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WHITE PAPER FINAL on August 13, 2010 Title: Proposed Components in A Molecular Imaging Curriculum Authors: Kurt R. Zinn, Carolyn Anderson, Michelle Bradbury, Kathy Cutler, Todd Peterson, Desiree Morgan, Julie Price, Kristina Wittstrom, Jeff Norenberg. Introduction Molecular imaging is the visualization, characterization and measurement of biological processes at the molecular and cellular levels in humans and other living systems (1). It is a developing technology that aims to significantly improve patient care by facilitating personalized medicine. The integration of this new technology has many challenges that include educational, technical, regulatory, and reimbursement issues that must be overcome prior to molecular imaging reaching its full potential. New training programs in molecular imaging have been recommended (2) and must extend beyond what are currently offered in biomedical engineering (3). It is critical to recruit the best scientists to contribute to the paradigm shift, especially those individuals that are early in their careers. As part of the effort, the Society of Nuclear Medicine (SNM) established an educational task force to begin to define the components that should be included in a curriculum for molecular imaging scientists. It is hoped that defining the components will assist academic institutions that seek to develop programs or curricula to prepare students for careers in this area, and to provide students with information to guide their Page 1 of 19 selection of this career path. This report provides a summary of the process that was used by the task force (Table 1), as well as its findings. The immediate goal of the task force was to provide general recommendations for the development of a curriculum for the education of scientists in the area of molecular imaging. It is envisioned that the publication of these recommendations would lead to discussions with other stakeholders and national organizations involved with molecular imaging (SNM, AMI, SMI, RSNA) in order to obtain feedback from their members. Importantly, the publication of this information should be regarded as the beginning of a dialogue. It is expected that there will be additional refinements of the curriculum and education guidelines proposed here, with more specific implementation plans in the future. The long-term goals are to develop and implement education and training for careers in molecular imaging, and to provide a process for harmonizing the curriculum. It is hoped that this effort will assist with recruitment of new scientists into the field; foster innovation of novel, cost-effective molecular imaging probes, equipment, and methods; and ultimately enhance patient care. The curriculum is targeted towards graduate or professional (M.D., D.O., Pharm.D., D.V.M., Ph.D.) students considering a career as a molecular imaging scientist. A prerequisite to the curriculum would be an undergraduate degree in science (biology, chemistry, physics, molecular biology), engineering or a professional degree in the health sciences. Participants in the program will develop an individual and unique program of studies building upon their Page 2 of 19 prior education, training and experiences, and in anticipation of their professional research goals, interests, and needs. A required core of entrylevel knowledge and skills assures that each student has a common base upon which to build. To this is then added the unique program of studies with appropriate emphasis on personal and professional goals. The core curriculum focuses on key areas of knowledge, referred to as domains, required for a career as a molecular imaging scientist. Each domain contains multiple levels of knowledge /expertise that reflect increasing competency in the domain area. Competency at Levels 1 and 2 are defined as the minimum needed by all molecular imaging scientists, regardless of specialty. Molecular imaging scientists should demonstrate competencies beyond Level 2 in more than one domain. Additional information on domains and competency is provided in Table 2. Domains of Knowledge for the Curriculum The education task force identified eight domains of knowledge that are critical components in a molecular imaging curriculum: 1. Math & Statistics 2. Imaging Physics and Instrumentation 3. Molecular Probe and Contrast Agent Development 4. Cell & Molecular Biology 5. Biological Model Systems Page 3 of 19 6. Pharmacology 7. Cross-Cutting Themes 8. Clinical Imaging of Disease. The domains are integrated with four developmental themes. The Basics includes the foundational sciences critical to molecular imaging. The Methodology uses the basic sciences to explore methods to highlight (contrast) potentially useful biological analysis. The Utility looks at the usefulness of the methods. Translation moves the methods from bench top to bedside. Integrated throughout the curriculum are the cross-cutting themes of communication, leadership and collaboration. Figure 1 highlights the vertical integration of the themes to achieve overall delivery of the program. The figure Illustrates how all the domains come together in the Cross-Cutting Themes and ultimately support Clinical Imaging of Disease. Figure 1: Summary of domains in relationship to overall themes. Domain 1: Mathematics and statistics are fundamental to understanding the nature of exponential growth and decay; exploring relationships between Page 4 