Genomic Data Has a Diversity Problem, But Global Efforts Are Underway to Fix It
Genetic data sets skew too European, threatening to narrow who will benefit from future advances.
Genomics has begun its golden age. Just 20 years ago, sequencing a single genome cost nearly $3 billion and took over a decade. Today, the same feat can be achieved for a few hundred dollars and the better part of a day . Suddenly, the prospect of sequencing not just individuals, but whole populations, has become feasible.
The genetic differences between humans may seem meager, only around 0.1 percent of the genome on average, but this variation can have profound effects on an individual's risk of disease, responsiveness to medication, and even the dosage level that would work best.
Already, initiatives like the U.K.'s 100,000 Genomes Project - now expanding to 1 million genomes - and other similarly massive sequencing projects in Iceland and the U.S., have begun collecting population-scale data in order to capture and study this variation.
The resulting data sets are immensely valuable to researchers and drug developers working to design new 'precision' medicines and diagnostics, and to gain insights that may benefit patients. Yet, because the majority of this data comes from developed countries with well-established scientific and medical infrastructure, the data collected so far is heavily biased towards Western populations with largely European ancestry.
This presents a startling and fast-emerging problem: groups that are under-represented in these datasets are likely to benefit less from the new wave of therapeutics, diagnostics, and insights, simply because they were tailored for the genetic profiles of people with European ancestry.
We may indeed be approaching a golden age of genomics-enabled precision medicine. But if the data bias persists then there is a risk, as with most golden ages throughout history, that the benefits will not be equally accessible to all, and existing inequalities will only be exacerbated.
To remedy the situation, a number of initiatives have sprung up to sequence genomes of under-represented groups, adding them to the datasets and ensuring that they too will benefit from the rapidly unfolding genomic revolution.
Global Gene Corp
The idea behind Global Gene Corp was born eight years ago in Harvard when Sumit Jamuar, co-founder and CEO, met up with his two other co-founders, both experienced geneticists, for a coffee.
"They were discussing the limitless applications of understanding your genetic code," said Jamuar, a business executive from New Delhi.
"And so, being a technology enthusiast type, I was excited and I turned to them and said hey, this is incredible! Could you sequence me and give me some insights? And they actually just turned around and said no, because it's not going to be useful for you - there's not enough reference for what a good Sumit looks like."
What started as a curiosity-driven conversation on the power of genomics ended with a commitment to tackle one of the field's biggest roadblocks - its lack of global representation.
Jamuar set out to begin with India, which has about 20 percent of the world's population, including over 4000 different ethnicities, but contributes less than 2 percent of genomic data, he told Leaps.org.
Eight years later, Global Gene Corp's sequencing initiative is well underway, and is the largest in the history of the Indian subcontinent. The program is being carried out in collaboration with biotech giant Regeneron, with support from the Indian government, local communities, and the Indian healthcare ecosystem. In August 2020, Global Gene Corp's work was recognized through the $1 million 2020 Roddenberry award for organizations that advance the vision of 'Star Trek' creator Gene Roddenberry to better humanity.
This problem has already begun to manifest itself in, for example, much higher levels of genetic misdiagnosis among non-Europeans tested for their risk of certain diseases, such as hypertrophic cardiomyopathy - an inherited disease of the heart muscle.
Global Gene Corp also focuses on developing and implementing AI and machine learning tools to make sense of the deluge of genomic data. These tools are increasingly used by both industry and academia to guide future research by identifying particularly promising or clinically interesting genetic variants. But if the underlying data is skewed European, then the effectiveness of the computational analysis - along with the future advances and avenues of research that emerge from it - will be skewed towards Europeans too.
This problem has already begun to manifest itself in, for example, much higher levels of genetic misdiagnosis among non-Europeans tested for their risk of certain diseases, such as hypertrophic cardiomyopathy - an inherited disease of the heart muscle. Most of the genetic variants used in these tests were identified as being causal for the disease from studies of European genomes. However, many of these variants differ both in their distribution and clinical significance across populations, leading to many patients of non-European ancestry receiving false-positive test results - as their benign genetic variants were misclassified as pathogenic. Had even a small number of genomes from other ethnicities been included in the initial studies, these misdiagnoses could have been avoided.
