Use cases for genetic epidemiology in malaria elimination

In recent years, public health campaigns have achieved major reductions in malaria morbidity and mortality globally, with incidence decreasing by 18% globally between 2010 and 2016 [1].

As many countries accelerate their efforts towards elimination (World Health Organization (WHO) E-2020 Initiative) and the world works towards global eradication (Sustainable Development Goal (SDG) 3.3), programmatic priorities are changing and new data needs emerging. Traditional epidemiological approaches to surveillance analysing the reported clinical-based incidence data available through the routing system and/or cross-sectional studies of prevalence in a population were previously sufficient for National Malaria Control Programmes (NMCPs), whose aim is to contain and estimate the burden of infection within its borders. However, higher resolution information—i.e., more detailed, comprehensive, accurate, and informative—about parasite transmission dynamics will be necessary to target interventions or even predict when, where, and which interventions will be most effective to eliminating remaining reservoirs of infection.

Genetic epidemiology is a discipline that deals with the role of genetic factors and their interaction with environmental factors in the occurrence of disease in populations [2]. Analysing parasite genetics has enormous potential to aid both NMCP efforts at elimination as well as international efforts toward eradication [3, 4]. To date the genetic epidemiology field has primarily focused on applied research. For example, the use of molecular markers of anti-malarial drug resistance has for some time been used to guide the efficacy studies that define treatment policy; more recently, the detection of parasites mutant for histidine-rich protein 2/3 (pfhrp2/pfhrp3) gene highlighted the need to develop rapid diagnostic tests (RDTs) with alternative targets of detection, and to provide countries with guidance on the implications for case management [5]. A global scientific network providing framework for generating, integrating and sharing malaria parasite and vector genetic and genomic data is available through the Malaria Genomic Epidemiology Network (MalariaGEN) [6].

Given this vision for genetic epidemiology approaches in NMCP elimination strategies and the need for WHO normative policy guidance to effect global implementation, there is an emerging need to clearly articulate the uses of these methods and how they can help advance programmatic and operational needs of NMCPs as well as accelerate progress toward SDG 3.3. To bridge the divide between research and implementation, use cases are a means to align research, technology development, and public health efforts using genetic epidemiology methods in support of NMCP priorities. Use case analysis is an analytic framework commonly employed in software and business industries to assess the ways a system can be used and illustrate its applications in real world contexts [7]. A use case provides a functional description of a system, as well as a framework to develop derivations of test cases based on available technologies. They are then used to inform the application and implementation of new technologies through ongoing engagement with stakeholders. Other health domains have deployed a use case methodology for emerging technologies, including soil-transmitted helminth diagnostics [8] and unmanned aerial vehicles [9]. This report represents a novel application of this methodology to genetic epidemiology and is intended to launch a cohesive collaboration by genetics researchers and public health programmes towards the use of these approaches (Fig. 1).

To begin, a review was conducted of literature regarding genetic epidemiology and malaria elimination strategies. The literature review engaged an exploratory search strategy in both published and grey literature databases such as the MESA research hub [10], starting with key search terms, and allowing those findings to inform the next cycle of search terms and contacts in a cascade search. Initial search terms included malaria transmission, genetic epidemiology, genetic sequencing, and population genetics.

To inform and complement the literature review, between March and September 2017, individual in-depth interviews were conducted with 15 international stakeholders identified through the review—including malaria disease experts, laboratory and field researchers, programme implementers, mathematical modellers, policymakers, and donors for their input as to the needs and opportunities for genetic information in malaria elimination. Interviews were conducted in person or over the phone using a semi-structured interview guide (Additional file 1).

The development of the list of use cases was informed by the critical review of the literature and informational interviews with experts. The use cases were aligned to activities specifically described in Pillars 2 and 3 of the updated 2017 WHO Framework for Malaria Elimination [11], stemming from the WHO Global Technical Strategy [12]. These two pillars comprise activities for which genetic epidemiology applications have the most promising applications: surveillance, case investigation, and stratification of areas for targeted interventions to reduce transmission and accelerate elimination. Activities falling outside the WHO framework, for example using genetic techniques to guide product development such as rapid diagnostic tests (RDTs), were considered out of scope. This use case framework is modeled on an early draft of use cases developed by a working group of soil-transmitted helminths diagnostic experts published last year [8]. Finally, the categorization and content of the use cases was iteratively developed and revised by sharing drafts with previously interviewed experts.

