Promoting a MOSAIC future in science.

Discoveries at the frontiers of science and finding solutions to pressing biomedical problems will be accelerated when talent, which is widely distributed, is better aligned with opportunities. Strategies to enhance a MOSAIC (Maximizing Opportunities for Scientific and Academic Independent Careers) professoriate and diversify the biomedical landscape are discussed.

Addressing Ancestry and Sex Bias in Pharmacogenomics.

The association of an individual's genetic makeup with their response to drugs is referred to as pharmacogenomics. By understanding the relationship between genetic variants and drug efficacy or toxicity, we are able to optimize pharmacological therapy according to an individual's genotype. Pharmacogenomics research has historically suffered from bias and underrepresentation of people from certain ancestry groups and of the female sex. These biases can arise from factors such as drugs and indications studied, selection of study participants, and methods used to collect and analyze data. To examine the representation of biogeographical populations in pharmacogenomic data sets, we describe individuals involved in gene-drug response studies from PharmGKB, a leading repository of drug-gene annotations, and showcaseCYP2D6, a gene that metabolizes approximately 25% of all prescribed drugs. We also show how the historical underrepresentation of females in clinical trials has led to significantly more adverse drug reactions in females than in males.

Biogeographic Perspectives on Human Genetic Diversification.

Modern humans originated in Africa 300,000 yr ago, and before leaving their continent of origin, they underwent a process of intense diversification involving complex demographic dynamics. Upon exiting Africa, different populations emerged on the four other inhabited continents, shaped by the interplay of various evolutionary processes, such as migrations, founder effects, and natural selection. Within each region, continental populations, in turn, diversified and evolved almost independently for millennia. As a backdrop to this diversification, introgressions from archaic species contributed to establishing different patterns of genetic diversity in different geographic regions, reshaping our understanding of our species' variability. With the increasing availability of genomic data, it has become possible to delineate the subcontinental human population structure precisely. However, the bias toward the genomic research focused on populations from the global North has limited our understanding of the real diversity of our species and the processes and events that guided different human groups throughout their evolutionary history. This perspective is part of a series of articles celebrating 40 yr since our journal, Molecular Biology and Evolution, was founded (Russo et al. 2024). The perspective is accompanied by virtual issues, a selection of papers on human diversification published by Genome Biology and Evolution and Molecular Biology and Evolution.

Evolving Concepts in Helicobacter pylori Management.

Helicobacter pylori is the most common chronic bacterial infection worldwide and the most significant risk factor for gastric cancer, which remains a leading cause of cancer-related death globally. H pylori and gastric cancer continue to disproportionately impact racial and ethnic minority and immigrant groups in the United States. The approach to H pylori case-finding thus far has relied on opportunistic testing based on symptoms or high-risk indicators, such as racial or ethnic background and family history. However, this approach misses a substantial proportion of individuals infected with H pylori who remain at risk for gastric cancer because most infections remain clinically silent. Moreover, individuals with chronic H pylori infection are at risk for gastric preneoplastic lesions, which are also asymptomatic and only reliably diagnosed using endoscopy and biopsy. Thus, to make a significant impact in gastric cancer prevention, a systematic approach is needed to better identify individuals at highest risk of both H pylori infection and its complications, including gastric preneoplasia and cancer. The approach to H pylori eradication must also be optimized given sharply decreasing rates of successful eradication with commonly used therapies and increasing antimicrobial resistance. With growing acceptance that H pylori should be managed as an infectious disease and the increasing availability of susceptibility testing, we now have the momentum to abandon empirical therapies demonstrated to have inadequate eradication rates. Molecular-based susceptibility profiling facilitates selection of a personalized eradication regimen without necessitating an invasive procedure. An improved approach to H pylori eradication coupled with population-level programs for screening and treatment could be an effective and efficient strategy to prevent gastric cancer, especially in minority and potentially marginalized populations that bear the heaviest burden of H pylori infection and its complications.

Genotype imputation accuracy and the quality metrics of the minor ancestry in multi-ancestry reference panels.

