

YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

enhances the translation of research findings into community practice. NetHaven’s major partners are the School of Nursing; Yale-New Haven Hospital; Yale University Health Services; YCCI; and community clinical practices, including the Fair Haven Community Health Center, the Cornell Scott Hill Health Center, and the Yale-New Haven Community Medical Group. Together these organizations represent approximately 800 health care providers and 210,000 racially and ethnically diverse consumers, many of whom are socioeconomically disadvantaged. Collaboration with YCCI has enabled us to expand this network to include additional providers from many disciplines and wider cooperation with academic health scientists. YCCI’s educational component has also been essential to the development of three of our faculty members, who are pursuing clinical research projects and have benefited greatly from the training and mentorship offered by the center. The concept of interdisciplinary research is appealing but the reality is sometimes difficult to achieve. YCCI has lowered long-standing barriers to true interdisciplinary research at Yale, especially in regard to clinical research and research training. Clearly this cooperation is beneficial not only to Yale but also to the health of the public at large. YSN faculty members have served on review committees and in leadership positions for such YCCI programs as the Community Alliance for Research and Engagement (CARE). I personally serve as a mentor and participate on the YCCI career oversight and executive committees, which has ensured that clinical research is pursued from diverse perspectives. During the next grant period, I look forward to expanding our joint work with YCCI because I believe that multidisciplinary and translational research is critical to solving serious health problems.

I’m confident that our combined efforts will continue to have an impact on the health of individuals in the surrounding community and beyond.

Paul Cleary, PhD Dean, Yale School of Public Health

The Yale School of Public Health (YSPH) has a rich history of research collaborations with faculty throughout the Yale community as well as with other institutions around the country and the world. We have worked increasingly closely with YCCI over the past four years, substantially expanding our research collaborations and educational activities in the School of Medicine. One important area of clinical and translational research—one in which we have made important improvements—is biostatistics and study design. This past year, the School of Public Health and YCCI established the Yale Center for Analytical Sciences (YCAS). YCAS provides a central organizational home for biostatisticians and experts in other analytic sciences—for example, those in outcomes research, decision analysis, and cost-effectiveness analysis— who are dedicated to facilitating and collaborating in the design, conduct, and analysis of clinical and translational research. YCCI and YSPH jointly recruited Peter Peduzzi, PhD, to head the new program. Peduzzi has more than 30 years of experience in the design, conduct, and analysis of clinical trials. YCAS is rapidly gaining support from departments, centers, and programs throughout the Schools of Medicine, Nursing, and Public Health. For example, the Yale Cancer Center (YCC) has situated its biostatistics core within the center. This new model for providing support and facilitating cooperation has also fostered multidisciplinary collaborations in a more effective and efficient manner than was previously possible. This efficiency in turn has resulted in a significant

increase in the number of consultations, publications, and grant preparations related to YCCIsupported research. YCCI and the School of Public Health have collaborated in a number of other areas as well. The YCCI Scholars program has funded four junior faculty members in the School of Public Health who are conducting translational research projects that will contribute greatly to our understanding of the causes of cancer and cardiovascular disease. The School of Public Health is helping YCCI advance its goals in community-based research through the support of the Community Alliance for Research and Engagement (CARE), which has made tremendous gains in improving communication between Yale research faculty and the New Haven community. This cooperative venture has led to a new level of trust, support, and enthusiasm for community-based research. Several members of the School of Public Health serve in leadership roles for YCCI, including the co-director of CARE. The School also participates on YCCI’s executive committee, which has been beneficial in coordinating our joint strategic activities. There is no question that by collaborating in these ways YCCI and YSPH have been able to support and conduct more translational research than if they had worked independently. Furthermore, we are already laying the groundwork for such future projects as the development of a statistical coordinating center to support a comparative effectiveness research program. Such a center has been identified as a critical need by YCCI and the Schools of Medicine and Nursing, as well as YCC. We are also seeking ways, along with YCCI and the School of Nursing, to invest in increasing our capacity for conducting community-engaged research and address minority recruitment in clinical trials. I’m confident that our combined efforts will continue to have an impact on the health of individuals in the surrounding community and beyond. ycci.yale.edu

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TRANSLATIONAL SCIENCE

Moving Science Forward

Combining basic science and cutting-edge approaches to cure disease

A model of a rare mutation in HDC, identified by a team led by Matthew State, MD, PhD, the Donald J. Cohen Associate Professor in the Yale  Child Study Center and in the departments of psychiatry and genetics. The study, which was published online May 5, 2010, in The New England Journal of Medicine, points to a potentially novel approach to treatment of tic disorders and Tourette syndrome.

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Yale is strongly committed to translating scientific discoveries from the laboratory to the clinic. With this goal in mind, YCCI has co-invested with the School of Medicine (YSM) to acquire platforms and technologies paving the way for the development of new diagnostic and therapeutic strategies. These resources, which are available to CTSA-supported investigators and in some cases directly supported by CTSA funds, foster such cutting-edge approaches as high-tech imaging of human tissues and organs, and mapping of genes related to disease. Mining Genes to Treat Disease Yale opened a center for genome analysis on its new West Campus in 2009, equipped with state-of-the-art Illumina instrumentation funded in part by the CTSA. Among the Genome Center’s rapidly expanding group of users, five faculty members in Yale’s neurogenomics program were recently awarded Grand Opportunities arra grants, designed to support large-scale high-impact projects to accelerate critical breakthroughs. These neurogenomics projects are attempting to provide a clearer understanding of neurological and psychiatric disorders from a genetic perspective. They include:

By leveraging the CTSA and the School of Medicine’s investments, we have been able to translate discoveries from our already strong basic science program into new therapeutic approaches.

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A study by David Hafler, MD, professor of neurology and immunobiology, of genetic risk factors for multiple sclerosis (MS), using the largest available collection of samples from MS patients. To date, genome-wide association studies of MS have focused on relatively common genetic variants that increase the risk of the disease. Leveraging the high-throughput power of the Illumina platform, Hafler will probe the role of rare variants in MS. This approach is increasingly regarded as a highly productive avenue for mapping genes in order to identify molecular and cellular mechanisms that will lead to targeted therapies.

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A project headed by Murat Gunel, MD, the NixdorffGerman Professor of Neurosurgery and Genetics, to sequence the complete protein coding regions in 250 families with structural brain disorders implicated in autism, epilepsy, and mental retardation. This study builds on Gunel’s recent work using whole-exome sequencing to show that mutations in a single gene critical to the development of the cerebral cortex can cause a number of brain deformities.

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A study by Matthew State, MD, PhD, the Donald J. Cohen Associate Professor in the Child Study Center, to take a close look at rare variants of two genes— CNTNAP2 and PCLO—that play a role in autism spectrum disorders. In addition, State recently used the CTSA-funded Sequenom system to conduct an snp genotyping analysis of a rare family in which the father and all eight children have Tourette syndrome. All carry the same mutation in hdc, a gene involved in histamine synthesis. Clinical trials are already under way to study the effect of histamine-modulating drugs on neuropsychiatric conditions, and State hopes to test their effectiveness in treating Tourette syndrome in the near future.

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 project by Nenad Sestan, MD, PhD, associate professor A of neurobiology, to compile a comprehensive atlas of gene regulation and expression in multiple regions of the human brain as it develops from the earliest embryonic stages to adolescence and adulthood.

Using the Immune System to Fight Cancer YCCI recently added a category for faculty members in basic science

departments who are collaborating with clinical investigators as part of a comprehensive review of its pilot award program. The first award in this new category was given to David A. Spiegel, md, phd, assistant professor of chemistry, for a project to develop small-molecule immune modulators for diagnosing and treating prostate cancer. Spiegel’s lab has already developed a class of molecules called antibody-recruiting molecules targeting prostate cancer (arm-ps), and demonstrated that the molecules bind simultaneously to antibodies in the bloodstream and a protein on the surface of prostate cancer cells, flagging them as a threat to be attacked by the body’s immune system. The pilot award will allow Spiegel to evaluate the efficacy of this novel therapeutic strategy in mice, preparing the way for treatments that may eliminate side effects related to nonhuman recombinant antibody proteins. Such treatment might also have the potential to induce long-lasting immunity against cancer. Spiegel’s study is particularly well suited to ctsa support because it is an interdisciplinary undertaking involving four different disciplines and represents a new molecular approach to treating prostate cancer.

TRANSLATIONAL SCIENCE

From l to r, Shrikant Mane, PhD, co-director of the Keck Biotechnology Resource Laboratory and director of the Center for Genome Analysis; Kenneth Williams, PhD, co-director of the Keck Biotechnology Resource Laboratory; Can Bruce, PhD, associate director of the Keck Bioinformatics Resource.

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 he use of both Affymetrix and Illumina microarrays in T a genome-wide association study of cocaine dependence by Joel Gelernter, MD, Foundations Fund Professor of Psychiatry.

Thomas Lynch Jr., MD, who was appointed director of the Yale Cancer Center in 2009, has long recognized the importance of genetic analysis and molecular profiling in the treatment of cancer. Lynch pioneered the use of molecular testing for mutations in the epidermal growth factor receptor gene to select patients who can benefit from targeted lung cancer therapies. Expanding this avenue of research is central to his vision for the cancer center. His plans for personalized medicine at Yale are closely linked to the newly created cancer biology institute on the West Campus, which will focus on such rapidly emerging areas of basic and translational research as cancer genetics and genomics, signal transduction, and tumor immunotherapy. Adding Depth through Tissue Banking Traditionally, many clinical investigators at Yale and other academic medical centers have maintained their own collections of blood and tissue samples, which often limits the scope and pace of their research. This limitation will be resolved with the implementation of a clinical trial management system (CTMS). Negotiations are currently under way to finalize a contract with a CTMS vendor whose platform includes a tissue-banking module that will add tremendous depth to research conducted at Yale. The new system will link to Epic, the new electronic health record (EHR) system, to create a comprehensive system for organizing and tracking blood and tissue samples. “This 12

YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

system will open new avenues for investigators by providing access to the vast collection of samples that are available at Yale,” said Kevan Herold, MD, YCCI’s deputy director for translational science. Access to the large volume of samples routinely collected across the medical center is an important step in accelerating the pace of clinical and translational research. It also opens the possibility of being able to work with other CTSA sites in the future to share access to biorepositories. Implementing the CTMS across the entire medical center is expected to take approximately 18 months; in the meantime, YCCI is providing resources and expertise to the Yale Cancer Center’s Thoracic Oncology Program (TOP) for a new lung cancer biorepository program. This program will enroll all lung cancer patients treated at Yale. It will also include samples from patients at risk for lung cancer who undergo biopsies and surgical resections that are found to be benign. Tracking and storing these samples and linking them to clinical information available through TOP will expand Yale’s capacity to develop targeted therapies for lung cancer. One example of this type of research was published in Clinical Cancer Research in 2009 by Lynn Tanoue, MD, professor of medicine, in collaboration with David Rimm, MD, PhD, professor of pathology. Tanoue and Rimm are examining tissue from the tumors of lung cancer patients with a particular gene signature in order to determine whether the protein products of those genes can be used to differentiate patients with lower survival rates due to more aggressive disease. Identifying these patients as early as possible could dramatically alter the course of their treatment during the initial stages of the disease when treatment is more effective. This molecular tool might also be used to help prevent lung cancer in high-risk patients.

Technologies to Unravel Cellular Mechanisms Rimm also heads the tissue microarray division of Yale Pathology Tissue Service, one of the largest collections of tissue microarrays in the country. The microarrays are used for quantitative measurements of protein expression in cells and subcellular compartments. They are also linked to a database that collects clinical information from the Yale Tumor Registry, making them even more valuable to researchers within the cancer center, as well as scientists in other departments conducting preclinical and translational studies. Another effort aimed at improving the access of clinical and translational scientists to technologies essential for their research includes merging Yale’s flow cytometry core with the immune monitoring core that was established with support from the CTSA. The ability to sort cells according to their molecular characteristics has revolutionized clinical and translational studies because analyses can be carried out on virtually any cell that can be placed in a fluid stream. Flow analysis has also become widely used in clinical trials by making it possible to monitor the effects of immune modulators and markers of clinical response. In addition to his studies on rare variants in MS, David Hafler, MD, professor of neurology and immunobiology, has recently developed a robotic platform to improve the throughput and reproducibility of assays developed by Yale investigators working on human studies. The platform will perform standard cell surface staining as well as activation

One measure of how the Yale CTSA is moving science forward is the fact that 107 studies linked to CTSA support have been published in leading peer-reviewed journals since receiving the award in 2007. Of these, 13 have been published since July 2010 in Cell (1), Journal of the American Medical Association (1), Proceedings of the National Academy of Sciences (5), Nature (3), Science (2), and Nature Medicine (1).

studies to analyze intracellular cytokine production and signaling molecules. The new technology will increase both the accuracy and capacity of these studies by processing thousands of samples in a uniform manner. While the flow core has historically been used for research in mice, the immune core is intended for research involving humans and is equipped for the demands involved in handling human cells. Consolidation of the two cores will provide an administrative link for all of Yale’s flow cytometry services and give investigators access to a full range of instrumentation and expertise. The new combined core is expected to serve as many as 40 interacting research groups and will function as the hub of clinical and translational immunology at Yale. “Our hope is to build a bridge from basic science to the clinic,” said YCCI director Robert Sherwin, MD. With the support of the CTSA, Yale will continue to invest in stateof–the-art technologies and foster collaboration among basic scientists and clinical investigators to develop promising new treatments for disease. ycci.yale.edu

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FROM THE LEADERSHIP TRANSLATIONAL SCIENCE

Insights into Human Biology

CTSA investments in the latest gene sequencing tools are allowing scientists like Richard Lifton, MD, PhD, (far left) to find rare genetic variants that contribute to disease in ways that were impossible just a few years ago. For example, in a study published in the August 7, 2009 issue of Cell, Lifton and Jesse Rinehart, PhD, associate research scientist in genetics, led a team that used innovative quantitative proteomics technologies to show how a protein within most cell membranes maintains normal cell size — a breakthrough that has implications for a variety of diseases, including sickle cell anemia.

