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Genotype analysis of Mycobacterium tuberculosis isolates from a sentinel surveillance population. (Tuberculosis Genotyping Network).

As part of the National Tuberculosis tuberculosis (TB), contagious, wasting disease caused by any of several mycobacteria. The most common form of the disease is tuberculosis of the lungs (pulmonary consumption, or phthisis), but the intestines, bones and joints, the skin, and the genitourinary,  and Genotyping Genotyping refers to the process of determining the genotype of an individual with a biological assay. Current methods of doing this include PCR, DNA sequencing, and hybridization to DNA microarrays or beads.  Surveillance Network, isolates obtained from all new cases of tuberculosis occurring in seven geographically separate surveillance sites from 1996 through 2000 were genotyped. A total of 10,883 isolates were fingerprinted by the IS6110-restriction fragment length polymorphism polymorphism, of minerals, property of crystallizing in two or more distinct forms. Calcium carbonate is dimorphous (two forms), crystallizing as calcite or aragonite. Titanium dioxide is trimorphous; its three forms are brookite, anatase (or octahedrite), and rutile.  method, yielding 6,128 distinct patterns. Low-copy isolates (those with six or fewer bands) were also spoligotyped. The distribution of specific genotype genotype (jēn`ətīp'): see genetics.

Genetic makeup of an organism. The genotype determines the hereditary potentials and limitations of an individual.
 clusters was examined. Databases were also examined for families of related genotypes. Analysis of IS6110 patterns showed 497 patterns related to the W-Beijing family; these pattens represent 946 (9%) of all isolates in the study. Six new sets of related fingerprint fingerprint, an impression of the underside of the end of a finger or thumb, used for identification because the arrangement of ridges in any fingerprint is thought to be unique and permanent with each person (no two persons having the same prints have ever been  patterns were also proposed for isolates containing 6-15 copies of IS6110. These fingerprint sets contain up to 251 patterns and 414 isolates; together, they contain 21% of isolates in this copy number range. These sets of fingerprints Impressions or reproductions of the distinctive pattern of lines and grooves on the skin of human fingertips.

Fingerprints are reproduced by pressing a person's fingertips into ink and then onto a piece of paper.
 may represent endemic endemic /en·dem·ic/ (en-dem´ik) present or usually prevalent in a population at all times.

 strains distributed across the United States United States, officially United States of America, republic (2005 est. pop. 295,734,000), 3,539,227 sq mi (9,166,598 sq km), North America. The United States is the world's third largest country in population and the fourth largest country in area. .


The National Tuberculosis Genotyping and Surveillance Network was created by the Centers for Disease Control and Prevention Centers for Disease Control and Prevention (CDC), agency of the U.S. Public Health Service since 1973, with headquarters in Atlanta; it was established in 1946 as the Communicable Disease Center.  (CDC See Control Data, century date change and Back Orifice.

CDC - Control Data Corporation
) to determine the relative frequency of Mycobacterium tuberculosis Mycobacterium tuberculosis
Tubercic bacillus.

Mycobacterium tuberculosis
 strains in specific geographic areas, the extent of spread of related strains in communities, and the impact of IS6110 fingerprinting fingerprinting

Act of taking an impression of a person's fingerprint. Because each person's fingerprints are unique, fingerprinting is used as a method of identification, especially in police investigations.
 on tuberculosis (TB) control. From 1996 through 2000, the TB genotyping network laboratories fingerprinted 10,883 isolates (one isolate per newly diagnosed case of TB) from seven sentinel sentinel /sen·ti·nel/ (sen´ti-n'l) one who gives a warning or indicates danger.


a recording mechanism, such as an animal, a farm or a veterinarian, posted explicitly to record a possible occurrence or series of
 surveillance sites in the United States: the states of Arkansas, Maryland, Massachusetts, Michigan, and New Jersey, along with four counties in Texas and six counties in California The U.S. state of California is divided into fifty-eight counties. Counties are responsible for all elections, property-tax collection, maintenance of public records such as deeds, and local-level courts within their borders, as well as providing law enforcement (through the county . Key components of the project included the establishment of standard methods and use of specialized spe·cial·ize  
v. spe·cial·ized, spe·cial·iz·ing, spe·cial·iz·es

1. To pursue a special activity, occupation, or field of study.

 software, the Biolmage Whole Band Analyzer analyzer /ana·ly·zer/ (an´ah-li?zer)
1. a Nicol prism attached to a polarizing apparatus which extinguishes the ray of light polarized by the polarizer.

 version 3.4 (Biolmage, Ann Arbor Ann Arbor, city (1990 pop. 109,592), seat of Washtenaw co., S Mich., on the Huron River; inc. 1851. It is a research and educational center, with a large number of government and industrial research and development firms, many in high-technology fields such as , MI), for pattern analysis. The following were created as part of this study: databases containing the images of IS6110 patterns for all isolates at each sentinel surveillance site; a network database that includes all distinct spoligotype patterns; and an epidemiologic ep·i·de·mi·ol·o·gy  
The branch of medicine that deals with the study of the causes, distribution, and control of disease in populations.

[Medieval Latin epid
 database (EpiInfo) for information about sentinel surveillance site, case report date, IS6110 pattern designation, and secondary typing results for each patient. The final network database of fingerprints contains 6,128 patterns.

We report here an overview of the contents of the TB genotyping network fingerprint database, including the distribution of isolates at sentinel surveillance sites, genotype patterns that occurred with high frequency, the extent of previously described genotype families, and new families of related fingerprints. This analysis should not be considered exhaustive but rather a summary of our observations and an introduction to the types of data that can be derived.


Methods for IS6110 fingerprinting, spoligotyping, and compiling the network databases are described elsewhere (1). The distribution of isolates by sentinel surveillance site, fingerprint pattern, and spoligotype (for isolates with six or fewer copies of IS6110) was derived from the Epi Info Epi Info is a public domain statistical software for epidemiology developed by Centers for Disease Control and Prevention.