Seven use cases are presented where genetic epidemiology approaches are informative to decision-making within the efforts of NMCPs. The use cases are intended to be technology-agnostic such that they may be generalizable across many endemic settings with different epidemiological characteristics (e.g. disease prevalence, drug resistance incidence, and transmission intensity), as well as applicable to emerging genetic epidemiology methods.

The use cases presented in this article represent a novel application of a common business technique, applied elsewhere in fields of public health and software, and here to address the research-implementation gap in malaria. They have already been used to guide discussions at two international meetings focusing on the interactions between NMCP representatives and genome scientists, hosted by the Harvard T. Chan School of Public Health and the Massachusetts Institute of Technology Broad Institute (July 2017), and the Mahidol-Oxford Research Unit (January 2018).

Successful development and implementation of genetic epidemiological methods, through the steps depicted in Fig. 1, will require continued buy-in and information sharing between technical and programmatic experts, as well as resource investments that advance the capacity of NMCPs to involve these methods in their activities. This will be especially important in the translation of these use cases into the technical specifications needed for Target Product Profile (TPPs) that are directly responsive to specific NMCP information needs, including specific endemic settings and parasite-species specific requirements. NMCPs should drive the design of TPPs, and it is expected that different use cases will be prioritized by different countries and regions, depending on both epidemiological and operational contexts. While many of the use cases span a range of transmission intensities, there is a need to validate use cases, and the methods themselves, in higher burden settings. For example, routine monitoring for emergence of known antimalarial resistance markers in P. falciparum may be demanded by NMCPs in sub-Saharan Africa, while high resolution information about the spread of antimalarial resistance in P. vivax populations would be more useful in the Greater Mekong Subregion, Latin America, and other regions with endemic P. vivax. The development of TPPs may suggest opportunities for developing genetic epidemiology methods that address multiple use cases.

Additional implementation constraints and limitations of these new methods will also need to be explored in pragmatic test cases led by NMCPs to ensure these methods are cost effective in achieving elimination targets. Feasibility of each use case per country context will depend on factors including, but not limited to, the analytical capacity available, what sampling frame is logistically and financially feasible for ascertaining useful information at different levels of geographic granularity, the strength of the routine surveillance system, and availability and throughput capacity of laboratory technologies. There are pros and cons for NMCPs to use genetic approaches to answering epidemiological questions, and it is necessary to conduct a cost–benefit analysis for each use case. Significant involvement of programme experts and malaria-endemic country stakeholders will be required to help genetic technology developers understand where methods could be standardized for cost and supplement or perhaps even existing programme activities. This will help NMCPs understand whether existing epidemiological methods are sufficient in their country compared to opting for combining those methods with a genetic epidemiology approach, whether it is preferential to conduct this analysis in-country or in regional or global centers, and how best to integrate genetic epidemiology data into existing analysis for their decision-making [42].

It is worth noting that as this framework focuses on use cases applicable to questions NMCPs would ask, there are many more applications of genetic epidemiology for a research agenda than the use cases listed here. As one example, genotyping data can help us understand how long parasites persist, a critical element for assessing the infectious reservoir and from there for predicting the impact of interventions. In addition, having a representative sample of parasites globally would allow for prospective screening of drug resistance candidates to identify emerging resistance before countries start to observe treatment failure. A research agenda is beyond the scope of this article and would be a very welcome way of focusing efforts of the research community. Finally, these use cases can be extended to include vector genomics as the genomes of more vector species are sequenced and new methods emerge to detect and predict insecticide resistance emergence and spread.

By providing a framework for the application of genetic epidemiology approaches, these use cases can launch the process towards developing normative guidance for their appropriate use in global malaria eradication, a key element for any new tool or method to get to scale.