Early Infectious Disease Diagnosis Using Genomics
A key pillar and unmet need in the defense against threats to health is the ability to recognize the etiological factor(s) and predict the course of disease, at early points in the timeline of the process. This ability would enable early intervention in the disease process when there is the greatest likelihood of benefit, as well as triaging of hosts, based on individual need. Genomic tools and approaches have enabled a more detailed description of host-microbe encounters, and shed light on fundamentally important processes, including the cellular responses associated with infection. Genome-wide transcript-abundance profiles, like other comprehensive molecular readouts of host physiological state, provide a detailed blueprint of the host-pathogen dialogue during microbial disease. Studies of cancer based on genome-wide transcript-abundance profiles have led to novel signatures that predict disease outcome and serve as useful clinical classifiers. The highly dynamic and compartmentalized aspects of the host response to pathogens complicate efforts to identify predictive signatures for infectious diseases. Yet, studies of systemic infectious diseases so far suggest the possibility of successfully discriminating between different types (classes) of infection and predicting clinical outcome. In addition, host gene expression analysis could lead to the identification of early signatures associated with a protective immune response, both to natural infection and to vaccination. Early explorations in some of these areas indicate the potential feasibility of this approach but also point to important unmet challenges.
David Relman is associate professor of medicine, and of microbiology and immunology at Stanford University. He is also chief, infectious diseases section, at the VA Palo Alto Health Care System in Palo Alto, California.
A native of Boston, Massachusetts, Relman holds an SB degree from the Massachusetts Institute of Technology and received his MD degree, magna cum laude, from Harvard Medical School in 1982. Following postdoctoral clinical training at Massachusetts General Hospital in internal medicine and in infectious diseases, Relman served as a postdoctoral research fellow in microbiology at Stanford University in the laboratory of Stanley Falkow from 1986 until 1992. He joined the Stanford University faculty in 1992 and was appointed associate professor (with tenure) in 2001. His research is directed towards the characterization of the human indigenous microbial communities of the mouth and gut, with emphasis on understanding variation in diversity, succession, the effects of disturbance, and the role of these communities in oral and intestinal disease.
Experimental approaches include molecular phylogenetics, ecological statistics, single cell genomics, and community-wide metagenomics. A second area of research concerns the classification structure of humans and non-human primates with systemic infectious diseases, based on patterns of genome-wide gene transcript abundance in blood and other tissues. The goals of this work are to recognize classes of pathogen and predict clinical outcome at early time points in the disease process, as well as gain further insights into virulence (e.g., of variola and monkeypox viruses). Past achievements include the description of a novel approach for identifying previously-unknown pathogens (selected as one of the 50 most important papers of the last century by the American Society for Microbiology), the identification of a number of new human microbial pathogens, including the agent of Whipple's disease, and the most extensive descriptions to date of the human indigenous microbial community. See http://relman.stanford.edu. Relman received the Squibb Award from the Infectious Diseases Society of America (2001), the Senior Scholar Award in Global Infectious Diseases from the Ellison Medical Foundation (2002), and is a recipient of an NIH Director's Pioneer Award (2006). He is a member of the American Society for Clinical Investigation and was named a Fellow of the American Academy of Microbiology in 2003.
Relman currently serves on the Board of Scientific Counselors of the National Institute of Dental and Craniofacial Research and was a member of the Board of Directors of the Infectious Diseases Society of America (2003-2006), and co-chair of the National Academy of Sciences' Committee on Advances in Technology and the Prevention of Their Application to Next Generation Biowarfare (2004-2006). He is a member of the National Science Advisory Board for Biosecurity, the Institute of Medicine's Forum on Microbial Threats, and advises several U.S. Government departments and agencies on matters related to microbial pathogen detection and future biological threats.
Reuben W. Hills Conference Room
Strategies for Combating Terrorism
Bioterrorism is a growing threat. While the U.S. government has spent considerable sums on programs designed to protect the United States from a biological attack, no clear strategy has been articulated to guide planning and expenditures. This talk will present the outlines of a coherent strategy for coping with bioterrorism that includes diplomacy, deterrence and defense, with the emphasis on defense.
Dean Wilkening directs the Science Program at CISAC. He holds a Ph.D. in physics from Harvard University and spent 13 years at the RAND Corporation prior to coming to Stanford in 1996. His major research interests have been nuclear strategy and policy, arms control, the proliferation of nuclear, biological, and chemical weapons, ballistic missile defense, and conventional force modernization. His most recent research focuses on ballistic missile defense and biological terrorism. His work on missile defense focuses on the broad strategic and political implications of deploying national and theater missile defenses, in particular, the impact of theater missile defense in Northeast Asia, and the technical feasibility of boost-phase interceptors for national and theater missile defense. His work on biological weapons focuses on understanding the scientific and technical uncertainties associated with predicting the outcome of hypothetical airborne biological weapon attacks, with the aim of devising more effective civil defenses, and a reanalysis of the accidental anthrax release in 1979 from a Russian military compound in Sverdlovsk with the aim of improving our understanding of the human effects of inhalation anthrax.
