Variations in the genomic profiles and clinical behavior of meningioma by racial and ethnic group.

OBJECTIVE: The influence of socioeconomic factors on racial disparities among patients with sporadic meningiomas is well established, yet other potential causative factors warrant further exploration. The authors of this study aimed to determine whether there is significant variation in the genomic profile of meningiomas among patients of different races and ethnicities and its correlation with clinical outcomes. METHODS: The demographic, genomic, and clinical data of patients aged 18 years and older who had undergone surgery for sporadic meningioma between September 2008 and November 2021 were analyzed. Statistical analyses were performed to detect differences across all racial/ethnic groups, as were direct comparisons between Black and non-Black groups plus Hispanic and non-Hispanic groups. RESULTS: This study included 460 patients with intracranial meningioma. Hispanic patients were significantly younger at surgery (53.9 vs 60.2 years, p = 0.0006) and more likely to show symptoms. Black patients had a higher incidence of anterior skull base tumors (OR 3.2, 95% CI 1.7-6.3, p = 0.0008) and somatic hedgehog mutations (OR 5.3, 95% CI 1.6-16.6, p = 0.003). Hispanics were less likely to exhibit the aggressive genomic characteristic of chromosome 1p deletion (OR 0.28, 95% CI 0.07-1.2, p = 0.06) and displayed higher rates of TRAF7 somatic driver mutations (OR 2.96 95% CI 1.1-7.8, p = 0.036). Black patients had higher rates of recurrence (OR 2.6, 95% CI 1.3-5.2, p = 0.009) and shorter progression-free survival (PFS; HR 2.9, 95% CI 1.6-5.4, p = 0.002) despite extents of resection (EORs) similar to those of non-Black patients (p = 0.745). No significant differences in overall survival were observed among groups. CONCLUSIONS: Despite similar EORs, Black patients had worse clinical outcomes following meningioma resection, characterized by a higher prevalence of somatic hedgehog mutations, increased recurrence rates, and shorter PFS. Meanwhile, Hispanic patients had less aggressive meningiomas, a predisposition for TRAF7 mutations, and no difference in PFS. These findings could inform the care and treatment strategies for meningiomas, and they establish the foundation for future studies focusing on the genomic origins of these observed differences.

A Systems Biology Approach to Understand the Racial Disparities in Colorectal Cancer.

Racial disparities between Black/African Americans (AA) and White patients in colorectal cancer are an ever-growing area of concern. Black/AA show the highest incidence and have the highest mortality among major U.S. racial groups. There is no definite cause other than possible sociodemographic, socioeconomic, education, nutrition, delivery of healthcare, screening, and cultural factors. A primary limitation in this field is the lack of and small sample size of Black/AA studies. Thus, this study aimed to investigate whether differences in gene expression contribute to this ongoing unanswered racial disparity issue. In this study, we examined transcriptomic data of Black/AA and White patient cohorts using a bioinformatic and systems biology approach. We performed a Kaplan-Meier overall survival analysis between both patient cohorts across critical colorectal cancer signal transduction networks (STN), to determine the differences in significant genes across each cohort. Other bioinformatic analyses performed included PROGENy (pathway responsive genes for activity inference), RNA sequencing differential expression using DESeq2, multivariable-adjusted regression, and other associated Kaplan-Meier analyses. These analyses identified novel prognostic genes independent from each cohort, 176 differentially expressed genes, and specific patient cohort STN survival associations. Despite the overarching limitation, the results revealed several novel differences in gene expression between the colorectal cancer Black/AA and White patient cohorts, which allows one to dive deeper into and understand the behavior on a systems level of what could be driving this racial difference across colorectal cancer. Concretely, this information can guide precision medicine approaches tailored specifically for colorectal cancer racial disparities. SIGNIFICANCE: The purpose of this work is to investigate the racial disparities in colorectal cancer between Black/AA and White patient cohorts using a systems biology and bioinformatic approach. Our study investigates the underlying biology of each patient cohort. Concretely, the findings of this study include disparity-associated genes and pathways, which provide a tangible starting point to guide precision medicine approaches tailored specifically for colorectal cancer racial disparities.

