Functional Requirements for Biosurveillance

1. INTRODUCTION

Chapters 2 and 3 described biosurveillance as the world has practiced it for the latter half of the 20th century. During that time, the basic methods for detecting cases, detecting outbreaks, and characterizing outbreaks changed little. The methods used to detect and characterize the 1975 Lyme disease outbreak and the 2003 severe acute respiratory syndrome (SARS) pandemic differed primarily in microbiological techniques (e.g., the increasing use of genetic analysis) and the speed at which outbreaks were investigated.

Around the beginning of the 21st century, however, researchers began to investigate new types of surveillance data and to automate methods for the collection and analysis of these data. A new requirement motivated these researchers—that of very early detection of disease outbreaks (Wagner et al., 2001a). The new methods were met with skepticism (Broome et al., 2002; Buehler et al., 2003; Reingold, 2003; Stoto et al., 2004). Their rate of adoption was slow until the fall of 2001, when the anthrax mail attacks in the United States effectively ushered in a new era of biosurveillance (Wagner, 2002).

We discuss these newer methods in detail in Parts III through V of this book. In this chapter, we discuss the redesign of biosurveillance systems from the perspective of an engineer or a system analyst. To satisfy the new requirement for very early detection, a designer must pay more attention to the systematic aspect of biosurveillance. The designer must examine how quickly outbreaks must be detected and characterized and design a system that can meet these requirements by collecting data that are available earlier than are case reports, collecting those data in real time from existing computer systems in hospitals and other organizations, and analyzing the data in real time.

2. FUNCTIONAL REQUIREMENTS AND SYSTEM SPECIFICATIONS

An engineer or a system analyst approaches design problems in a manner that is fundamentally different from how a doctor or an epidemiologist approaches diagnostic problems. Engineers and systems analysts first develop functional requirements, which for biosurveillance are specifications of the diseases that must be detected, the smallest size outbreak that must be detected, and the time frame within which detection must occur. From the functional requirements, the designer then develops system specifications and finally builds a system.

When designing and building a commercial information system, the elucidation of functional requirements is a first step in the process, and it is a prerequisite for subsequent steps. If the information system is an early warning system for missile attack, for example, the functional requirements might prominently feature the detection of the attack within several minutes of launch. In the case of a biosurveillance system for an aerosol release of anthrax, the functional requirements might similarly emphasize detection as quickly as possible, but no later than within days of release.

Although a biosurveillance system is fundamentally an information system, the process of functional-requirement specification is often less rigorous than in the commercial world. Even when organizations develop functional requirements (e.g., for an electronic disease reporting system), the requirements do not specify how quickly an outbreak of disease must be detected, rather they are formulated in terms of the data that should be collected, the properties of the user interface, and system security. The functional requirements of the Public Health Information Network (PHIN) of the Centers for Disease Control and Prevention (CDC) are an example of current functional requirement specifications (www.cdc.gov/phin). To our knowledge, no organization has published functional requirements derived from explicit consideration of timeliness requirements for specific diseases. System designers have been let off the hook, so to speak, by their customers for this—arguably, the most difficult— requirement. The two published analyses that considered timeliness requirements were partial analyses: one analyzed gaps in current biosurveillance systems (Dato et al., 2001), and the second analyzed the data requirements for earlier detection (Wagner et al., 2001b).

3. EXAMPLE: FUNCTIONAL REQUIREMENTS AND SPECIFICATIONS FOR ANTHRAX BIOSURVEILLANCE

To illustrate the approach that an engineer or systems analyst (henceforth referred to as designers) would take when designing a biosurveillance system, let us consider a special purpose system for detection of outbreaks caused by the organism Bacillus anthracis, a bacterium that can form a spore that can survive for extended periods in nature. The spores can infect humans or animals through the skin, through ingestion, and through inhalation. B. anthracis causes the disease anthrax, which was once a common disease among wool handlers but now is of concern as a terrorist threat (Henderson, 1999).

A designer tasked with the design of an anthrax biosurveillance system has available two outbreaks of anthrax from which to derive timeliness (and other) functional requirements. He has available the 1979 Sverdlovsk release of B. anthracis (Kirov strain) from Soviet Biological Weapons Compound 19, described in Chapter 2, and the 2001 U.S. postal attacks (Jernigan et al., 2001; Greene et al., 2002). The Sverdlovsk outbreak was a result of accidental release of anthrax spores into the air. Unknown individuals used envelopes containing anthrax spores to carry out the U.S. postal attacks.

3.1. Large Aerosol Release

Kaufmann et al. (1997) analyzed the available information from the Sverdlovsk outbreak and information about the disease anthrax. They demonstrated that the requirement for timeliness of detection of an aerosol release of anthrax is ideally the moment of release, but no later than 5 days after release.

Wagner et al. (2003b) used a taxonomy of surveillance data depicted in Table 4.1 to identify the types of surveillance data that might be available in this time window. They concluded that the system specifications for a biosurveillance system capable of meeting the time requirement would include components to obtain and process data from biosensors, preclinical data sources (e.g., sales of cough syrup), and early clinical data (e.g., symptoms and radiological reports). A system would have to collect and analyze these data in near real time with attention to corroborating and discriminating data from other sources, such as wind patterns and physical location of individuals in the days preceding onset of illness. They concluded that conventionally trained physicians could not be relied on to detect an outbreak of this type. In the Sverdlovsk outbreak, the earliest suspicion of anthrax came from an autopsy finding of a cardinal's cap (hemorrhagic meningitis, a pathognomonic finding for the disease anthrax) on the eighth day after the release (Abramova et al., 1993), by which time 14 individuals had died (Guillemin, 2001). At least six victims had their early symptoms dismissed by physicians as not serious, and 21 individuals had died by the time that the laboratory confirmation of anthrax was broadcast to area hospitals on the 10th day after the accidental release (Guillemin, 2001).

TABLE 4.1.

