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Setting the Agenda for Investigating the Evolution of Antimicrobial Drug Resistance:
An Interdisciplinary Systems Approach
Betsy Foxman and Carl Simon
A. Statement of nature, objectives, and expected outcome of proposed research/creative
activity:
Antimicrobial resistance has been identified as a major public health problem in several Institute
of Medicine (IOM) and other government reports [1-5], and is first on the list of targeted areas in
the CDC strategy for preventing emerging infectious diseases [6]. Antimicrobial resistance
poses a direct threat to human health by decreasing the effectiveness of treatment, thus requiring
the use of alternative, more toxic treatments, and prolonging illness, all of which increase the risk
of more serious morbidity and the potential for mortality. The American Society of
Microbiology estimated in 1995 that treating resistant infections in the United States cost $4
billion annually or approximately 0.5% of total health care costs. A research goal identified in
the 2003 IOM report [2] is to “develop a fuller understanding of how microbes evolve when
faced with drugs that threaten their survival” as a means to identify more effective control
methods.
Our goal is to develop theories regarding the emergence and maintenance of antimicrobial
resistance and design appropriate public policies implementing those theories. We will create
models, develop methods, and conduct studies, including simulation studies, to test these theories
and the potential effectiveness of proposed policies.
Specific Aims:
1. Develop methods via workshops & interdisciplinary working groups to inform model
building.
2. Develop theories via models & pilot studies, to address questions such as:
a) How do community and individual factors (antibacterial products, food stuffs, pets,
agriculture, aquaculture, medical prescribing, etc.) modify/effect community acquired
resistance?
b) What are the mechanisms of resistance within the infectious agent, the host, and
community?
3. Prepare working papers and publications via interdisciplinary working groups.
4. Develop grant proposals. Working groups and workshops will build a common vision and
set of priorities, as well as establish collaborative relationships that will enhance capacity to
pursue grant proposals effectively. In particular, we hope to respond to the upcoming NIH
Roadmap RFA (May 2006 deadline) with a consortium proposal on antimicrobial resistance.
The individual components of the consortium proposal can be submitted to other appropriate
government and private funding opportunities, including NIH (as R01s), NSF, Robert Wood
Johnson Foundation, Kellogg and General Motors. Our long-term goal is to establish an
internationally recognized, externally supported, multi-unit, interdisciplinary center on
antimicrobial resistance.
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B. Description of the significance of proposed research/creative activity: in the discipline
or field, for the applicant’s scholarship, and for the University
Tackling antimicrobial resistance requires a systems approach because complex interactions
among health care, the environment, the individual and society impact the spread of disease and
possible solutions. However, no overall theoretical framework currently exists for understanding
antimicrobial resistance, perhaps because that framework cannot come from within the bounds of
a single discipline. Rather, the framework must synthesize the genetics of microbial evolution,
the molecular aspects of antimicrobial resistance, the transmission dynamics of evolved strains in
human populations, and the social forces affecting antimicrobial use. Table A1 (in the
Appendix) shows opportunities for interventions at various levels from molecular to societal.
The NIH has recently highlighted the compelling need for incorporating social and cultural
dimensions into understanding health and disease, and the need to incorporate five major levels
of analysis into health research, from the social and environmental to behavioral and
psychological to the organ system, cellular and molecular levels. Mathematical modeling
provides a way to integrate information from each level, and to estimate the impact of variations
of each level on projected outcomes. Thus, we propose a multi-scale modeling effort that links
the molecular aspects of antimicrobial resistance in the microbe to the dynamics of infection
within host organisms, to the population dynamics of transmission, to forces affecting the use of
antimicrobials at the population level. These models can be used to identify gaps in current data,
plan experiments and observational studies to fill those gaps, test theories and estimate the
potential impact of public policies. Therefore, models are central to the proposed multi-unit,
interdisciplinary group of investigators studying antimicrobial resistance.
Models of Antimicrobial Resistance: Several different types of models have been developed to
understand the emergence and spread of antimicrobial resistance, but the frameworks have been
limited to between host, within host, and population models without integrating across levels.
