This study includes verified cases of TB reported to the US National Tuberculosis Surveillance System (NTSS) by the 50 states and the District of Columbia. Clinical, demographic, and epidemiologic variables for each case-patient are collected for surveillance purposes and are described elsewhere (21). M. tuberculosis complex isolates were characterized by using a standardized protocol for spacer oligonucleotide typing (spoligotyping) and 12-locus mycobacterial interspersed repetitive unit–variable-number tandem repeats (MIRU-VNTRs) (22). NTGS results for each submitted isolate were linked to NTSS case records by state and local TB control programs; a standardized case identification number and a unique laboratory accession number were used to form discrete individual isolate-case records (20). When multiple isolates were genotyped for the same person in the same surveillance year, case-patients with discordant genotyping results were excluded from analysis for clustering assignment and risk factor analysis. The final study population included all persons with verified culture-positive TB cases reported during January 2005–December 2009 with a complete spoligotype and 12-locus MIRU-VNTR result.

Four major phylogenetic lineages for M. tuberculosis, along with speciation of M. africanum and M. bovis, were identified by using spoligotyping motifs that referred to an international standard (23). Substance abuse was defined by using previously published methods (24). Persons with TB who received a positive HIV test result at the time of TB diagnosis were classified as TB/HIV case-patients. Persons with TB and negative HIV results or unknown HIV status were classified as having non-HIV TB.

Genotype clusters were defined as cases with matching spoligotype and 12-locus MIRU-VNTR results (i.e., exact match on all loci) reported within statistically significant geospatial zones determined by a spatial scan statistic (25). SaTScan version 9.1.0 (26) was employed to identify geographic areas with a larger-than-expected rate of discrete genotype clustering, and all other culture-positive TB cases counted during the study were considered as the background rate. In brief, all cases were aggregated by genotype according to residential ZIP code where they were reported. Each genotype was then scanned separately, applying a purely spatial analysis, in which the number of events in an area was assumed to be Poisson-distributed to generate circular zones of various sizes up to a maximum radius of 50 km. An evaluation of outbreak investigations conducted by CDC demonstrated no difference in cluster membership when 50-km and 100-km SaTScan search radii were used to identify known epidemiologically linked genotype cases (CDC, unpub. data).

A log-likelihood ratio was calculated for each zone in comparison with all possible zones, with the maximum likelihood ratio representing the zone most likely to identify spatial clustering for each genotype. A Monte Carlo simulation with 999 repetitions was used to determine the distribution of the scan statistic under the null hypothesis of spatial randomness; significant spatial clusters were chosen at an α of p<0.05. Three scans comprised of 3-year overlapping intervals (scan A, 2005–2007; scan B, 2006–2008; scan C, 2007–2009) were performed to identify spatial clusters occurring within a 3-year period. If cases were identified as a member of a statistically significant spatial cluster in any of the 3 periods, they were considered clustered. No duplicative case counting occurred. The purpose of this spatial scan was to characterize each case for a dichotomous outcome: clustered or not clustered. Cases that were both genotypically and spatially clustered were considered recent TB transmission for the purposes of this study. All cases that were not genotypically and spatially clustered were considered reactivation of remotely acquired TB infection, or reactivation TB. For comparative purposes, national-, state- and county-level clustering definitions were created. National-level clustering was defined as >2 culture-positive cases with identical genotypes reported anywhere in the United States during 2005–2009. State-level clustering was defined as >2 culture-positive cases with identical genotypes reported from the same state during 2005–2009. County-level clustering was defined as >2 culture-positive cases with identical genotypes reported from same county during 2005–2009.

A predictive logistic regression model was used to determine potential associations between clinical (e.g., sputum-smear status, known HIV positivity, site of disease and cavitation on chest radiograph, and previous TB diagnosis) and demographic and risk characteristic variables (e.g., race/ethnicity, age, country of birth, homelessness, substance abuse, incarceration at time of diagnosis, and residence at long-term care facility at diagnosis) and the outcome of interest: geospatial and genotype clustering as a proxy for recent TB transmission. Univariate analysis of the categorical independent variables was done by using Pearson χ². Any variable with a significance value of <0.20 was included in a best subset, multivariate logistic regression model. We built our final model using backward elimination of nonsignificant independent variables (p>0.01). The log-likelihood ratio was used to assess the overall significance of the final models, and the Hosmer-Lemeshow statistic was used to evaluate the fit of each of the final models. To test the hypothesis that factors associated with recent TB transmission events varied by geographic region of the United States, an additional 4 independent models were created following the same process but subset to western, midwestern, northeastern, and southern states, respectively (27).

During 2005–2009, a total 65,529 verified cases of TB were reported to CDC. Of these, 51,015 (77.9%) were culture-positive (Figure 1). During this period, the overall incidence of TB in the United States declined from 4.8 to 3.8 per 100,000 persons, representing a decline of 20.1% in the overall case count (21).

