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Clinical Investigations: INFECTION |

Value of Mycobacterium tuberculosis Fingerprinting as a Tool in a Rural State Surveillance Program* FREE TO VIEW

Kimberly G. Dobbs, MD; Kerry H. Lok, MD; Frank Bruce, BS; Donna Mulcahy, BS; William H. Benjamin, PhD; Nancy E. Dunlap, MD, PhD
Author and Funding Information

*From the Department of Internal Medicine (Dr. Dobbs), Division of Pulmonary, Allergy and Critical Care Medicine (Drs. Lok and Dunlap), and Department of Microbiology (Dr. Benjamin), University of Alabama at Birmingham, Birmingham; and Division of Tuberculosis Control (Mr. Bruce and Ms. Mulcahy), Department of Public Health, Montgomery, AL.

Correspondence to: Nancy E. Dunlap, MD, PhD, Professor of Medicine, 398 DREB, University of Alabama at Birmingham, Birmingham, AL 35294; e-mail: ndunlap@uabmc.edu



Chest. 2001;120(6):1877-1882. doi:10.1378/chest.120.6.1877
Text Size: A A A
Published online

Objective: This study demonstrates the value of Mycobacterium tuberculosis fingerprinting used in conjunction with traditional epidemiologic methods to identify smoldering outbreaks of tuberculosis in endemic areas where background rates of tuberculosis are high.

Methods: IS6110 DNA fingerprinting was performed on isolates of M tuberculosis from verified cases of tuberculosis in Alabama from 1994 to 1998. A statewide database groups isolates into“ clusters” and tracks them cumulatively over time. A large cluster was identified and was secondarily investigated using traditional epidemiologic methods.

Results: Twenty-five isolates were found to be identical by fingerprinting analysis. Patients were living within 10 counties across the state, and 12 cases were localized to a single county. This represented an ongoing, statewide tuberculosis outbreak previously unrecognized by local and state health officials. Secondary investigation of the cases revealed the primary sites of transmission to be a correctional facility and two homeless shelters.

Conclusions: Population surveillance using M tuberculosis fingerprinting was successfully utilized to detect a significant and smoldering tuberculosis outbreak. Measures are currently in place to identify and prevent further transmission in the involved locations.

Figures in this Article

Over the past 10 years, DNA fingerprinting has become an increasingly useful tool, when coupled with traditional epidemiologic methods, for the study of tuberculosis transmission. Numerous studies have illustrated the use of DNA fingerprinting inepidemic settings, both as an adjunct to the investigation of discrete outbreaks and as an indicator of recent transmission in populations with high case rates of tuberculosis.110 Few studies, however, have demonstrated the use of DNA fingerprinting in an endemic setting.11

Tuberculosis is endemic in Alabama. Although Alabama has a relatively low incidence of tuberculosis among known high-risk groups, such as foreign-born or HIV-positive individuals, in 1998 the annual case rate per 100,000 population was the sixth highest in the nation.12 Tuberculosis is scattered across the state, affecting all segments of the population (Fig 1 ). In populations such as ours where tuberculosis is endemic, there are many patients in whom reactivation tuberculosis develops several years after infection with the Mycobacterium tuberculosis organism. In this setting, recent transmission of tuberculosis may become obscured by the high background incidence of reactivation tuberculosis, thus escaping detection by traditional epidemiologic investigations. Surveillance using DNA fingerprinting serves as a useful tool to denote ongoing transmission of a single strain. This study describes the investigation of a statewide tuberculosis outbreak initially detected by routine surveillance using DNA fingerprint clustering.

