A major milestone towards malaria control
Capacity-building efforts from research consortium Target Malaria have accelerated research outputs in novel vector control approaches towards disease transmission
|A multidisciplinary consortium of researchers from around the world are coordinating efforts to co-develop novel genetic approaches to eradicate malaria in Africa. The consortium has recently published the entomological results of a first release study of non gene drive genetically modified sterile male mosquitoes conducted in July 2019 in Burkina Faso. The field entomology coordinator of the consortium, Professor Frederic Tripet, Director of the Centre for Applied Entomology and Parasitology at Keele University, explains that having access to powerful user-friendly analytical software is important for field data analysis. However, delays in organizing access to such tools slows capacity building for many research collaborations focusing on public health in Africa. Prof. Tripet notes that it is a pervasive form of injustice that prevents access to science and innovation for malaria, a disease that each year afflicts over 200 million people and causes over 600,000 deaths.
|JMP® Statistical Discovery granted consortium-wide access to JMP Pro software for Target Malaria researchers in Europe and Africa through a license with its lead institution, Imperial College London. In contrast to open-source packages such as R, JMP facilitates high-quality, publication-ready data visualization, exploration, analysis and reporting – all without a single line of code. As a result, field researchers are now empowered to explore and analyze their own data, thereby removing their reliance on external biostatistical support that had previously delayed research output.
|“Access to JMP has been so important for capacity building,” says Professor Tripet. Having a statistical tool that is both powerful and accessible, he says, has accelerated not only research but also the publication of that research, bringing scientists one step closer to the inclusion of novel genetic vector control strategies in the broader malaria control toolkit.
Malaria afflicts approximately 229 million people around the world each year, with sub-Saharan Africa accounting for as much as 95% of the global disease burden, according to estimates by the World Health Organization (WHO). Despite scientific and policy progress in recent years, however, efforts to reduce the global malaria burden with a combination of antimalarial insecticides, the distribution of bed nets and chemical interventions have failed to significantly curb the disease’s spread. The malaria parasite evolves rapidly and the advent of a variety of drug-resistant strains has only increased the threat to human health – a trend reflected in WHO findings that the impact of malaria control strategies has waned since 2017.
In recognition of the need for novel approaches, the international nonprofit research consortium Target Malaria aims to develop cost-effective, sustainable genetic technologies to complement existing malaria control strategies. The consortium, led by Imperial College London and funded primarily through the Bill & Melinda Gates Foundation and Open Philanthropy, brings together experts in molecular biology, population genetics, entomology, risk and regulatory affairs, and statistical modeling to develop both evidence-based methods and a knowledge base that will pave the way for future work toward malaria eradication.
In February 2022, an international cohort of scientists affiliated with the consortium announced in Nature Communications that they had completed the first-ever release of genetically modified sterile mosquitoes into the wild in Burkina Faso – representing a major scientific step in eradication efforts.
In a press release, lead author and principal investigator of Target Malaria Burkina Faso Dr. Abdoulaye Diabaté wrote of the result: "Although this small-scale release is not intended to be used as a malaria control tool, it was an important stepping-stone for the team to gather information, build knowledge and develop local skills. The scientific data we obtained will be essential in the development of our next phases.”
Developing genetic modifications to disrupt disease transmission
At the center of Target Malaria’s research is an innovative vector control approach that draws on molecular biology, genomics and entomology to disrupt disease transmission by introducing genetic modifications into the genome of the African malaria mosquito species complex Anopheles gambiae. These modifications are designed to reduce transmission by affecting the reproductive capacity of the target mosquito population.
“Ultimately, we’re interested in a genetic technology called gene drive that transfers to all progeny a certain beneficial gene,” explains coauthor and entomologist Frederic Tripet. “That gene will either limit the fertility of female mosquitoes or increase the number of males. If such traits are passed on to all progeny, this can spread quite effectively through the mosquito population; resulting in a malaria mosquito population reduction to the point of stopping malaria transmission. For these reasons, gene drive is seen as a new tool with significant potential. But because they involve genetic modifications, our development pathway involves taking small steps at a time to make sure that we engage with regulators and stakeholders about all aspects of the science.” Gene drive mosquitoes currently only exist in labs in Europe. The genetically modified mosquitoes being studied in Africa do not carry the gene drive technology.
Notable among those first steps, the results published in Nature Communications used maximum-likelihood and Bayesian model fitting to show a statistically significant reduction in both the daily survival and dispersal rates of released non gene drive genetically modified sterile males. “For the project in general, [this result] is a crucial step,” Tripet says. “It’s the first time that genetically modified mosquitoes have been released [into the wild] in Africa – the first time ever. It’s a major milestone for the team at the IRSS in Burkina and for the whole project.”
A Professor of Medical and Molecular Entomology and Director of the Centre for Applied Entomology and Parasitology at Keele University in Staffordshire, UK, Tripet works closely with an international team of Target Malaria researchers across Africa to help coordinate field studies. It is in this remit that he provides significant statistical support and facilitates the exchange of data sets between field research teams and other consortium participants, all with an eye to fulfilling all regulatory requirements for the safe development of novel genetic tools.
The team’s experimental field release study compared the survival of male mosquitoes that have been genetically altered to be sterile with wild-type sibling males released simultaneously using general linear models. The results of the field study confirmed the findings generated by cage studies conducted by the consortium partners in London and Italy. “In cage studies, we typically look for differences in fitness components at both the cage and replicate level, and we often have covariates such as gender or size of the mosquito, for example,” Tripet explains. “That means we often do modeling on fully balanced designs… and Kaplan-Meier proportion hazards because we’re interested in mosquito emergence.” Simple ANOVAs, parametric versus nonparametric testing and other tools are also fundamental to the team’s research process and are used by entomologists across the consortium.
