F.2.2 Design, Biostatistics and Clinical Research Ethics

Principal Investigator/Program Director (Last, first, middle): Mulshine, James Lawrence

F.2.2 Design, Biostatistics and Clinical Research Ethics F.2.2.A. Overview: Successful conduct of all forms of translational research requires excellent design and statistical resources, and a central purpose of the activity proposed here is to provide Rush investigators with access to the relevant knowledge and resources in this area. In doing so, the focus is on supplying design and biostatistics knowledge and support that are practically suited to investigator needs. Relevant knowledge and support in clinical research ethics is also essential to translational research. Our goal is integration of knowledge of clinical research ethics into all aspects of the Rush Translational Science Consortium (RTSC), both research and operational. Achieving this goal requires emphasis on specific aspects of research ethics: practical application to the design, development and conduct of protocols, everyday situations, particularly the fundamental tenets underlying the establishment of federal regulations for oversight of human subjects research, and providing comprehensive education and training in clinical research ethics not only for trainees but also the larger research community. Although design, biostatistics, and clinical research ethics resources at Rush are strong in established research groups, we seek to transform the existing resources by using the RTSC as a catalyst to provide a point-of- contact for investigators who do not have established statistical, design or ethics collaborators. To do so, we propose the following Specific Aims:

F.2.2.B. Specific Aims Specific Aim # 1: Provide design, biostatistics and ethics support for the activities of the RTSC and increase resources devoted to projects outside established research groups. Specific Aim # 2: Prioritize the allocation of design, biostatistics, and ethics resources of the RTSC to best achieve the goals of the RTSC and of the CTSA program overall Specific Aim # 3: Achieve integration of knowledge of clinical research ethics with all aspects of the RTSC Specific Aim # 4: Inculcate an environment of research ethics awareness within the research community. F.2.2.C. Background and Significance: Studies involving the translation of scientific knowledge into practical clinical application require careful attention to ethical principles. History teaches that intellectual advances alone do not guarantee successful innovations in human medicine, and studies should guard against the assumption that new approaches will result in improved care. Research ethics therefore demand rigorous evaluation of innovative practice. Design and biostatistics knowledge and resources are also essential to the development and conduct of translational research. As 21st century translational research continues to evolve to address more adequately the complex health issues that confront our society, design, biostatistics and ethics will remain essential. Changes in several areas are especially important: Studies in many area of translational research have become more interdisciplinary in character. Rarely are the knowledge and skills of a single discipline sufficient to address the complex health challenges confronting us today. This need for involving multiple disciplines is especially relevant to study design and biostatistics, as skill in this discipline is often crucial to achieving success in translational research. Studies in clinical areas are increasingly able to call on advanced techniques of great complexity to address their issues. In many areas of research, highly complex techniques that were limited to the laboratory have been adapted for use in large-scale clinical studies. As a result, translational research studies produce information that is unprecedented in quantity and complexity.

A range of design and biostatistics techniques and skills have developed to meet these challenges and it is essential to make knowledge and resources in these areas, as well as in somewhat more conventional areas, available to translational researchers. The teams of investigators must include people with varied training and the capacity to adapt ideas to new areas and to develop new methods, and must emphasize connecting experts with scientists leading translation projects.

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F.2.2.D. Preliminary Studies: Efforts in design, biostatistics, and ethics at Rush have been productive in a number of discrete centers, but have not been widely accessible to investigators outside these groups. The current design and biostatistics efforts will be discussed in three broad categories: clinical trials, longitudinal observational studies, and other RTSC studies and activities. The statistical support provided to the Rush Research Mentoring Program shows that small percentages of effort contributed by several skilled people has been very efficient in supporting new investigators of the RTSC; this experience demonstrates that this model can be very effective. (See Section F.2.3. Research Education and Training) We outline the personnel and achievements of the main centers and their achievements, and the ethics work in progress. F.2.2.D.1. Design and Analysis of Clinical Trials: Historically, Rush has been an active and valued clinical center in numerous major national clinical trials, often through the Rush Department of Preventive Medicine. A few examples of large-scale trials of important health issues in which Rush has been a clinical center include the Multiple Risk Factor Intervention Trial (MRFIT), the Trials of Hypertension Prevention (TOHP), the Women’s Health Initiative (WHI), the African American Study of Kidney Disease and Hypertension (AASK), the Antihypertensive and Lipid Lowering to Prevent Heart Attack Trial (ALLHAT), and the Enhancing Recovery In Coronary Heart Disease trial (ENRICHD). Rush continues to participate as a clinical center for many trials in a wide range of areas and disciplines. Three areas in the conduct of clinical trials have received increasing effort at Rush. One area is behavioral trials, evident already in studies such as MRFIT, ENRICHD, and the dietary intervention component of the WHI above. Current behavioral trial efforts include the Heart Failure Adherence and Retention Trial (HART), a trial of self-management training in patients with systolic or diastolic heart failure, and the Mexican-American Trial of Community Health Workers (MATCH), as well as the recently awarded project entitled Developing an Intervention to Prevent Visceral Fat in Premenopausal Women (U01HL097894, L. Powell PI). A second area receiving greater emphasis is that Rush investigators are playing a larger role in the design and overall supervision of trials, including direction of national coordinating, data management, and statistics centers. A recent (1995-2003) example is the African American Antiplatelet Stroke Prevention Study (AAASPS) (R01NS33430, P. Gorelick PI), a multicenter trial of 1,809 African American stroke patients from over 60 sites in the United States, showing that aspirin was as effective as ticlopidine for prevention of a second stroke in this population. The national coordinating and data management centers, as well as a clinical center, were located at Rush. Statisticians who designed and led the data management center are part of the proposed core. The population of Chicago is approximately one-third non-Hispanic black, one-third non Hispanic white, and one-third Hispanic, facilitating a third developing trend in clinical trials at Rush: conduct of trials among ethnic minority subjects. Rush’s activities have been prominent both as a clinical center responsible for the enrollment of substantial numbers of minority subjects in large multi-center trials and as the home of the leading investigator in studies of issues of particular interest to ethnic minority groups. An example of the first role is serving as a productive clinical center in the WHI trial. Examples of the second role include the African American Antiplatelet Stroke Prevention Study, the African American Study of Kidney Disease and Hypertension, and the Mexican-American Trial of Community Health Workers (MATCH, R01DK061289, S. Rothschild PI, described in the Community Engagement Core (See F.2.7.D.2.d.).

