{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T04:28:58Z","timestamp":1774412938354,"version":"3.50.1"},"posted":{"date-parts":[[2023,3,19]]},"group-title":"Infectious Diseases (except HIV\/AIDS)","reference-count":30,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,3,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Eight lineages of\n                  <jats:italic>Mycobacterium tuberculosis sensu stricto<\/jats:italic>\n                  are described. Single-country or small observational data suggest differences in clinical phenotype between lineages. We present strain lineage and clinical phenotype data from 12,246 patients from 3 low-incidence and 5 high-incidence countries. We used multivariable logistic regression to explore the effect of lineage on site of disease and on cavities on chest radiography, given pulmonary TB; multivariable multinomial logistic regression to investigate types of extra-pulmonary TB, given lineage; and accelerated failure time and Cox proportional-hazards models to explore the effect of lineage on time to smear and culture-conversion. Mediation analyses quantified the direct effects of lineage on outcomes. Pulmonary disease was more likely among patients with lineage(L) 2, L3 or L4, than L1 (adjusted odds ratio (aOR) 1.79, (95% confidence interval 1.49-2.15), p&lt;0.001; aOR=1.40(1.09-1.79), p=0.007; aOR=2.04(1.65-2.53), p&lt;0.001, respectively). Among patients with pulmonary TB, those with L1 had greater risk of cavities on chest radiography versus those with L2 (aOR=0.69(0.57-0.83), p&lt;0.001) and L4 strains (aOR=0.73(0.59-0.90), p=0.002). L1 strains were more likely to cause osteomyelitis among patients with extra-pulmonary TB, versus L2-4 (p=0.033, p=0.008 and p=0.049 respectively). Patients with L1 strains showed shorter time-to-sputum smear conversion than for L2. Causal mediation analysis showed the effect of lineage in each case was largely direct. The pattern of clinical phenotypes seen with L1 strains differed from modern lineages (L2-4). This has implications for clinical management and could influence clinical trial selection strategies.\n                <\/jats:p>","DOI":"10.1101\/2023.03.14.23287284","type":"posted-content","created":{"date-parts":[[2023,3,19]],"date-time":"2023-03-19T17:55:11Z","timestamp":1679248511000},"source":"Crossref","is-referenced-by-count":7,"title":["The effect of\n                  <i>M. tuberculosis<\/i>\n                  lineage on clinical phenotype"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9181-3386","authenticated-orcid":false,"given":"Duc Hong","family":"Du","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronald B","family":"Geskus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7890-4312","authenticated-orcid":false,"given":"Yanlin","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6825-2050","authenticated-orcid":false,"given":"Luigi Ruffo","family":"Codecasa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6415-1535","authenticated-orcid":false,"given":"Daniela Maria","family":"Cirillo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reinout","family":"van Crevel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dyshelly Nurkartika","family":"Pascapurnama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lidya","family":"Chaidir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Niemann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8304-7709","authenticated-orcid":false,"given":"Roland","family":"Diel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaheed Vally","family":"Omar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louis","family":"Grandjean","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sakib","family":"Rokadiya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arturo Torres","family":"Ortitz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nguy\u1ec5n H\u1eefu","family":"L\u00e2n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u0110\u1eb7ng Th\u1ecb","family":"Minh H\u00e0","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E. Grace","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esther","family":"Robinson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Dedicoat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Le