Large-scale imputation reference panels are currently available and have contributed to efficient genome-wide association studies through genotype imputation. However, whether large-size multi-ancestry or small-size population-specific reference panels are the optimal choices for under-represented populations continues to be debated. We imputed genotypes of East Asian (180k Japanese) subjects using the Trans-Omics for Precision Medicine reference panel and found that the standard imputation quality metric (Rsq) overestimated dosage r2 (squared correlation between imputed dosage and true genotype) particularly in marginal-quality bins. Variance component analysis of Rsq revealed that the increased imputed-genotype certainty (dosages closer to 0, 1 or 2) caused upward bias, indicating some systemic bias in the imputation. Through systematic simulations using different template switching rates (θ value) in the hidden Markov model, we revealed that the lower θ value increased the imputed-genotype certainty and Rsq; however, dosage r2 was insensitive to the θ value, thereby causing a deviation. In simulated reference panels with different sizes and ancestral diversities, the θ value estimates from Minimac decreased with the size of a single ancestry and increased with the ancestral diversity. Thus, Rsq could be deviated from dosage r2 for a subpopulation in the multi-ancestry panel, and the deviation represents different imputed-dosage distributions. Finally, despite the impact of the θ value, distant ancestries in the reference panel contributed only a few additional variants passing a predefined Rsq threshold. We conclude that the θ value substantially impacts the imputed dosage and the imputation quality metric value.

Adapting STEMM in Hawai'i: Necessary actions for one of the most diverse places in the United States.

Hawai'i's diverse population prime it to be an exemplary environment to study representation in science, technology, engineering, mathematics, and medicine (STEMM). In actuality, Hawai'i has low STEMM enrollment and therefore, low representation in STEMM. What primarily inhibits Hawai'i from having a strong STEMM workforce is the lack of education in STEMM, resources allocated to STEMM, and mentorship to succeed in STEMM. Other factors such as cultural values, high costs of living, and geographical barriers also contribute to Hawai'i's low STEMM enrollment. To combat these issues, I offer suggestions to encourage STEMM enrollment, such as directing funds toward after-school education. I also suggest combatting the lack of resources by providing more online opportunities for students and workers. As for Hawai'i's low mentorship, I suggest that more programs be created within communities and universities to create a platform for mentors and mentees to network. This manuscript seeks to highlight these areas of improvement and recognize lessons to be learned from Hawai'i, thus serving as a resource for individuals internationally.

How to be an effective ally.

Inclusivity in biomedical research provides many positive attributes, including increased productivity, higher creativity, and improved wellness for all. While marginalized individuals work tirelessly to achieve equity and inclusion, this task should not be left solely to those most affected by exclusionary tactics. These individuals and the organizations with whom they are affiliated would benefit from the support of an ally. An ally is defined as a person or organization that actively supports the rights of a marginalized group without being a member of it. Allies have a unique opportunity to play a pivotal role in promoting fairness, equity, and inclusion, and thus serve as positive change agents within an organizational setting. We summarize here the importance of being an effective and dynamic ally and offer guidance on how to achieve that goal.

Establishing the short course in transferable skills training program.

While PhD programs prepare graduate students to perform biomedical research, a defined systematic training program for transferable skills is generally lacking. When provided, this training is often informal, unstructured, or inconsistent. Therefore, there is a need to provide critical skills in marketing, relationship building, project management, and budgeting to prepare trainees to navigate into a productive, engaging, and rewarding biomedical research career. To address this gap in training, the School of Graduate Studies at Meharry Medical College has developed the SHort Course In transFerable skills Training (SHIFT) Program, a 1-year professional development program accessible to graduate students in the United States who are enrolled in graduate biomedical research related programs. The SHIFT Program has been launched to equip trainees with skills essential for success in all biomedical science careers. PhD students will be taught the primary constituents of career management through the use of four training modules. In Module I, students complete self-assessments and are assigned to a small peer-mentoring team with mentors. Module II consists of a 5-day workshop that encompasses instruction on the transferable skills identified as essential for career success. Module III entails monthly interactive discussions over a 6-month period involving case study review and mentor-guided discussions to further reinforce skills learned. In Module IV, students compile the information learned from Modules I-III to develop an Individual Development Plan that incorporates 3-5 specific, measurable, attainable, relevant, and time-based career goals. Collectively, the SHIFT Program will allow participants to train, practice, and refresh skills, empowering them to navigate career transitions and obtain success in the career of their choice.