Yielding clinical breakthroughs In the mid-1990s, Richard Lifton, MD , PhD , and his colleagues used classical methods to identify five genes controlling a single common pathway that regulates salt handling in the kidney. The team went on to show that mutations in these genes affect salt reabsorption and are thus critical to the body’s regulation of blood pressure. This discovery led to such changes in treatment as combining diuretics with ace inhibitors and reducing sodium intake— currently the gold standard in controlling hypertension. It’s difficult to find a better example of the ways in which elucidating molecular pathways has the potential to lead to new approaches to treating disease. Lifton, Sterling Professor and chair of the department of genetics, is continuing to pursue this line of inquiry along with other Yale investigators. The research is now being driven by spectacular advances in DNA sequencing. The ability to find and rapidly identify common variants via SNP genotyping has yielded insights into the mechanisms of many diseases over the last five years. Murat Gunel, MD, professor of neurosurgery, and his collaborators including 14

Lifton have used this approach to identify genes associated with increased susceptibility to intracranial aneurysms—a devastating neurologic disorder that is often fatal or severely debilitating. The team’s laboratories identified six genes that contribute to the risk of this condition in a large genome-wide association study. This work, which was made possible with instrumentation funded by the CTSA, represents the first molecular insights into the pathogenesis of intracranial aneurysms; it has the potential to identify people at risk for developing the disorder. Sometimes investigators identify genes whose role in disease is unclear, making it necessary to unravel the underlying biology. That was the case in a group of genes encoding wnk kinases, a type of enzyme identified in families of patients with a unique combination of hypertension and high serum potassium levels. Using CTSAfunded quantitative proteomics technologies available in the Keck Biotechnology Resource Laboratory, Jesse Rinehart, PhD, associate research scientist in genetics, went on to show that wnk kinases also regulate intracellular volume. Rinehart and his colleagues identified phosphorylation sites that switch potassium chloride cotransporter proteins on or off in response to environmental changes, thereby causing water to move into or out of the cell. This breakthrough discovery has implications for a variety of diseases including sickle cell anemia, in which improper regulation of cell volume is believed to be one of the events that precipitate sickle cell crisis. Spectacular advances in high-throughput dna sequencing have now led to the

YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

ability to identify rare genetic variants that offer clues about the causes of disease. In 2010 the Lifton group succeeded in making the first new clinical diagnosis based on highthroughput whole-exome dna sequencing of the entire set of protein-coding genes. In a matter of days, they analyzed 34 million base pairs in a five-month-old Turkish infant and discovered a mutation in both copies of the gene associated with congenital chloride diarrhea—a rare birth disorder in which the gastrointestinal tract fails to properly absorb chloride and water. Yale has since used whole-exome sequencing to demonstrate that mutations in a single gene critical to the development of the cerebral cortex can cause a number of brain deformities that were previously thought to be unrelated. Using instruments funded by the CTSA, Gunel and his colleagues discovered mutations in both copies of the WDR62 gene in two cousins from Turkey who were born with underdeveloped cerebral cortices and other deformities. The team later identified six additional families with the same mutations. This discovery is a major advance in understanding the growth and normal function of the cerebral cortex. Lifton and Keith Choate, MD, PhD, assistant professor of dermatology, have used CTSA-funded instrumentation to map and identify disease-causing mutations in a rare skin disease, ichthyosis with confetti, characterized by normal patches of skin interspersed with diseased areas. In these patients, the normal tail end of a critical protein is replaced by a protein sequence that causes it to end up in the wrong part of the cell. The areas of normal skin then result from the recombination of chromosomes prior to cell division. Lifton and Choate believe that this process contributes to both the severity of the disease and the appearance of clones of normal skin cells. They hope the discovery will lead to a way of mimicking this process to develop treatments for other genetic diseases. While identifying common variants has yielded promising results for intracranial aneurysms and IgA nephropathy, it explains almost none of the variations in blood pressure in the general population. In collaboration with the Framingham Heart Study, Lifton conducted a study showing that rare variation in genes previously identified as linked to forms of high and low blood pressure play a significant role in blood pressure variation. The two percent of the population that carries a particular mutation in one of these three genes has lower blood pressure at age 60 than those without the mutation—with a 60 percent reduction in risk of hypertension. “We can explain more of the variation in blood pressure in the population from rare variants in just these three genes than have been explained by the common variants in 100,000 individuals,” said Lifton, who is currently working on another study to look for rare variants in a large cohort of patients with blood pressure at both ends of the spectrum. He has thus far sequenced over 400 whole exomes, and reports that potential genes are already emerging. In the meantime, genetic studies of infants with severely low blood pressure are yielding promising results. Lifton

In a study published in the September 9, 2010 issue of Nature, Lifton collaborated with a team led by Murat Gunel, MD, professor of neurosurgery, to identify mutations in both copies of the WDR62 gene in two cousins from Turkey who were born with underdeveloped cerebral cortices and other deformities. The results are a major advance in understanding brain development.

and his colleagues have identified a rare genetic mutation in a new potassium channel that could serve as a novel target for hypertension. Antagonists of this channel have been manufactured by the pharmaceutical industry and are now in clinical trials in humans. This development illustrates the completion of a loop that begins with clinical observation of a rare disease, progresses to the clarification of its pathophysiology, and leads to the development of new therapies relevant to the general population. By supporting genomic studies of this kind through the purchase of state-of-the-art instrumentation, the Yale CTSA is making significant contributions to research and training at the very forefront of American medicine.

The nano-electrospray ionization source front end of a ctsa-funded ab qtrap 4000 triple quadrupole mass spectrometer system, used to quantitate the state of protein phosphorylation.

ycci.yale.edu

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CLINICAL SCIENCE

Translating Science into Clinical Practice Moving discoveries from the laboratory to the patient quickly and efficiently

Jeffrey Gruen, md, professor of pediatrics and associate professor of genetics and of investigative medicine, in his lab with postdoctoral fellow Anastasia Wise and graduate student John Eicher where they conduct research on the genetics of dyslexia.

“Our investment in the infrastructure and facilities to support innovative clinical and translational research enables us to provide outstanding patient care that is at the forefront of medicine.” Peter Herbert, MD, chief of staff and senior vice president, medical affairs, YNHH

Yale has been engaged in clinical research since the early 1940s, when a group of scientists discovered that nitrogen mustards, close relatives to the mustard gas used as a weapon in World War I, killed lymphoma cells in mice—ushering in the dawn of chemotherapy. YCCI was created to continue this tradition by moving discoveries from the laboratory to patient settings as quickly and efficiently as possible. Under the ctsa, YCCI is investing in Yale’s resources and creating an expanded robust infrastructure to support investigators—strategies conducive to novel approaches to treating disease. From Theories to Treatments Kurt Roberts, md, assistant professor of gastrointestinal surgery, is performing groundbreaking procedures using a device he developed with the help of a ctsa-funded pilot award for the development of novel clinical and translational methodologies. The device facilitates single-incision laparoscopic surgery (sils) and natural orifice transluminal endoscopic surgery (notes) to give the surgeon access to the abdominal cavity. Roberts has used these techniques to perform pioneering appendectomies and gallbladder surgery using a minimum number of incisions, with lower risk of postoperative complications and a much easier and faster recovery period for the patient. “I am pleased that YCCI is able to participate in helping a Yale clinical scientist translate his academic research from the lab directly into better patient care,” said YCCI director Robert Sherwin, md. Yale’s Office of Cooperative Research recently helped spin off a medical device company to commercialize the new device so that it can be more widely adopted in this rapidly growing field. Diabetes is another area in which research results are being translated into improved treatment. Researchers know that diabetes affects not just the beta cells in the pancreas but also causes changes that adversely affect the functions of liver and muscle tissue. At the same time, there is an ongoing debate about how the drugs used to treat diabetes work. Gerald Shulman, md, phd, George R. Cowgill Professor of Medicine, is trying to uncover the root causes of the cellular mechanism that causes insulin resistance—the metabolic dysfunction at the core of Kurt Roberts, MD, assistant professor of gastrointestinal surgery, prepares for surgery in which he will use a device he developed with the help of a CTSA-funded pilot award. The device facilitates single-incision laparoscopic surgery (SILS) and natural orifice transluminal endoscopic surgery (NOTES) to give him easy access to the abdominal cavity. ycci.yale.edu

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CLINICAL SCIENCE

type 2 diabetes—in order to develop new ways to target and treat the disease. Thanks to ctsa-supported upgrades at Yale’s world-class Magnetic Resonance Research Center, Shulman was able to use magnetic resonance spectroscopy to create chemical profiles of muscle tissue without having to perform a muscle biopsy, a considerably more invasive procedure. His group found that insulin resistance in muscle is caused primarily by defective insulin-stimulated glucose transport. In the liver, increased synthesis of glucose from amino acids and lactate is the main cause of hyperglycemia in type 2 diabetes. In a novel unifying hypothesis of insulin resistance, Shulman and his colleagues have proposed that an imbalance between the delivery and oxidation of fatty acids in liver and muscle cells causes biochemical changes that block insulin signaling.

2008 YCCI Scholar Robert Douglas Bruce, MD, MSC, MA, assistant professor of medicine and epidemiology, examines a patient in YCCI’s Hospital Research Unit for his research on integrating hepatitis C treatment with methadone maintenance therapy. 18

He and his collaborators have also identified two common genetic variants that predispose patients to nonalcoholic fatty liver disease and insulin resistance, providing new insights into the gene-environment interactions that promote the development of type 2 diabetes. Shulman’s work is pointing to new drug targets as well as exercise and dietary strategies to “melt fat away” from liver and muscle. This treatment could reverse insulin resistance, thereby preventing type 2 diabetes. “Just about every drug that we currently have to treat type 2 diabetes was discovered serendipitously, and just treats the symptom of diabetes: hyperglycemia,” Shulman said. “Now that we are beginning to understand the cellular mechanisms of insulin resistance, which is at the root of type 2 diabetes, we will have better therapeutic targets.” Besides insights into the mechanism of insulin resistance, Shulman’s work has led to the development of a noninvasive method of measurement that is now the gold standard for quantifying liver fat in humans. Alcohol and tobacco dependence are two conditions that also take a large toll on health. Unlike other drugs whose biomarkers of their metabolites are present in the urine or blood for several days, alcohol is cleared from the body within a few hours. As a result, clinicians have had to rely on such imperfect indications as liver function tests to measure alcohol dependence. Stephanie O’Malley, phd, professor

Under the CTSA, YCCI is expanding and investing in Yale’s resources and creating a robust infrastructure to support investigators and strategies that are leading to novel approaches to treating disease. of psychiatry, is conducting a study funded by the National Institute on Alcohol Abuse and Alcoholism (niaaa) on ethyl glucuronide (EtG), a promising new biomarker for ethanol use that is highly specific, highly sensitive, and detectable in the body for a longer period of time than ethanol, having a half-life of 20 hours. Results of this study will be combined with the results of two parallel clinical trials with the ultimate goal of developing guidelines for EtG measurement and use of this biomarker in clinical practice. Helping Investigators Navigate Today’s Research Landscape The work of these clinical investigators highlights a few examples of advances in treatment that are being made possible under the ctsa. This ability to bring disease-related discoveries to patients has been enhanced by the robust infrastructure and expansion of clinical research facilities that YCCI has undertaken to support innovative clinical and translational research throughout the Schools of Medicine, Nursing, and Public Health. The current stringent regulatory environment coupled with progressively more sophisticated analytical tools and the need to ensure the safety and effectiveness of clinical studies have combined to form a complex maze that is difficult for investigators to navigate on their own. YCCI’s response to this situation has been to create the Office of Research Services (ors). Services provided by ors represent a vast enhancement of those previously provided by the former gcrc system, which focused on hospital-based facilities needed to carry out approved study protocols. Support from the institution and the ctsa has allowed YCCI to move well beyond the capabilities of the gcrc. In fact, YCCI isn’t the gcrc with a new name—it’s an entirely new organization with a much more diversified mission. While the gcrc was charged with providing settings for medical investigators to conduct clinical trials, YCCI is charged with transforming the ways in which clinical and translational research is conducted. ors provides the comprehensive resources investigators require to move from study concept to completion as rapidly, efficiently, and safely as possible. The support it offers allows the University to be more competitive in obtaining extramural funding, including industry investment in translational research for new drugs and devices. ors brings together a wide range of support expertise, functioning as the centerpiece of research services across the medical campus. With 24 staff members and 11 units,

real faces of our research The Rosenfeld family agreed to be interviewed for our advertising campaign because they strongly believe that clinical trials are the key to developing new treatments for diseases. When 10-year-old Hannah was diagnosed with type 1 diabetes mellitus in 2008, her mother Amy immediately looked for a clinical trial that offered treatment beyond the present standard of care because she was terrified when her child was found to have a lifelong life-threatening disease. Hannah was enrolled in a trial run by Kevan Herold, md, for a new drug that offers the promise of keeping the beta cells in the pancreas intact for newly diagnosed type 1 diabetes patients. The Rosenfelds speak highly of the care they received at Yale and the attention given Hannah by the medical staff both during and after the study. Hannah finished that trial and completed a second one; the rest of the family is now enrolled in TrialNet, a natural history study of the development of type 1 diabetes. When Hannah was enrolled in the first trial, Amy was concerned solely with its potential benefit to her daughter; three years later, she is able to view the larger picture. “I think research is really important and it’s the only way things are going to change,” she said. “Look at what research has done. Look at the diseases research has eradicated. Maybe diabetes could be the next one— but it will never happen if there’s no research.”