Between-host epidemiologic models have been employed to examine emergence and
maintenance of resistance in both hospital and community settings [7, 8]. These models address
the question, at what level of population use does resistance emerge and what is the impact of
reducing use on limiting resistance spread? Within host models have modeled emergence of
resistance within the human host [9, 10] in order to address the effects of varying levels of drug
use on emergence of resistance within the individual. A small system dynamics model that
portrays changes over time among populations of antibiotic-susceptible, intermediately resistant
and highly resistant bacteria has been developed based on S. pneumoniae [11]. This model
addresses the impact of reducing the magnitude of antibiotic use and the timing of that reduction
on the emergence of antibiotic resistance. Each type of model has provided important insights,
but none of the models have provided a framework for using molecular and host infection
dynamics data within the context of population transmission models -- a major barrier to
successful modeling of the problem. There is considerable molecular data on the nature of genetic
sequences associated with resistance, but without an appropriate framework, within host and
between individual scales can not be integrated and used in the same model.
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A second barrier is determining the extent to which the characteristics of individual organisms
and the associated epidemiology are important determinants of the model predictions. Scaling
this barrier requires better data also: until we have more specific and robust models, it is hard to
determine the extent to which they are generalizable, but validating models and understanding
their strengths and limits requires appropriate data.
A third barrier is in perspective: antimicrobial use is not merely a function of medical practice
and biological action but is a response to cultural, economic, and social factors. Policy
recommendations cannot be made without considering these other perspectives and the
alternative solutions suggested by them.
Implications for the University: Our long term goal is to establish a multi-unit, interdisciplinary,
internationally recognized Center on antimicrobial resistance at the University of Michigan
which uses modeling approaches in the development, analysis and interpretation of observational
and experimental studies. We propose modeling as an integrative force providing common
understanding across the multiple participating disciplines. This novel integrative strategy will
generate new theories, methods and the development of new laboratory techniques, which will,
in turn, lead to multiple externally supported research projects.
C. Plans for accomplishing objectives
1. Build a pilot model of antimicrobial resistance that takes into account molecular and host
infection dynamics data within the context of population transmission models. We will use this
model to begin testing our theories, and to show the feasibility and utility of a multi-level, mutlidisciplinary approach of the type we are advocating.
Current models of bacterial infection and of drug resistance either focus on the level of
susceptible and infected individuals, basically ignoring the within-body dynamics, or focus on
the bacterial colonies, ignoring the population level transmission dynamics. The former
approach models drug resistance merely by a change in some arbitrary parameter. The latter
cannot handle transmission and thus only indirectly treats the pernicious effects of drug
resistance. In addition to lacking a relevant theoretical framework, all modeling efforts have been
severely hampered by a lack of data [12-14]. An early task of our collaboration will be to write
survey articles that summarize the essence of these simpler models and pinpoint their
contributions and their limitations.
Our main task is to build a multi-level agent-based model that includes:
1. Individuals transmitting and avoiding bacterial infection,
2. Medical personnel treating these infections with a variety of interventions in a variety of
settings,
3. Within each individual a colony of heterogeneous bacteria sometimes in and sometimes
out of equilibrium, with drug resistant strains ready to become active when the
opportunity arrives.
Population epidemiologists and networks experts will focus on level (1), medical and public
health researchers will focus on (2), while laboratory epidemiologists, ecologists, evolutionary
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biologists and microbiologists will work on aspects of (3). Complex systems modelers will work
with these various “domain experts” to build these multi-level models and to use mathematical
analysis and computer simulation to analyze them. The resulting multi-level model will be the
first attempt to include the many levels at which bacteria operate and build drug resistance. Each
researcher will be able to tinker with those parts of the model that lie within his or her expertise
and will help other members of the team and the health profession to understand the intricate
workings of this complex system and their policy implications.
2. Hold meetings of the Planning Group and establish two working groups, one on
methodological development the other on theory development. A student will support the
working groups, by running simulations using the model to test theories, conducting literature
reviews, and general support functions. Interdisciplinary research requires that researchers in
each field have an understanding and appreciation for the accomplishments, needs and
vocabulary of other fields. Thus, much work is required before we will have sufficient
preliminary work to convince NIH and/or NSF to support our program, including preliminary
models, and identification of model organisms or systems, and some preliminary results. Each
working group will set a goal of preparing a position or review paper and/or submitting a grant
proposal by October 1, 2006. These activities will confirm Michigan as a major player in this
evolving field.
