STATISTICAL METHODS AND ISSUES FOR IMPLEMENTING ADAPTIVE PHASE I TRIALS
P Daniel
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 5R01CA148713-03 from National Cancer Institute
Keywords: Accounting; Address; cancer therapy; Clinical; clinical practice; Clinical Research; Clinical Trials; Clinical Trials Design; Computer Programs and Programming; Computer software; Data; design; Dose; Dose-Limiting; drug discovery; Drug Formulations; Enrollment; Event; experience; Future; Goals; Grant; Health; Heterogeneity; Housing; improved; insight; Journals; Literature; Logistic Regressions; Malignant Neoplasms; meetings; Methodology; Methods; Mission; Modeling; New Agents; novel; oncology; Patients; Pattern; Phase; phase 1 study; Phase I Clinical Trials; Process; programs; Publishing; Recording of previous events; Research; Research Personnel; skills; software development; Statistical Methods; success; Tail; Time; Toxic effect; Uncertainty; United States National Institutes of Health; user friendly software; Work
Relevance: Phase I trials are a crucial first step in the discovery of new agents, either alone or in combination with existing agents, for the treatment of cancer. Successful drug discovery hinges on superior clinical trial designs, as well as freely available software to implement those designs. This proposal will examine needed improvements to adaptive Phase I trial designs and provide user-friendly software that facilitates the implementation of those improvements into actual clinical research. The findings will be relevant to the NIH mission and provide new insight to those who either design adaptive Phase I trials or administer actual adaptive Phase I trials
Project start date: 2010-02-08
Project end date: 2013-12-31
Budget start date: 1-JAN-2012
Budget end date: 31-DEC-2012
5R01CA148713-03 (2012): $245568
Sponsored Links Excellgen http://Excellgen.com
STATISTICAL METHODS AND ISSUES FOR IMPLEMENTING ADAPTIVE PHASE I TRIALS
P Daniel
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 5R01CA148713-02 from National Cancer Institute
Abstract: The six aims in this proposal are motivated by important and relevant issues in the design of adaptive Phase I trials where focused research is needed. The investigators in this proposal bring a uniquely strong combination of statistical methodology, applied clinical trial experience, and computer programming skills to impact the future of oncology clinical trials. Successful completion of the proposed research will substantially augment existing Phase I methodology and provide new insight into novel adaptive Phase I trials approaches that will be important to both methodologic and applied statisticians. Most important, our findings will be relevant to the NIH mission of making important discoveries that improve peoples health and save lives. Aim 1 concerns fundamental issues in model construction for the Continual Reassessment Method (CRM) that are ignored in published literature but have a direct impact on the success of the trial. Aims 2, 3, and 4 share an underlying theme of improving the efficiency of Phase I trials by incorporating additional patient information into the dose-finding process. This information relates to both the prior history of the patient as well as the treatment of their cancer during the trial, data that are routinely collected for general clinical purposes that could impart additional information about the toxicity profile of an agent, but that are often ignored in Phase I studies. Aim 2 proposes four modeling approaches to incorporate patient heterogeneity in adaptive designs, Aim 3 investigates two approaches for incorporating non-dose-limiting toxicities into the estimation of the MTD, while Aim 4 examines approaches to incorporate non-monotonic efficacy patterns. Aim 5 proposes methods for inference about the DLT rate for each dose after a Phase I trial has completed enrollment, information that is rarely considered once a trial is completed and the recommended MTD is found, but provides information for the uncertainty surrounding the selected MTD and its neighboring doses. The lack of freely available and modifiable software remains the major barrier to the implementation of adaptive Phase I trial designs into routine clinical practice. Therefore, this proposal contains a final, sixth aim, spanning all four years of the proposal, focused solely on the programming, in both SAS and R, of all methods described in this proposal, as well as existing methods that have yet to be housed in a single software package. Through this final aim, we will provide a suite of software packages that meet the general needs of researchers working on Phase I design methodology and the specific day-to-day needs of those who administer actual Phase I trials, with the eventual goal of making adaptive Phase I trial designs commonplace in oncology trials published in the coming decade. Phase I trials are a crucial first step in the discovery of new agents, either alone or in combination with existing agents, for the treatment of cancer. Successful drug discovery hinges on superior clinical trial designs, as well as freely available software to implement those designs. This proposal will examine needed improvements to adaptive Phase I trial designs and provide user-friendly software that facilitates the implementation of those improvements into actual clinical research. The findings will be relevant to the NIH mission and provide new insight to those who either design adaptive Phase I trials or administer actual adaptive Phase I trials
