3
Detection and Diagnostics

OVERVIEW

Workshop presentations on infectious disease detection and diagnostics surveyed current capacity, needs, and challenges; anticipated forthcoming developments; and imagined a future in which diseases can be diagnosed prior to the appearance of symptoms (see Summary and Assessment).

Diagnostics for Developing Countries

The session began with a reminder from Mark Perkins of the Foundation for Innovative New Diagnostics (FIND) that while emerging diseases and bioterrorism threaten public health, infectious diseases such as tuberculosis and malaria have long imposed a severe burden on the developing world. In their contribution to this chapter, Perkins and Peter Small of the Gates Foundation discuss the need for rapid, accurate, inexpensive, robust diagnostics in developing countries—a need that could be met by recent advances in genomics, proteomics, and materials science if there was a profitable market. To fill this gap, FIND guides the development and adoption of novel diagnostic products for diseases of the developing world in much the same way as public–private partnerships have been established to produce drugs and vaccines for low-resource settings. With FIND’s support, companies that produce low-cost diagnostics for use in developing countries realize sufficient cost savings (in manufacturing, approval procedures, and marketing) to sustain profits.



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Global Infectious Disease Surveillance and Detection: Assessing the Challenges—Finding Solutions: Workshop Summary 3 Detection and Diagnostics OVERVIEW Workshop presentations on infectious disease detection and diagnostics surveyed current capacity, needs, and challenges; anticipated forthcoming developments; and imagined a future in which diseases can be diagnosed prior to the appearance of symptoms (see Summary and Assessment). Diagnostics for Developing Countries The session began with a reminder from Mark Perkins of the Foundation for Innovative New Diagnostics (FIND) that while emerging diseases and bioterrorism threaten public health, infectious diseases such as tuberculosis and malaria have long imposed a severe burden on the developing world. In their contribution to this chapter, Perkins and Peter Small of the Gates Foundation discuss the need for rapid, accurate, inexpensive, robust diagnostics in developing countries—a need that could be met by recent advances in genomics, proteomics, and materials science if there was a profitable market. To fill this gap, FIND guides the development and adoption of novel diagnostic products for diseases of the developing world in much the same way as public–private partnerships have been established to produce drugs and vaccines for low-resource settings. With FIND’s support, companies that produce low-cost diagnostics for use in developing countries realize sufficient cost savings (in manufacturing, approval procedures, and marketing) to sustain profits.

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Global Infectious Disease Surveillance and Detection: Assessing the Challenges—Finding Solutions: Workshop Summary Rapid Diagnostics Soldiers at risk of contracting infectious disease—either from the natural environment or from bioweapons—need diagnostics that are rugged, rapid, and easy to use, according to speaker Mark Wolcott of the Diagnostic Systems Division at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID). In their contribution to this chapter, Wolcott and co-authors discuss the rationale, design, and development of rapid diagnostic assays for infectious diseases. They offer brief, comparative descriptions of a variety of platform technologies that in the future may be combined to produce comprehensive, integrated diagnostic systems—perhaps in the guise of miniaturized “labs on chips” that process samples, perform assays, and automatically report their results. “As technologies mature and new technologies are developed, rapid infectious disease diagnostics will become available and practical,” the authors predict. Rapid diagnostic tools are also improving infectious disease surveillance in animals. Workshop presenter Alex Ardans, who directs the California Animal Health and Food Safety Laboratory System, described the development of polymerase chain reaction-based (PCR-based) assays to screen for diseases that have caused devastating outbreaks in livestock, such as exotic Newcastle disease (END) in poultry and foot-and-mouth disease (FMD) in cattle. California also developed a highly efficient tuberculosis testing program after the disease was detected in several of the state’s large dairies. Based on such experiences, Ardans argued that the state’s laboratory system plays its most crucial role when recognizing and responding to unusual disease events. For example, following a recent END outbreak among fighting cocks, whose handlers worked in and spread the disease to commercial poultry operations, the laboratory optimized an existing real-time PCR assay for END that was used to perform more than 85,000 tests (Crossley, 2005). Such emergencies present unique opportunities to improve disease diagnosis, Ardans said, although not necessarily with the latest technology. He noted that laboratory researchers, in pursuit of the source of E. coli O157:H7 following a recent outbreak in spinach, discovered that a gauze swab used to sample irrigation waters for contaminants performed better than newer concentration devices. Emerging Diagnostics Although Koch’s postulates remain diagnostic standards, adapting them to a vastly expanded understanding of disease states has become increasingly problematic, observed presenter Ian Lipkin and co-author Thomas Briese of Columbia University’s Jerome L. and Dawn Greene Infectious Disease Laboratory. Their paper discusses contemporary problems in proving causality, and illustrative case studies that reveal how these challenges are shaping pathogen surveillance and discovery. The authors also provide a taxonomy and comparative guide to proven