Developed by the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia (USA), Epi Info has been in existence for over 20 years and is
 database. The spoligotype patterns are reported in octal A numbering system that uses eight digits. It is used as a shorthand method for representing binary characters that use six-bits. Each three bits (half a character) is converted into a single octal digit. Okta is Greek for 8.  code by the convention previously described (2). IS6110 fingerprint patterns start with the prefix The beginning or to add to the beginning. To prefix a header onto a packet means to place the header characters in front of the packet. "To prefix" at the beginning is the opposite of "to append" characters at the end. See prepend.

 FP and spoligotype patterns with SP.

We used the BioImage Whole Band Analyzer software package version 3.4 to analyze fingerprint patterns in the genotyping network fingerprint database. The bands in two patterns were compared at two levels. First, bands in two patterns were identified as matched bands if the size of the bands differed by <2.5%. Next, the interband spacing between matched bands in the two patterns was compared; a limit of 95% for variation in interband spacing was used. The Jaccard coefficient coefficient /co·ef·fi·cient/ (ko?ah-fish´int)
1. an expression of the change or effect produced by variation in certain factors, or of the ratio between two different quantities.

 of similarity between two patterns, A and B, was used to calculate the percentage match between two patterns: 100 x number of matched bands/(number bands in A + number bands in B - number of matched bands).

Results and Discussion

Isolates from 10,883 patients from seven sentinel surveillance sites were fingerprinted by using the IS6110 restriction fragment length polymorphism restriction fragment length polymorphism
n. Abbr. RFLP
Intraspecies variations in the length of DNA fragments generated by the action of restriction enzymes and caused by mutations that alter the sites at which these enzymes act, changing
restriction fragment length polymorphism


restriction fragment length polymorphism.

) method: Arkansas, 709; California, 2,514; Massachusetts, 986; Maryland, 1,180; Michigan, 1,471; New Jersey, 2,113; and Texas, 1,910. From these isolates, 6,128 distinct fingerprint patterns were identified and included in the final genotyping network database. Analysis of the IS6110 copy number of the isolates confirmed the previously described bimodal distribution bimodal distribution

a distribution with two peaks separated by a region of low frequency of observations.
 (Figure 1) (3). This distribution has been used to separate isolates of M. tuberculosis M. tuberculosis,
n the bacterium responsible for tuberculosis, generally a respiratory infection in man; nonrespiratory tuberculosis is considered an indicator disease for AIDS. See also tuberculosis.
 into two groups: isolates with six or fewer copies of IS6110 are classified as low-copy isolates and those with more than six copies as high-copy isolates. The greatest numbers of patterns occurred in the 9-14 copy-number range (Figure 1). Clustering of isolates on the basis of matching fingerprint patterns is summarized in Table 1. Clustering was very high among the low-copy isolates, which supports the requirement for secondary typing of these isolates. Clustering decreased with increasing copy number; copy numbers 21 and 22, which included large outbreaks, were the exceptions.


High-Copy Isolates

The 8,245 isolates with more than six copies of IS6110 yielded 5,640 fingerprint patterns. Of these patterns, 4,846 (85.9%) were identified for a single isolate, and 3,399 isolates were grouped into 794 fingerprint-defined clusters. Of these clusters, 557 contained isolates from a single site. The clusters contained up to 105 isolates, but 683 (86.0%) of the clusters contained only two to five isolates. In fact, only 18 clusters contained 20 or more isolates. The distribution of isolates in these 18 clusters is shown in Table 2, and the fingerprint patterns are shown in Figure 2. For 11 of the 18 largest clusters, [greater than or equal to] 90% of the isolates in the cluster were from a single site.


One of the largest clusters (FP 00237, 100 isolates) corresponds to M. tuberculosis strain 210, a member of the W-Beijing family that was shown in previous studies to be disseminated disseminated /dis·sem·i·nat·ed/ (-sem´i-nat?ed) scattered; distributed over a considerable area.

Spread over a large area of a body, a tissue, or an organ.
 across the United States (3). In the network, FP 00237 was associated with large clusters in Arkansas and Texas and was also reported by Maryland and New Jersey. Two additional patterns associated with large clusters, FP 00027 (102 isolates in Michigan) and FP 01284 (46 isolates in Texas), were similar to FP 00237. The Beijing family of strains has received considerable attention because of its association with several large outbreaks, frequent association with multidrug resistance multidrug resistance,
n the adaptation of tumor cells or infectious agents to resist chemotherapeutic agents.
, and emergence in selected populations, particularly in the former Soviet Union (4,5). All Beijing isolates share a characteristic spoligotype (000000000003771); however, in this study, spoligotyping was not performed for high-copy isolates. Other molecular criteria that define W-Beijing strains include insertions of IS6110 in the dnaA-dnaN region (A1 insertion) and in the NTF NTF No Transaction Fee
NTF National Turkey Federation
NTF No Trouble Found
NTF National Transfer Format (UK Geographic Data Standard) aka BS7567
NTF Nigeria Trust Fund
NTF National Transonic Facility
NTF Noise Transfer Function
 region and an empirical fingerprint pattern that contains 15 to 24 bands and is similar to that of strain W (4). To estimate the occurrence of Beijing isolates in our study, all patterns with 16 to 24 bands were visually compared to FP 00237. The W fingerprint was easily identified among the patterns with 17 or more bands; however, we were less confident about identifying it in those with 16 bands and did not include them in this analysis. Of the 688 patterns analyzed an·a·lyze  
tr.v. an·a·lyzed, an·a·lyz·ing, an·a·lyz·es
1. To examine methodically by separating into parts and studying their interrelations.

2. Chemistry To make a chemical analysis of.

, 497 (72.2%) were similar to FP 00237. Examples can be seen in Figure 3. Nearly all of the individual patterns, 480 (97%), were reported by a single site. These 497 patterns represent 946 isolates, 82% of all isolates with [greater than or equal to] 17 copies of IS6110 and 9% of all isolates in the study (Arkansas 3%; Maryland, 4%; New Jersey, 7%; Massachusetts, 9%; and California, Michigan, and Texas, 11%). The distribution of these isolates by site is reported in Table 3.