Taxonomy of Surveillance Data

• Preoutbreak data: This category refers to data obtained during the period before the onset of the outbreak. Examples of data that might contribute to detection include intelligence that heightens suspicion or host factors such as vaccinations that determine susceptibility. • Attack, release, or exposure data refers to data obtained at or very near the time of an accidental of intentional contamination. Data from this time might come from biosensor arrays, unauthorized airplane flights, or other activities. • Presymptomatic data (incubation period data) refers to data obtained between the time that a person or animal becomes infected until the recognition of first symptoms. Examples of presymptomatic data are serology or cultures from presymptomatic individuals that are obtained serendipitously, through routine screening, or through enhanced screening because environmental conditions are favorable for an outbreak (e.g., there has been a natural disaster such as a flood). • Prediagnostic data refers to data from the period between the onset of symptoms in an individual and when the illness becomes more fully developed and distinguishable from other illnesses. Examples of prediagnostic data include diarrheal symptoms or upper respiratory symptoms. Examples of data sources of potential value for the detection of individuals experiencing early symptoms include sales of over-the-counter cold medicines, vital signs, physical findings, and absenteeism. • Specific syndrome data are data that either singly or in combination strongly suggest a specific agent. Examples include selected symptoms, histories of exposures, vital signs, physical findings, laboratory results, radiology results, and preliminary results from microbiology laboratories (e.g., Gram stains). • Diagnostic data are data that are sufficient on their own to conclude that a patient has a disease. Examples include microbiology cultures or autopsy reports. Diagnostic data usually can be obtained during the specific syndrome period but can also be found during other periods through screening, routine testing, or testing of the environment. Three additional categories of data in the table do not fit neatly on a timeline. They are: • Epidemiologic data, which refers to the whereabouts of individuals before onset of disease, food and water consumption, contacts with affected individuals, and location information (work, home addresses; feedlot number). These data are often only available for analysis after the onset of the outbreak because they are not routinely collected, but some characteristics may be routinely recorded electronically in various databases. • Zoonotic data, which refer to data from veterinary and public health sources. Examples include small animal deaths, positive mosquito pools for malaria, animal vaccination status, and sentinel chicken serology. • Environmental data refer to data about the environment. Examples include weather, refrigeration temperature, ventilation plans, and water supply areas.

From Dato et al. (2001).

© 2006

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

3.2. Postal Attack (2001)

After the fall 2001 attack, the U.S. Postal Service developed the biohazard detection system (BDS), an air monitoring system based on a DNA polymerase chain reaction (PCR) test for B. anthracis (U.S. Postal Service, 2004; Military Postal Service Agency, 2004). BDS attaches to mail-sorting machines. There is little doubt that the U.S. Postal Service designed this system with the functional requirement of early detection of an anthrax postal attack based on a careful postincident analysis of the 2001 postal attack. A mail-sorting machine is both a single point through which all mail passes (except locally routed rural mail and larger packages) and a nearly ideal device for expressing spores from all but the most tightly sealed envelops (because the sorting process compresses envelops), enabling the detection of spores by BDS.

A comprehensive system for detection of a postal attack, however, would require additional components to monitor human health to detect individuals that become infected via envelops and packages that were either well sealed or not sorted by a monitored mail sorting machine. The additional components would have to detect (1) an individual case of anthrax in a recipient of a single envelop, (2) a cluster of cases in a home or office in which the envelop was opened, or (3) a pattern of individuals or building clusters that might indicate an attack that used multiple letters or packages. The system would also have to monitor for suspicious cases in local postal facilities not defended by locally installed sensors either directly or through sensing upstream of their facility in the mail processing network.

3.3. Building/Vessel Contamination

An analysis by Wagner et al. (2003b) identified two additional anthrax attack scenarios: building/vessel contaminations and premonitory release. Specifically, a building or vessel contamination refers to the distribution of anthrax (or other agent) via the mechanical components in a building or ship. This is a serious threat because of our modern reliance on heating, ventilation, and air-conditioning systems, which can effectively disseminate spores throughout a building. The functional requirement for time of detection is similar to that of an outdoor release because many individuals would be exposed simultaneously. Recognition of a release contained within a structure, however, produces somewhat different requirements. Specifically, the requirement is the detection of a cluster of illnesses common to a relatively small number of individuals sharing a domicile, a place of employment, or a social facility. This detection requires recognition and analysis of these relationships. A detection system ideally would have access to data about heating, ventilation, and air-conditioning systems, identity of occupants, and hours of occupation. The building contamination with B. anthracis of a postal facility in New Jersey during the 2001 postal attack is an interesting example for study (Greene et al., 2002). Tracing the illnesses to the specific building required the knowledge of work times, responsibilities, and routines for a large number of postal workers.

3.4. Small Premonitory Release or Contamination

The term premonitory release refers to intentional or accidental infection of one or a limited number of individuals with an unusual organism such as B. anthracis. The functional requirement here is one of sensitivity for single cases and small outbreaks, not extreme timeliness. To detect a single case, a biosurveillance system must have extremely high case detection sensitivity, specificity, and diagnostic precision (or the prior probability must be extremely high, e.g., owing to intelligence information). A biosurveillance system would have to rely either on case detection by the healthcare system or on computer-based case detection. Computer-based case detection would have to be capable of diagnostic precision at least at the level of finding individuals with Gram-positive rods in the blood or cerebrospinal fluid and pneumonia on chest radiograph (which would be highly suggestive of anthrax). Examples of potential computer-based components include clinical information systems with decision support at the point of care, systems to monitor laboratory reporting of microbiology cultures; and free-text processing algorithms that scrutinize autopsy reports, newspaper stories, and obituaries for unusual deaths of animals or humans. If there are multiple cases, the demographics of the victims or the discovery of a geographic clustering of victims could help to identify a common cause with case detection at lower levels of diagnostic precision. In the absence of astute clinical diagnosis, it is likely that a single case of disease caused by a weaponized organism will progress to fatality. The requirements, therefore, include biosurveillance components (manual or automatic) that analyze unexplained deaths.

The problem of detecting a single case is identical to the problem of accurate diagnosis in medicine, and there is great deal of literature on clinical decision support describing relevant techniques, which is summarized in Miller (1994).

4. THE COMPLEXITY OF BIOSURVEILLANCE SYSTEM DESIGN

A designer of a comprehensive biosurveillance system for a city or a country would have to elucidate functional requirements for detection of hundreds of biological agents that can cause disease in animals and humans (and, through mutation, the number continues to expand). As in the case of anthrax, many of these agents can infect humans or animals through diverse pathways (amplified by the ingeniousness of terrorists), resulting in an almost infinite variety of outbreaks that a biosurveillance system must be capable of recognizing in a timely manner. This section provides but a sample of these biological agents, those identified by international and national organizations as being of the greatest concern. Our purpose in this section is to indicate the magnitude and complexity of the design problem.