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Global Infectious Disease Surveillance and Detection: Assessing the Challenges—Finding Solutions: Workshop Summary and proposed methods for characterizing infectious agents without recourse to cultivation, including two platforms of their own creation: MassTag PCR and the GreeneChip. In the future, Lipkin and Briese predict, substantial advances against chronic disease will occur “not from technical improvements but from investments in prospective serial sample collections and an appreciation that many diseases reflect intersections of genes and environment in a temporal context.” Pre-Symptomatic Diagnosis Imagining a future in which bioterrorism agents are continually reengineered to elude standard detection and diagnostic methods as well as therapeutics, speaker and Forum member Stephen Johnston offers a model of diagnosis for exposure to a pathogen before symptoms appear: a host-based detection system, capable of analyzing hundreds to thousands of components in samples of blood, sputum, or urine, and thereby capable of detecting any type of engineered or natural threat agent. In the final paper of this chapter, Johnston discusses the feasibility of developing such a system and its potential not merely to detect biothreats, but to “convert standard health practice from one that treats symptoms to one that detects disease very early—even presymptomatically.” PARTNERING FOR BETTER MICROBIAL DIAGNOSTICS1 Mark D. Perkins, M.D.2 Foundation for Innovative New Diagnostics Peter M. Small, M.D.3 Bill and Melinda Gates Foundation Timely and accurate diagnosis is critical to the global efforts to prevent and treat infectious diseases. And yet, those on the front lines of this battle struggle to make do with inadequate and antiquated testing technology. For example, a 100-year old test is used to diagnose tuberculosis, a disease that kills someone every 16 seconds, and precious new antimalarial drugs are being rolled out with the same diagnostic imprecision that currently mistreats several hundred million cases every year. The tragic reality is that diagnostic uncertainty exacts a huge toll in morbidity and mortality. Reliance on underperforming diagnostic technologies limits the control of the world’s greatest killers, especially in settings with high 1 Reprinted with permission from Nature Biotechnology. Copyright 2006 Nature Publishing Group. Perkins MD, Small PM. 2006. Partnering for better microbial diagnostics. Nature Biotechnology 24(8):919-921. 2 Chief Scientific Officer. 3 Global Health Program.

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Global Infectious Disease Surveillance and Detection: Assessing the Challenges—Finding Solutions: Workshop Summary human immunodeficiency virus (HIV) prevalence. We contend that innovative mechanisms are needed to produce, develop and deploy new and better diagnostic tools for infectious diseases in developing countries. Global Public Health Goals at Risk Acknowledging the impact of the global tuberculosis epidemic in the early 1990s, the World Health Assembly of the World Health Organization (WHO; Geneva) declared tuberculosis a global emergency and ratified goals for case detection and cure under the DOTS (directly observed therapy shortcourse) strategy by the year 2005. Although important successes in fighting tuberculosis have been achieved in recent years, reliance on weak diagnostic tools has slowed progress. Case detection targets for smear-positive tuberculosis have not been met, and fewer than 25 percent of all cases are now detected and reported as smear positive (WHO, 2004). The data available suggest that the Millennium Development Goal of halving tuberculosis prevalence by 2015 also cannot be achieved universally without improved methods for diagnosing tuberculosis (Dye et al., 2005). The weaknesses of standard diagnostic tests for tuberculosis are well documented. Even in controlled research settings, the average sensitivity of sputum microscopy for pulmonary tuberculosis is only 60 percent in immunocompetent populations, and it is substantially lower among people infected with HIV. Conventional culture methods are so slow that testing often loses clinical relevance, and the poor predictive value of the tuberculin skin test renders it essentially worthless in disease-endemic areas. The weaknesses of the available diagnostic technologies are only amplified in high-burden countries, which typically have insufficient infrastructure and inadequate staffing. Reliance on inadequate diagnostic tools cripple TB control efforts. Because of limited access to diagnostic services and the low sensitivity of conventional testing, patients in many high-burden countries remain undiagnosed for three to six months (Madebo and Lindtjørn, 1999; Liam and Tang, 1997). These delays result in increased morbidity and mortality, mounting costs combined with loss of work, and continuing tuberculosis transmission to families and communities. Unlike tuberculosis, which requires months of treatment to cure, malaria can be treated with a few doses of unsupervised treatment. This dramatically reduces the motivation to confirm the diagnosis. Microscopy for malaria is notoriously difficult, and experienced microscopists give substantially different results on up to a third of all slides. In most settings where malaria is endemic, quality microscopy is poorly available and malaria treatment is given by default to almost all patients with fever. Fever is an exceedingly common symptom in the tropics, and an estimated 800 million malaria treatments are given each year for fevers, the great majority of which are not caused by malaria (Amexo et al., 2004). This massive mistreatment of hundreds of millions of people results in

