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False-negative malaria rapid diagnostic test results and their impact on community-based malaria surveys in sub-Saharan Africa
  1. Oliver J Watson1,
  2. Kelsey Marie Sumner2,
  3. Mark Janko3,
  4. Varun Goel4,
  5. Peter Winskill1,
  6. Hannah C Slater1,
  7. Azra Ghani1,
  8. Steven R Meshnick2,
  9. Jonathan B Parr5
  1. 1MRC Centre for Global Infectious Disease Analysis, Imperial College London, London, UK
  2. 2Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
  3. 3Global Health Institute, Duke University, Durham, North Carolina, USA
  4. 4Department of Geography, University of North Carolina, Chapel Hill, North Carolina, USA
  5. 5Division of Infectious Diseases, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
  1. Correspondence to Oliver J Watson; o.watson15{at}imperial.ac.uk

Abstract

Surveillance and diagnosis of Plasmodium falciparum malaria relies predominantly on rapid diagnostic tests (RDT). However, false-negative (FN) RDT results are known to occur for a variety of reasons, including operator error, poor storage conditions, pfhrp2/3 gene deletions, poor performance of specific RDT brands and lots, and low-parasite density infections. We used RDT and microscopy results from 85 000 children enrolled in Demographic Health Surveys and Malaria Indicator Surveys from 2009 to 2015 across 19 countries to explore the distribution of and risk factors for FN-RDTs in sub-Saharan Africa, where malaria’s impact is greatest. We sought to (1) identify spatial and demographic patterns of FN-RDT results, defined as a negative RDT but positive gold standard microscopy test, and (2) estimate the percentage of infections missed within community-based malaria surveys due to FN-RDT results. Across all studies, 19.9% (95% CI 19.0% to 20.9%) of microscopy-positive subjects were negative by RDT. The distribution of FN-RDT results was spatially heterogeneous. The variance in FN-RDT results was best explained by the prevalence of malaria, with an increase in FN-RDT results observed at lower transmission intensities, among younger subjects, and in urban areas. The observed proportion of FN-RDT results was not predicted by differences in RDT brand or lot performance alone. These findings characterise how the probability of detection by RDTs varies in different transmission settings and emphasise the need for careful interpretation of prevalence estimates based on surveys employing RDTs alone. Further studies are needed to characterise the cost-effectiveness of improved malaria diagnostics (eg, PCR or highly sensitive RDTs) in community-based surveys, especially in regions of low transmission intensity or high urbanicity.

  • malaria diagnosis
  • rapid diagnostic tests
  • RDTs
  • pfhrp2
  • pfhrp2 deletion
  • Plasmodium falciparum
  • mathematical modelling
  • mapping

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

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Footnotes

  • OJW and KMS are joint first authors.

  • OJW and KMS contributed equally.

  • Handling editor Alberto L Garcia-Basteiro

  • Contributors JBP, SRM and KMS conceptualised the study. OJW, KMS, SRM and JBP designed the study with additional input from AG, HCS, PW and MJ. OJW and HCS collated the DHS and MIS data set. KMS and OJW conducted the summation of the data. KMS and VG carried out the spatial clustering analysis, and MJ and OJW created the hierarchal model. PW performed the model simulations with additional input from HCS. OJW and KMS wrote the first draft of the manuscript. All authors contributed to writing the manuscript and approved the final draft.

  • Funding This study received funding from the Wellcome Trust (OW), the National Institutes of Health (KMS, SRM and JBP), the National Aeronautics and Space Administration (MJ), an Imperial College Research Fellowship (HCS), the Bill and Melinda Gates Foundation (AG, PW), the MRC and UK Department for International Development under their research concordat agreement (AG) and grants from the National Institutes of Allergy and Infectious Diseases (SRM). This study also received funding from the American Society for Tropical Medicine and Hygiene-Burroughs Wellcome Fund grant (JBP).

  • Competing interests JBP and SRM report a non-financial interaction with Abbott, which has performed laboratory testing in-kind as part of their hepatitis research.

  • Ethics approval University of North Carolina at Chapel Hill IRB determined that this study did not constitute human subjects research as defined under US Federal Regulations (IRB number 17-2505). The data set was deidentified by the DHS Program for all personal identifiers. GPS coordinates of the DHS sampling cluster sites were included in the data set; however, these were offset by the DHS to protect participants’ information. These GPS coordinates were therefore not representative of participants’ physical locations.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available in a public, open access repository.

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