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. 2024 Oct 25;25(1):717.
doi: 10.1186/s13063-024-08537-4.

Whole genome sequencing of M. tuberculosis for disease control in high-burden settings: study protocol for a cluster randomized controlled trial evaluating different community-wide intervention strategies in rural Madagascar

Emmanuelle Sandra Adjoa Ametepe #  1   2 , Noela Andriamanoha #  3 , Fanantenana Randria Andrianomanana  4 , Floriane Point  2 , Reziky Tiandraza Mangahasimbola  3 , Alina Dyachenko  2 , Michael Hall  5   6 , Theodora Mayouya Gamana  3 , Astrid M Knoblauch  7   8 , Yemimah Yededyah Razafindrasoa  3 , Arianminpathy Nimalan  9 , Marcel Behr  10 , Madeleine Durand  2   11 , Mira Johri  1   2 , Zamin Iqbal  5   12 , Andry Rivo Rakotoarivelo  11 , Rindra Vatosoa Randremanana  3 , Niaina Rakotosamimanana  4 , Simon Grandjean Lapierre  13   14   15
Affiliations

Whole genome sequencing of M. tuberculosis for disease control in high-burden settings: study protocol for a cluster randomized controlled trial evaluating different community-wide intervention strategies in rural Madagascar

Emmanuelle Sandra Adjoa Ametepe et al. Trials. .

Abstract

Background: Retrospective and descriptive molecular epidemiology studies have shown that Mycobacterium tuberculosis whole genome sequencing can identify outbreaks and disease transmission events with higher resolution than conventional epidemiological investigations. Those studies have strengthened our understanding of genomic polymorphisms correlating with person-to-person transmission and helped resolve putative transmission clusters. To date, systematic genomic surveillance programs implemented for M. tuberculosis were only implemented in low-incidence settings. The purpose of this study is to determine whether there is an impact of routine M. tuberculosis whole genome sequencing on tuberculosis case detection in a high-incidence setting.

Methods: A cluster randomized controlled trial will be performed. Forty-eight rural village groups (or Fokontany) in the Vohibato district of Madagascar will be randomized to one of three interventions arms. Arm 1 (standard of care) involves healthcare facility-based passive case detection with smear microscopy testing. Arm 2 (best practice) consists of active case finding and Xpert MTB/RIF Ultra PCR testing followed by household contact investigations. Arm 3 (novel intervention) includes the same interventions as arm 2, with addition of sputum culture and M. tuberculosis whole genome sequencing for all newly diagnosed cases. In arm 3, molecular suggested putative outbreaks are investigated, and additional TB suspects are appropriately tested. The intervention observational period will be 2 years. The primary outcome will be the number of detected cases/100,000/year in each arm after 1 year of intervention.

Discussion: This study is designed to determine whether there is an impact of prospective whole genome sequencing-based molecular typing on tuberculosis case detection in high-incidence settings. Investigating potential outbreaks and focusing active case finding in spatiotemporal settings where disease transmission is suggested by genomic typing is hypothesized to improve case detection in rural communities.

Trial registration: ClinicalTrials.gov NCT05406453 . Retrospectively registered on June 6, 2022.

Keywords: Cluster randomized controlled trial; Disease outbreak; Molecular epidemiology; Tuberculosis; Whole genome sequencing.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
cRCT study arms, sample size, anticipated outcomes, and intervention strategies
Fig. 2
Fig. 2
cRCT anticipated outcomes, data sources, and assumptions
Fig. 3
Fig. 3
Schedule of enrolment, interventions, and assessment SPIRIT figure
See this image and copyright information in PMC

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