Precision health equity for racialized communities.

In the last three decades, a cohort of genomicists have intentionally sought to include more racially diverse people in their research in human genomics and precision medicine. How such efforts to be inclusive in human genomic research and precision medicine are modeled and enacted, specifically if the terms of inclusion are equitable for these communities remains to be explored. In this commentary, we review the historical context in which issues of racial inclusion arose with early genome and genetics projects. We then discuss attempts to include racialized peoples in more recent human genomics research. In conclusion, we raise critical issues to consider in the future of equitable human genomics and precision medicine research involving racialized communities, particularly as it concerns working towards what we call Precision Health Equity (PHE). Specifically, we examine issues of genetic data governance and the terms of participation in inclusive human genomics and precision health research. We do so by drawing on insights and protocols developed by researchers investigating Indigenous Data Sovereignty and propose exploring their application and adaptation to precision health research involving racialized communities.

Polygenic scoring accuracy varies across the genetic ancestry continuum.

Polygenic scores (PGSs) have limited portability across different groupings of individuals (for example, by genetic ancestries and/or social determinants of health), preventing their equitable use1-3. PGS portability has typically been assessed using a single aggregate population-level statistic (for example, R2)4, ignoring inter-individual variation within the population. Here, using a large and diverse Los Angeles biobank5 (ATLAS, n = 36,778) along with the UK Biobank6 (UKBB, n = 487,409), we show that PGS accuracy decreases individual-to-individual along the continuum of genetic ancestries7 in all considered populations, even within traditionally labelled 'homogeneous' genetic ancestries. The decreasing trend is well captured by a continuous measure of genetic distance (GD) from the PGS training data: Pearson correlation of -0.95 between GD and PGS accuracy averaged across 84 traits. When applying PGS models trained on individuals labelled as white British in the UKBB to individuals with European ancestries in ATLAS, individuals in the furthest GD decile have 14% lower accuracy relative to the closest decile; notably, the closest GD decile of individuals with Hispanic Latino American ancestries show similar PGS performance to the furthest GD decile of individuals with European ancestries. GD is significantly correlated with PGS estimates themselves for 82 of 84 traits, further emphasizing the importance of incorporating the continuum of genetic ancestries in PGS interpretation. Our results highlight the need to move away from discrete genetic ancestry clusters towards the continuum of genetic ancestries when considering PGSs.

Personalising Social Ills: An Analysis of Race-based Genomics and Personalised Medicine.

The mapping and sequencing of the human genome at the turn of the new millennium marks a pivotal reassessment of genomic science in its potential to replace traditional "one-size-fits-all" medicine with a personalised approach. The use of racial proxies in the development of pharmacogenomic products risks conflating genetics with race under the guise of alleviating health disparities. This article argues that the current genomic approaches to realising personalised medicine do not deliver on the promise for optimised health for all and may result in irreversible harm, including psychological, social and medical harm, to racial minority groups. In light of recent epigenetic findings, the article provides a reconceptualisation of the genome and race, which is necessary to understand enduring racial disparities and the cumulative effects of racial discrimination. It then addresses the need for regulatory oversight of the approval of race-based pharmacogenomic products.

Excess mortality from COVID and non-COVID causes in minority populations.

The 2020 US mortality totaled 2.8 million after early March, which is 17.3% higher than age-population-weighted mortality over the same time interval in 2017 to 2019, for a total excess death count of 413,592. We use data on weekly death counts by cause, as well as life tables, to quantify excess mortality and life years lost from both COVID-19 and non-COVID-19 causes by race/ethnicity, age, and gender/sex. Excess mortality from non-COVID-19 causes is substantial and much more heavily concentrated among males and minorities, especially Black, non-Hispanic males, than COVID-19 deaths. Thirty-four percent of the excess life years lost for males is from non-COVID-19 causes. While minorities represent 36% of COVID-19 deaths, they represent 70% of non-COVID-19 related excess deaths and 58% of non-COVID-19 excess life years lost. Black, non-Hispanic males represent only 6.9% of the population, but they are responsible for 8.9% of COVID-19 deaths and 28% of 2020 excess deaths from non-COVID-19 causes. For this group, nearly half of the excess life years lost in 2020 are due to non-COVID-19 causes.