Keywords: Accounting; Address; anticancer therapy; cancer therapy; Cancer Treatment; Cancer, Oncology; Cancers; Clinical; clinical investigation; clinical practice; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials Design; Clinical Trials, Phase I; Clinical Trials, Unspecified; computer program; computer program/software; computer programming; Computer Programs; Computer Programs and Programming; Computer software; Data; design; designing; develop software; developing computer software; Dose; Dose-Limiting; doubt; drug discovery; Drug Formulations; Early-Stage Clinical Trials; enroll; Enrollment; Event; experience; Formulation; Formulations, Drug; Future; Goals; Grant; Health; Heterogeneity; History; Housing; improved; insight; Investigators; Journals; Literature; Logistic Regressions; Magazine; malignancy; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Neoplasms; Malignant Tumor; meetings; Method LOINC Axis 6; Methodology; Methods; Mission; Modeling; National Institutes of Health; National Institutes of Health (U.S.); neoplasm/cancer; New Agents; NIH; novel; oncology; Patients; Pattern; Phase; Phase 1 Clinical Trials; phase 1 study; phase 1 trial; Phase I Clinical Trials; Phase I Study; phase I trial; Process; programs; Programs (PT); Programs [Publication Type]; protocol, phase I; public health relevance; Publishing; Recording of previous events; Research; Research Personnel; Researchers; skills; Software; software development; Statistical Methods; success; Tail; Time; Toxic effect; Toxicities; Uncertainty; United States National Institutes of Health; user friendly computer software; user friendly software; Work
Relevance: Phase I trials are a crucial first step in the discovery of new agents, either alone or in combination with existing agents, for the treatment of cancer. Successful drug discovery hinges on superior clinical trial designs, as well as freely available software to implement those designs. This proposal will examine needed improvements to adaptive Phase I trial designs and provide user-friendly software that facilitates the implementation of those improvements into actual clinical research. The findings will be relevant to the NIH mission and provide new insight to those who either design adaptive Phase I trials or administer actual adaptive Phase I trials
Project start date: 2010-02-08
Project end date: 2013-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-07-070
5R01CA148713-02 (2011): $253162
Grants awarded to P Daniel
BEFORE CONSENT: CANCER PATIENTS´ DELIBERATIONS ABOUT EARLY PHASE CLINICAL TRIALS
P Daniel, Associate Professor
University Of California San Franciscocity: San Francisco country: United States (us)
Grant 5R01CA152195-02 from National Cancer Institute
Abstract: This proposal by a new investigator examines decisions made by advanced cancer patients regarding early phase clinical trials. Advances in basic and translational research may herald the arrival of new, targeted therapies that will improve cancer treatment and reduce mortality, but all of these therapies must be tested for safety in early phase (EP) clinical trials before they can benefit the public. Recruiting more patients to EP trials may speed the development of new cancer therapies, and some have argued that trials< participation is a societal obligation. But, those who participate in early phase trials - advanced cancer patients who have run out of standard therapeutic options - are a highly vulnerable population, and current procedures to ensure informed consent are not robust. Even as bioethicists and social and behavioral scientists seek to improve the informed consent process in EP cancer trials, less attention has focused on patients< decision-making in the period before the consent process begins. This study provides a rich descriptive and longitudinal perspective of the "pre-consent" period via three specific aims. For aim 1, focus groups are used to describe providers< role in early phase recruitment. In aim 2, an Advanced Cancer Cohort (ACC, n=150) is assembled using validated quantitative instruments, qualitative interviews, and clinic participant- observation to gather data on ACC patients´ EP experiences and decisions as well as the perspectives of family caregivers and providers. Aim 3 analyzes ACC patients< awareness and knowledge of early phase trials (aim 3a), which patients decide to participate in trials and how they make this decision (aim 3b), and the nature and outcome of the informed consent process (aim 3c). Through the development of rich understandings of early phase decision-making before consent, the study findings may have relevance for clinician-investigators and early phase trial programs throughout the United States. The study may identify approaches that can increase EP trial enrollment while also improving patients< ability to provide meaningful informed consent for EP participation. Developing new cancer therapies is a national priority, but the advanced cancer patients in whom these therapies are first tested are highly vulnerable. This study examines how advanced cancer patients make decisions about participating in a trial of a new therapy. The study aims to gather information that can improve the system for developing cancer therapies without putting vulnerable cancer patients at undue risk
Keywords: Address; Administrator; advanced disease; Advanced Malignant Neoplasm; Affect; Attention; Awareness; Basic Science; Behavioral; Bioethics Consultants; cancer care; Cancer Patient; cancer therapy; Caregivers; Cessation of life; Clinic; Clinical; Clinical Nursing Research; Clinical Research; Clinical Trials; cohort; Communication; Communications Media; Consent; Consent Forms; Data; Databases; Decision Making; Demographic Factors; Development; Disease; Emotions; Employee Strikes; Enrollment; Ensure; Equipoise; Ethics; exhaust; expectation; experience; Face; Family; Family Caregiver; Family health status; Focus Groups; Funding Agency; Goals; Health Personnel; Health Professional; high reward; high risk; Human; improved; Individual; information gathering; Informed Consent; Institution; instrument; Intervention; Interview; Investments; Judgment; Knowledge; Lead; Literature; longitudinal database; Malignant Neoplasms; Methods; Mission; Mortality Vital Statistics; Motivation; Nature; novel strategies; Outcome; Participant; Patient Recruitments; Patients; Pattern; Phase; Physicians; Procedures; Process; programs; Provider; public health relevance; Qualitative Research; Quality of life; Randomized; Recruitment Activity; Research; Research Methodology; Research Personnel; Risk; Role; Running; safety testing; Sampling; Scientist; Shapes; social; Social Characteristics; social science research; Speed (motion); standard care; Surveys; Symptoms; System; Testing; Therapeutic; Time; Translational Research; Trust; United States; Vulnerable Populations