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Global Infectious Disease Surveillance and Detection: Assessing the Challenges—Finding Solutions: Workshop Summary the fatal under-treatment of other diseases, such as pneumonia and sepsis, which present with similar symptoms. Having watched at least two generations of malaria medicines fall to mounting drug resistance, the international malaria community has called for greater diagnostic accuracy before treatment, especially as expensive artemisinin-based therapies are introduced. In 2004, the WHO recommended that malaria should be confirmed by parasitologic examination before treatment in all patients older than five years of age. In this setting, the development of simple and rapid diagnostic tests (RDTs) that can detect circulating Plasmodium antigens in a drop of finger-prick blood is a key recent development. The success of RDTs in improving the targeting of drug therapy, and their acceptance in malaria management by remote health workers and patients, will depend on the reliability and accuracy of the tests. There are now more than three dozen manufacturers of such tests, many of which show inadequate sensitivity, thermostability and geographic applicability. Though RDTs are now in wide use in some areas, the lack of true performance data on most of these tests, the variability in published performance of others and the lack of a global quality assurance mechanism has generated chaos and confusion with regard to test selection and has resulted in many end-users rejecting test results in favor of presumptive treatment. The lethal convergence of these diseases and HIV exacerbates the negative impact of weak diagnostic tools. The rise of HIV in tuberculosis-endemic settings dramatically increases tuberculosis incidence, the number of symptomatic individuals and the pressures on already overburdened health systems. HIV coinfection decreases the sensitivity of microscopy for TB at the same time that it increases the urgency for rapid diagnosis and treatment. From South Africa to Brazil (Pronyk et al., 2004; Gutierrez et al., 2002), 30 to 50 percent of HIV-infected people die with undiagnosed tuberculosis, and Mycobacterium tuberculosis is now a leading cause of bacteremia in febrile patients visiting emergency rooms in sub-Saharan Africa (Archibald et al., 1998). Fever in HIV endemic areas cannot be assumed to be benign if nonmalarial. Thus, for many countries burdened by HIV, the need for improved diagnostic tests is increasingly urgent. New Opportunities Recent trends in science and technology, and in the diagnostics industry, indicate that there may be important new opportunities to improve diagnostic tests suitable for developing countries. Availability of the complete genomic sequence of M. tuberculosis allows a comprehensive assessment of potential diagnostic targets. Massive investment in biodefense has generated a range of diagnostic technologies intended for front-line use. The growing diagnostics industry can develop new diagnostic tests at a fraction of the cost and time needed to bring drugs and vaccines to licensure.