4.1. Biological Agents that Threaten Human Populations

Table 4.2 is a list of biological agents that we created by consolidating lists developed by internationally recognized organizations and experts. Five of the primary sources listed bioterrorism threats; the sixth, nationally notifiable diseases (Wagner et al., 2003b). We sorted the list by the number of lists each threat appeared on to bring the consensus threats to the top. Note that several of the viral entries in the table represent classes of viruses that contain many individual viruses (e.g., the entry alphaviruses includes Venezuelan, eastern, western, and equine encephalomyelitis)

TABLE 4.2.

Human Disease Threats

Threat	DTRA Bioterrorism List	CDC	NATO	Russian Experts Top 11 Threats	USAMRIID	Reportable List
Anthrax, inhalational	X	A list	X	Top 4	X	X
Botulism	X	A list	X	Top 4	X	X
Plague (pneumonic)	X	A list	X	Top 4	X	X
Smallpox	X	A list	X	Top 4	X	X
Tularemia (inhaled)	X	A list	X	X	X	X
Hemorrhagic fever viruses (e.g., Omsk, Korean, Ebola, Crimean-Congo, Marburg, Junin)	X	A list	X	X	X
Brucellosis	X	B list	X		X	X
Glanders (Melioidosis)	X	B list	X	X	X
Q fever (Coxiella burnetti)	X	B list	X	X	X
Cholera	X	B list	X		X	X
Clostridium perfringens (epsilon toxin)	X	B list	X		X
Ricin toxin	X	B list	X		X
Lassa fever		A list	X		X
Yellow fever		C list	X		X	X
Shigellosis	X	B list				X
Staphylococcal enterotoxins	X	B list	X
Encephalitis (e.g., Russian spring summer, eastern equine, Saint Louis, West Nile, Venezuelan)	X		X		X	X
Alphaviruses (Venezuelan, eastern, western, equine encephalomyelitis)		B list			X
Cryptosporidiosis		B list				X
Escherichia coli 0157:H7		B list				X
Salmonellosis		B list				X
Mycotoxins (trichothecene)	X		X		X
Rickettsial diseases			X		X	X
Typhoid fever	X		X			X
Venezuelan equine encephalitis			X	X	X
Hantaviral diseases		C list			X
Tickborne hemorrhagic fever viruses		C list			X
Tickborne encephalitis viruses		C list			X
Tuberculosis		C list				X
Chikun gunya fever			X		X
Diphtheria					X	X
Encephalomyelitis viruses	X				X
Histoplasmosis			X
Influenza				X		X
Marine toxins	X				X
Palytoxin			X		X
Psittacosis			X
Rocky mountain spotted fever			X			X
Saxitoxin			X		X
Tetrodotoxin			X		X
Typhus (epidemic rickettsial)			X	X
Typhus (scrub)			X	X
Viral infections					X	X
Western equine			X		X
Yersinia					X	X

This table is a merger of lists of disease threats developed by the Defense Threats Reduction Agency (DTRA), Centers for Disease Control and Prevention (CDC), North Atlantic Treaty Organization (NATO), interviews with Russian experts, United States Army Medical Research Institute for Infectious Diseases (USAMRIID) and nationally notifiable diseases.

Diseases appearing on only one list (not included in the table): Nipah virus (CDC C list); coccidiomycosis and dengue (NATO); Machupo (USAMRIID); acquired immunodeficiency syndrome (AIDS), amebiasis, Campylobacter, carbon monoxide poisoning, Chlamydia trachomatis, congenital rubella syndrome, food poisoning, giardiasis, Haemophilus influenza type B (HIB), hepatitis A, hepatitis B, hepatitis C, Kawasaki syndrome, Legionnaires' disease, leptospirosis, Lyme disease, lymphogranuloma venereum, malaria, measles, meningitis, mumps, neisseria gonorrhea, neisseria meningitis in blood or cerebrospinal fluid, pertussis, poliomyelitis, rabies, Reye syndrome, rheumatic fever, rubella, syphilis, tetanus, toxic shock syndrome, toxoplasmosis, and trichinosis (Reportable List).

Reprinted from Journal of Biomedical Informatics, Vol. 36, Michael Wagner, Virginia Dato, John N. Dowling, and Michael Allswede, Representative Threats for Research in Public Health, pp. 177–188, Copyright 2003, with permission from Elsevier.

© 2006

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

4.2. Animal Diseases

The Office International des Epizooties (OIE) is the world organization for animal health (see Chapter 7) The OIE sets guidelines and provides recommendations to minimize the risk of the spread of animal diseases and pests while facilitating trade between nations. The OIE develops policy, standards, and techniques that member countries can apply to help protect themselves from animal diseases by establishing valid import barriers for the trade of certain animals or animal products. The OIE documents these standards in the International Terrestrial Animal Health Code and the International Aquatic Animal Health Code (Office International des Epizooties, 2004a,b). These standards include lists of diseases, organized by priority.

Table 4.3 includes a selection of OIE diseases that produce high morbidity/mortality, spread rapidly, and can easily cross national boundaries. These diseases represent the greatest potential to disrupt international trade. These diseases (formerly called List A diseases) can produce significant socioeconomic upheaval or present a major public health risk; therefore, OIE establishes more stringent requirements for demonstrating freedom from the disease agent.

TABLE 4.3.