Project start date: 2010-06-01
Project end date: 2015-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-09-122
5R01CA152195-02 (2011): $478295
ELECTRICAL NEUROIMAGING OF BRAIN PROCESSES DURING HUMAN GAIT
P Daniel, Associate Professor
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 1R01NS073649-01A1 from National Institute Of Neurological Disorders And Stroke
Abstract: There is an important clinical need to develop functional imaging techniques that can quantify brain processes during human locomotion and relate them to body dynamics. Mobile brain imaging could assist with the diagnosis and treatment of patients with numerous movement disorders and neurological injuries. We propose that Independent Component Analysis of high-density electroencephalography (EEG) can quantify distinct brain processes involved in the control of human gait. Furthermore, we contend that electrocortical brain processes identified using Independent Component Analysis of EEG correlate with whole body dynamics. We will study healthy young subjects performing various locomotor tasks while we record movement kinematics and 256-channel EEG using active scalp electrodes. In Specific Aim 1, we will examine subjects walking at a range of speeds to determine if intra-stride patterns of activation and deactivation synchronized to the gait cycle are consistent across walking speeds. In Specific Aim 2, we will examine subjects performing passive recumbent stepping and active recumbent stepping to determine the relative effects of sensory feedback vs. motor feed forward commands with sensory feedback on electrocortical brain processes. We hypothesize that passive recumbent stepping will engage fewer electrocortical sources than active recumbent stepping. We will also compare active recumbent stepping with treadmill walking to determine the similarities between recumbent stepping and walking in activating cortical brain processes. In Specific Aim 3, we will examine subjects walking on a split-belt treadmill to quantify sensorimotor hemispheric independence using coherence. In Specific Aim 4, we will study subjects walking on a narrow treadmill-mounted balance beam to identify the electrocortical processes involved in maintaining and monitoring balance. The results from this study will advance our understanding of electrocortical dynamics related to the control of human walking, and will lead to new studies probing mechanisms of neurological gait impairments. The findings could also facilitate new brain- machine interface technologies for controlling robotic orthoses or prostheses. We will use head mounted electrodes and signal processing techniques to identify brain activity related to the control of human walking. The results may lead to new imaging techniques for studying brain function during diagnosis and rehabilitation of movement disorders
Keywords: Anterior; Area; Attention; base; Brain; Brain imaging; brain machine interface; Clinical; Cognitive; computerized data processing; Contralateral; cranium; Data; density; Diagnosis; disability; Electrodes; Electroencephalography; Equilibrium; Event; feeding; Functional Imaging; Functional Magnetic Resonance Imaging; Gait; Head; Human; Image; Imaging Techniques; Impairment; improved; independent component analysis; kinematics; Lead; Learning; Left; Locomotion; Locomotor adaptation; locomotor tasks; Methods; Monitor; Motion; Motor; Movement; Movement Disorders; Musculoskeletal Equilibrium; Near-Infrared Spectroscopy; Nervous System Trauma; neuroimaging; Neurologic; Neuronal Plasticity; novel; Orthotic Devices; Parietal Lobe; patient population; Patients; Pattern; Prefrontal Cortex; Process; Prosthesis; Rehabilitation therapy; relating to nervous system; Relative (related person); Research; Resolution; Robotics; Scalp structure; sensory feedback; Sensory Process; Source; Speed (motion); stroke; Study Subject; Systems Analysis; Techniques; Technology; Time; Training; Validation; Walking; Work
Relevance: We will use head mounted electrodes and signal processing techniques to identify brain activity related to the control of human walking. The results may lead to new imaging techniques for studying brain function during diagnosis and rehabilitation of movement disorders
Project start date: 2011-09-01
Project end date: 2015-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-10-067
1R01NS073649-01A1 (2011): $326324
BONE STRUCTURAL INTEGRITY PROFILING TO ADVANCE SKELETAL GENETICS AND BIOMECHANICS
P Daniel, Assistant Scientist
Texas Biomedical Research Institutecity: San Antonio country: United States (us)
Grant 1R01AR060341-01A1 from National Institute Of Arthritis And Musculoskeletal And Skin Diseases
Abstract: The structural integrity of bone in any mechanical loading environment is an integrative function of a multitude of complex and interrelated characteristics of bone at the macro-, micro- and ultrastructural levels of bone´s structural organization. Bone fragility and increased fracture risk result from multiple, distinct combinations of scores of bone traits. A dynamic process of co-adaptation of traits provides for redundant combinations of traits through which structures are produced that provide adequate functionality under "normal" loading conditions. However, some of these combinations of traits can result in structures that are suboptimal when subjected to atypical or traumatic loads, such as those encountered in a fall. The dominant study design in skeletal genetics and biomechanics focuses on the role of one or a limited set of morphological and/or compositional factors in bone fragility. This approach is effective for identifying discrete traits that contribute to bone fracture resistance, but we cannot get a complete picture of the mechanobiological processes underlying fracture risk without a