More and more large biobanks and studies are being set up to collect a huge array of different health related data, including genetic or genomic information, to help facilitate a new era of preventative precision medicine. It is becoming increasingly clear that participants in these studies want and deserve to receive all their health data, but returning these results can come with some complications, particularly when it comes to genetic findings.

It is estimated that samples from more 100 million research participants around the world have been genotyped for genetic variants of interest, or undergone exome or whole genome sequencing, but only a small number of these individuals have been offered return of actionable genomic findings.

“I think the way that the industry has evolved is that generally when you collect data for research, the primary use of that data is research… The idea that you might discover incidental findings along the way is something that was always thought of as on the side of the main research aim, so it hasn’t received as much attention in the past, especially when it comes to these large-scale genomics studies,” Alicia Zhou, chief scientific officer at population genomics company Color Health, told Inside Precision Medicine.

We are living in the age of information and big data; it is now possible to sequence a genome in less than a day and for hundreds rather than millions of dollars. But genetic technology and research is still relatively young in comparison to the wider field of medicine. It is also a rapidly advancing field with new, clinically relevant discoveries being published every day.

“If you think about any drug, epidemiology, or research study, if you walk into that research study and they discover on taking your blood pressure that it is high, they are immediately going to tell you that… that’s been the standard for a long time,” explained Robert C. Green, a professor at Harvard medical school and geneticist at Brigham and Women’s Hospital. “In precision medicine, the difference is that it’s a fast-moving set of clinical data, particularly in genomics, where there was not a clinical standard in place is for what should be returned.”

This problem led Green and colleagues to propose that the American College of Medical Genetics and Genomics (ACMG) should adopt a clinical standard for secondary or incidental genomic findings. In 2013, the ACMG published the first official list of recommendations for genetic variants in 56 genes that should be returned to participants of research studies. The genetic variants on the list have largely been chosen because they are ‘actionable’, meaning they cause or increase risk for conditions that are treatable or that early warning can help to mitigate. Since then, this document has become a clinical standard in the U.S. for returning genetic results. The list is reviewed regularly and version 3.1, published in June, contains 78 genes.

International organizations and regulatory bodies are also increasingly promoting the sharing of genetic research findings. For example, last year the Global Alliance for Genomics and Health published a policy for the return of clinically actionable genomic research results.

Over the last 10 years, research has increasingly moved towards making returning clinical genetic results to study participants standard practice, but it can be a complex and expensive process and improvements are still needed for this to become more widespread. Newer population studies such as All of Us and eMERGE in the U.S., and Genomics England’s proposed Newborn Genomes Programme in the U.K., are learning from earlier studies and are aiming to set best practice for how to share potentially sensitive genetic information with study participants of all ages and backgrounds.

Learning from experience

Part of the reason newer studies are able to put in place comprehensive return of results plans for participants is because researchers have observed what has and hasn’t worked during earlier studies.

Robert Green has been involved in a number of large studies that decided to return genomic results, either as an openly specified part of the research, or as a less obvious component of the research.

One project he worked on was the Mass General Brigham Biobank. Founded in 2008, it comprises an ongoing collection of biospecimens, extensive electronic health record data and survey results for more than 135,000 participants.

Between 2017 and 2021, Green and colleagues analyzed genomic results from 36,417 biobank participants and offered to confirm and return pathogenic and likely pathogenic variants in 59 genes. After a lot of work, 425 individuals with actionable variants were identified, 153 of whom have now received results.

“At the time we performed this study the consent form said in general terms, we will be analyzing your DNA. And it also said, we will try to return to you anything we think is of medical importance,” Green told Inside Precision Medicine.

“It was complicated, because the research sequencing was done in a non CLIA, non-clinically regulated environment. There’s a general agreement that you should not give back results that are not done in a clinically regulated environment, so we had to insert a second step, which was asking for another sample.”