CLINICAL SCIENCE

it provides assistance from the early stages of protocol development, budgeting, and regulatory approval through the conduct of the study itself. Its units include grant development, biostatistics/study design, bioinformatics, protocol development, budgeting and financial management, industry contracting, ind assistance, patient recruitment, human subject advocate programs, and clinical research resources and facilities—including both a hospital-based research unit and an outpatient research unit. The services initially integrated into ors were identified through a strategic planning process completed in 2006, but they have been continually refined as a result of feedback from the user community, changes in federal regulations, institutional needs, and best practices disseminated through the ctsa consortium. The ors has marked significant increases in the number of protocols and new investigators supported since opening its doors: It supported 357 projects and 225 investigators during the past grant year—an increase of about 100 percent over the previous grant year. One example of the ors’s impact is that the budget unit has been able to obtain an increase of 49 percent in the total dollars contracted for industry-sponsored studies as well as an increase in the average startup costs negotiated for these studies—from about $1,300 to $19,000 per trial. YCCI has made it a priority to reduce the barriers to initiating studies through the work of the ors. One important accomplishment has been a major overhaul of the

protocol review process. By eliminating the redundancies that previously existed between review by the former gcrc and its general advisory committee and working with the irb, the average time to study approval has been reduced by 35 days. The addition of trained regulatory staff who work with investigators to prepare better submissions and the implementation of the new Coeus irb electronic system for protocol approvals have also been important factors in reducing barriers to study initiation. Since YCCI’s inception, we have sought to break down research silos, promote interdisciplinary collaboration, and leverage resources to maximize efficient use of research dollars. One of the ways we are doing this is by establishing collaborations among Yale’s nih centers. This undertaking has been both challenging and rewarding. One of our first and most successful collaborations has been with the Yale Cancer Center (ycc), a logical partner because of its similar needs and infrastructure. Our joint endeavors include recruiting and hiring a clinical trials director; merging ind support, research IT, regulatory, budgeting, contracts and education/training services for both centers; launching a statewide cancer clinical

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YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

institutional review board

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recruitment/marketing

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pediatrics cancer radiation research recombinant dna molecules

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trials network to accelerate the development and translation of innovative cancer therapies for Connecticut residents; and co-investing in shared core resources. Refining and Creating Research Facilities There is no doubt that the former gcrc, which is now known as the Hospital Research Unit (hru), is crucial to furthering Yale’s clinical research enterprise. This facility, located at Yale-New Haven Hospital, plays a central role in advancing clinical research at Yale by ensuring optimal patient care and safety for moderate- to high-risk studies. Well known for its skilled nursing staff, the hru supports many nih-sponsored intensive research studies. It is in great demand by a large contingent of well-funded investigators from numerous departments conducting high-impact clinical studies. Although the gcrc had many elements that functioned well, one of YCCI’s tasks has been to examine the efficiency with which clinical research is conducted. A targeted review of the hru by external advisors from other ctsa sites resulted in an in-depth efficiency evaluation by Carpedia International, a consulting firm with deep expertise in evaluating similar facilities. Carpedia worked directly with unit managers to address inefficiencies and reduce labor expenses. The project was challenging because it required change management at all levels, but the result is a “leaner and meaner” inpatient research unit poised to continue Yale’s longstanding track record of high-quality nih-funded patient-based research.

A team meets monthly to devise innovative ways of reducing the time it takes to finalize contracts in order to get studies off the ground more quickly. From l to r: Tanisha Asbery, senior grant and contract administration (GCA) Manager; Michael Glasgow, executive director, GCA; Donald Deyo, director, clinical trials, GCA; Henry Durivage, PharmD, associate director for clinical trials, YCCI

The hru offers investigators core laboratory services and a bionutrition unit, which played an important role along with its expert nursing staff in the research of both Shulman and O’Malley. Shulman relied for his metabolic research on diabetes on the hru for overnight studies, during which he employed the bionutrition unit to control food intake and the core lab to analyze blood samples. These services also helped O’Malley implement studies on EtG. During patients’ overnight stays in the hru, they consume menus devised to minimize variability in alcohol absorption, while the core lab is used to measure levels of EtG both during and after hospitalization. O’Malley has also used the bionutrition unit in studies examining whether food deprivation undermines a smoker’s ability to resist smoking. Such studies would not be feasible without the ability to carefully monitor patients. While the hru is focused on complex inpatient studies, YCCI also recognized the need for a facility for investigators conducting low-risk outpatient studies. To accommodate this need, YCCI opened the Church Street Research Unit (csru), which is located on the medical campus near the ycci.yale.edu

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CLINICAL FROM THESCIENCE LEADERSHIP

highway and provides a pleasant environment conducive to clinical research. Clinical exam rooms, a phlebotomy room, and meeting rooms make it an ideal choice for studies that do not require the specialized resources provided by the hru. Together, the hru and csru provide research resources for 225 study protocols involving 97 investigators from across the institution. YCCI also offers investigators the services of a group of experienced and well-trained support personnel employed and managed by YCCI who have access to the appropriate structure, management, and ongoing training needed to

implement and support the researchers’ studies in a safe and efficient manner. Having these personnel as members of YCCI limits an investigator’s risk, allowing for the possibility of contributing portions of staff salaries at the level and effort needed, and providing an economical solution that eliminates some of the issues confronting investigators in finding parttime staff. Marketing Yale to Study Volunteers ors is investing considerable resources to help investigators

recruit study participants in order to allow them to meet

Bioengineering Vessels for Heart Surgery Christopher Breuer, md, used a ctsa-funded award granted through YCCI’s translational and interdisciplinary pilot program to develop a unique tissue-engineered vascular graft. Breuer and his colleagues developed a biodegradable vascular scaffold seeded with the patient‘s own cells. The innovative vessel can be used in surgery to repair the hearts of children born with single-ventricle anomalies. Unlike conventional approaches using synthetic vessels that are fixed in size and must be replaced as the child grows, the bioengineered version grows as the child grows, and the vessels are therefore permanent. Data generated from the pilot award have led to an R01 grant as well as the submission of two manuscripts and two other grant proposals. YCCI recently assisted Breuer in preparing an fda ide application, which has been approved and will lead to a Phase I clinical trial—the first step in translating this new technology from the bench to the clinic.

their accrual requirements. In order to discard the outdated model of posting flyers in the community to find study volunteers, YCCI is pursuing a more sophisticated approach to subject recruitment. YCCI has hired a local advertising firm to develop a multimedia umbrella marketing campaign for clinical trials that will include a presence on social networks and the Internet. Materials will also be developed for specific populations with an initial focus on diabetes, pediatrics, psychiatry, and minority recruitment. One of the first campaigns will involve the work of Jeffrey Gruen, md, professor of pediatrics and associate professor of genetics and of investigative medicine, whose discovery of a gene involved in dyslexia was named by Science as one of the top 10 scientific breakthroughs of 2005. Gruen received a $5.2 million grant from the New York-based Manton Foundation to further his research on the genetics of dyslexia. He is conducting a study to compare the complete genomes of 1,000 dyslexic children with those of 1,000 fluent readers to obtain a fine-grained view of genes known to play a role in reading disabilities, and possibly to identify new genes that increase the risk of developing dyslexia. The ultimate goal of this work is to devise a practical genetic test for dyslexia, making it possible for parents and teachers of children with the disorder to begin educational interventions early in life when interventions have the most significant and lasting impact on reading ability. YCCI has already developed a clinical trials website with a searchable database that interfaces with clinicaltrials.gov and allows participants to search for trials based on disease area, gender, age range, keyword, or investigator. It is also possible to search for trials seeking healthy volunteers—a feature that has already drawn 1,000 participants. Additional pages on the site answer questions about the nature and requirements of clinical trials and what volunteers should consider when participating in a study, as well as stories about discoveries that took place at Yale thanks to volunteer participation. This resource, which did not exist prior to the ctsa, is updated and expanded on a regular basis. A Work in Progress The creation of ors and its service units has been a massive undertaking but remains a work in progress. As YCCI aims to respond to the needs of investigators by seeking feedback through surveys and other mechanisms, it will incorporate additional refinements into the organization. Meanwhile, ors is already facilitating clinical and translational research at Yale in a manner aligned with both the ctsa’s vision and YCCI’s goals. “The ctsa has enabled us to provide research resources on a level that wasn’t possible before,” said Sherwin. “Many investigators have told me that it’s had a huge impact on their work.”

Research that Benefits Patients The impact of ORS can best be illustrated through the work of Yale investigators. One example of this is Pramrod Mistry, MD, PhD, professor of pediatrics and medicine and medical director of the Pediatric Liver Transplant program. A world-renowned expert in Gaucher disease, Mistry developed a mouse model that showed that the disorder affects many types of cells in the body. While the enzyme therapy normally used to treat the disease works on macrophage cells and alleviates some symptoms, it doesn’t address osteoporosis, which affects nearly all Gaucher patients. It turns out that the osteoporosis results from a defect in bone formation rather than calcium absorption. This finding has led to treating patients with small molecules that work on bone-producing osteoblasts and appear to affect the larger disease process. Mistry recently began an international multicenter trial to examine the effect of small-molecule therapy on reducing production of the lipid that accumulates in this devastating disease. ORS helped the study get off the ground quickly by guiding it through IRB approvals, grants and contracts, and providing support for other logistical issues. The study also utilizes YCCI’s Hospital Research Unit, whose skilled nursing staff provides expertise for inpatient studies. Mistry believes that the ability to move seamlessly from clinic to bench and back to the clinic has greatly enhanced the quality of care he can provide for his patients, and that the infrastructure provided by YCCI has been invaluable in creating an outstanding environment for patient-oriented research at Yale.

INFORMATICS

Building an informatics Infrastructure

A comprehensive informatics platform for patient care and clinical research

Information technology is increasingly essential for clinical and translational research; therefore, a comprehensive informatics platform is part of the Yale School of Medicine’s (YSM) overall strategic plan. Accordingly, YCCI is part of an effort to develop and implement an informatics initiative that involves YSM, the Yale Medical Group (YMG) and Yale-New Haven Hospital (YNHH). By working together to build and integrate a strong informatics infrastructure for patient care and clinical research, we expect CTSA-supported activities to grow and flourish.

Peter N. Herbert, MD, chief of staff and senior vice president, medical affairs, YNHH, views Yale’s investment in an EHR as critical to providing optimal patient care.

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YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

Combining Patient Care with Research Needs On the surface, Yale’s efforts to develop an informatics infrastructure that supports the clinical research enterprise are overdue; in reality, however, the institution has been studying and devising strategies to address this issue for several years. Historically, the technology available at the national level for managing clinical trials and data has been suboptimal, but there is now a much more competitive array of vendors offering systems to meet Yale’s needs. The advantage of not being among the first academic research centers to adopt this type of technology is that we have had an opportunity to learn what works—and what doesn’t— from other institutions. The first major undertaking in Yale’s informatics transformation was to purchase an enterprise-wide electronic health record (EHR) system that would serve patients and physicians across the Yale New-Haven health system while also meeting Yale’s clinical research needs. “Our commitment to high-quality, safe patient care defines our culture and all that we do,” said Peter Herbert, MD, YNHH chief of staff. “A comprehensive electronic health record is a critical component in helping us provide that.” At the same time, such a record needs to be integrated with Yale’s research enterprise. “Providing an optimum environment for conducting clinical research is an important component of our vision, because a very large number of faculty members who conduct clinical research are clinicians who are doing it in the context of their practice, and even the

A well-implemented EHR is more than a technology to assist in the delivery of medical care; it is an opportunity to leverage the information available about patients with the vast amount of knowledge available on the research side.

physician-scientists are drawing patients from the clinical environment,” said David J. Leffell, MD, CEO of YMG. Leffell, Herbert, Dean Alpern, and other leaders across the medical campus are unanimous in their view that a well-implemented EHR is more than a technology to assist in the delivery of medical care; it is an opportunity to leverage patient information with the vast amount of knowledge available on the research side. The EHR is in effect a powerful tool for clinical and translational research. YSM and YNHH initiated a comprehensive analysis with Deloitte Consulting in 2008. The initial objective was to identify a vendor for an ambulatory EHR; but as described below, the result of this process has a much wider focus. This analysis involved more than 150 faculty and staff members, including a number of clinical and translational investigators. Researchers were included at the earliest stages of the project in order to ensure that it incorporated elements critical to the research enterprise. YCCI chief operating officer Tesheia Johnson and Abe Lopman, MBA, executive director of the Smilow Cancer Hospital, led the due diligence phase for the research aspects of the project, co-chairing a special work group to determine whether the selected platform met the functional requirements for research at the medical school and hospital. This group examined the advantages and drawbacks of using this system as a clinical research platform; whether it would allow greater efficiencies in providing viable research data; issues regarding integration with a clinical trials management system (CTMS); and implementation sequencing concerns regarding the creation of strong research capabilities. Yale signed a multiyear contract with Epic Systems in July 2010 after an exhaustive year-long evaluation process.

David J. Leffell, MD, deputy dean for clinical affairs for the Yale School of Medicine and CEO of Yale Medical Group, has been instrumental in efforts to integrate the new EHR with Yale’s research enterprise.

Epic is presently the number-one vendor of integrated EHR solutions in the United States. Epic’s broad range of features make it an ideal choice for an EHR that will allow for greater collaboration between YSM and the hospital. Implementing the system is expected to take at least four years and cost more than $250 million but it will get a boost from two recent arrivals. Daniel Barchi recently joined Yale as the chief information officer for YSM and Yale-New Haven Health System. He was previously senior vice president and chief information officer of the Carilion Health System in Roanoke, Virginia, which includes seven hospitals and 10,000 employees, and where he led a successful Epic ycci.yale.edu

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INFORMATICS

implementation. Steven Schlossberg, MD, recently accepted the new joint position of chief medical information officer at YSM and Yale-New Haven Hospital. Schlossberg is a urologic reconstructive surgeon who most recently served as vice president and senior medical director for hospital-based and surgical specialties at the Sentara Medical Group in Norfolk, Virginia. While there, he helped to guide Sentara’s Epic installation, which began in 2005 and is now being completed in eight hospitals. The two informatics/IT leaders are assembling a strong implementation team of 120 people who will spend the first half of 2011 standardizing definitions and practices among their different organizations before beginning a collaborative build, during which Epic’s software will be configured for Yale’s workflow practices. Meanwhile, a team of about 30 YMG staff members traveled to the Epic campus in Verona, Wisconsin, to receive training on various aspects of the Epic application. Thus Yale may have deliberated for some months while deciding its direction, but once the decision was made, the five-year implementation of Epic has been carried out on schedule. One of the most important considerations when examining EHR systems was the degree to which the software could serve Yale’s clinical research needs. YCCI’s External Scientific Advisory Board pointed out several years ago that Yale needed to overhaul its medical center-wide

March-May 2010

Clinical Research Review

CONTRACT DUE DILIGENCE 3/2010–7/25/2010

PHASE 1 Planning 8/23/2010–7/25/2010

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YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

institutional informatics infrastructure—a recommendation that YCCI took seriously. The ability to interface with a clinical trials management system ( CTMS) to permit seamless integration of all of the components of clinical trial activity was considered crucial. It is widely recognized that clinical trials are increasingly difficult to administer given potential compliance and financial issues. Purchasing and implementing a CTMS was therefore a central element in Yale’s informatics strategy. During an evaluation process spearheaded by YCCI that took place in conjunction with the selection of Epic, the CTMS vendor has been identified and negotiations are currently under way to finalize a contract for a well known and widely used system. The new customized platform will include the following functions:

•• •• •• •• •• •• ••

Clinical research operations and reporting Project management Budgeting and financial management Research subject management Tracking of IRB approval and compliance Biospecimen and biorepository management Tools for electronic data capture and analysis