Alleviating misclassified germline variants in underrepresented populations: A strategy using popmax.

PURPOSE: Germline variant interpretation often depends on population-matched control cohorts. This is not feasible for population groups that are underrepresented in current population reference databases. METHODS: We classify germline variants with population-matched controls for 2 ancestrally diverse cohorts of patients: 132 early-onset or familial colorectal carcinoma patients from Singapore and 100 early-onset colorectal carcinoma patients from the United States. The effects of using a population-mismatched control cohort are simulated by swapping the control cohorts used for each patient cohort, with or without the popmax computational strategy. RESULTS: Population-matched classifications revealed a combined 62 pathogenic or likely pathogenic (P/LP) variants in 34 genes across both cohorts. Using a population-mismatched control cohort resulted in misclassification of non-P/LP variants as P/LP, driven by the absence of ancestry-specific rare variants in the control cohort. Popmax was more effective in alleviating misclassifications for the Singapore cohort than the US cohort. CONCLUSION: Underrepresented population groups can suffer from higher rates of false-positive P/LP results. Popmax can partially alleviate these misclassifications, but its efficacy still depends on the degree with which the population groups are represented in the control cohort.

Improving access to exome sequencing in a medically underserved population through the Texome Project.

PURPOSE: Genomic medicine can end diagnostic odysseys for patients with complex phenotypes; however, limitations in insurance coverage and other systemic barriers preclude individuals from accessing comprehensive genetics evaluation and testing. METHODS: The Texome Project is a 4-year study that reduces barriers to genomic testing for individuals from underserved and underrepresented populations. Participants with undiagnosed, rare diseases who have financial barriers to obtaining exome sequencing (ES) clinically are enrolled in the Texome Project. RESULTS: We highlight the Texome Project process and describe the outcomes of the first 60 ES results for study participants. Participants received a genetic evaluation, ES, and return of results at no cost. We summarize the psychosocial or medical implications of these genetic diagnoses. Thus far, ES provided molecular diagnoses for 18 out of 60 (30%) of Texome participants. Plus, in 11 out of 60 (18%) participants, a partial or probable diagnosis was identified. Overall, 5 participants had a change in medical management. CONCLUSION: To date, the Texome Project has recruited a racially, ethnically, and socioeconomically diverse cohort. The diagnostic rate and medical impact in this cohort support the need for expanded access to genetic testing and services. The Texome Project will continue reducing barriers to genomic care throughout the future study years.

Analysis of financial barriers experienced by prospective genetic counseling students.

PURPOSE: High costs of applying to genetic counseling graduate programs (GCGPs) are likely a barrier to workforce diversification. We sought to determine application costs and assess differences between individuals of historically underrepresented racial and ethnic backgrounds in medicine (hURM) and non-hURM applicants. METHODS: Applicants to GCGPs between 2005 to 2020 were surveyed about application history, related expenses, volunteer hours, and financial resources; 383 responses were analyzed. RESULTS: Median total application costs (MTAC) were $2634, $4762, and $5607 (1, 2, and 3 or more application cycles, respectively). Interview-related items (which includes travel) had the highest median cost (1 application cycle: $879). Among those who applied to multiple cycles, hURM respondents had higher MTAC than those of non-hURM ($6713 versus $4762, P = .03) and lower median total volunteer hours (246 versus 381, P = .03). Parental education level differed by hURM status (P = .04). Median financial contribution from parents with and without advanced degrees varied significantly (60% versus 2%, P = .0009). CONCLUSION: Significant costs are incurred during the GCGP application process, but notable differences in costs and resources were observed between hURM and non-hURM applicants. Stakeholders within the profession should implement strategies to reduce financial barriers and the resulting inequities in the application process.

The prevalence of major depressive disorder in people with HIV: Results from the All of Us Research Program.