Background

In 1998, Alabama had 8.8 cases of tuberculosis per 100,000 population, compared with an average national case rate of 6.8 per 100,000.12Although Alabama has demonstrated a progressive decrease in the annual case rates over the past decade, the magnitude of this decrease has been substantially less than that of other states. From 1992 to 1998, the national average number of reported cases decreased by 31%; however, the reported cases in Alabama decreased by only 9%.13This slow rate of decline is consistent with the intrinsic dynamics of endemic tuberculosis.14

Alabama is a predominantly rural state, with a population of approximately 4 million. From 1994 to 1998, the period investigated in this study, tuberculosis case rates in Alabama ranged from 8.8 to 10.6 per 100,000 population.15 Unlike most states with high case rates of tuberculosis, the age group with the highest percentage of cases in 1998 was the group aged ≥ 65 years. Furthermore, in 1998, only 5.8% of tuberculosis patients in Alabama were foreign born (US average, 41.3%); 12.9% of tuberculosis patients aged 25 to 45 years were HIV positive, and no tuberculosis cases were found to be multidrug resistant. Five percent of tuberculosis patients in 1998 were defined as homeless in the past year (US average, 6.3%).12 The lack of significant association of tuberculosis in Alabama with known risk factors, as evidenced by the preceding sociodemographic characteristics, creates a setting in which detection of ongoing transmission may be quite difficult.

Molecular Analysis

In Alabama, by law, all initial M tuberculosis cultures must be sent to the state laboratory for verification and susceptibility testing. Since January 1, 1994, isolates of all positive culture findings of verified cases of tuberculosis available to the state laboratory have been sent to the University of Alabama at Birmingham (UAB) for DNA fingerprinting. These isolates represent 80% of all tuberculosis cases within the state. Restriction fragment length polymorphism (RFLP) analysis using the mycobacterial insertion sequence IS6110 as a probe is performed on all viable samples by an internationally standardized method.16Films are subsequently scanned into a computerized database. The resulting DNA fingerprints are analyzed using Whole Band Analyzer, version 4.01 (Genomic Solution; Ann Arbor, MI), and clusters with identical patterns or patterns differing by one band are confirmed by visual inspection. Clusters that have low band numbers (five or fewer bands) as well as certain clusters that warrant further molecular characterization are subtyped using at least one polymerase chain reaction (PCR) method. The PCR methods that have been used for this purpose include spoligotyping in all cases and variable number tandem repeat typing when further characterization is desired, each performed according to previously published methods.1720

Laboratory cross-contamination is suspected when two specimens from different patients are processed in the same laboratory on the same day and yield identical DNA fingerprints. We monitor for statewide laboratory cross-contamination by checking culture dates and sites for all isolates with matching fingerprints. In addition, the possibility of laboratory cross-contamination is investigated when a patient produces a single isolate with low colony count (< 10) from a specimen that is negative for acid-fast bacilli on microscopy.21 Laboratory data are correlated with the patient’s clinical course, and isolates identified as contaminants are removed from our database.

Definition of Cluster

In this study, two or more M tuberculosis isolates from different patients were considered to be the same strain if DNA fingerprinting patterns with IS6110 revealed the following: (1) six or more fragments of identical size; (2) six or more fragments of identical size except one or two additional fragments, or one or two fragments of different size and identical patterns by secondary typing; or (3) five or fewer bands of identical size and identical patterns by secondary typing.8 Although this method is not exact and in some instances overestimates and in other instances underestimates the amount of true transmission, it was a practical definition given the large number of M tuberculosis isolates needing to be analyzed. Initial evaluation of DNA fingerprinting patterns was performed by individuals blinded to clinical information regarding the cases.

Surveillance Program in Alabama

A statewide DNA fingerprint database has been established based on IS6110 genotype; PCR-based secondary typing data are included as a separate variable. The DNA fingerprint database is maintained at UAB and contains the following information: patient demographics and residence, specimen collection site and date, drug susceptibilities, date sent to UAB, fingerprint characterization and cluster designation, and results from secondary typing methods. Matching fingerprints are grouped into clusters and tracked cumulatively over time. There is no time limitation for inclusion in a particular cluster. There are clusters that decrease over time or disappear from the population. Other clusters persist in the population and over time may represent ongoing transmission; from this group of persistent clusters, cases are chosen for secondary investigation as demonstrated by this study. Overall, since 1994, we have found a total of 119 clusters representing 47% of all fingerprinted isolates. Thirty-two clusters have had five or more cases since 1994. This study represents one of six clusters with ≥ 25 cases.