At the beginning of these experimental studies, Tripet, who used to teach statistics to all second year life science students at Keele University, was alone in providing statistical support to the field research team in their work towards reports and publications. However, it soon became clear, as the project grew, that greater statistical capacity was needed. And with Target Malaria’s genetic approaches entering the next phase of development and testing, Tripet says, one of the team’s biggest challenges was to overcome research bottlenecks.
Capacity building, he explains, is an important project in that it has a real impact on the pace at which scientific research can advance. Moreover, in an area like the eradication of malaria – which kills more than 600,000 people every year – increased research capacity has a concomitant human impact.
Reliance on open-source coding languages stalls research output
To identify areas where improvements can help increase research output, Tripet explains, one must first understand the source of bottlenecks that impede collaborations. Given the consortium’s cohort of international researchers – many of whom are affiliated with public institutions in sub-Saharan Africa – one of the key sticking points Tripet identified was a reliance on open-source languages like R to acquire, prepare, explore, analyze and share data.
“Most people have had to use R because it’s the only freely available option,” Tripet explains. “But using R takes a lot of time and effort – and even then, [researchers] still need to seek training elsewhere.” With most of Target Malaria’s field researchers coming from a medical entomology background, few possess the coding skills needed to use R effectively, and training has not been readily available. Moreover, he adds, graphics in R are extremely limited for inexperienced coders. In the absence of a more efficient high-capacity software tool, researchers’ reliance on a coding language like R was introducing delays that constrained the team’s ability to make progress.
Not a mathematician or statistician himself, Tripet says biologists’ frustration with coding languages is understandable; he himself learned applied statistics not only in the classroom and workshops but mostly through accumulated experience garnered in his career – albeit with access to a more complete range of tools. It was while working towards a PhD that Tripet first came across JMP® statistical discovery software – a tool he says made his own data processes much faster and more visual. Since then, he has always made a point of analyzing most data produced through his research group 'in house' to ensure that everyone trained in his laboratory leaves with basic to intermediate statistical skills.
Local access to a statistical tool transforms the quality and pace of research
Having seen the impact of JMP in his own research, Tripet made the case for Target Malaria’s researchers to secure their own software licenses through Imperial College London. “I’ve given them JMP because that’s the software I like,” he explains. “Compared to other software, it’s user-friendly and guides you toward the right analyses for your type of data. Thus, there is less risk of doing an analysis incorrectly. The graphs are crisp and visually appealing, which is important in publications, and we can play with colors and customizations…I’ve continued with JMP since I was a PhD student myself and I’ve found that it’s terrific. It’s a very intuitive and practical system.”
“With other software, you have to know a lot before you can be sure that your model is right. But with JMP, I really feel confident that I have the tools right there and that we can cross-check a few models very quickly and easily. That’s really a strength for JMP.”
Increased access to the tool has since contributed to a significant streamlining of research on several fronts: helping research teams standardize around best practices, facilitating more seamless sharing of data sets, providing a platform for visual exploratory analysis, and making possible advanced analyses that researchers were not able to perform in R.
Tripet has since enlisted the support of a postgraduate researcher associate Dr. Nwamaka Akpodiete who also conducts her own work on mosquito population dynamics and molecular ecology in addition to running weekly training sessions in biostatistics for the Target Malaria field entomologists. Tripet and Akpodiete previously found themselves deeply involved as intermediaries – helping local research teams with data acquisition and preparation and then revising analyses prior to publication. Through this training, much of that statistical work can now be done in the field by the researchers themselves. As a result Tripet will in the future be able to concentrate on providing solely higher-level guidance on data visualization and analyses towards the team's reports and publications.
“Having local access to a powerful statistical tool and training opportunities means when [researchers] have to analyze data, it’s so much easier because they know the basics, and it means that we [as an organization] build capacity,” Tripet explains. “I’m hoping that as time goes by, the colleagues I work with will know more and more about JMP so that we save time. We’ll be able to get to the analysis much faster…Access to JMP has been so important for capacity building.”
Empowering researchers to embrace data-driven approaches independently
An internal JMP users group, JMP training and biostatistics seminars attended by Target Malaria partner institutions all now play an important role in international collaboration and skills building. Tripet explains that though JMP has a low barrier to entry, training can go a long way in instilling best practices and getting new users up to speed, particularly in the areas of exploratory data analysis and data visualization.
In addition to the online classes led by Akpodiete, for which she relies heavily on JMP journals, Tripet aims to organize week-long in-person workshops focused on developing practical skills and analyzing specific data types.
The last in-person workshop in Senegal, Tripet says, was a great success, bringing together researchers from across the continent and a teaching team from Keele University, Imperial College and the University of Oxford, adding: “We all worked very hard, and participants came away from it having learned the basics. Unfortunately, Covid prevented further in-person meetings, so we are looking forward to the next edition of the biostatistics workshop.”
More than just developing a statistical skillset, access to JMP – and the confidence to use it – has been a source of empowerment for a research cohort that previously relied on external biostatistical support. “Once [researchers] start doing some of the analysis themselves – that ability is very empowering,” Tripet says. “Knowing what stats you’re going to do ahead of time means that as a scientist, you can plan ahead and design better experiments which result in a positive feedback loop, and more solid research and stronger inferences.”
“Therefore it improves your design. It improves your science in general…Once you have JMP, you can fly on your own.”