OBJECTIVES: The All of Us (AoU) Research Program is a national-scale effort to build a dataset to help transform the future of health research by equipping researchers with comprehensive health data from diverse populations, especially those underrepresented in biomedical research. Our objectives were to evaluate the burden of HIV and major depressive disorder (MDD) in underrepresented groups and the frequency of the HIV/MDD comorbidity. METHODS: We conducted a cross-sectional analysis combining collected survey and electronic health record (EHR) data. We ascertained HIV and MDD cases using Observational Medical Outcomes Partnership codes. We used multivariable logistic regression to obtain the odds ratio of HIV in AoU participants and MDD in AoU participants with HIV. RESULTS: The latest AoU data release includes 412 211 participants: 254 700 have at least one medical condition concept in their EHR, of whom 5193 (1.3%) had HIV, and 2238 (43%) of those with HIV had a diagnosis of MDD. Black AoU participants had approximately 4.58 times the odds of having an HIV diagnosis compared with the combined odds of all other racial groups. AoU participants with HIV were more likely to have MDD (p = 0.001) than were participants without HIV. CONCLUSION: Among AoU participants, Black individuals have a disproportionately high burden of HIV, pointing to underlying factors such as social determinants of health, limited access to healthcare or prevention resources, and potential systemic biases that contribute to these differences. In addition, HIV is a risk factor for mental health issues like MDD. Further data collection from people with HIV will elucidate contributing factors and the need for interventions.

Does Sponsorship Promote Equity in Career Advancement in Academic Medicine? A Scoping Review.

Sponsorship describes a set of actions wherein an influential champion (sponsor) uses their position to actively support a colleague's career by helping them gain visibility, recognition, and/or positions. There is growing awareness of the importance of sponsorship for career advancement in academic medicine, particularly for women and those who are historically underrepresented and excluded in medicine (UIM). This scoping review examines the current landscape of evidence, and knowledge gaps, on sponsorship as it relates to career advancement in academic medicine for women and UIM faculty. We searched peer-reviewed literature in PubMed, Embase, and Web of Science (WoS) over the past 50 years (from 1973 through July 2023). Sixteen studies were included in the final review. We found relative consensus on sponsorship definition and value to career advancement. Heterogeneity in study design limited our ability to directly compare study outcomes. All included studies focused on gender differences in sponsorship: two of four quantitative studies found men were more likely to receive sponsorship, one reported no gender differences, and one was insufficiently powered. All but one of the qualitative studies reported gender differences, with women less likely to access or be identified for sponsorship. The mixed-methods studies suggested sponsorship may vary by career stage. Only two studies analyzed sponsorship for UIM populations. The existing data are inconclusive regarding best ways to measure and assess sponsorship, what institutional support (e.g., structured programs, formal recognition, or incentives for sponsorship) should look like, and at what career stage sponsorship is most important. Addressing this knowledge gap will be critically important for understanding what sponsorship best practices, if any, should be used to promote equity in career advancement in academic medicine. We advocate for commitment at the institutional and national levels to develop new infrastructure for transparently and equitably supporting women and UIM in career advancement.

Plasma ADAM10 Levels and Their Association with Alzheimer's Disease Diagnosis in Older Adults with Fewer Years of Formal Education.

INTRODUCTION: Low educational attainment is a potential risk factor for Alzheimer's disease (AD) development. Alpha-secretase ADAM10 plays a central role in AD pathology, attenuating the formation of beta-amyloid peptides and, therefore, their aggregation into senile plaques. This study seeks to investigate ADAM10 as a blood-based biomarker in mild cognitive impairment (MCI) and AD in a diverse group of community-dwelling older adults, focusing on those with limited educational attainment. METHODS: Participants were recruited from public health services. Cognition was evaluated using Mini-Mental State Examination (MMSE) and Addenbrooke's Cognitive Examination - Revised (ACE-R) batteries. Blood samples were collected to analyze plasma ADAM10 levels. A logistic regression was conducted to verify the influence of plasma ADAM10 on the AD diagnosis. RESULTS: Significant differences in age, years of education, prescribed medications, and cognitive test scores were found between the MCI and AD groups. Regarding cognitive performance, both ACE-R and MMSE scores displayed significant differences between groups, with post hoc analyses highlighting these distinctions, particularly between AD and cognitively unimpaired individuals. Elevated plasma ADAM10 levels were associated with a 4.5-fold increase in the likelihood of a diagnosis of MCI and a 5.9-fold increase in the likelihood of a diagnosis of AD. These findings suggest ADAM10 levels in plasma as a valuable biomarker for assessing cognitive status in older individuals with low education attainment. CONCLUSION: This study underscores the potential utility of plasma ADAM10 levels as a blood-based biomarker for cognitive status, especially in individuals with low educational backgrounds, shedding light on their relevance in AD development and diagnosis.

