MICA: Radio+ TB trial development: Determining the optimal regimen for bacteriologically negative, radiographically apparent TB diagnosed usingnewtest

Lead Research Organisation: University College London
Department Name: MRC Clinical Trials Unit


Tuberculosis (TB) is the leading cause of death from an infectious disease globally, with most of the cases in Africa and Asia. There is now a strong, international political commitment to ending the TB epidemic over the next 15 years. At the moment, each year only 70% (7 million) of the world's estimated 10 million TB cases are picked up and started on treatment. A major goal of the End-TB strategy over the next few years is to "find these missing millions" starting at least 90% of TB cases on treatment. To do this it is recognised that we need a much more proactive approach and need to embrace technological advances. Digital chest X-Ray (where image appears on a computer screen rather than a film) is increasingly being recommended as an important screening tool to do this as it can pick up the earliest signs of disease on the lungs before the patient has any symptoms and therefore identify people who need testing for TB (on a coughed up sample of sputum). Each year millions of people in Africa and Asia are now being screened for TB with digital chest X-Ray (>400,000 in one city in Pakistan alone). Although this has proved very effective, an emerging issue with this approach is that it finds lots of people who look like they have TB on the chest X-ray but their sputum test is negative. We know some of these people are at very high risk to developing TB in subsequent years, but there is currently no agreed simplified approach on how to treat this group in these settings and they often are not followed up and become part of the lost TB cases. Part of the problem is than no clinical trials have been done for this group for over 35 years.

We want to directly address this problem in a modern trial to find out, how much of what drug treatment is needed to treat people who have abnormal chest X-Ray but negative sputum tests for TB to stop them from developing TB in the future. We will use two new tests to identify those most likely to have TB and benefit from treatment, these tests are ready to be used if found to work well. Firstly we will use software which uses artificial intelligence to analyse the chest x-ray image to see if the pattern suggests TB. This software provides an answer in minutes at low cost and now is so sophisticated that it performs better and more consistently than human readers. If the software thinks the chest X-Ray looks like TB, we will conduct a second test on a small volume of blood (ultimately may only be a finger prick). This blood sample is placed directly into a cartridge and loaded onto a machine and analysed for a genetic pattern which suggests the body is fighting TB, with an answer available in 2 hours. This new blood test is made by the same company (Cepheid) as the most widely used sputum test for TB (Xpert) and run on exactly the same machine, therefore the machine is even found on mobile X-ray vans that travel into hard to reach communities to find TB.

In order to undertake this trial we need to address some key questions which we propose to do in this development grant namely:

1) There are several artificial intelligence software packages that have been trained in different ways. What is the best artificial intelligence software package for our trial, to detect and predict TB in the settings we are interested in?

2) By how much will adding the new TB blood test improve this detection/prediction?

3) If a thousand people were screened with X-Ray how many will the artificial intelligence software call abnormal and how many of those will have a positive TB blood test?

4) What do patients and their doctors think of our approach and what would they value the most in treatment? Short duration, high success rate or certainty of diagnosis?

5) Where should we conduct our trial? Which setting has the right combination of seeing enough patients and expertise to conduct a trial?

Technical Summary

Obj 1+2 - How these two tests are optimally combined to predict TB?
From a completed South African household contact study, 518 baseline chest X-rays will be analysed with three CAD packages with 48 prevalent and incident (by culture and Xpert) as reference standards. By ROC analysis maximal sensitivity threshold scores will be identified. 250 of these participants have baseline FDG-PET/CT available and Blood RNA stored. CAD abnormality heat maps will be compared to CT component as radiological reference standard. All 250 participants will have blood tested on the TB Host Response cartridge with disease scores determined. Optimal cut off for TB Host Response test will be determined when combined with chest x-ray CAD scores to maintain sensitivity but increases positive predictive value.

Obj 3 - Proportion expected to be positive in two clinical settings?
a. (Active case finding) In an ongoing cohort in Zimbabwe and Mozambique, 1400 household contacts will have chest X-Ray and a single sputum Xpert, blood RNA at baseline. Blood samples from 100 with CAD above threshold matched with 100 below will have TB Host Response test run to determine proportion positive.
b. (Primary care) In an ongoing cohort in Malawi, 200 presenting for TB assessment will have chest X-Ray and a single sputum Xpert, blood RNA at baseline. Blood samples from all 200 will have TB Host Response test run to determine proportion positive.

