Why early participant engagement is now a top priority in genetic disease research

In 2016, scientists behind a study called the Resilience Project analysed genetic data from 589,000+ people and found 13 adults who carried genetic variants that should have resulted in serious – even deadly – childhood disease, but who were apparently healthy.

The DNA of these so-called ‘genetic superheroes’ may contain clues about how to treat severe disease. By studying their natural resilience and using it to design new therapies, it could help so many people.

However, the Resilience Project’s scientists had used genomic data originally collected for other studies and, due to limitations in the original studies' informed consent policies and a lack of infrastructure to recontact participants, none of the 13 individuals could be contacted with follow-up questions or requests.

Whether these people were truly naturally resistant to severe disease, and why that might be the case, remains a mystery.

At the time, Stephen Friend, one of the project’s co-founders, said: “There's an important lesson here for genome scientists around the world: the value of any project becomes exponentially greater when informed consent policies allow other scientists to reach out to the original study participants. If we could contact these 13 people, we might be even closer to finding natural protections against disease.”

Fast forward to today and, while many large-scale genomics studies still lack the infrastructure and consent policies to enable recontact, this is starting to change. High-profile programmes like the NIHR BioResource and Our Future Health in the UK, and All of Us in the United States, are making recontact and participant engagement integral to their design and operations.

Pharmaceutical companies and biotechs are also adapting their approaches, launching patient finding and engagement programmes that can start years before clinical trials begin and allow them to run ‘recontact by genotype’ studies that the Resilience Project would have liked to do.

Giving participants something in return

The idea of ‘genetic superheroes’ and precision medicine is captivating for researchers, but the concept can be abstract and distant for participants. To make precision medicine a reality, and reach everyone who can help or benefit, we need to design research studies much like consumer experiences – and offer clear value, beyond altruism, for taking part.

In our experience of running 20+ precision medicine studies, there are a few design principles that every research programme – from biobanks to clinical trials – should consider.

First, start co-development with participants early on in the process. This will help you to answer the fundamental questions about what participants want, what their problems are, and how your research goals align (or don’t!) with their priorities.

Second, build a concrete plan for communication and ‘return of value’ to participants in the short-, medium-, and long-term, and include this in your recruitment communications. Return of value can be monetary – including direct payments or donations to community organisations on behalf of participants – but rarely is it effective to rely solely on this. Non-monetary return-of-value can include access to data, with insightful, personalised reports or summaries, access to specialist care or resources, or access to lay summaries of the research.

Third, design an experience that minimises the burden on participants, and maximises the benefits to them, while also achieving the scientific aims. In short, remove as many barriers to entry as possible.

What we’ve learned is that participants come with clear expectations about the research experience, which are often not met. They expect the process to be straightforward and convenient, and they want regular communications and feedback on results. They also want opportunities to contribute details about their own experiences living with chronic and rare diseases, and the option to connect with experts, as well as other people just like them. After all, today’s participants are used to a high level of online user experience, from food delivery to entertainment to shopping. Why should research be any different?

Navigating the right not to know

A decidedly contentious area in genomics is the patient’s ‘right not to know’. Not every individual wants to contribute to a study and learn they have an increased risk of a particular disease, so technology and processes have to be designed so participants are not shocked or surprised if they don’t wish to be.

Too often, researchers, ethics boards, and other stakeholders take a binary position that either all participants want to know, or information should not be returned to participants at all. In reality, participants even with genetic risk for devastating diseases have legitimate reasons to want control over how they receive information, such as giving them time to review insurance policies, or to speak to family members, or indeed to not know at all, due to the psychological impact. By designing research with participants involved from the start, and with autonomy as a core principle, we can escape from the often binary and paternalistic views that dominate.

And if participants have opted in to be made aware of their risks of genetic diseases, then communication has to be carefully considered. Researchers in population genomics programmes, biobanks, and clinical research are grappling with this challenge, as millions of participants worldwide have had their genetic data generated and carry risk factors for both common diseases and rare diseases. Large-scale genetics studies like Our Future Health, All of Us, the NIHR BioResource, and Genomics England, FinnGen, and DECODE have collectively genetically tested millions of people, and have both consent and the infrastructure to recontact participants about their genetic results.

At the same time, the fraction of clinical trials that include genetic markers is increasing. In the next decade, ‘recontact by genotype’ to identify people at-risk or living with genetic diseases who are eligible for a new therapy or clinical trial will be a major force shaping research and healthcare.

In the coming years, we will need to build a blueprint for the ethical framework, and the technological framework for running this process at the scale of millions of participants. In the United States, Genomes2People – a research group led by Robert Green at Harvard Medical School – has published a number of studies on the impact of recontact by genotype and genome sequencing in a healthcare screening setting.

An independent report by the PHG Foundation, commissioned by Genomics England, has since given us a framework for the digital recontact by genotype and return of value in the context of UK law. And a pilot study by FinnGen, a consortium of Finnish biobanks with >500,000 enrolled volunteers, found that recontacting participants many years after enrolment to engage in a digital platform had a very low uptake rate of ~28%, and therefore now encourages engagement from the start as a better way forward.

It’s a careful balancing act: to significantly speed up the development of new medicines and dramatically improve the experience of taking part in groundbreaking research hasn’t been done before. We have a great opportunity to rebuild healthcare to be more personalised and preventative, but the framework has to be right from the start. Building technology collaboratively and developing new methodologies for participant-centred design is the answer. Not only drawing on participant panels and co-development, but also by subjecting features and functions to rigorous external scrutiny by independent bodies, early on in the development phase.

About the author

Dr Patrick Short is CEO and co-founder of Sano Genetics, a start-up that provides access to dynamic health and genetic data for precision medicine research and that is transforming the experience of taking part in research for participants.