Identification of 12-Bander Cluster

Routine surveillance of cumulative DNA fingerprint data obtained from January 1994 through December 1998 identified a cluster of 27 isolates having a unique 12-band pattern by RFLP analysis with IS6110. Five isolates differed by one band. Spoligotyping was performed on genomic DNA derived from each of the 27 isolates and yielded identical fingerprints in 25 cases. Two of the five cases differing by one band by IS6110 RFLP analysis also demonstrated unique patterns by spoligotyping. These two strains did not meet cluster criteria and were therefore excluded from the investigation.

Data Collection

Once clustering was identified, records were obtained on the 25 patients from the Alabama case registry, maintained by the Alabama Department of Public Health. Initial data included information reported routinely such as county, date reported, age, sex, race, sputum smear results, homeless status, and drug sensitivities. Information obtained from this initial review of the records revealed a suspected focus of transmission in northeast Alabama, possibly involving the homeless population. As a result, we conducted a retrospective survey of the registries of the two local homeless shelters and the jail, focusing on the cluster cases. This aspect of the investigation was performed in conjunction with the local health department officials. Information on homeless status and time in jail from 1994 to 1998 was obtained on all but five individuals.

Data Analysis

The dates that the tuberculosis cases were reported ranged from April 1994 to July 1998. Ten counties across the state were involved, and 12 of the 25 cases (48%) were reported in Madison County (Fig 2 ). This represented a possible statewide outbreak previously unrecognized by local and state officials. Characteristics of the 25 patients in this cluster are presented in Table 1 .

Our investigation indicated that the primary sites of transmission appeared to be the Madison County jail and the two local homeless shelters (Fig 3 ). It is likely that spread of this strain of M tuberculosis originated in the Madison County homeless population, with secondary spread to the local community. Although six of the cluster case patients were incarcerated together in 1995, only three of these cases had been previously linked by local public health officials. Fifteen cases were directly linked to the jail, the homeless community, or their contacts. Four cases were linked to homeless communities in other cities, but no definite contact with the Madison County cases could be established. For six patients, no evidence of epidemiologic linkage with the cluster cases could be identified. As a result of the newly recognized extent of ongoing tuberculosis transmission, local health officials have initiated targeted screening of the homeless and jail populations in this community to identify and treat those with latent tuberculosis infection and disease.

To our knowledge, this is the first report from a largely rural state with a high rate of endemic disease demonstrating an ongoing statewide outbreak of tuberculosis initially detected by routine surveillance using molecular epidemiologic techniques. Other similar but more focal outbreaks have been detected in Alabama since implementation of DNA fingerprinting as part of the statewide surveillance strategy in 1994. The outbreak investigated in this study involved 10 counties with a statewide distribution; however, as previously stated, a substantial number of cases were localized to northeast Alabama (Fig 2). Why then were the local health officials in this area unaware of such significant ongoing transmission? One reason is that the cases were distributed over a 5-year period, thereby decreasing the likelihood that traditional information gathering techniques would detect epidemiologic associations among the involved patients.

In addition, 14 of the 25 patients (56%) had been homeless at some point during the past 6 years. Studies in urban centers with large homeless populations have shown that conventional contact investigations among the homeless often fail to detect clustered patients, perhaps because contacts in this setting are frequently multiple and transient.89 Given the inherent difficulties of establishing epidemiologic associations in this setting, information provided by molecular techniques yielded an important clue to the presence of this ongoing outbreak.

Several interesting points are suggested by this study. First of all, initial review of patient records indicated that only seven patients had been homeless within the past 1 year. This information was obtained from official patient records (report of verified case of tuberculosis), completed according to Centers for Disease Control and Prevention guidelines that limit the definition of “homeless” to 1 year. However, when further investigation of the cluster cases was pursued, 14 patients were found to have been homeless during the past 6 years. Because tuberculosis infection can persist in an individual without detection for many years, it is imperative to identify known risk factors for transmission such as homelessness, even if this occurred longer than 1 year prior to clinical detection of disease.