Because only one of the molecular criteria (overall fingerprint pattern) could be applied, isolates with these patterns cannot be definitively called W-Beijing. Ali of the insertion sites in strain 210, FP 00237, have been defined by sequencing (6). To identify conserved insertion sites, we determined the percentage of the 497 patterns that contained each of the bands in FP 00237 (Figure 4). Nine bands were found in >50% of the patterns, and two were present in >85%. A common feature of these fingerprint patterns is a group of smaller bands (1.0 to 1.5 kb) that are difficult to resolve. Variation in band identification resulted in some of the heterogeneity het·er·o·ge·ne·i·ty
The quality or state of being heterogeneous.


the state of being heterogeneous.
 of the patterns in the database. W-Beijing strains likely account for a large portion of Beijing isolates, but other Beijing strains exist. FP 00242 (reported for 96 isolates in Texas; fingerprint pattern shown in Figure 2) shares only a few bands with FP 00237, but isolates with this pattern have the Beijing spoligotype (Teresa Quitugua, pets. comm.).


To identify other large families in the database, we analyzed all patterns having 6 to 15 bands (4,846 patterns). Since the BioImage software cannot create a dendrogram A dendrogram is a tree diagram frequently used to illustrate the arrangement of the clusters produced by a clustering algorithm (see cluster analysis). Dendrograms are often used in computational biology to illustrate the clustering of genes.  for more than 1,250 patterns, patterns were compared to each other by using an arbitrarily chosen matching threshold of 50% to identify those that matched a large number of other patterns. For a 50% match, two thirds of the bands in two patterns with equal band number must match. Six sets of related fingerprints, designated A through F, were defined; each consisted of six prototype patterns A prototype pattern is a creational design pattern used in software development when the type of objects to create is determined by a prototypical instance, which is cloned to produce new objects.  (Figure 5) along with all of the patterns that matched the prototypes. Data on these sets are summarized in Table 3. The isolates in each set appear widely dispersed dis·perse  
v. dis·persed, dis·pers·ing, dis·pers·es
a. To drive off or scatter in different directions: The police dispersed the crowd.

 across the sites, and the patterns likely represent endemic strains in the United States. Key bands in each set were determined in comparison to the common bands in the prototype patterns as described above for FP 00237 (Figure 4). Sequencing the IS6110 insertion sites corresponding to these key bands would allow isolates belonging to these sets to be rapidly identified with microarray See micro array.

microarray - A technique for performing many DNA experiments in parallel. Nothing to do with computers.
 techniques or the reverse dot-blot ("insite") assay we have described previously (7).


The sets described here are certainly not the only sets of related patterns in the database, nor are they necessarily novel. The patterns in set A are similar to the patterns for M. tuberculosis strains H37Rv and H37Ra (8); the eight common bands in the prototype patterns for set A are also found in the patterns for these two laboratory strains. The patterns in set D appear similar to those of the Haarlem family (9). Interestingly, 1,404 (29.0%) of the patterns with 6 to 15 bands did not match any other pattern at the 50% matching threshold, suggesting a substantial number of orphan orphan: see adoption; foundling hospital; guardian and ward.

See widow & orphan.
See also Abandonment.

Adverse, Anthony

finally, at middle age, discovers origins. [Am. Lit.
 strains in this study.

Low-Copy Isolates

Of the 457 fingerprint patterns identified among the 2,507 low-copy isolates, 314 (68.7%) were reported for a single isolate, and 143 patterns grouped 2,193 isolates into clusters. Clustering was much higher in low-copy isolates (87.5%) than in high-copy isolates (41.2%). Most isolates were in a few large clusters; 14 clusters contained 1,601 (63.9%) low-copy isolates. The distribution of isolates in the largest clusters across the sentinel surveillance sites is shown in Table 4, and the fingerprint patterns are shown in Figure 6.


Spoligotype results were available for most low-copy isolates (2,507 of 2,638 isolates). Isolates collected in Arkansas before 1998 were not spoligotyped (97 of 210 isolates) nor were most isolates collected in Maryland before 1998 that had unique fingerprint patterns (23 of 323 isolates). Of the 495 spoligotypes identified among the low-copy isolates, 322 were reported for a single isolate, and 173 grouped 2,185 isolates into clusters. In this study, the clustering of low-copy isolates by spoligotyping (87.2%) was only slightly lower than clustering by fingerprinting (87.5%). Analysis of the isolates by IS6110 copy number showed that spoligotyping performed better than fingerprinting only for those isolates with fewer than four copies of IS6110 (data not shown). Similar to the results obtained with fingerprinting, most isolates are in large clusters; 1,481 isolates are in the 20 largest clusters. The spoligotypes for these clusters as well as the distribution of these isolates by site and IS6110 copy number are listed in Table 5.

Neither fingerprinting nor spoligotyping provided great discriminatory dis·crim·i·na·to·ry  
1. Marked by or showing prejudice; biased.

2. Making distinctions.

 power among low-copy isolates, but the combination of the two methods gave slightly better results. The number of spoligotypes identified per fingerprint pattern ranged from 1-92 spoligotypes, and the number of fingerprint patterns identified per spoligotype ranged from 1-77 patterns. Combining the fingerprinting and spoligotyping data resulted in the identification of 987 distinct genotypes; 745 genotypes were unique, and 242 grouped 1,762 isolates into clusters. These genotype clusters contained up to 167 isolates. Performing the secondary typing method decreased the number of clustered isolates by nearly 20%, but clustering was still much higher among the low-copy isolates (70.2%) than among the high-copy isolates (41.2%).

In our recent study of low-copy isolates from Michigan, we noted numerous patterns with similarities to FP 00017 (10). In this study, 201 isolates from all seven sites had FP 00017. When the three lower bands (1.39, 2.32, and 3.03 kb) in FP 00017 were matched to all patterns having three to six bands, 54 patterns representing 411 isolates were identified. The distribution of these isolates by site can be seen in Table 3. Of note, M. tuberculosis strain CDC1551 has FP 00017 (11), but none of the study isolates with this fingerprint had the spoligotype corresponding to strain CDC1551 (7000767577 60771).