more comprehensive study design that captures variation at each of bone´s hierarchical levels, since all of these traits work synergistically to control fracture risk. We propose a multi-disciplinary, integrative approach that is a major departure from traditional approaches to skeletal biomechanics and genetics. Our study is designed to identify composite traits comprising uncorrelated expression patterns of specific measures of bone quality and density that are linked to bone structural performance, to estimate the heritability (h2) of these composite traits, and to prioritize genes and gene networks most likely to affect fracture risk. Specifically, we aim to 1) measure a thorough suite of bone traits in the femurs of 100 pedigreed baboons, then use variable reduction methods to distill the multitude of interrelated, highly correlated traits down to a small set of uncorrelated descriptors of variation in bone morphology and composition. Hypothesis There is a set of uncorrelated, composite traits that efficiently disentangles the elaborate network of compositional and morphological traits responsible for population-level normal variation in bone biomechanical behavior. 2) Characterize age and sex effects on these composite traits, 3) Assess femoral apparent biomechanical properties under normal and non-habitual loading conditions. Hypothesis Differential expression of these traits in individuals results in structures that support normal functional musculoskeletal activities, a subset of which perform poorly when loaded in a non-habitual manner. 4) Detect and quantify the proportion of variation in each composite descriptor that is due to the additive effects of genes (h2), and 5) Identify genes and networks that are differentially active in bone tissue from strong for size vs. weak for size femurs. Such fundamental knowledge would allow for development of vastly improved preventative and therapeutic strategies for osteoporosis-related fractures. Osteoporosis is an age-related health problem of immediate public health concern that results in 1.5 million fractures in the U.S. each year. Great strides have been made in identifying a vast number of bone composition and shape traits that affect fracture risk, but traditional study designs limit our ability to understand how these traits work together to result in strong vs. weak bones. We will employ a more comprehensive study design that captures variation at each of bone´s hierarchical levels to get a more complete picture of the mechanobiological processes underlying fracture risk, and to discover genes that mediate fracture risk. Such fundamental knowledge will speed development of vastly improved preventative and therapeutic strategies
Keywords: Adherence (attribute); Affect; Age; age effect; age related; Area; Behavior; Biological; Biomechanics; Body Size; bone; Bone Density; bone quality; bone strength; Bone Tissue; Characteristics; Complex; Computer Simulation; Descriptor; design; Development; Disease; Environment; Exhibits; falls; Female; Femur; Fracture; Future; gene discovery; Gene Expression Profile; Genes; Genetic; Goals; H2 gene; Health; Heritability; improved; Individual; Knowledge; Length; Link; Maintenance; male; Measures; Mechanics; Mediating; Methods; Molecular; Morphology; Musculoskeletal; Osteoporosis; Papio; Pathway Analysis; Pattern; Performance; Population; Principal Component Analysis; Process; Property; public health medicine (field); Research Design; Resistance; Risk; Role; sex; Shapes; Simulate; skeletal; Speed (motion); Structure; substantia spongiosa; Testing; Therapeutic; Tissues; trait; Variant; Variation (Genetics); Work
Relevance: Osteoporosis is an age-related health problem of immediate public health concern that results in 1.5 million fractures in the U.S. each year. Great strides have been made in identifying a vast number of bone composition and shape traits that affect fracture risk, but traditional study designs limit our ability to understand how these traits work together to result in strong vs. weak bones. We will employ a more comprehensive study design that captures variation at each of bone´s hierarchical levels to get a more complete picture of the mechanobiological processes underlying fracture risk, and to discover genes that mediate fracture risk. Such fundamental knowledge will speed development of vastly improved preventative and therapeutic strategies
Project start date: 2011-07-15
Project end date: 2016-05-31
Budget start date: 15-JUL-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-10-067
1R01AR060341-01A1 (2011): $723535
P Daniel
University Of Pittsburgh At Pittsburghcity: Pittsburgh country: United States (us)
Abstract: The Biostatistics Core will provide the five Projects and Core G (Radiobiological Standardization) with dedicated support for the statistical aspects of study design, data analysis, and research reporting; participate in the evaluation of proposed CMCR pilot projects and provide statistical support of funded proposals; provide advice on database designs for all projects and cores to ensure efficient workflows
Keywords: ing; Biometry; Biostatistics Core; Data Analyses; Data Collection; database design; Databases; design; Development; Ensure; Evaluation; Funding; In Vitro; in vivo; Manuscripts; Mitochondria; novel; Pilot Projects; Progress Reports; Radiation; Reporting; Research; Research Design; Research Personnel; research study; Selection for Treatments; Standardization; Toxic effect; Work; Writing
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
5U19AI068021-07_6554 (2011): $132843
MULTINATIONAL COLLABORATION TO INCREASE PA IN HISPANICS
P Daniel, Associate Professor
University Of Houstoncity: Houston country: United States (us)
Grant 1R13CA162816-01 from Office Of The Director, National Institutes Of Health