Selected Office International des Epizooties (OIE) Former List A Diseases

Disease	Species	Distribution (see OIE HandiStatus at http://www.oie.int/hs2/report.asp)	Source/Transmission	Clinical Signs	Diagnosis
African horse sickness	Horses, mules, donkeys	Sub-Saharan Africa, occasional outbreaks in northern Africa, Middle East, and Europe	Arthropod vector. Disease is not transmitted from animal to animal.	Supraorbital swelling	Clinical signs can be confused with other diseases. Laboratory diagnosis essential. Serology. Culture of blood, spleen, lung, or lymph nodes.
African swine fever	Pigs	Sub-Saharan Africa, Europe, South America, Caribbean	Direct transmission from infected animals. Virus can shed from animal for several months after recovery and contaminate environment.	Peracute disease generally produces death in absence of signs following 1- to 2-week incubation period. Acute, subacute, and chronic forms produce signs of varying severity that include abortion, fever, and inappetence. Incoordination, cyanosis, dyspnea, vomiting, and bloody diarrhea may develop in more severe cases.	Serology. Clinical signs and gross pathology (e.g., hemorrhages in organs and lesions seen in reticuloendothelial system) are suggestive.
Bluetongue	Sheep, goats, cattle, deer, bighorn sheep	Africa, Middle East, China, United States, Mexico, southeast Asia, Australia, northern South America	Insect vector. Disease has seasonal occurrence based on conditions that promote vector survival.	Fever, facial edema, congestion, ulceration of mucous membranes. Tongue may become swollen and protrude from mouth. This hyperemia may extend to groin, axilla, and perineum. Signs in cattle are much milder.	Serology. Culture of infected tissue.
Classical swine fever (hog cholera)	Pigs	Europe, Asia, Central and South America	Direct contact and fecaloral route. Maintained in endemic areas by carrier animals. Transplacental infection can lead to chronically infected piglets that shed significant amount of virus over their lifetime.	Sudden fever, depression, and inappetence in acute cases. Vomiting and diarrhea develop along with skin blotching and ocular discharge. Mild cases may only present with abortion and failure to thrive.	Serology. Hemorrhages and necrosis within the gut are common. Lesions are seen in reticuloendothelial system.
Contagious bovine pleuropneumonia	Cattle, buffaloes, sheep, goats	Africa, Asia, parts of Europe	Direct contact between animals. Agent does not persist in the environment.	Anorexia, fever, dyspnea, cough, and nasal discharge. Clinical signs not always present.	Serology. Culture from nasal discharge, pleural fluid or bronchial washings, lung tissue.
Foot and mouth disease (hoof and mouth disease)	Cattle, buffalo, signs highly pigs, sheep, goats, deer	Europe, Africa, Middle East, Asia, South America	Respiratory, mechanical transmission; virus can survive for weeks in bedding. Recovered animals may serve as carriers.	Fever, depression, inappetence, and vesicle emergence followed by painful ulcers.	Serology, clinical signs highly suggestive of disease.
Highly pathogenic avian influenza (fowl plague)	Domestic poultry, waterfowl, wild game birds, pigs, humans	All continents	Direct contact with infected birds or material (e.g., feces, meat).	Sudden increases in death rates within flocks before signs appear. Clinically affected birds are depressed and have ruffled feathers, inappetence, fever, and generalized weakness. Birds will also develop profuse diarrhea, their combs will become swollen, and they will have respiratory signs.	Necrotic foci in the spleen, liver, kidney, and lungs. Exudate may be present in air sacs. Virus can be isolated from tracheal and cloacal cultures.
Lumpy skin disease	Cattle	Africa, one confirmed outbreak in Israel in 1989	Transmission thought to be via insect vector.	Can be subclinical. In acute animals, persistence fever with nasal and ocular discharge. Lactating cattle will have a marked reduction in milk production. Nodules develop on head, neck, udder, and perineum. Swollen lymph nodes and animal may be reluctant to move.	Serology. Identification of capripox virions in biopsy material.
Newcastle disease	Domestic poultry, waterfowl, wild game birds, infrequently in humans	Worldwide	Contact with carrier bird or contaminated items (e.g., equipment, feed, personnel).	Marked depression, inappetence, decreased production, recumbency, and death. Edema of the comb and diarrhea are common. A nervous form may present with limb paralysis, head tremors, dyspnea, and coughing.	Necrosis and hemorrhage of gastrointestinal tract. Microscopic changes to brain. Virus isolated from cloacal culture of live birds.
Peste des petit ruminants	Small ruminants, especially goats; white-tailed deer have been infected experimentally	Africa, Arabian Peninsula, Middle East, southwest Asia	Transmitted from animal to animal via aerosol transmission.	Resembles rinderpest in cattle. Fever, ocular and nasal discharge, diarrhea, pneumonia, stomatitis. Oral lesions develop with excessive salivation. Does not produce clinical disease in cattle.	Serology. Tentative diagnosis based upon clinical signs. Linear hemorrhages (zebra stripes) present in large intestine. Necrotic enteritis, enlarged lymph nodes, necrotic lesions on spleen, and apical pneumonia.
Rift valley fever	Ruminants, dogs, cats, monkeys, humans	Africa, Middle East. Potential spread to other parts of world given wide host and vector range.	Disease in animals usually by mosquito vector. Human infection most commonly arises from contact with contaminated tissue and discharge.	Sever fever, vomiting, nasal discharge, bloody diarrhea beginning after 1 day after exposure, with 95% mortality in young animals. Adult animals often present with less severe signs. Severe influenza-like signs common in humans.	Liver of ruminants is enlarged, focally necrotic, and friable at necropsy. Serology.
Rinderpest	Cattle, buffalo, sheep, goats, pigs	North Africa, Middle East, India, parts of Asia	Respiratory, feces, and urine. Introduction of infected animal to naïve population generally results in explosive outbreak with high morbidity.	Nasal and ocular discharge followed by high fever, depression, restlessness, inappetence, and decreased production. Progresses with oral, respiratory, and gastrointestinal ulcers. Death typically 6 to 12 days after onset of signs.	Clinical signs are highly suggestive. Confirmed by serology in early stage of disease.
Sheep pox and goat pox	Sheep, goats	Africa, Middle East, Asia	Direct contact with infected animal saliva, nasal secretions, feces, or lesions. Inhalation of aerosols. Indirect via contaminated objects (e.g., vehicles, litter). Virus can survive for years in dried scabs.	Cases may be subclinical. Fever, depression, conjunctivitis, nasal discharge, and swelling of eyelids. Lesions evolving into papules form, beginning on hair/wool-free parts of body. Cough develops as papules in lungs cause pneumonia.	Serology. Identification of agent from full skin biopsy or lung lesions needed to differentiate from lumpy skin disease.
Swine vesicular disease	Pigs	Asian and European countries	Contact with infected animal, ingestion of raw waste and feed containing infected products. Transport in contaminated vehicle.	Sudden lameness in close animal groups. Slight fever. Development of vesicles on the snout, coronary band, and interdigital spaces. Young pigs may lose the horny hoof following vesicle rupture.	Serology. Culture of vesicular fluid, blood, or feces. Clinical signs easily confused with foot and mouth disease.
Vesicular stomatitis (Indiana fever)	Cattle, horses, pigs, sheep, wild animals, and rarely goats	Western Hemisphere	Ecology of agents not well understood. Arthropod-involved transmission cycle may be likely.	Very similar to foot and mouth disease. Brief febrile period and formation of papules and vesicles in mouth, udder, and coronary band. Profuse salivation.	Serology. Rapid laboratory diagnosis of animal disease important to distinguish from foot and mouth disease.