Spoligotypes have been divided into clades or families on the basis of commonly observed motifs (Figure 7) (12). First, spoligotypes can be subdivided on the basis of spacers 33-36. Only M. tuberculosis complex genotypic genotypic

emanating from or pertaining to genotype.

genotypic selection
selection of breeding stock on the basis of known inherited characteristics.
 group 1 strains (M. bovis, M. africanum, and some M. tuberculosis strains) have spacers 33-36 (13,14). Four spoligotype motifs have been identified among group 1 isolates: bovis (15), africanum (16), Beijing (5), and East African-Indian (EA-I) (12,17) (Figure 7). The remaining spoligotypes that lack spacers 33-36 can be subdivided into two subgroups on the basis of spacers 29-32. Isolates with at least one of spacers 29-32 are likely to be isolates in M. tuberculosis genotypic groups 2 or 3. Isolates without spacers 29-32 have a deletion deletion /de·le·tion/ (de-le´shun) in genetics, loss of genetic material from a chromosome.

Loss, as from mutation, of one or more nucleotides from a chromosome.
 in the direct repeat locus that is too large to definitively assign to a genotypic group. Four specific motifs have been identified among the spoligotypes associated with non-genotypic group 1 isolates: Haarlem (9), Latin American and Mediterranean 1 and 2 (12,17), and X (12) (Figure 7). Of the 495 spoligotypes observed for low-copy isolates, 323 contained one of the eight defined motifs. This allowed 2,007 (80.1%) low-copy isolates to be assigned to a spoligotype family; the data for each family are summarized in Table 3. The majority (51.5%) of the low-copy isolates belonged to family X. The only published information regarding this motif indicated that it is highly prevalent in some English-speaking countries (12). In our study, 1,036 (70.3%) of isolates with two to four copies of IS6110 belonged to family X. The second largest spoligotype family was family EA-I. Isolates with this motif belong to group 1 (13) and have up to nine copies of IS6110 (17). Our isolates that belonged to this family had one to six copies of IS6110, but 378 (67.7%) possessed a single copy. In fact, 62.7% of isolates with a single copy of IS6110 belonged to the EA-I family. The remaining spoligotype families grouped only a few isolates, probably because isolates in these families are mostly high copy (9,17), and this occurrence should not suggest that these spoligotype families are uncommon in the United States. Thirty-two isolates were classified as M. bovis and 19 as M. africanum, solely by spoligotype motifs; no additional tests were conducted to confirm this classification.


After isolates were assigned to a spoligotype family, fingerprint clusters of isolates were examined for consistency with the spoligotype family assignment. We were surprised to identify several fingerprint patterns that have isolates with very different spoligotype patterns. For example, FP 00017 (Figure 6) and FP 00104 (a five-band pattern) share four bands in common with a size difference of <1% and also have two spoligo-patterns in common. SP 3 (777776777760771) is a very common pattern among M. tuberculosis group 2 and 3 isolates (13), whereas SP 290 (330777777767671) has a motif associated with M. africanum isolates (group 1). The spoligotype patterns are clearly divergent di·ver·gent  
1. Drawing apart from a common point; diverging.

2. Departing from convention.

3. Differing from another: a divergent opinion.

, indicating either that the strains independently acquired three copies of IS6110 at the same insertion sites or that they have different IS6110 insertions that coincidentally co·in·ci·den·tal  
1. Occurring as or resulting from coincidence.

2. Happening or existing at the same time.

 yield PvuII fragments of the same length.

Most of the other examples of isolates clustered by IS6110 with divergent spoligotypes are among isolates with one or two copies of IS6110. Mathema et al. (18) investigated differences among 66 isolates with FP 00129 (one band of 1.40 kb); 26 had group 1 spoligotypes, and 40 had group 2 or 3 spoligotypes. In most isolates with a single copy of IS6110, the IS6110 is inserted in the direct repeat locus in the repeat located between spacers 24 and 25. The predicted fragment size for this insertion in isolates with group 1 spoligotypes is 1.30-1.45 kb, depending on the number of spacers between spacers 25 and 36, where the PvuII site is located. The predicted fragment size for this insertion in isolates with group 2 or 3 spoligotypes is 4.51-4.58 kb, depending on the number of spacers between spacers 25 and 43 (the next PvuII site occurs outside of the direct repeat locus). Since the predicted fragment size for these 40 isolates was not consistent with the observed size, the insertion site in these isolates was sequenced. Sequencing showed that the isolates had a different insertion site (DK1) (19), which is very common among isolates with two copies of IS6110. The predicted fragment size for this insertion is 1.38 kb. This size is the one predicted for group 1 isolates and is a clear example of two isolates with different IS6110 insertions yielding PvuII fragments that are indistinguishable by the standard RFLP method.


The TB genotyping network database demonstrates the diversity of strains that cause TB in the United States. The 10,883 patients in the study represented approximately 11.6% of all new cases of TB in the United States from 1996 through 2000. The sentinel sites were reasonably representative of the geographic and demographic diversity in the United States. Compiling this database from results submitted from seven laboratories was a considerable undertaking, and analyzing such a large collection of fingerprint patterns is difficult. From our quality assurance program and personal experience, we know that, even under the most carefully-controlled conditions, IS6110 fingerprinting results are not 100% reproducible. We are certain that some of the fingerprint patterns, which were classified as different and received different designations, would have been identical had they been run side by side on the same gel. Also, as we have described, some fingerprint patterns for low-copy isolates appear identical but do not represent the same IS6110 insertions and thus do not represent closely related strains. Some of these difficulties resulted from the application of a rigid standard for defining distinct patterns, a process that is often subjective.

Even though some individual results may have been questionable, several clear conclusions emerged. Large sets of strains with related fingerprint patterns, not previously recognized, are spread across the United States. Given the rather slow rate of change in fingerprints, these must represent endemic strains that have circulated in the United States for decades. Consistent with this conclusion is the presence in the database of fingerprint patterns resembling the pattern of the laboratory strain H37 that was originally isolated in New York New York, state, United States
New York, Middle Atlantic state of the United States. It is bordered by Vermont, Massachusetts, Connecticut, and the Atlantic Ocean (E), New Jersey and Pennsylvania (S), Lakes Erie and Ontario and the Canadian province of
 in 1905 (8). Many of the patterns in these sets represent single isolates, which suggests that they are the result of reactivation reactivation

to become active after a period of quiescence or, as in bacterial and viral infections, latency.

cross reactivation
 of remote infections acquired years or decades earlier. Analysis of the demographic characteristics of the patients will be required to confirm this observation. Among these large sets, outbreak strains (patterns) were generally restricted to a single sentinel site, as were clustered isolates in general.