F.2.2.D.2. Design and Analysis of Longitudinal Observational Studies: Longitudinal observational studies are a central part of the current Rush translational research effort, and the design and biostatistics knowledge and resources necessary for investigations in this general area are well developed, although they have not yet been organized into an optimal mechanism for supporting translational research as envisioned in the CTSA program. Current NIH-funded, large-scale, observational studies include the Chicago Health and Aging Project (CHAP) (Risk Factors for Incident AD in a Biracial Community, R01AG11101, D. Evans PI). CHAP is a population-based study of all residents over-age-65 of a geographically defined area that has been funded since 1993, described by the Community Engagement Core (See F.2.7.D.1.a.). More than 50 publications have resulted from the study. A noteworthy characteristic of the study is that it has provided an efficient base for additional studies such as “Long- Term Dietary Risk Factor Assessment and Incident AD”, R01AG021972, M.C. Morris PI; “SES and Age- Related Disability in a Biracial Community”, R01ES10902, C. Mendes de Leon PI, and “Epidemiologic Study of Persons with Alzheimer's Disease”, R01AG 09966, D. Evans PI. Two statisticians from CHAP will participate in this core. Another large-scale, longitudinal observational study is The Religious Orders Study (ROS), a core of the “Rush Alzheimer’s Disease Core Center” (P30AG10161 D. Bennett PI), a study of Alzheimer’s disease and cognitive decline that combines intensive longitudinal clinical observation with obtaining brain tissue at death. (Section F.27.D.1.). Subjects are Catholic nuns, priests, and brothers over age 65 whol agree to brain autopsy at death. Compliance with brain autopsy at death is excellent (459 of 488 deaths, 94%). The average interval between death and autopsy is 8.3 hours. Brain tissue and data obtained in the study are very widely distributed to other investigators nationally. Over 140 publications (published or accepted) have resulted from the study. This study has also served as a highly efficient base for additional studies, including “Risk Factors, Pathology, and Clinical Expressions of AD”, R01AG015819, D. Bennett PI; Epidemiology of Neural Reserve and Neurobiology in Aging, R01AG017917, D. Bennet PI; and “Epidemiologic Study of Vitamin E, Diet and Age-Related Neurologic Diseases”, R01AG031553, M.C. Morris PI. These studies are in turn bases for more studies, including “Stroke and aPL: Community-Based Clinicopathological Study” (R01HL096944, S. Levine PI, Mount Sinai School of Medicine, New York University) recently funded by NHLBI. Two statisticians who work on ROS will participate in this core. Another noteworthy longitudinal observational study conducted at Rush and six other sites across the nation is the Study of Women’s Health Across the Nation (SWAN) (U01AG012505, L. Powell PI) (SWAN), with the Rush site directed by Dr. Lynda Powell. SWAN is a multi-center, multiethnic, community based longitudinal study designed to characterize the biological, symptomatic and psychosocial changes that occur during the menopausal transition and the effects of these changes on women's health during and after the transition. Specimens from baseline and follow-up visits are stored in the SWAN biological specimen repository. The population studied by the Chicago center of the SWAN study is drawn from the same geographically defined area of the south side of Chicago as the CHAP study. The Chicago center of the SWAN study has also served as a highly efficient base for additional studies, including “Prevalence & Progression of Subclinical Atherosclerosis” (R01HL067128, L. Powell PI), “A Longitudinal Study of the Menopause and Fat Patterning” (R01HL065581, L. Powell PI) and “Psychosocial Factors, Chronic Stress and Progression of SCD [Subclinical Disease] in Women” (R01HL089862, I. Janssen, PI). Statisticians associated with SWAN will participate in this core.

F.2.2.D.3. Design and Analysis of Other Translational Studies: Rush has many translational research projects that do not fall into the two categories above. Many of these other studies require the use of fairly straightforward designs and analytical procedures, and RTSC design and biostatistics resources are fully adequate to the requirements of these studies. The design and biostatistics support of operational and administrative functions is a function at which design and biostatistics personnel function well and which will expand as necessary to support the operational requirements of the RTSC. A category deserving fuller consideration is support of developing research areas with extensive design and biostatistics requirements. A relevant example is formed by studies with exceptionally large numbers of variables per subject, such as genome-wide association studies (GWASs). Rush’s approach to this situation is to

PHS 398/2590 (Rev. 09/04) Page ___170__ Continuation Format Page Principal Investigator/Program Director (Last, first, middle): Mulshine, James Lawrence collaborate with other institutions that are nationally recognized for achievements in these sophisticated areas. A current example is “Genetic Epidemiology of Cognitive Decline in an Aging Population Sample” (R01AG030146, D. Evans PI), an recently funded investigation with an initial GWAS conducted in the ROS and subsequent validation of the 1500 strongest associations in a confirmatory cohort from the CHAP study. (Both ROS and CHAP are described briefly, above.) As described in sub-section F.2.2.E.2.C., the statistical analysis of GWAS is being conducted in collaboration with the Broad Institute of the Massachusetts Institute of Technology and the Department of Genetics of Harvard University to permit more efficient utilization of the knowledge in design and biostatistics gained from such collaborations in translational research. F.2.2.D.4. The Rush Research Mentoring Program: The Rush Research Mentoring Program, as described in the Research, Training, Education and Career Development (see Section F.2.3.) was started in July, 2006 to prepare junior faculty members at Rush University Medical Center and Stroger Hospital of Cook County to lead funded programs to support the goals of the RTSC. Mentees are nominated by their section heads/chiefs. Their department must commit to provide least 20% protected research time, and mentees are expected to dedicate an additional 20% of their personal time to research. The program has evolved to serve participants in three translational research tracks (clinical, population-based, and laboratory-based), all four Rush colleges –the colleges of Medicine, Nursing, Graduate and Health Sciences, and John Stroger Cook County Hospital. One of the components is an organized system to access statistical analysis. Mr. Todd Beck, a master’s level statistician with over 10 years experience at the Rush Institute for Healthy Aging (RIHA), has provided statistical consulting services to mentees since the program’s inception, consulting with 20 mentees and investigators associated with the program in the past 3 years. A faculty statistician (currently, Dr. K. B Rajan) has been available to Mr. Beck for advice on multivariate models or complicated methods. Typically, mentees require power calculations for grant applications, as well as straightforward analyses for their preliminary data sections. The program has successfully employed two modes: (1) a “drop-in statistician” model with fixed office hours and (2) email consultations triaged through Dr. K. Skarupski, a Medical Sociologist and the program’s director. As described in the Research, Training, Education and Career Development Core (see Section F.2.3.), the mentees have been productive in grant submission, grant receipt and publications, in sharp contrast to 2007 when the program began and only one mentee secured competitive research funding. One of many elements in this significant transformation was the statistical core resource. F.2.2.D.5. Clinical Research Ethics: Rush as an institution encourages a culture of integrity, and the specific steps taken to implement adherence to these values in the area of research are detailed in the Regulatory Knowledge and Support Core Section (see Section F.2.1.) of this application and interwoven throughout the research education, training and career development section. These steps facilitate achievement of RTSC clinical research ethics aims because they provide a strong infrastructure on which to build. Briefly, Rush has established an Office of Research Integrity (ORI) and Regulatory Affairs and fostered the tight integration of this office’s activities with those of the Research and Clinical Trials Administration Office. Coordination with the ORI’s infrastructure emphasizing novel education and with the Rush Research Portal providing computerization of investigator interactions with the IRB will be especially valuable to clinical research ethics activities. The Office of Research Integrity and Regulatory Affairs will function as the lynchpin among the three divisions to assure integration and avoid duplication since it is responsible for the development of the comprehensive educational program for the research community.