DNA fingerprinting provides valuable information for a statewide surveillance program in an area in which tuberculosis is endemic. However, when using clustering of tuberculosis fingerprints to identify ongoing, smoldering outbreaks, the definition of clustering must not specify a time limitation. In a recent analysis of tuberculosis trends in San Francisco, Jasmer et al22limited the definition of clustering to 1 year. However, like our program, van Soolingen et al23 placed no time limitation on clustering in a study of tuberculosis trends in the Netherlands. Because transmission of tuberculosis may have occurred recently or more remotely, we feel that limiting the definition of clustering to 1 year would result in a substantial number of missed associations. Such associations might elucidate important sites of ongoing tuberculosis transmission as indicated by this study. For example, if the definition of cluster were limited to 1 year in this study, only one of the three cases linked to the jail outbreak by DNA fingerprinting would have been identified (Fig 3). Furthermore, evidence linking this strain throughout the homeless population would have been missed, and the overall extent of this outbreak would have been vastly underestimated. Not only is the tracking of clusters over time useful on a statewide basis, but transmission across state borders may also be elucidated. Recently, three individuals in West Virginia were found to have the same DNA fingerprint as the cluster in this study; furthermore, these individuals are known to be homeless. Further investigation of this situation is currently in progress.

DNA fingerprinting of M tuberculosis can signal outbreaks within a population, but traditional epidemiologic techniques must be employed to identify specific connections between individuals or sites of transmission. And once smoldering outbreaks are identified, traditional and innovative public health measures must be employed to eliminate ongoing transmission. For example, in homeless shelters air sterilization with ultraviolet lights, improved ventilation, and spot sputum screening of clients have resulted in dramatic decreases in tuberculosis cases in some areas.24

In the United States, intensified public health measures, improved living conditions, and more efficacious chemotherapeutic agents have effected a substantial decline in tuberculosis case rates over the past 4 decades. Nevertheless, > 1,000 deaths per year in the United States can be attributed to this essentially treatable, preventable disease.12 As case rates of tuberculosis continue to decline, the public health resources directed to the control of tuberculosis decrease. If background rates of reactivation tuberculosis remain high, it will become increasingly difficult to recognize ongoing, smoldering outbreaks when public health resources are redirected. In endemic areas such as Alabama, new tools and strategies are required if we are to eliminate tuberculosis (defined as less than one case per 1 million population per year).25

From 1994 to 1998, the time period addressed in this investigation, patients in 94.6% of cases in Alabama completed therapy in 12 months, and 94.2% of sputum culture-positive patients converted to sputum-culture negative 3 months after initiating therapy. An average of 10 contacts were identified for each tuberculosis case patient, and 80.4% of all patients started on preventive therapy with isoniazid completed at least 6 months of treatment. Despite such outstanding indicators of program performance, the rate of decline in tuberculosis case rates has lagged behind the rest of the nation,13 thus demonstrating the need for improved strategies to control endemic tuberculosis.

If we are to eliminate tuberculosis from endemic regions of this country, as advocated by the Institute of Medicine in its 2000 report entitled, “Ending Neglect: The Elimination of Tuberculosis in the United States,”26 we must better understand the local epidemiology and transmission patterns of tuberculosis. Conventional epidemiologic methods are not adequate as demonstrated by this study. New tools must be adopted. Fingerprinting of M tuberculosis is one such tool, but it is only useful for surveillance if a large percentage of cultures are available for analysis. As more, large, regional reference laboratories are established, specimens are increasingly sent out of state for processing. Public health policies need to be established that require that positive M tuberculosis culture findings are returned to the patient’s state of residence so that fingerprinting of the isolates can be performed.

In summary, in an area in which tuberculosis is endemic, small foci of ongoing transmission may be missed by traditional epidemiologic techniques. Such microepidemics can then persist unrecognized in a community for months or years, as was the case in our study. This study demonstrates the effective use of DNA fingerprinting as part of a multifaceted control strategy to identify ongoing transmission of tuberculosis in an endemic setting.