"Unless we have a data set which is unbiased and representative, we're never going to achieve the success that we want," Jamuar says.
"When Siri was first launched, she could hardly recognize an accent which was not of a certain type, so if I was trying to speak to Siri, I would have to repeat myself multiple times and try to mimic an accent which wasn't my accent so that she could understand it.
"But over time the voice recognition technology improved tremendously because the training data was expanded to include people of very diverse backgrounds and their accents, so the algorithms were trained to be able to pick that up and it dramatically improved the technology. That's the way we have to think about it - without that good-quality diverse data, we will never be able to achieve the full potential of the computational tools."
While mapping India's rich genetic diversity has been the organization's primary focus so far, they plan, in time, to expand their work to other under-represented groups in Asia, the Middle East, Africa, and Latin America.
"As other like-minded people and partners join the mission, it just accelerates the achievement of what we have set out to do, which is to map out and organize the world's genomic diversity so that we can enable high-quality life and longevity benefits for everyone, everywhere," Jamuar says.
Empowering African Genomics
Africa is the birthplace of our species, and today still retains an inordinate amount of total human genetic diversity. Groups that left Africa and went on to populate the rest of the world, some 50 to 100,000 years ago, were likely small in number and only took a fraction of the total genetic diversity with them. This ancient bottleneck means that no other group in the world can match the level of genetic diversity seen in modern African populations.
Despite Africa's central importance in understanding the history and extent of human genetic diversity, the genomics of African populations remains wildly understudied. Addressing this disparity has become a central focus of the H3Africa Consortium, an initiative formally launched in 2012 with support from the African Academy of Sciences, the U.S. National Institutes of Health, and the UK's Wellcome Trust. Today, H3Africa supports over 50 projects across the continent, on an array of different research areas in genetics relevant to the health and heredity of Africans.
"Africa is the cradle of Humankind. So what that really means is that the populations that are currently living in Africa are among some of the oldest populations on the globe, and we know that the longer populations have had to go through evolutionary phases, the more variation there is in the genomes of people who live presently," says Zane Lombard, a principal investigator at H3Africa and Associate Professor of Human Genetics at the University of the Witwatersrand in Johannesburg, South Africa.
"So for that reason, African populations carry a huge amount of genetic variation and diversity, which is pretty much uncaptured. There's still a lot to learn as far as novel variation is concerned by looking at and studying African genomes."
A recent landmark H3Africa study, led by Lombard and published in Nature in October, sequenced the genomes of over 400 African individuals from 50 ethno-linguistic groups - many of which had never been sampled before.
Despite the relatively modest number of individuals sequenced in the study, over three million previously undescribed genetic variants were found, and complex patterns of ancestral migration were uncovered.
"In some of these ethno-linguistic groups they don't have a word for DNA, so we've had to really think about how to make sure that we communicate the purposes of different studies to participants so that you have true informed consent," says Lombard.
"The objective," she explained, "was to try and fill some of the gaps for many of these populations for which we didn't have any whole genome sequences or any genetic variation data...because if we're thinking about the future of precision medicine, if the patient is a member of a specific group where we don't know a lot about the genomic variation that exists in that group, it makes it really difficult to start thinking about clinical interpretation of their data."
From H3Africa's conception, the consortium's goal has not only been to better represent Africa's staggering genetic diversity in genomic data sets, but also to build Africa's domestic genomics capabilities and empower a new generation of African researchers. By doing so, the hope is that Africans will be able to set their own genomics agenda, and leapfrog to new and better ways of doing the work.
"The training that has happened on the continent and the number of new scientists, new students, and fellows that have come through the process and are now enabled to start their own research groups, to grow their own research in their countries, to be a spokesperson for genomics research in their countries, and to build that political will to do these larger types of sequencing initiatives - that is really a significant outcome from H3Africa as well. Over and above all the science that's coming out," Lombard says.