Abstract: Project Summary Regularly done physical activity (PA) has been associated with numerous health outcomes, yet the majority of Americans still struggle to meet minimum PA guidelines, making physical inactivity an ongoing, significant health challenge particularly among women and minorities, especially Hispanics. Traditional behavior change programs have had little sustainability, in part attributable to ecologic factors part of the complex system in which individuals exist, grounded in environment, policy, cultural or social origins. The Ecologic Model of Physical Activity (EMPA) identifies micro-, exo-, meso- and macro-environmental influences on PA that rapidly shape behavior back to its origin after individual interventions are completed and posits that both relatively static micro-environmental factors such as the presence or absence of a PA resource, as well as dynamic exo- and meso-environmental factors such as the shared goals, supportive social networks, and frequent prompts, are critical in the adoption and maintenance of PA. Increasing PA is not only a US but also an international health priority, suggesting collaborative, transdisciplinary strategies are needed to address this growing public health problem. This project aims to capitalize on the unique opportunities presented in the City of Houston and an existing collaboration between the University of Houston and University of Guadalajara. We will develop a partnership to refine the EMPA and a collaborative scientific research agenda focusing on PA maintenance across the lifespan with particular attention to Hispanic women and children. The Texas Obesity Research Center (TORC) in the Department of Health and Human Performance at the University of Houston (UH) will serve as a framework organization to support the collaboration and research agenda and will rely on longstanding organizational, scientific and community ties. The partnership will hold monthly teleconference meetings, semi-annual face to face meetings, and a research conference in year 2 to accomplish project objectives. The monthly teleconferences and semiannual meetings will aid the development of shared trust among the scientific partnership and the refining of the model. Partners will share successes of moving the science, both in terms of refining theory but also in terms of reviewing empirical findings to consider best practices and future directions. Project findings will be disseminated via four scientific publications that will (1) review and critically evaluate PA research in Hispanics, (2) develop and/or modify existing theoretical models to propose a more refined model based on available data, (3) develop consensus guidelines and posit recommendations for research, practice and policy derived from empirical data and theory, and (4) document the evaluation process and describe lessons learned. Findings will also be included in grant reports and be presented at scientific meetings. It is expected that this project will provide a forum for the development of a scientific collaborative structure that will support an eventual research project with a focus on addressing and eliminating health disparities and improving PA among Hispanics. Physical inactivity rates are higher among Hispanics than Whites, despite increased vulnerability to related health compromising conditions. The problem is particularly evident in the United States and Mexico. A collaborative, transdisciplinary approach and model that incorporates individual, social and environmental influences of physical activity behavior and maintenance is needed to address this growing public health problem
Keywords: Address; Adoption; African American; Age; American; Attention; Back; base; Behavior; behavior change; behavioral/social science; Brain; Caucasians; Caucasoid Race; Child; Cities; Collaborations; Communities; Complex; Consensus; Data; Development; Environment; Environmental Risk Factor; Evaluation; Future; Goals; Government Officials; Grant; Group Meetings; Guidelines; Health; Health behavior; health disparity; Health Priorities; Healthcare; Hispanics; Home environment; Human; improved; Individual; International; Intervention; Learning; Life; Linguistics; Longevity; Maintenance; Manuscripts; meetings; member; Mexican; Mexican Americans; Mexico; Minority; Modeling; Obesity; Outcome; Pattern; Performance; Physical activity; Policies; Population; Prevalence; Process; programs; public health medicine (field); Publications; Recommendation; Reporting; Research; Research Infrastructure; Research Personnel; Research Priority; Research Project Grants; Resources; Science; Scientist; Shapes; social; Social Network; social science research; Structure; success; symposium; System; Teleconferences; Texas; Theoretical model; theories; Trust; United States; Universities; Walking; Woman; Work
Relevance: Physical inactivity rates are higher among Hispanics than Whites, despite increased vulnerability to related health compromising conditions. The problem is particularly evident in the United States and Mexico. A collaborative, transdisciplinary approach and model that incorporates individual, social and environmental influences of physical activity behavior and maintenance is needed to address this growing public health problem
Project start date: 2011-09-23
Project end date: 2013-08-31
Budget start date: 23-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: RFA-CA-10-017
1R13CA162816-01 (2011): $50000
MORPHOGENESIS: BIOPHYSICS AND GENETICS OF DORSAL CLOSURE
P Daniel, Professor And Chair
Duke Universitycity: Durham country: United States (us)
Grant 5R01GM033830-28 from National Institute Of General Medical Sciences
