Limits...
Large-scale whole genome sequencing of M. tuberculosis provides insights into transmission in a high prevalence area.

Guerra-Assunção JA, Crampin AC, Houben RM, Mzembe T, Mallard K, Coll F, Khan P, Banda L, Chiwaya A, Pereira RP, McNerney R, Fine PE, Parkhill J, Clark TG, Glynn JR - Elife (2015)

Bottom Line: High-quality sequences were available for 1687 disease episodes (72% of all culture-positive episodes): 66% of patients linked to at least one other patient.The between-patient mutation rate was 0.26 SNPs/year (95% CI 0.21-0.31).Transmissions resulting in disease decreased markedly over time.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.

ABSTRACT
To improve understanding of the factors influencing tuberculosis transmission and the role of pathogen variation, we sequenced all available specimens from patients diagnosed over 15 years in a whole district in Malawi. Mycobacterium tuberculosis lineages were assigned and transmission networks constructed, allowing ≤10 single nucleotide polymorphisms (SNPs) difference. We defined disease as due to recent infection if the network-determined source was within 5 years, and assessed transmissibility from forward transmissions resulting in disease. High-quality sequences were available for 1687 disease episodes (72% of all culture-positive episodes): 66% of patients linked to at least one other patient. The between-patient mutation rate was 0.26 SNPs/year (95% CI 0.21-0.31). We showed striking differences by lineage in the proportion of disease due to recent transmission and in transmissibility (highest for lineage-2 and lowest for lineage-1) that were not confounded by immigration, HIV status or drug resistance. Transmissions resulting in disease decreased markedly over time.

Show MeSH

Related in: MedlinePlus

Clusters built using SeqTrack.Each polygon represents a patient, with larger polygons representing twoor more patients with identical sequences. The patient details arewritten inside the polygon: F = female, M = male. Thenumber is the year of the start of the disease episode. The shapesdescribe drug resistance of the strain: squares = drug sensitive,circles = drug resistant, octagons = unknown. The colour ofthe polygon refers to HIV status of the patient: red = positive,blue = negative, grey = unknown. The colour of the edgerefers to the lineage: Lineage 1 (Indo Oceanic) dark blue, Lineage 2(Beijing/East Asian) light blue, Lineage 3 (East African Indian) green,and Lineage 4 (Europe American) red. The numbers on the arrows betweenthe polygons are the number of SNPs between them.DOI:http://dx.doi.org/10.7554/eLife.05166.008
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4384740&req=5

fig3s1: Clusters built using SeqTrack.Each polygon represents a patient, with larger polygons representing twoor more patients with identical sequences. The patient details arewritten inside the polygon: F = female, M = male. Thenumber is the year of the start of the disease episode. The shapesdescribe drug resistance of the strain: squares = drug sensitive,circles = drug resistant, octagons = unknown. The colour ofthe polygon refers to HIV status of the patient: red = positive,blue = negative, grey = unknown. The colour of the edgerefers to the lineage: Lineage 1 (Indo Oceanic) dark blue, Lineage 2(Beijing/East Asian) light blue, Lineage 3 (East African Indian) green,and Lineage 4 (Europe American) red. The numbers on the arrows betweenthe polygons are the number of SNPs between them.DOI:http://dx.doi.org/10.7554/eLife.05166.008

Mentions: To construct the transmission network, we included links of up to 10 SNPs difference.We included one sample per person-episode of disease and excluded extra-pulmonarycases as they cannot transmit. Example clusters are shown in Figure 3, and the full transmission network in Figure 3—figure supplement 1. Overall,after excluding relapses (recurrences with ≤10 SNPs difference from theinitial episode), 66% of patients were in clusters with at least one other patient.Clusters ranged in size from 2 to 36 (Figure4A), with 23% of patients in clusters of 10 or more. The size of theclusters varied by lineage (Figure 4B):compared to lineage-4 (the commonest lineage), lineage-2 and lineage-3 strains weremore likely to be clustered and in larger clusters and lineage-1 strains were lesslikely to be clustered and were in smaller clusters. The median cluster size andinterquartile range (IQR) for lineages 1–4 were 3 (1, 6), 13 (7, 24), 7 (2,22), and 3 (1, 8), respectively. The p-values for differences between lineages weresimilar if non-clustered strains were excluded.10.7554/eLife.05166.007Figure 3.Examples of clusters built using SeqTrack.