We conclude that a large-scale, prospective comparison of fingerprint patters from wide geographic regions is useful for research studies but is of limited value for TB control purposes. Comparisons of isolates from smaller areas are not only more meaningful but also more feasible. This limitation does not mean that searching multiple databases for specific fingerprint patterns, for example the "W" strain, is not useful in some circumstances.

The difficulties in analyzing IS6110 fingerprint patterns and the often slow turnaround time (1) In batch processing, the time it takes to receive finished reports after submission of documents or files for processing. In an online environment, turnaround time is the same as response time.  for obtaining results limit the value of this procedure to TB control programs. As an alternative, rapid, polymerase polymerase /po·lym·er·ase/ (pah-lim´er-as) an enzyme that catalyzes polymerization.

 chain reaction-based testing, such as spoligotyping or mycobacterial mycobacterial

emanating from or pertaining to mycobacterium.

mycobacterial granuloma
may be caused by Mycobacterium tuberculosis (see cutaneous tuberculosis), M.
 interspersed repetitive units variable number of tandem repeats This is a term from genetics, which describes a pattern that helps determine an individual's inherited traits.

Tandem repeats and variable number tandem repeats in DNA occur when a pattern of two or more nucleotides is repeated and the repetitions are directly adjacent to
 (MIRU-VNTR) analysis, would be a logical first step for universal genotyping of isolates. These methods provide greater reproducibility and give digital results, which simplify analysis. However, this approach has the following limitations. Many common spoligotypes were seen among low-copy-number isolates, although even IS6110 fingerprinting does not greatly improve resolution with these isolates. We also found that 9% of the isolates have W-Beijing fingerprint patterns that are known to have the same spoligotype; all isolates yielding the Beijing spoligotype would require IS6110 typing. Sufficient data are not available to predict the discriminatory power of MIRU-VTNR. However, preliminary results suggest that the combination of spoligotyping and VNTR VNTR Variable Number of Tandem Repeat(s)  typing will provide adequate resolution for most uses, thus limiting the need for additional typing by IS6110 fingerprinting.
Table 1. Distribution of isolates and fingerprint patterns by number of
copies of IS6110

IS6110                                            No.
copy no.    No. patterns     No. isolates     clusters (a)

 0                 1                22              1
 1                17               610              9
 2                36               759             16
 3                92               345             40
 4               102               456             28
 5               119               237             37
 6               121               209             21
 7               217               332             40
 8               364               474             56
 9               489               699             78
10               681             1,108            112
11               737             1,143            116
12               738             1,067            114
13               663               906             83
14               505               653             51
15               333               428             35
16               225               282             17
17               169               236             16
18               128               143              9
19               121               149             17
20               118               172             23
21                81               248             15
22                48               182             12
23                13                13              0
24                 5                 5              0
25                 2                 2              0
26                 1                 1              0
27                 1                 1              0
28                 1                 1              0
All            6,128            10,883            946

IS6110      No. clustered    Average cluster
copy no.    isolates (%)      size (range)

 0              22 (100)      22 (22)
 1             602 (99)       67 (2-291)
 2             739 (97)       46 (2-456)
 3             293 (85)        7.3 (2-49)
 4             382 (84)       14 (2-212)
 5             155 (65)        4.2 (2-13)
 6             109 (52)        5.2 (2-20)
 7             155 (47)        3.9 (2-29)
 8             166 (35)        3.0 (2-12)
 9             288 (41)        3.7 (2-20)
10             539 (49)        4.8 (2-105)
11             522 (46)        4.5 (2-70)
12             443 (42)        3.9 (2-27)
13             326 (36)        3.9 (2-23)
14             199 (30)        3.9 (2-27)
15             130 (30)        3.7 (2-15)
16              74 (26)        4.4 (2-21)
17              83 (35)        5.2 (2-46)
18              24 (17)        2.7 (2-5)
19              45 (30)        2.6 (2-7)
20              77 (45)        3.3 (2-14)
21             182 (73)       12 (2-100)
22             146 (80)       12 (2-102)
All          5,701 (52)        6.0 (2-456)

(a) Number of fingerprint patterns reported for more than one isolate.

Table 2. Distribution of isolates with high-copy fingerprint patterns
reported with high frequency (a, b)

                                           No. isolates/site

 FP     No. bands   No. isolates   AR   CA   MA   MD   MI    NJ   TX

00015       7            29         0    0    0    2     0   27    0
00019      12            27         4    7    0    2     3    2    9
00027      22           102         0    0    0    0   102    0    0
00028      11            70         0    0    0    0    70    0    0
00035      13            33         0    0    0    0     0    0   33
00159      11            24         0    0    0    0     0    0   24
00237      21           100        12    0    0    2     0    1   85
00242      10           105         6    1    1    0     1    0   96
00316      14            27         3   22    2    0     0    0    0
00325      11            20        15    1    0    0     0    4    0
00372      12            20        11    0    0    0     0    0    9
00469      16            21         1    0    0    0     0    0   20
00673      11            25         0   19    0    0     0    4    2
00757      11            20         0    0    0   17     0    3    0
00768       9            20         0    0    0    0     0   20    0
00867      14            24         0   24    0    0     0    0    0
01284      17            46         0    0    0    0     0    0   46
01693      21            40         0    0    1    0     0   39    0

(a) FP, fingerprint; AR, Arkansas, CA, California; MA, Massachusetts;
MD, Maryland; MI, Michigan; NJ, New Jersey, TX, Texas.

(b) Patterns reported for [greater than or equal to] 20 isolates.