F.2.2.D.6. Network and mentoring among the statistical community at Rush: As Rush University does not offer degree programs in biostatistics, several distinct research centers have statisticians. The challenge in this environment is to develop professional collegial interactions among the statisticians. In 2009, three different groups at the Rush University Medical Center have added statistical staff: three M.S. biostatisticians and 3.5 FTE Ph.D. statisticians. With this expansion, Dr. Sue Leurgans and Dr. DeJuran Richardson, biostatisticians who started at the Rush Medical Center in 1992 and 1993, respectively, are committed to reinforce the collegial network by coordinating a monthly meeting for statisticians, mostly recently attended by 7 Ph.D.s and 9 M.S. Statisticians. This network is supported by email, and will include short research and problem presentations, thus providing essential support for further professional development of biostatisticians working at Rush and facilitating the rapid integration of a new senior faculty biostatistician, to be hired to increase the attention to researchers outside of established groups. F.2.2.D.7. Prioritization and Tracking of Statistical Effort within Research Groups: The Design Biostatistics Ethics and Design Core is committed to demonstrating a clear and efficient method of tracking and prioritizing projects. Two groups at Rush, those in the Rush Alzheimer’s Disease Center and in the Rush Institute for Healthy Aging, have been using simple databases to track projects and requests for over a year. Both track standard information on each project and a written analysis request, with a priority and a target date attached. The managing statisticians can assign the requests to specific analysts, and can monitor progress. Multiple users can use the dataset at the same time. Output is loaded up onto the server and is stored in the same database. Investigators can see the progress on the projects for which they are collaborators. The location of the program used to run the analyses is also stored, so that repeating analyses or extending them requires only minimal effort to locate the starting point. Replacement of email as the mode of providing output and reports to investigators has proven to be a substantial boon for rapid research by providing a central catalog of the accurate and final reports. Many statistical requests (averaging over 10 per week) have been tracked efficiently using these systems. The experience we have gained with these systems will prepare us to develop rapidly for rapid development of a Sharepoint application for the larger community of Rush researchers early in the operations of the CTSA. F.2.2.D.8. Achievements of Staff who will work with the RTSC: The Biostatistics, Ehics and Design Core faculty who will work with the RTSC investigators are all actively collaborating with translational researchers, and are represented in more than 50 publications since the last submission from Rush. The senior biostatisticians have extensive collaborative experience, including working with investigators outside of Rush. F.2.2.D.8.a. Sue Leurgans, Ph.D., has been a Professor at Rush since 1992, in the Departments of Preventive Medicine and (since 2000) Neurological Sciences. She also is a member of the Graduate Faculty, Division of Neurological Sciences. Her record includes work on clinical trials, longitudinal studies, and other investigations, together with many clinicians and other medical scientists, including many of the statisticians to participate in this Core. Her 15 publications in the last two years are coauthored with neurologists, neuroscientists, and other researchers. Many of them arise from her work as the Senior Statistician in the Rush Alzheimer’s Disease Center, where she now leads a team of 7 statisticians. Since 2000, she has also been Core Leader for two NIH-sponsored program project grants described in section F.2.7. Community Engagement. She seeks to exploit modern statistical methods (such as extensions of proportional hazards models to multiple events or multiple outcomes) to best advance knowledge about the brain. F.2.2.D.8.b. DeJuran Richardson, Ph.D., first joined the faculty at Rush in 1992 in the Department of Preventive Medicine. He is a Biostatistician who possesses considerable expertise in data management operations and the design and analysis of clinical trials. Dr. Richardson’s experience extends over twenty years and includes being a Director of data management operations and Chief Biostatistician. Among his many appointments, he has served on numerous NIH panels and data monitoring committees. In the last two years, he has 5 publications in cardiology and neurology settings, while holding a senior administrative appointment at Lake Forest College. These publications include two invited chapters on data management and statistical analysis issues included in the recently published text Clinical Trials in the Neurosciences. He has a longstanding interest in the recruitment of diverse students to the study of statistics.

F.2.2.D.8.c. Sanjib Basu, Ph.D., joined the Rush faculty 2003 in the Department of Preventive Medicine and in the Graduate College, while maintaining an appointment at Northern Illinois University, where he is now Professor. Dr. Basu has published extensively in premier statistical methodological journals, has been PI of a federally funded statistical methodological grant and is an associate editor of two statistics journals. In the past two years, he has 15 publications ranging from applications of Bayesian methods in survival analysis to applications in thoracic surgery and oncology. The biomedical publications employ random forests, classification trees and other sophisticated statistical methods for biomarker selection, classification and prediction. He is a proven versatile collaborator and thoughtful researcher. In the two years since the last Rush CTSA submission, he has 15 papers published or accepted for publication. F.2.2.D.8.d. Imke Janssen, Ph.D., joined the faculty of the Department of Preventive Medicine in 2001. She has worked extensively on analyses of data collected about the menopausal transition Studies of Women Across the Nation (described in Section F.2.7.D.2.a.) and on clinical trials (HART). She has particular interest in the relationship between hormone measures, risk factors, and subclinical disease. In the two years since the last Rush CTSA submission, she has 8 papers published or accepted for publication. F.2.2.D.8.e. Three biostatisticians completed their doctorates and joined the Rush faculty in the last year. Kumar Bharat Rajan, Ph.D., joined the Research Institute for Healthy Aging in December 2008. His research interests include statistical methods for epidemiological studies, methods for missing data, methods for diagnostic studies, and methods for correlated and clustered data. Bichon Ouyang, Ph.D., joined the Department of Neurological Sciences in April, 2009. Her research focuses on methods for analysis of survival data, especially recurrent events data. She is also interested in clinical trials. Lei Yu, Ph,D. joined the Alzheimer’s Disease Research Center and Department of Neurological Sciences in July, 2009. He has particular interest in longitudinal data analysis, generalized linear mixed modeling and stochastic process. His recent papers focus on multi-state Markov model for longitudinal data with categorical responses, and long- term behavior of the k-step transition probability matrix for a nonstationary discrete time Markov chain in the context of modeling transitions from intact cognition to dementia. F.2.2.D.8.f. Jennifer Weuve, Sc.D., Dr. Weuve is an epidemiologist whose training and expertise is in epidemiologic methods, aging and environmental health. Over the past ten years, she has been involved in critical aspects of several epidemiologic studies, including study design, data collection and management, data analysis and manuscript-writing. She has worked with a range of conventional study design (longitudinal cohort studies and case-control studies) and unconventional study design (a study based on birth cohorts, a co- twin study, and studies nested within clinical trials). Dr. Weuve also has experience mentoring in and teaching epidemiology. She recently co-organized and taught a popular seminar for an international audience on the use of causal diagrams in environmental epidemiology studies. Her research career has been characterized by in-depth, cross-disciplinary collaboration. The new, non-epidemiologist researchers who she has mentored have produced important contributions to the public health and clinical scientific literature. This experience is well-suited to consulting with a variety of investigators on study design. In the past two years, she has 13 papers published or accepted for publication. F.2.2.D.8.g. Clayton Thomason, JD, M.Div., Reverend Thomason, the chair of the Department of Religion, Health, and Human Values at Rush, is a well qualified ethicist with formal training in divinity, law and bioethics. He is a practitioner-educator engaged in the clinical delivery of care and the education of health care professionals. He has served on three different Institutional Review Boards. His programs emphasize the study of ethics, pastoral counseling and preparation for careers in health care ethics and clinical chaplaincy. Reverend Thomason currently runs a Clinical Ethics Consultation Service. F.2.2.E. Research Design and Methods: Overall Approach. We are mindful of the challenges in meeting our aims. We are aware of the national experience in which there is a gap between the supply of statistical effort and the requests for help, and we plan to address this gap by engaging our best staff and using their efforts efficiently. Based on the strengths of several cooperating groups of statisticians, and on the success of collaboration for mentees, we are following one of two models used in many CTSA Biostatistics cores: our staff is assembled from around the university. We understand that the success in providing design,