The new CTMS system is expected to increase data accuracy, decrease collection time, improve FDA compliance, simplify quality assurance and safety auditing, allow for an easy transition to statistical analysis when studies are completed, and reduce administrative costs. The third component of Yale’s informatics initiative is the development of a clinical research data repository (CRDR). An institutional CRDR will enable the collection of a large amount of clinical data that can be used for outcomes studies, quality of care analyses, and populationbased research; identify patients with particular clinical conditions who might be appropriate subjects for specific clinical and translational research projects; and enable data storage to define the clinical phenotype to be analyzed along with genomic and proteomic data in order to understand the genetic components of many important diseases. The CRDR can also be used in second-stage translational research, translating clinical research back to the practice setting. Building a robust institutional CRDR is an important component of our vision; it will be a formidable resource for clinical and translational research and will enhance Yale’s ability to conduct hypothesis-driven research. Building this informatics infrastructure has involved an unprecedented level of collaboration among physicians, nurses, informatics specialists, business professionals, and others from across the health system—many of whom are working together for the first time. Although it is a work

From l to r: Daniel Barchi, chief information officer for YSM and Yale-New Haven Health System; David Leffell, MD, CEO of Yale Medical Group and deputy dean for clinical affairs for the Yale School of Medicine; and Steven Schlossberg, MD, chief medical information officer at YSM and Yale-New Haven Hospital.

in progress, YSM, the hospital, YMG, and YCCI are right on schedule to meet this challenge in order to serve the needs of patients, clinicians, and researchers. A Leader in Biomedical Informatics While Yale has embarked on this comprehensive medical center-wide institutional informatics infrastructure only recently, the University has always been viewed as a leader in the field of biomedical informatics research and development. Yale is nationally recognized for its expertise in biomedical informatics, focusing on the creative use of computing in clinical, neuro- and genome informatics and at the translational intersection of these areas. Top-notch training programs are helping prepare tomorrow’s leaders in this field, which is increasingly critical in carrying out ever more sophisticated clinical and translational studies. YCCI’s biomedical informatics activities are coordinated by the Yale Center for Medical Informatics (YCMI), which is based at YSM. YCMI’s excellence is widely recognized; its staff of 35 is headed by Perry Miller, MD, PhD, professor of ycci.yale.edu

27

INFORMATICS

Clinical Research Management Software Functionality Clinical Research Management

Patient Registry Management

Biospecimen Management

• Protocol and subject life cycle management

• Offers de-identified views of data

• Inventory management

• Subject safety management

• Provides sophisticated handling of relationships and linkage between records

•A  nnotation management

• Protocol and subject calendar management

• Tracks regulatory items

•R  equisition and distribution management

• Study financial management

• Provides aggregate results

• Correlative study sample Management

• Electronic data capture and data management

• Enforces use of standards

• Flexible reporting capabilities

• Paperless committee management and custom reporting technology

anesthesiology and molecular, cellular, and developmental biology. Miller is a recognized expert in the field of biomedical informatics. Co-director Cynthia Brandt, MD, mph, associate professor, is an expert in informatics infrastructure for clinical research. Co-director Michael Krauthammer, MD, PhD, assistant professor, is involved in national data-sharing and translational bioinformatics. He is working closely with the University of Pittsburgh’s Michael Becich, MD, on skin cancer genetics research carried out at both institutions. These studies require more than one site to procure a sufficient number of specimens. The skin cancer project is part of a larger initiative called the Sharing Partnership for Innovative Research in Translation, or spirit. spirit is led by the University of Pittsburgh and includes CTSAs from the University of Pennsylvania, Johns Hopkins University, Washington University, the University of Chicago, and Yale. These CTSAs are developing collaborations in clinical trials management and recruitment of study volunteers; promoting data sharing; establishing a shared infrastructure for research networking and discovery; and planning to expand collaboration to such other major CTSA functions as education and career

28

YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

development, pilot studies, and regulatory knowledge and support cores. YCMI faculty have been either directors or co-directors of YCCI’s Hospital Research Unit, the Yale Cancer Center, the Yale NHLBI Proteomics Center, the Yale / nida Neuroproteomics Center, the Yale Keck Neuroscience Microarray Database project, Yale’s ongoing Human Brain Project activities, and Yale’s informatics activities for the nihsupported Neuroscience Information framework. YCMI works closely with the newly created Yale Center for Analytical Sciences (YCAS), which oversees biostatistics collaborations and services for YCCI. To further ensure effective collaboration between the two centers, Miller serves on the steering committee of YCAS, and YCAS Director Peter Peduzzi, PhD, serves on YCMI’s steering committee. One of YCMI’s top priorities is to educate the next generation of informatics researchers. Miller directs Yale’s National Library of Medicine (NLM)-supported Biomedical Informatics Research Training Program, which includes 12 predoctoral and six postdoctoral trainees. Brandt directs the West Haven VA ’s postdoctoral t ra i n i n g p r o g ra m i n m e d i c a l informatics, which trains two to three postdoctoral fellows and is fully integrated with the NLM-supported

training program. Trainees in both programs work at the crossroads of clinical research and translational informatics. Miller also co-directs Yale’s interdepartmental PhD program in computational biology and biology, which admits four to six graduate students each year, many of whom are working on translational dissertation topics. Informatics plays an increasingly important role in clinical and translational research because researchers are required to manipulate progressively larger sets of clinical, genomic, and proteomic data for patients with particular diseases. Investigators require robust but flexible databases and tools for genomic and proteomic analyses, and computational modeling that can be used to focus on specific genes, proteins, and pathways that may be implicated in disease. YCMI is exploring new avenues to assist them. In one recent cooperative venture, YCMI faculty who included Miller, Brandt, and Kei-Hoi Cheung, PhD, launched a joint project with Geoffrey Chupp, MD, associate professor of medicine, to build a database that will allow Chupp to collect and integrate clinical, laboratory, and high-throughput data from analysis of specimens from asthma patients. Chupp’s research staff will populate the database on an ongoing basis, and YCMI will then work with the team to help them perform the analyses they deem appropriate. For example, because elevated levels of chitinase 3-like 1 protein have been linked to asthma and other disorders, one current project will compare gene expression profiles across a spectrum of asthma severity and chitinase 3-like 1 genotypes and phenotypes. Working with collaborators like Chupp will allow YCMI to build informatics capabilities incrementally during the process of translational research in this important clinical area. The experience gained from this project should serve as a model that can be used for other diseases.

PERRY MILLER, MD, PhD Perry Miller, MD, PhD, has been active nationally in the field of biomedical informatics for almost three decades. He helped found the Yale Center for Medical Informatics (YCMI) in 1991 and has served as the center’s director since that time. He also serves as principal investigator and director of Yale’s National Library of Medicine (NLM)-supported training program in biomedical informatics and as co-director of graduate studies for Yale’s interdepartmental PhD program in computational biology and bioinformatics. Miller’s research includes clinical, genomic, and neuroinformatics; he is particularly interested in working at the intersections of these broad areas, including translational bioinformatics projects. Miller plays a significant role in national ctsa activities. He serves on the education subcommittee and the recently formed biomedical informatics data sharing initiative of the biomedical informatics key function committee (KFC), of which he was a founding member. During his tenure on the KFC, Miller coled the CTSA informatics priorities project group, for which he wrote an initial draft of a memo outlining CTSA-wide informatics requirements. This memo provided a context for the subsequent process that helped define CTSA informatics priorities. Miller and his group are working closely on a project at the national level with four other CTSA biomedical informatics groups from the University of Pittsburgh, University of Pennsylvania, Washington University, and Johns Hopkins University as part of the Sharing Partnership for Innovative Research in Translation (SPIRIT) initiative. The goal is to help forge a growing number of informatics collaborations involving multiple CTSAs nationwide.

From left to right: Robert Sherwin, MD, with Geoffrey Chupp, MD, and Steven Greenberg, co-founders of the Research Accelerator, a comprehensive online tool that contains a database for collecting and integrating clinical, laboratory, and high-throughput data related to asthma patients. ycci.yale.edu

29

BIOSTATISTICS

Integrating Biostatistics Expertise to Benefit Research YCAS is a hub for biostatistical support

It is becoming increasingly difficult to even read medical literature without knowledge of biostatistics; consequently, equipping investigators with biostatistics know-how is crucial to their ability to succeed in today’s clinical research environment. In the past, clinical and translational investigators at Yale were largely on their own when they needed biostatistical support. The Yale Center for Analytical Sciences (YCAS), established in early 2010 by YCCI and the School of Public Health, has changed that. YCAS integrates biostatistical, epidemiological, and health economics expertise for researchers within one center. It serves as a clearinghouse for a steadily growing number of biostatistics faculty and staff members; permits cost sharing; provides better service; and fosters collaborations in clinical and translational research. Starting from Scratch YCCI created a small biostatistics service unit when it was

established in 2006. The unit grew over the next three years, but it became clear from the steadily rising number of investigators seeking assistance that a larger investment was justified. “When I arrived here in 2006, one of the first things I identified was the lack of centralized services for biostatistical support,” said Paul Cleary, PhD, dean of the School of Public Health. “It seemed to me and a lot of other people here that establishing a center for biostatistics would be a tremendous boon to research at Yale.” Recruiting a leader for the new center involved a yearlong national search culminating with the hiring of Peter Peduzzi, PhD, in January 2010. Peduzzi brings more than 30 years’ experience in design, conduct, and analysis of clinical trials to his position as YCAS director. Prior to this appointment, he served for more than a decade as the director

YCAS deputy director James Dziura, PhD, (left), consults with

Thomas Carpenter, MD, professor of pediatrics (endocrinology).

30

YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

of the VA Cooperative Studies Program Coordinating Center at the VA Connecticut Healthcare System in West Haven, and is still affiliated with this center. In addition to his YCAS position, Peduzzi is professor of public health (biostatistics). His primary research interests focus on the efficient design and analysis of comparative effectiveness clinical trials and geriatric studies. Along with Peduzzi, YCAS deputy director James Dziura, PhD, research scientist in internal medicine, has been instrumental in getting the center off the ground. Dziura has managed the biostatistics core resources for YCCI since 2006. He has successfully collaborated with a diverse group of Yale investigators to develop grant applications, design research studies, and analyze data, publishing more than 80 collaborative articles based on this work. His close interactions with faculty members throughout YSM and YSN make him a valuable point of contact for YCCI, facilitating collaborations among investigators at these schools with ysph faculty. His primary research interests are the design and analysis of longitudinal studies. Peduzzi and Dziura both serve on the ctsa consortium’s Biostats, Epidemiology, and Research Design ( berd ) work group, which serves as a forum for the exchange of information on current approaches to the integration of biostatistics, epidemiology, and research design into clinical and translational science research programs within and across ctsa institutions. A Full Spectrum of Expertise YCAS enhances Yale’s infrastructure for clinical and translational research by bringing together biostatistical activities that previously took place in isolated silos around the medical campus. The center offers investigators ready access to statisticians, epidemiologists, and health economists able to assist them with designing clinical, genomic, population, qualitative, and prevention studies as well as analyzing the resulting data. The center’s highly interactive team of experts works with investigators through consultation and development of relevant methods and tools. YCAS serves as a nexus for

“My vision is to be a world leader in the development and application of innovative biostatistical, epidemiological, and health services research methods. The YCAS leadership team that’s now in place is a key element in attaining this goal.” Paul Cleary, PhD, Dean of the School of Public Health

BIOSTATISTICS

Peter Peduzzi, PhD, was recruited to head YCAS in January 2010.

Hongyu Zhao, PhD, director of the Keck Biostatistics Resource, co-director of the Keck Bioinformatics Resource, professor of biostatistics in the School of Public Health.

the development and application of new approaches to study design and data analysis. The research conducted by its faculty enhances the quality of the analytical and computational tools needed in clinical and translational science. YCAS has experienced tremendous growth since opening its doors; there are now 20 full-time biostatisticians on staff, one of whom is always based in YCCI’s Office of Research Services to facilitate interactions with clinical investigators. This growth has allowed the pooling of resources so that investigators who could not afford a biostatistician’s services in the past can contribute a percentage of the staff member’s salary to the center. This policy ensures that researchers have biostatisticians at their disposal at the appropriate level for their projects. The center offers additional assistance through its weekly research design clinic in which investigators have the opportunity to review concepts for new studies and develop testable hypotheses; and its weekly analytic clinic to discuss analytical challenges for ongoing or completed studies. Besides providing support and promoting research, YCAS ’s aims include training the next generation of clinical and translational investigators in research methodology as well as training young biostatisticians in analytical sciences. YCAS faculty members offer courses, workshops, and seminars to meet the varying needs and interest of YCCI trainees. The center is involved in two T32 nih training grants: the Yale Training Program in

Peter Peduzzi, PhD, director of YCAS and professor of public health (biostatistics), and YCAS deputy director James Dziura, PhD, (right). 32

YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

CTSA Supports Development of Parent Training to Help Children with Autism Reproductive, Perinatal, and Pediatric Epidemiology; and Research Training in Mental Health Epidemiology. YCAS also runs a paid internship program for School of Public Health graduate students, two of whom were subsequently hired as staff biostatisticians. In addition, the center developed the Young Scholars program offering a two-week curriculum for local high school students interested in biostatistics. A Joint Endeavor YCCI and the School of Public Health have invested jointly in the YCAS infrastructure, including funding for new staff positions and dedicated space. The center is located in newly renovated offices at 300 George Street, in the same building as the Keck Biotechnology Center, and adjacent to the Center for Medical Informatics and the Center for Statistical Genomics and Proteomics. All four centers work closely with one another and are actively engaged in partnerships with YCCI. The current explosion of opportunities to link genomic and proteomic analysis to human disease has led to a rapidly growing group of nih-funded clinical and translational research projects. To help meet this demand, YCAS is expanding its collaborations with the Center for Statistical Genomics and Proteomics, directed by Hongyu Zhao, PhD, professor of biostatistics in the School of Public Health. Zhao’s research interests include developing mathematical, statistical, and computational methods to address scientific questions in molecular biology and genetics. YCAS is rapidly gaining the support of departments, centers, and programs throughout the Schools of Medicine, Nursing, and Public Health. For example, ycc has located its biostatistics core within the center. YCAS has also developed strong affiliations with the Program on Aging, the Diabetes/ Endocrinology Research Center, the Liver Center, the departments of anesthesiology, internal medicine, ob/gyn, surgery, and emergency medicine, the School of Nursing, and the VA hospital in West Haven. These relationships have fostered multidisciplinary collaborations and resulted in a significant increase in the number of consultations, publications, and grant preparations related to ctsa supported research. Future plans for the center include collaborating with the Yale Center for Medical Informatics (ycmi) and the VA Cooperative Studies Program to develop and staff a statistical coordinating center, identified by YCCI, YSM, and ycc as a critical need. Meanwhile, YCAS will continue to expand as investigators increasingly come to rely on its substantial resources. “There’s no question that YCAS wouldn’t exist without the ctsa,” said Cleary. “I couldn’t be more pleased with how quickly YCAS is growing and the phenomenal reception it has received from groups around the health sciences campus.”