of 19 outcome variables, assessing basic qualities of a given scientific dataset, and evaluating meaningful differences between mean outcome values or subject groups. Of additional importance is the consideration of sources of error and statistical limitations (i.e., sample size, multiple comparison correction, and counting statistics) that are valuable for the planning of experiments and exploring data relationships. The prominent role of image databases in Nuclear Medicine and Radiology requires a basic understanding of picture archiving and communication systems (PACS) system and is included in this domain. Domain 1 knowledge also supports pharmacokinetic data analysis, statistical data modeling to test study hypotheses, numerical methods relevant to image processing, multivariate approaches for voxel-level image analyses, and computer vision approaches for classification and diagnosis. Domain 2: Imaging physics and instrumentation are part of the foundation of molecular imaging. The concepts and basic principles are important to every trainee and professional in molecular imaging. An important goal in this domain is to understand signal and image formation processes and the factors influencing image quality and quantitative capabilities. This includes a fundamental knowledge of the different modalities of molecular imaging, including the capabilities, advantages, and limitations. An appreciation is needed for the underlying physics of signal generation and propagation through tissue, signal detection, and image formation. The ability to extract quantitative functional and biochemical information from the image often differentiates molecular imaging techniques from those that provide primarily Page 5 of 19 qualitative anatomical information. Therefore it is important to understand the physical factors that impact both the precision and the accuracy of the data and how the information from different modalities can be used together, particularly with the advent of hybrid imaging instruments. Knowledge of imaging physics is applicable in understanding the basic image formation mechanisms of a modality and the factors that influence the quality of images produced. Domain 3. Molecular probe and contrast agent development provides an overall foundation in the design and characterization of molecular imaging agents. Molecular imaging agents are defined as probes used to visualize, characterize, and measure biological processes in living systems (1). Both endogenous molecules and exogenous probes can be molecular imaging agents (1). Knowledge of the basic physical properties of different types of molecular probes and contrast agents is needed to optimize images obtained with those probes. For example, how do the decay properties of radionuclides affect the resultant single-photon and PET images? How do the relaxation properties of Gd-based MRI contrast agents affect MRI images? How do microbubbles enhance contrast in ultrasonography? A basic understanding of probe and contrast materials includes how radionuclides, paramagnetic metals, dyes, etc, are incorporated into small molecule compounds as well as how they are attached to biological molecules such as peptides and antibodies. Similarly, the conjugation of peptides and antibodies to nanoparticles or microbubbles for targeting is part of the Page 6 of 19 chemistry included in this domain. This domain incorporates the fundamental characterization of the agent; ensuring the chemical identity of the material, validating bioactivity, and evaluating the in vivo performance. It also addresses all regulatory issues that include Good Manufacturing Practices (GMP) and the chemistry, manufacturing, and control (CMC) component. Knowledge of the general principals of molecular probe and contrast agent development will allow imaging professionals to better understand the physics, chemistry, and biology that are inherent in the development of any molecular probe or contrast agent. This will allow a better understanding of the strengths and limitations of different imaging modalities. Domain 4. Cell and molecular biology include all aspects of cell biology, including structure, function, communication pathways, apoptosis, and processes such as phagocytosis and pinocytosis. Molecular biology (cell biology at the molecular level) covers interactions between DNA, RNA, and proteins and how the processes are regulated. The combination of cell biology with molecular biology enables the understanding of how “reporter” genes can be exploited for imaging; how gene transfer agents can afford delivery of the reporter genes; and how “genetic” contrast can be enhanced. Building upon this information, the scientist can expand their appreciation to molecular genetics, and how genetic mutations and/or changes in levels of gene and protein expression can lead to disease. Finally, methods to study the entire complement of genes, proteins, and metabolites for a cell or tissue should be understood, in the context of disease, therapeutic interventions, biomarkers, Page 7 of 19 systems biology, and potential roles for imaging. This knowledge is applicable for the development of imaging probes and methods to assess important diseases, including cancer, cardiovascular disease, diabetes, autoimmune and neurological disorders, and would be applicable to evaluate new therapies, including stem cell and gene therapy. Domain 5. Model systems are used for screening and evaluating new probes and for