Thanh","family":"Hoang Nhat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guy E","family":"Thwaites","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Le Hong","family":"Van","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nguyen Thuy","family":"Thuong Thuong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0421-9264","authenticated-orcid":false,"given":"Timothy M","family":"Walker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023032204550835000_2023.03.14.23287284v1.1","unstructured":"World Health Organization. Global tuberculosis report 2021 [Internet]. Geneva: World Health Organization; 2021 [cited 2021 Oct 14]. Available from: https:\/\/apps.who.int\/iris\/handle\/10665\/346387"},{"key":"2023032204550835000_2023.03.14.23287284v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16626-6"},{"key":"2023032204550835000_2023.03.14.23287284v1.3","doi-asserted-by":"crossref","unstructured":"Coscolla M , Gagneux S , Menardo F , Loiseau C , Ruiz-Rodriguez P , Borrell S , et al. Phylogenomics of Mycobacterium africanum reveals a new lineage and a complex evolutionary history. Microbial Genomics. 2021 February 1;7(2).","DOI":"10.1099\/mgen.0.000477"},{"key":"2023032204550835000_2023.03.14.23287284v1.4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0511240103"},{"key":"2023032204550835000_2023.03.14.23287284v1.5","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.meegid.2013.02.015","article-title":"Allopatric tuberculosis host\u2013pathogen relationships are associated with greater pulmonary impairment","volume":"16","year":"2013","journal-title":"Infection, Genetics and Evolution"},{"key":"2023032204550835000_2023.03.14.23287284v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3704"},{"issue":"6","key":"2023032204550835000_2023.03.14.23287284v1.7","first-page":"e01916","article-title":"Atypical Genetic Basis of Pyrazinamide Resistance in Monoresistant Mycobacterium tuberculosis","volume":"65","year":"2021","journal-title":"Antimicrob Agents Chemother"},{"issue":"6","key":"2023032204550835000_2023.03.14.23287284v1.8","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1093\/jac\/dkac070","article-title":"Ancient and recent differences in the intrinsic susceptibility of Mycobacterium tuberculosis complex to pretomanid","volume":"77","year":"2022","journal-title":"Journal of Antimicrobial Chemotherapy"},{"key":"2023032204550835000_2023.03.14.23287284v1.9","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cir788"},{"key":"2023032204550835000_2023.03.14.23287284v1.10","doi-asserted-by":"crossref","unstructured":"Saelens JW , Sweeney MI , Viswanathan G , Xet-Mull AM , Jurcic Smith KL , Sisk DM , et al. An ancestral mycobacterial effector promotes dissemination of infection. Cell. 2022 Nov; S0092867422013617.","DOI":"10.1016\/j.cell.2022.10.019"},{"issue":"5","key":"2023032204550835000_2023.03.14.23287284v1.11","first-page":"e10753","article-title":"Influence of M","volume":"5","year":"2010","journal-title":"tuberculosis Lineage Variability within a Clinical Trial for Pulmonary Tuberculosis. Marais B, editor. PLoS ONE"},{"key":"2023032204550835000_2023.03.14.23287284v1.12","doi-asserted-by":"crossref","first-page":"e12128","DOI":"10.7717\/peerj.12128","article-title":"Whole-genome comparative analysis at the lineage\/sublineage level discloses relationships between Mycobacterium tuberculosis genotype and clinical phenotype","volume":"9","year":"2021","journal-title":"PeerJ"},{"key":"2023032204550835000_2023.03.14.23287284v1.13","unstructured":"Robert Koch Institute. Report on the Epidemiology of Tuberculosis in Germany -2020 [Internet]. 