"What has been created through H3Africa is just this locus of researchers and scientists and bioethicists who have the same goal at heart - to work towards adjusting the data bias and making sure that all global populations are represented in genomics."
Are the gains from gain-of-function research worth the risks?
Gain-of-function research can make pathogens more infectious and deadly. It also enables scientists to prepare remedies in advance.
Scientists have long argued that gain-of-function research, which can make viruses and other infectious agents more contagious or more deadly, was necessary to develop therapies and vaccines to counter the pathogens in case they were used for biological warfare. As the SARS-CoV-2 origins are being investigated, one prominent theory suggests it had leaked from a biolab that conducted gain-of-function research, causing a global pandemic that claimed nearly 6.9 million lives. Now some question the wisdom of engaging in this type of research, stating that the risks may far outweigh the benefits.
“Gain-of-function research means genetically changing a genome in a way that might enhance the biological function of its genes, such as its transmissibility or the range of hosts it can infect,” says George Church, professor of genetics at Harvard Medical School. This can occur through direct genetic manipulation as well as by encouraging mutations while growing successive generations of micro-organism in culture. “Some of these changes may impact pathogenesis in a way that is hard to anticipate in advance,” Church says.
In the wake of the global pandemic, the pros and cons of gain-of-function research are being fiercely debated. Some scientists say this type of research is vital for preventing future pandemics or for preparing for bioweapon attacks. Others consider it another disaster waiting to happen. The Government Accounting Office issued a report charging that a framework developed by the U.S. Department of Health & Human Services (HHS) provided inadequate oversight of this potentially deadly research. There’s a movement to stop it altogether. In January, the Viral Gain-of-Function Research Moratorium Act (S. 81) was introduced into the Senate to cease awarding federal research funding to institutions doing gain-of-function studies.
While testifying before the House COVID Origins Select Committee on March 8th, Robert Redfield, former director of the U.S. Centers for Disease Control and Prevention, said that COVID-19 may have resulted from an accidental lab leak involving gain-of-function research. Redfield said his conclusion is based upon the “rapid and high infectivity for human-to-human transmission, which then predicts the rapid evolution of new variants.”
“It is a very, very, very small subset of life science research that could potentially generate a potential pandemic pathogen,” said Gerald Parker, associate dean for Global One Health at Texas A&M University.
“In my opinion,” Redfield continues, “the COVID-19 pandemic presents a case study on the potential dangers of such research. While many believe that gain-of-function research is critical to get ahead of viruses by developing vaccines, in this case, I believe that was the exact opposite.” Consequently, Redfield called for a moratorium on gain-of-function research until there is consensus about the value of such risky science.
What constitutes risky?
The Federal Select Agent Program lists 68 specific infectious agents as risky because they are either very contagious or very deadly. In order to work with these 68 agents, scientists must register with the federal government. Meanwhile, research on deadly pathogens that aren’t easily transmitted, or pathogens that are quite contagious but not deadly, can be conducted without such oversight. “If you’re not working with select agents, you’re not required to register the research with the federal government,” says Gerald Parker, associate dean for Global One Health at Texas A&M University. But the 68-item list may not have everything that could possibly become dangerous or be engineered to be dangerous, thus escaping the government’s scrutiny—an issue that new regulations aim to address.
In January 2017, the White House Office of Science and Technology Policy (OSTP) issued additional guidance. It required federal departments and agencies to follow a series of steps when reviewing proposed research that could create, transfer, or use potential pandemic pathogens resulting from the enhancement of a pathogen’s transmissibility or virulence in humans.
In defining risky pathogens, OSTP included viruses that were likely to be highly transmissible and highly virulent, and thus very deadly. The Proposed Biosecurity Oversight Framework for the Future of Science, outlined in 2023, broadened the scope to require federal review of research “that is reasonably anticipated to enhance the transmissibility and/or virulence of any pathogen” likely to pose a threat to public health, health systems or national security. Those types of experiments also include the pathogens’ ability to evade vaccines or therapeutics, or diagnostic detection.