3. Conduct a workshop on Antimicrobial Resistance in the Spring, 2006. We are largely
developing a new conceptual framework for studying antimicrobial resistance. Thus, we plan to
put on a workshop to ‘jump start’ the process. The workshop will provide a deadline for
synthesis of initial ideas by each working group, a forum for presenting them to colleagues and
the opportunity to get feedback from external experts in the field.
We have invited Martin J. Blaser, Frederick H. King Professor of Internal Medicine and
Chairman of the Department of Medicine and Professor of Microbiology at New York
University Medical Center, Carl Bergstrom, Assistant Professor at the University of Washington
and Elizabeth Bancroft, MD, Hospital Infections and Bloodborne Pathogens, Acute
Communicable Disease Control, Los Angeles County Department of Health Services to
participate in the workshop. These speakers cover the molecular (Blaser), modeling (Bergstrom)
and public health (Bancroft) aspects of antimicrobial resistance. Dr. Blaser has already accepted
our invitation. The workshop will consist of closed meetings of the planning group with the
invitees, public lectures by the invitees followed by round table discussions. Thus, the planning
group will have time to interact and ask specific questions, while the open portion will help
identify additional interested investigators and students.
Planning Group: We have identified an interdisciplinary group of investigators with expertise in
antimicrobial resistance, bacteriology, ecology, economics, epidemiology, genetics, health
policy, history of science, mathematics, medicine, molecular biology, multi-level analysis, and
transmission system modeling. Each discipline brings a different perspective, skill set and focus;
a major task will be developing a common vision and set of priorities. We believe that
developing the model will be central to both developing the vision and setting priorities, as it will
require agreement on the conceptual model and key parameters.
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Many of the planning group members are members of MAC-EPID, CSCS or both, and have
collaborated either formally or informally. As the planning progresses, and working groups
develop, we anticipate that we may invite additional investigators to join our group as we
identify gaps in our collective knowledge that cannot be filled via the workshop mechanism.
A brief description of each investigator is included in the Appendix.
Conclusion:
Antimicrobial resistance is an important public health problem that requires a systems approach
and interdisciplinary collaboration, and has high potential for continued funding. We propose
the development of a framework synthesizing the genetics of microbial evolution, the molecular
aspects of antimicrobial resistance, the transmission dynamics of evolved strains in human
populations, and the social forces affecting antimicrobial use, using mathematical models as a
way to transcend disciplinary boundaries and perspectives. Our novel strategy of using
mathematical models as an integrating and cohering force to generate new theories, methods and
the development of new laboratory techniques, will lead to multiple externally supported
interdisciplinary research projects.
Our long-term goal is to establish a multi-unit, interdisciplinary, internationally recognized
externally supported Center on antimicrobial resistance at the University of Michigan which
fully integrates mathematical models into the design, analysis and interpretation of research
projects. This strategy will result in the development of new modeling methods, novel research
designs and laboratory techniques that will have broader applications. Most importantly, the
efforts of our interdisciplinary team will protect the public’s health by increasing understanding
of the overall system of antimicrobial resistance, leading to effective policies to reduce resistance
and preserve antimicrobial drugs for the future.
References
1. Harrison, P. F. and J. Lederberg (1998). "Antimicrobial Resistance: Issues and Options."
Workshop Report, Forum on Emerging Infections, Institute of Medicine. (Washington,
DC: National Academy Press.)
2. Knobler, S. L., S. M. Lemon, et al. (2003). "The Resistance Phenomenon in Microbes and
Infectious Disease Vectors: Implications for Human Health and Strategies for
Containment." Workshop Report, Forum on Emerging Infections, Institute of Medicine.
(Washington, DC: National Academy Press.)
3. Davis, J. R. and J. Lederberg (2001). "Emerging infectious diseases from the global to the
local perspective: workshop summary." Workshop Report, Forum on Emerging
Infections, Institute of Medicine. (Washington, DC: National Academy Press.)
4. National Research Council (1999). "The Use of Drugs in Food Animals: Benefits and Risks."
Committee on Drug Use in Food Animals, Panel on Animal Health, Food Safety, and
Public Health, Board on Agriculture, National Research Council. (Washington, DC:
National Academy Press.)