Lawrence Scahill, msn, PhD, professor of nursing and child psychiatry in the Yale School of Nursing and his colleagues at the Yale Child Study Center saw the need to conduct studies to assemble parent-based interventions for autism into a structured exportable manual to be tested in a large-scale trial. Yale and other institutions in the National Institute of Mental Health (nimh) Research Units on Pediatric Psychopharmacology ( rupp) Autism Network developed such a training manual for school-age children with autism spectrum disorders. The rupp group tested the benefits of the antipsychotic medication risperidone alone compared to risperidone plus parent training. Although both groups of subjects improved during the trial, the children receiving combination therapy showed greater reduction in disruptive behavior, tantrums, and aggression compared to the group receiving medication alone. The children treated with combination therapy also ended the trial taking a lower dose of risperidone. The first report from this trial, which utilized biostatistical support provided by ycas, was published in the December 2009 issue of the Journal of the American Academy of Child and Adolescent Psychiatry. Karen Bearss, PhD , associate research scientist in the Yale School of Nursing, was part of the rupp research group and went on to receive a YCCI Junior Scholar Award to conduct a pilot study on applying the rupp manual to preschoolers. The results of her study were promising: the children’s noncompliant and disruptive behavior was significantly reduced by the end of the intervention. In addition, the pilot study permitted a refinement of the manual for this age group. These results, which were incorporated into a multisite nimh grant application, were instrumental in the recent awarding of a five-year $7.5 million grant to study autism in young children.

FROM AT A GLANCE THE LEADERSHIP

MEASUREMENTS AND MILESTONES Highlights from the first four years of the CTSA

$186

2006

YCCI was launched and Yale was one of the first 12 institutions to receive the ctsa.

million

The amount of NIH research funding presently connected to investigators, trainees, and mentors who benefited

2006

2007

from the CTSA during the fourth grant year. This figure is a continuation of a trend from the previous two years, when the amounts of CTSA-connected NIH funding were $157 and $193 million

respectively.

50% Yale-New Haven Hospital and the School of Medicine each contribute approximately half the costs of clinical trials infrastucture — a commitment totaling almost $5 million.

34

YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

2007

The Office of Research Services (ors) was created to provide a robust infrastructure and expand research facilities for clinical and translational researchers. Three years after its inception, ors has 24 staff members and 11 units that supported 357 projects and 225 investigators during the last grant year.

The amount that the School of Medicine has committed to YCCI during the next funding

cycle. The School of Medicine contributed $70 million during the first grant cycle.

2011

2009

YCCI established the Master of Health Science research

YCCI has partnered with the Children’s Fund of Connecticut

program to augment its Investigative Medicine Program, which awards a PhD in investigative medicine to physicians training in either laboratory-based or clinically-based patient-oriented research.

to jointly fund the Children’s Health Innovation grants in order to stimulate research that benefits the community. Three grants of up to $100,000 each will be awarded in 2011 to projects that promote and enhance quality health and mental health care services for children and families.

2008

2009

2008

YCCI launched the Church Street research unit (csru) to augment its hospital research unit (hru) by providing investigators with a setting for

conducting low-risk outpatient studies. The two facilities together provide research resources for 225 study protocols involving 97 investigators from across the institution.

2010

2011

2010

Yale signed a contract with Epic Systems for an enterprise-wide electronic health record (ehr) platform for the Yale-New Haven Health System. The new system will be integrated with a clinical trials management system (ctms) and a clinical research data repository (crdr) as part of a comprehensive plan to overhaul Yale’s informatics infrastructure.

136 ACRES Three core facilities are already located on Yale’s West Campus (former home of Bayer HealthCare), with plans for four new cores and five new interdisciplinary research institutes that will carry out transformative science and advance the knowledge of basic biology and human disease. The amount of independent funding ycci.yale.edu awarded to 44 ycci junior faculty Scholars

COMMUNITY

Broadening Community-Based Research A transformed vision for moving medical advances from the bench to the bedside to the community

Listening to the Community Several health research priorities have been identified through a series of surveys and meetings involving Yale faculty members and New Haven community organizations and agencies. This information is helping ycci and Yale investigators to coordinate and align research efforts with community health needs. The purpose is targeting priority areas identified by the community in order to bring faster results to those who need them. The areas include: ycci ’s vision of moving medical discoveries from the

laboratory to the clinic and then from the hospital setting and into the community has recently been transformed. This change involves developing an integrated effort to increase access to health care; creating a two-way avenue to translate the benefits of research breakthroughs into rapid improvements in people’s health; and harnessing the community’s resources and patient population to support and enhance clinical research.

1. Access to health care 2. Addressing health disparities 3. Asthma prevention and treatment 4. Cancer care 5. C  ommunity involvement in research and dissemination of results 6. Diabetes 7. Environmental health

Reaching Out to Patients 8. Health promotion/activity/exercise In line with the belief that access to 9. hiv/aids prevention and treatment health care is a fundamental right 10. Infant mortality and health disparities and in response to the fact that the community has identified this 11. Mental health issues issue as a top priority, Yale provides 12. Substance abuse (including tobacco) prevention and interventions approximately $8 million each year in 13. Obesity and related chronic medical conditions noncompensated health care to New Haven residents. Access to health care 14. Teen pregnancy and sti prevention remains problematic, however. Yale has 15. Violence and crime prevention a history of seeking ways to provide and expand health services to the community, but until now it has lacked an integrated approach to linking its services to its research programs. There to the community are two sides of the same coin,” he said. are currently 2,400 active research “We can do a better job with both by reaching out to patients, protocols involving human subjects at which benefits both our research initiatives and the patients Yale. Many of these projects focus on we serve.” disease areas that have been identified One outreach initiative is the creation of a new website as priorities by the surrounding to gather existing information in one location along with community. In some of these areas— new communication features and services to help patients such as diabetes, cancer, and substance meet their health care needs, and also encourage them to abuse—Yale already has world-class participate in clinical research. Led by Leffell and ymg, the research and clinical programs. Yale website will focus on patients in the community and serve Medical Group (ymg) has also been as the new front door for clinical trials at Yale. Features will include such healthy living initiatives as health screenings, expanding its clinical practice in recent health and wellness programs, and names of speakers years, with an eye toward recruiting available to participate in community events. The website will clinician-scientists with expertise in also provide information about clinical research conducted at both clinical care and research. Yale; clinical research opportunities; a clinical trials registry; ycci is developing new ways to resources for organizations interested in learning more about align Yale’s research efforts with the research; and a page listing Yale’s community partners. community’s health needs. This effort The existing clinical trials registry site, which is already is being led by David J. Leffell, md, up and running, will be incorporated into the new larger site. ceo of ymg, who believes that Yale’s research studies should be entwined with improving patient access to its David J. Leffell, MD, deputy dean for clinical affairs for the Yale School clinical practice. “Developing medical of Medicine and CEO of Yale Medical Group, is leading efforts to align advances and providing health care Yale’s research enterprise with the community’s health needs. ycci.yale.edu

37

COMMUNITY

Natalia Xiomara, JUNTA’s, program coordinator for Economic Development & Employment.

The registry features a searchable clinical trials database that interfaces with clinicaltrials.gov, as well as pages listing trials recruiting healthy volunteers; frequently asked questions about clinical research; and discussion of the considerations that people should weigh when deciding whether to participate in a study. The website also features stories about Yale discoveries made possible by volunteer participation. As part of a proactive approach to recruiting patients for clinical trials, ycci is currently working with a local advertising firm to develop a full-fledged marketing campaign that will focus on both general and disease-specific patient recruitment. Plans also include developing brochures about clinical trials and creating a video about trials at Yale to be posted on ycci’s website as well as YouTube; it will also be shown at health fairs. Expanding the participation of minorities and other underrepresented populations in clinical trials is an important component of ycci’s recruitment efforts. ycci has recently developed two new partnerships to assist this effort: one with junta, the oldest Latino advocacy group in the New Haven area; and a second partnership with leaders of the African Methodist Episcopal Zion Church. Representatives of these groups will serve as cultural ambassadors to Yale’s research programs, working both within the community and with Yale faculty to develop new recruitment approaches. These community leaders will receive intensive training in all aspects of clinical research theory and practice. This

Lois Sadler, PhD, RN, co-director of Community-Based Research and Engagement for YCCI and associate professor at YSN and the Yale Child Center, at the Peabody Museum of Natural History. YCCI co-sponsored two exhibits at the museum through a Science Education Partnership Award (SEPA).

training will enable them to become research advocates in the community and educate members of their respective groups about the research process. Involving these leaders on a deeper level and earlier in the process—at the stage of research design—will ensure that clinical studies incorporate the needs of the community and at the same time foster trust, thereby enhancing community participation throughout the research process. ycci’s goal in developing both partnerships is to increase the participation of Hispanics and African Americans in clinical trials that directly benefit these groups. ycci recognizes that broadening its communitybased research programs involves listening not only to the community but also to investigators. Those engaged in community-based research need different kinds of services from those established by ycci under the ctsa for investigators engaged in university-based clinical and translational research. The partnership with junta is an excellent example of the kind of partnership ycci seeks to develop, as junta will provide not only insights into the Hispanic population but also Spanish translation services for consent forms and other study documents. The new website will also take these needs into account via a gateway offering access to Yale’s practice-based research network; information on translation services; access to community advisors who can assist in reaching specific populations; and help in setting up recruitment events and educational opportunities related to community-based research. Training the Next Generation of Community-Based Researchers Training investigators in community-based research methodology plays a critical role in ycci’s drive to support this research. These efforts have been greatly expanded under the ctsa and extend beyond educating the faculty to include educational programs at schools and other community-based institutions that reach all age groups.

Helping Connecticut’s Children

The ycci Scholars program created under the ctsa furthers the training of junior faculty members who are strongly committed to careers in clinical and translational research. Since the program’s inception in 2006, approximately 20 percent of its scholars have pursued research projects that engage the community; and 15 percent of the external grants that have been awarded to this group sponsor community-based projects. ycci’s education efforts extend to the youngest members of the community through a Science Education Partnership Award (sepa) in partnership with the Peabody Museum of Natural History. This initiative included two exhibits at the museum, Solving the Puzzle: Lyme Disease, West Nile Virus & You, and Disease Detectives, as well as accompanying science curricula, teacher training and workshops, and traveling exhibits for schools, community events, and other community sites. This year ycci has greatly enhanced its communitybased training efforts by partnering with the Robert Wood Johnson Foundation (rwjf) Clinical Scholars Program. Yale is one of four sites in the country to offer research training through the rwjf program, a two-year clinical and health services research fellowship that includes a communitybased research component. Scholars spend 15 percent of their time working on a hands-on community-partnered project in New Haven; this experience allows them to understand

As part of its program and to stimulate research that benefits the community, ycci also offers funding for pilot projects led by investigators outside Yale. This year, ycci has partnered with the Children’s Fund of Connecticut to jointly fund the Children’s Health Innovation Grants. Three grants of up to $100,000 each will be awarded to projects that promote and enhance quality health care services for children; or for community-based mental health care services for children and families that advance the integration of health and mental health care at the policy, systems, and practice levels; or that strengthen the link between child health and child mental health systems and other systems or support programs.

health issues from consumer and community perspectives. The concept behind the program is to strengthen the scholars’ ability to translate research into practice—a skill that should contribute to reducing the long time lag between the conduct and implementation of research. Examples of projects developed and carried out to address community-identified priorities include: a project with the New Haven Family Alliance to understand youthrelated gun violence; partnering with the New Haven County Medical Association and community health providers to increase access to specialty care for the uninsured; working with New Haven Healthy Start to evaluate the success of health education in changing behaviors of childbearing women; and reducing the incidence of pertussis by working with the departments of medicine and pediatrics at the Hospital of Saint Raphael and with NetHaven, Yale’s practice-based research network.

Addressing Community Health Needs In a sample of about 300 women who received glucose tolerance tests at Fair Haven Community Health Center, more than 40 percent had pre-diabetes and another 5 percent had undiagnosed diabetes. Those disturbing figures led William Tamborlane, md, professor of pediatrics and deputy director of ycci, to apply for a grant from the Donaghue Foundation to conduct a four-year clinical trial in order to demonstrate that interventions targeting obesity can improve health outcomes for inner-city women at risk of type 2 diabetes. In collaboration with a team led by Anne Camp, md, Fair Haven’s diabetes program director, the study offers nutrition education, behavior modification instruction, and a structured exercise program. Participants in this intensive program attend sessions three to four times per week. They are encouraged to bring their children to take part in fitness games and activities. This approach to behavior modification focuses on the entire family to ensure that changes continue over the long term. Intensive lifestyle modifications have been shown to help prevent diabetes, and the researchers hope their results will demonstrate that this particular model is effective and should be adopted by other clinics.

COMMUNITY

Practice-Based Research Network Windham Litchfield

Hartford

Tolland

New London Middlesex New Haven Fairfield

n = 30 (each star represents one enrolled member) Towns represented: Ansonia, Branford, Bridgeport, Glastonbury, Hamden, New Haven, Niantic, North Haven, Stamford, Waterbury, West Haven, and Willimantic.