Transmissible diseases that have the potential for very serious and rapid spread, irrespective of national borders, that are of serious socioeconomic or public health consequences, and that are of major importance in the international trade of animals and animal products.

The OIE also lists diseases that cause significant socioeconomic disturbance or health risk within an affected country but generally do not cross national boundaries (Table 4.4 ). These diseases (formerly called List B diseases) are associated with requirements for reporting and demonstrating freedom from the disease or agent that are less severe than those for the pandemic agents described above; nonetheless, they are still quite restrictive.

TABLE 4.4.

Selected Office International des Epizooties (OIE) former List B Diseases

Disease	Species	Distribution (see OIE HandiStatus at http://www.oie.int/hs2/report.asp)	Source/Transmission	Clinical Signs	Diagnosis
Anthrax (woolsorter's disease, malignant pustule, malignant carbuncle)	Cattle, sheep, goats, deer, horses, fogs, pigs, humans	Worldwide	Spores from soil. Eating undercooked meat from infected animals, exposure to hide/wool of infected animals.	Fever, behavioral changes, seizures, hematuria, gastroenteritis, pharyngeal edema, In horses; colic, enteritis, followed by edema, hemorrhage and death.	Identification of etiologic agent in stained smears or culture of blood or aspirate from pustules.
Echinococcosis	Dog, cattle, sheep, pigs, goats, camels, horses, humans	Worldwide	Infection via fecal oral route. Dog is definitive host, shedding Echinococcus cestodes. Intermediate host infected via ingestion of contaminated water, food, or soil.	After ingestion, cestodes hatch and larvae encyst primarily in lungs or liver. Location, size, and number of cysts will dictate signs. Symptoms usually those associated with slow-growing tumor.	Identification of larval cyst in affected organ of intermediate host via sonogram or necropsy/autopsy. Identification of cestodes in dog feces.
Heartwater (cowdriosis, malkopsiekte)	All domestic and wild ruminants	Sub-Saharan Africa, Madagascar, Caribbean	Transmitted by Amblyomma ticks. Wild animals could play role as reservoir.	Sudden high fever (drops shortly before death), inappetence, diarrhea, lung edema; nervous signs develop gradually.	Culture of capillary endothelial cells of brain. Brain smears for dead animals.
Johne's disease (paratuberculosis)	All domestic and wild ruminants, horses, pigs, deer, alpaca, rabbits, foxs, weasels	Worldwide	Under natural conditions, ingestion of agent from contaminated environment. Infection can be spread to unborn fetus. Calves contract infection through milk of infected cow.	Slowly progressive wasting. Diarrhea that progressively becomes more severe. Diarrhea is less common in smaller ruminants.	Fecal smears. Fecal/tissue culture. Serology. Lesions in small intestine. Lesions progress to occur in cecum, colon, and mesenteric lymph nodes as disease progresses.
Leishmaniasis (Chiclero ulcer, buba, oriental sore, Aleppo boil, Baghdad sore, espundia)	Mammals	Southern Mexico to northern Argentina, Dominican Republic, South America, Middle East, Asia, northern China, northwest India, Africa	Vector-borne parasite. Rodents are reservoir. Once inside vertebrate host, organism invades cutaneous macrophages.	Begins as itchy lesion then forms papules and painless ulcers. Lesions may persist for a year or more.	Identification of parasite through lesion scraping or aspiration.
Leptospirosis (Weil's disease, swineherd's disease, cane-cutter's fever, mud fever, Stuttgart disease)	Cattle, pigs, horses, sheep, goats, dogs, many wild animals, including rodents	Worldwide	Environment is contaminated through infected animal's urine. Direct or indirect transmission through abraded skin or mucosa. Ingestion of contaminated water, soil, or foods.	May remain subclinical. Sudden onset of fever, anorexia, birth of weak/stillborn animals. Infertility. Some may present with jaundice. Chronic phase of disease may last months after clinical recovery.	Culture of agent from blood (early) or urine. Serology requires repeated samples.
New and Old World screwworm (traumatic myiasis)	Mammals, birds (rarely)	Old World: Africa, Gulf countries, Indian subcontinent, and southeast Asia to Papua New Guinea New World: southern United States to northern Argentina (area contracts in winter and expands in summer)	Female screwworm flies lay eggs on edges of wounds on live animals. Eggs laid on mucous membranes can result in infections of natural openings. Larvae burrow into flesh upon emerging. Larvae leave wound after maturing and purpurate in the soil where they further develop into an adult fly.	Extensive tissue destruction from burrowing larvae. Severe infections can result in death.	Identification of larvae collected from the deepest part of the wound
Pseudorabies (Aujesky's disease, mad itch)	All mammals, especially pigs, except humans and tailless apes	Worldwide except Canada and Oceania	Pigs are natural host and will remain latently infected after clinical recovery. Raccoons in the United States and wild boar in Europe may be healthy carriers. Airborne transmission possible.	Abortions and stillbirths. Nervous signs (young animals), respiratory disease (older animals). Intense itching.	Culture of agent from nasal fluid or tonsil biopsy from live animals, brain tissue from dead. Affected animals, other than pigs, do not survive long enough for marked seroconversion.
Q-fever (Balkan influenza, coxiellosis, abattoir fever, nine-mile fever)	Sheep, cattle, goats, cats, rabbits, dogs, humans (has been found in almost all domestic and wild animal species)	Worldwide	Domestic cycle of disease mainly exists in cattle, sheep, and goats. Infection through inhalation of aerosols from contaminated placenta, amniotic fluid, and excreta. In natural setting, agent is circulated between wild animals and ticks.	Spontaneous abortion and fever. Otherwise clinically inapparent. In man, sudden onset of fever, chills, profuse sweating, myalgia, and malaise following a 2- to 5.5-week incubation. Acute hepatitis also possible. Chronic disease mainly affects the cardiovascular system.	Serology since few laboratoriess have adequate installations and equipment to safely isolate the agent (Coxiella burnetii).
Rabies (hydrophobia, lyssa)	All mammals	All continents (except I Oceania) with many rabies-free countries, including Japan, Ireland, the Netherlands, Portugal, Spain, and the United Kingdom	Inoculation (e.g., bite) or Infection can be obtained through inhalation of agent. Exposure to infected material.	Incubation period may be affected by amount of virus introduced. Reported as long as years. Anxious feeling, sensory alteration, headache, slight fever followed by extreme sensitivity to light, increased salivation, and pupil dilation. Liquids are violently rejected by muscular contractions as disease progresses. May prevail until death or develop generalized paralysis until death.	Diagnosis can only be made in laboratories utilizing brain tissue to identify Negri bodies microscopically or virus nucleocapsid antigen via ELISA techniques.
Trichinellosis (trichiniasis, trichinosis)	Pigs, rats, bears, other flesh-eating mammals, including humans	Worldwide, not confirmed in Australia or several tropical countries in Africa, Latin America, and Asia	Ingestion of cyst in contaminated meat. Larvae can live for months in badly decayed flesh.	No clinical disease in wild animals. Anorexia, nausea, vomiting, diarrhea. Followed by fever, muscle pain, swollen eyelids, headache and chills. Muscle pain may last several months.	Muscle biopsy. Identification of larvae. Clinical diagnosis difficult owing to nonspecific signs.