preclinical development and validation of targets. The imaging scientist uses model systems in the study of human diseases, including cells and tissues in culture, and animal models. Models systems are used to evaluate the targeting of imaging probes, and to determine suitability of probes to detect disease, monitor progress and to evaluate response. In recent years there has been an explosion of preclinical models, driven by the advances in molecular biology. For example, transgenic mice can now be established with genes “knocked in” or “knocked out”. Physiology and anatomy are essential in model development, including an understanding of similarities and differences between animal models and humans. Further, a comprehensive knowledge of all biological systems (respiratory, circulatory, nervous, digestive, endocrine, skeletal, etc.) is necessary. Compliance with regulatory requirements (IACUC, biosafety, chemical safety, and radiation safety) are included in this domain. Domain 6. Pharmacology studies the interactions of chemical and physical compounds with living organisms. Compounds that alter or change a process within the organism are often referred to as drugs, or pharmaceuticals. Molecular imaging takes advantage of these chemical interactions to Page 8 of 19 noninvasively image function on the molecular level through the use of molecular imaging agents. Radiopharmaceuticals are a special case because of their use as imaging agents at extremely low concentrations. Chemical properties and preparation of a molecular probe can affect the interaction of the probe with living systems and biochemical function-from the molecular level to the whole body. More specifically, the properties of the probe affect pharmacokinetics (effect of the body on the compound, e.g., half-life and volume of distribution), pharmacodynamics (effect of the compound on the molecular target, e.g., desired or toxic) and therapeutic efficacy. An imaging scientist must understand how to test molecular imaging agents, first in vitro (in the laboratory) for biochemical activity and then in vivo (on animals, human volunteers and patients) for safety, effectiveness, side effects, interactions with other drugs and how to find the best dose, timing and route of administration (oral, intravenously, subcutaneously, etc.). Knowledge of basic pharmacology is applicable in understanding the basic biological function that underlies both normal and disease states and how molecular probes will be handled by each and in the development and evaluation of new probes. Domain 7. The Cross-Cutting Themes refers to knowledge, skills, and abilities that will enhance success. These include effective communication, leadership, and collaboration as part of a team. Research ethics and regulatory compliance are also included. While there are no specified competency levels, future success of the scientist will be enhanced by recognizing the importance of these skills in professional success. Page 9 of 19 Domain 8. Clinical imaging of disease, especially routine use in clinical practice, is a key application of molecular imaging agents and techniques. Improving patient outcomes is the ultimate goal of molecular imaging with the greatest impact expected in oncology, cardiology and neurology. The molecular imaging scientist must become familiar with aspects of anatomy, physiology, and pathophysiology necessary to design and implement translational imaging applications relating to human oncologic, neurological and cardiovascular disease. An understanding of the various imaging options available for answering key biological questions of interest in preclinical models at the cellular and molecular-genetic levels, and their translation to applicable clinical imaging tools is mandatory. This translation includes knowledge of targeted molecular probes used for metabolic imaging or receptor-based imaging, in addition to the use of standard, clinically approved imaging agents (i.e., non-targeted PET tracers, freely diffusible magnetic resonance or computed tomography contrast agents) and methods to quantify tissue metabolic and/or physiologic imaging parameters. Extraction of quantitative functional and biochemical information from the image differentiates molecular and physiologic imaging techniques from those that provide primarily anatomical (structural) information, and familiarity with image quantification and post-processing software tools is critical. For the effective application of these techniques, the relationships between anatomy and physiology must be considered in the context of probe or contrast agent pharmacokinetics and pharmacodynamics in disease states. Finally, clinical Page 10 of 19 trials are necessary to establish the safety and efficacy of molecular imaging agents, requiring Investigational New Drug (IND) applications to the Food and Drug Administration (FDA) and therefore extensive knowledge is required on all applicable regulatory requirements (IRB, CMC, GMP, etc). In summary, this domain builds on and integrates the other domains to provide a mechanism for exploring biological/clinical questions of interest through the application of suitable molecular imaging probe(s) and methods. The goal is to identify promising disease-specific diagnostic imaging biomarkers and/or therapeutics, and enhance our understanding of human pathophysiology in oncology, cardiovascular, and neuropsychiatric disorders. The imaging scientist will understand the