Reuben W. Hills Conference Room
Roundtable Forum - Anxious Times: Seeing Beyond a World of Perpetual Threats
Timely reunion panel hosted by Stanford president John Hennessy, moderated by Stanford alum Ted Koppel, and featuring Bill Perry and George Shultz.
The final decade of the 20th century was a time of great optimism. The fall of the Iron Curtain ushered in a new era of democracy and freedom for millions. The expansion of the European Union promised to open borders to trade and opportunity. The technology revolutions of the 1990s promised to bridge cultural gaps and unite diverse people.
Yet, in the first decade of the 21st century, this optimism has faded in the face of myriad threats: the menace of terrorism and nuclear proliferation, the danger of virulent pandemics, the global dependence on oil from volatile regions, and the far-reaching and often unsettling implications of an interconnected planet.
In such uneasy times, is it safe to feel safe? What is the way forward in the midst of these challenges? What will it take? What is Stanford doing to help address these issues?
Panelists
John L. Hennessy, Stanford President and Bing Presidential Professor
Jean-Pierre Garnier, MBA '74, CEO, GlaxoSmithKline
The Hon. Anthony M. Kennedy, '58, Supreme Court Justice
William J. Perry, '49, MS '50, former Secretary of Defense, Berberian Professor in the School of Engineering
Dr. Lucy Shapiro, Ludwig Professor of developmental biology and cancer researcher
George P. Shultz, former Secretary of State, Ford Distinguished Fellow, Hoover Institution
Jerry Yang, '90, MS '90, co-founder, Yahoo!
Reducing Mortality from Anthrax Bioterrorism: Strategies for Stockpiling and Dispensing Medical and Pharmaceutical Supplies
A critical question in planning a response to bioterrorism is how antibiotics and medical supplies should be stockpiled and dispensed. The objective of this work was to evaluate the costs and benefits of alternative strategies for maintaining and dispensing local and regional inventories of antibiotics and medical supplies for responses to anthrax bioterrorism. We modeled the regional and local supply chain for antibiotics and medical supplies as well as local dispensing capacity. We found that mortality was highly dependent on the local dispensing capacity, the number of individuals requiring prophylaxis, adherence to prophylactic antibiotics, and delays in attack detection. For an attack exposing 250,000 people and requiring the prophylaxis of 5 million people, expected mortality fell from 243,000 to 145,000 as the dispensing capacity increased from 14,000 to 420,000 individuals per day. At low dispensing capacities (14,000 individuals per day), nearly all exposed individuals died, regardless of the rate of adherence to prophylaxis, delays in attack detection, or availability of local inventories. No benefit was achieved by doubling local inventories at low dispensing capacities; however, at higher dispensing capacities, the cost-effectiveness of doubling local inventories fell from $100,000 to $20,000/life year gained as the annual probability of an attack increased from 0.0002 to 0.001. We conclude that because of the reportedly rapid availability of regional inventories, the critical determinant of mortality following anthrax bioterrorism is local dispensing capacity. Bioterrorism preparedness efforts directed at improving local dispensing capacity are required before benefits can be reaped from enhancing local inventories.
Toward a Comprehensive Safeguards System: Keeping Fissile Materials out of Terrorists' Hands
The nexus of terrorism and nuclear weapons is today's greatest security concern. The importance of keeping fissile materials out of the hands of terrorists is now generally accepted. The difficulty of doing so is not. Lack of appreciation, especially for the technical difficulties, is hampering our ability to build a comprehensive safeguards system and prevent nuclear terrorism.
Pediatric Anthrax: Implications for Bioterrorism Preparedness
Objectives:
To systematically review the literature about children with anthrax to describe their clinical course, treatment responses, and the predictors of disease progression and mortality.
Data Sources:
MEDLINE® (1966-2005), 14 selected journal indexes (1900-1966) and bibliographies of all retrieved articles.
Review Methods:
We sought case reports of pediatric anthrax published between 1900 and 2005 meeting predefined criteria. We abstracted three types of data from the English-language reports:
Patient information (e.g., age, gender, nationality).
Symptom and disease progression information (e.g., whether the patient developed meningitis).
Treatment information (e.g., treatments received, year of treatment).
We compared the clinical symptoms and disease progression variables for the pediatric cases with data on adult anthrax cases reviewed previously.
Results:
We identified 246 titles of potentially relevant articles from our MEDLINE® search and 2253 additional references from our manual search of the bibliographies of retrieved articles and the indexes of the 14 selected journals. We included 62 case reports of pediatric anthrax including two inhalational cases, 20 gastrointestinal cases, 37 cutaneous cases, and three atypical cases.
