Pathotypr expands lineage classification for tuberculosis genomic surveillance

Whole-genome sequencing can support tuberculosis surveillance, but incomplete lineage schemes may leave isolates unclassified or assign them incorrectly. Researchers developed Pathotypr, an open-source tool that accepts genome assemblies or raw sequencing reads and reports lineage assignments, WHO-cataloged resistance-associated variants, and a closely related reference genome. Its marker set was derived from 26,813 *Mycobacterium tuberculosis* complex genomes. The authors evaluated the software using independent datasets, an 88,071-sample benchmark, and 7,148 CRyPTIC genomes.

In validation, the assembly-based methods matched phylogenetic lineage assignments in 498 complete reference genomes (498 for Predict; 497 for Classify), while the read-based module assigned all 162 clinical read datasets to the expected lineage. In the 88,071-sample benchmark, Pathotypr and TB-Profiler agreed on major-lineage assignments for directly comparable samples; Pathotypr also identified uncommon L10, A1, and A2 isolates not identified by TB-Profiler’s marker set. For the 7,148 CRyPTIC isolates, genotypic and phenotypic resistance profiles agreed in 86.4%; sensitivity for multidrug-resistant or pre-extensively drug-resistant status was 93.5%, with a positive predictive value of 92.3%.

The findings support Pathotypr’s potential use in genomic surveillance, not replacement of phenotypic drug-susceptibility testing. Agreement was lower for several drugs, including bedaquiline and linezolid. The article is an early-release version, and the authors note that uncommon lineages are sparsely sampled; CRyPTIC is also enriched for drug-resistant isolates and is not population-based.