Ancillary Studies

Improving pediatric and HIV-associated TB diagnostics has been set as a research priority by the scientific community. From an efficiency point of view, the Stool4TB consortium would like to generate maximum scientific knowledge with the least possible resources. Therefore, the study platform is open to outside researchers to implement scientifically sound ancillary research studies. Ancillary studies are independent research projects with their own source of funding that use samples or data from the parent study to extend knowledge in scientific areas beyond the original scope of Stool4TB. An ancillary study may require additional data or sample collection and it cannot interfere with the primary objectives or execution of the parent study. All are approved by the Stool4TB Steering Committee.

 

  • Title: A stool-based multi-omic approach to unravel novel biomarkers of tuberculosis

    Study Investigators: Elisa López Varela, Sergio Serrano-Villar

    Affiliations: ISGlobal, Barcelona, Hospital Ramón y Cajal, Madrid

    Participating Study Site: CISM, Uganda

    Objectives: To identify in children and PLHIV a candidate set of bacterial and host biomarkers for TB to improve TB diagnosis accuracy compared to a composite reference standard (sputum and stool Xpert Ultra, sputum culture and urine TB-LAM) and clinical diagnosis. Bacterial biomarkers may include bacterial taxa, their proteins and metabolites in stools at baseline. Host biomarkers may include proteins and metabolites in stools at baseline.

    To perform an external validation of the diagnostic accuracy of this multi-omic-based diagnosis of TB in an external cohort of children and PLHIV prior to TB treatment.

    To generate a model that allows linking metabolically active bacteria to proteins being actively expressed and subsequently to fluxes of metabolites being produced in the context of tuberculosis in children and PLHIV and to identify novel pathways of TB susceptibility prior to TB treatment that may help explain the observed clinical outcomes.

  • Title: Volatile organic compounds in stool for the diagnosis of TB

    Principal Investigator: Debbie van den Brink, Wieger Voskuijl

    Affiliations: The Amsterdam Institute for Global Health and Development (Amsterdam University Medical Center), Warwick University

    Participating Study Site: CISM, Uganda

    Objectives:

    1. Identify groups of volatile organic compounds through GC-IMS in children that are TB-positive and compare this to TB negative children

    2. Identify specific volatile organic compounds through TOFF-MS in children that are TB-positive and compare this to TB negative children.

    This will enable us to:

    a. accurately discriminate between TB-positive and TB-negative children using faecal volatile organic compound profiles.

    b. further our understanding of the microbiome and gut dysbiosis in TB.

  • Title: The Impact of TB and other respiratory infections on lung health Mozambican children

    Study Investigators: Justina Bramugy, Elisa Lopez Varela, Marieke van der Zalm, James Seddon, Lilly Verhagen, Quique Bassat, Cathryn Tonne, Isabelle Munyangaju

    Affiliations: Centro de Investigaçao em Saude de Manhiça (CISM), ISglobal, Desmond Tutu TB center (DTTC); Wilhelmina Children’s Hospital, UMC Utrecht / Radboud UMC Nijmegen

    Participating Study Site: CISM, Uganda

    Objectives: To investigate the impact of PTB and other respiratory infections on lung health at diagnosis and after treatment completion/ cure in HIV infected and uninfected children.

  • Title: Indoleamine 2,3-diogygenase activity in breath as a biomarker of active TB disease.

    Study Investigators: Sabine Hermans and Frank Cobelens

    Affiliations: Amsterdam Institute for Global Health and Development

    Participating Study Site: CISM, Uganda

    Objectives: To compare serum and breath kyn/try ratios among adults living with HIV with and without a diagnosis of active TB disease, at the time of presentation with presumptive TB.

    To investigate the evolution of serum and breath kyn/try ratios among adults living with HIV bacteriologically confirmed TB patients overtime during TB treatment.

  • Title: Oral And Serum dIagnosticS in Stool4TB

    Study Investigators: Grant Theron, Shima Abdulgader, Anna Okunula

    Affiliations: Stellenbosch University

    Participating Study Site:

    Objectives:

    1. Evaluate the sensitivity and specificity of tongue swabs tested by Ultra for the detection of active TB at baseline from children and PLHIV

    2. Determine the yield of SARS-CoV-2 testing (by an antigen-based assay) from the same tongue swabs collected for MTB detection at baseline from children and PLHIV.

    3. Evaluate the proportion of SARS-CoV-2 positive nasal swabs tested by an antigen-based assay in symptomatic patients suspected of TB at baseline and how this proportion changes over time

    4. Evaluate the sensitivity and specificity of the SeroSelect TB assay (as a triage) for TB detection in children and PLHIV at baseline

    5. Evaluate the sensitivity and specificity of CRP for TB detection (as a triage) in children and PLHIV at baseline and compare the levels of the biomarkers overtime.