The importance of pathway programs in increasing diversity in dermatology: Efforts made by the American Academy of Dermatology.

Our country's population continues to diversify, highlighting the need for an equally diverse physician workforce to care for patients. Unfortunately, the percentage of underrepresented minority residents in dermatology has remained relatively unchanged over the past several years. To address this disparity, the American Academy of Dermatology created the Pathways Programs to focus on early exposure to dermatology, skill-building workshops, research, and mentorship. The overarching goal is to increase the number of underrepresented minority dermatologists, which will result in improved patient care and mitigation of healthcare disparities.

Cognitive Performance Between Latino and White Non-Latino Individuals With Parkinson's Disease.

OBJECTIVE: Cognitive impairment is a common nonmotor symptom in Parkinson's disease (PD). Individuals of Latino background are traditionally underrepresented in research on PD. Despite the fact that Latinos comprise 18% of the U.S. population, they commonly make up less than 5% of samples in studies of PD. Emerging evidence suggests that Latino individuals with PD may experience disparities relative to White non-Latinos in terms of having more severe motor symptoms, more severe depressive symptoms, and worse health-related quality of life. The purpose of the present study was to investigate differences in cognitive performance between Latino and White non-Latino individuals with PD and examine correlates of cognitive performance. METHODS: Data were obtained from the Parkinson's Progression Markers Initiative. Participants included 60 Latino individuals with PD and 1,009 White non-Latino individuals with PD, all of whom were followed annually for up to 5 years. Participants completed neuropsychological tests of attention and working memory, processing speed, visuospatial functioning, verbal fluency, and immediate and delayed memory and recall. RESULTS: Relative to White non-Latino individuals with PD, Latino individuals with PD had significantly lower scores on the global measure of cognitive functioning, a test of processing speed, and tests of working memory and attention. Years of education was the strongest correlate of performance in these three cognitive domains among individuals in the Latino group. CONCLUSIONS: These findings provide initial evidence of disparities in cognitive functioning among Latino individuals with PD. Educational disadvantages may be one potential driver of these disparities.

Immunomodulator adherence in multiple myeloma patients with lower socioeconomic status: a retrospective study.

OBJECTIVE: Poor adherence to oral chemotherapy adversely impacts clinical outcomes and escalates overall healthcare costs. Despite barriers to medication adherence, a significant gap remains in assessing adherence to oral chemotherapy among multiple myeloma (MM) patients with lower socioeconomic status. Hence, our study aims to evaluate immunomodulator adherence in MM patients at a county hospital, primarily serving underrepresented and indigent individuals with low socioeconomic status across the greater Houston area. METHODS: Inclusion criteria composed of patients diagnosed with MM, aged at least 18 years, and treated with lenalidomide or pomalidomide-two widely used immunomodulators-for a minimum of 2 months or having two or more records of dispensation between May 2019 and May 2021. Adherence was gauged using an adjusted version of the medication possession ratio (MPR). RESULTS: Sixty-two patients were enrolled, yielding a mean MPR value of 88% (SD, ± 18.9). Of these, 43 patients (69.3%) demonstrated adherence with an MPR of ≥ 0.90. A significant difference was found in treatment duration between the adherent (mean 8.8 months; SD, ± 7.2) and non-adherent (mean 13.4 months; SD, ± 7.9) groups (p = 0.027). Notably, race/ethnicity demonstrated a significant difference (p = 0.048), driven by disparities in African American and Hispanic representation across adherence levels. CONCLUSION: In summary, our findings highlight race and treatment duration to be predictors of immunomodulator adherence among MM patients with lower socioeconomic status. Further research is imperative to devise and test innovative interventions aimed at enhancing medication adherence, thereby contributing to improved survival and healthcare quality in this population.

A pilot recruitment strategy to enhance ethical and equitable access to Covid-19 pediatric vaccine trials.