The rwjf program has recently partnered with ycci to offer community-based participatory research training to investigators from Yale’s health schools. This training is both didactic and experiential; it includes classroom work, direct community engagement, and community research mentoring from the rwjf community research faculty. Investigators for the inaugural class include faculty from the Schools of Medicine, Nursing, and Public Health. Collaborations Making a Difference While ycci has many new initiatives under way to broaden community-based research, much work has already been done in this area. Collaborations with the School of Nursing and the School of Public Health are already having an impact on the health of the community and the research conducted in connection with the community. The School of Nursing and ycci are working together to translate evidence-based methods and new Yale research findings into improved outcomes for health issues identified as critical to the community. Building on the School of Nursing’s Advanced Practice Registered Nurses’ Research Network (aprnet), ctsa support has enabled ycci and ysn to form a new and larger interdisciplinary practicebased research network (pbrn) known as NetHaven. The network merges aprnet’s infrastructure and community practices with ycci resources and expertise in study design, analysis, and regulatory support to prepare the way for larger and more sophisticated clinical research studies within 40

YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

the community. “Practice-based research networks are ideal for bringing larger and cutting-edge research into the community,” said Margaret Grey, drph, rn, dean of the Yale School of Nursing. One of NetHaven’s current projects focuses on preventing pediatric obesity and type 2 diabetes in New Haven. Yale investigators are disseminating American Academy of Pediatrics ( aap ) guidelines in this area and training participating practice sites and members of the Yale-New Haven Community Medical Group. The investigators will evaluate changes in practice, and test whether Bright Bodies, an evidence-based healthy lifestyle program developed at Yale, improves glucose metabolism among obese children with impaired glucose tolerance. A study showed that children who participated in Bright Bodies maintained their weight and decreased their body mass index (bmi), body fat, cholesterol, and insulin levels after one year compared to children who did not participate in the program. A new Bright Bodies site is now operating at the Celentano School in New Haven, where clinicians can refer obese children in need of intervention. This effort to translate an evidencebased program for practice guidelines and intervention into community settings has the potential to have a positive impact on the health of New Haven’s children. The Community Alliance for Research and Engagement (care), created under the ctsa in collaboration with the School of Public Health, is one component of ycci’s strategy to engage the community at different levels. care has made intensive efforts to bring together University and community participants and educate both academic researchers and community members about community-based research. A two-day consensus conference in 2007 brought together 70 university, community, civic, and business leaders and led to a report, Working Together: The Future of Health in New Haven. care also convened a working group of community and university participants to formulate a set of Principles and Guidelines for Community-University Research Partnerships that was disseminated to investigators and community partners and is used by NetHaven. care oversees the research component of Community Interventions for Health ( cih ), an international collaboration funded by the Donaghue Foundation in West Hartford that incorporates evidence-based health promotion

Jeannette Ickovics, PhD, co-director of Community-Based Research and Engagement for YCCI and professor of epidemiology (chronic diseases) and psychology.

Leaders of the RWJ Clinical Scholars Program representing diverse disciplines from across the medical campus include, from left: program director Harlan Krumholz, MD, Harold H. Hines Jr. Professor of Medicine; assistant director and RWJ alumna Marcella Nunez Smith, MD, MHS, former YCCI Junior Scholar and assistant professor of medicine; core faculty Leslie Curry, PhD, MPH, research scientist in public health; codirector Cary Gross, MD, associate professor of medicine; and deputy director Georgina Lucas, MSW, lecturer in medicine.

and community involvement. This unique project included a door-to-door health survey of more than 1,200 residents conducted by 32 surveyors recruited from the New Haven community and trained in community-based research. The survey findings were distributed directly to New Haven residents through a series of community forums and will be used to develop evidence-based interventions to improve health. “care has done a fantastic job of engaging the community,” said Paul Cleary, phd, dean of the School of Public Health. “It’s a perfect partnership between ycci and the School of Public Health that fits in with my vision of improving the health of New Haven residents.”

training a new generation of scientists, including those engaged in community and participatory-based research, and facilitating the translation of research findings are most important to me,” said Sherwin. “That’s why our new initiatives are so exciting to me. We are poised to really make a difference in this area.” ycci is intent on transforming community-based research in much the same way that it has already changed clinical and basic science. Collaborations with the Schools of Nursing and Public Health, coupled with new collaborations within the School of Medicine, position ycci to cover the entire spectrum of clinical and translational research, bringing together investigators across disciplines to facilitate discoveries—in addition to rapid translation and application of those discoveries—to benefit the surrounding community and beyond.

A New Perspective “I am exceedingly proud of what we’ve been able to accomplish through our program so far, particularly the trainees, the partnerships with Nursing to support the pbrn and with Public Health to establish care,” said Robert S. Sherwin, md, director of ycci and PI of the ctsa, “but I realized we needed to do more to support the faculty in this area.” ycci created a pilot award program with funding allocated to translational and interdisciplinary research and promotion of T2 and T3 research to stimulate community-based research conducted not only by Yale investigators but also by organizations outside the university. “I agreed to take on the challenge of ycci and the ctsa because ycci.yale.edu

41

COLLABORATIONS

One is Better  than Two

  YCCI and YCC join forces to advance clinical research

Bringing new medical treatments from bench to bedside requires the pooling of resources and expertise. To facilitate this process, YCCI seeks to break down research silos by promoting collaborations among different departments, schools, and centers. Partnerships have been created with the Diabetes and Endocrine Research Center, the Program on Aging, the Polycystic Kidney Center, the Liver Center, the section of gastroenterology, and the departments of internal medicine, psychiatry, emergency medicine, and anesthesiology. A new collaboration with the department of pediatrics includes weekly research-in-progress conferences and didactic sessions on a variety of child health research topics as well as small startup grants available to faculty members that include assistance from a full-time biostatistician and administrative staff. YCCI also supports research nursing personnel in the Yale Newborn Special Care Unit, which conducts NIH-sponsored multicenter trials focused on treating premature infants. YCCI ’s earliest and most successful collaboration, however, has been with the Yale Cancer Center (YCC). By identifying shared goals and seeking joint funding and resources, this partnership has become mutually beneficial to both centers. The School of Medicine fully supports this collaboration; it is committed to investing in infrastructure and recruiting faculty who are leaders in their fields in order to build on efforts already under way. “This is an ideal partnership. In this tight economy we need to maximize our resources to ensure that Yale is a premier research institution and this is an excellent way of accomplishing that.” said Robert Alpern, MD, dean of the School of Medicine and Ensign Professor of Medicine. 42

YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

“Our partnership with YCCI is a wonderful opportunity for us to advance the mission of both centers, which is to train the next generation of researchers and improve patient care. I believe it could serve as a model for other institutions seeking innovative ways of conducting clinical and translational research.� Thomas Lynch Jr., MD, Director, Yale Cancer Center

FROM THE LEADERSHIP COLLABORATIONS

A Cooperative Effort to Train the Next Generation ycci, the Yale Cancer Center (ycc), and the department

of therapeutic radiology have collaborated to fund two 2010 Junior Faculty Scholar awards in an agreement that embodies the ctsa’s spirit of collaboration. Joseph Contessa, md, phd (left), assistant professor of therapeutic radiology, will investigate combined N-linked glycosylation (nlg) and epidermal growth factor receptor (egfr) inhibition to enhance cell death in tumors and develop a preclinical model to image egfr protein levels in vivo. His goal is to expand these studies toward human clinical trials. Contessa’s research will contribute to a better understanding of the mechanisms of tumor resistance to egfr-targeted therapies and will potentially provide clinical imaging strategies to measure egfr expression in tumors. Abhijit A. Patel, md, phd (right) assistant professor of therapeutic radiology, will use a novel approach employing barcoded polymerase chain reaction (pcr) followed by deep sequencing to assess the utility of circulating mutant dna as a biomarker of response to radiation treatment in lung cancer. He will also assess whether the persistence or disappearance of mutations correlates with clinical outcomes. “This is a fantastic opportunity that will help boost the careers of two of our most promising young investigators,” said Peter Glazer, md, phd, chair of the department of therapeutic radiology and director of ycc’s Radiobiology and Radiotherapy Research Program. “I’m pleased my department was able to contribute to this worthwhile award.”

The partnership between the two centers is well aligned with the vision of Thomas J. Lynch Jr., MD, who was appointed director of YCC in 2009. Lynch wants the center to be known for innovation and has spent the last 18 months recruiting translational researchers and expanding clinical trials. He believes that Yale’s taking advantage of its strengths in basic science along with its improved clinical trial infrastructure will increase patients’ access to the newest therapies. This objective requires an investment in infrastructure, for which YCCI is a logical partner due to its many similar needs. “It’s been a wonderful opportunity for us to develop programs and expertise that jointly benefit both enterprises and ultimately improve patient care,” said Lynch. The two centers have merged several aspects of their management structure for clinical trials, combining many support functions. This includes joint financial administration of clinical trials for budgeting, contract negotiations, and implementation of systems for billing related to clinical trials; protocol development and IND applications; and supplemental staff for data management and support—a much more cost-effective approach. When the cancer center folded its billing office for clinical trials into YCCI’s financial management unit, staff members conducted a full review of trials closed during the prior year. They discovered approximately $2 million in previously unpaid trial receivables and were able to recover the funds. YCCI and YCC have further combined their tasks by working with the institutional review board ( IRB ) to

Yale Cancer Center (CCSG)

YCC (CCSG)

Yale Center for Clinical Investigation

(CTSA) YCCI (CTSA)

Director, Yale Comprehensive Cancer Center Thomas Lynch Jr., MD Deputy Director for Administration Kevin Vest

Director, Yale Center for Clinical Investigation Robert Sherwin, MD Chief Operating Officer Tesheia Johnson Associate Director, Clinical Trials Henry Durivage, PharmD

YCCC Clinical Trials Teams

Central Office

YCCI Services

Research Nurses Project Managers Data Managers Clinical Trial Coordinators

IND Support Research IT Regulatory Budgeting Contracts Education & Training

Flexible Staffing Pool Protocol Development Recruitment Clinical Research Spaces Core Laboratory

streamline the approval process and establish training programs for faculty and staff related to clinical trials. There is now a joint quality assurance program, and a new initiative is under way to better organize the management of scientific and safety review committees by integrating support staff. This reorganization reduces the workload of faculty reviews, with the ultimate goal of encouraging increased faculty participation in the review/regulatory process. Besides merging support functions, the two centers have jointly invested in equipment for the Immune Monitoring Core Facility, which supports the work of investigators carrying out clinical trials related to immunologically based diseases, and the Keck Microarray Resource. YCCI and YCC also jointly supported the recruitment of Peter Peduzzi, PhD, to lead the Yale Center for Analytical Sciences ( YCAS ). The center houses a team of biostatisticians, clinical epidemiologists, and health economists to provide biostatistical support services and methodological expertise to investigators. YCCI is one part of an initiative to expand Yale’s informatics infrastructure. Lynch has taken a leading role in exploring the purchase of a clinical trial management system (CTMS) and clinical research data repository ( CRDR ). “Tom’s input has been invaluable as we try to determine the optimal system for integrating these systems in terms of our clinical research needs,” said YCCI director Robert Sherwin, MD, C.N.H. Long Professor of Medicine. YCCI and YCC are joined in other ways as well. The two centers have co-funded a pilot grant to form the Breast Cancer Consortium of Connecticut to focus on increasing access to clinical trials; developing a task force to examine state and national standards for breast cancer treatment; and reducing health disparities through various outreach initiatives. YCCI has also

YCCI and YCC have merged several aspects of their management structure for clinical trials, including joint support of the position of associate director of clinical trials.

worked with the cancer center to launch a statewide clinical trials network to promote innovative cancer research. In the current environment of reduced budgets, decreased funding, and increased regulatory requirements, collaborations that jointly respond to the clinical research needs of different centers are both practical and forwardlooking. According to Sherwin, future plans include expanding this approach as a way to broaden activities for other centers and programs. “There hasn’t been a lot of collaboration between cancer centers and clinical trials centers, so we’re excited that what we’ve put in place so far has been successful,” he said. “Hopefully our efforts will serve as a model for other academic institutions that are interested in both leveraging their resources and conducting innovative research.” The two centers have increased efficiency by sharing the administration and management of protocol review, scientific and safety committees and combining training, education, and auditing activities.

YCCC (CCSG)

Scientific and Accrual Review Prioritization and Monitoring

YCCI (CTSA)

• Committee Management

• Protocol Review Committee (PRC)

• Training

• Clinical Research Steering Committee (CRSC)

• Auditing

• Education

Science, Safety, Special Population and Utilization Review • Science and Safety Committee (SSC) • Pediatric Protocol Review Committee (PPRC)

• Quality Assurance Compliance and Safety Committee (QUACS)

Robert J. Alpern, MD, dean of YSM and Thomas J. Lynch Jr., MD, director of YCC, view the collaboration between the medical school and the cancer center as an ideal partnership. ycci.yale.edu

45

NATIONAL COLLABORATIONS

COLLABORATING FOR BETTER SCIENCE Translation of science requires strategic partnerships Managing and administering a Clinical and Translational Science Award involves collaborating with colleagues in every corner of the medical campus. For Yale, it also involves working with colleagues outside the institution in a mutually beneficial process that benefits everyone. “Clinical and translational research is about knocking down silos,” said Robert Sherwin, md, director of ycci and principal investigator of Yale’s ctsa. “You have to do it at your own institution, but you also have to do it between institutions. Every time I meet with someone from another

ctsa, I learn something that helps me do this work better. I’m very proud of the role Yale’s played in facilitating that kind of exchange.” Yale takes a broad-based approach that involves national and regional partnerships, creating opportunities for investigators from different ctsa sites to interact, working with industry, and sharing information across ctsa sites. This collaborative approach enables the efficient conduct of clinical and translational research.