Table 3. Distribution of isolates in genotype families (a)

                     No. patterns    No. isolates

FP sets
  W-Beijing              497             946
  Set A                  141             190
  Set B                   97             162
  Set C                  251             414
  Set D                  181             275
  Set E                  119             137
  Set F                  177             321
  FP 17                   54             411
Spoligotype family
  EA-I                   161             558
  X                      113           1,291
  Haarlem                 11              47
  LAM-1                    5               6
  LAM-2                    4              54
  bovis                   19              32
  africanum               10              19

                                  No. isolates/site

                     AR    CA     MA    MD    MI     NJ     TX

FP sets
  W-Beijing          22    279    88    49    162    144    202
  Set A              37     18    14    19     43     29     30
  Set B              14     33    20     4     15     33     43
  Set C               4    295     9    15     20     53     18
  Set D              11     37    44    32     27    102     22
  Set E               0     37     5    16     16     56      7
  Set F              24     44    31    47     47     71     57
  FP 17              31     59    31    64     65     72     89
Spoligotype family
  EA-I                7    247    71    46     62     51     74
  X                  61    267    73    98    232    270    290
  Haarlem             1      1     5    23      2      5     10
  LAM-1               0      1     2     2      0      1      0
  LAM-2               0      0     0    51      0      2      1
  bovis               2      8     1     2      5      8      6
  africanum           0      1     1    11      2      3      1

                      Clustered      Average no. copies of
                     isolates (%)    IS6110/isolate (range)

FP sets
  W-Beijing               56              19.9 (17-27)
  Set A                   39              13.1 (10-15)
  Set B                   52              11.0 (7-15)
  Set C                   52              11.9 (8-15)
  Set D                   48               8.9 (6-13)
  Set E                   20              12.9 (9-15)
  Set F                   55               9.4 (6-14)
  FP 17                   70               4.5 (3-6)
Spoligotype family
  EA-I                    56               1.8 (1-4)
  X                       83               3.1 (1-6)
  Haarlem                 45               4.9 (1-6)
  LAM-1                   33               3.7 (1-4)
  LAM-2                   81               2.6 (1-6)
  bovis                   41               1.4 (1-5)
  africanum               47               4.4 (3-4)

(a) FP, fingerprint; AR, Arkansas; CA, California; MA, Massachusetts;
MD, Maryland; MI, Michigan; NJ, New Jersey; TX, Texas; EA-I, East
African-India; LAM, Latin American-Mediterranean.

Table 4. Distribution of isolates with low-copy fingerprint patterns
reposed with high frequency (a,b)

        No.     No.                                    spoligotypes
FP     bands  isolates  AR  CA   MA  MD  MI   NJ  TX       (c)

00000    0        21     0   11   0   7    1   0    2       11
00003    1        87     2   32  13  12   11  12    5       26
00016    2       429    47    0  22  67  116  56  121       70
00017    4       201    12   15  13  39   29  48   45       45
00077    3        49     0    0   7  12   16   0   14       14
00129    1       289     1   84  60  35   29  66   14       92
00143    4        28     2    1   0   9    5  10    1        5
00195    1       148     5   76   0   5   13   3   46       52
00256    1        28     2    7   1   2    4   7    5       16
00370    3        38     0    9   0   0    0  26    3        9
00434    3        21     1    4   1   0   10   2    3        9
00456    1        32     0    0   0   0    0  32    0       18
00708    2       207     0  184   0   0    3  20    0       19
01285    4        23     0    0   0   0    0   1   22        4

(a) FP, fingerprint, AR, Arkansas; CA, California; MA, Massachusetts;
MD, Maryland; MI, Michigan; NJ, New Jersey, TX, Texas.

(b) patterns reposed for [greater than or less than to] 20 isolates.

(c) Number of different spoligotypes reported for isolates with this

Table 5. Distribution of isolates with spoligotypes reported with high
frequency (a,b)

                                    No. isolates/site

SP   Octal code (c)   No. isolates  AR  CA   MA  MD  MI  NJ  TX

  2  777777777760771        84       8   25  10   2   8  14   17
  3  777776777760771       331      16   57  16   3  40  48  151
  9  777776777760601       288      20   35  18   3  89  51   72
 15  777777777413771        50       0   19  11   2   5   3   10
 16  777777777416761        21       0    0  16   0   0   2    3
 19  777777774413771        99       0   69  18   0   7   4    1
 27  701776777760601       131       0  130   1   0   0   0    0
 28  700036777760771        34       0    4   7   1   2  18    2
 29  700076777760771        46       2    7   5   1   7  13   11
 30  700036777760731        44       0    3   3   0  l0  16   12
 72  700076777760671        38       4    2   2   0  13  14    3
 75  777776407760601        57       0    1   0   0   0  55    1
 91  477777777741071        24       0    0   1   0   0  23    0
300  777756777760601        41       0    0   1  38   2   0    0
540  477777777413071        44       1   17   5   9  10   1    1
545  037776777760601        31       0    0   0   0  30   0    1
546  777777777413731        26       0   17   0   3   4   0    2
560  777777777760601        20       8    0   0   0   0   0   12
562  777777776413771        21       4    0   0   0   0   0   17
900  776377777740731        51       0    0   0  51   0   0    0

       No. isolates/IS6110
          copy number

                               No. fingerprint
SP    1    2   3    4   5   6   patterns (d)

  2  40   11   5   15   3  10        30
  3   5   82  25  122  61  36        77
  9   3  190  72   17   6   0        44
 15  26    6   3    7   4   4        21
 16  10    2   0    2   6   1        10
 19  83    5   6    3   1   1        17
 27   0  129   1    0   1   0         4
 28   1    6  19    0   8   0        12
 29   0    0   0   27  11   8        13
 30   0    2  42    0   0   0         4
 72   0    0   0   28   9   1         7
 75  41   14   2    0   0   0         4
 91  18    3   0    0   1   2         8
300   0    4   9   14   0  14         9
540  25    4   5    3   1   6        21
545   0   30   1    0   0   0         2
546  20    3   0    2   0   1         7
560   0   17   2    1   0   0         4
562  18    2   1    0   0   0         4
900   0   36  11    2   0   2        11

(a) AR, Arkansas; CA, California; MA, Massachusetts; MD, Maryland; MI,
Michigan; NJ, New Jersey; TX, Texas.

(b) Spoligotype; reported [greater than or less than to] 20 isolates.

(c) The 43-digit spoligotype pattern is reposed in the standard octal
code format (2).

(d) Number of different fingerprint patterns reported for isolates with
this spoligotype.


We thank Steve Kammerer, and Charles L. Woodley for assistance in database analysis, and Barbara A. Schable, Christopher R. Braden, and the participants in the National Tuberculosis Genotyping and Surveillance project for their extensive efforts in compiling the databases on which this article is based.