Transmissible diseases that are considered to be of socioeconomic and/or public health importance within countries and that are significant in the international trade of animals and animal products. ELISA indicates enzyme-linked immunosorbent assay.

Commercial farming and trade of aquatic animals is increasing dramatically. The aquatic environment provides unique transmission modes for disease. Therefore, the OIE has developed an Aquatic Animal Code (Table 4.5 ). OIE includes diseases based on the potential for international spread and the potential for transmission to humans.

TABLE 4.5.

OIE Aquatic Animal List Diseases

FISH
Epizootic hematopoietic necrosis
Infectious hematopoietic necrosis
Oncorhynchus masou virus disease
Spring viremia of carp
Viral haemorrhagica septicemia
Channel catfish virus disease
Viral encephalopathy and retinopathy
Infectious pancreatic necrosis
Infectious salmon anaemia
Epizootic ulcerative syndrome
Bacterial kidney disease (Renibacterium salmoninarum)
Enteric septicemia of catfish (Edwardsiella ictaluri)
Piscirickettsiosis (Piscirickettsia salmonis)
Gyrodactylosis (Gyrodactylus salaris)
Red sea bream iridoviral disease
White sturgeon iridoviral disease
MOLLUSCS
Infection with Bonamia ostreae
Infection with Bonamia exitiosus
Infection with Mikrocytos roughleyi
Infection with Haplosporidium nelsoni
Infection with Marteilia refringens
Infection with Marteilia sydneyi
Infection with Mikrocytos mackini
Infection with Perkinsus marinus
Infection with Perkinsus olseni/atlanticus
Infection with Haplosporidium costale
Infection with Candidatus Xenohaliotis californiensis
CRUSTACEANS
Taura syndrome
White spot disease
Yellowhead disease
Tetrahedral baculovirosis (Baculovirus penaei)
Spherical baculovirosis (Penaeus monodon–type baculovirus)
Infectious hypodermal and hematopoietic necrosis
Crayfish plague (Aphanomyces astaci)
Spawnerisolated mortality virus disease

Reprinted from Journal of Biomedical Informatics, Vol. 36, Michael Wagner, Virginia Dato, John N. Dowling, and Michael Allswede, Representative Threats for Research in Public Health, pp. 177–188, Copyright 2003, with permission from Elsevier.

5. REDUCING COMPLEXITY: THREAT PATTERNS

Although to our knowledge no organization has attempted to develop functional requirements for an “all-biological threats” system, it makes for an interesting gedanken experiment (thought experiment), which may reveal whether such a system can even be specified given the large number of organisms and variability in their presentation, or how such a specification might best be accomplished.

To design an all-threats system, a designer would have to speak with many disease experts to understand the requirements for each disease. In particular, the designer would have to understand the required timeliness of detection for each disease and the smallest size outbreak that should be detected. Just understanding these functional requirements for all biological agents would be an enormous undertaking and would only represent a first step in the development of a system specification, which would require additional analysis for each threat of the types of surveillance data and analytic methods that could satisfy the requirements at lowest cost and effort.

There is another way, however, to manage this design complexity, which is to identify a smaller number of general “patterns” that a biosurveillance system must be capable of recognizing. This idea is not terribly new; the field has appreciated the disease-independent value of looking for patterns ever since John Snow used a spatial pattern of cases to elucidate the cause of a cholera outbreak in London in 1854 (Snow, 1855). What is novel here is taking that idea to its logical conclusion, which entails systematically examining all threats (biological agents and their various presentations as outbreaks) to identify a set of patterns (more multidimensional than spatial patterns) that most or ideally represent all of the patterns that a biosurveillance system must be capable of recognizing.

Table 4.6 is the result of such an analysis conducted by Wagner et al. (2003b) for the diseases listed in Table 4.2. Note that the following discussion relates only the threats to human health. A similar analysis would be required for diseases that threaten only animals.

TABLE 4.6.