National and Regional Partnerships Richard Carson, PhD, director of the Yale PET Center, and his team benefit from Yale’s CTSA-supported alliance with Pfizer to conduct collaborative research studies.

ycci is a member of the Clinical and Translational Science Awards (ctsa) consortium. It aims to speed the translation

of laboratory discoveries into treatments for patients, engage communities in clinical research activities, and train a new generation of clinical and translational researchers.

basic research

•• •• •• •• ••

translation

from basic science to clinical studies

clinical research

The ctsa consortium has five goals:  uilding national clinical and translational B research capability  raining and career development of clinical T and translational scientists Enhancing consortium-wide collaborations  nhancing the health of local communities E and the nation Encouraging T1 translational research

ycci is also a founding member of a consortium of the seven ctsas in the New York-Connecticut area to promote collaborations, best practices, and student interchanges. As this group has grown, it has found new opportunities for its members to work together. For example, the regional consortium’s pediatrics group has generated National Center for Research Resources (ncrr)-funded grants for research on hypertension and sickle cell anemia.

clinical and community practice

translation

from clinical research to patients and communities

“The Rockefeller partnership has been extremely helpful to me,” said Yasuko Iwakiri, a ycci scholar studying portal hypertension. “Simply getting an inside look at an institution with a very different culture than your own is valuable. Perhaps the most valuable piece for me was meeting a Rockefeller hepatologist who asked me a question during a poster session that made me look at my work in a new way.” In addition to the Rockefeller partnership, Yale is one of 14 ctsas participating in the mentoring training trial led by the University of Wisconsin-Madison. The trial involves a randomized controlled test of the effectiveness of a training program for clinical research mentors. Industry as a Key Partner in Discovery Creating innovative opportunities to work with industry is critical to moving science forward into discoveries that benefit patients. The Yale-Pfizer Bioimaging Alliance is an excellent example of academia and industry collaborating on a world-class research program that builds upon the excellence of research in both institutions. Pfizer enhances capabilities at the discovery and preclinical stage with increased critical scientific input while Yale leverages resources to apply scientific knowledge to problem-solving in translational medicine. Such Pfizer departments as discovery, cardiovascular/metabolic disease, central nervous system, and technology and molecular medicine have been involved in collaborative research with

A Community of Scholars Interacting with investigators from other institutions is an important part of Sherwin’s vision of providing training for Yale investigators that stimulates them in new ways. He spearheaded the idea of holding a joint retreat for Rockefeller University and Yale ctsa scholars each year. The retreat alternates between the two locations. “ We’re asking these young investigators to look at problems in a new way,” explained Sherwin. “It’s important for them to make connections with colleagues doing the same.” A typical full-day program WA is designed by scholars and faculty members at the host site, with talks and OR panel discussions on such topics as new ID translational techniques, bioinformatics methods, clinical trials, approaches NV to community-based research, and CA UT career development. Poster sessions are included and are widely advertised to the faculty, fellows, and students of the AZ host institution. As a result, the retreats serve to increase the visibility of the ctsas within the two institutions, just as they have widened the horizons = New Members 2010 of the scholars beyond their own = Members institutions. = CTSA states

Yale was one of the first 12 institutions to receive a CTSA award when the program was implemented in 2006. Currently, 55 institutions are part of the CTSA consortium; when fully implemented the consortium will comprise 60 institutions linked together to advance clinical and translational science. ME MT

WY

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ycci.yale.edu

47

NATIONAL COLLABORATIONS

“The CTSA Consortium is a complex, diverse, dispersed, and growing organization, involving thousands of faculty and staff from 55 academic health centers as well as the NIH. Communication is just as essential to success as strategic planning, organizational management, and a clear sense of priorities.” Thomas T. Fogg, MS, MPH , University of Rochester School of Medicine and Dentistry Rebecca Moen, MBA, CTSA program manager for the Duke Translational Medicine Institute.

a number of departments at Yale, including diagnostic radiology, psychiatry, and internal medicine. Yale contributed most of the funds required for planning and construction of the state-of-the-art Yale pet Center as well as substantial investments in bringing its pet imaging program to the cutting edge of research expertise and technology. Yale’s funds were augmented by a grant from Pfizer to purchase equipment. An agreement by Pfizer to fund an annual portfolio of imaging research conducted collaboratively between Yale and Pfizer scientists is the core of the alliance. The collaborative studies, both preclinical and clinical, conducted under the alliance aid in understanding the action of pharmaceuticals and other therapeutic agents, and validate drug targets for early decision making. The results of these studies not only facilitate a better understanding of biological processes in the human body but also accelerate reaching mutual research goals dedicated to improving human health. More than 60 jointly authored peer-reviewed publications have been issued in the first six years of the alliance and have provided valuable pilot data to leverage additional funding. Reducing the Research Timeline Yale and the Mayo Clinic have set up a formal structure for sharing innovation under American Recovery and Reinvestment Act (arra) supplements linked to ctsa funding. “This has been a great model for us,” said Tesheia Johnson, associate director for clinical research for the Yale School of Medicine and ycci’s chief operating officer. “By sharing across sites, we can establish best practices at each institution and truly make each other better.” The partnership has led to Yale’s pilot study of a rapid quality improvement method used at Mayo. “We try to make alterations to a best practice so that it works in the particular structures of our own institution,” explained Sandra Alfano, chair of the human investigations committee at Yale. “Then we try to make those practices generic so that they can be widely used.” Yale and Mayo also share training opportunities for junior researchers and staff. The safety of human subjects, a common concern for ctsa sites, is often the impetus for collaborations. Kathleen 48

YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

Uscinski, deputy director of the Yale human investigations committee, works closely with sites throughout the consortium as the co-chair of the ctsa’s institutional review board task force to ensure the safety of research volunteers while streamlining the irb process. She participated in a study of that process at consortium sites. “Just looking at how you compare with your colleagues is amazingly helpful,” she said. Team Science and Administration Yale subscribes to the view that a successful research enterprise involves different kinds of expertise—including administration, which plays a large role in efficiently managing research efforts. “Research involves equal partnerships and administrators have a lot to bring to the table,” said Rebecca Moen, mba, ctsa program manager for the Duke Translational Medicine Institute. “Our job is to operationalize the broad-based vision of clinical research using management strategies that have been proven to work.” Tesheia Johnson, associate director for clinical research for the Yale School of Medicine and YCCI’s chief operating officer.

ycci leaders and staff members sit on the external scientific advisory boards of other ctsas and chair many national work groups. ycci leaders have also reviewed grant proposals for other institutions seeking a ctsa, many of which have gone on to receive awards. Sherwin leads by example through his position as chair of the advisory board for Washington University and as a member of the boards of Columbia University and Mount Sinai School of Medicine. Tesheia Johnson, associate director for clinical research for the Yale School of Medicine and ycci’s chief operating officer, is a member of the advisory boards of the ctsas of the Mayo Clinic, New York University, and the University of Florida; she has also co-chaired four national ctsa key function committees, including the administration committee, the clinical research management committee, and the regulatory knowledge and support committee. She currently co-chairs the consortium management group ( cmg ), which applies such accepted business and organizational practices as enhanced communication strategies and project management to the work of the consortium. The cmg was formed in October 2009, and presently consists of five ctsa administrators selected by principal investigator nomination and approved by the National Center for Research Resources (ncrr); one ncrr supervisory medical officer; one staff member from the office of the ncrr director; one ncrr senior management/operations official; and one project manager from the contract coordinating center. “It’s an unusual model and an exciting one,” said Johnson, referring to the cmg. “We’ve known for centuries that science advances when professionals get together and build on each other’s discoveries. Clinical and translational research demand a sophisticated infrastructure, so administration is critical to this work.” This view is shared by ycci leadership, which is the reason why the Yale ctsa organized and hosted the first national meeting of ctsa administrators in Washington, D.C., in 2008. In 2009 Yale hosted meetings of ctsa administrators from Duke University, the Mayo Clinic, Washington University, and the University of California, San Francisco to compare notes on strategies, best practices, and programs. And in September 2010, the Yale ctsa organized and hosted an orientation meeting for administrators from the University of Michigan, the University of North Carolina at Chapel Hill, and Yale who serve with Johnson on the consortium’s child health oversight committee. This group provides a unique national forum for ctsa investigators and nih scientists to identify opportunities to collaborate on facilitating child health clinical and translational research through the ctsa program.

Face-to-Face Interactions National conferences have been an important strategy to advance work through collaboration between sites. To promote this strategy, Yale has organized a series of three annual national meetings in Washington, D.C., focused on enhancing clinical research management. ycci also manages a grant for the National Center for Research Resources

Stacey Scirocco, associate director for administration and operations for YCCI, plays an important role in national leadership in the CTSA consortium. Scirocco is co-leader of the Yale-Mayo Clinic project on sharing best practices and is a member of both the administration and communication key function committees (KFCs). She also led a “Tiger Team” from the CTSA communications KFC to develop a CTSA consortium communications plan. Thomas T. Fogg, MS, MPH, executive director of operations of the Clinical and Translational Science Institute (CTSI) of the University of Rochester School of Medicine and Dentistry.

(ncrr) of the National Institutes of Health, which funds the meeting. The proceedings of the second annual meeting will be published in the journal, Clinical and Translational Science, so that the findings discussed at the conference can be shared with a much wider audience. An increasingly popular event, the third annual national workshop drew 400 people. “Last year’s workshop was a wonderful opportunity for participants from across nih and ctsa and non-ctsa sites to come together and exchange ideas,” said Johnson. “We are hoping for an even larger gathering next June, with more opportunities to learn from each other.” “The ctsa consortium is a complex, diverse, dispersed, and growing organization, involving thousands of faculty and staff from 55 academic health centers as well as the nih,” said Thomas T. Fogg, ms, mph, executive director of operations of the Clinical and Translational Science Institute (ctsi) of the University of Rochester School of Medicine and Dentistry. “Communication is just as essential to success as strategic planning, organizational management, and a clear sense of priorities.” Worth the Time For ycci’s leadership, the time spent working with other ctsa sites, serving on national committees to develop best practices, and organizing events at which trainees can interact with their peers is an important component of what ycci intends to accomplish. By adopting a scientific approach to managing clinical trials—using metrics to measure the efficiency of time to study initiation, for example—the faster clinical trials can get under way, and the faster new treatments can be developed. “It’s worth the extra effort to forge relationships with other ctsas because it helps us do our job better,” said Sherwin. “And that means better care for patients.” ycci.yale.edu

49

EDUCATION

Training the Next Generation

Establishing a home for the education and support of clinical and translational investigators One of the reasons for creating ycci was to attract the best and brightest students, fellows, and junior faculty members to careers in clinical research—and offer them the training needed to master a daunting array of research approaches and technologies as well as to work effectively within complex teams. The goal was fourfold: creating a home for the education and support of clinical and translational investigators; expanding Yale’s existing programs; establishing new ones to fill gaps; and gathering them all under the YCCI umbrella. Research Training for Junior Faculty Integration of the Investigative Medicine and Yale K12 programs and incorporation of relevant T32 programs into a new YCCI Scholars program were among the first priorities. The program would provide advanced training in clinical and translational research to a diverse group of scholars from across the entire medical campus. YCCI made a strategic decision at the outset to triple the number of junior faculty previously supported by Yale’s K12 grant and double the number of md fellows admitted to the innovative Investigative Medicine Program (imp), which confers a PhD in investigative medicine. Since the awarding of the ctsa, a total of 44 Junior Faculty Scholars have received training and mentoring from the Society of Faculty Mentors, a distinguished group of 30 senior faculty members chosen for the quality and breadth of their research as well as their track records in mentoring young scientists. The Scholars have included faculty from the schools of medicine, nursing, and public health. Collectively, this outstanding group has published 147 papers, given conference presentations, and collaborated with colleagues both nationally and internationally. They have also competed successfully for a total of almost $50 million in independent funding.

Educational co-directors Eugene Shapiro, MD, and Judy Cho, MD, lead the program. 50

YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

The Scholars program is intended to train the next generation of clinical and translational researchers. It is succeeding admirable—with the exception of one scholar who has entered research in industry, all are pursuing careers in academic medical research. While many have remained at Yale, some have gone on to successful careers at other institutions. Former trainee Kristina Crothers, md, is continuing her research on hiv-associated pulmonary disease at the University of Washington, where she is assistant professor of medicine. Crothers has made excellent use of her mentored training in projects that include an R01 grant to investigate the progression of copd in hiv-positive patients compared to uninfected subjects; and an nih Challenge Grant in Health and Science Research to study risk factors, severity, and outcomes of bacterial pneumonia in hiv infection. The work of other Yale Scholars, highlighted in the following pages, illustrates the depth and breadth of their research projects; all have benefited from the support of the ctsa. YCCI augmented its educational program last year by launching the Master of Health Science Research program, specifically designed for junior faculty Scholars. This program is required for those who do not already hold an advanced degree in a field related to clinical or translational science. In addition to courses in biostatistics, principles of clinical research, and ethical and practical issues in clinical investigation, Scholars meet periodically with a mentoring committee. They are required to produce a manuscript based on original research suitable for publication in a peerreviewed journal. Although still in its infancy, the program is already well under way. Lei Chen, md, mhs, assistant

“One of the primary reasons I wanted to be part of YCCI was to establish a home for the training of the next generation of clinical and translational scientists because I am convinced that we must provide an environment that encourages the transition from clinician to clinician-scientist in order to have an impact on clinical research.” Robert Sherwin, MD, Director, YCCI

professor of pediatrics, received his degree in May; Raimund Herzog, md, instructor in endocrinology, is currently enrolled in the program, while another Scholar is undergoing the application review process. Expanding Training through Existing Programs YCCI has also expanded existing educational programs since receiving the ctsa, bringing together programs for fellows, medical students, and graduate students under one umbrella. Students in these programs pursue training in community-based research and health policy, pathobiology, chronic disease epidemiology, laboratory science related to translational and clinical research, and specialty disciplines within public health, nursing, and biomedical engineering. The Investigative Medicine Program (imp) has been enlarged to include scholars in nursing, public health, biomedical engineering, and biological and biomedical sciences who are seeking a phd with a focus on clinical investigation. A total of 40 trainees have matriculated

since the imp began admitting students in 2000; and approximately 250 faculty members and trainees from other programs take the program’s courses each year. imp alumni have gone on to academic positions at Yale and other highly ranked institutions. The TL1 training program provides expanded clinical/ translational training for predoctoral medical, nursing, mdphd, and biomedical engineering students, and supports one-year clinical research projects. It also provides training

for medical students for short-term clinical research projects. Yale students supported by the TL1 training grant have achieved a remarkable record of scientific productivity. In all, 77 students have co-authored 148 full-length publications during or shortly after completing medical school, many of them appearing in outstanding peer-reviewed journals. Judy Cho, MD, YCCI co-director for education pictured second from left, with YCCI scholars, l to r, Raimund Herzog, MD; Tore Eid, MD, PhD; Kelly Cosgrove, PhD; Sarah Jaser, PhD; and Annette Molinaro, PhD.

EDUCATION

Kelly Cosgrove, PhD World-class imaging and a clinician’s eye Assistant Professor of Psychiatry and of Diagnostic Radiology PhD – University of Minnesota YCCI Scholar

52

YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

“People who can quit smoking easily already have,” said Kelly Cosgrove. The would-be former smokers who volunteer for her research have been using cigarettes for decades. “That’s 20 years, 20 cigarettes a day, 10 puffs a cigarette. More than a million puffs!” Cosgrove explains. “It’s a compulsion that’s learned and hard to stop.” She’s determined to make smoking cessation a bit easier. Cosgrove began her career as a clinical psychologist working with individuals suffering from drug addiction. The shortage of effective and well-researched therapies that helped her patients drove her into the laboratory. Now she uses positron emission tomography (pet) and singlephoton emission computed tomography (spect) scans to gain valuable insights into what happens in the brain after its owner stops using alcohol or tobacco. These technologies are the only way to look at receptors—cells that play an important role in human reactions to drugs—in a living brain. “It’s really hard for young investigators to do brain imaging because the cost is prohibitive,” said Cosgrove. As a ycci Scholar, she had access to the Yale pet Center, one of the top facilities in the country, as well as such other resources as labs that process volunteers’ blood samples. Various studies have found that smokers develop an increase in nicotine receptors. Cosgrove learned that it takes up to 12 weeks for those receptors to decrease in number. This finding suggests that smokers may need long-term support to kick the habit. She discovered that cravings were higher in abstinent smokers who had the highest receptor levels. “Your behaviors and your thoughts don’t live in a vacuum,” explained Cosgrove. “They’re biologically based. Your behavior can also affect your brain. It’s a two-way street.”