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5. Interagency Task Force on Antimicrobial Resistance (2001). Annual Report on A Public
Health Action Plan To Combat Antimicrobial Resistance. CDC Publication:
http://www.cdc.gov/drugresistance/.
6. Centers for Disease Control and Prevention (1998). "Preventing Emerging Infectious
Diseases: A Strategy for the 21st Century."
7. Austin, D. J., M. Kakehashi, et al. (1997). "The transmission dynamics of antibiotic-resistant
bacteria: the relationship between resistance in commensal organisms and antibiotic
consumption." Proc Royal Soc Lond Ser B 264: 1629-1638.
8. Lipsitch M, Bergstrom CT, Levin BR. The epidemiology of antibiotic resistance in hospitals:
paradoxes and prescriptions. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1938-43.
9. Lipsitch, M. and B. R. Levin (1997). "The population dynamics of antimicrobial
chemotherapy." Antimicro Agents Chemother 41(2): 363-373.
10. Davis, S. A. and D. M. Gordon (2002). "The influence of host dynamics on the clonal
composition of Escherichia coli populations." Enviro Microbio 4: 306-313.
11. Homer, J., J. Ritchie-Dunham, et al. (2000). "Toward a dynamic theory of antibiotic
resistance." Syst Dyn Rev 16(4): 287-319.
12. Levin, B. R., (2002). "Models for the spread of resistant pathogens." J Med 60:58-64.
13. Levin, B. R., R. Anita, et al. (1998). "Resistance to antimicrobial chemotherapy: a
prescription for research and action." Amer J Med Sci 315: 87-94.
14. Levin, B. R., V. Perrot, et al. (2000). "Compensatory mutations, antibiotic resistance and the
population genetics of adaptive evolution in bacteria." Genetics 154: 985-997.
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Budget Justification
The requested funds are intended as seed monies. The Bioterrorism Initiative has agreed to
allocate $10,000 in matching funds (see attached letter).
We request funds to hire a percentage of Rick Riolo, Associate Research Scientist at the UM
Center for the Study of Complex Systems (CSCS), to work with the other investigators to build a
multi-scale model of bacterial infection. ($9500). As described in the text of the proposal, this
model will be a pilot simulator that group members will use to test their current theories and to
serve as a proof-of-concept simulator to show the feasibility and utility of this multi-level, multidisciplinary approach. As such, the computational model is an essential component of this pilot
project. Building this model will take not only Dr. Riolo’s time, and that of the student
programmer (see below) but considerable input from the working groups. For exploratory/novel
projects like this it is expected that the model building will be a continual work in progress. As
we learn more, we will feed back the information and improve the model so it can address
additional questions.
We request $9500 to cover costs of a student (475 hours @$20/hour) to 1) assist Dr. Riolo in
building the model; 2) support each working group by running simulations using the model, and
conducting comprehensive literature reviews. We will establish two working groups, one on
methodological development the other on theory development. Interdisciplinary research
requires that researchers in each field have an understanding and appreciation for the
accomplishments, needs and vocabulary of other fields. Thus, much work is required before we
will have sufficient preliminary work to convince NIH and/or NSF to support our program,
including preliminary models, and identification of model organisms or systems, and some
preliminary results.
The student will have primary responsible for running all requested simulations of the
interdisciplinary working groups as well as assisting Rick Riolo in the initial programming. In
addition, the student will conduct comprehensive literature reviews, and provide general support
for the interdisciplinary working groups.
We request $6000 to conduct a workshop on antibiotic resistance. We are largely developing a
new conceptual framework for studying antimicrobial resistance. Thus, we plan to put on a
workshop to ‘jump start’ the process. The workshop will provide a deadline for synthesis of
initial ideas by each working group, a forum for presenting them to colleagues and the
opportunity to get feedback from external experts in the field.
