TERMINOLOGY AND PROXY MEASURES IN NEUROSCIENCE RESEARCH

Several workshop speakers said that opportunities to apply equitable practices in the basic science research community extend beyond the bench scientists working in laboratories. Shari Wiseman, the chief editor of Nature Neuroscience, spoke about the importance of transparency and reporting in research, which includes using the correct terminology to reflect biological and social differences. She emphasized that this distinction is especially necessary when reporting on race (a social construct which may provide insight on lived/living experience) and ancestry (which is more closely related to genetics) because conflating the two terms, which are often used synonymously, may perpetuate biases.

Ekemini Riley, the founder and president of the Coalition for Aligning Science and the managing director of Aligning Science Across Parkinson’s, complemented Wiseman’s comments by explaining that race is currently used as a proxy for disease prevalence, diagnosis, and outcomes despite the absence of evidence that race can explain biologic differences. Therefore, the focus of current and future research should be identifying biological, genetic, and molecular mechanisms of the disease. Moving forward, she said that the goal is to develop clinical trials that can eventually achieve targeted therapies that are based on the expression of specific proteins rather than race. Until science reaches a point where race and ethnicity are no longer needed, Riley said, understanding and using the correct terminology specifically and accurately will be essential to describing people in scientific literature and prevent misinterpretation of biological data.

“There has been a major push toward health equity research as opposed to health disparities research,” said Kacie Deters, an assistant professor in the Department of Integrative Biology and Physiology at the University of California, Los Angeles. Race and ethnicity are often added as factors to research studies that were not designed with equity in mind, Deters said, and the outcomes resulting from this approach can be damaging to racialized communities.⁵ She continued by explaining that research in racialized and minoritized populations must be intentional about examining social and genetic risks and their potential intersection(s) to prevent any misunderstanding that there is a biological basis for race (which is purely a social construct). Deters suggested that researchers collaborate with experts who specialize in health equity research to help prevent the conflation of social and biological differences.

DIVERSE REPRESENTATION IN BIOLOGICAL MATERIALS AND CLINICAL TRIALS

Biomedical research has largely centered on White males, said both Wiseman and Deters. Daniel Weinberger, the director and chief executive officer of the Lieber Institute for Brain Development and a professor of psychiatry, neurology, neuroscience, and genetic medicine at the Johns Hopkins University School of Medicine, spoke about the rejection of studies including African Americans that he had proposed earlier in his career. He attributed this rejection to the belief that the genomes of individuals with African ancestry would be “more complicated” than those of individuals with European ancestry, which would increase the difficulty of finding the genes for common illnesses. Now, the Lieber Institute for Brain Development⁶ has received 4,000 donations of human brains, with 700 of them coming from African American individuals, Weinberger said. This has led to the development of the African Ancestry Neuroscience Research Initiative,⁷ which was developed in collaboration with Morgan State University, a historically Black university, and an African American faith-based community in Baltimore, Maryland, he added.

The use of more diverse biologic material in basic neuroscience research is not only important to achieve health equity but also improves the quality of the science, Wiseman said. Weinberger said that “many brain disorders vary in their frequency and severity based on an individual’s ancestry, which is their genetic lineage.” An individual’s genetic variation can determine how susceptible they may be to a disease or environmental factors. For example, he said, the average African American has between 0 and 60 percent European ancestry, and “Your proportion of ancestry, European versus African, has a rather substantial effect on what genes are turned on or what genes are turned off in the brain.” Weinberger explained that his research predicts the quantitative change in gene activation based on the proportion of European and African ancestry and investigates how that might impact disease prevalence. In a disease-specific example, he explained that Parkinson’s disease may be less common among people of African ancestry because of the number of genes that are active or inactive based on the proportion of African ancestry present. Weinberger’s research also suggests that the proportion of African ancestry only explains about 30 percent of the probability that someone will develop Alzheimer’s disease (AD). Examining biologic material from those with more diverse ancestry may offer opportunities to investigate these theories and “provide insights as to why different ancestry groups vary in their prevalence of some of these diseases and probably also why the biology to some degree varies across populations,” Weinberger concluded.

Koroshetz said he has seen conflicting findings on how the misunderstanding of biologic mechanisms can potentially pose medical harm to communities that are underrepresented in research. He explained that people of African ancestry with early state dementia had faced high rates of exclusion from recent anti-amyloid AD treatment trials because their positron emission tomography (PET) scans often did not demonstrate elevated levels of amyloid. This suggests that their dementia has a cause other than AD. “[In addition], the main risk factor for the anti-amyloid therapy [which is used to treat Alzheimer’s disease] is leakage and bleeding from a damaged blood vessel,” he said. Because African Americans have a predisposition towards hypertension-related damage to the vascular system and there were so few African Americans in the anti-amyloid trials, it is more difficult to counsel African Americans about the risk versus benefit of the new treatment.

Riley said that objective measures could help address these complex challenges. “In thinking about the Alzheimer’s [disease] trials, if there was some objective measure of vascular integrity, imagine a world where everyone was simply screened for that measure,” she said, “no matter what your ancestry is, if you don’t have good vascular integrity, you’re in one bucket, and if you have good vascular integrity, you’re in another bucket regardless of what your ancestry is.” Having objective measures would promote more inclusive practices for the clinical trial recruitment of people from various ancestries in neurological research, she concluded.