Green also acknowledged how much time and effort it took to try and contact participants. “It averaged about 10 contacts attempts before we got somebody say yes, fewer before you got somebody say no.” While this may not be sustainable for many research groups in terms of effort, time and money, Green suggests that a portion of funding should be dedicated to return of results in any large research study collecting genetic data. “I have called for funding agencies to simply not fund grants that collect DNA for analysis, without also funding a reasonable amount for return of the information,” he added.

Green is also helping efforts to return genetic results in older studies where it was not an option on enrollment, for example, the Framingham Heart Study (founded in 1948) and the Jackson Heart Study (founded in 1998). “People’s DNA was collected a long time ago. It’s been analyzed, has been used in research, but they’ve never had a chance to get anything back and we’ve been changing that,” he explained.

Careful and clear presentation of the aims of a study at an early stage is crucial for minimizing later disruption or problems, according to Green and other experts. The wording of the consent forms for potential participants also needs to be clear and unambiguous.

For example, the Framingham Heart Study told participants undergoing genetic testing that they may be contacted in the future with genetic findings, whereas the Jackson Heart Study did not. “In the Jackson study it’s more complicated, because the original consent form said we won’t be returning anything… they’ve had to go back through a reconsent process,” noted Green.

In the U.K., the 100,000 Genomes Project is a highly cited example of a large genomic study that agreed to return results to participants. “People joined our program because they had a health condition, or a relative of theirs did,” explained Richard Scott, Chief Medical Officer of Genomics England.

The 100,000 Genomes Project ran between 2013–2018 in the U.K. It sequenced the genomes of 100,000 participants with a focus on rare diseases, cancer and infectious diseases. Results have been returned to some participants already, but the process has been fairly slow, not helped by the COVID-19 pandemic.

Scott, who is also a consultant at Great Ormond Street Hospital for Children and the UCL Institute of Child Health, says a learning experience from the project was that the speed of return for some kinds of genetic results is more important than others. “The cancer journey can be very long, but the bit where the genomics element that we were adding to is relevant is primarily early on in the process… That was something that was genuinely really hard in 100,000 Genomes Project because it was so new and often the findings arrived well after that.”

In contrast, for people with rare diseases, or with undiagnosed family members with these conditions, receiving results very quickly is less important than for cancer patients. “It’s a longer period of relevance,” said Scott. “The average diagnostic odyssey is five or six years. If a diagnosis is found, that remains relevant.” There may also be trials of new treatments in the future that the result lets someone know they are eligible for, he added.

Alicia Zhou has worked on developing better systems for returning genetic results to study participants over the last decade. For example, Color is working with the All of Us project to help them to return participant results.

“It’s about making it super easy. That’s what Color has thought about. [From us] you get clinical tests, you get data generation, you get interpretation and a clinical lab result with genetic counselling. Having that sort of turnkey solution for something like this, so that you’re not trying to piece together different parts, I think is very, very important.”

Scott agrees: “In all of these clinically relevant programs, logistics is often the thing that’s the least sexy and the most important.” He adds that this is an area where the U.K. has an advantage over the U.S. by having a more joined up public health system that is able to more easily run nationwide projects. “You don’t need to think so much about the joins in the system as in some health systems. Don’t get me wrong, it’s not that it’s suddenly simple, but it just means that there’s definitely a unity of purpose.”

Next generation studies

All of Us is a National Institutes of Health research program and biobank that began in 2018 and is aiming to recruit 1 million participants, with a current total of around 555,000. It is making a concerted effort to recruit people from racial or ethnic minority groups (currently around 50%) and also those typically underrepresented in biomedical research.

From the beginning, the organizers have taken great care to plan the return of medical and other genetic findings to participants taking part in the program. Anastasia Wise is the director of scientific return to participants and impact at All of Us.

“We really want people to think about our participants as being partners in the research with us,” she explained. “It really was a very important piece to be able to think about being able to return value back to our participants, for them to be able to have a say in what information is able to be returned to them and what they’re interested in being able to receive.”

