Cloud-based biomedical data storage and analysis for genomic research: Landscape analysis of data governance in emerging NIH-supported platforms.

The storage, sharing, and analysis of genomic data poses technical and logistical challenges that have precipitated the development of cloud-based computing platforms designed to facilitate collaboration and maximize the scientific utility of data. To understand cloud platforms' policies and procedures and the implications for different stakeholder groups, in summer 2021, we reviewed publicly available documents (N = 94) sourced from platform websites, scientific literature, and lay media for five NIH-funded cloud platforms (the All of Us Research Hub, NHGRI AnVIL, NHLBI BioData Catalyst, NCI Genomic Data Commons, and the Kids First Data Resource Center) and a pre-existing data sharing mechanism, dbGaP. Platform policies were compared across seven categories of data governance: data submission, data ingestion, user authentication and authorization, data security, data access, auditing, and sanctions. Our analysis finds similarities across the platforms, including reliance on a formal data ingestion process, multiple tiers of data access with varying user authentication and/or authorization requirements, platform and user data security measures, and auditing for inappropriate data use. Platforms differ in how data tiers are organized, as well as the specifics of user authentication and authorization across access tiers. Our analysis maps elements of data governance across emerging NIH-funded cloud platforms and as such provides a key resource for stakeholders seeking to understand and utilize data access and analysis options across platforms and to surface aspects of governance that may require harmonization to achieve the desired interoperability.

Awareness and utilization of genetic testing among Hispanic and Latino adults living in the US: The Hispanic Community Health Study/Study of Latinos.

We investigated the awareness, perceived usefulness, and use of genetic testing among Hispanic and Latino individuals. Annual follow-up surveys for the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) from 2019 to April 2020 assessed participants' level of awareness and use of genetic tests to determine disease risks, likelihood of passing disease to children, disease treatment, or drug selection. They also were asked to rate the usefulness of the tests for managing a person's health on a 1 (not at all useful) to 10 (extremely useful) scale. There were 5,769 HCHS/SOL participants who completed at least one survey question. Of the target population, 55.2% was aware of at least one type of genetic test. Awareness varied between HCHS/SOL enrollment sites and was higher among individuals who had higher educational attainment and had higher incomes. Only 3.3% of the target population reported receiving one or more of the tests described. HCHS/SOL individuals rated the usefulness as 8.4, on average, with lower scores observed among U.S.-born individuals compared to individuals born outside the United States, with differences by HCHS/SOL enrollment sites. In conclusion, while awareness of genetic testing among Hispanic and Latino individuals varies by location, education, and income, perceptions about its usefulness are high while experiences with testing are rare. Results identify groups and locations that may benefit from greater outreach about the capabilities of genetic testing and precision medicine.

Valsalva Maneuver to Identify Dermal Bleeders after Paramedian Flap Elevation Under Local Anesthesia.

The paramedian forehead flap (PFF) provides a reliable reconstruction option for complex nasal tip defects. The robust blood supply from a well perfused pedicle allows for reconstruction of large defects of the nasal tip for which simpler methods/techniques would provide inadequate coverage or result in inferior cosmesis. A well-designed PFF containing the supratrochlear artery inherently predisposes to small vessel bleeding from the pedicles cut edge. Due to the well perfused nature of the pedicle, there is an increased risk of post-operative bleeding. We describe a technique for better identifying bleeding points from the pedicle to optimise intra-operative haemostasis by performing the Valsalva maneuver using a syringe intraoperatively.

Social and scientific motivations to move beyond groups in allele frequencies: The TOPMed experience.

For the genomics community, allele frequencies within defined groups (or "strata") are useful across multiple research and clinical contexts. Benefits include allowing researchers to identify populations for replication or "look up" studies, enabling researchers to compare population-specific frequencies to validate findings, and facilitating assessment of variant pathogenicity in clinical contexts. However, there are potential concerns with stratified allele frequencies. These include potential re-identification (determining whether or not an individual participated in a given research study based on allele frequencies and individual-level genetic data), harm from associating stigmatizing variants with specific groups, potential reification of race as a biological rather than a socio-political category, and whether presenting stratified frequencies-and the downstream applications that this presentation enables-is consistent with participants' informed consents. The NHLBI Trans-Omics for Precision Medicine (TOPMed) program considered the scientific and social implications of different approaches for adding stratified frequencies to the TOPMed BRAVO (Browse All Variants Online) variant server. We recommend a novel approach of presenting ancestry-specific allele frequencies using a statistical method based upon local genetic ancestry inference. Notably, this approach does not require grouping individuals by either predominant global ancestry or race/ethnicity and, therefore, mitigates re-identification and other concerns as the mixture distribution of ancestral allele frequencies varies across the genome. Here we describe our considerations and approach, which can assist other genomics research programs facing similar issues of how to define and present stratified frequencies in publicly available variant databases.

