A National Tuberculosis Archive

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Science  03 Mar 2006:
Vol. 311, Issue 5765, pp. 1245-1246
DOI: 10.1126/science.1125762

Currently, no disease has the type of large-scale, systematic biological and informatic integration that permits researchers to cross easily between field-relevant and research-relevant isolates in the context of clinical, epidemiological, and phylogenetic characterizations. This is due, in large part, to the intense demands systematic data collection and organization place on clinicians and the public health apparatus. However, the complete population-based data collection infrastructure necessary for such a resource is already in place for tuberculosis (TB) in the United States.

About one-third of the world's population is infected with Mycobacterium tuberculosis (MTB) (1). TB disproportionately burdens the world's poorest countries (2, 3). [HN1] The threat of emerging multidrug-resistant (MDR) strains (4) is severe. [HN2] The number of TB cases in the United States is relatively small: just under 15,000 per year (5). Yet TB is fundamentally a “transnational” disease, with more than half of all U.S. cases occurring in non-U.S.-born persons (5). Schwartzman et al. (6) [HN3] estimate that under current practices the United States will spend about $2 billion over the next 20 years just treating immigrants from Mexico. And although “only” 15,000 cases is a public health success story compared with historic epidemics, indolence in efforts to combat the disease would be unwise (7). It is estimated that cutbacks in TB-related resources in the late 1970s and 1980s contributed to a resurgence in TB among predominately immunocompromised and socially marginalized patients that cost more than $1 billion to control in New York City alone (8). [HN4]

Every verified TB case in the United States is reported to the Centers for Disease Control and Prevention (CDC), along with clinical and epidemiological information, in a document called the Report of Verified Case of Tuberculosis (RVCT) [HN5] (9). In 2004, CDC began a program to genotype a MTB isolate from every patient reported in the United States under its TB Universal Genotyping Program [HN6] (10, 11). Other laboratories already have substantial information on strains from countries in which epidemiologic trends are well described (12) or drug-resistant MTB is epidemic (13, 14). The genome of MTB has been sequenced (15). [HN7] Collections of genotypic, epidemiological, and/or clinical data are available in electronic databases but are not integrated, and phylogenetic data relating strains are incomplete. What is missing is an integrated, comprehensive, population-based biologic and informatic resource that can drive evidence-based decision-making.

We propose creation of a National Tuberculosis Archive, a comprehensive repository of characterized M. tuberculosis isolates along with their genomic, clinical, and epidemiological data (see figure, this page). Such an integrated resource would close the loop between clinical isolates and research data, allowing users to search on metadata criteria and to obtain samples of isolates matching field-relevant criteria. Molecular variation could be readily linked with phenotypic characteristics, and geographic distribution with temporal sampling. Bench scientists could explore fundamental questions about the relation between molecular variation and clinical consequences, health-care providers could alter patient care on the basis of strain-specific pathogen properties, and public health officials could track outbreaks across jurisdictions and back through time. Disparate data would be integrated in a Web-accessible platform for easy access.

Differences between the current configuration of clinical isolates, research strains, and data and the proposed National Tuberculosis Archive.

(Bottom) Current unintegrated configuration.


Archiving etiologic material along with an integrated information resource has previously proved to be a prescient step in public health preparedness, as was seen in the 1993 hantavirus epidemic [HN8] when museum archives of rodent sera and tissue samples were crucial in demonstrating that the virus had been widely endemic for years (1618). This gave public health policy-makers invaluable baseline information to determine appropriate and targeted responses, while removing biowarfare concerns.

Results from prior molecular epidemiologically based efforts [HN9] are a harbinger of the value of a comprehensive national archive for TB. A population biologic analysis of 10 years of data in San Francisco suggests that strains of M. tuberculosis may spread more efficiently in human populations when they are within the sympatric populations in which they evolved (19). [HN10] So knowing an outbreak's characteristic molecular and phylogenetic signature can help in identifying new human ethnic groups at risk. A clinical study in New York City suggests that patients afflicted with specific clades of bacteria manifest a more profound disease (20, 21). [HN11] Other public health jurisdictions are seeing the full extent of unsuspected transmission and the need for new interventions (22). For the MDRTB outbreaks caused by strain W [HN12] in New York in the early 1990s, availability of archived samples linked to public health surveillance data enabled investigators to identify the origin of strain W, trace its acquisition of drug resistances, track its spread in New York City and around the country, and develop public health control measures (8, 23, 24).

The RVCT-based public health infrastructure and CDC Universal Tuberculosis Genotyping Program are already in place. We estimate the cost of integration for TB to be $15 million over 3 years.

Because M. tuberculosis is a human pathogen, but a poor candidate for bioterrorism, it is an excellent pilot for a more systematic program of human pathogen socioecological-genomic characterization. Improvements in disaster preparedness will result from a more focused and thoughtful integration of science, medicine, and public health.