2021 Dec [cited 2022 May 30]. Available from: https:\/\/www.rki.de\/EN\/Content\/infections\/epidemiology\/inf_dis_Germany\/TB\/summary_2020.html"},{"key":"2023032204550835000_2023.03.14.23287284v1.14","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2010.136242"},{"key":"2023032204550835000_2023.03.14.23287284v1.15","doi-asserted-by":"publisher","DOI":"10.1037\/a0031034"},{"issue":"3","key":"2023032204550835000_2023.03.14.23287284v1.16","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1093\/oxfordjournals.aje.a114254","article-title":"The role of model selection in causal inference from nonexperimental data","volume":"123","year":"1986","journal-title":"American Journal of Epidemiology"},{"key":"2023032204550835000_2023.03.14.23287284v1.17","doi-asserted-by":"crossref","unstructured":"Van der Weele TJ. Explanation in causal inference: developments in mediation and interaction. Int J Epidemiol. 2016 Nov 17;dyw277.","DOI":"10.1093\/ije\/dyw277"},{"key":"2023032204550835000_2023.03.14.23287284v1.18","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwq332"},{"issue":"5","key":"2023032204550835000_2023.03.14.23287284v1.19","doi-asserted-by":"crossref","first-page":"e20","DOI":"10.1097\/EDE.0000000000001378","article-title":"CMAverse: A Suite of Functions for Reproducible Causal Mediation Analyses","volume":"32","year":"2021","journal-title":"Epidemiology"},{"key":"2023032204550835000_2023.03.14.23287284v1.20","unstructured":"R Core Development Team. A language and environment for statistical computing. R Foundation for Statistical Computing 2022 [Internet]. Available from: Available from: https:\/\/www.R-project.org\/"},{"key":"2023032204550835000_2023.03.14.23287284v1.21","doi-asserted-by":"crossref","unstructured":"Wickham H. Ggplot2: elegant graphics for data analysis. New York: Springer; 2009. 212 p. (Use R!).","DOI":"10.1007\/978-0-387-98141-3"},{"key":"2023032204550835000_2023.03.14.23287284v1.22","doi-asserted-by":"crossref","unstructured":"Anderson-Bergman C. icenReg : Regression Models for Interval Censored Data in R. J Stat Soft [Internet]. 2017 [cited 2022 Aug 24];81(12). Available from: http:\/\/www.jstatsoft.org\/v81\/i12\/","DOI":"10.18637\/jss.v081.i12"},{"key":"2023032204550835000_2023.03.14.23287284v1.23","doi-asserted-by":"crossref","first-page":"100361","DOI":"10.1016\/j.lanepe.2022.100361","article-title":"Mycobacterium tuberculosis transmission in Birmingham, UK, 2009\u201319: An observational study","volume":"17","year":"2022","journal-title":"The Lancet Regional Health -Europe"},{"issue":"6","key":"2023032204550835000_2023.03.14.23287284v1.24","doi-asserted-by":"crossref","first-page":"e117","DOI":"10.1016\/S1473-3099(20)30148-1","article-title":"Cavitary tuberculosis: the gateway of disease transmission","volume":"20","year":"2020","journal-title":"The Lancet Infectious Diseases"},{"key":"2023032204550835000_2023.03.14.23287284v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2744"},{"key":"2023032204550835000_2023.03.14.23287284v1.26","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cix169"},{"issue":"9","key":"2023032204550835000_2023.03.14.23287284v1.27","doi-asserted-by":"crossref","first-page":"972","DOI":"10.5588\/ijtld.18.0710","article-title":"Indo-Oceanic Mycobacterium tuberculosis strains from Thailand associated with higher mortality","volume":"23","year":"2019","journal-title":"Int J Tuberc Lung Dis"},{"key":"2023032204550835000_2023.03.14.23287284v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0117-9."},{"issue":"1","key":"2023032204550835000_2023.03.14.23287284v1.29","doi-asserted-by":"crossref","first-page":"6099","DOI":"10.1038\/s41467-021-26248-1","article-title":"Population structure, biogeography and transmissibility of Mycobacterium tuberculosis","volume":"12","year":"2021","journal-title":"Nat Commun"},{"issue":"7","key":"2023032204550835000_2023.03.14.23287284v1.30","doi-asserted-by":"crossref","first-page":"878","DOI":"10.5588\/ijtld.12.0732","article-title":"Association between Mycobacterium tuberculosis lineage and time to sputum culture conversion","volume":"17","year":"2013","journal-title":"Int J Tuberc Lung Dis"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.03.14.23287284","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:30:00Z","timestamp":1768505400000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2023.03.14.23287284"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,19]]},"references-count":30,"URL":"https:\/\/doi.org\/10.1101\/2023.03.14.23287284","relation":{},"subject":[],"published":{"date-parts":[[2023,3,19]]},"subtype":"preprint"}}