We have tentatively identified Martin J. Blaser M.D. Frederick H. King Professor of Internal
Medicine and Chairman of the Department of Medicine and Professor of Microbiology, Carl
Bergstrom, PhD, Assistant Professor, University of Washington, and Elizabeth Bancroft, MD,
Hospital Infections and Bloodborne Pathogens, Acute Communicable Disease Control, Los
Angeles County Department of Health Services as workshop speakers. The expenses for the
workshop are as follows:
Travel for Drs. Blaser, Bergstorm and Bancroft: 3 @$1500 or $4500
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Honorarium for Drs. Blaser, Bergstorm and Bancroft: 3@ $250 each or $750
Dinner for workshop participants: 22 people @ $25 each or $550.
The rental of meeting space and providing luncheon to participants will be supported by
the Center for the Study of Complex Systems and the Center for Molecular and Clinical
Epidemiology of Infectious Diseases (no OVPR funds will be spent for these expenses).
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Appendix
Table A1: Levels, associated constructs and relevant disciplines impacting the development,
spread, and establishment of antimicrobial resistant organisms
Level
Constructs
Relevant Disciplines
I. Society
Animal husbandry
Bioethics
Cultural norms, values,
Economics
traditional practices & beliefs
Health Services Research
Legislation/ Regulation
History
National & International
Human & Veterinary Medicine
Politics and Economics
Law
Pharma
Marketing
Trade
Operations Research
Use in humans/ animals
Political Science
Public policy
Social Science
IIa. Health Care
Best Practice/ HEDIS
Health Policy & Management
Delivery Systems Formularies
Health Services Research
Reimbursement Policies
Human & Veterinary Medicine
IIb. Environmental/
Age structure of population
Computer Science
Ecology
Disease patterns
Demography
Exposure to other species
Ecology
Marketing strategies
Environmental Health Science
Poverty
Epidemiology
Prevalent norms of
Evolutionary Biology
antimicrobial use
Geography
Seasonality
Mathematics
Urbanicity
Social Science/ Network Theory
IIIa. Institutions, e.g.,
hospitals, day
care, schools,
nursing homes
Age structure
Disease susceptibility patterns
Institutional exclusionary &
other policies
Institutional formularies
Mixing patterns
Pharma
Poverty
Size
Epidemiology
Health Services Research
Human Medicine
Infection Control
Nursing
Sociology/ Network Theory
IIIb. Individual
healthcare
providers
Age
Pharma
Specialty
Training
Age
Behavior
Beliefs
Health Behavior
Health Services Research
Medicine
Nursing
Anthropology
Epidemiology
Genetics
IV.
Individual
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Level
VI. Organ System
(within host
ecology)
VIIa. Host Cellular
VIIb. Agent
VIII. Molecular
Constructs
Gender
Genetics
Health insurance
Hygiene
Immune status (health)
SES
Antimicrobial use
Exposures to organisms, e.g.
diet, contacts
Host immune response
Sex (male or female)
Immune repertoire
Targets cells
Relevant Disciplines
Human Medicine
Psychology
Sociology
Biology
Ecology
Immunology
Microbiology
Physiology
Cell Biology
Immunology
Molecular Biology
Agent type, e.g., virus, bacteria Epidemiology
Inherent mutability
Microbiology
Innate & acquired sensitivity
Molecular Biology
to antimicrobials
Metabolic requirements
Replication rates
Transmission system
Agent gene transfer
Biochemistry
mechanisms
Genetics of host and agent
Antimicrobial resistance
Molecular Biology
mechanisms
Organic Chemistry
Target molecules for hostPharmacology
agent interaction
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Description of Participating Faculty
Dr. Allison Aiello is Assistant Professor in the Department of Epidemiology at the University of
Michigan. She has been involved in research comparing the benefit of alcohol based hand
hygiene products versus traditional hand wash methods among hospital personnel at New York
Columbia Presbyterian Hospital. In addition, she has been conducting research on antibiotic
resistance within the community setting, where she is examining whether there is a risk of
increasing resistance associated with the use of antibacterial cleaning and hygiene products
within the home environment.
