Mixed infections in genotypic drug-resistant Mycobacterium tuberculosis
Abstract Tuberculosis disease (TB), caused by Mycobacterium tuberculosis, is a major global public health problem, resulting in more than 1 million deaths each year. Drug resistance (DR), including multi-drug (MDR-TB), is making TB control difficult and accounts for 16% of new and 48% of previously...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-10-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-44341-x |
| _version_ | 1797452573033103360 |
|---|---|
| author | Linfeng Wang Susana Campino Jody Phelan Taane G. Clark |
| author_facet | Linfeng Wang Susana Campino Jody Phelan Taane G. Clark |
| author_sort | Linfeng Wang |
| collection | DOAJ |
| description | Abstract Tuberculosis disease (TB), caused by Mycobacterium tuberculosis, is a major global public health problem, resulting in more than 1 million deaths each year. Drug resistance (DR), including multi-drug (MDR-TB), is making TB control difficult and accounts for 16% of new and 48% of previously treated cases. To further complicate treatment decision-making, many clinical studies have reported patients harbouring multiple distinct strains of M. tuberculosis across the main lineages (L1 to L4). The extent to which drug-resistant strains can be deconvoluted within mixed strain infection samples is understudied. Here, we analysed M. tuberculosis isolates with whole genome sequencing data (n = 50,723), which covered the main lineages (L1 9.1%, L2 27.6%, L3 11.8%, L4 48.3%), with genotypic resistance to isoniazid (HR-TB; n = 9546 (29.2%)), rifampicin (RR-TB; n = 7974 (24.4%)), and at least MDR-TB (n = 5385 (16.5%)). TB-Profiler software revealed 531 (1.0%) isolates with potential mixed sub-lineage infections, including some with DR mutations (RR-TB 21/531; HR-TB 59/531; at least MDR-TB 173/531). To assist with the deconvolution of such mixtures, we adopted and evaluated a statistical Gaussian Mixture model (GMM) approach. By simulating 240 artificial mixtures of different ratios from empirical data across L1 to L4, a GMM approach was able to accurately estimate the DR profile of each lineage, with a low error rate for the estimated mixing proportions (mean squared error 0.012) and high accuracy for the DR predictions (93.5%). Application of the GMM model to the clinical mixtures (n = 531), found that 33.3% (188/531) of samples consisted of DR and sensitive lineages, 20.2% (114/531) consisted of lineages with only DR mutations, and 40.6% (229/531) consisted of lineages with genotypic pan-susceptibility. Overall, our work demonstrates the utility of combined whole genome sequencing data and GMM statistical analysis approaches for providing insights into mono and mixed M. tuberculosis infections, thereby potentially assisting diagnosis, treatment decision-making, drug resistance and transmission mapping for infection control. |
| first_indexed | 2024-03-09T15:10:37Z |
| format | Article |
| id | doaj.art-4060938ee1d841fbaf20a1b20dd12b2e |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-09T15:10:37Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-4060938ee1d841fbaf20a1b20dd12b2e2023-11-26T13:23:46ZengNature PortfolioScientific Reports2045-23222023-10-011311810.1038/s41598-023-44341-xMixed infections in genotypic drug-resistant Mycobacterium tuberculosisLinfeng Wang0Susana Campino1Jody Phelan2Taane G. Clark3Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical MedicineDepartment of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical MedicineDepartment of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical MedicineDepartment of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical MedicineAbstract Tuberculosis disease (TB), caused by Mycobacterium tuberculosis, is a major global public health problem, resulting in more than 1 million deaths each year. Drug resistance (DR), including multi-drug (MDR-TB), is making TB control difficult and accounts for 16% of new and 48% of previously treated cases. To further complicate treatment decision-making, many clinical studies have reported patients harbouring multiple distinct strains of M. tuberculosis across the main lineages (L1 to L4). The extent to which drug-resistant strains can be deconvoluted within mixed strain infection samples is understudied. Here, we analysed M. tuberculosis isolates with whole genome sequencing data (n = 50,723), which covered the main lineages (L1 9.1%, L2 27.6%, L3 11.8%, L4 48.3%), with genotypic resistance to isoniazid (HR-TB; n = 9546 (29.2%)), rifampicin (RR-TB; n = 7974 (24.4%)), and at least MDR-TB (n = 5385 (16.5%)). TB-Profiler software revealed 531 (1.0%) isolates with potential mixed sub-lineage infections, including some with DR mutations (RR-TB 21/531; HR-TB 59/531; at least MDR-TB 173/531). To assist with the deconvolution of such mixtures, we adopted and evaluated a statistical Gaussian Mixture model (GMM) approach. By simulating 240 artificial mixtures of different ratios from empirical data across L1 to L4, a GMM approach was able to accurately estimate the DR profile of each lineage, with a low error rate for the estimated mixing proportions (mean squared error 0.012) and high accuracy for the DR predictions (93.5%). Application of the GMM model to the clinical mixtures (n = 531), found that 33.3% (188/531) of samples consisted of DR and sensitive lineages, 20.2% (114/531) consisted of lineages with only DR mutations, and 40.6% (229/531) consisted of lineages with genotypic pan-susceptibility. Overall, our work demonstrates the utility of combined whole genome sequencing data and GMM statistical analysis approaches for providing insights into mono and mixed M. tuberculosis infections, thereby potentially assisting diagnosis, treatment decision-making, drug resistance and transmission mapping for infection control.https://doi.org/10.1038/s41598-023-44341-x |
| spellingShingle | Linfeng Wang Susana Campino Jody Phelan Taane G. Clark Mixed infections in genotypic drug-resistant Mycobacterium tuberculosis Scientific Reports |
| title | Mixed infections in genotypic drug-resistant Mycobacterium tuberculosis |
| title_full | Mixed infections in genotypic drug-resistant Mycobacterium tuberculosis |
| title_fullStr | Mixed infections in genotypic drug-resistant Mycobacterium tuberculosis |
| title_full_unstemmed | Mixed infections in genotypic drug-resistant Mycobacterium tuberculosis |
| title_short | Mixed infections in genotypic drug-resistant Mycobacterium tuberculosis |
| title_sort | mixed infections in genotypic drug resistant mycobacterium tuberculosis |
| url | https://doi.org/10.1038/s41598-023-44341-x |
| work_keys_str_mv | AT linfengwang mixedinfectionsingenotypicdrugresistantmycobacteriumtuberculosis AT susanacampino mixedinfectionsingenotypicdrugresistantmycobacteriumtuberculosis AT jodyphelan mixedinfectionsingenotypicdrugresistantmycobacteriumtuberculosis AT taanegclark mixedinfectionsingenotypicdrugresistantmycobacteriumtuberculosis |