Spatio-temporal patterns of tuberculosis revealed by routine Mycobacterium tuberculosis sequencing in Australia: an extended patient cohort analysis (2017–2023)

Background: facilitates accurate transmission tracking, but its integration into public health response remains limited. This study conducted spatiotemporal analyses of routine WGS data and assessed its potential value to guide programmatic TB control responses. Methods: isolates were examined, representing 94.9% of culture-confirmed and 64.2% of all notified TB cases in New South Wales, Australia (2017-2023). We performed genomic clustering, assessed genetic and geographic distances between cases, and applied Bayesian dated phylogeny to estimate the likely time of strain introduction. Findings: Most notified TB cases were successfully sequenced and geolocated, with 88.3% (2200/2492) residing in metropolitan Sydney. The local health districts (LHDs) with the highest case counts were South Western (523/2492, 21.0%) and Western Sydney (476/2492, 19.1%). Using a 5-SNP threshold, WGS identified 106 putative transmission clusters involving 288 cases (11.7%), with 50% spanning multiple LHDs. Eight large clusters (≥5 members) were identified, containing 64 cases (2.6%). The largest cluster (17 members) was caused by a Lineage 1 strain, although most large clusters were associated with Lineage 2 strains; two were isoniazid resistant. There was poor correlation between genetic and geographic distances, which showed some improvement with removal of outliers. Most recent common ancestor estimates suggested recent introduction of strains associated with local transmission. Strain clustering and lineage-through-time analyses revealed temporal patterns in cluster expansion and contraction, facilitating accurate monitoring of cluster spread across all of NSW. Interpretation: The findings demonstrate the added value of integrating genomic and spatiotemporal clustering data to detect persistent transmission and guide targeted interventions to pursue the aspirational goal of "zero local TB transmission". Funding: NHMRC Centre for Research Excellence in Tuberculosis (www.tbcre.org.au) and New South Wales Health Prevention Research Support Program.