Karen Dorsey, PhD Fighting the obesity epidemic with knowledge Assistant Professor of Pediatrics MD – Washington University School

of Medicine

PhD – Yale University

(Investigative Medicine Program) Robert Wood Johnson Clinical Scholar YCCI Scholar

As the incidence of childhood obesity in the United States has more than tripled in the past 30 years, keeping kids fit has become a national priority. Karen Dorsey wants to make sure that the programs springing up to help youngsters achieve a healthy weight really work. “There’s this rush to intervene without that foundation of research,” says Dorsey. Much of Dorsey’s research is based at Fair Haven Community Health Center, a New Haven clinic that serves many low-income and Latino families—whose children are at especially high risk of obesity. Dorsey literally became part of the center, seeing patients as an urgent visit physician and coming up with research questions in collaboration with the clinic staff. Dorsey has done work to help identify which children are at greatest risk of obesity, and has developed an improved methodology for measuring children’s levels of physical activity. Dorsey also investigated whether clinicians were following the American Academy of Pediatrics (aap ) guidelines on counseling patients about weight control. Many did not—“out of a sense of futility,” says Dorsey, who believes the doctors were discouraged by a shortage of resources families could use to become or stay fit. Concerns about the safety of children playing outside present a major barrier to exercise in low-income neighborhoods. So Dorsey plans to look at lowincome families whose children do manage to keep active. “Is it something about the families? Or something about the kids, something innate?” she asks. “That could guide what format our interventions should take. ycci.yale.edu

53

EDUCATION

Yasuko Iwakiri, ms, PhD A new angle on liver disease Assistant Professor of Medicine MS – Oregon State University PhD – Colorado State University YCCI Scholar

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YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

Most research on liver disease focuses on the organ itself. But a side effect known as portal hypertension is the direct cause of many complications and often death. Portal hypertension refers to the rise in blood pressure in the portal vein that carries blood to the liver. In advanced liver disease, that blood flow is impeded by the formation of scar tissue. Portal hypertension is also accompanied by a dangerous thinning of the vascular walls. Yasuko Iwakiri wants to know what’s happening on the molecular level in portal hypertension—knowledge that could lead to the development of drugs to provide more effective therapy. While much of her work is done in the laboratory, she’s also collaborating with her former mentor, Roberto Groszmann, professor emeritus and senior research scientist in medicine, to extend the work to human patients. With the data she was able to compile as a ycci Scholar, Iwakiri successfully applied for an R01 grant from the nih to continue her research. ycci gave Iwakiri not only the chance to establish a research program but also a community of colleagues. “I don’t probably know the people upstairs,” she says, waving a hand toward her office ceiling. But as a ycci Scholar she met a variety of researchers at Yale and Rockefeller University—two ctsa sites that schedule frequent exchanges. “People in areas that don’t seem related to my work had excellent ideas and helped me think of problems in new ways,” says Iwakiri. “They continue to be an important part of my research.”

Rebelling against parents and striving to fit in with peers are par for the course in adolescence. “In teenagers with diabetes, all these normal adolescent events play out with higher stakes,” explains Sarah Jaser. Managing diabetes in teens is difficult, in part because of hormonal changes but also because teens may not perform necessary blood glucose monitoring when parents ask, or because they want to eat “what all their friends are eating without stopping to think about it,” says Jaser. She is studying a trio of social factors that may influence how well teens control their diabetes: maternal depression, parent-child communication, and coping strategies. Jaser received the funding to do this research as a ycci Scholar and has since obtained a five-year nih grant to continue it. She observes parent-child interactions by videotaping conversations between mothers and children. “You’d think they’d change their behavior when the camera is on. But within a minute or two, they fall into their normal patterns,” says Jaser, who has captured laughter, hugs, and tears on the videos. Almost 30 percent of the mothers and 15 percent of the children in her study scored high on a depression inventory—higher rates than are seen in the general population. Jaser got interested in children with diabetes while doing a clinical psychology rotation in a diabetes clinic. “A lot of the families that came in are otherwise pretty healthy,” she says. “But this [disease] is one huge stressor.” Ultimately, she hopes to develop a way to use video playback to coach parents and teens on how to manage diabetes with more cooperation and less conflict.

Sarah Jaser, ma, PhD Keeping teens with diabetes on track Associate Research Scientist, Yale School of Nursing MA, PhD – Vanderbilt YCCI Scholar

ycci.yale.edu

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EDUCATION

Richard Kibbey, md, PhD A new take on diabetes Assistant Professor of Medicine and of Cellular and Molecular Physiology MD, PhD – University of Texas Southwestern

Medical School

YCCI Scholar

Type 2 diabetes involves a problem with insulin, the hormone that lowers blood glucose levels. A patient becomes resistant to insulin at the same time that beta cells fall down on their job of producing it—a two-pronged assault on metabolism. Richard Kibbey decided to test that common understanding of the disorder by overwhelming beta cells with glucose. “We found quite a surprise,” remembers Kibbey. The beta cells continued to produce insulin, but the alpha cells that make glucagon, a hormone that raises blood glucose levels, were malfunctioning. His findings suggest that type 2 diabetes may not be solely a result of the body’s failure to put the brakes on glucose but also one of stepping too hard on the accelerator. Several companies are trying to develop drugs that control glucagon as a new option for managing diabetes. For Kibbey, who also cares for patients in a general endocrine clinic, the recognition that his findings have the potential to change treatment is exciting. “Lots of my ideas for research come from observations in patients,” he says. That’s the value of having physicians who double as investigators. But the proportion of nih grants awarded to doctors has declined in recent years, as many medical students are discouraged from research—in part by the prospect of uncertain funding as they begin their careers. “That early support from ycci was absolutely essential to me,” says Kibbey.

Tené T. Lewis, ma, PhD How mistreatment hurts Assistant Professor of Public Health MA, PhD – University of California, Los Angeles YCCI Scholar Prejudice is bad for the heart—quite literally if you are on the receiving end. Tené Lewis has shown that there is a physiological connection between discrimination and cardiovascular disease, the leading cause of death among African Americans. A stress expert, Lewis was curious about the effects of “everyday discrimination,” such discourtesies as poor service in a restaurant or a frosty stare from a neighbor. “Years and years of having these experiences actually manifest in people’s bodies,” says Lewis. She found that African American women who reported frequent slights also had high levels of coronary calcification, a frequent precursor of cardiovascular disease. She has also established that discrimination is linked to C-reactive protein (crp), a blood protein that rises in response to inflammation; and visceral fat around internal organs—two conditions associated with heart disease. Lewis calls the work “provocative but exciting.” The obvious next step is prevention. “There are no easy or simple solutions,” says Lewis. But she’s already exploring whether coping skills can have a protective effect and whether discrimination occurs more frequently in certain environments. Being a ycci scholar accelerated her work, Lewis says. She had dedicated time as a junior faculty member to pursue her research and was able to use ycci resources to get help with study design, blood analysis, and other tasks. Having made landmark findings regarding a health problem early in her career, Lewis has decades ahead of her to contribute to a solution.

African American women: • Are more at risk of heart disease than any other major ethnic group in US • Have higher incidence of diabetes and hypertension • Are underepresented in major research trials • Are up to 60% less likely to receive aggressive diagnostic testing ycci.yale.edu

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EDUCATION

Chiang-Shan (Ray) Li, md, PhD Getting control over cocaine Associate Professor of Psychiatry and Neurobiology MD – National Taiwan University PhD – California Institute of Technology YCCI Scholar If a restaurant you’ve long patronized serves you a badly cooked meal, you’re less likely to return. This kind of behavioral adjustment rests on an ability called cognitive control. People who abuse drugs often have poor cognitive control. “None of them will tell you that substance abuse is great,” says Chiang-Shan (Ray) Li. But despite lost jobs and fractured relationships, the signal to change is weak and makes quitting that much harder. Li tested his subjects’ cognitive control by asking them to press or stop pressing a button according to the signal

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YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

displayed on a screen in front of them. Then he adjusted the signal timing to make the test more difficult. People with no history of drug use were better able to slow down to increase their accuracy than were former cocaine users. As a ycci Scholar, Li had access to functional magnetic resonance imaging (FmRI). This type of scan allowed him to see what parts of the subjects’ brains were actually at work. The prefrontal cortices of the two groups were responding differently, but there was a range of responses even among the former cocaine users. Li sees potential here to screen for poor cognitive control as people enter drug treatment and provide them with additional support when necessary. When Li administered Ritalin, the stimulant used to treat attentiondeficit/hyperactivity disorder (adhd), to former cocaine users, they performed better on the test. That finding suggests a therapy that could aid recovery under controlled conditions. Again, the subjects’ responses varied. Li is now seeking additional nih support to take his work a step further and see whether there is a genetic basis for the difference he’s seen in former cocaine users. Determining that a genetic basis does exist may lead to developing new drugs to help people remain in recovery. 

Peter Morgan, ms, md, PhD It’s easy to get inside a sea slug’s head. In Peter Morgan’s earliest experiments, he would wave seaweed in front of the creatures and record their neural activity. Finding out what makes people tick, of course, is more challenging but ultimately far more rewarding. Morgan is particularly interested in substance abuse, a disorder that has a shortage of research to inform treatment. “It leaves clinicians wondering what they can and should do,” he explains. Morgan studied men in recovery in their first weeks off cocaine. They reported sleeping well, but they were actually sleeping less than they believed and were particularly deficient in high-quality “slowwave” sleep. Could the stress caused by poor sleep contribute to relapse? Though the subjects are unaware of their sleep deficits, the effects are clear. Morgan’s volunteers performed poorly on cognitive tests, as sleep-deprived patients generally do. These men may be tricked into thinking they sleep well by a defect in their homeostatic sleep drive—the inner clock that regulates sleep and wakefulness. Morgan is investigating whether a stimulant called modafinil might reset that faulty drive and give users better quality sleep. Morgan terms this kind of work “patientoriented research” and says that it demands an investigator be readily available for study volunteers. Most junior faculty members spend a significant portion of their day working as clinicians. “That leaves you without the time or the desire to do this kind of work. Because I had a career award through ycci, I was able to spend all my time doing research. I couldn’t have done this study otherwise.”

Resetting the inner clock to aid addiction recovery Assistant Professor of Psychiatry MS – University of California, Davis – LLNL MD, PhD – Mount Sinai School of Medicine YCCI Scholar

ycci.yale.edu

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EDUCATION

Elijah Paintsil, md Research with a global impact Assistant Professor of Pediatrics and of Pharmacology MD – Ghana Medical School YCCI Scholar

“I was watching children die of measles,” remembers Elijah Paintsil. As a district health director in his native Ghana, he desperately needed more measles vaccine. External donors were giving ample resources for family planning but they would not consider his request to divert funds to fight infectious disease. “This is happening to us in Africa just because we don’t have the capacity to do research,” the young doctor thought. He came to the United States determined to obtain training as an investigator. Though a practicing physician, he had to repeat residency training. He had had virtually no lab experience when he arrived as a fellow at the Yale School of Medicine. “ycci, personally and professionally, was great because it offered me that transitional period,” he says. As a ycci Scholar, he received the mentoring and training he needed to reach his goal. Paintsil investigated how long hepatitis C survives in used syringes and found that the virus can live longer than 60 days. This finding offered a valuable clue as to why hepatitis C is spreading so fast, particularly in resource-limited countries. Paintsil has applied for nih funding to build on these findings and translate them into public health strategies to prevent hepatitis C transmission. Combining his own experience living and working in Ghana with the research skills he’s acquired at Yale, Paintsil is hopeful that he can improve the systems that once so badly frustrated him. “I see myself as a bridge,” he says. 60

YCCI: A Bridge Across Disciplines to Strengthen Clinical and Translational Research

Erik Shapiro, ms, PhD Waking up the body’s own repair crew  ssistant Professor of Diagnostic Radiology A and Biomedical Engineering MS, PhD – University of Pennsylvania

New Innovator Award, National Institutes of Health YCCI Scholar

Medicine has struggled to find a way to repair neurological damage in a host of disorders ranging from Alzheimer’s disease to stroke. Erik Shapiro is betting that the body has its own powerful healing tool; the trick is figuring out how to use it. Shapiro works with dormant stem cells that are present in all our bodies, and like embryonic stem cells, able to develop into useful tissue. In theory, these cells could migrate to a stroke lesion, for example, and replace damaged tissue. Using magnetic particles as markers, Shapiro has been able to use magnetic resonance imaging (mri) to observe stem cells as they move through living tissue. “For every reason why it does work, I can think of 20 reasons why it shouldn’t have worked,” says Shapiro, who terms his work “high-risk, highreward science.” Ultimately, he hopes to manipulate these cells to effect repairs where they are needed. As a ycci Scholar, Shapiro was able to access the multimillion-dollar imaging and stem cell resources the project required. “Here we can move very, very fast. There aren’t a lot of barriers,” says Shapiro. His work demonstrated enough promise to win a highly competitive New Innovator Award from the National Institutes of Health, which comes with $1.5 million in support funding. ycci helped him not only to design a better study, he says, but also to envision the clinical applications of his laboratory work. “I don’t have to just hand this off to somebody else. I want to see this through,” he says.

ycci.yale.edu

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National Center for Research Resources Clinical and Translational Science Award Recipient

Design: Group C Inc | Writers: Jill Max, Colleen Shaddox | Copyeditor: Rebecca Frey, PhD | Photography: Robert A. Lisak; Terry Dagradi; Jerry Domian; Henry Douglas; Nick Gaich; Michael Greenwood; Brad Horrigan; Jared Lazarus; Nicholas Licht; Michael Marsland; Kristen Myers; Frank Poole; Harold Shapiro | Printing: RR Donnelley – Andrews CT Plant

2 Church Street South, Suite 114 New Haven CT 06519 203-785-3482 ycci.yale.edu


2010 YCCI Annual Report