Nine Patterns

Pattern	Representative Outbreak	Other Threats
Large aerosol release	1979 Sverdlovsk release of B. anthracis (Kirov strain) from Soviet Biological Weapons Compound 19 (Mangold and Goldberg, 2000)	Weaponized anthrax, weaponized staph enterotoxin B, weaponized tularemia, weaponized botulism, weaponized Coxiella burnetti, Q Fever, weaponized Pseudomonas mallei: Glanders, weaponized Clostridia perfringens toxin, weaponized Brucellae sp.,weaponized, ricin aerosol, T2 mycotoxin aerosol, histo-coccidiomycosis
Building/vessel contamination	Epidemiologic investigations of bioterrorism-related anthrax, New Jersey, 2001 (Greene CM et al., 2002)	Any bioaerosol, marine toxin: saxitoxin, ciguatoxin, tetrodotoxin, palytoxin
Small premonitory release or contamination	Laboratory-acquired human Glanders, Maryland, May 2000 (CDC, 2000)	Weaponized anthrax, weaponized staph enterotoxin B, weaponized tularemia, weaponized botulism, weaponized Coxiella burnetti, Q Fever, weaponized Pseudomonas mallei: Glanders, weaponized clostridia perfringens toxin
Continuous or intermittent release of an agent	Legionella, Pennsylvania (CDC, 1976a,b)	Legionella pneumophila, histo-coccidiomycosis, Chlamydia psittici: Psitticosis
Contagious person-to-person	Outbreak of Influenza A Infection Among Travelers– Alaska and the Yukon Territory, May–June 1999 (CDC, 1999a)	Influenza, variola, rubeola, rubella, mycobacterium tuberculosis, mumps, smallpox, diphtheria, Haemophilus influenza, mycobacterium leprae, Neisseria meningititus, group A strep: rheumatic fever, toxic shock, necrotizing fascitis
Commercially distributed products	A large community outbreak of salmonellosis caused by intentional contamination of restaurant salad bars (Torok TJ et al., 1997)	Salmonellosis, Shigella sp., Escherichia coli 0157, Brucella sp., Staph enterortoxin B. vibrio cholera, B anthracis, toxic alimentary aleukia: T2 Mycotoxin, Clostridium botulinum: botulism, hepatitis A and C. Perfringins E toxin, ricin toxin, heavy metals: iron, mercury, arsenic, Nipah virus, marine toxin: saxitoxin, ciguatoxin, tetrodotoxin, palytoxin, trichinella: trichinosis, norwalk, cyclosporiasis
Water-borne	Large community outbreak of cryp-tosporidiosis due to contamination of a filtered public water supply (Hayes EB et al., 1989)	cryptosporidiosis, Shigella sp, camphylobacter, giardiasis, staph enterotoxin B, Escherichia coli 0157, botulism, bioterroristic, ricin toxin, entamoeba histolytica, cyclosporiasis
Vector/Host-borne	Outbreak of West Nile–like viral encephalitis, New York (CDC, 1999b,c)	Malaria, West Nile, yellow fever, dengue, Yersinia pestis–Tularemia, ebola, marburg, hantaviruses, Q fever, Glanders, melioidosis, Lassa, Machupo, Junin, Rift Valley, Crimean-Congo hemorrhagic fever, Hantaan, Alphaviridae: Venezuelan equine encephalitis, eastern equine encephalitis, western equine encephalitis, Chikungunya, Flaviviridea Encephalitis (e.g., Russian spring summer, eastern equine, St Louis, West Nile, Venezuelan), Nipah virus, rabies, Lyme, Rickettsia sp.: Rocky Mountain spotted fever, typhus
Sexual or parenteral transmission	Cluster of HIV-positive young women, New York, 1997-1998 (Anonymous, 1999)	HIV, Neisseria gonorrhea, Hemophillus ducrei, Treponema pallidum, Chlamydia trachomatis, hepatitis B and C

The analysis resulted in a final set of nine patterns, each of which represents a fundamentally different pattern recognition problem for a biosurveillance system. For example, large-scale aerosol releases, in general, have the same requirements for a large-scale aerosol release of B. anthracis described above. Building contaminations in general have the same requirements as described for a building contamination with B. anthracis. They also searched the literature for actual outbreaks of diseases in each category for which detailed descriptions were available for study by system designers.

The previous section on the functional requirements and specifications for anthrax biosurveillance already discussed the first three of the nine patterns in Table 4.5. We discuss the other six patterns in the following sections.

5.1. Continuous or Intermittent Release of an Agent

The fourth pattern is that produced by a continuous or intermittent release of an infectious agent or biologic toxin over time. Under such conditions, individuals entering a limited area develop disease over an extended period. The Philadelphia Legionnaires outbreak was of this type, as would have been the attempt by the Aum Shinrikyo cult to sicken the population of Tokyo by disseminating continuously liquid anthrax slurry over a period of 4 days from the rooftop of their building, had it succeeded (Mangold and Goldberg, 2000). Pets and birds were sickened, but no human cases were reported.

Early detection of this type of outbreak would require analysis of surveillance data both spatially and temporally, that is, searching for clusters of diseases or syndromes in both space and over time. This pattern requires a different kind of manipulation of epidemiological data, such as the use of detection algorithms based on cumulative sums or cut point statistics. It also requires detection algorithms capable of searching a large space of possible time intervals and spatial locations. Several chapters in Part III of this book discuss such algorithms.

5.2. Contagious Person-to-Person

The fifth pattern results from person-to-person transmission of a contagious disease, such as influenza, SARS, measles, or rubella (German measles). The timeliness requirement for this type of outbreak is not paramount because people become infected in waves. The recognition of this pattern involves biosurveillance components capable of collecting and analyzing social networks and contact information.

5.3. Commercially Distributed Products

The sixth pattern is contamination of commercially distributed products, especially food. Food contamination may be as simple as contamination at the site of preparation, which is what the Rajneesh cult attempted in The Dalles, Oregon, or as involved as tampering with distribution or production facilities (Torok et al., 1997). The timeliness requirement may be anthrax-like, as many individuals can be infected nearly simultaneously.

Improving the timeliness of detection of threats in this category requires biosurveillance components that can monitor the food supply directly for contamination. It also requires components that can correlate patterns of disease in a population with knowledge of food production and distribution systems. These analyses must be longitudinal to detect intermittent or ongoing contaminations and must consider that many foods can be stored for relatively long periods before consumption.

5.4. Water-Borne

The seventh pattern is contamination of the water supply (well or surface water), as illustrated by the example of cryptosporidium in Chapter 2. The timeliness requirement may be “anthrax-like,” as a cohort of individuals can be exposed nearly simultaneously. To achieve the required timeliness of detection, a surveillance system would require in-line monitoring of the water system for contamination, as well as components that correlate the spatial distribution of disease data with the branching anatomy and vulnerabilities of the water supply system, to allow a subtle increase in cases to be noticed as early as possible.

5.5. Vector/Host-Borne

The eighth pattern results from disease transmission through an intermediate, nonhuman vector, such as mosquitoes or even contaminated blood products. Similar to diseases that are contagious and passed from human to human, outbreaks of this type do not have anthrax-like timeliness requirements. Detection of outbreaks in this category, however, requires that a biosurveillance system monitor for the presence of organisms in vectors (e.g., mosquitoes and blood products). It must also be capable of collecting and analyzing data about sick individuals and their exposures to vectors to find clusters of cases that otherwise would not be apparent above the background level of disease.