Deters suggested that the neuroscience research community think critically about opportunities to be more inclusive in their studies. She recalled a report that Black individuals were more likely to have been excluded from an AD study and that they were less likely to demonstrate elevated amyloid than White individuals (Deters et al., 2021). This caused Deters to wonder if the Black individuals who are participating in these studies are representative of the broader population since they may be more resilient or high performers.

Discussions about increased diversity in research extend beyond racial and ethnic diversity. Wiseman said that cis-gender women, transgender individuals, and non-binary people have also been historically underrepresented in biomedical research, which has contributed to health disparities and left gaps in research. In response to a question from the audience regarding how to embrace intersectionality and the wide diversity of genetic circumstantial expressions that are determined by life experiences, heritage, and culture, Wiseman suggested using “big data” from biobanks such as the All of Us⁸ in the United States and the UK biobank.⁹ Admittedly, she added, most of the material in these biobanks comes from more affluent populations, but regardless, these models are a good starting place. She then echoed Riley’s point regarding the intention to eventually move away from these proxy measures to start examining more individualized, complex biomarkers.

INCLUDING INDIVIDUALS WITH LIVED/LIVING EXPERIENCE

Phil Gutis, an Alzheimer’s Association former early-stage advisor and an individual living with AD, described the need for improved communication between researchers and diverse participants, especially those with lived/living experience. He shared that he was notified of his diagnosis via email, “which basically said, ‘Congratulations, you have been diagnosed with early onset Alzheimer’s [disease] and are now eligible to participate in the Biogen trial.’” While that may not be standard practice, the email was an example of how the communication to patients can feel unempathetic and dehumanizing, Gutis said. “The other challenge is that when there is generally information about these trials, we’re not hearing about it from the researchers or the clinical trials. We’re hearing about it, particularly if it’s large biopharma, in the media.” He said that he had learned that Aducanumab failed its futility test through the news despite being an active participant in the trials. Wiseman added that to build trust with the community, there must be clear and bi-directional communication between researchers and the public. This includes the community sharing their concerns with researchers and researchers clearly articulating clinical results and the short and long-term benefits of research.

Developing a workforce that is more reflective of the communities that have been historically underrepresented in research is essential to building trust and strengthening communication between the research community and those underserved populations, Koroshetz said. He said that NIH is committed to supporting people from underrepresented communities in entering the neuroscience workforce, believing that more diverse perspectives improve the quality of science produced.¹⁰ According to Koroshetz, NIH has developed pipeline programs that support undergraduate through postdoctoral students. But being committed to developing a more diverse workforce is not enough, Koroshetz said, as the responsibility to achieve health equity should not rest solely on those who have been historically underserved, but rather that responsibility should be shared among the entire scientific community.

From a publishing perspective, Wiseman said, “we don’t want to see what is sometimes called helicopter science.” Journal editors are less interested in seeing researchers drop into communities, extract data, leave, and reap the benefits of the research; she explained, “I would be hesitant to publish a genetic study in a certain population that did not include members of the population as authors.” Instead, researchers may consider engaging someone from the community which they are studying as an investigator or build a longer-term, bi-directional relationship with the communities that they are interested in investigating.

Although research has become increasingly diverse and accessible, only a very small percentage of the nation’s population is ever involved in research, Koroshetz said. Gutis added, “I hope that we start engaging people with lived experience more broadly through all corridors of research and for all people. There are tons of people who are desperate to engage with the research community, and it would be great if folks were interested in hearing more from us.” People living with the diseases being studied rarely hear about the research, and trust is needed to engage those who are aware of the research, Koroshetz responded.

THE INTERSECTIONALITY OF CREDIBILITY, INCLUSIVITY, AND EQUITY IN SCIENCE

In summarizing the workshop discussions, Krystal said that they highlighted five important points: the complexity of the study of race versus ancestry, the importance of removing bias from study methods, the opportunity to create partnerships with lived/living experience communities, the importance of having a diverse workforce across all levels, and the opportunity to be intentional about including individuals with lived/living experience and creating systemic change. Trust, engagement, and inclusivity are all required to build credibility with the general public, Krystal said, “and if we want to address the disparities in health that plague our society [and achieve health equity], our science has to become more credible.”

REFERENCES

• Brown AF, Ma GX, Miranda J, Eng E, Castille D, Brockie T, Jones P, Airhihenbuwa CO, Farhat T, Zhu L, Trinh-Shevrin C. Structural interventions to reduce and eliminate health disparities. American Journal of Public Health. 2019;109(Suppl 1):S72–S78. https://doi​.org/10.2105/AJPH.2018.304844 . [PMC free article: PMC6356131] [PubMed: 30699019]
• Deters KD, Napolioni V, Sperling RA, Greicius MD, Mayeux R, Hohman T, Mormino EC. Amyloid pet imaging in self-identified non-Hispanic Black participants of the anti-amyloid in asymptomatic Alzheimer’s disease (a4) study. Neurology. 2021;96(11):e1491–e1500. [PMC free article: PMC8032379] [PubMed: 33568538]
• National Education Association. Racial justice in education: Key terms and definitions. 2021. [January 8, 2024]. https://www​.nea.org/resource-library​/racial-justice-education-resource-guide .
• Rosendale N. Social determinants of health in neurology. Neurologic Clinics. 2022;40(1):231–247. https://doi​.org/10.1016/j​.ncl.2021.08.012 . [PubMed: 34798972]

Suggested citation:

National Academies of Sciences, Engineering, and Medicine. 2024. Mitigating health disparities in brain disorders starting with basic science: Proceedings of a workshop—in brief. Washington, DC: The National Academies Press. https://doi.org/10.17226/27479.