Recommendations on the use and reporting of race, ethnicity, and ancestry in genetic research: Experiences from the NHLBI TOPMed program.

How race, ethnicity, and ancestry are used in genomic research has wide-ranging implications for how research is translated into clinical care and incorporated into public understanding. Correlation between race and genetic ancestry contributes to unresolved complexity for the scientific community, as illustrated by heterogeneous definitions and applications of these variables. Here, we offer commentary and recommendations on the use of race, ethnicity, and ancestry across the arc of genetic research, including data harmonization, analysis, and reporting. While informed by our experiences as researchers affiliated with the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, these recommendations are applicable to basic and translational genomic research in diverse populations with genome-wide data. Moving forward, considerable collaborative effort will be required to ensure that race, ethnicity, and ancestry are described and used appropriately to generate scientific knowledge that yields broad and equitable benefit.

Consent for Use of Genetic Data among US Hispanics/Latinos: Results from the Hispanic Community Health Study/ Study of Latinos.

Inclusion of historically underrepresented populations in biomedical research is critical for large precision medicine research initiatives. Among 13,721 Hispanic Community Health Study/Study of Latinos (HCHS/SOL) enrollees, we used multivariable-adjusted prevalence ratios to describe characteristics associated with participants' willingness to consent to different levels of biospecimen and genetic data analysis and sharing. At baseline (2008-2011), HCHS/SOL participants almost universally consented to the use of biospecimens and genetic data by study investigators and their collaborators (97.6%; 95%CI: 97.1, 98.0). Fewer consented to biospecimen and genetic data sharing with investigators not affiliated with the HCHS/SOL research team (81%, 95%CI: 80, 82) or any data sharing with commercial/for-profit entities (75%, 95%CI: 74, 76). Those refusing to share their data beyond the study investigators group were more often females, Spanish language-speakers and non-US born individuals. As expected, participants who were retained and reconsented at the six-year follow up visit tended to embrace broader data sharing, although this varied by group. Over time, Puerto Ricans and Dominicans were more likely to convert to broader data sharing than individuals of a Mexican background. Our analysis suggests that acculturation and immigration status of specific Hispanic/Latino communities may influence decisions about participation in genomic research projects and biobanks.

The trans-ancestral genomic architecture of glycemic traits.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.

Recipient and donor genetic variants associated with mortality after allogeneic hematopoietic cell transplantation.

Many studies have suggested that genetic variants in donors and recipients are associated with survival-related outcomes after allogeneic hematopoietic cell transplantation (HCT), but these results have not been confirmed. Therefore, the utility of testing genetic variants in donors and recipients for risk stratification or understanding mechanisms leading to mortality after HCT has not been established. We tested 122 recipient and donor candidate variants for association with nonrelapse mortality (NRM) and relapse mortality (RM) in a cohort of 2560 HCT recipients of European ancestry with related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1710 HCT recipients. We found that the donor rs1051792 A allele in MICA was associated with a lower risk of NRM. Donor and recipient rs1051792 genotypes were highly correlated, making it statistically impossible to determine whether the donor or recipient genotype accounted for the association. Risks of grade 3 to 4 graft-versus-host disease (GVHD) and NRM in patients with grades 3 to 4 GVHD were lower with donor MICA-129Met but not with MICA-129Val, implicating MICA-129Met in the donor as an explanation for the decreased risk of NRM after HCT. Our analysis of candidate variants did not show any other association with NRM or RM. A genome-wide association study did not identify any other variants associated with NRM or RM.

Who's on third? Regulation of third-party genetic interpretation services.

In recent years, third-party genetic interpretation services have emerged to help individuals understand their raw genetic data obtained from researchers, clinicians, and direct-to-consumer genetic testing companies. The objectives of these services vary but include matching users to genetic relatives, selling customized diet and fitness plans, and providing health risk assessments. As these services proliferate, concerns are being raised about their accuracy, safety, and privacy practices. Thus far, US regulatory agencies have not taken an official position with respect to third-party genetic interpretation services, which has caused uncertainty regarding whether and how they might be regulated. To clarify this area, we analyzed their potential oversight by four US agencies that generally have been active in the regulation of genetic testing services and information: the Centers for Medicare and Medicaid Services, the Food and Drug Administration, the Department of Health and Human Services' Office of Civil Rights, and the Federal Trade Commission. We conclude that the scope of federal jurisdiction over third-party genetic interpretation services-while limited-could be appropriate at this time, subject to agency clarification and appropriate exercise of oversight.

Genetic analyses of diverse populations improves discovery for complex traits.