HyperNotes Related Resources on the World Wide Web

General Hypernotes

This issue of Science also has an Enhanced Policy Forum by Seth W. Glickman et al. titled “A portfolio model of drug development for tuberculosis.”

Dictionaries and Glossaries

The On-line Medical Dictionary is provided by CancerWeb.

A glossary of tuberculosis terms is provided by the Centre for Infections of the UK Health Protection Agency.

Web Collections, References, and Resource Lists

The Karolinska Institutet Library, Stockholm, provides biomedical links. Sections of Internet resources on tuberculosis and evidence-based medicine are included.

The World Health Organization (WHO) provides links to Internet resources on tuberculosis.

The Centre for Infections of the UK Health Protection Agency provides links to Internet resources related to tuberculosis.

The Charles P. Felton National Tuberculosis Center at Harlem Hospital, New York, provides links to Internet resources on tuberculosis.

Online Texts and Lecture Notes

Tuberculosis: Old Disease, Continuing Threat is a presentation of the CBC.

The National Institute of Allergy and Infectious Diseases provides a resource page on TB.

The Tuberculosis Division of the International Union Against Tuberculosis and Lung Disease provides information and educational materials for health care professionals.

Internet resources on tuberculosis include those provided by WHO's Stop TB Department, WHO's Special Programme for Research and Training in Tropical Diseases (TDR), the Division of Tuberculosis Elimination of the U.S. Centers for Disease Control and Prevention (CDC), the World Bank, the UK Health Protection Agency, and the Global Fund to Fight AIDS, Tuberculosis and Malaria.

The Stop TB Partnership Web site provides tuberculosis news, information, and other resources. The Global Plan to Stop TB, 2006–2015 is presented.

General Reports and Articles

WHO makes available the 2005 report on global tuberculosis control (2).

The Institute of Medicine's 2000 report Ending Neglect: The Elimination of Tuberculosis in the United States is made available by the National Academies Press.

The 15 March 2002 issue of Science had a Review by C. Dye et al. titled “Erasing the world's slow stain: Strategies to beat multidrug-resistant tuberculosis.”

CDC makes available, in the 3 November 2005 Morbidity and Mortality Weekly Report (MMWR), the report titled “Controlling tuberculosis in the United States: Recommendations from the American Thoracic Society, CDC, and the Infectious Diseases Society of America.”

Numbered Hypernotes

1. Tuberculosis. Todar's Online Textbook of Bacteriology has a presentation on tuberculosis (TB). The Francis J. Curry National Tuberculosis Center offers summaries about global TB and TB in the U.S. The Global Fund to Fight AIDS, Tuberculosis and Malaria provides a presentation on the global tuberculosis epidemic. The Johns Hopkins Center for Tuberculosis Research summarizes information on the global epidemiology and natural history of TB. The CDC makes available the Surveillance Report titled “Reported tuberculosis in the United States, 2004,” as well as a press release titled “Tuberculosis in the United States, 2004” and a presentation titled “Progress toward tuberculosis elimination in the United States.” The 1 March 2006 issue of the American Journal of Respiratory and Critical Care Medicine had an article by W. W. Yew and C. C. Leung titled “Update in tuberculosis 2005.”

2. Multidrug-resistant TB. An introduction to multidrug-resistant TB is provided by the Charles P. Felton National Tuberculosis Center. A multidrug-resistant tuberculosis fact sheet is provided by the American Lung Association. A resource page on drug-and multidrug-resistant tuberculosis is provided by WHO's Stop TB Department. The Global Alliance for TB Drug Development offers information about multidrug-resistant tuberculosis. The 15 April 2002 issue of the Journal of Infectious Diseases had an article by C. Dye et al. titled “Worldwide incidence of multidrug-resistant tuberculosis.” WHO makes available the 2004 report by M. Abdel Aziz et al. titled “Anti-tuberculosis drug resistance in the world: Third global report 1999-2002” (4).

3. Kevin Schwartzman and Dick Menzies are in the Respiratory Epidemiology and Clinical Research Unit, Montreal Chest Institute. The 8 September 2005 issue of the New England Journal of Medicine had an article by K. Schwartzman, D. Menzies et al. titled “Domestic returns from investment in the control of tuberculosis in other countries” (6). The Rockefeller Foundation issued a news release about this study.

4. TB in New York City. The 27 July 1995 issue of the New England Journal of Medicine had an article (free registration required) by T. R. Frieden, P. I. Fujiwara, R. M. Washko, and M. A. Hamburg titled “Tuberculosis in New York City—Turning the tide” (8). New York City's Bureau of Tuberculosis Control makes available in PDF format historical annual reports from 1900 to 1999.

5. CDC's Report of Verified Case of Tuberculosis. CDC provides TB Surveillance Reports; the technical notes provide information on the Report of Verified Case of Tuberculosis. The CDC's Online Tuberculosis Information System contains information on verified tuberculosis cases reported to the CDC.