Abbreviations: PCR = polymerase chain reaction; RFLP = restriction fragment length polymorphism; UAB = University of Alabama at Birmingham

Figure Jump LinkFigure 1. Distribution of tuberculosis cases in Alabama in 1998.Grahic Jump Location
Figure Jump LinkFigure 2. Distribution of cases included in the 12-bander cluster from 1994 to 1998Grahic Jump Location
Table Graphic Jump Location
Table 1. Characteristics of Cluster Patients
Figure Jump LinkFigure 3. Timeline indicating when the diagnosis of tuberculosis was made for each patient in the cluster. Homeless individuals have a triangle (Madison County), circle (Birmingham), square (Montgomery), or hexagon (Mobile) depending on the city of their homelessness. Cases that were linked through contact with a patient in the Madison County Jail are indicated by a solid line. Cases that were linked through a contact investigation are indicated by a dotted line.Grahic Jump Location
Jereb, JA, Burwen, DR, Dooley, SW, et al (1993) Nosocomial outbreak of tuberculosis in a renal transplant unit: application of a new technique for restriction fragment length polymorphism analysis ofMycobacterium tuberculosisisolates.J Infect Dis168,1219-1224. [PubMed] [CrossRef]
 
Griffith, DE, Hardeman, JL, Zhang, Y, et al Tuberculosis outbreak among healthcare workers in a community hospital.Am J Respir Crit Care Med1995;152,808-811. [PubMed]
 
Coronado, VG, Beck-Sague, CM, Hutton, MD, et al Transmission of multidrug-resistantMycobacterium tuberculosisamong persons with human immunodeficiency virus infection in an urban hospital: epidemiologic and restriction fragment length polymorphism analysis.J Infect Dis1993;168,1052-1055. [PubMed]
 
Ritacco, V, Di Lonardo, M, Reniero, A, et al Nosocomial spread of human immunodeficiency virus-related multidrug-resistant tuberculosis in Buenos Aires.J Infect Dis1997;176,637-642. [PubMed]
 
Tuberculosis outbreaks in prison housing units for HIV-infected inmates–California, 1995–1996. MMWR Morb Mortal Wkly Rep 1999; 48:79–82.
 
Transmission of multidrug-resistant tuberculosis among immunocompromised persons in a correctional system–New York, 1991. MMWR Morb Mortal Wkly Rep 1992; 41:507–509.
 
Valway, SE, Greifinger, RB, Papania, M, et al Multidrug-resistant tuberculosis in the New York State prison system, 1990–1991.J Infect Dis1994;170,151-156. [PubMed]
 
Barnes, PF, Yang, Z, Preston-Martin, S, et al Patterns of tuberculosis transmission in Central Los Angeles.JAMA1997;278,1159-1163. [PubMed]
 
Small, PM, Hopewell, PC, Singh, SP, et al The epidemiology of tuberculosis in San Francisco: a population-based study using conventional and molecular methods.N Engl J Med1994;330,1703-1709. [PubMed]
 
Alland, D, Kalkut, GE, Moss, AR, et al Transmission of tuberculosis in New York City: an analysis by DNA fingerprinting and conventional epidemiologic methods.N Engl J Med1994;330,1710-1716. [PubMed]
 
Chevrel-Dellagi, D, Abderrahman, A, Haltiti, R, et al Large-scale DNA fingerprinting ofMycobacterium tuberculosisstrains as a tool for epidemiological studies of tuberculosis.J Clin Microbiol1993;31,2446-2450. [PubMed]
 
Reported tuberculosis in the United States, 1998. Atlanta, GA: Centers for Disease Control and Prevention, August 1999.
 
Progress toward the elimination of tuberculosis–United States, 1998. MMWR Morb Mortal Wkly Rep 1999; 48:732–736.
 
Blower, SM, McLean, AR, Porco, TC, et al The intrinsic transmission dynamics of tuberculosis epidemics.Nature Med1995;1,815-821. [PubMed]
 
Reported tuberculosis in the United States, 1994–1998. Atlanta GA: Centers for Disease Control and Prevention, 1999.
 
van Embden, JD, Cave, MD, Crawford, JT, et al Strain identification ofMycobacterium tuberculosisby DNA fingerprinting: recommendations for a standardized methodologyJ Clin Microbiol1993;31,406-409. [PubMed]
 
Kamerbeek, J, Schouls, L, Kolk, A, et al Simultaneous detection and strain differentiation ofMycobacterium tuberculosisfor diagnosis and epidemiology.J Clin Microbiol1997;35,907-914. [PubMed]
 
Aranaz, A, Liebana, E, Mateos, A, et al Spacer oligonucleotide typing ofMycobacterium bovisstrains from cattle and other animals: a tool for studying epidemiology of tuberculosis.J Clin Microbiol1996;34,2734-2740. [PubMed]
 