5.6. Sexual or Parenteral Transmission

The ninth and final pattern is that caused by a disease transmitted through sexual or other intimate contact, such as the sharing of needles. This pattern resembles the contagious person-to-person pattern, but the analysis separated this pattern because the data collection enabling the analysis of sexual contact patterns is difficult, requires sensitivity, and may infringe on legal rights. A key detection problem raised by this category is identifying a carrier who is infecting other individuals (either intentionally or unintentionally). The timeliness requirement is not severe, as illustrated by AIDS, but the difficulty in detecting cases and identifying contacts is high.

5.7. Strengths and Limitations of Using Patterns to Reduce Design Complexity

The goal of the above analysis was to identify a set of patterns that would dramatically reduce the complexity of designing biosurveillance systems. By using these patterns, a system designer avoids the paralysis induced by the complexity of developing specifications for hundreds of organisms.

Each of these nine patterns represents an important and different problem in detection. This set of patterns may be more useful to system designers than are priority lists, as in Table 4.2. Table 4.2 does not identify explicitly requirements to detect premonitory cases, building contaminations, or continuous releases; hence, a designer may overlook these requirements if Table 4.2 is used.

Wagner and colleagues noted that five of the nine patterns happen to correspond to organizational divisions within governmental public health (sexually transmitted, communicable, vector-borne, water-borne, foodborne disease). They conjectured that the specialization that has occurred in governmental public health (in response to complexity) over the years might have been shaped by similarities among diseases, especially with respect to the types of data and analyses required to detect and characterize outbreaks of these diseases.

It is worth noting that four of the nine patterns do not correspond to organizational divisions in health departments (large-scale aerosol release, small premonitory release, building contamination, and continuous or intermittent release). This observation suggests that these patterns may require special attention. We note that the Department of Homeland Security is addressing the large-scale aerosol release, and the U.S. Postal Service is addressing the problem of building contamination— at least for the tiny subset of buildings in the United States that they own.

It is also worth noting that designers can benefit from focusing their attention on an even smaller subset of patterns. Two patterns—the communicable person-to-person and the large-scale release pattern—cover many of the design issues raised by the larger set of patterns (Wagner et al., 2003a).

6. SPECIFYING BIOSURVEILLANCE DATA

As we discuss in Parts II and IV, a system designer has a large selection of surveillance data from which to construct a biosurveillance system. This abundance is a result of the increasing amounts of data collected electronically about the health of individuals and their purchasing, travel, attendance, and other behaviors (Sweeney, 2001).

For a designer, the task of data selection may be simple or complex. It is simple if the organization planning a system requests that the designer automate the collection of data that the organization is already receiving. It may be quite challenging if the organization specifies an engineering goal of earlier detection and leaves it to the designer to select data. In part, the designer's difficulty stems from the current lack of full understanding of the value of many of these types of data. The designer must weigh whether data can meet functional requirements for timeliness and accuracy of detection, the availability of the data, and the cost and efforts to acquire the data. Cost and effort may be dominant factors for data that either require effort on the part of many individuals or organizations to obtain the data, or data that are distributed among many computer systems, especially if the biosurveillance system will monitor at the national or international level. The chapters in Parts II and IV of this book provide detail about data availability and the cost and effort to obtain different types of data.

The complexity of the design process is further increased by the amount of data that must be specified, especially for a system that supports outbreak characterization. The data may include data about human health, animal health, environmental data, locations, and relationships of people. Just the data potentially needed to diagnosis a single sick human are staggeringly large-there are more than 4,000 symptoms and laboratory tests that bear on the diagnosis of disease in humans. Appendix A provides tables that may be useful to system designers. This appendix contains tables of surveillance data that have been pivotal in detecting and characterizing outbreaks in the past, data that are required to satisfy published case definitions, and data currently being collected routinely for biosurveillance by governmental public health. The tables also include types of data that may be very early indicators of diseases, identified by a review of the literature on health psychology, especially the subliterature relevant to behaviors of ill individuals between the onset of symptoms and presentation (if ever) for medical care. The tables also identify data systems that routinely collect the data either for the purposes of biosurveillance or, more typically, for other purposes.

7. SUMMARY

Because of a new requirement for biosurveillance (very early detection of disease outbreaks), biosurveillance systems are undergoing a process of re-engineering and de novo construction. Designers of biosurveillance systems have an opportunity to adopt a more formal engineering approach that begins with specification of functional requirements. At this time, the understanding of such requirements for most diseases, however, is incomplete. There is a general recognition that systems should detect outbreaks “as early as possible” however, this level of specification is less than ideal because designers must consider many tradeoffs between earliness and cost when designing systems. A designer may simplify the process of functional requirement specification by recognizing that a relatively small number of patterns can guide this process. The state of the art in functional requirement definition for biosurveillance is “perhaps the end of the beginning,” as Winston Churchill so aptly put it.

This chapter is also the end of the beginning. We continue our discussion of the design of biosurveillance systems in Part II by reviewing the organizations that participate in biosurveillance and their missions. Part III discusses newer data analytic methods, Part IV considers new types of surveillance data that designers may consider, and Part V addresses the question of how biosurveillance systems can be designed to support decision making. We finally return explicitly to the topic of building biosurveillance systems in Part VI.

3a MHON UNTaTeUb! [Follow me, reader!] (Bulgakov, 2001).

ADDITIONAL RESOURCES

Five papers about high priority disease threats:

Arnon, S.S., et al. (2001). Botulinum Toxin as a Biological Weapon: Medical and Public Health Management. JAMA 285:1059–1070.

Dennis, D.T., et al. (2001). Tularemia as a Biological Weapon: Medical and Public Health Management. JAMA 285:2763-2773.

Henderson, D.A., et al. (1999). Smallpox as a Biological Weapon: Medical and Public Health Management: Working Group on Civilian Biodefense. JAMA vol. 281:2127–2137.

Inglesby, T.V., et al. (2000). Plague as a Biological Weapon: Medical and Public Health Management: Working Group on Civilian Biodefense. JAMA 283:2281–22-90.

Inglesby, T.V., et al. (2002). Anthrax as a Biological Weapon, 2002: Updated Recommendations for Management. JAMA 287:2236–2252. Review covering six papers.

ACKNOWLEDGMENTS

The material in this chapter evolved from studies commissioned by the Agency for Healthcare Research and Quality under its Bioterrorism Initiative; Contract No. 290-00-0009 Task Order No. 2 Using Information Technology to Improve Preparedness for Bioterrorism. We thank Dr. William Hogan for providing details about the 1979 Sverdlovsk outbreak and the Journal of Biomedical Informatics for permission to use material previously published.