Differences in the Platelet mRNA Landscape Portend Racial Disparities in Platelet Function and Suggest Novel Therapeutic Targets.

The African American (AA) population displays a 1.6 to 3-fold higher incidence of thrombosis and stroke mortality compared with European Americans (EAs). Current antiplatelet therapies target the ADP-mediated signaling pathway, which displays significant pharmacogenetic variation for platelet reactivity. The focus of this study was to define underlying population differences in platelet function in an effort to identify novel molecular targets for future antiplatelet therapy. We performed deep coverage RNA-Seq to compare gene expression levels in platelets derived from a cohort of healthy volunteers defined by ancestry determination. We identified > 13,000 expressed platelet genes of which 480 were significantly differentially expressed genes (DEGs) between AAs and EAs. DEGs encoding proteins known or predicted to modulate platelet aggregation, morphology, or platelet count were upregulated in AA platelets. Numerous G-protein coupled receptors, ion channels, and pro-inflammatory cytokines not previously associated with platelet function were likewise differentially expressed. Many of the signaling proteins represent potential pharmacologic targets of intervention. Notably, we confirmed the differential expression of cytokines IL32 and PROK2 in an independent cohort by quantitative real-time polymerase chain reaction, and provide functional validation of the opposing actions of these two cytokines on collagen-induced AA platelet aggregation. Using Genotype-Tissue Expression whole blood data, we identified 516 expression quantitative trait locuses with Fst values > 0.25, suggesting that population-differentiated alleles may contribute to differences in gene expression. This study identifies gene expression differences at the population level that may affect platelet function and serve as potential biomarkers to identify cardiovascular disease risk. Additionally, our analysis uncovers candidate novel druggable targets for future antiplatelet therapies.

Racial Experience as an Alternative Operationalization of Race.

The study of human variation is central to both social and biomedical sciences, but social and biomedical scientists diverge in how variation is theorized and operationalized. Race is especially problematic because it is a cultural concept that contains implicit and explicit understandings of how collective bodies differ. In this moderately updated article, originally published in Human Biology in 2015 (vol. 87, no. 4, pp. 306-312), we propose an operationalization of race that addresses both racial experience and human biological diversity, placing them within the same ontological sphere. Furthermore, this approach can more effectively advance antiracist pedagogy and politics. We argue that human biological diversity does not have to be in opposition to constructivist notions of race. Rather, racial experience is emphasized as an embodied experience that is as real and as valid as biological variation. By focusing on both racial experience and biological diversity, it becomes more feasible to operationalize race to fruitfully inform the pedagogy and politics of antiracism. To do so, racial experience must be more broadly conceived and should not always equate to negative outcomes. With the recognition that racial experience has the potential to be something other than damaging, an antiracist anthropology can more effectively address issues pertaining to racial health disparities.

Is genetic ancestry a tool to combat health disparities?

The use of race and ethnicity in medicine has become a matter of intense debate. Currently the social construct of race and ethnicity is far from precise, serving as a poor proxy for ancestry. In this issue of Cell, Belbin et al. provide an interesting framework for better characterizing population substructure in a diverse urban environment.

A transdisciplinary approach to understand the epigenetic basis of race/ethnicity health disparities.

Health disparities correspond to differences in disease burden and mortality among socially defined population groups. Such disparities may emerge according to race/ethnicity, socioeconomic status and a variety of other social contexts, and are documented for a wide range of diseases. Here, we provide a transdisciplinary perspective on the contribution of epigenetics to the understanding of health disparities, with a special emphasis on disparities across socially defined racial/ethnic groups. Scientists in the fields of biological anthropology, bioinformatics and molecular epidemiology provide a summary of theoretical, statistical and practical considerations for conducting epigenetic health disparities research, and provide examples of successful applications from cancer research using this approach.

