Using spatial statistics and genomics to develop epidemiologically relevant definitions of insecticide resistance in African Malaria Vectors

In the last 15 years 260 million clinical cases of malaria have been prevented in Sub Saharan Africa, overwhelmingly through the use of insecticides that target the mosquito vector. Insecticide resistance is therefore a major threat to the sustained control of malaria. Whole genome sequencing of malaria mosquitoes has the power to revolutionise our understanding of the evolution of insecticide resistance; allowing us to design new insecticides and to develop strategies that delay the onset of resistance. However genomic technologies will only reach their full potential with improved sampling design and when extensive individual and population level metadata (collection location, infection/ disease state etc) accompany each sequenced sample. For the problem of insecticide resistance in the major malaria vector Anopheles gambiae a deep understanding of the biology lies with SSA scientists whilst the skills to sequence and analyse the data are held by centres in the North. This foundation proposal is designed to draw together these two groups with support from a world-leading spatial statistics group around the key issue of insecticide resistance evolution. Our vision is to further develop the programme to a Pan-African level, eventually devolving leadership to our SSA partners who will have the skills and experience to sustain the network.

Malaria is a major cause of mortality and morbidity in Sub-Saharan Africa (SSA) and one of the biggest impediments to economic development. Malaria control is threatened by insecticide resistance which demands improved insecticide resistance management (IRM). Molecular markers could greatly aid improved IRM, but are currently underused. Our proposal will develop and train control programme linked SSA vector biologists to design and analyse genomic data to assess Anopheles population structure and to identify resistance-linked genetic variation. The overarching aim is to develop a nucleus of SSA scientists best able to exploit the power of whole genome sequencing to address questions of public health importance.

Using the key phenotype of insecticide resistance as an exemplar we will:
1. develop and implement standardised, server-based pipelines for the analysis of whole genome sequence data to identify patterns of population structure, genetic diversity and insecticide resistance candidate genes/variants
2. develop spatially- and temporally-explicit sampling frameworks for malaria vectors to permit local-scale genetic tracking and prediction of (i) population connectivity, (ii) temporal stability and (iii) insecticide resistance.
3. test extant and novel DNA markers for prediction of resistance in females of malaria transmission age

Pathways to impact
The proposed foundation award is directly aligned to the 2014-2019 MRC Strategic Plan, specifically Strategic Aim 3: Global Health. To "deliver improved health outcomes in infectious diseases, which impact heavily on the health and wellbeing of populations in resource-poor settings" and to "develop investment in the translation of research findings into health systems to ensure that the outcomes of research can be better implemented into practice."

Moreover in line with the specific MRC Global Challenges Research Fund Foundation call the proposal encompasses:Early phase discovery and translation research
-Extending scope of existing research to wider global settings
-Population studies, sample/data collection, data integration
-New research tools and techniques
-Development of collaborations, partnerships, teams
-Creating pathways to impact in LMICs

Translating the potential of genomic science from early phase discovery into translational 'real-world' public health impacts is reliant upon cohesive interdisciplinary research within effective partnerships. Thus far the Low and Middle Income Country partners who work at the interface between applied and translational science have not been able to adequately shape the basic science studies that are needed to address public health priorities. The key to this foundation award is that we will engage beneficiaries from the outset of the project so that they can help us develop the research agenda to meet their needs.

Impact Pathway 1: Inception network meeting. Target Audience: Key stakeholders in malaria control programmes
Year 1 meetings will be held in all countries to present our objectives and long term goals to local stakeholders. These key stakeholders will include NMCP representatives, WHO-Regional Officers, CDC country representatives, President's Malaria Initiative representatives, Abt associates managers. Our objective is to solicit feedback on how best our activities can dovetail with the requirements of implementers to provide timely and relevant information for control programme design and monitoring. In addition we will establish collaborative links with a stakeholder network which can be maintained throughout the course of the foundation and beyond.

Impact Pathway 2: Capacity strengthening and resource provision for regional skill dissemination. Target Audience: Vector control scientists in SSA
As part of Aim 1 of the project we will train staff from our network, and/or members of their groups to analyse genomic data within a supported Galaxy pipeline framework. This will become a semi-devolved self-supporting dissemination mechanism for knowledge and skills, providing impact to in-country scientists beyond that of the immediate network in a sustainable way.

Impact Pathway 3: Integration of knowledge and tools into malaria control programme decision making. Target Audience: National malaria control programme managers and practitioners.
From the links established at the inception meetings we will be able to disseminate findings directly, and in an adaptive manner to control programme managers and practitioners, sharing data and soliciting feedback, e.g. on geographical areas of interest which could be incorporated into our sampling. In addition in year 2 we will present findings directly to in-country NMCPs and communicate findings via international conference presentation and publication in open access journals. Lay summaries will also be produced with translations into French and Kiswahili.