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 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 prior education, training and experiences, and in anticipation of their professional research goals, interests, and needs. A required core of entry-level 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
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 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 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 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, 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 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.
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 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.