(1.) Crawford JT, Braden CE, Schable BA, Onorato IM. National Tuberculosis Genotyping and Surveillance network: design and methods. Emerg Infect infect /in·fect/ (in-fekt´)
1. to invade and produce infection in.

2. to transmit a pathogen or disease to.

 Dis 2002;8;1192-6.

(2.) Dale JW, Brittain D, Cataldi AA, Cousins D, Crawford JT, Driscoll J, et al. Spacer oligonucleotide Oligonucleotide

A deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) sequence composed of two or more covalently linked nucleotides. Oligonucleotides are classified as deoxyribooligonucleotides or ribooligonucleotides.
 typing of bacteria of the Mycobacterium tuberculosis complex: recommendations for standardized standardized

pertaining to data that have been submitted to standardization procedures.

standardized morbidity rate
see morbidity rate.

standardized mortality rate
see mortality rate.
 nomenclature nomenclature /no·men·cla·ture/ (no´men-kla?cher) a classified system of names, as of anatomical structures, organisms, etc.

binomial nomenclature
. Int J Tuberc Lung Dis 2001;5;216-9.

(3.) Yang yang (yang) [Chinese] in Chinese philosophy, the active, positive, masculine principle that is complementary to yin; see yin, under principle.  Z, Barnes PF, Chaves F, Eisenach KD, Weis SE, Bates Bates   , Katherine Lee 1859-1929.

American educator and writer best known for her poem "America the Beautiful," written in 1893 and revised in 1904 and 1911.
 JH, et al. Diversity of DNA fingerprints DNA fingerprint
An individual's unique sequence of DNA base pairs. Also called genetic fingerprint.
 of Mycobacterium tuberculosis isolates in the United States. J Clin Microbiol 1998;36:1003-7.

(4.) Bifani PJ, Mathema B, Kurepina NE, Kreiswirth BN. Global dissemination dissemination Medtalk The spread of a pernicious process–eg, CA, acute infection Oncology Metastasis, see there  of the Mycobacterium tuberculosis W-Beijing family strains. Trends Microbiol 2002;10:45-52.

(5.) van Soolingen D, Qian, L, de Haas de Haas as a surname can refer to:
  • Dirk de Haas(17th century), Dutch merchant
  • Jacob de Haas
  • John Philip De Haas (1735-1786), American soldier
  • William de Haas (1830-1880), Dutch-born American painter
 PE, Douglas JT, Traore H, Portaels F, et al. Predominance pre·dom·i·nance   also pre·dom·i·nan·cy
The state or quality of being predominant; preponderance.

Noun 1. predominance - the state of being predominant over others
predomination, prepotency
 of a single genotype of Mycobacterium tuberculosis in countries of East Asia East Asia

A region of Asia coextensive with the Far East.

East Asian adj. & n.
. J Clin Microbiol 1995;33:3234-8.

(6.) Beggs ML, Eisenach KD, Cave MD. Mapping of TS6110 insertion sites in two epidemic strains of Mycobacterium tuberculosis. J Clin Microbiol 2000;38:2923-8.

(7.) Steinlein LM, Crawford JT. Reverse dot blot Dot blot (or Slot blot) is a technique in molecular biology used to detect biomolecules. It replaces either northern blot, Southern blot or western blot. In dot blot the biomolecules to be detected are not separated by chromatography.  assay (insertion site typing) for precise detection of sites of IS6110 insertion in the Mycobacterium tuberculosis genome genome: see genetics.

all the genetic content contained within an organism. An organism's genome is made up of molecules of deoxyribonucleic acid (DNA) that form long strands that are tightly wound into chromosomes, which are found in the
. J Clin Microbiol 2001;39:871-8.

(8.) Bifani P, Moghazeh S, Shopsin B, Driscoll J, Ravikovitch A, Kreiswirth, BN. Molecular characterization A rather long and fancy word for analyzing a system or process and measuring its "characteristics." For example, a Web characterization would yield the number of current sites on the Web, types of sites, annual growth, etc.  of Mycobacterium tuberculosis H37Rv/ Ra variants: distinguishing the mycobacterial laboratory strain. J Clin Microbiol 2000;38:3200-4.

(9.) Kremer K, van Soolingen D, Frothingham R, Haas WH, Hermans PWM (Pulse Width Modulation) A modulation technique that generates variable-width pulses to represent the amplitude of an analog input signal. Like its fixed-width pulse density modulation (PDM) cousin, the output switching transistor is on more of the time for a , Martin C, et al. Comparison of methods based on different molecular epidemiological epidemiological

emanating from or pertaining to epidemiology.

epidemiological associations
the associative relationships between the frequency of occurrence of a disease and its determinants, its predisposing and precipitating
 markers for typing of Mycobacterium tuberculosis complex strains: interlaboratory study of discriminatory power and reproducibility. J Clin Microbiol 1999;37:2607-18.

(10.) Cowan LS, Mosher A mosher is a person who is crossed between goth/punk/skater they have long hair and listen to music like slipknot and metal music. Some people call them headbangers. At certain music shows they have something called a mosh pit, basically its a fight pit with loads of people bashing each other.  L, Diem L, Massey JP, Crawford JT. Variable-number tandem repeat typing of Mycobacterium tuberculosis isolates with low-copy numbers of IS6110 by using mycobacterial interspersed repetitive units. J Clin Microbiol 2002;40:1592-602.

(11.) Plikaytis BB, Kurepina N, Woodley CL, Butler WR, Shinnick TM. Multiplex See multiplexing.  PCR PCR polymerase chain reaction.

polymerase chain reaction

Polymerase chain reaction (PCR) 
 assay to aid in the identification of the highly transmissible transmissible /trans·mis·si·ble/ (trans-mis´i-b'l) capable of being transmitted.

Capable of being conveyed from one person to another.
 Mycobacterium tuberculosis strain CDC1551. Tuber tuber, enlarged tip of a rhizome (underground stem) that stores food. Although much modified in structure, the tuber contains all the usual stem parts—bark, wood, pith, nodes, and internodes.  Lung Dis 1999;79:273-8.