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry1-3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific4-10. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations11,12. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States-where minority populations have a disproportionately higher burden of chronic conditions13-the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities.

Third-Party Genetic Interpretation Tools: A Mixed-Methods Study of Consumer Motivation and Behavior.

In an effort to meet ethical obligations and/or participant expectations, researchers may consider offering "raw" or uninterpreted genetic data for result return. It is therefore important to understand the motivations, behaviors, and perspectives of individuals who might choose to access raw data before such return becomes routine. In the direct-to-consumer (DTC) context, where raw data are often made available to customers, the use of third-party interpretation tools has raised concerns about genotype accuracy, data privacy, reliability of interpretation, and consumption of limited health care resources. However, relatively little is known about why individuals access raw data or what they do with the information received from third-party interpretation. Accordingly, we conducted a survey on raw data access and third-party tool usage among 1,137 DTC customers recruited through social media. Most survey respondents (89%) reported downloading their raw data. Among downloaders, 94% used at least one tool, most commonly Promethease (63%) or GEDmatch (84%). More than half (56%) used both health-related and non-health-related tools and differed significantly from those who used only one tool type in terms of demographics, participation in research, DTC tests ordered, and testing motivations. Exploratory interviews were conducted with 10 respondents and illustrated how social networking, initial lack of interesting findings, and general curiosity contributed to use of multiple tool types. These results suggest that even when initially motivated by ancestry and genealogy, consumers frequently also pursue health information in a largely unregulated and expanding suite of third-party tools, raising both challenges and opportunities for the professional genetics community.

Discovery of common and rare genetic risk variants for colorectal cancer.

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males.

Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide association study assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified 3 distinct loci that were significant in combined or sex-segregated analyses. A single-nucleotide polymorphism on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio = 2.9, 95% confidence interval: 2.02-4.27, P = 2.2 × 10). This association was nominally replicated in a meta-analysis of 7 independent orofacial pain cohorts including 160,194 participants (odds ratio = 1.16, 95% confidence interval: 1.0-1.35, P = 2.3 × 10). Functional analysis in human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = -0.51, P = 2.43 × 10). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men.

Can I take my normal painkillers doctor? Therapeutic management of pain following dermatological procedures.

Dermatological procedures performed purely under local anaesthesia can provide excellent intraoperative analgesia. However, post-procedure patients can have significant pain. Consequences of pain include patient distress, poor compliance with dressings and subsequent delayed wound healing as well as the potential fear and avoidance of further procedures. Anecdotally the same postoperative analgesia regime is given to all dermatology patients. There is a general fear by dermatologists of nonsteroidal anti-inflammatory drugs (NSAIDs) due to perceived risk of postoperative bleeding and of tramadol due to its sedative effects. Understanding of pharmacology within the patient population and their comorbidities is necessary in choosing the appropriate analgesic regime. We reviewed the most commonly used analgesics, giving a summary of the important pharmacology and evidence of their use in the literature in order to allow clinicians to give individual approach to managing post-procedure analgesia.

Pathways to ethnic-racial identity development and psychological adjustment: The differential associations of cultural socialization by parents and peers.

Ethnic-racial identity (ERI) development is a central developmental process for youth of color. Although a great deal of research establishes the importance of cultural socialization by parents to the development of ERI, limited empirical work has examined peers' role in these processes. This study uses 4 cross-sectional data sets (N = 127, 312, 257, and 238, mean age = 17.96-18.24) followed by a meta-analytic summary to test a path model of ERI development and parent and peer cultural socialization and their associations with psychological adjustment in a diverse sample of emerging adults. The final sample size adjusted meta-analytic model indicated that parent ethnic socialization predicted both ERI exploration and commitment while only peer preparation for bias predicted ERI commitment. In turn, ERI commitment and exploration predicted more positive mental health. The findings of this study highlight the importance of both parents and peers to cultural socialization processes during emerging adulthood. In particular, this study suggests that the messages peers impart about prejudice play a unique role in the development of ERI. The findings have important implications about the unique role peers play in communicating messages about prejudice as well as for ERI and the psychological adjustment of youth of color at this developmental stage. Additionally, these cross-sectional findings provide a preliminary but robust model from which researchers can frame future longitudinal work in this area. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Ethnic-racial typicality and its relation to ethnic identity and psychological functioning.