Abstract: Drosophila´s Dorsal Closure is a model system for cell sheet morphogenesis during development and wound healing. We plan to investigate the molecular, cellular, and emergent properties that drive morphogenesis during closure using biophysical (laser microsurgery), genetic, pharmacological and modeling approaches. Previously, we showed that nonmuscle myosin II drives contractility in the amnioserosa and in the supracellular, actomyosin-rich purse-strings and that both tissues drive the bulk of progress toward closure. In addition we showed that the tissue forces are coordinated by adhesion- mediated zipping, that there is an asymmetry between the anterior and posterior zipping rate constants, and that the zipping rate constant can be upregulated in response to laser perturbation. We also showed that the removal of one or another force leads to upregulation of the forces that remain and closure proceeds to completion at wild type rates. Furthermore, the upregulation of the amnioserosa force and the zipping rate constant together address the robustness and resiliency of closure. Finally, we showed that the vector sum of the forces that drive closure is two to three orders of magnitude smaller than the individual forces that contribute. This indicates that regulation of these large forces is required so that cell sheets move inexorably to closure. Here we focus on applying laser-surgical, pharmacological and quantitative-modeling tools to explore the emergent properties that are the consequence of the cellular and molecular machines that drive cell sheet morphogenesis in wild type and mutant animals. By applying these methods to the analysis of wild type embryos an selected mutant embryos that fail in on or another aspect of closure, we plan the following. 1) We will investigate the hypotheses that mechanically gated channels and/or cell-matrix and cell-cell junctions sense and respond to forces to regulate the rate of closure. 2) We will measure the absolute magnitude of the forces each tissue contributes to closure. 3)We will investigate the role of microtubules in regulating actin function for closure. 4) We will formulate mathematical models that recapitulate at tissue and/or cellular resolution the behavior of closure in mutant, pharmacologically perturbed or laser investigated embryos. These studies on cell sheet morphogenesis in Drosophila will provide insight into the cellular and molecular basis for the biological processes that coordinate cell shape changes in vertebrate morphogenesis and wound healing. PUBLIC HEALTH RELEVANCE This work focuses on dorsal closure, a process in the fruit fly Drosophila melanogaster that models cell sheet movements in vertebrates. Drosophila offers unique opportunities for multidisciplinary approaches and many of the proteins involved in movement are highly conserved between flies and humans (some are > 90% identical and many human proteins can experimentally rescue genetic defects in their fly orthologs). In addition, comparable sheet movements characterize early stages of human development (for example, neural tube formation) and wound healing. Moreover, the programmed interplay between cell-cell junctions and cell-matrix junctions that occurs during closure is crucial for the epidermal-mesenchymal transition that is activated when epithelial cells become metastatic and cause cancer. These studies in Drosophila will provide insight into the molecular and cellular basis of motility and provide a window onto the emergent behaviors that characterize morphogenesis and wound healing
Keywords: Actins; Actomyosin; Address; Adhesions; Affect; Animals; Anterior; Area; base; Behavior; Biological Models; Biological Process; Biophysics; Bypass; Cancer Etiology; Cell model; cell motility; Cell Shape; Cell-Matrix Junction; Cells; Complex; Dependence; design; Development; Dominant-Negative Mutation; Dorsal; driving force; Drosophila genus; Drosophila melanogaster; Embryo; Epithelial Cells; Excision; flexibility; fly; Genetic; Health; Human; Human Development; Image Analysis; image processing; Individual; inhibitor/antagonist; insight; Intercellular Junctions; interdisciplinary approach; kinematics; Knowledge; Laser Surgery; Lasers; Magnetism; mathematical model; Measurement; Measures; Mediating; Mesenchymal; Methods; Microsurgery; Microtubules; Modeling; Molecular; Molecular Genetics; Molecular Machines; Morphogenesis; Movement; mutant; Mutation; Myosin Type II; Neural tube; non-muscle myosin; Operative Surgical Procedures; Orthologous Gene; Pattern; Process; programs; Property; protein function; Proteins; Regulation; Relative (related person); Resolution; response; RNA Interference; Role; Staging; Stress; Sum; Technology; Time; Tissues; tool; Up-Regulation (Physiology); vector; Vertebrates; Width; Work; Wound Healing
Project start date: 1984-09-30
Project end date: 2012-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-07-070
5R01GM033830-28 (2011): $528701
A PATIENT-SPECIFIC DECISION SUPPORT TOOL FOR BARIATRIC SURGERY
P Daniel
University Of Cincinnaticity: Cincinnati country: United States (us)
Grant 5K23DK075599-05 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Background. Obesity and obesity-associated conditions have been shown to greatly decrease both quality of life and life expectancy. Currently, bariatric surgery is the only proven treatment for sustained weight loss in the morbidly obese patient. However the decision to undergo surgery is a difficult one because of the risks involved in surgery and the uncertain outcome. Objectives. As an outcomes researcher with an interest in decision analysis, the specific objectives of this application are to a) broaden my skills in the construction of decision analytic models, the decision sciences, and the conduct of patient-oriented research and b) use these skills to develop and test an interactive decision support tool that provides tailored information about the individual patient´s surgical risk and the expected benefit of bariatric surgery. My long- term career goal is to develop and test a variety of patient-specific decision support tools for patients with morbid obesity. Training. For my career development, I plan to take additional coursework in the decision sciences, focusing on the design of decision analytic models for simulations. My mentorship team is comprised of leading experts in the fields of decision analysis, obesity and research methodology Mark H. Eckman, MD, MS, Joel Tsevat, MD, MPH, David D´Alessio, MD, David Fischer, MD, David Arterburn, MD, MPH, Richard Hornung, DrPH, Thomas Inge, MD, PhD, and Meg Zeller, PhD. Research Design. For this proposal, we will first develop a population based decision analytic model that examines two