Frothingham, R, Meeker-O’Connell, WA Genetic diversity in theMycobacterium tuberculosiscomplex based on variable numbers of tandem DNA repeatsMicrobiology1998;144(pt 5),1189-1196. [PubMed]
 
Kremer, K, van Soolingen, D, Frothingham, R, et al Comparison of methods based on different molecular epidemiological markers for typing ofMycobacterium tuberculosiscomplex strains: interlaboratory study of discriminatory power and reproducibility.J Clin Microbiol1999;37,2607-2618. [PubMed]
 
Dunlap, N, Harris, RH, Benjamin, WH, Jr, et al Laboratory contamination ofMycobacterium tuberculosiscultures.Am J Respir Crit Care Med1995;152,1702-1704. [PubMed]
 
Jasmer, RM, Hahn, JA, Small, PM, et al A molecular epidemiologic analysis of tuberculosis trends in San Francisco, 1991–1997.Ann Intern Med1999;130,971-978. [PubMed]
 
van Soolingen, D, Borgdorff, MW, de Haas, P, et al Molecular epidemiology of tuberculosis in the Netherlands: a nationwide study from 1993 through 1997J Infect Dis1999;180,726-736. [PubMed]
 
Kimerling, ME, Shakes, CF, Carlisle, R, et al Spot sputum screening: evaluation of an intervention in two homeless shelters.Int J Tuberc Lung Dis1999;3,613-619. [PubMed]
 
A strategic plan for the elimination of tuberculosis in the United States. MMWR Morb Mortal Wkly Rep 1989; 38:269–272.
 
Geiter, L. Institute of Medicine (US) Committee on the Elimination of Tuberculosis in the United States. Ending neglect: the elimination of tuberculosis in the United States. 2000; National Academy Press. Washington, DC:.
 

Figures

Figure Jump LinkFigure 1. Distribution of tuberculosis cases in Alabama in 1998.Grahic Jump Location
Figure Jump LinkFigure 2. Distribution of cases included in the 12-bander cluster from 1994 to 1998Grahic Jump Location
Figure Jump LinkFigure 3. Timeline indicating when the diagnosis of tuberculosis was made for each patient in the cluster. Homeless individuals have a triangle (Madison County), circle (Birmingham), square (Montgomery), or hexagon (Mobile) depending on the city of their homelessness. Cases that were linked through contact with a patient in the Madison County Jail are indicated by a solid line. Cases that were linked through a contact investigation are indicated by a dotted line.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Characteristics of Cluster Patients

References

Jereb, JA, Burwen, DR, Dooley, SW, et al (1993) Nosocomial outbreak of tuberculosis in a renal transplant unit: application of a new technique for restriction fragment length polymorphism analysis ofMycobacterium tuberculosisisolates.J Infect Dis168,1219-1224. [PubMed] [CrossRef]
 
Griffith, DE, Hardeman, JL, Zhang, Y, et al Tuberculosis outbreak among healthcare workers in a community hospital.Am J Respir Crit Care Med1995;152,808-811. [PubMed]
 
Coronado, VG, Beck-Sague, CM, Hutton, MD, et al Transmission of multidrug-resistantMycobacterium tuberculosisamong persons with human immunodeficiency virus infection in an urban hospital: epidemiologic and restriction fragment length polymorphism analysis.J Infect Dis1993;168,1052-1055. [PubMed]
 
Ritacco, V, Di Lonardo, M, Reniero, A, et al Nosocomial spread of human immunodeficiency virus-related multidrug-resistant tuberculosis in Buenos Aires.J Infect Dis1997;176,637-642. [PubMed]
 
Tuberculosis outbreaks in prison housing units for HIV-infected inmates–California, 1995–1996. MMWR Morb Mortal Wkly Rep 1999; 48:79–82.
 
Transmission of multidrug-resistant tuberculosis among immunocompromised persons in a correctional system–New York, 1991. MMWR Morb Mortal Wkly Rep 1992; 41:507–509.
 
