Defining the Genetic Basis for Radiological Pathology in Tuberculosis

Background:
Tuberculosis remains the worlds single most deadly pathogen1 responsible for the deaths of 1 billion people over the last 200 years. Despite this very little is known about the genetic determinants of pathology in tuberculosis disease2. Defining the genomic determinants of pathology would enable enhanced treatments and contract tracing efforts to be targeted to those strains most likely to cause extensive disease and cause secondary cases of disease3. This study benefits from two large parallel funded studies: 1) The cryptic consortium which is sequencing 100,000 global TB genomes and 2) An NIH R01 funded study examining the genomic determinants of transmission in tuberculosis.

Aims/Objectives:
1. To undertake a household cohort study of new TB patients (children and adults) in Lima, Peru and collect sputum samples/metadata/radiological data for comparison.
2. To use new Genome Wide Association Study techniques in pathogen genomics to determine the genomic signatures of radiological pathology in tuberculosis.
3. To determine the genomic markers of transmissibility-to-disease in tuberculosis households.

Methods:
This PhD will be partly undertaken in Lima, Peru together with the UCL/LSHTM/Imperial/Johns Hopkins Bloomberg School of Public Health research facility at the University Peruana Cayetano Heredia. The candidate will undertake a prospective cohort study of households in which sputum samples, clinical, demographic and radiologic metadata (chest radiographs and CT's) will be collected in parallel. Samples will be sequenced either as part of the Cryptic Consortium or as part of a recently funded NIH study of tuberculosis transmission genetics. Households will be followed up to determine the incidence of secondary cases of disease. The candidate will learn how to implement new techniques in pathogen genome wide association studies (SeerWas4 and TreeWas5) in order to determine the genetic determinants of radiological pathology and transmission in tuberculosis.

Timeline:
Month 1-12: Undertake a household cohort study in Peru.
Month 12-24: Training in phylogenetics and household follow up study.
Month 24-36:  Analyse data and write up PhD.

References:
1.  Paulson. Epidemiology a Mortal Foe – Nature 2013
2.  Grandjean. Association Between Bacterial Homoplastic Variants and Radiological Pathology in Tuberculosis. Thorax 2019
3.  Grandjean Investigating the Pathogen Genomic Determinants of Tuberculosis Transmission AmJRCCM 2017
4.  Lees. Sequence element enrichment analysis to determine the genetic basis of bacterial phenotypes. Nature Communications 2016
5.  Collins. A phylogenetic method to perform genome-wide association studies in microbes that accounts for population structure and recombination. Plos Computational Biology 2018