role of targeted molecular imaging for the evaluation of critical pathophysiological processes of the specific organ system or area of interest. Competency Table 3 provides examples of competencies at Levels 1 and 2 for the 7 domains. Additional details are provided on the SNM web site (reference). This list should not be considered comprehensive since one of the goals of this white paper is to obtain feedback from the stakeholders to expand the list of competencies for each domain. There is some overlap expected between the domains, and this is not considered to be a problem. Conclusions Page 11 of 19 The identification of domains and competencies (Level 1 and 2) represents the first step to structure the basic knowledge requirements in education and training programs for molecular imaging scientists. It is anticipated that molecular imaging scientists will specialize in more than one domain and achieve competency beyond Level 2 within those domains. More detailed curricula must be developed and expanded for each of the domains, including identification of competencies at levels 3 and 4. While beyond the scope of the current report, students must acquire the appropriate depth of knowledge and competencies associated with such a subject-matter expert. This may be done more easily for some domains. For example, one can envision a chemistry program having a track for probe development. Similarly, a biomedical engineering program could have a track for instrument development. These tracks could be supplemented with courses and/or rotations in other departments. Interdisciplinary programs represent another solution, where several schools and departments contribute expertise and experiences to enable the students to achieve the competencies in the domains. Translation of molecular imaging approaches to the clinical realm is the critical aspect dominating domain 7. While other domains may have existing infrastructure supported by academic departments, this culminant domain differs in that regard. Universities do not typically have a Department of Translational Medicine, although many institutions now have National Institutes of Health funding for Clinical and Translational Science Awards Page 12 of 19 (CTSAs) that provide training in translation of technologies into human studies and the design of clinical trials. Scientists are needed with a unique set of skills that is typically acquired by experience over many years, and molecular imaging is just one of many areas for clinical translation. There is extreme competition for these individuals. This is yet another reason to give priority to expand the curriculum for this domain since it will aid with recruitment and help focus resources. Skills necessary for the practice of translational medicine and clinical trials are different from those used in clinical practice. The SNM Clinical Trials Network has focused efforts on training imaging site personnel in the conduct of clinical trials and in improved standardization of imaging acquisition, reconstruction, and interpretation. Commitment and support for the necessary quantitative approaches required of this domain are exemplified by the recently announced “Center of Quantitative Imaging Excellence (CQIE)” project from the National Cancer Institute (NCI) awarded to the American College of Radiology Imaging network (ACRIN) for the specific purpose of qualifying interested NCI-designated cancer centers in the performance of advanced quantitative imaging. Importantly, the cooperation of all stakeholders is desired. Page 13 of 19 References: 1. Mankoff D. A definition of molecular imaging. JNM. 2007: 48:17N. 2. Sullivan DC. Biomedical Imaging Symposium: Visualizing the Future of Biology and Medicine. Radiology. 2000: 215:634–638. 3. Louie A, Izatt J, Ferrara K. Biomedical Imaging Graduate Curricula and Courses: Report from the 2005 Whitaker Biomedical Engineering Educational Summit. Annals of Biomedical Engineering 2006: 34:239–247. Page 14 of 19 Table 1: Task Force Members Kurt R. Zinn, DVM, MS, Ph.D Task Force Chair Professor of Radiology, Medicine, and Pathology University of Alabama at Birmingham Michelle S. Bradbury MD, PhD Assistant Professor Molecular Imaging & Neuroradiology Sections Memorial Sloan Kettering Cancer Center Michael M. Graham, PhD, MD Immediate Past President, SNM Professor of Radiology Director of Nuclear Medicine Department of Radiology University of Iowa Heather Jacene, MD Staff Radiologist Dana-Farber Cancer Institute Assistant Professor of Radiology Harvard Medical School Steven M. Larson, MD Chief, Nuclear Medicine Service; Donna and Benjamin M. Rosen Chair in Radiology Memorial Sloan-Kettering Cancer Center Desiree Morgan, MD Professor of Radiology Abdominal Imaging Section Medical Director MRI, Chief Body MRI The University of Alabama at Birmingham Todd E. Peterson, PhD Assistant Professor of Radiology and Radiological Sciences Vanderbilt University Carolyn J. Anderson, Ph.D. Professor of Radiology, Biochemistry & Molecular Biophysics and Chemistry Washington University Stuart S. Berr, PhD Professor of Radiology and Biomedical Engineering University of Virginia Christopher Contag, PhD Associate Professor, Pediatrics – Neonatology; Microbiology & Immunology; Radiology Stanford University Cathy Sue Cutler, PhD Adjunct Professor University of Missouri, Research Reactor Center Bennett S. Greenspan, MD, MS Assistant Professor Washington University School of Medicine D. Scott