During 2005–2009, a total of 45,188 isolates were submitted to NTGS for molecular characterization; 39,474 (87.4%) were successfully matched to a case-patient with reported TB. Two hundred seventy isolates (0.7%) had incomplete results on spoligotype, MIRU-VNTR, or both; 344 case-patients (0.9%) had multiple isolates with discordant genotyping results and were excluded from the analysis. The total number of genotyped TB cases available for analysis was 36,860, representing 72.3% of all reported culture-positive cases. The proportion of reported case-patients for whom complete genotype results were available increased over time, with 6,863 (62.7%) of 10,953 in 2005 and 7,845 (88.4%) of 8,876 in 2009. The number of individual genotype strains (i.e., distinct spoligotype and 12-locus MIRU-VNTR combinations) identified over the study period was 11,722. The proportion of new strains identified per year gradually decreased over time. In 2006, 40.7% of strains identified were new; this percentage was reduced to 14.2% in 2009 (data not shown).

Of the 36,860 cases for which genotyping had been performed, 8,499 (23.1%) were considered clustered by both genotype and spatial concentration and therefore were thought to be members of a putative recent TB transmission event. The average number of spatially concentrated genotype clusters identified per 3-year scanning period was 1,039 (range 970–1,128). Nationally, the overall mean cluster size was 5.7 members (range 2–173 members) (Figure 2). The median cluster size was 3 members, and almost half (46.1%) of the clusters had only 2 members. Other clustering definitions that use geopolitical boundaries had higher average clustering percentages when the same 3-year window periods were used (national-level, 77.3%; state-level, 57.1%; county-level, 38.7%) (Figure 1).

Cluster members were more likely to be male (66.3% vs. 61.7%), to have been born in the United States (57.4% versus 34.4%), to abuse substances (28.4% versus 14.8%), and to have a history of homelessness (11.1% versus 5.0%) than those thought to have reactivation TB (Table 1). The proportion of cluster members also varied by race compared with those with cases due to reactivation TB: Asian, non-Hispanic (17.6% vs. 29.8%); black, non-Hispanic (39.7% versus 21.6%); Hispanic (25.5% versus 28.5%); and white, non-Hispanic (15.0% versus 17.9%).

Cluster members with recent TB transmission events were also more likely to have reported HIV-positive results (8.7% versus 5.5%), pulmonary disease exclusively (78.4% versus 72.2%), and positive sputum smear results (61.5% versus 55.3%) and to have had a cavitary chest radiograph at time of diagnosis (36.8% versus 32.2%) than those thought to have reactivation TB. Of the 8,499 persons with cases believed to be caused by recent TB transmission, only 2.1% and 4.4% resided in a long-term care or correctional facility at the time of diagnosis, respectively.

The proportions of isolates in each phylogenetic lineage were as follows: Euro-American, 64.2%; Indo-Oceanic, 15.4%; East-Asian, 13.5%; East-African/Indian, 4.3%. M. bovis isolates accounted for 1.6% of reported cases of TB. Seventy-two percent of reported case-patients with M. bovis isolates were non–US-born. M. africanum isolates were identified among 179 patients (0.5%), with 88.6% non–US-born. Among members with recent TB transmission events, 69.2% had TB isolates with Euro-American lineage; 14.9% had isolates with East-Asian lineage, 11.8% had isolates with Indo-Oceanic lineage, 2.3% had isolates of East-African/Indian lineage, 1.5% had M. bovis isolates, and 0.3% had M. africanum isolates.

In our final adjusted model, the following odds ratios were noted for variables significantly associated with a higher odds of having a case attributed to putative recent TB transmission (Table 1): age (0–4 years of age: adjusted odds ratio [aOR] 3.1, 99% CI 1.4–6.8); black, non-Hispanic (aOR 2.4, 99% CI 2.2–2.7); Hispanic (aOR 1.7, 99% CI 1.5–2.0); Native Hawaiian/Pacific Islander (aOR 2.6, 99% CI 1.5–4.4); US-born (aOR 2.4, 99% CI 2.1–2.7); homeless persons (aOR 1.4, 99% CI 1.2–1.6); persons who abuse substances (aOR 1.4, 99% CI 1.3–1.7); East-Asian lineage (aOR 1.9, 99% CI 1.5–2.6); and Indo-Oceanic lineage (aOR 1.7, 99% CI 1.3–2.3).

Best-fit models to predict those with recent TB transmission were conducted for each of the 4 US geographic regions. Many of the main effects associated with recent TB transmission remained constant (US-born, substance abuse, homeless), although factors varied in both magnitude and risk factor across the United States (Table 2).

Ethnic disparities for recent TB transmission were found among black, non-Hispanic persons living in midwestern and southern states (aOR 2.1, 99% CI 1.7–2.6; aOR 3.6, 99% CI 1.5–8.6), whereas Hispanic persons had the highest odds among those living in northeastern (aOR 2.3, 99% CI 1.7–8.8) and western states (aOR 2.1, 99% CI 1.5–3.0).

Phylogenetic lineage also varied among the different regions. Euro-American lineage (aOR 2.2, 99%,CI 1.1–4.3) had the strongest association for recent transmission in the south, whereas the East-Asian lineage was most strongly associated with recent transmission in western (aOR 2.4, 99% CI 1.4–4.2) and northeastern states (aOR 2.0, 99% CI 1.1–3.6).