Ex Ante Economic Evaluation of Arg389 Genetically Targeted Treatment with Bucindolol versus Empirical Treatment with Carvedilol in NYHA III/IV Heart Failure.

OBJECTIVE: The Beta-Blocker Evaluation Survival Trial showed no survival benefit for bucindolol in New York Heart Association (NYHA) class III/IV heart failure (HF) with reduced ejection fraction, but subanalyses suggested survival benefits for non-Black subjects and Arg389 homozygotes. We conducted an ex ante economic evaluation of Arg389 targeted treatment with bucindolol versus carvidolol, complementing a previous ex ante economic evaluation of bucindolol preceded by genetic testing for the Arg389 polymorphism, in which genetic testing prevailed economically over no testing. METHODS: A decision tree analysis with an 18-month time horizon was performed to estimate the cost effectiveness/cost utility of trajectories of 100%, 50%, and 0% of patients genetically tested for Arg389 and comparing bucindolol with empirical carvedilol treatment as per prior BEST subanalyses. Incremental cost-effectiveness/cost-utility ratios (ICERs/ICURs) were estimated. RESULTS: Race-based analyses for non-White subjects at 100% testing showed a loss of (0.04) life-years and (0.03) quality-adjusted life-years (QALYs) at an incremental cost of $2185, yielding a negative ICER of ($54,625)/life-year and ICUR of ($72,833)/QALY lost; at 50%, the analyses showed a loss of (0.27) life-years and (0.16) QALYs at an incremental cost of $1843, yielding a negative ICER of ($6826)/life-year and ICUR of ($11,519)/QALY lost; at 0%, the analyses showed a loss of (0.33) life-years and (0.30) QALYs at an incremental cost of $1459, yielding a negative ICER of ($4421)/life-year and ICUR of ($4863)/QALY lost. Arg389 homozygote analyses at 100% testing showed incremental gains of 0.02 life-years and 0.02 QALYs at an incremental cost of $378, yielding an ICER of 18,900/life-year and ICUR of $18,900/QALY gained; at 50%, the analyses showed a loss of (0.24) life-years and (0.09) QALYs at an incremental cost of $1039, yielding a negative ICER of ($4329)/life-year and ICUR of ($9336)/QALY lost; at 0%, the analyses showed a loss of (0.33) life-years and (0.30) QALYs at an incremental cost of $1459, yielding a negative ICER of ($4421)/life-year and ICUR of ($4863)/QALY lost. CONCLUSION: This independent ex ante economic evaluation suggests that genetically targeted treatment with bucindolol is unlikely to yield clinicoeconomic benefits over empirical treatment with carvedilol in NYHA III/IV HF.

Familial DNA analysis and criminal investigation: Usage, downsides and privacy concerns.

Since the discovery of Deoxyribonucleic acid (DNA) capability in forensic investigation, it has been an important part of the criminal justice system. In most criminal cases DNA profile originating from evidence sample collected from the crime scene is compared with the DNA profile from the reference sample. However, when a reference sample is not available for comparison, familial DNA analysis can provide important investigation leads in a criminal investigation process by identifying an individual. Moreover, this analysis is also proving effective in the identification of ethnicity and ancestry of an individual. A number of different methodologies and software are being used for familial DNA analysis. This review describes the importance of familial DNA analysis, methodologies used for familial DNA searching and identification, and its advantages in forensic. Moreover, ethical, legal and social issues associated with familial DNA analysis have also been discussed along with future directions for the proper implementation of this technology.

Janus-faced race: Is race biological, social, or mythical?

As belief in the reality of race as a biological category among U.S. anthropologists has fallen, belief in the reality of race as a social category has risen in its place. The view that race simply does not exist-that it is a myth-is treated with suspicion. While racial classification is linked to many of the worst evils of recent history, it is now widely believed to be necessary to fight back against racism. In this article, I argue that race is indeed a biological fiction, but I critique the claim that race is socially real. I defend a form of anti-realist reconstructionism about race, which says that there are no races, only racialized groups-groups mistakenly believed to be races. I argue that this is the most attractive position about race from a metaphysical perspective, and that it is also the position most conductive to public understanding and social justice.