  • Title: Profiling changes in the microbiome and antimicrobial resistance in children and adult PLHIV on tuberculosis treatment

    Study Investigators: Grant Theron, Shima Abdulgader, Anna Okunula

    Affiliations: Stellenbosch University

    Participating Study Site:

    Objectives:

    To evaluate the longitudinal effect of TB treatment on diversity of the gut microbiota and emergence of antimicrobial resistance in children and adult PLHIV.

  • Title: Investigating Mycobacterium tuberculosis heterogeneity detected in stool and respiratory samples analyzed via next generation sequencing (Stool4SEQ)

    Study Investigators: Tara Ness, Busizwe Sibandze, Muyalo Dlamini, Sindi Dlamini, Gugu Maphalala, Alex Kay, Anna Mandalakas

    Affiliations:

    Participating Study Site:

    Objectives:

    1. Validate existing proof-of-concept evidence demonstrating the ability to complete stool based NGS within children and adults with HIV-associated TB.

    2. Evaluate the capacity of stool and respiratory specimen-based NGS to identify mixed infections, including heteroresistance as compared to WGS.

    3. Determine if mixed infections, especially those with heteroresistance, proliferate over time and are associated with delays in culture conversion and worse clinical outcomes.

  • Title: Pediatric TB CXR systematic assessment using a telemedicine platform and automatic analysis using artificial intelligence techniques.

    Study Investigators: María J. Ledesma Carbay, Elisa López Varela

    Affiliations: Electronic Engineering Department at Universidad Politécnica de Madrid.

    Objectives: Given the current diagnostic challenges of childhood TB [1], Universidad Politécnica de Madrid in collaboration with ISGlobal and the Spanish network for pediatric TB (pTBRed) has developed a telemedicine platform to facilitate the reading of anonymized pediatric CXR by experts in a standardized and quick manner. The case information is stored in a database ensuring image quality and linked to a brief anonymized health record. Mean reading time is about 2 min, analyzing up to 11 radiological findings categories. The platform includes a statistical module that displays graphically main findings in the cohort and allows monitoring the reading process. Additionally, this module enables the export of all the collected data to external statistical tools facilitating analysis. This tool will be made available to the Stool4TB project to enable the Chest X-Ray (CXR readings). This tool also enables remote assessment to areas with low availability of specialized radiologists.

    Additionally, an artificial intelligent methodology, which could be a useful diagnostic tool, has been developed and is currently being evaluated to assess TB compatible radiological findings in pediatric datasets. The techniques that have been developed include convolutional neural networks detection techniques as well as whole image classification schemes. Merging the image derived information with clinical data and results from other tests is also being considered to increase the diagnosis accuracy.

    The main aims of this project are:

    1. To provide a telemedicine platform that can serve to systematically assess the CRX images generated through the Stool4TB Project and to analyze the relation of radiological findings with other variables collected in the study.

    2. To validate previously developed artificial intelligence techniques to detect and diagnose PTB in the independent cohort from Stool4TB.

  • Title: Diagnostic accuracy of the Totally Optimized PCR (TOP) TB assay for TB diagnosis among Children and People Living with HIV

    Study Investigators: Dr. Willy Ssengooba

    Affiliations: Makerere University-Uganda

    Objectives: Evaluate the performance of Totally Optimized PCR (TOP) assay to detect TB using stool sample in children and PLHIV.

  • Title: Diagnostic accuracy of Molecular Bacterial Load Assay for TB diagnosis among Children and People Living with HIV using Stool

    Study Investigators: Dr. Willy Ssengooba

    Affiliations: Makerere University College of Health Sciences, Kampala, Uganda

    Objectives:

    1. To evaluate an RNA based Molecular Bacterial Load Assay (MBLA) for TB diagnosis in children and PLHIV using stool.

    2. To determine the ability of STOOLTB-MBLA as a tool for TB treatment response monitoring.

  • Study title: Association of human cytomegalovirus and other viral exposure with susceptibility and progression to tuberculosis disease

    Study investigators: Derrick Semugenze, Moses L. Joloba, Willy Ssengooba, Alberto Garcia-Basteiro and Frank G.J Cobelens

    Affiliations: University of Amsterdam and Makerere University

    Participating Study site: Makerere University

    Objectives:

    1. Association of human cytomegalovirus exposure with tuberculosis susceptibility in TB presumptive adults

    2. Association of human cytomegalovirus exposure with tuberculosis susceptibility in TB presumptive children

    3. Association of human cytomegalovirus and other viral infections with tuberculosis progression among household and close contacts to TB index cases

 

If you would like more information about one of the additional studies above or if you are interested in submitting a proposal for an additional ancillary study, please contact Joanna Ehrlich.