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Global Infectious Disease Surveillance and Detection: Assessing the Challenges—Finding Solutions: Workshop Summary Motivated primarily by the small but significant market in industrialized countries, the tuberculosis diagnostics industry has produced several new tests in recent years. For example, shortcuts around the slow growth of M. tuberculosis using phage-based or molecular methods allow tuberculosis detection and screening for rifampin resistance within 48 hours (Albert et al., 2002; Johansen et al., 2003). Other new tests exploit tuberculosis-specific proteins to detect latent infection with much improved specificity, especially in BCG (BacilleCalmette Guérin)-vaccinated populations (Lalvani et al., 2001; Mori et al., 2004). Likewise, for malaria diagnosis, several rapid immunochromatographic tests detecting Plasmodium antigens in blood have been developed over the past 15 years, and they now reach a market of some 25 million people. Forging a Public–Private Initiative Market forces alone, however, will not yield the diagnostic tools needed to improve global health. Private companies often avoid developing products that will primarily be used in developing countries out of skepticism about the return on their investment. Developing countries have little capacity to pay the higher prices typically attached to new products, even when these costs result in overall savings to health care systems. The processes by which these countries license, purchase, and distribute products are often inadequately developed and poorly understood by industry. The drive to develop new diagnostics for the developing world is unlikely to succeed without the private sector, with its expertise in product development, manufacturing capacity, product distribution and quality control. Unless measures are put in place to address current market dynamics, the number of companies engaged in diagnostics development will likely remain limited, and most will continue to tailor their products to markets in industrialized countries. The resulting products, such as the molecular amplification systems and automated systems for early detection of mycobacterial growth—which have markedly improved the diagnosis of tuberculosis in industrialized countries—may be little used in developing countries and thus have no impact on the global tuberculosis problem. Most of the companies manufacturing rapid malaria tests are small and do not have the resources to redevelop their assays to address important deficiencies in sensitivity and shelf life, especially at tropical temperatures. Goal-driven public sector action is needed across the development pathway to forge a strong and sustainable partnership with industry to generate new diagnostics (Figure 3-1). Public sector actors must be prepared to sponsor basic research, partner equitably with industry on product development, evaluate products in a regulatory-quality fashion (Small and Perkins, 2000), demonstrate the efficacy of implementation, change technical and financial policies to foster new diagnostics, and actively facilitate the latter’s distribution and use. In pursuit of these goals, the public sector should explore such innovative approaches as the

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Global Infectious Disease Surveillance and Detection: Assessing the Challenges—Finding Solutions: Workshop Summary FIGURE 3-1 Product development path for microbial diagnostics.

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Global Infectious Disease Surveillance and Detection: Assessing the Challenges—Finding Solutions: Workshop Summary creation of novel financing mechanisms and distribution strategies to increase industry confidence that a viable market will exist in resource-limited settings. There are many examples of innovative public–private partnership for the development of drugs and vaccines. Few are, however, focused on diagnostics. The Foundation for Innovative New Diagnostics (FIND; Geneva, Switzerland; of which Mark D. Perkins is Chief Scientific Officer), is one such entity. Launched in 2003, FIND aims to develop a model for public sector action to drive the development of diagnostic products for diseases of the developing world, using the search for new diagnostics as the test case for the model’s development. FIND seeks to identify the most promising product candidates and accelerate the process of development, testing, approval, distribution and incorporation into routine public health policy. Although motivated by the desire to create new public goods, FIND has many of the attributes of a private company, pursuing a clear business plan and using rigorous scientific criteria to identify priority product candidates. RAPID INFECTIOUS DISEASE DIAGNOSTIC ASSAYS4 Mark J. Wolcott, Ph.D.5 U.S. Army Medical Research Institute of Infectious Diseases Randal J. Schoepp, Ph.D.5 U.S. Army Medical Research Institute of Infectious Diseases David A. Norwood, Ph.D.5 U.S. Army Medical Research Institute of Infectious Diseases David R. Shoemaker, Ph.D.5 U.S. Army Medical Research Institute of Infectious Diseases Rapid disease diagnostics (“serving to identify a particular disease or pathogen”) for many infectious agents are not as well developed as other laboratory technologies. Laboratory tests for many infectious agents still rely on decades-old technologies and techniques. Culture remains the gold standard for identifying organisms, but not all pathogens can be cultured, making alternative tests necessary. When culture is difficult or not available (virus cultures in field laboratories), serological diagnosis of the antibody response to the organism is typically used. 4 Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Army. Funding was provided in part by the Defense Threat Reduction Agency, Joint Science and Technology Office for Chemical and Biological Defense (JSTO-CBD). 5 Diagnostic Systems Division.

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Global Infectious Disease Surveillance and Detection: Assessing the Challenges—Finding Solutions: Workshop Summary However, a problem with both traditional culture and immunodiagnostics is the time required to obtain results. Culture may take several days and immunodiagnosis is limited by the time required to mount an antibody response, often a week or more (Figure 3-2). Current efforts in rapid diagnostics are shifting the window of detection closer to the point at which clinical disease symptoms become evident. Ultimately, future rapid diagnostics will shift the window to a point soon after exposure, giving the clinician the greatest opportunity to intervene in the disease process. Orthogonal diagnostic testing is the key to improving the reliability of rapid diagnostic technologies. Orthogonal testing refers to tests that are statistically independent or non-overlapping but, in combination, provide a higher degree of certainty of the final result. Although orthogonal testing is not a standard perspective in the clinical diagnostic industry, the concept and its application are paramount when investigating some infectious agents. Any single detection technology has a set of limits with regard to sensitivity and, most importantly, specificity. Orthogonal testing seeks to overcome the inherent limitations of individual test results with the strength of data combinations (Henchal et al., 2001). The application of orthogonal diagnostic testing uses an integrated testing strat- FIGURE 3-2 Infection and response time course. Various detection methodologies have highly different entry points in their use on human disease. As the time points extend out, the ability of medical interventions have less success. The earlier the time of medical intervention, the more successful the prognosis is for most diseases. SOURCE: Wolcott (2006).

