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Practical implementation of the WHO 2nd edition mutation catalogue in genotypic drug resistance detection pipelines

J E Phelan(1) P W Fowler(2) C Meehan(3)

1:London School of Hygiene and Tropical Medicine; 2:University of Oxford; 3:Nottingham Trent University

In November 2023 the World Health Organisation released an updated catalogue of mutations found in M. tuberculosis clinical isolates and their association to phenotypic drug resistance to enable the use of genome sequencing for the prediction of resistance. This catalogue was published as a combination of Microsoft Excel document, VCF positions file and report (PDF) which included some additional rules, notably a series of epigenetic rules. Here we describe the process to implement this mutation catalogue within two bioinformatic pipelines, TB-Profiler and GPAS.

Firstly, we describe how straightforward it was to parse the various and combined formats provided by the WHO, including implementing additional specific additional grading rules before integrating the catalogue into our pipelines. We note some practical considerations that were not described by the WHO report, such what to do when a mutation in a tier 1 gene not seen in the catalogue is detected. Finally, we describe the development of a genetically-diverse dataset which will aid developers of bioinformatic tools to implement this and future catalogues. The test dataset was developed using publicly available sequences from clinical isolates to cover commonly seen resistance patterns as well as simulated data to cover edge cases that may not yet have been observed yet. We hope this dataset can be utilised by the community to ensure new versions of the catalogue are rapidly integrated into existing pipelines as well as expediting the testing phase of new prediction tools.

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