However, Parker says that dangers of generating a pandemic-level germ are tiny. “It is a very, very, very small subset of life science research that could potentially generate a potential pandemic pathogen.” Since gain-of-function guidelines were first issued in 2017, only three such research projects have met those requirements for HHS review. They aimed to study influenza and bird flu. Only two of those projects were funded, according to the NIH Office of Science Policy. For context, NIH funded approximately 11,000 of the 54,000 grant applications it received in 2022.
Guidelines governing gain-of-function research are being strengthened, but Church points out they aren’t ideal yet. “They need to be much clearer about penalties and avoiding positive uses before they would be enforceable.”
What do we gain from gain-of-function research?
The most commonly cited reason to conduct gain-of-function research is for biodefense—the government’s ability to deal with organisms that may pose threats to public health.
In the era of mRNA vaccines, the advance preparedness argument may be even less relevant.
“The need to work with potentially dangerous viruses is central to our preparedness,” Parker says. “It’s essential that we know and understand the basic biology, microbiology, etc. of some of these dangerous pathogens.” That includes increasing our knowledge of the molecular mechanisms by which a virus could become a sustained threat to humans. “Knowing that could help us detect [risks] earlier,” Parker says—and could make it possible to have medical countermeasures, like vaccines and therapeutics, ready.
Most vaccines, however, aren’t affected by this type of research. Essentially, scientists hope they will never need to use it. Moreover, Paul Mango, HSS former deputy chief of staff for policy, and author of the 2022 book Warp Speed, says he believes that in the era of mRNA vaccines, the advance preparedness argument may be even less relevant. “That’s because these vaccines can be developed and produced in less than 12 months, unlike traditional vaccines that require years of development,” he says.
Can better oversight guarantee safety?
Another situation, which Parker calls unnecessarily dangerous, is when regulatory bodies cannot verify that the appropriate biosafety and biosecurity controls are in place.
Gain-of-function studies, Parker points out, are conducted at the basic research level, and they’re performed in high-containment labs. “As long as all the processes, procedures and protocols are followed and there’s appropriate oversight at the institutional and scientific level, it can be conducted safely.”
Globally, there are 69 Biosafety Level 4 (BSL4) labs operating, under construction or being planned, according to recent research from King’s College London and George Mason University for Global BioLabs. Eleven of these 18 high-containment facilities that are planned or under construction are in Asia. Overall, three-quarters of the BSL4 labs are in cities, increasing public health risks if leaks occur.
Researchers say they are confident in the oversight system for BSL4 labs within the U.S. They are less confident in international labs. Global BioLabs’ report concurs. It gives the highest scores for biosafety to industrialized nations, led by France, Australia, Canada, the U.S. and Japan, and the lowest scores to Saudi Arabia, India and some developing African nations. Scores for biosecurity followed similar patterns.
“There are no harmonized international biosafety and biosecurity standards,” Parker notes. That issue has been discussed for at least a decade. Now, in the wake of SARS and the COVID-19 pandemic, scientists and regulators are likely to push for unified oversight standards. “It’s time we got serious about international harmonization of biosafety and biosecurity standards and guidelines,” Parker says. New guidelines are being worked on. The National Science Advisory Board for Biosecurity (NSABB) outlined its proposed recommendations in the document titled Proposed Biosecurity Oversight Framework for the Future of Science.
The debates about whether gain-of-function research is useful or poses unnecessary risks to humanity are likely to rage on for a while. The public too has a voice in this debate and should weigh in by communicating with their representatives in government, or by partaking in educational forums or initiatives offered by universities and other institutions. In the meantime, scientists should focus on improving the research regulations, Parker notes. “We need to continue to look for lessons learned and for gaps in our oversight system,” he says. “That’s what we need to do right now.”
