Download WHITE PAPER FINAL on August 13, 2010 Title: Proposed

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
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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
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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
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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
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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
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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
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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,
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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
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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.
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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
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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
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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
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(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.
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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.
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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
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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.
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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.
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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.
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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
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Targeted imaging
Anatomy &
physiology
Informatics
Compliance for IND