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Global Infectious Disease Surveillance and Detection: Assessing the Challenges—Finding Solutions: Workshop Summary egy where more than one technology, technique, or biomarker is used to produce diagnostic results, which are then interpreted collectively (Figure 3-3). The Department of Defense has an acquisition program to acquire quality diagnostic products that satisfy the needs of commanders with missions to support the warfighter. This acquisition program is designed to be timely with fair and reasonable associated costs. The acquisition program includes design, engineering, test and evaluation, production, and operations and support of defense systems (Table 3-1). To simplify and expedite the acquisition timeline for the fielding of a rapid diagnostic system, commercial off-the-shelf technology is evaluated and a formal selection process is used to select a system for further development and fielding. The Joint Biological Agent Identification and Diagnostic System (JBAIDS) acquisition program was formally launched in September 2003 with the award of the first phase, a molecular diagnostic system, in fall 2005 (Figure 3-4). FIGURE 3-3 Orthogonal diagnostic testing. Although each method provides an independent assessment, together the power of the diagnostic becomes large. The failure of any one independent assessment does not fail the system. SOURCE: Wolcott (2006).

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Global Infectious Disease Surveillance and Detection: Assessing the Challenges—Finding Solutions: Workshop Summary TABLE 3-1 Department of Defense (DoD) Acquisition Program for Diagnostic Devices Predevelopment Advanced Development Procurement Operations and Support Basic research Technology evaluation Demonstration and validation Engineering and manufacturing development Procurement and deployment Operations and support New technologies Technology demonstrations Prototypes PMA/510K approval Initial operational testing Final production Follow-up evaluation NOTE: The acquisition process moves from left to right through defined operational activities. Each activity is designed to provide a value-added service and ensure that DoD obtains the product needed at a reasonable cost investment for the country. SOURCE: Wolcott (2006). FIGURE 3-4 Acquisition program—evolutionary strategy. The acquisition process for developing and fielding a rapid infectious disease diagnostic assays system is designed around an evolutionary strategy. By leveraging commercial technologies that currently exist in the commercial market, and furthering development on those platforms, the final field-deployable system will be quicker and cheaper than trying to obtain the final product up front. SOURCE: Wolcott (2006).

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Global Infectious Disease Surveillance and Detection: Assessing the Challenges—Finding Solutions: Workshop Summary FIGURE 3-18 Upper respiratory disease incubation periods. SOURCES: Adapted from Meneghetti (2006); Basu (1998); Smith et al. (2006). sion can also detect presymptomatic responses in primates (Rubins et al., 2004). We have preliminary evidence (Johnston and Magee, unpublished) from a model of cowpox infection in mice that the infected mice can be distinguished from mock-infected mice three hours after infection, also by microarray analysis of blood cells. Clearly, more definitive studies of the limitations of presymptomatic diagnosis are needed. The other issue is the technological challenge of creating the diagnostic system. This will be a formidable challenge. It will involve a coordinated, highly interdisciplinary effort that will include new instrumentation, modeling/algorithm development, data handling and transmission as well as judicious use of animal models and clinical testing (Figure 3-19). One challenge we have been addressing is how to develop the binding agents to measure thousands of blood components. Though the technological challenges are great, such a diagnostic system is probably feasible. If developed it would be a major factor in preventing large-scale loss from a biothreat attack and may serve as a serious deterrent. However, the effort and cost to put such a system in place could not be justified based solely on the probability of a biothreat attack. Though its application to detection of natural outbreaks could be more easily supported, even this use would probably not drive an economic imperative to initiate this development program.