strategies bariatric surgery versus the natural history of morbid obesity. Using this model we will identify those patients for whom the decision to have bariatric surgery is a "close call". This model will then be the basis for the development of a patient-specific model that will serve as the foundation for our decision support tool. Using a randomized controlled trial, we will assess patients´ understanding of the risks and benefits of bariatric surgery, decisional conflict, satisfaction with the decision making process and decision self efficacy when using the decision support tool compared to a control group with access to generic information about bariatric surgery. Relevance. At the completion of this project, we will have developed and tested an interactive web-based decision support tool to be used by morbidly obese patients considering bariatric surgery. This will assist patients in making a more informed decision when weighing the treatment options for morbid obesity
Keywords: Adult; Affect; Age; arm; bariatric surgery; Bariatrics; base; Benefits and Risks; Body mass index; Body Weight decreased; cardiovascular risk factor; Cardiovascular system; career; career development; Characteristics; Clinical; clinical care; Clinical Trials; Computer software; Conflict (Psychology); Control Groups; cost; cost effective; Decision Analysis; Decision Making; Decision Modeling; design; Development; Diabetes Mellitus; diet and exercise; Doctor of Philosophy; Effectiveness; Equilibrium; follow-up; Foundations; Gender; Generic Drugs; Goals; Health; Health Benefit; Health Care Costs; Hyperlipidemia; Hypertension; Individual; innovation; insight; interest; Knowledge; Life Expectancy; Literature; Measures; Medical center; Mentorship; model design; Modeling; models and simulation; Morbid Obesity; Morbidity - disease rate; Mortality Vital Statistics; Natural History; Obesity; Online Systems; Operative Surgical Procedures; Outcome; Outcomes Research; Output; patient oriented research; Patients; Perioperative; Pharmaceutical Preparations; population based; preference; Probability; Procedures; Process; Process Measure; programs; Psychosocial Factor; Quality of life; Randomized; Randomized Controlled Trials; Recruitment Activity; Research; Research Design; Research Methodology; Research Personnel; Risk; Safety; satisfaction; Science; Self Efficacy; Series; skills; Subgroup; systematic review; Testing; Time; tool; Training; Uncertainty; Universities; usability; user-friendly; web based interface; Work
Project start date: 2007-08-03
Project end date: 2012-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-05-143
5K23DK075599-05 (2011): $134438
BIOPHYSICAL STUDIES OF AMYLOID FORMATION BY POLYPEPTIDE HORMONES
P Daniel, Professor
State University New York Stony Brookcity: Stony Brook country: United States (us)
Grant 5R01GM078114-04 from National Institute Of General Medical Sciences
Abstract: Amyloid deposition occurs in more than twenty different human diseases. This project is concerned with amyloid formation by Islet Amyloid Polypeptide (IAPP), the endocrine hormone responsible for pancreatic islet amyloid in type 2 diabetes. Islet amyloid significantly contributes to the pathology of type 2 diabetes and is also a major problem in islet cell transplantation. Comparatively little is known about amyloid formation by IAPP despite its obvious importance and the mechanism underlying islet amyloid formation is not understood. The studies outlined here will; (1) determine the mechanism of amyloid formation by IAPP; (2) deduce the role of proIAPP processing intermediates in amyloid formation, a topic which has emerged as a critical issue in the last year (3) develop inhibitors of amyloid formation by IAPP and proIAPP and (4) test a general strategy for improving existing inhibitors of amyloid formation. The lessons learned will provide insight into strategies for the treatment and prevention of type 2 diabetes, and are expected to aid efforts to better control pathological amyloid formation in other diseases. An interdisciplinary combination of experimental biophysics, cell biology, and molecular dynamics simulations will be used to address these issues. Three specific aims will be carried out. The first involves studies of the mechanism of amyloid formation by IAPP and is made up of four synergistic sub aims A) The effects of modulating the conformational ensemble of monomeric IAPP on the kinetics of fibril formation will be determined; B) The hypothesis that a helical intermediate plays a critical role in amyloid formation by IAPP will be tested; C) The changes in secondary structure that occur during IAPP fibril formation will be defined with residue specific resolution; D) The role individual side chains play in amyloid formation by IAPP will be defined. The second aim will define the role of pro-IAPP processing intermediates in amyloid formation. The third aim will lead to the development of new inhibitors of amyloid formation by IAPP and test their ability to inhibit cell death. A general methodology for improving existing inhibitors will be tested as part of aim-3. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page Principal Investigator/Program Director (Last, First, Middle) Raleigh, Daniel P. PUBLIC HEALTH RELEVANCE Amyloid formation refers to the pathological aggregation of proteins and occurs in more than twenty different human diseases including Alzheimer´s disease and type-2 diabetes. This proposal is concerned with amyloid formation by Islet Amyloid Polypeptide (IAPP), the endocrine hormone responsible for pancreatic islet amyloid in type 2 diabetes. Islet amyloid significantly contributes to the pathology of type 2 diabetes The lessons learned from this work will provide insight into strategies for the treatment and prevention of type 2 diabetes, and will aid efforts to better control pathological amyloid formation in other diseases. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page