Indeed, participant satisfaction and engagement can make a big impact, particularly at the early stages of a large study when recruitment is key. “I think people are realizing that it’s a great way to help drive enrollment into your clinical study or in your clinical trial,” commented Zhou.

The research team behind All of Us consulted with scientific experts when planning how to return results, as well as working with Zhou’s team at Color to help streamline the process. They also involved community partners and participant ambassadors right from the beginning to make sure their views were considered.

So far, the participants enrolled in the program have had the chance to receive non-health related genetic ancestry and trait information. Approximately 100,000 individuals have chosen to receive this information and this process has allowed Wise and colleagues to test the system and look for any teething problems before returning health-related genetic information, which will begin rolling out to consenting participants before the end of the year.

A clear goal of the program was to return health-related results directly to participants. But this was not without challenges. “We did qualitative and quantitative comprehension testing of our reports with participants to be able to provide that information to the FDA all as part of our investigational device exemption approval that we had to receive in order to be able to give these reports back to our participants,” said Wise.

“We are very clear on all of our reports that are related to health-related results, that these are research results and that they need to be confirmed with a clinical genetic test in order to be used in care. But for the participants who have a pathogenic or likely pathogenic finding on their hereditary disease risk report, we are also offering them a clinical DNA test to be able to follow up on those results.”

eMERGE (Electronic MEdical Records & GEnomics) is a U.S. network and series of studies organized and funded by the National Human Genome Research Institute. It began in 2007 and is now in Phase IV of its funding cycle. It combines the collection and storage of genetic information with electronic medical records to enable large scale, high-throughput genetic research assessing important factors influencing the role genomic medicine on a wider scale. Participants in the network are from a wide range of backgrounds including racial or ethnic minorities and varying socioeconomic status.

Jodell (Linder) Jackson is manager of translational research at Vanderbilt University Medical Center and one of the lead co-ordinators for the for the eMERGE Network. She says one thing she and other researchers from eMERGE have learned is that although returning results is important, “you can’t data dump all of this stuff onto people who have no context for it. You have to balance giving people their results with the context and the support that they need to make that actionable.”

Taking into account the priorities and resources of the participants is also important when considering return of genetic results. “I think you need networks like eMERGE in order to lay the groundwork for this kind of thing,” commented Jackson. “How do you do this equitably when some people can’t even drive to the clinic to get the results and some people don’t have access to fresh food, let alone additional screening that they’re going to need.”

The latest phase of eMERGE is unusual amongst large genomic studies in that it is analyzing monogenic and polygenic risks for more common conditions, such as asthma, type 1 and 2 diabetes and obesity, as well as taking non-genetic health factors and family history into account.

“There’s no guidelines for polygenic risk right now,” said Jackson. “We spent over a year at the network going through each condition we were looking at and developing recommended next steps.”

A key goal of the network is to assess what does and does not work in the clinic with a view to introducing genomic medicine to all in the future. “Does returning genetic results actually change provider processes? Do the patients actually go for those additional screenings? And if not, why not? Is it because they don’t care, don’t understand, or is it because they can’t afford it?” says Jackson.

“If you can’t tell the government funding agencies or the companies that this is actually changing and here’s the impact that it’s having, then they’re not going to put these resources in place.”

This is something that Scott and his colleagues at Genomics England are considering for the upcoming Newborn Genomes Programme, which aims to sequence the genomes of 200,000 apparently healthy newborns to look for genetic conditions that are actionable in childhood. “We need to do a research program on whether the benefits outweigh the complexities and at reasonable cost,” he explained. “Through those children participating in research, we can learn what will make screening better and also diagnostics and other health care improvements.”

The U.K. -based program is also planning to investigate practicalities and public attitudes around long-term genetic data storage and understanding the value of storing the genome for future healthcare use.

Creating a safe space for genomic medicine

The field of precision medicine has come a long way since the first human genome sequence was completed in 2003, but routine inclusion of genomics in health care is still far from widespread.

“We’re in an intermediate period in history, where we can easily analyze people’s genomes in a research context. But we aren’t offering this to every human being in a reasonable way in our healthcare system,” said Green.