6. TB genotyping program. The 21 January 2005 issue of the CDC's MMWR had an article titled “Notice to readers: New CDC program for rapid genotyping of Mycobacterium tuberculosis isolates” (10). The CDC's Division of Tuberculosis Elimination makes available the Guide to the Application of Genotyping to Tuberculosis Prevention and Control (11); an overview of the CDC Tuberculosis Genotyping Program is included. The November 2002 issue of the CDC's Emerging Infectious Diseases had a collection of articles on tuberculosis and genotyping TB strains.

7. Genome of multidrug-resistant TB. The 11 June 1998 issue of Nature had an article by S. T. Cole et al. titled “Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence” (15). The Sanger Institute provides a resource page on this sequencing. The Institute for Genomic Research provides genome resource pages for Mycobacterium tuberculosis H37Rv and Mycobacterium tuberculosis CDC1551.

8. 1993 hantavirus epidemic. The CDC's Special Pathogens Branch provides a hantavirus resource page with information about the 1993 outbreak. Hantavirus.net is an online information service pertaining to the New World hantavirus. The 5 November 1993 issue of Science had a Perspective by J. M. Hughes, C. J. Peters, M. L. Cohen, and B. W. Mahy titled “Hantavirus pulmonary syndrome: An emerging infectious disease” (16). The November 2002 issue of BioScience had an article (full text available in PDF format) by T. L. Yates et al. titled “The ecology and evolutionary history of an emergent disease: Hantavirus pulmonary syndrome” (18).

9. Molecular epidemiology of TB. The July 2002 issue of the European Respiratory Journal had an article by M. V. Burgos and A. S. Pym titled “Molecular epidemiology of tuberculosis.” The March 2001 issue of the Journal of Clinical Investigation had a review article by M. Kato-Maeda, P. J. Bifani, B. N. Kreiswirth, and P. M. Small titled “The nature and consequence of genetic variability within Mycobacterium tuberculosis.” The 6 April 2004 issue of the Proceedings of the National Academy of Sciences had an article by A. G. Tsolaki et al. titled “Functional and evolutionary genomics of Mycobacterium tuberculosis: Insights from genomic deletions in 100 strains,” an article by A. E. Hirsh et al. titled “Stable association between strains of Mycobacterium tuberculosis and their human host populations,” and a commentary by M. Tibayrenc titled “A molecular biology approach to tuberculosis.” The April 2000 issue of the Western Journal of Medicine had a review article by M. Kato-Maeda and P. M. Small titled “How molecular epidemiology has changed what we know about tuberculosis.” (22) The February 2004 issue of Occupational and Environmental Medicine had a review article by A. Seidler, A. Nienhaus, and R. Diel titled “The transmission of tuberculosis in the light of new molecular biological approaches.”

10. San Francisco study. Sympatric and sympatric speciation are defined in the On-line Medical Dictionary. The 21 February 2006 issue of the Proceedings of the National Academy of Sciences had an article by S. Gagneux et al. titled “Variable host-pathogen compatibility in Mycobacterium tuberculosis” (19).

11. New York City study. The November 2002 issue of Emerging Infectious Diseases had an article by S. S. Munsiff et al. titled “Molecular epidemiology of multidrug-resistant tuberculosis, New York City, 1995–1997” (20). The 1 August 2003 issue of the Journal of Infectious Diseases had an article by S. S. Munsiff et al. titled “Persistence of a highly resistant strain of tuberculosis in New York City during 1990–1999” (21).

12. Strain W. The July 1999 issue of Clinical Infectious Diseases had an article (PDF format) by T. B. Agerton et al. titled “Spread of strain W, a highly drug-resistant strain of Mycobacterium tuberculosis, across the United States” (24). The August 2002 issue of Emerging Infectious Diseases had an article by J. R. Glynn et al. titled “Worldwide occurrence of Beijing/W strains of Mycobacterium tuberculosis: A systematic review.” The September 2004 issue of the Journal of Clinical Microbiology had an article by K. Kremer et al. titled “Definition of the Beijing/W lineage of Mycobacterium tuberculosis on the basis of genetic markers.”

13. Damian Gessler is at the National Center for Genome Resources, Santa Fe, NM. Christopher Dye is in the Stop TB Department, World Health Organization. Paul Farmer is in the Department of Social Medicine, Harvard Medical School, Boston. Megan Murray is in the Department of Epidemiology, Harvard School of Public Health, Boston. Thomas Navin and Thomas Shinnick are in the Division of Tuberculosis Elimination, Centers for Disease Control and Prevention. Randall Reves is at Denver Public Health, Denver Health and Hospital Authority. Peter M. Small is at the Institute for Systems Biology, Seattle, WA. Terry Yates is in the Department of Biology and the Museum of Southwestern Biology, University of New Mexico. Gary Simpson is at the New Mexico Department of Health.


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