PHS 398/2590 (Rev. 09/04) Page ___173__ Continuation Format Page Principal Investigator/Program Director (Last, first, middle): Mulshine, James Lawrence biostatistics, and ethics support will require close coordination, and we already employ appropriate bioinformatics tools that facilitate the necessary interactions. Our approach to meeting RTSC goals in design and biostatistics emphasizes three organizational features that we label selection, access and collaboration. F.2.2.E.1. Selection denotes a strong orientation toward the design and biostatistics knowledge and resources that are most suitable for meeting Rush translational research goals. From the very wide range of statistical knowledge appropriate to translational research in general we have selected the elements most suited to current areas of emphasis and future growth at Rush. The translational research areas receiving emphasis are summarized in subsequent sections as clinical trials, longitudinal observational studies, and other studies. For each the design and biostatistics approaches are described. F.2.2.E. 2. Access denotes providing this expertise to investigators in a manner that is convenient and efficient. Excellent access is crucial to translational research because the clinician researchers have busy schedules. Access is a major consideration in setting our approach to design, biostatistics, and clinical research ethics. After review of the experience reported nationally [2] we anticipate that there will be a gap between the demand for statistical assistance/collaboration and the supply of statistical effort. Our plan includes two methods to “mind the gap”: consistent drop-in consulting and electronic requests submitted through the portal established by the Biomedical Informatics Core (see Section F.2.8.). Our approach is particularly suited to Rush, since most Rush departments, especially the more clinical departments, have few if any experts in study design, statistical analysis and clinic ethics support, even while established Rush groups have strong epidemiologic and biostatistical expertise collaborating on substantial amounts of NIH funded research. Those researchers outside these groups who want to perform clinical research either do so without this expertise, or beg for resources from the few major research groups at Rush, often too late and too little for optimal impact. The provision of trained research ethicists is also a limited resource that is largely confined to the Institutional Review Board process. The role of this Core will be to increase the extent to which statistical resources are available by removing barriers, while ensuring efficient use of statistics and research ethicist efforts. This challenge has lead the Rush leadership to provide new institutional resources to address this challenge, but we would also leverage the CTSA resource to support meritorious research that advances the CTSA mission. Consistent open-door walk-in consulting will be offered at fixed times at a single central location. Four faculty biostatisticians (Drs. Basu, Janssen, Rajan, Yu) and four experienced MS. Statisticians (Beck, Avery, Cursio, Carlson), will staff open-door consulting for two hour sessions. Each person will provide at most one session per week, and sessions will be held two days per week in the first year, with a planned increase to four days per week for the remaining years. Drop-in consulting will serve those with specific and focused questions requiring well-defined work without a series of follow-up meetings, such as responses to referee’s comments or early planning. Faculty biostatisticians will be on call to advise the MS statisticians, when needed. The second method of access will be investigator-initiated requests submitted through the portal whose construction and operation is Aim 2 of the Biomedical Informatics Core (see Section F.2.8.). Some of these requests will be linked to this portal from the Science and Technology Kiosk to be developed by the Novel Technologies Core as part of its Specific Aim1, described in Section F.2.4.B. above. Requests will be reviewed by core staff to determine the optimal design and biostatistics resources necessary to meet the investigator’s needs and identify a person with the appropriate skills to address these needs, whether for design advice, research ethics review or statistical planning or analysis. The director will consult with the investigator in the event that further definition of the request is sought. If the investigator’s needs are clear from previous experience, this step is directly with the biostatistician with whom the investigator has a productive relationship. Once the new project request is entered in the Sharepoint application described below, it will be assigned to additional staff as needed, and the Core Director will track its progress. Efforts will be made to maintain continuity so that the assigned staff member will typically remain associated with that investigator. Projects funded outside of the CTSA and including a statistical collaborator will of course remain the responsibility of that collaborator. The value of biostatistics and especially design and ethics input being considered at the earliest possible time, very early in the conceptualization of a study, will be strongly emphasized to investigators. Only before study operations begin can central design and ethics issues be adequately considered. Design issues often have a note of irreversibility that is typically absent from analytic issues: Design issues influence the nature of a study, its

PHS 398/2590 (Rev. 09/04) Page ___174__ Continuation Format Page Principal Investigator/Program Director (Last, first, middle): Mulshine, James Lawrence purpose, and its operations. For example, if the research design emphasizes a particular population [Hmong, Ashkenazi, etc.], the possibility of unintended consequences as a result of the research findings must be considered. If a protocol is focused on a particular population, ethicists can help ensure that the appropriate mechanism has been built-in to the research design to ensure that leaders in the particular community are identified, community input is sought, focus groups are held, etc. in advance of the research being designed and conducted. Moreover, if analytic issues are not considered as they should be, there is typically an opportunity to redo data analyses more appropriately. Clear informative and accurate analytic plans contribute dramatically to the effectiveness of the group. F.2.2.E.3. Collaboration among the several core activities of the RTSC is necessary to provide investigators with access to knowledge and resources in the many specialized areas that they need to conduct high-quality translational research. To provide smooth coordinated access to design and biostatistics resources, strong active collaboration between this activity and the activities proposed in the Pilot Studies, the Participant and Clinical Interactions Resources Section, Research, Training, Education and Career Development Section, and in the Biomedical Informatics Section is especially important. In general, Participant and Clinical Interactions Resources activities and Biomedical Informatics activities provide operational support, while meeting initial design and subsequent analytic needs are the goal of this activity. A substantial portion of the design and biostatistics services provided to investigators by the system outlined above will constitute direct costs of funded research. Thus, the cost budgeted for these activities is limited to those necessary to extend and transform existing resources into a system for developing interdisciplinary translational research within the RTSC. Specifically, these budgeted costs include those for creating a system to accomplish these goals and for providing the design and statistical knowledge that is essential to advancing important developing ideas in translational research that are not yet to the point of being ready for applications for funding. No CTSA resources will be used in the direct preparation of applications for funding, however. The steps for meeting clinical research ethics goals may be considered under the same three interlinked central organizational features noted above: selection, access and collaboration. As regards selection of the clinical research ethics material to receive emphasis, the emphasis will be given to material essential to meeting federal regulatory requirements for translational research. Access to this material is important for all RTSC personnel, and, computerized methods will be used both in providing personnel with access to this material in a manner that makes efficient use of their time and in assessing the knowledge required. Special emphasis will be given to instruction of RTSC trainees in clinical research ethics, and, again, computerized methods will be integral to this effort although, in view of the special importance of trainee instruction, direct face-to-face instruction will also be used. Close collaboration between this activity and the activities proposed in the Research Education, Training and Career Development Section and in the Regulatory Knowledge and Support Section is crucial to achieving these goals efficiently. The specific staffing and operational policies of the core would be managed by the Director with the advice of a 6-person Steering Committee. The Steering Committee members would be 3 biostatisticians (Leurgans, Richardson, Rajan), 2 design experts (Kornblitt, Weuve), and one ethicist (Thomason). The three biostatisticians include the Director and experts in clinical trials and longitudinal studies. The two design experts proposed include one clinician researcher/IRB chair and one epidemiologist (Weuve). We intend that one clinician researcher would be a current member of an IRB to strengthen the connection with the IRB.