Dr. Patricia Brown is an Associate Professor in the Division of Infectious Diseases at Wayne
State University School of Medicine. As a clinician-educator, she spends approximately 50% of
her time in direct patient care. Her research interests include the impact of emerging resistance
among bacteria that cause common, community-acquired infections, especially urinary tract
infection. She is actively involved in formulary decision making at the Detroit Medical Center,
serving as a member of the Antimicrobial Subcommittee and as chairman of the Detroit Medical
Center Pharmacy and Therapeutics Committee. She is also active in the Michigan Antibiotic
Resistance Reduction Coalition, an organization devoted to addressing the problems of
antimicrobial resistance through provider and community education. Dr. Brown will be able to
provide the perspective of the practicing infectious diseases clinician to the project.
Dr. Ana Diez-Roux is Associate Professor of Epidemiology at the University of Michigan.
Originally trained as a pediatrician, Dr. Diez Roux is an epidemiologist with expertise in
multilevel analysis and social epidemiology. Her prior work has focused on the application of
multilevel analysis to examine how factors defined at multiple levels impact the health of
individuals. Dr. Diez Roux will bring to this project expertise in multilevel analysis, and more
generally, in conceptualizing how factors at multiple levels may be related to antibiotic
resistance. Dr. Diez Roux will collaborate with other modeling experts on this project in
considering the most appropriate ways to examine these multilevel determinants in empirical
analyses. Of special interest is the inter-phase between multilevel models and transmission
models in the study of infectious disease-related outcomes, including antibiotic resistance. Dr.
Diez Roux brings to the project a unique combination of clinical training with expertise in
epidemiology, multilevel analysis and population health.
Dr. Betsy Foxman is Professor of Epidemiology and Director of the Center for Molecular and
Clinical Epidemiology of Infectious Diseases (MAC-EPID) at the University of Michigan.
MAC-EPID provides and intellectual locus for researchers interested in the transmission,
pathogenesis and evolution of infectious agents. Dr. Foxman is a molecular epidemiologist; her
work focuses on the epidemiology of acute, chronically recurring bacterial infections,
particularly urinary tract infections, otitis media, and lactation mastitis. In collaboration with
Drs. Marrs, Koopman and Zhang she has described the transmission of uropathogenic E. coli,
and Group B streptococcus, and is currently hunting for new genes associated transmission and
pathogenesis, and describing frequency and mechanisms of antibiotic resistance of these two
organisms. She also has a longstanding interest in the translation of science to public policy. In
that regard, Dr. Foxman was a founding member of the Executive Council of the Michigan
Antibiotic Resistance Reduction Coalition (MARR), and is past-chair of the American Public
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Health Association Epidemiology Section, and first past chair, and founder of the Michigan
Public Health Association Epidemiology Section.
Dr. James Koopman is Professor of Epidemiology at the University of Michigan. Dr.
Koopman’s research focusds on new methods for a science of infection transmission. He is
advancing two cornerstones of that new science. The first is the integration of diverse modeling
methods into a single coherent analytic approach called Model Transition Sensitivity Analysis.
The second involves using the nucleotide sequences of infectious agents isolated from
individuals with documented exposure points in the transmission system to make inferences
about transmission systems. Dr. Koopman trained as a pediatrician and as a member of the
Epidemiology Intelligence Service. Thus, along with his stong modeling skills he brings a
clinical and public health perspective to the project.
Dr. Jeffrey C. Long is currently Professor in the Department of Human Genetics at the
University of Michigan Medical School and a member of the Center for Statistical Genetics. His
research focuses on human population genetics and the genetic basis of common diseases. He
has conducted several studies on alcohol dependence, including a full genome linkage scan and
evaluation of the roles candidate genes with neurobiological functions. He has also conducted
research on the genetic structure of human populations from diverse global regions, including
Northern Europeans, Native Americans, and New Guinea Highlanders. A major focus of current
research in his laboratory is the population genetics and molecular evolution of alleles at the
ALDH2 locus. Other current research foci of his include the analysis of genetic and geographical
structure in human populations and quantifying the information on ancestry provided by human
genetic polymorphisms.
Dr. Bobbi Low is Professor of Natural Resources at the University of Michigan. Her research
focuses on the use of evolutionary theory to assist in understanding human activities, particularly
patterns of resource use. Specific areas include: degree of sexual dimorphism and mating
systems; ecological aspects of marriage systems; sex differences in resource use; the behavioral
ecology of conservation; dynamic modeling of ecosystems and human decision systems, and
their interactions; evolutionary and behavioral ecology of wildlife species; resource control and
reproductive success in vertebrates, parental strategies in vertebrates; integration of evolutionary
theory and resource management. Dr. Low will bring an ecological and evolutionary perspective
to the project.