Large-scale whole genome sequencing of M. tuberculosis provides insights into transmission in a high prevalence area.

Guerra-Assunção JA, Crampin AC, Houben RM, Mzembe T, Mallard K, Coll F, Khan P, Banda L, Chiwaya A, Pereira RP, McNerney R, Fine PE, Parkhill J, Clark TG, Glynn JR - Elife (2015)

Clusters built using SeqTrack.Each polygon represents a patient, with larger polygons representing twoor more patients with identical sequences. The patient details arewritten inside the polygon: F = female, M = male. Thenumber is the year of the start of the disease episode. The shapesdescribe drug resistance of the strain: squares = drug sensitive,circles = drug resistant, octagons = unknown. The colour ofthe polygon refers to HIV status of the patient: red = positive,blue = negative, grey = unknown. The colour of the edgerefers to the lineage: Lineage 1 (Indo Oceanic) dark blue, Lineage 2(Beijing/East Asian) light blue, Lineage 3 (East African Indian) green,and Lineage 4 (Europe American) red. The numbers on the arrows betweenthe polygons are the number of SNPs between them.DOI:http://dx.doi.org/10.7554/eLife.05166.008
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4384740&req=5

fig3s1: Clusters built using SeqTrack.Each polygon represents a patient, with larger polygons representing twoor more patients with identical sequences. The patient details arewritten inside the polygon: F = female, M = male. Thenumber is the year of the start of the disease episode. The shapesdescribe drug resistance of the strain: squares = drug sensitive,circles = drug resistant, octagons = unknown. The colour ofthe polygon refers to HIV status of the patient: red = positive,blue = negative, grey = unknown. The colour of the edgerefers to the lineage: Lineage 1 (Indo Oceanic) dark blue, Lineage 2(Beijing/East Asian) light blue, Lineage 3 (East African Indian) green,and Lineage 4 (Europe American) red. The numbers on the arrows betweenthe polygons are the number of SNPs between them.DOI:http://dx.doi.org/10.7554/eLife.05166.008
Mentions: To construct the transmission network, we included links of up to 10 SNPs difference.We included one sample per person-episode of disease and excluded extra-pulmonarycases as they cannot transmit. Example clusters are shown in Figure 3, and the full transmission network in Figure 3—figure supplement 1. Overall,after excluding relapses (recurrences with ≤10 SNPs difference from theinitial episode), 66% of patients were in clusters with at least one other patient.Clusters ranged in size from 2 to 36 (Figure4A), with 23% of patients in clusters of 10 or more. The size of theclusters varied by lineage (Figure 4B):compared to lineage-4 (the commonest lineage), lineage-2 and lineage-3 strains weremore likely to be clustered and in larger clusters and lineage-1 strains were lesslikely to be clustered and were in smaller clusters. The median cluster size andinterquartile range (IQR) for lineages 1–4 were 3 (1, 6), 13 (7, 24), 7 (2,22), and 3 (1, 8), respectively. The p-values for differences between lineages weresimilar if non-clustered strains were excluded.10.7554/eLife.05166.007Figure 3.Examples of clusters built using SeqTrack.

Bottom Line: High-quality sequences were available for 1687 disease episodes (72% of all culture-positive episodes): 66% of patients linked to at least one other patient.The between-patient mutation rate was 0.26 SNPs/year (95% CI 0.21-0.31).Transmissions resulting in disease decreased markedly over time.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.

ABSTRACT
To improve understanding of the factors influencing tuberculosis transmission and the role of pathogen variation, we sequenced all available specimens from patients diagnosed over 15 years in a whole district in Malawi. Mycobacterium tuberculosis lineages were assigned and transmission networks constructed, allowing ≤10 single nucleotide polymorphisms (SNPs) difference. We defined disease as due to recent infection if the network-determined source was within 5 years, and assessed transmissibility from forward transmissions resulting in disease. High-quality sequences were available for 1687 disease episodes (72% of all culture-positive episodes): 66% of patients linked to at least one other patient. The between-patient mutation rate was 0.26 SNPs/year (95% CI 0.21-0.31). We showed striking differences by lineage in the proportion of disease due to recent transmission and in transmissibility (highest for lineage-2 and lowest for lineage-1) that were not confounded by immigration, HIV status or drug resistance. Transmissions resulting in disease decreased markedly over time.

Show MeSH
Related in: MedlinePlus