The rise of remote work is a win-win for people with disabilities and employers
Disability advocates see remote work as a silver lining of the pandemic, a win-win for adults with disabilities and the business world alike.
Any corporate leader would jump at the opportunity to increase their talent pool of potential employees by 15 percent, with all these new hires belonging to an underrepresented minority. That’s especially true given tight labor markets and CEO desires to increase headcount. Yet, too few leaders realize that people with disabilities are the largest minority group in this country, numbering 50 million.
Some executives may dread the extra investments in accommodating people’s disabilities. Yet, providing full-time remote work could suffice, according to a new study by the Economic Innovation Group think tank. The authors found that the employment rate for people with disabilities did not simply reach the pre-pandemic level by mid-2022, but far surpassed it, to the highest rate in over a decade. “Remote work and a strong labor market are helping [individuals with disabilities] find work,” said Adam Ozimek, who led the research and is chief economist at the Economic Innovation Group.
Disability advocates see this development as a silver lining of the pandemic, a win-win for adults with disabilities and the business world alike. For decades before the pandemic, employers had refused requests from workers with disabilities to work remotely, according to Thomas Foley, executive director of the National Disability Institute. During the pandemic, "we all realized that...many of us could work remotely,” Foley says. “[T]hat was disproportionately positive for people with disabilities."
Charles-Edouard Catherine, director of corporate and government relations for the National Organization on Disability, said that remote-work options had been advocated for many years to accommodate disabilities. “It’s a little frustrating that for decades corporate America was saying it’s too complicated, we’ll lose productivity, and now suddenly it’s like, sure, let’s do it.”
The pandemic opened doors for people with disabilities
Early in the pandemic, employment rates dropped for everyone, including people with disabilities, according to Ozimek’s research. However, these rates recovered quickly. In the second quarter of 2022, people with disabilities aged 25 to 54, the prime working age, are 3.5 percent more likely to be employed, compared to before the pandemic.
What about people without disabilites? They are still 1.1 percent less likely to be employed.
These numbers suggest that remote work has enabled a substantial number of people with disabilities to find and retain employment.
“We have a last-in, first-out labor market, and [people with disabilities] are often among the last in and the first out,” Ozimek says. However, this dynamic has changed, with adults with disabilities seeing employment rates recover much faster. Now, the question is whether the new trend will endure, Ozimek adds. “And my conclusion is that not only is it a permanent thing, but it’s going to improve.”
Gene Boes, president and chief executive of the Northwest Center, a Seattle organization that helps people with disabilities become more independent, confirms this finding. “The new world we live in has opened the door a little bit more…because there’s just more demand for labor.”
Long COVID disabilities put a premium on remote work
Remote work can help mitigate the impact of long COVID. The U.S. Centers for Disease Control and Prevention reports that about 19 percent of those who had COVID developed long COVID. Recent Census Bureau data indicates that 16 million working age Americans suffer from it, with economic costs estimated at $3.7 trillion.
Certainly, many of these so-called long-haulers experience relatively mild symptoms - such as loss of smell - which, while troublesome, are not disabling. But other symptoms are serious enough to be disabilities.
According to a recent study from the Federal Reserve Bank of Minneapolis, about a quarter of those with long COVID changed their employment status or working hours. That means long COVID was serious enough to interfere with work for 4 million people. For many, the issue was serious enough to qualify them as disabled.
Indeed, the Federal Reserve Bank of New York found in a just-released study that the number of individuals with disabilities in the U.S. grew by 1.7 million. That growth stemmed mainly from long COVID conditions such as fatigue and brain fog, meaning difficulties with concentration or memory, with 1.3 million people reporting an increase in brain fog since mid-2020.
Many had to drop out of the labor force due to long COVID. Yet, about 900,000 people who are newly disabled have managed to continue working. Without remote work, they might have lost these jobs.
