A general framework to support cost-efficient fecal egg count method and study design choices for large-scale STH deworming programs – monitoring of therapeutic drug efficacy as a case study

Background Soil-transmitted helminth (STH) control programs currently lack evidence-based recommendations for cost-efficient survey designs for monitoring and evaluation. Here, we present a framework to provide evidence-based recommendations, using a case study of therapeutic drug efficacy monitoring based on the examination of helminth eggs in stool. Methods We performed an in-depth analysis of the operational costs to process one stool sample for three diagnostic methods (Kato-Katz, Mini-FLOTAC and FECPAKG2). Next, we performed simulations to determine the probability of detecting a truly reduced therapeutic efficacy for different scenarios of STH species ( Ascaris lumbricoides, Trichuris trichiura and hookworms), pre-treatment infection levels, survey design (screen and select ( SS ); screen, select and retest ( SSR ) and no selection ( NS )) and number of subjects enrolled (10 – 2,000). Finally, we integrated the outcome of the cost assessment into the simulation study to estimate the total survey costs and determined the most cost-efficient survey design. Principal Findings Kato-Katz allowed for both the highest sample throughput and the lowest cost per test, while FECPAKG2 required both the most laboratory time and was the most expensive. Counting of eggs accounted for 23% (FECPAKG2) or ≥80% (Kato-Katz and Mini-FLOTAC) of the total time-to-result. NS survey designs in combination with Kato-Katz were the most cost-efficient to assess therapeutic drug efficacy in all scenarios of STH species and endemicity. Conclusions/significance We confirm that Kato-Katz is the fecal egg counting method of choice for monitoring therapeutic drug efficacy, but that the survey design currently recommended by WHO ( SS ) should be updated. Our generic framework, which captures laboratory time and material costs, can be used to further support cost-efficient choices for other important surveys informing STH control programs. In addition, it can be used to explore the value of alternative diagnostic techniques, like automated egg counting, which may further reduce operational costs. Author Summary Large-scale deworming programs are implemented worldwide to reduce morbidity caused by intestinal worms. As these programs operate in resource-poor-settings, it is important that their operational costs are minimized without jeopardizing the quality of decision-making. We present a framework for evidence-based recommendations for cost-efficient decision-making in deworming programs, using monitoring of therapeutic drug efficacy via stool examination as a case study. To this end, we first assessed the time and the cost of processing stool samples in a laboratory according to different diagnostic methods. Then for each diagnostic method, survey design, and a range of settings (pre-dominant worm species and pre-treatment infection levels), we calculated the probability of correctly detecting a truly reduced therapeutic drug efficacy and the associated operational costs. Generally, the estimated operational costs varied across diagnostic method, survey design, worm species and disease endemicity. Based on our findings, we conclude that the use of the current diagnostic standard, the Kato-Katz method, is justified to assess drug efficacy, but that a change in survey design is warranted. Our methodology, which leverages detailed data on laboratory time and material costs, can also be used to provide evidence-based recommendations for other types of decisions in large-scale deworming programs. ### Competing Interest Statement The FECPAKG2 technology was produced and distributed by Techion Group Ltd, of which ET is an employee and GM is managing director. Both hold stocks in Techion Group Ltd. The Mini-FLOTAC device is a commercial product distributed by GC, LR and MPM through the University of Napoli Federico II. All other authors declared that they have no competing interests. ### Funding Statement LEC acknowledges funding from the Dutch Research Council (NWO, grant 016.Veni.178.023). JV was financially supported through an International Coordination Action of the Flemish Research Foundation. This study and PC were financially supported by a grant from the Bill and Melinda Gates foundation (OPP1120972, PI is BL, [www.starworms.org][1]). The collection of the Ethiopian National Mapping data that were used to define endemicity scenarios was financially supported by the Schistosomiasis Control Initiative and the Partnership for Child Development, both based at Imperial College London, and by the Children’s Investment Fund Foundation, The End Neglected Diseases Fund, and UKAID-DFID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocols for this trial were reviewed and approved by the Ethics Committee of the Faculty of Medicine and Health Sciences, the University Hospital of Ghent University, Belgium (Ref. No B670201627755 2016/0266) and the national ethical committees associated with each trial site (Ethical Review Board of Jimma University, Jimma, Ethiopia: RPGC/547/2016 National Ethics Committee for Health Research (NECHR), Vientiane, Lao PDR: 018/NECHR Zanzibar Medical Research and Ethics Committee, United Republic of Tanzania: ZAMREC/0002/February/2015 and the Institutional Review Board from Centro de Pesquisas René Rachou, Belo Horizonte, Brazil: 2.037.205). The trial was retrospectively registered on [Clinicaltrials.gov][2] (ID: [NCT03465488][3]) on March 7, 2018. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Not Applicable All relevant data are within the manuscript, its Supporting Information files, and a preceding paper (). [1]: http://www.starworms.org [2]: http://Clinicaltrials.gov [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03465488&atom=%2Fmedrxiv%2Fearly%2F2023%2F01%2F07%2F2023.01.06.23284253.atom