Keywords: Address; Affect; Alzheimer`s Disease; Amyloid; Amyloid deposition; Amyloid Fibrils; amyloid formation; analog; Area; Attenuated; Biophysics; Cell Culture Techniques; Cell Death; Cells; Cellular biology; Collaborations; Collection; Combined Modality Therapy; Data; Defect; Development; Disease; Endocrine; Event; experience; Extracellular Matrix; Fluorescence; Goals; Hand; Health; Hormones; human disease; improved; Individual; inhibitor/antagonist; insight; Insulin; islet; islet amyloid polypeptide; Islets of Langerhans; Islets of Langerhans Transplantation; Joints; Kinetics; Label; Lead; Learning; Methodology; Methods; molecular dynamics; mutant; Non-Insulin-Dependent Diabetes Mellitus; novel; Pathology; Pathway interactions; Play; Point Mutation; polypeptide; Polypeptide Hormones; Prevention; Principal Investigator; Process; Production; professor; programs; protein aggregation; protein folding; Proteins; Reporting; Research; research study; Resolution; Role; Side; Structure; success; Testing; Time; Toxic effect; treatment strategy; Universities; Wisconsin; Work
Project start date: 2008-07-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-070
5R01GM078114-04 (2011): $257268
BIO-BEHAVIORAL MARKERS OF BIPOLAR CONVERSION
P Daniel, Director, Pedimind Program
Brown Universitycity: Providence country: United States (us)
Grant 5R01MH087513-03 from National Institute Of Mental Health
Abstract: Although we know less about bipolar disorder (BD) in children and adolescents, recent data indicate that pediatric BD (PBD) is a burgeoning health problem whose incidence has risen 40-fold in the past decade and now accounts for 20% of all minors discharged from psychiatric hospitals. Determining if a child has BD or not is problematic because current psychiatric nosology is based entirely on clinical history, which is considerably more difficult to elicit from children and adolescents than from adults. Thus, there is a pressing need to identify bio-behavioral markers of BD, especially to indicate which children will develop full-blown BD with distinct episodes of mania, and which will remain sub-syndromal (the latter known as BD "not otherwise specified" [NOS]). THE CHALLENGE AND GOAL OF THIS BRAINS R01 RESEARCH APPLICATION is to identify bio-behavioral markers of BD conversion. OUR CENTRAL HYPOTHESIS is that BD-converters will be differentiable from those who remained sub-syndromal BD-NOS by (a) neural alterations in a prefrontal cortex- amygdala-striatal circuit that mediate (b) behavioral performance on cognitive flexibility and face processing, as moderated by (c) genetic and (d) personal factors. RESEARCH METHOD To test this hypothesis, we will study young adults ages 18-25 years who have been followed since childhood by Brown University´s site of the Course and Outcome of Bipolar Youth study (COBY), so that retrospective recall bias about diagnosis will be minimized. In particular, we will study (1) those who converted from sub-syndromal BD-NOS to full-blown BD (BD-converters), (2) those who remained BD-NOS (BD-NOS), and (3) those who remained BD type I (BD- remain). We will also recruit a new group of age/sex matched typically-developing healthy adult controls (HC). We will collect behavioral task (reversal learning, face processing), multi-modal magnetic resonance imaging (MRI; including structural MRI, functional MRI, DTI, neural connectivity), and genetic data evaluated using principles of meditational analysis. SIGNIFICANCE The proposed studies are innovative and significant because they represent the first time that multi-disciplinary neuroscience methods will be used in a prospectively phenotyped sample to identify bio-behavioral markers of conversion from BD-NOS to full-blown BD, and with remaining sub-syndromal BD-NOS. Such bio-behavioral markers of BD conversion could ultimately augment clinical history in a personalized medicine approach, resulting in improved (more specific or earlier) diagnosis and treatment
Keywords: Accounting; Address; Adolescent; Adult; Age; age group; Amygdaloid structure; base; Behavioral; Bipolar Disorder; Brain; Brain scan; Child; Childhood; childhood bipolar disorder; Clinical; Cognitive; Corpus striatum structure; Data; Diagnosis; disease classification; Early Diagnosis; Face Processing; flexibility; Functional Magnetic Resonance Imaging; Genetic; Goals; Health; improved; Incidence; innovation; Magnetic Resonance Imaging; Manic; Mediating; Medicine; Methods; Minor; Neurosciences; Outcome; Performance; Phenotype; Prefrontal Cortex; Psychiatric Hospitals; public health medicine (field); Recording of previous events; Recruitment Activity; relating to nervous system; Research; Reversal Learning; Sampling; sex; Site; Specific qualifier value; Symptoms; Testing; Time; To specify; Universities; young adult; Youth
Relevance: Pediatric bipolar disorder (BD) is a growing health problem, whose incidence has risen 40-fold in the past decade and now accounts for 20% of all minors discharged from psychiatric hospitals. At present, the diagnosis of BD is based solely on clinical history, including distinct episodes of mania, that is considerably more difficult to elicit from children and adolescents than from adults. To address this important public health problem, this proposal will use behavioral, brain scan, and genetic data to identify bio- behavioral markers of developing full-blown BD versus having less distinct symptoms
Project start date: 2009-09-18
Project end date: 2014-04-30
Budget start date: 1-JUL-2011
Budget end date: 30-APR-2012
PFA/PA: RFA-MH-09-100
5R01MH087513-03 (2011): $333011
P Daniel, Director, Upci Biostatistics
University Of Pittsburgh At Pittsburghcity: Pittsburgh country: United States (us)
Keywords: anticancer research; Area; base; Biometry; Cancer Center Support Grant; Clinical trial protocol document; Clinical Trials; Commit; Computing Methodologies; Data Analyses; Epidemiologic Studies; Funding; Investigation; Laboratories; member; novel; Paper; Research Design; Services; University of Pittsburgh Cancer Institute
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
5P30CA047904-23_6522 (2011): $220839
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