For example, a software engineer at one of my client companies has struggled with brain fog related to long COVID. With remote work, this employee can work during the hours when she feels most mentally alert and focused, even if that means short bursts of productivity throughout the day. With flexible scheduling, she can take rests, meditate, or engage in activities that help her regain focus and energy. Without the need to commute to the office, she can save energy and time and reduce stress, which is crucial when dealing with brain fog.
In fact, the author of the Federal Reserve Bank of New York study notes that long COVID can be considered a disability under the Americans with Disability Act, depending on the specifics of the condition. That means the law can require private employers with fifteen or more staff, as well as government agencies, to make reasonable accommodations for those with long COVID. Richard Deitz, the author of this study, writes in the paper that “telework and flexible scheduling are two accommodations that can be particularly beneficial for workers dealing with fatigue and brain fog.”
The current drive to return to the office, led by many C-suite executives, may need to be reconsidered in light of legal and HR considerations. Arlene S. Kanter, director of the disability law and policy program at the Syracuse University College of Law, said that the question should depend on whether people with disabilities can perform their work well at home, as they did during Covid outbreaks. “[T]hen people with disabilities, as a matter of accommodation, shouldn’t be denied that right,” Kanter said.
Diversity benefits
But companies shouldn’t need to worry about legal regulations. It simply makes dollars and sense to expand their talent pool by 15% of an underrepresented minority. After all, extensive research shows that improving diversity boosts both decision-making and financial performance.
Companies that are offering more flexible work options have already gained significant benefits in terms of diverse hires. In its efforts to adapt to the post-pandemic environment, Meta, the owner of Facebook and Instagram, decided to offer permanent fully remote work options to its entire workforce. And according to Meta chief diversity officer Maxine Williams, the candidates who accepted job offers for remote positions were “substantially more likely” to come from diverse communities: people with disabilities, Black, Hispanic, Alaskan Native, Native American, veterans, and women. The numbers bear out these claims: people with disabilities increased from 4.7 to 6.2 percent of Meta’s employees.
Having consulted for 21 companies to help them transition to hybrid work arrangements, I can confirm that Meta’s numbers aren’t a fluke. The more my clients proved willing to offer remote work, the more staff with disabilities they recruited - and retained. That includes employees with mobility challenges. But it also includes employees with less visible disabilities, such as people with long COVID and immunocompromised people who feel reluctant to put themselves at risk of getting COVID by coming into the office.
Unfortunately, many leaders fail to see the benefits of remote work for underrepresented groups, such as those with disabilities. Some even say the opposite is true, with JP Morgan CEO Jamie Dimon claiming that returning to the office will aid diversity.
What explains this poor executive decision making? Part of the answer comes from a mental blindspot called the in-group bias. Our minds tend to favor and pay attention to the concerns of those in the group of people who seem to look and think like us. Dimon and other executives without disabilities don’t perceive people with disabilities to be part of their in-group. They thus are blind to the concerns of those with disabilities, which leads to misperceptions such as Dimon’s that returning to the office will aid diversity.
In-group bias is one of many dangerous judgment errors known as cognitive biases. They impact decision making in all life areas, ranging from the future of work to relationships.
Another relevant cognitive bias is the empathy gap. This term refers to our difficulty empathizing with those outside of our in-group. The lack of empathy combines with the blindness from the in-group bias, causing executives to ignore the feelings of employees with disabilities and prospective hires.
Omission bias also plays a role. This dangerous judgment error causes us to perceive failure to act as less problematic than acting. Consequently, executives perceive a failure to support the needs of those with disabilities as a minor matter.
Conclusion
The failure to empower people with disabilities through remote work options will prove costly to the bottom lines of companies. Not only are limiting their talent pool by 15 percent, they’re harming their ability to recruit and retain diverse candidates. And as their lawyers and HR departments will tell them, by violating the ADA, they are putting themselves in legal jeopardy.
By contrast, companies like Meta - and my clients - that offer remote work opportunities are seizing a competitive advantage by recruiting these underrepresented candidates. They’re lowering costs of labor while increasing diversity. The future belongs to the savvy companies that offer the flexibility that people with disabilities need.