High-resolution mapping of tuberculosis transmission: Whole genome sequencing and phylogenetic modelling of a cohort from Valencia Region, Spain

Autoři: Yuanwei Xu aff001;  Irving Cancino-Muñoz aff002;  Manuela Torres-Puente aff002;  Luis M. Villamayor aff003;  Rafael Borrás aff004;  María Borrás-Máñez aff005;  Montserrat Bosque aff006;  Juan J. Camarena aff007;  Ester Colomer-Roig aff003;  Javier Colomina aff005;  Isabel Escribano aff008;  Oscar Esparcia-Rodríguez aff009;  Ana Gil-Brusola aff010;  Concepción Gimeno aff011;  Adelina Gimeno-Gascón aff012;  Barbará Gomila-Sard aff013;  Damiana González-Granda aff014;  Nieves Gonzalo-Jiménez aff015;  María Remedio Guna-Serrano aff011;  José Luis López-Hontangas aff010;  Coral Martín-González aff016;  Rosario Moreno-Muñoz aff013;  David Navarro aff004;  María Navarro aff017;  Nieves Orta aff018;  Elvira Pérez aff019;  Josep Prat aff020;  Juan Carlos Rodríguez aff012;  María Montserrat Ruiz-García aff014;  Herme Vanaclocha aff019;  Caroline Colijn aff001;  Iñaki Comas aff002
Působiště autorů: Centre for Mathematics of Precision Healthcare, Department of Mathematics, Imperial College London, London, United Kingdom aff001;  Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas, Valencia, Spain aff002;  Genomics and Health Unit, FISABIO Public Health, Valencia, Spain aff003;  Microbiology Service, Hospital Clínico Universitario, Valencia, Spain aff004;  Microbiology and Parasitology Service, Hospital Universitario de La Ribera, Alzira, Spain aff005;  Microbiology Service, Hospital Arnau de Vilanova, Valencia, Spain aff006;  Microbiology Service, Hospital Universitario Dr. Peset, Valencia, Spain aff007;  Microbiology Laboratory, Hospital Virgen de los Lírios, Alcoy, Spain aff008;  Microbiology Service, Hospital de Denia, Denia, Spain aff009;  Microbiology Service, Hospital Universitari i Politècnic La Fe, Valencia, Spain aff010;  Microbiology Service, Hospital General Universitario de Valencia, Valencia, Spain aff011;  Microbiology Service, Hospital General Universitario de Alicante, Alicante, Spain aff012;  Microbiology Service, Hospital General Universitario de Castellón, Castellon, Spain aff013;  Microbiology Service, Hospital Lluís Alcanyis, Xativa, Spain aff014;  Microbiology Service, Hospital General Universitario de Elche, Elche, Spain aff015;  Microbiology Service, Hospital Universitario de San Juan de Alicante, Alicante, Spain aff016;  Microbiology Service, Hospital de la Vega Baixa, Orihuela, Spain aff017;  Microbiology Service, Hospital San Francesc de Borja, Gandía, Spain aff018;  Subdirección General de Epidemiología y Vigilancia de la Salud, Dirección General de Salud Pública, Valencia, Spain aff019;  Microbiology Service, Hospital de Sagunto, Sagunto, Spain aff020;  Department of Mathematics, Simon Fraser University, Burnaby, British Columbia, Canada aff021
Vyšlo v časopise: High-resolution mapping of tuberculosis transmission: Whole genome sequencing and phylogenetic modelling of a cohort from Valencia Region, Spain. PLoS Med 16(10): e32767. doi:10.1371/journal.pmed.1002961
Kategorie: Research Article
doi: 10.1371/journal.pmed.1002961



Whole genome sequencing provides better delineation of transmission clusters in Mycobacterium tuberculosis than traditional methods. However, its ability to reveal individual transmission links within clusters is limited. Here, we used a 2-step approach based on Bayesian transmission reconstruction to (1) identify likely index and missing cases, (2) determine risk factors associated with transmitters, and (3) estimate when transmission happened.

Methods and findings

We developed our transmission reconstruction method using genomic and epidemiological data from a population-based study from Valencia Region, Spain. Tuberculosis (TB) incidence during the study period was 8.4 cases per 100,000 people. While the study is ongoing, the sampling frame for this work includes notified TB cases between 1 January 2014 and 31 December 2016. We identified a total of 21 transmission clusters that fulfilled the criteria for analysis. These contained a total of 117 individuals diagnosed with active TB (109 with epidemiological data). Demographic characteristics of the study population were as follows: 80/109 (73%) individuals were Spanish-born, 76/109 (70%) individuals were men, and the mean age was 42.51 years (SD 18.46). We found that 66/109 (61%) TB patients were sputum positive at diagnosis, and 10/109 (9%) were HIV positive. We used the data to reveal individual transmission links, and to identify index cases, missing cases, likely transmitters, and associated transmission risk factors. Our Bayesian inference approach suggests that at least 60% of index cases are likely misidentified by local public health. Our data also suggest that factors associated with likely transmitters are different to those of simply being in a transmission cluster, highlighting the importance of differentiating between these 2 phenomena. Our data suggest that type 2 diabetes mellitus is a risk factor associated with being a transmitter (odds ratio 0.19 [95% CI 0.02–1.10], p < 0.003). Finally, we used the most likely timing for transmission events to study when TB transmission occurred; we identified that 5/14 (35.7%) cases likely transmitted TB well before symptom onset, and these were largely sputum negative at diagnosis. Limited within-cluster diversity does not allow us to extrapolate our findings to the whole TB population in Valencia Region.


In this study, we found that index cases are often misidentified, with downstream consequences for epidemiological investigations because likely transmitters can be missed. Our findings regarding inferred transmission timing suggest that TB transmission can occur before patient symptom onset, suggesting also that TB transmits during sub-clinical disease. This result has direct implications for diagnosing TB and reducing transmission. Overall, we show that a transition to individual-based genomic epidemiology will likely close some of the knowledge gaps in TB transmission and may redirect efforts towards cost-effective contact investigations for improved TB control.

Klíčová slova:

Epidemiology – Genetic networks – Infectious disease control – Infectious disease epidemiology – Medical risk factors – Phylogenetic analysis – Tuberculosis – Tuberculosis diagnosis and management


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