F.2.4.E.2. Specific Aim 1: Provision of design, biostatistics and ethics support for the activities of the Rush Translational Science Center (RTSC). For the sake of clarity, design, ethics, and biostatistics support activities may be discussed into the three categories outlined below: clinical trials, longitudinal observational studies, especially large-scale ones, and other studies. This division is for clear discussion and to indicate the availability of suitable resources in relevant areas, not to indicate a pattern of artificial division between designs. Workers in the three areas will be aware of each other's activities and active collaborators when appropriate. As Director, Dr. Leurgans will have overall responsibility for aligning needs with staff expertise and informing the leadership of the CTSA about the balance between resources and needs. F.2.2.E.2.a. Support for Design and Analysis of Clinical Trials. The design and analysis of clinical trials may be discussed in five overlapping phases: design, initiation, operation, analysis, and close-out. The biostatistics support of clinical trials is typically most intense in the design and analysis phases. In all phases, this expertise will be accessible to RTSC investigators. All of the senior staff are experienced collaborators who take pride in making appropriate statistical methods accessible to busy clinical researchers. Dr. Richardson will have particular oversight over development of clinical trials, ensuring that appropriate methods are used, and that statistical analysts have the particular skills needed for the translational studies of interest. This Core will assist with planning and development; other resources will be used to support large clinical trials. Necessary design phase activities include clear specification of study aims and outcomes, both primary and secondary. A preliminary idea of the questions allows the investigative team to conduct a thought experiment to imagine the operation and analysis phases. A major purpose of this phase is to review any biases that may confound interpretation. We anticipate that the great majority of RTSC investigators will work with a biostatistician to draft an analysis plan and determine the power of the study for a range of feasible sample sizes for the primary aims at this stage. The sample size determines resources; constraints may result in major changes in eligibility, design, or outcomes. In turn, such major changes typically result in a new analysis plan and new estimation of the sample size. Before a protocol is completed, Design, Biostatistics and Ethics Core (DBEC) staff will review with the clinical trial investigators of the latest Consolidated Standards for Reporting Trials (CONSORT) [3-7] to verify that all necessary information is collected. This review of CONSORT will lead into study initiation, including setting up visit schedules, databases, randomization schemes, and training study staff in new procedures. Optimal performance of this review will require close collaboration between the team of trial investigators, DBEC staff and Biomedical Informatics staff. DBEC staff, typically the statistical analysts, will carefully verify that the datasets to emerge will contain all of the information required for the planned analyses in suitable format and will collaborate in the design of appropriate interim reports. During study operation, DBEC Staff will perform any interim analyses designed as part of the study or any reports requested by a monitoring board or a Safety Officer. For masked studies, masking will be maintained unless unmasking is directed by a person authorized to specify unmasked analyses. At least one internal interim analysis will typically be performed to verify data processing and to expedite final analyses. Biostatistics work will be most intense during the analysis phase, when the study analysis plan will be carried out on data established by the principal investigator. This phase will again require close collaboration of the team of trial investigators, DBEC staff and Biomedical Informatics staff. Typically, the DBEC staff most involved will be the Senior Biostatistician and the Statistical Analyst who worked on the analysis plan to assure continuity. The primary analysis will be performed in SAS, with command files documented carefully and saved. Supporting tables and graphs will be provided, and appropriate diagnostic methods used to check that the statistical methods planned before data were collected remain appropriate. The goal of the DBEC team will be to assist the principal investigator in acquiring complete understanding of the analytic findings of the study. The close out phase will include archiving data and providing a copy of the final locked data set to the investigator. DBEC will maintain copies of all programs and final output files to permit review of all analyses as required.

F.2.2.E.2.b. Support for Design and Analysis of Longitudinal Observational Studies. As discussed above, RTSC translational investigators will be strongly encouraged to seek consultation with DBEC staff at the initiation of a study rather that at its conclusions. The study design chosen to address an issue often has a decisive effect on the validity of study results, and it is at the starting point of a study that design and ethics advice can be most useful and make the greatest contribution. We are not under an illusion that this will be the invariable course followed by investigators, and will make it thoroughly clear that DBEC resources are available to investigators at any point in the course of a study that they find them useful. Nonetheless, the earliest possible use of these resources will be strongly encouraged. Dr. Janssen will have particular oversight over development of longitudinal studies, ensuring that appropriate methods are used. She will work closely with Dr. Weuve and Dr. Yu. Early consideration of design is especially relevant to observational studies, in which the advantages of a prospective longitudinal design are well suited to investigation of many issues in translational research. A well- designed study can give researchers the ability to answer questions about outcomes that change over time; for example, one could examine risk factors for a disease or condition, evaluate the success of a community-based program, measure the natural course of a disease in a community or clinic setting as preparation for designing an intervention. Before a protocol is completed, DBEC staff will review with the investigator team the latest Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement [8, 9] to verify that all necessary features are present. This review of STROBE will lead into study initiation, including setting up visit schedules, databases, and training study staff in new procedures. Optimal performance of this review will require close collaboration between the team of trial investigators, Design and Biostatistics staff and Biomedical Informatics staff. Design and Biostatistics staff, will carefully verify that the datasets to emerge will contain all of the information required for the planned analyses in suitable format and will collaborate in the design of appropriate interim reports. Reports will be designed by MS statisticians working with the Biomedical Informatics Core, and benchmarks will be identified for key baseline and longitudinal analyses. Analyses will be based on written detailed plans, and will use appropriate models. Data will be reviewed both statistically and graphically. When models are run, appropriate statistical and graphical diagnostics will be checked. As manuscripts are completed, final tables and graphs will be prepared, and the entire manuscript reviewed. F.2.2.E.2.c. Support for Design and Analysis of All Other RTSC Studies and Activities. Other studies and activities is a heterogeneous category. Among its most important components is that of studies, not falling clearly into either of the two categories above, but highly important to the development of future RTSC research areas. Dr. Basu will have particular responsibility for these studies, in collaboration with Dr. Leurgans and Dr. Rajan, with Dr. Weuve consulting on epidemiologic design considerations as needed. Such a category is composed of studies involving exceptionally large numbers of variables per subject, such as genome-wide association studies in which current genotyping technology allows approximately one million single nucleotide polymorphisms (SNPs) and copy number polymorphisms (CNPs) to be generated and analyzed per subject. Nationally, this area is of rapid and intense statistical and design interest. In such a rapidly developing area, active collaboration with nationally recognized groups is often the best way to achieve state-of-the-art statistical approaches. For a middle-size research university such as Rush, with research strength concentrated in certain areas, emphasizing partnerships in which Rush can bring an area of strength to the collaboration and the partner can bring strength in the novel area is often an efficient strategy for becoming familiar with expert knowledge in new areas. In current collaborations in the area outlined above, the role of RTSC investigators is typically expert phenotyping for disorders affecting cognitive function of large rigorously defined cohorts of subjects, e.g., from the Religious Orders Study or the Chicago Health and Aging Project. For genotyping and techniques of statistical analysis the principal contribution is typically from the collaborating groups, e.g., the Broad Institute of the Massachusetts Institute of Technology and the Department of Genetics of Harvard University in two recent collaborations (Genetic Epidemiology of Cognitive Decline in an Aging Population Sample, R01AG030146, D. Evans PI; Risk Factors, Pathology, and Clinical Expressions of AD, R01AG015819 D. Bennett PI), and overall study design reflects contributions from all collaborating groups. To assist Rush investigators in developing partnerships with novel methods, the RTSC