BACKGROUND/AIMS: The SARS-CoV-2 pandemic disproportionately impacted communities with lower access to health care in the United States, particularly before vaccines were widely available. These same communities are often underrepresented in clinical trials. Efforts to ensure equitable enrollment of participants in trials related to treatment and prevention of Covid-19 can raise concerns about exploitation if communities with lower access to health care are targeted for recruitment. METHODS: To enhance equity while avoiding exploitation, our site developed and implemented a three-part recruitment strategy for pediatric Covid-19 vaccine studies. First, we publicized a registry for potentially interested participants. Next, we applied public health community and social vulnerability indices to categorize the residence of families who had signed up for the registry into three levels to reflect the relative impact of the pandemic on their community: high, medium, and low. Finally, we preferentially offered study participation to interested families living in areas categorized by these indices as having high impact of the Covid-19 pandemic on their community. RESULTS: This approach allowed us to meet goals for study recruitment based on public health metrics related to disease burden, which contributed to a racially diverse study population that mirrored the surrounding community demographics. While this three-part recruitment strategy improved representation of minoritized groups from areas heavily impacted by the Covid-19 pandemic, important limitations were identified that would benefit from further study. CONCLUSION: Future use of this approach to enhance equitable access to research while avoiding exploitation should test different methods to build trust and communicate with underserved communities more effectively.

Engaging underrepresented groups in community physical activity initiatives: a qualitative study of parkrun in the UK.

BACKGROUND: Underrepresented groups, including racial/ethnic minority groups and individuals with low socioeconomic status face complex barriers to engaging in community-based health initiatives. This research uses parkrun, an outdoor, mass-participation, weekly physical activity and volunteering initiative, to explore the engagement strategies ('outreach activities') that have been used to promote the inclusivity and diversity of parkrun events. METHODS: Ten adult parkrun Ambassadors who fulfilled volunteer roles that involved promoting parkrun to underrepresented groups in the UK were interviewed. Interviews took place via telephone or video call in April-July 2021. Interview transcripts were analysed thematically. RESULTS: Engagement strategies implemented by Ambassadors varied from opportunistic promotion within communities to strategic negotiations at higher decision-making levels. Approaches were characterised by a community-centred focus that ensured community networks and assets were utilised. Stories were considered valuable indicators of successful outreach. A common challenge to outreach for Ambassadors was limited personal and organisational capacity that impeded the widescale scope, reach and scalability of parkrun's engagement attempts. CONCLUSIONS: Parkrun Ambassadors have used a wide range of outreach activities at different levels of influence. A number of challenges to doing sustainable and effective outreach have been highlighted that need to be addressed. Working with and alongside communities where community-based health initiatives events take place to understand how to address inclusivity issues could contribute to greater participation by underrepresented groups.

Families' experiences accessing care after genomic sequencing in the pediatric cancer context: "It's just been a big juggle".

Access to genomic sequencing (GS) and resulting recommendations have not been well described in pediatric oncology. GS results may provide a cancer predisposition syndrome (CPS) diagnosis that warrants screening and specialist visits beyond cancer treatment, including testing or surveillance for family members. The Texas KidsCanSeq (KCS) Study evaluated implementation of GS in a diverse pediatric oncology population. We conducted semi-structured interviews (n = 20) to explore experiences of KCS patients' families around learning about a CPS diagnosis and following up on recommended care. We used qualitative content analysis to develop themes and subthemes across families' descriptions of their experiences accessing care and to understand which factors presented barriers and/or facilitators. We found participants had difficulty differentiating which follow-up care recommendations were made for their child's current cancer treatment versus the CPS. In families' access to follow-up care for CPS, organizational factors were crucial: travel time and distance were common hardships, while coordination of care to streamline multiple appointments with different providers helped facilitate CPS care. Financial factors also impacted families' access to CPS-related follow-up care: having financial assistance and insurance were facilitators for families, while costs and lack of insurance posed as barriers for patients who lost coverage during transitions from pediatric to adult care, and for adult family members who had no coverage. Factors related to beliefs and perceptions, specifically perceiving the risk as less salient to them and feeling overwhelmed with the patient's cancer care, presented barriers to follow-up care primarily for family members. Regarding social factors, competing life priorities made it difficult for families to access follow-up care, though having community support alleviated these barriers. We suggest interventions to improve coordination of cancer treatment and CPS-related care and adherence to surveillance protocols for families as children age, such as care navigators and integrating longitudinal genetic counseling into hereditary cancer centers.