(12.) Sebban M, Mokrousov I, Rastogi N, Sola C. A data-mining approach to spacer oligonucleotide typing of Mycobacterium tuberculosis. Bioinformatics Using computers in biological research to analyze or predict the composition of molecules (nucleic acids, proteins, etc.) and model biologic systems. Bioinformatics is most prominent in the Human Genome Project, which has recorded the three billion chemical base pairs that make up the  2002;18:235-43.

(13.) Soini H, Pan X, Amin A, Graviss EA, Siddiqui A, Musser JM. Characterization of Mycobacterium tuberculosis isolates from patients in Houston, Texas “Houston” redirects here. For other uses, see Houston (disambiguation).
Houston (pronounced /'hjuːstən/) is the largest city in the state of Texas and the
, by spoligotyping. J Clin Microbiol 2000;38:669-76.

(14.) Sreevatsan S, Pan X, Stockbauer K, Connell ND, Kreiswirth BN, Whittam TS, et al. Restricted structural gene polymorphism in the Mycobacterium tuberculosis complex indicates evolutionarily recent global dissemination. Proc Natl Acad Sci U S A 1997;94:9869-74.

(15.) Kamerbeek J, Schouls L, Kolk A, van Agterveld M, van Soolingen D, Kuijper S, et al. Simultaneous detection and strain differentiation of Mycobacterium tuberculosis for diagnosis and epidemiology epidemiology, field of medicine concerned with the study of epidemics, outbreaks of disease that affect large numbers of people. Epidemiologists, using sophisticated statistical analyses, field investigations, and complex laboratory techniques, investigate the cause . J Clin Microbiol 1997;35:907-14.

(16.) Viana-Niero C, Gutierrez C, Sola C, Filliol I, Boulahbal F, Vincent V, et al. Genetic diversity of Mycobacterium africanum Mycobacterium africanum Epidemiology
M.africanum is most commonly found in West African countries, causing up to a quarter of cases of tuberculosis in countries such as the Gambia.
 clinical isolates based on IS6110-restriction fragment length polymorphism analysis, spoligotyping, and variable number of tandem DNA DNA: see nucleic acid.
 or deoxyribonucleic acid

One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes.
 repeats. J Clin Microbiol 2001;39:57-65.

(17.) Sola C, Filliol I, Legrand E, Mokrousov I, Rastogi N. Mycobacterium tuberculosis phylogeny reconstruction based on combined numerical analysis numerical analysis

Branch of applied mathematics that studies methods for solving complicated equations using arithmetic operations, often so complex that they require a computer, to approximate the processes of analysis (i.e., calculus).
 with IS1081, IS6110, VNTR, and DR-based spoligotyping suggests the existence of two new phylogeographical clades. J Mol Evol 2001;53:680-9.

(18.) Mathema B, Bifani PJ, Driscoll J, Steinlein L, Kurepina N, Moghazeh SL, et al. Identification and evolution of an IS6110 low-copy Mycobacterium tuberculosis cluster. J Infect Dis 2002;185:641-9.

(19.) Fomukong N, Beggs M, El Hajj hajj (häj), the pilgrimage to Mecca, Saudi Arabia, one of the five basic requirements (arkan or "pillars") of Islam. Its annual observance corresponds to the major holy day id al-adha,  H, Templeton G, Eisenach K, Cave MD. Differences in the prevalence of IS6110 insertion sites in Mycobacterium tuberculosis strains: low and high-copy numbers of IS6110. Tuber Lung Dis 1998;78:109-16.

Lauren S Lauren as a surname may refer to:
  • Ralph Lauren, American fashion designer (changed his last name to Lauren)
Lauren is a given name for a female and more rarely a name for a male.
. Cowan * and Jack T. Crawford *

* Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Dr. Cowan is a service fellow in the Tuberculosis/Mycobacteriology Branch, Division of AIDS, STD (Subscriber Trunk Dialing) Long distance dialing outside of the U.S. that does not require operator intervention. STD prefix codes are required and billing is based on call units, which are a fixed amount of money in the currency of that country. , and TB Laboratory Research, National Center for Infectious Diseases infectious diseases: see communicable diseases. , Centers for Disease Control and Prevention. Her current research interests include DNA fingerprinting DNA fingerprinting or DNA profiling, any of several similar techniques for analyzing and comparing DNA from separate sources, used especially in law enforcement to identify suspects from hair, blood, semen, or other biological materials found at  and the molecular epidemiology molecular epidemiology Molecular medicine An evolving field that combines the tools of standard epidemiology–case studies, questionnaires and monitoring of exposure to external factors with the tools of molecular biology–eg, restriction endonucleases,  of Mycobacterium tuberculosis.

Dr. Crawford is Chief of the Immunology immunology, branch of medicine that studies the response of organisms to foreign substances, e.g., viruses, bacteria, and bacterial toxins (see immunity). Immunologists study the tissues and organs of the immune system (bone marrow, spleen, tonsils, thymus, lymphatic  and Molecular Pathogenesis pathogenesis /patho·gen·e·sis/ (path?ah-jen´e-sis) the development of morbid conditions or of disease; more specifically the cellular events and reactions and other pathologic mechanisms occurring in the development of disease.  Section, Tuberculosis/Mycobacteriology Branch, Division of AIDS, STC STC Supplemental Type Certificate (FAA)
STC Society for Technical Communication
STC Subject to Change
STC Surf the Channel (website)
STC Sound Transmission Class
STC Singapore Turf Club
, and TB Laboratory Research, Centers for Disease Control and Prevention. His research interests include application of molecular methods to epidemiology and diagnostics of mycobacterial diseases Mycobacterial diseases

Diseases caused by mycobacteria, a diffuse group of acid-fast, rod-shaped bacteria in the genus Mycobacterium. The two most important species are M. tuberculosis (the cause of tuberculosis) and M.

Address for correspondence: Jack T. Crawford, Centers for Disease Control and Prevention, Mailstop F08, 1600 Clifton Rd., NE, Atlanta, GA 30333 USA; fax: 404-639-1287; e-mail:
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Author:Crawford, Jack T.
Publication:Emerging Infectious Diseases
Geographic Code:1USA
Date:Nov 1, 2002
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