Obj 4 - Patient and provider attitudes to management?
Discrete choice experiments (DCE) will be designed to understand patient and provider preferences. Focus groups and existing literature will guide attributes and attribute levels for the choice set which from the basis of the DCE questionnaire. Sample size of 150.

Obj 5 - Best sites for trial?
We will develop a set of criteria focusing on existing screening activity/numbers and trial expertise/experience to evaluate additional/optimal sites in both clinical settings in Africa and Asia.

Planned Impact

We anticipate the development grant itself will have considerable impact as outlined below.

Policymakers such as WHO and National TB Programs will benefit from this research. National and international guidelines vary in their recommendations, without clear consensus for those who are bacteriologically negative with chest X-Ray abnormalities (particularly for ambulatory, HIV-uninfected adults), generally suggesting use of clinical judgement, seeking alternative diagnosis or keeping under follow-up unless severe or rapidly progressing illness. In practice patients often get lost to follow-up representing a missed opportunity to prevent disease. Several clinical trials conducted in this group with culture negative, radiographically apparent disease prior to 1985 demonstrated with close active monitoring 29-58% became culture positive over follow-up and showed number needed to treat of < 4 with empirical treatment. This data has largely been forgotten (and is now out-dated) but is becoming more relevant with increasing use of chest X-ray screening. A major impact of this development work will be to bring this neglected aspect of TB management onto the agenda and highlight the role new diagnostics could play and make them aware of plans for our trial which seeks to define a programmatic solution to the problem.

Non-governmental organisations, funders and major global initiatives recommending and conducting active case finding will also benefit from this research. The Zero TB cities Initiative for example promotes a Search-Treat-Prevent strategy in numerous major cities in high TB burden countries. The Zero TB Karachi initiative which utilises 20 mobile x-ray vans and 10 fixed X-ray stations in 2018 screened 419,169 people in Karachi with chest X-ray of which 34,853 were abnormal of which 2,304 had positive sputum Xpert. Our work in the development grant will highlight the need to define optimal management for those with negative sputum Xpert and we will actively seek to engage with such groups.

This proposal will contribute to capacity development in training of laboratory technicians in Malawi, Mozambique and Zimbabwe to undertake running of the Cepheid TB Host Response test. This training will be conducted by a post-doctoral fellow from Cape Town contributing to strengthening of South-South research collaboration. In addition the discrete choice experiment work conducted in Malawi will contribute to a Master's project for a Malawian student.

Our project will directly engage with patients and providers in conducting discrete choice experiments. Through this we will develop a patient group in Malawi initially to conduct focus groups. We will continue to engage with this group in aspects of trial design and seek views on public engagement activities. We also have close links with public engagement groups in Cape Town that we will seek to involve to promote understanding and engagement around chest x-ray screening and computer aided diagnosis.


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Description Evaluation of paediatric CXR using CAD software 
Organisation University College London
Department Medical Research Council Clinical Trials Unit (MRC CTU) at UCL
Country United Kingdom 
Sector Public 
PI Contribution Our study focused on the use of CAD software to evaluate the chet X-rays of adults. As a result of the award we have develped a collaboration within MRC CTU with FIND to evaulate the utility of CAD software in children where there is much less data.
Collaborator Contribution The collaborators are providing 1200 images from there study for assessment and identified someone to analyse results
Impact Nil yet
Start Year 2021
Description Evaluation of the use of face mask sampling for TB 
Organisation University of Leicester
Department Department of Health Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution As a result of the award we developed a new collaboration with University of Leicester to evaluate a novel diagnostic test they have developped to capture Mycobacterium tuberculosis within espiratory secretions within a face mask. This came about as we had a prospective cohort in Malawi as a result of the funding and led to oportunities to evaluate more novel diagnostics prosepectively
Collaborator Contribution They have provided prototype face mask samplers for the study at cost and suppoted with the training of the site to undertake this work and with analysis
Impact Nil yet
Start Year 2021
Description WHO collaboration on Global Survey of National TB Program on approach to systematic screening for TB 
Organisation World Health Organization (WHO)
Department Global TB Program
Country Switzerland 
Sector Public 
PI Contribution Our research focuses on developing new approaches to identifying patients at risk of developing TB that can be identified through systematic screening. In order to find out what current practices are globally for this population what what the perceived challeges are we approached the WHO suggesting this global survey which they supported.
Collaborator Contribution The WHO have helped by co-developing the survey and providing contacts for national TB programmes globally.
Impact Survey
Start Year 2021