DBE core will sponsor visits by experts from nationally recognized groups, including other CTSA’s. The format of these meetings would include both a public lecture and more targeted discussions. These discussions might include consultations with Rush investigators or a master class reviewing questions from the RTSC DBE Core staff. The goal would be for RTSC statisticians and RTSC investigators to learn how to best collaborate with those whose collaboration could most rapidly advance translational research. An important area for some of the T1 studies of methods moving from the laboratory to clinical investigations is the study of the diagnostic effectiveness of the methods. The traditional summaries of clinical testing via sensitivity and specificity are now subsumed for methods under development in the methods of Receiver- Operating-Characteristic (ROC) curves. An ROC curve is a function of the pairs of possible sensitivity and specificity as the cut-off level varies. This methodology is essential for the development of new biomarkers, in both continuous and discrete outcome settings. A biomarker has to undergo several stages of rigorous testing, before it can be accepted and implemented. These biomarkers need to show high classification accuracy, in terms of correctly classifying the diseased and non-diseased populations. Dr. Rajan is an active researcher in development and application in ROC curve methodology; his expertise will be available through this Core. A third area in this heterogeneous group is design and biostatistics support of all RTSC operational activities. For support of these activities, statistical or design complexity is typically not the decisive issue, but rather provision of appropriate resources in a timely fashion. Usually it is important to provide the support at the initiation of the operational activity and thereafter at appropriate intervals chosen to permit the efficient conduct of operational tasks. Active collaboration between this activity and the Core Biomedical Informatics activity is typically required because it is sometimes not clear to operational staff if a particular need is best met by a data management reporting mechanism or by a biostatistics analyst. F.2.2.E.2.e. Privacy and Security Protections. The ethicists, the design experts, and the biostatisticians are all very sensitive to the importance of protecting health information by storing it securely, limiting access, and protecting privacy and physical integrity. In addition to annual training required of all Rush University Medical Center employees, the staff of the core will be reminded regularly of the importance of protecting privacy. Since the data sources will be disparate, the staff will be vigilant in preventing receipt/storage of personal identifiers (such as name, address, phone number, social security number) by the core. Moreover, all data will be stored on password protected accounts on medical center computers and servers located behind the Rush University firewall. Access from outside the medical center will only be via personal SecurID, which supplies a personal suffix to the password for a given account. The personal suffix changes every 90 seconds, so that only someone who knows the account name, the fixed personal password, and has the SecurID available can be approved to access data through the firewall. Any paper copies of data will be stored only in locked files. F2.4.E.3. Specific Aim 2: Prioritization and evaluation of allocation of design, biostatistics and ethics resources. The considerations that will guide prioritization of design and biostatistics resources are the overall research and operational priorities of the RTSC, the strategic priorities of Rush University Medical Center, and of the CTSA program as a whole. The DBEC Core Director will report to the Director of the RTSC and sit on the Scientific Leadership Council (SLC), the senior representative body of the RTSC research community. The Director will convene Core Steering Committee meetings, link with the Biomedical Informatics Core and other cores as needed, and monitor the status of requests for statistical, design and ethics consultation. For design, biostatistics and ethics activities to adhere to these overall priorities, the priorities must be clearly communicated and there must be procedures to resolve any questions about the application of the priorities to a particular research project. Communication of overall priorities is anticipated to be straightforward as the Director of these activities will meet regularly with RTSC leadership and will take care that the leadership priorities are well understood by all other members of the design and biostatistics effort. These priorities will be set by the Director, in consultation with the Core Steering Committee. The priorities will be integrated into the SharePoint application that we describe below. Some specific principles for prioritization will guide the efforts. As part of the effort to develop promising research that is in an early stage, the pilot projects Section F.2.6. will have top priority, followed by projects be conducted by the lead mentees in the Training in Mentored Translational Research (TIMTR) program,