Holbrook, BS, CNMT, PET, RT(N), FSNMTS Vice President Precision Nuclear Joel Karp, PhD Professor of Radiology and Physics University of Pennsylvania Suzanne Lapi, PhD Assistant Professor Washington University Daniel Lee, MD Assistant Professor of Radiology, Fellowship Director of Nuclear Medicine and Molecular Imaging Emory University Hospital Darlene Metter, MD, FACR Professor, Vice-Chair Clinical Education Department of Radiology University of Texas Health Science Center at San Antonio Alan Packard, PhD Sr. Research Associate, Children's Hospital Boston/ Assistant Professor of Radiology, Harvard Medical School Kooresh Isaac Shoghi, PhD Assistant Professor of Radiology Washington University Michael G. Stabin, PhD, CHP Associate Professor of Radiology and Radiological Sciences Vanderbilt University Joseph C. Wu, MD, PhD Assistant Professor of Radiology and Cardiovascular Medicine Stanford University Lily Wu, MD, PhD Biomedical Research Scientist University of California, Los Angeles Michael R. Zalutsky, PhD Professor of Radiology Professor of Biomedical Engineering Duke University Medical Center Marybeth Howlett, MEM Managing Director Molecular Imaging Center of Excellence and Clinical Trials Network SNM Lynn Barnes Director of Education SNM Jennifer Rice Senior Program Manager SNM Molecular Imaging Center of Excellence Jeffrey P. Norenberg, MS, PharmD, BCNP, FASHP, FAPhA Director, Radiopharmaceutical Sciences College of Pharmacy University of New Mexico Health Sciences Center Julie C. Price, PhD Associate Professor of Radiology University of Pittsburgh Page 15 of 19 Henry D. Royal, MD Professor of Radiology; Associate Director of Nuclear Medicine Mallinckrodt Institute of Radiology, Washington University Julie L. Sutcliffe, Ph.D. Assistant Professor of Biomedical Engineering University of California, Davis Members of the MICoE Education Task Force are also affiliated with the following organizations: HPS, ICRP, AAPM, IEEE, APS, ACS, SRS, ISRS, AACR, ISRS, AMI, SMI, ACNM, ACR and RSNA. Page 16 of 19 Table 2: Competency Levels Key to Competency Level Each of the competencies listed is designed to be taught to/for a particular level of expertise as defined in the table. The competency levels are defined as a standard of reference for the development of students’ expertise, as adapted from Bloom’s Taxonomy (reference). It is estimated that core competency in specific domains for molecular imaging students should include competency levels 1 and 2. Areas of specialization should approach level 3. Level 4 is developed after completion of essential basic education and significant practice in the field of expertise. Page 17 of 19 Level: Pre-requisite Competency: Minimal working knowledge/skill. Has minimum familiarity with basic sciences including chemistry, biochemistry, physiology, human anatomy, physics and molecular biology. May have some skills applicable to one or more domains. Level 1 Introductory Some functional knowledge/skill but usually requires guidance or input from more experienced users. At this level develops understanding and application of key concepts well enough to effectively communicate and interact with those more expert within the specific domain. Level 2 Novice Still developing but has sufficient knowledge/skill to function autonomously the majority of the time. Capable of using information, knowledge and skills to develop independent research. Identifies when assistance is needed. Level 3 Expert Uses knowledge/skill to increase understanding in area. Uses knowledge and skills to design and implement innovative research. Applies concepts to problem solving associated with primary research. Rarely needs assistance. Level 4 Master Established/recognized expert whose input is sought by others within the field. Established innovator. Page 18 of 19 Competency Level 2 Examples Competency Level 1 Examples Table 3: Competency Levels 1 and 2 examples for the domains Mathematics and statistics Imaging physics and instrumentation Exponential Functions Production of radio-nuclides Sensitivity & Specificity Interaction of radiation with matter Detectors Basic descriptive statistics Probability Distribution Nuclear Statistics Differential equations Curve fitting Hypothesis Testing Power, Sample Size Survival Curves Formation of images Imaging modalities X-ray production Gamma camera performance PET perfor-mance Tomographic reconstruction Image Processing Molecular probe and contrast agent development Probe design Coordination chemistry Conjugation chemistry Quality control Probe evaluation Automated synthesis MR & optical probes Combinatorial chem. Synthetic chem. GMP issues; CMC component Domain Cell and molecular biology Model systems Pharmacology Clinical imaging of disease Cell culture Target selection Modality selection Animal models, Anatomy, physiology Anesthesia, Biological systems Imaging & biodistribution Ethics & compliance Pharmacokinetics Probe selection Pharmacodynamics Sampling & analyses Toxicology Imaging methods Biomarker metrics Regulatory Gene mapping Gene profiling Stem Cell & trafficking 3 D organ cultures Response metrics Protein profiling Genomics Pathophysiology models Animal monitoring Epigenetics Specialized surgery Pharmacology class. Receptor interactions Use of radiotracers Analyses methods IND preparation Cell processes/ structure Metabolic pathways Molecular biology Gene transfer vectors Gene therapy Page 19 of 19 Targeted imaging Anatomy & physiology Informatics Compliance for IND