Anthrax is a relatively common and historically well-recognized disease and yet rarely reported among children, suggesting the possibility of significant under-diagnosis, underreporting, and/or publication bias. Children with anthrax present with a wide range of clinical signs and symptoms, which differ somewhat from the presenting features of adults with anthrax. Like adults, children with gastrointestinal anthrax have two distinct clinical presentations:
Upper tract disease characterized by dysphagia and oropharyngeal findings.
Lower tract disease characterized by fever, abdominal pain, and nausea and vomiting.
Additionally, children with inhalational disease may have "atypical" presentations including primary meningoencephalitis. Children with inhalational anthrax have abnormal chest roentgenograms; however, children with other forms of anthrax usually have normal roentgenograms. Nineteen of the 30 children (63%) who received penicillin-based antibiotics survived; whereas nine of 11 children (82%) who received anthrax antiserum survived.
Conclusions:
There is a broad spectrum of clinical signs and symptoms associated with pediatric anthrax. The limited data available regarding disease progression and treatment responses for children infected with anthrax suggest some differences from adult populations. Preparedness planning efforts should specifically address the needs of pediatric victims.
2006 FSI International Conference: A World at Risk
An invigorating day of addresses, debate, and discussion of major sources of systemic and human risk facing the global community.
7:30 AM | REGISTRATION |
8:00 - 9:00 AM | BREAKFAST AND WELCOME John W. Etchemendy, Provost, Stanford University Coit D. Blacker, Director, Freeman Spogli Institute OPENING REMARKS Warren Christopher, 63rd Secretary of State William J. Perry, 19th Secretary of Defense George P. Shultz, 60th Secretary of State |
9:15 AM - 12:00 PM | MORNING SESSION PLENARY I Understanding, Measuring, and Coping with Risk: What We Know Coit D. Blacker, Director, Freeman Spogli Institute, Chair Understanding and Measuring Risk Elisabeth Paté-Cornell The Collapse of the Nuclear Non-Proliferation Regime? Scott D. Sagan Keeping Fissile Materials Out of Terrorist Hands Siegfried S. Hecker CONCURRENT BREAKOUT SESSIONS Food Security and the Environment Rosamond L. Naylor, Chair Pandemics, Infectious Diseases, and Bioterrorism Alan M. Garber, Chair Insurgencies, Failed States, and the Challenge of Governance Jeremy M. Weinstein, Chair |
12:30 - 2:00 PM | LUNCHEON Infectious Diseases, Avian Influenza, and Bioterrorism: Risks to the Global Community Michael T. Osterholm, Director, Center for Infectious Disease Research and Policy, University of Minnesota |
2:30 - 5:30 PM | AFTERNOON SESSION PLENARY II Natural, National, and International Disasters Michael A. McFaul, Deputy Director, FSI and Director, Center on Democracy, Development, and the Rule of Law, Chair Terror, U.S. Ports, and Neglect of Critical Infrastructure Stephen E. Flynn Energy Shocks to the Global System David G. Victor CONCURRENT BREAKOUT SESSIONS Responding to a World at Risk: U.S. Efforts at Democracy Promotion in Russia, Iraq, and Iran Michael A. McFaul, Chair The European Union: Politics, Economics, Terrorism Amir Eshel, Chair China's Rise: Implications for the World Economy and Energy Markets Thomas C. Heller, Chair Cross Currents: Nationalism and Regionalism in Northeast Asia Daniel C. Sneider, Chair |
6:00 - 8:00 PM | COCKTAIL RECEPTION AND DINNER Cocktail Reception 6:00 - 7:00 PM Dinner 7:00 - 8:00 PM |
8:00 - 9:00 PM | A WORLD AT RISK Peter Bergen, CNN Terrorism Analyst Author of Holy War, Inc.: Inside the Secret World of Bin Laden Paul H. Nitze School of Advanced International Studies, Johns Hopkins University |
Frances C. Arrillaga Alumni Center
Sverdlovsk Revisited: Modeling Human Inhalation Anthrax
Several models have been proposed for the dose-response function and the incubation period distribution for human inhalation anthrax. These models give very different predictions for the severity of a hypothetical bioterror attack, when an attack might be detected from clinical cases, the efficacy of medical intervention and the requirements for decontamination. Using data from the 1979 accidental atmospheric release of anthrax in Sverdlovsk, Russia, and limited nonhuman primate data, this paper eliminates two of the contending models and derives parameters for the other two, thereby narrowing the range of models that accurately predict the effects of human inhalation anthrax. Dose-response functions that exhibit a threshold for infectivity are contraindicated by the Sverdlovsk data. Dose-dependent incubation period distributions explain the 10-day median incubation period observed at Sverdlovsk and the 1- to 5-day incubation period observed in nonhuman primate experiments.