PHS 398/2590 (Rev. 09/04) Page ___178__ Continuation Format Page Principal Investigator/Program Director (Last, first, middle): Mulshine, James Lawrence followed by funded mentees and mentees in the TIMTR Section F.2.3. The next priority will go to strategic translational research priorities at Rush. An essential task for this core will be the efficient tracking of requests for assistance and of progress on these tasks. We will use a Microsoft Sharepoint application to track requests for statistics, design, and ethics resources. The Sharepoint application will allow for web-based submission, prioritization and tracking of requests. Personnel from Information Services and from the Biomedical Informatics Core will work closely with the Director to establish and test the application (for which Rush has an enterprise license) during the 12- week set-up phase, a development phase that will utilize the experience at Rush with tracking systems and also be informed by local and national CTSA experience The Biomedical Informatics Core will provide ongoing maintenance of this application, which will track investigators, their home departments or sections, any requests for consultation on design, analysis or ethics, and target dates. The Core Director will use the Sharepoint application to track work and record priorities. Any member of the staff of the core will be able to initiate requests, and direct them to appropriate staff members, so that the Director will not constitute a bottleneck. Walk-in consultations will also be tracked in the same system. Ethicists would be able to review all projects, and design experts would also be able to contribute. The type of assistance needed (design, ethics, data management, bioinformatics, statistical analysis) will be tracked. Core staff will record the location of all programs used to obtain results. Output will be stored by the Sharepoint application, as well. The Core staff will track resulting grant submissions and publications. The Sharepoint application will reside on a secure server, but will be accessible from the Rush Intranet, or by SecurID, from any computer with an internet connection. Routine Evaluation of the status of all requests will be essential for the Core Director and Steering Committee to identify areas in which improvement would be important. The Sharepoint application will be programmed to provide routine reports, with the intent of identifying areas for improvement, documenting the range of investigators who are receiving service, the submissions of grants and manuscripts, and the publication and funding successes. The Core Steering Committee will also monitor the tasks and the timeliness of completion. This will give direct evidence of the size of the gap at Rush between demand and resources. This information will be reported to the SLC, so that resources can possibly be sought to reduce any gap. This information can also be used to guide the expectations of researchers. Questions about the application of priorities to a particular research project will come up most strongly and will be most important to resolve clearly for projects that require the most substantial expenditures of design and biostatistics resources, and such projects will receive the most attention in this regard. Any priority questions about projects that do not require substantial resources will tend to resolve quickly and will have less impact on resource expenditure. The Director will track projects on a monthly basis, and will use the Sharepoint application to identify projects which appear to be in the top 25% of all projects in amount of effort required. On the basis of the scientific aims of the project, the Director determine whether the expenditure of design and biostatistics effort matches the priority of the project. Situations in which there is any doubt will be taken to Core Steering Committee by email poll and to RTSC leadership meetings for definitive resolution of the priority. It is anticipated that such definitive resolution will be most often necessary for developmental projects requiring substantial early design and biostatistics effort. Having this effort at an early stage of the project is often vital to achieving success, but whether this expenditure of effort is warranted by the scientific importance of the project to RTSC future development can frequently require consultation with RTSC leaders. The Director will be a member of the SLC and will report to the Steering Committee quarterly. An early focus will be on effort, on timeliness of projects, and on outcomes (submissions of manuscripts and grant proposals and rates of success). The RTSC evaluation system will be reviewed at start-up of the center so as to ensure that the metrics used nationally can be implemented, as well. The Core Steering Committee will also discuss allocation of effort between the two modes of assistance (drop-in and specific assignment) and among the three types of studies (pilot studies, RTSC investigators, other studies according to the strategic plan.) The Core Steering Committee will also be aware of the national experience.

F2.4.E.3. Specific Aim 3: Clinical Research Ethics: Achieving Integration of Knowledge across All RTSC Activities. Knowledge of clinical research ethics is crucial to RTSC activities, both research and operational. The selection of ethical topics for emphasis is facilitated by the substantive content contained in the large body of federal standards and regulations in this area. With some inevitable exceptions, the substance of these regulations reflects consensus about the topics deserving the most attention. Further, knowledge of these topics is typically of the most practical value to translational investigators and staff as close compliance with relevant federal regulations is essential. For the sake of discussion and not to create artificial divisions, as emphasized above, two relevant general ethical areas of knowledge may be distinguished: research integrity, and human-subjects research ethics. For research integrity, major relevant topics include responsible conduct of research/avoidance of scientific misconduct and avoidance of conflicts of interest. Many of the principles of research integrity that must be emphatically conveyed to investigators and staff are inherent in the widely accepted federal Department of Health and Human Services (DHHS) Office of Research Integrity (ORI). The definition of research misconduct is “Research misconduct means fabrication, falsification, or plagiarism in proposing, performing, or reviewing research, or in reporting research results, ” where specifically “(a) Fabrication is making up data or results and recording or reporting them, (b) Falsification is manipulating research materials, equipment, or processes, or changing or omitting data or results such that the research is not accurately represented in the research record, (c) Plagiarism is the appropriation of another person's ideas, processes, results, or words without giving appropriate credit. (d) Research misconduct does not include honest error or differences of opinion.” (http://ori.hhs.gov/misconduct/definition_misconduct.shtml)

Responsibility for avoidance of conflicts of interest is recognized as a responsibility of institutional IRBs. Mechanisms for avoiding and handling of conflicts of interest at Rush are described in more detail in the Regulatory Knowledge and Support Section of this application. Briefly, Rush requires disclosure of any financial interests of $5 thousand or greater, research and the Rush ORI Conflict of Interests Committee monitors the involvement of research personnel, evaluates particular scenarios and, when necessary prescribes approaches to address any issues of concern. In the area of human-subjects research ethics, major relevant topics include: ethics codes and standards and the regulations that flow from them (The Common Rule), Privacy (both considerations of The Health Insurance Portability and Accountability Act (HIPAA) and of maintenance of confidentiality), and IRB procedures. For conveying understanding of and compliance with ethics codes and standards and the regulations that flow from them to RTSC faculty and staff, the methods used will be fully compatible with those outlined in the Regulatory Knowledge and Support Section. This approach will emphasize faculty and staff clearly understanding the rational basis for adherence to human-subjects regulations and conducting themselves in accord with relevant regulations. Assurance of privacy for all subjects is especially important for RTSC faculty and staff to understand and comply with. An area of great relevance to the conduct of translational research studies is understanding the practical steps that must be taken to maintain of subject confidentiality, ranging from use of appropriate procedures in contact with subjects while others are present, while maintaining an appropriately friendly and productive relationship with the subject, to maintenance of confidentiality of computerized datasets. Knowledge and understanding of the ethical basis of IRB procedures and of the ethical rationale for the foundations of the overall IRB system is crucial to achieving full compliance with the IRB procedures described in detail in Regulatory Knowledge and Support Core, a core with which we will work closely. Meeting the goals outlined above will require the full cooperation of all RTSC faculty and staff. We believe that the best way to secure this cooperation is threefold: by emphasizing the rational basis for understanding and complying with these ethical imperatives, by making access to the necessary knowledge as convenient as possible to all faculty and staff, and by testing each person’s understanding of the necessary knowledge with refreshment of this knowledge as indicated. We will approach this goal in collaboration with the personnel of the Regulatory Knowledge and Support activities, and of other core activities as appropriate, e.g., of Biomedical Informatics for assuring confidentiality of computer files. These collaborations will minimize the burdens on