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Global Infectious Disease Surveillance and Detection: Assessing the Challenges—Finding Solutions: Workshop Summary FIGURE 3-19 Program to create DocInBox diagnosis. SOURCE: Johnston (2006). Fortunately, a presymptomatic diagnostic system is also needed for another more easily justifiable application—the impending crisis in standard health care. The cost of U.S. health care was approximately $2.2 trillion in 2006. This cost is estimated to be approximately $4 trillion by 2015 (Figure 3-20). Currently this cost accounts for approximately 19 percent of our Gross Domestic Product (GDP), rising to 25 percent or more by 2015 (Figure 3-21). By comparison, health-care costs have outpaced energy costs since the 1980s (Figure 3-22). Because most health costs are in the later years of life, with an aging population these trends are expected to continue (Figure 3-23). Clearly, we spend an enormous amount of our wealth on health care. If this investment contributes substantially to the productivity and creative output of the population it is money well spent. However, approximately 85 percent of this expenditure is on taking care of sick people and only about 15 percent on drugs and diagnostics. Our health-care system costs so much because it is largely postsymptomatic focused, and therefore centered on taking care of sick people. This system is clearly unsustainable economically. It will require either reducing care or revolutionizing medicine. If we opt for the latter, the key aspect will be converting medicine to a focus on presymptomatic diagnosis. A corollary of this transition will be improvement in quality of life. This will afford a “squaring” of the life curve (Figure 3-24) such that we not only live longer, but better. We are fortunate that a key technology required for being prepared for the biothreats of the future is also the exact capability we have basically no choice but to develop for standard health care of the future, as well as for more prob-

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Global Infectious Disease Surveillance and Detection: Assessing the Challenges—Finding Solutions: Workshop Summary FIGURE 3-20 Health-care spending projections. SOURCE: Adapted from HHS (2007).

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Global Infectious Disease Surveillance and Detection: Assessing the Challenges—Finding Solutions: Workshop Summary FIGURE 3-21 In 2005, 18 percent of GDP was spent on health care. By 2015, it is projected to be 25 to 30 percent. SOURCE: Adapted from HHS (2007).

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Global Infectious Disease Surveillance and Detection: Assessing the Challenges—Finding Solutions: Workshop Summary FIGURE 3-22 Comparison of U.S. spending on energy and health care, 1970–2004. NOTE: The 2001 to 2004 numbers were projected based on oil prices. Total energy costs 2002–2004: Numbers are estimates based on extrapolation of energy price increase based on increases in petroleum prices, applied to Department of Defense known energy use figures. OPEC basket price averaged $50.71 per barrel in 2005, $36.05 per barrel in 2004, $28.10 per barrel in 2003, $24.36 per barrel in 2002, $23.12 per barrel in 2001, and $27.60 per barrel in 2000 (DoE, 2006). SOURCES: EIA (2005); HHS (2007). FIGURE 3-23 Average annual health-care expenditures by age, 2005. SOURCE: DoL (2007).

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Global Infectious Disease Surveillance and Detection: Assessing the Challenges—Finding Solutions: Workshop Summary FIGURE 3-24 Human species needs to square life’s curve: Higher quality = less cost. SOURCE: Johnston (2007). able threats from natural infections. From the perspective of being prepared for engineered biothreats, we should take advantage of the valley of the shadow of death (Figure 3-11) to get ahead of the threat curve. Presymptomatic diagnosis should be a key element in this preparedness. From the perspective of standard of care, this same technology could be key to revolutionizing us as a species. Such potential merits an Apollo-like effort to complete. REFERENCES Albert, H., A. Heydenrych, R. Brookes, R. J. Mole, B. Harley, E. Subotsky, R. Henry, and V. Azevedo. 2002. Performance of a rapid phage-based test, FastplaqueTB™, to diagnose pulmonary t-berculosis from sputum specimens in South Africa. International Journal of Tuberculosis and Lung Disease 6(6):529-537. Amexo, M., R. Tolhurst, G. Barnish, and I. Bates. 2004. Malaria misdiagnosis: Effects on the poor and vulnerable. Lancet 364(9448):1896-1898. Archibald, I. K., M. O. den Dulk, K. J. Pallangyo, and L. B. Reller. 1998. Fatal Mycobacterium tuberculosis bloodstream infections in febrile hospitalized adults in Dar es Salaam, Tanzania. Clinical Infectious Diseases 26(2):290-296. Asnis, D. S., R. Conetta, A. A. Teixeira, G. Waldman, and B. A. Sampson. 2000. The West Nile Virus outbreak of 1999 in New York: The Flushing Hospital experience. Clinical Infectious Diseases 30(3):413-418. Bailey, T. L., and M. Gribskov. 1998. Combining evidence using p-values: Application to sequence homology searches. Bioinformatics 14(1):48-54.

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