Dr. Carl Marrs, Associate Professor of Epidemiology brings expertise on bacterial genetics and
transposable elements. His interest in resistance goes back to his doctoral thesis project on
bacteriophage Mu, which is both a bacterial virus and a transposable element. Dr. Marrs has
remained up-to-date on IS elements, transposons, integrons, etc. both through use of transposons
in his own laboratory research, and through teaching about bacterial genetics and transposable
elements in several courses each year. Similarly his laboratory has carried out studies on a
variety of bacteria expressing different antibiotic resistances, and each year he gives extensive
lectures on the mechanisms of antibiotic resistance in two different courses.
Dr. Marrs will
bring extensive expertise and interests in the molecular mechanisms of antibiotic resistance and
the genetics means by which such resistances arise and spread to the more global discussions.
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Dr. Rick Riolo, Associate Research Scientist and Director of CSCS Computer Lab, brings
expertise on using Agent (Individual) Based Computational Modeling. He has worked on many
interdisciplinary projects aimed at creating a wide variety of agent-based models, including:
(1) models of land use and cover change in the context of “urban sprawl”, as determined by the
interactions of heterogeneous individual and institutional agents, (2) models of decision making
in closed regimes as a result of the interactions of powerful individuals, parties and institutions,
(3) models of the role of phenotypic plasticity on food web dynamics and stability, (4) models of
the transition to a possible hydrogen production and distribution infrastructure, and concomitant
changes to consumer preferences, and (5) models of the interactions between dental health
providers, other providers and Medicaid patients, and how that affects the access of patients to
dental services. More broadly Dr. Riolo also was worked on: (1) how evolutionary algorithms
work, e.g., when and how recombination is a useful evolutionary operator; (2) how interaction
topology affects the ability of populations to establish and maintain cooperation and other group
structures and behavior; and (3) how coordinated behavior emerges from populations of agents
with co-evolving models of each other.
Dr. Carl Simon is jointly appointed as professor in the departments of Mathematics and
Economics in the School of Letters, Arts and Sciences, and in the Gerald R. Ford School of
Public Policy at the University of Michigan. Since 1999, he has been the director of the UM
Center for the Study of Complex Systems. His research interests center around the theory and
applications of dynamical systems. He has worked on generic and stable properties of smooth
dynamical systems and on the properties of equilibria of area-preserving systems of classical
mechanics. In economic models, he has studied the dynamics that occur as an economy moves to
a balance of supply and demand and as an economy moves to long-run equilibrium with a
continuum of products. Currently, his research focuses on dynamic models of the spread of
communicable diseases, especially HIV and influenza, with a special interest in the role of nonrandom mixing on the transmission process. Dr. Simon will take the lead in development of
conceptual and simulation models of the transmissions and development of antibiotic resistance.
Dr. Chuanwu Xi is an Assistant Professor in the Department of Environmental Health Sciences.
Dr. Xi has extensive experiences in the application of molecular techniques and nanotechnology
to problems of environmental microbiology. His research tries to understand molecular
mechanisms of persistence of pathogens in natural, engineered and industrial environments,
transmission routes of pathogens from environments to hosts, and their health impacts on general
public and industrial workers. He is particularly interested in the role of biofilms in these
processes.
Dr. Zhenhua Yang is an Assistant Professor in the Department of Epidemiology at the University
of Michigan. Her research uses molecular epidemiologic approaches to identify tuberculosis
genes associated in pathogenesis, transmission and resistance.
Dr. Lixin Zhang is an Assistant Research Scientist in the Department of Epidemiology at the
University of Michigan. Dr. Zhang received bachelor training in biochemical engineering
followed by two years' work experience as an engineer in bioremediation. He later received
master training in molecular and cellular biology with focus on bacterial pathogenesis. His
doctoral training and research is epidemiology of infectious diseases. Microbiology is the
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common thread that connects his diverse training and research background. Dr. Zhang's current
research is focused on applying microarray technology to study genetic diversity of microbial
species and understand the evolution of infectious agents.
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