Valway, SE, Greifinger, RB, Papania, M, et al Multidrug-resistant tuberculosis in the New York State prison system, 1990–1991.J Infect Dis1994;170,151-156. [PubMed]
 
Barnes, PF, Yang, Z, Preston-Martin, S, et al Patterns of tuberculosis transmission in Central Los Angeles.JAMA1997;278,1159-1163. [PubMed]
 
Small, PM, Hopewell, PC, Singh, SP, et al The epidemiology of tuberculosis in San Francisco: a population-based study using conventional and molecular methods.N Engl J Med1994;330,1703-1709. [PubMed]
 
Alland, D, Kalkut, GE, Moss, AR, et al Transmission of tuberculosis in New York City: an analysis by DNA fingerprinting and conventional epidemiologic methods.N Engl J Med1994;330,1710-1716. [PubMed]
 
Chevrel-Dellagi, D, Abderrahman, A, Haltiti, R, et al Large-scale DNA fingerprinting ofMycobacterium tuberculosisstrains as a tool for epidemiological studies of tuberculosis.J Clin Microbiol1993;31,2446-2450. [PubMed]
 
Reported tuberculosis in the United States, 1998. Atlanta, GA: Centers for Disease Control and Prevention, August 1999.
 
Progress toward the elimination of tuberculosis–United States, 1998. MMWR Morb Mortal Wkly Rep 1999; 48:732–736.
 
Blower, SM, McLean, AR, Porco, TC, et al The intrinsic transmission dynamics of tuberculosis epidemics.Nature Med1995;1,815-821. [PubMed]
 
Reported tuberculosis in the United States, 1994–1998. Atlanta GA: Centers for Disease Control and Prevention, 1999.
 
van Embden, JD, Cave, MD, Crawford, JT, et al Strain identification ofMycobacterium tuberculosisby DNA fingerprinting: recommendations for a standardized methodologyJ Clin Microbiol1993;31,406-409. [PubMed]
 
Kamerbeek, J, Schouls, L, Kolk, A, et al Simultaneous detection and strain differentiation ofMycobacterium tuberculosisfor diagnosis and epidemiology.J Clin Microbiol1997;35,907-914. [PubMed]
 
Aranaz, A, Liebana, E, Mateos, A, et al Spacer oligonucleotide typing ofMycobacterium bovisstrains from cattle and other animals: a tool for studying epidemiology of tuberculosis.J Clin Microbiol1996;34,2734-2740. [PubMed]
 
Frothingham, R, Meeker-O’Connell, WA Genetic diversity in theMycobacterium tuberculosiscomplex based on variable numbers of tandem DNA repeatsMicrobiology1998;144(pt 5),1189-1196. [PubMed]
 
Kremer, K, van Soolingen, D, Frothingham, R, et al Comparison of methods based on different molecular epidemiological markers for typing ofMycobacterium tuberculosiscomplex strains: interlaboratory study of discriminatory power and reproducibility.J Clin Microbiol1999;37,2607-2618. [PubMed]
 
Dunlap, N, Harris, RH, Benjamin, WH, Jr, et al Laboratory contamination ofMycobacterium tuberculosiscultures.Am J Respir Crit Care Med1995;152,1702-1704. [PubMed]
 
Jasmer, RM, Hahn, JA, Small, PM, et al A molecular epidemiologic analysis of tuberculosis trends in San Francisco, 1991–1997.Ann Intern Med1999;130,971-978. [PubMed]
 
van Soolingen, D, Borgdorff, MW, de Haas, P, et al Molecular epidemiology of tuberculosis in the Netherlands: a nationwide study from 1993 through 1997J Infect Dis1999;180,726-736. [PubMed]
 
Kimerling, ME, Shakes, CF, Carlisle, R, et al Spot sputum screening: evaluation of an intervention in two homeless shelters.Int J Tuberc Lung Dis1999;3,613-619. [PubMed]
 
A strategic plan for the elimination of tuberculosis in the United States. MMWR Morb Mortal Wkly Rep 1989; 38:269–272.
 
Geiter, L. Institute of Medicine (US) Committee on the Elimination of Tuberculosis in the United States. Ending neglect: the elimination of tuberculosis in the United States. 2000; National Academy Press. Washington, DC:.
 
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