OBJECTIVES: Ethnic identity development is considered a central task of adolescence and emerging adulthood for ethnic minority individuals. Although the process of developing a coherent ethnic identity has received attention from researchers, there has been little work done to elucidate the content of ethnic identity. This study uses an inductive mixed-methods approach to address 1 aspect of ethnic identity content: typicality, or the degree of perceived similarity individuals feel to their ethnic-racial group. METHOD: Participants included 974 college students at 3 universities-66% women, average age 20.4 years, 5% Black, 30% Asian, 10% Latinx, 40% White, 11% Multiracial, 1% American Indian, and 4% Other race-ethnicity. Thematic analysis was used to code qualitative categories on what makes individuals typical of and atypical of their ethnic group. Codes were used to quantitatively assess relations between aspects of typicality, ethnic identity, and mental health. RESULTS: Findings suggest that individuals judged their typicality and atypicality to their ethnic group by focusing on skin color, hair, facial features; values related to family, achievement, and religion-spirituality; and behaviors related to arts-media, sports, spending time with others, and food. Additionally, findings demonstrated that most individuals feel typical of their ethnic group and, of importance, that level of perceived typicality was inversely related to measures of ethnic identity and well-being. Finally, participants differed in their feeling of being typical by ethnic-racial group identifications. CONCLUSIONS: Ethnic-racial typicality provides valuable information about ethnic identity content and is related to important mental health outcomes. (PsycINFO Database Record

Identity and the body: Trajectories of body esteem from adolescence to emerging adulthood.

Although Erikson (1968) originally conceptualized identity development as a process of becoming at home in one's body, little work has been done linking identity development and research on the body. This study examines how trajectories of the development of body esteem over time are related to young people's sense of identity and psychological functioning in a longitudinal sample from age 10 to 24 (N = 967). Using group-based trajectory modeling, three cubic subgroups were determined for each of the three types of body esteem: appearance, weight, and attribution. These groups demonstrated significant variations in the ways in which body esteem changes over time. These trajectory groups importantly differed in relationship to gender, identity coherence, identity confusion, and psychological functioning. Results are discussed in terms of the need to use a sociocultural perspective to explore the body's relation to identity development and the importance of disaggregating mean-level findings using person-centered approaches to determine high-risk groups. (PsycINFO Database Record

"Bridge to the Literature"? Third-Party Genetic Interpretation Tools and the Views of Tool Developers.

Patients and health care consumers can obtain access to their "raw," or uninterpreted, genetic data from direct-to-consumer genetic testing companies, researchers, or providers and pursue self-directed analysis via third-party interpretation tools. Yet relatively little is known about the nature of currently available interpretation tools or the motivations of tool developers. We conducted a structured content analysis of 23 third-party interpretation tool websites and supporting information, tracking features such as types of information returned, modes of generating and presenting that information, and privacy and security measures. We additionally conducted qualitative interviews with a subset of 10 tool developers. A majority of tools (16 of 23, or 70%) offer some type of health or wellness-related information, often extracted from publicly available variant annotation databases. Half of those interviewed characterized their activities as "bridging" users to the scientific literature rather than interpretation, for which they gave a variety of scientific, ethical, and regulatory justifications. The scale, heterogeneity, and complexity of information available from third-party interpretation are unprecedented. While developers aim to enlighten and empower tool users, interpretation-free "bridging" to rapidly evolving databases may instead impose burdens on genetic counselors and other health care providers asked to provide further contextualization and explanation.

Genetic variants in sex hormone pathways and the risk of type 2 diabetes among African American, Hispanic American, and European American postmenopausal women in the US.

BACKGROUND: Sex hormones are implicated in the development of diabetes. However, whether genetic variations in sex hormone pathways (SHPs) contribute to the risk of type 2 diabetes mellitus (T2DM) remains to be determined. This study investigated associations between genetic variations in all candidate genes in SHPs and T2DM risk among a cohort of women participating in the Women's Health Initiative (WHI). METHODS: Single nucleotide polymorphisms (SNPs) located within 30 kb upstream and downstream of SHP genes were comprehensively examined in 8180 African American, 3498 Hispanic American, and 3147 European American women in the WHI. In addition, whether significant SNPs would be replicated in independent populations was examined. RESULTS: After adjusting for age, region, and ancestry estimates and correcting for multiple testing, seven SNPs were significantly associated with the risk of T2DM among Hispanic American women were identified in the progesterone receptor (PGR) gene, with rs948516 showing the greatest significance (odds ratio 0.67; 95% confidence interval 0.57-0.78; P = 8.8 × 10-7 ; false discovery rate, Q = 7.8 × 10-4 ). These findings were not replicated in other ethnic groups in the WHI or in sex-combined analyses in replication studies. CONCLUSION: Significant signals were identified implicating the PGR gene in T2DM development in Hispanic American women in the WHI, which are consistent with genome-wide association studies findings linking PGR to glucose homeostasis. Nevertheless, the PGR SNPs-T2DM association was not statistically significant in other ethnic populations. Further studies, especially sex-specific analyses, are needed to confirm the findings and clarify the role of SHPs in T2DM.