A platform for equitable global access to whole genome sequencing-guided management and control of drug resistant tuberculosis (MAGMA). (MAGMA)

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the world's most deadly infectious disease with 1.6 million people dying from TB each year. A combination of several antibiotics for 6 to 9 months can cure TB if the infecting Mtb strain is not drug resistant. Every year, there are about 450,000 new cases of rifampicin-resistant TB (RR-TB), which is much more difficult and expensive to treat. To cure RR-TB, it is crucial to have a precise and comprehensive diagnosis of drug resistance for individual patients. To stop the continued global spread of RR-TB, halting the chain of transmission is key. Thanks to the genomic revolution, accurate insights in both drug resistance and transmission events can now be obtained by whole genome sequencing (WGS). At present, WGS of Mtb is done on purified Mtb DNA obtained after one or more lengthy culturing steps. Sequencing Mtb straight from sputum or early positive primary liquid cultures would reduce the sample-to-interpretation timeframe. Analyzing Mtb DNA extracted from these samples is however extremely challenging because of the low amount of Mtb DNA and the high level of human and other micro-organisms contamination in such samples. The TORCH consortium, founded by Prof Van Rie at the University of Antwerp, developed MAGMA (Maximum Accessible Genome for Mtb Analysis), an easy-to-use bioinformatics pipeline specifically created for the analysis of Mtb sequencing data for clinical and public health applications. Even though MAGMA was developed with end-users in mind, the interpretation of resistance profiles and transmission clusters will remain challenging for doctors and public health workers who typically lack bioinformatics expertise. The MAGMA databases and software will also need regular updates and maintenance to remain up-to-date with the rapid scientific developments. To use MAGMA for improved RR-TB care and control, the next steps are valorisation, user-testing, accreditation and endorsement by international organizationssuch as the World Health Organization (WHO). To achieve this, we will work in tandem with Sequentia Biotech, a commercial bioinformatics company with experience in clinical bioinformatics pipelines. Information obtained through surveys with end-users and stakeholders, Sequentia Biotech will be able to create a web platform that generates automated, reliable, and actionable outputs. For doctors, we aim to report and visualize the drug resistance profiles and translate these into the optimal treatment regimen for their patients, thus enabling the use of precision medicine for RR-TB. For regional and national DR-TB reference laboratories, we aim to create a dashboard that monitors resistance to 'old' TB drugs (such as rifampicin, isoniazid, pyrazinamide and fluoroquinolones) and emergence of resistance to new TB drugs (including bedaquiline, linezolid, delanamid and pretonamid). For contact tracing units, we aim to translate the phylogenetic data generated by MAGMA into a dynamic and interactive display of transmission events with identification of superspreading and 'high risk' drug resistance profiles to target public health actions, thus enabling a precision public health approach to RR-TB control.

Keywords:PERSONALIZED HEALTH CARE, BIOINFORMATICS

Disciplines:Bioinformatics of disease, Other medical and health sciences not elsewhere classified