PHS 398/2590 (Rev. 09/04) Page ___180__ Continuation Format Page Principal Investigator/Program Director (Last, first, middle): Mulshine, James Lawrence faculty and staff time and will combine similar activities whenever possible. Multiple modes of presentation will be used, e.g. presentations at meetings such as departmental grand rounds and face-to-face lectures, but the efforts will make strong use of computer technology whenever possible both in communicating knowledge and in subsequently assessing that knowledge and preparing for re-instruction as necessary. F2.4.E.4. Specific Aim 4: Inculcate an environment of research ethics awareness within the research community. A group of RTSC personnel that deserves special attention with respect to clinical research ethics is trainees. In general, trainees are younger and at more formative stages of their careers than are other RTSC faculty and staff. The knowledge that they acquire about clinical research ethics at this stage will likely influence their entire careers and accurate, meaningful initial knowledge is especially important as it leaves no necessity of “un-learning” inaccurate knowledge. To achieve the goal of full and accurate instruction of trainees in clinical research ethics requires close collaboration between the activities outlined here and the activities described in the Section of the application on Research Education, Training and Career Development. Some of the knowledge in this area that should be conveyed to trainees is as outlined above in describing the knowledge that is appropriate for all RTSC staff and faculty, i.e. basic knowledge of the principles of research integrity, and human-subjects research ethics. Further, as the RTSC is to provide trainees with a solid basis of knowledge to prepare them for successful and productive careers in clinical translational research, expanded attention will be paid to ethical issues directly pertinent to clinical research. A thoughtful summary of the basic principles to be conveyed is provided by Emanuel, Wendler, and Grady of the NIH Clinical Center’s Department of Clinical Bioethics in JAMA [10] and forms a suitable basis for this expanded instruction of trainees. They provide a universal framework for the ethical evaluation of clinical research studies that must be adapted to the health, economic, cultural and technological conditions in which the clinical research is conducted. They identify seven principles: “(1) value—enhancements of health or knowledge must be derived from the research; (2) scientific validity—the research must be methodologically rigorous; (3) fair subject selection—scientific objectives, not vulnerability or privilege, and the potential for and distribution of risks and benefits, should determine communities selected as study sites and the inclusion criteria for individual subjects; (4) favorable risk-benefit ratio—within the context of standard clinical practice and the research protocol, risks must be minimized, potential benefits enhanced, and the potential benefits to individuals and knowledge gained for society must outweigh the risks; (5) independent review—unaffiliated individuals must review the research and approve, amend, or terminate it; (6) informed consent—individuals should be informed about the research and provide their voluntary consent; and (7) respect for enrolled subjects— subjects should have their privacy protected, the opportunity to withdraw, and their well-being monitored.” This framework provides the foundation for a tool that can be developed for trainees to consider when developing their research design. These principles will be used to organize the material to be presented to trainees. Instruction will be tightly integrated with Research Education, Training and Career Development activities. Multiple modes of instruction will be used: presentations, face-to-face lectures, and computerized instruction. Instructional material concerning clinical research ethics will be integrated into many trainee courses (approach to clinical research, conduct of clinical trials) as well as given in a dedicated course. Although trainees’ knowledge in clinical research ethics will not be evaluated exclusively by computerized tests, most test questions will employ a multiple-choice format because of its ease of administration and scoring with objective criteria.

F.2.2.F. Timeline: The Timeline indicates Design, Biostatistics, and Clinical Research Ethics activities in all areas at most times because the start-up time for each is fairly short, varying from none to one year. The first three months will include the development, testing, and implementation of the Sharepoint application for tracking requests, while consulting in design, biostatistics and ethics will phase in. We plan to increase from two days per week to four days per week of open-door consulting. The Director will track the number of sections and departments receiving help, with the expectation that this number will increase each year.

F.2.2.G. Linkage to other Key Components of the RTSC: The Design, Biostatistics, and Clinical Research Ethics will interface with all components of the RTSC, as well as national CTSA activities. F.2.2.G.1. Interfacing with Leadership: The Core Director will report to the SLC and is an ex officio member of the SLC, the senior representative body of the RTSC research community. F.2.2.G.2. Interfacing with Novel Methodologies Core: The Design, Biostatistics, and Clinical Research Ethics Core will work closely with the Novel Methodologies core, particularly as statistical evaluation of novel methods is required. As these activities will be a key priority of the RTSC, the director of the Novel Methodologies Core will have privileges to track the design, biostatistics, and ethics projects on the Sharepoint application used by the Design, Biostatistics and Clinical Research Ethics Core. Dr. Basu will have particular responsibility for interface with this core. In addition, there will be a link to the Design, Biostatistics, and Clinical Research Ethics core on the Science and Technology Kiosk to be developed by the Novel Technologies Core, Specific Aim 1, Section F.2.4.B. F.2.2.G.3. Interfacing with Pilot Studies: The Design Biostatistics and Clinical Research Ethics Core will work closely with the investigators who have approved pilot studies, as these studies have particular promise for timely translation. Projects arising from pilot studies will have top priority in the Sharepoint application. F.2.2.G.4. Interfacing with Biomedical Informatics: The Core Director will be a member of the Research Informatics Infrastructure Advisory Committee to assist in coordination of biostatistics activities with the Biomedical Informatics Core. She will also serve as the head of the Biostatistics and Bioinformatics task force group of the RTSC. The Biomedical Informatics Core will work closely with the DBEC to design a system (using sharepoint application) to track and prioritize projects, as well as the portal that investigators can use to reach the application. Staff of the Design, Biostatistics, and Clinical Research Ethics Core will coordinate database design and data management with staff of the medical bioinformatics core. F.2.2.G.5. Interfacing with Regulatory Knowledge and Support: The Design, Biostatistics, and Clinical Research Ethics core will work with the Regulatory Knowledge and Support core to ensure that clinical research ethics are considered at all steps. Dr. Thomason will work closely with Ms. Kate Gottfried in that core to assure that those who seek consulting are linked smoothly with regulatory support. F.2.2.G.6. Interfacing with Participants and Clinical Interactions Resources: The Design Biostatistics and Clinical Research Ethics Core will work closely with the PCIR core. The epidemiologist on the staff of the DBCRE core will assist with study design of studies to be implemented using the Provider Based Research Network, with design work commencing in earnest in year 2. The epidemiologist will identify any needs for biostatistical analyses. F.2.2.G.7. Interfacing with Community Engagement: The Design Biostatistics and Clinical Research Ethics Core will work closely with the Community Engagement core as needed. For example, the DBCRE core will provide random samples of providers for surveys.

F.2.2.G.8. Interfacing with Translational Technology and Resources: The Design, Biostatistics, and Clinical Research Ethics Core will work closely with the TTRC. Appropriate research designs are needed for investigators to use the research cores effectively. In many cases, the endpoints are quantitative and require statistical analyses of variable complexity. Often times, researchers need advice on designing studies to learn the most from their work; the staff of the Design, Biostatistics and Clinical Research Ethics core will assist with design, including estimating sample sizes needed to detect treatment effects of interest. F.2.2.G.9. Interfacing with Research, Training, Education, and Career Development: The Design Biostatistics and Clinical Research Ethics Core will work closely with the RTEC core by providing design, statistics and clinical research ethics activities for participants in the Training in Mentored Translational Research program, with particular attention to mentees. Dr. Skarupski, Director of Mentoring Support Services, will have privileges to enter projects in the Sharepoint application, and will be able to indicate their high priority and to track their progress. F.2.2.G.10. Interfacing with Tracking and Evaluation and Administration: The Design Biostatistics and Clinical Research Ethics Core will provide analytic support to the tracking and evaluation core as requested, and will ensure that administrative matters concerning the core or requiring the attention of the core are handled in a timely fashion. F.2.2.G.12. Interfacing with K12 and T32 programs: The Design Biostatistics and Clinical Research Ethics Core will work closely with K12 recipients, and will have the ability to offer reading courses tailored to the interests of the particular recipient.

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