A notable change in recent years has been the widespread uptake of the ACMG secondary findings list among researchers and changing attitudes about returning genetic findings to research participants.

“It’s been really fascinating, because in the last 10 years of my career Institutional Review Boards have gone from asking, ‘Why are you returning genetic results?’ to ‘You better justify to me why you’re not returning genetic results?’ noted Green. “So, I think there is a new standard afoot.”

Jennifer Wagner is an assistant professor of law, policy, and engineering at Penn State University, and specializes in legal issues surrounding return of results and research in genetics and other areas of healthcare.

She cautions that it is becoming increasingly more likely that clinicians involved in large health-related studies that also involve caring for patients may become liable if they don’t return actionable genomic results to patients.

“On the legal side, one of the doctrines that I think will become increasingly important is the loss of chance medical malpractice doctrine,” she explained. This doctrine essentially means that a healthcare provider does something that leads to a worse outcome for patients. Not causing the outcome, or the disease to progress, but reducing the chances of a better outcome. For example, this could potentially include something like not disclosing an actionable genetic test result.

“That applies in medical practice, not research, per se… But the more we have the learning healthcare system model where research is really embedded into the provision of care, I think that there might be some willingness to extend that doctrine into the research realm,” said Wagner.

Part of the move towards returning genetic or genomic findings in research studies aligns with a broader move towards making medicine more preventive rather than treatment focused, which is an important part of implementing precision medicine more broadly.

“I firmly believe that the future of medicine rests on a foundation of genomics and I think what genomics allows us to do is have a much richer and more accurate signal on prevention than we ever did before,” says Zhou.

“People want information that may keep them healthy, rather than waiting for information that they are already sick,” adds Green.

However the complexities of state-based medical regulation in the U.S. and increasingly strict data regulations around the world may continue to block wider rollout of genomic data sharing and its use in routine medical care.

Wagner has recently carried out research looking into whether healthcare providers could exploit an exception in the Health Insurance Portability, Accountability Act (HIPAA) to inform family members of patients with familial ovarian cancer of their risk status.

While this could theoretically be allowed via HIPAA, Wagner and colleagues found that many state laws introduce additional barriers to this. “We looked at the laws of the 50 states and territories that we could access to assess whether or not those obstacles were in play. And basically, our conclusion was that this is not a viable pathway yet,” she explained.

“In the U.S. right now, I don’t know that there’s going to be a lot of public support to broaden information that’s being shared under HIPAA. Part of that has to do with the Dobbs decision and the fallout there. I think the interest in protecting privacy and keeping that information as narrowly disclosed as possible is going to continue for some time. But recognizing the benefits that could accrue if we were to engage in this, I think are hard to ignore.”

Another factor that may make the rollout of genomic medicine more complex, is the recently released blueprint for an AI Bill of Rights by the White House. Many large genomic studies and biobanks, as well as healthcare systems, are now using AI and similar tools to help process large amounts of ‘omics-related’ and healthcare data. The blueprint proposes guidelines that companies or researchers using AI can follow to protect people from abuse or misuse of these systems. While this proposal has good intentions, it may add a significant amount of additional work and regulatory administration to already overburdened research and healthcare systems.

Helen Albert is senior editor at Inside Precision Medicine and a freelance science journalist. Prior to going freelance, she was editor-in-chief at Labiotech, an English-language, digital publication based in Berlin focusing on the European biotech industry. Before moving to Germany, she worked at a range of different science and health-focused publications in London. She was editor of The Biochemist magazine and blog, but also worked as a senior reporter at Springer Nature’s medwireNews for a number of years, as well as freelancing for various international publications. She has written for New Scientist, Chemistry World, Biodesigned, The BMJ, Forbes, Science Business, Cosmos magazine, and GEN. Helen has academic degrees in genetics and anthropology, and also spent some time early in her career working at the Sanger Institute in Cambridge before deciding to move into journalism.

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