Integrating genetic and socioeconomic data to predict the progression of nonalcoholic fatty liver disease.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease globally, with an estimated prevalence exceeding 25%. Variants in the PNPLA3 and HSD17B13 genes have been a focus of investigations surrounding the etiology and progression of NAFLD and are believed to contribute to a greater burden of disease experienced by Hispanic Americans. However, little is known about socioeconomic factors influencing NAFLD progression or its increased prevalence among Hispanics. MATERIALS AND METHODS: We cross-sectionally analyzed 264 patients to assess the role of genetic and socioeconomic variables in the development of advanced liver fibrosis in individuals at risk for NAFLD. RESULTS: Adjusting for age, sex, body mass index, and PNPLA3 genotype, lacking a college degree was associated with 3.3 times higher odds of advanced fibrosis (95% confidence interval [CI]: 1.21-8.76, p = 0.019), an effect comparable to that of possessing the major PNPLA3 risk variant. Notably, the effect of PNPLA3 genotype on advanced fibrosis was attenuated to nonsignificance following adjustment for education and other socioeconomic markers. The effect of the protective HSD17B13 variant, moreover, diminished after adjustment for education (odds ratio [OR]: 0.39 [95% CI: 0.13-1.16, p = 0.092]), while lower education continued to predict advanced fibrosis following multivariable adjustment with an OR of 8.0 (95% CI: 1.91-33.86, p = 0.005). DISCUSSION: Adjusting for education attenuated the effects of genotype and Hispanic ethnicity on liver fibrosis, suggesting that social factors-rather than genes or ethnicity-may be driving disease severity within some populations. Findings reveal the importance of including socioenvironmental controls when considering the role of genetics or ethnicity in complex disease.

Clinicians' perspectives on race-specific guidelines for hypertensive treatment.

Despite the general consensus that there is no biological basis to race, racial categorization is still used by clinicians to guide diagnosis and treatment plans for certain diseases. In medicine, race is commonly used as a rough proxy for unmeasured social, environmental, and genetic factors. The American College of Cardiology's Eighth Joint National Committee's (JNC 8) guidelines for the treatment of hypertension provide race-specific medication recommendations for Black versus non-Black patients, without strong evidence for race-specific physiological differences in drug response. Clinicians practicing family or geriatric medicine (n = 21) were shown a video of a mock hypertensive patient with genetic ancestry test results that could be viewed as discordant with their phenotype and self-identified race. After viewing the videos, we conducted in-depth interviews to examine how clinicians value and prioritize different cues about race -- namely genetic ancestry data, phenotypic appearance, and self-identified racial classifications - when making treatment decisions in the context of race-specific guidelines, particularly in situations when patients claim mixed-race or complex racial identities. Results indicate that clinicians inconsistently follow the race-specific guidelines for patients whose genetic ancestry test results do not match neatly with their self-identified race or phenotypic features. However, many clinicians also emphasized the importance of clinical experience, side effects, and other factors in their decision making. Clinicians' definitions of race, categorization of the patient's race, and prioritization of racial cues greatly varied. The existence of the race-specific guidelines clearly influences treatment decisions, even as clinicians' express uncertainty about how to incorporate consideration of a patient's genetic ancestry. In light of widespread debate about removal of race from medical diagnostics, researchers should revisit the clinical justification for maintaining these race-specific guidelines. Based on our findings and prior studies indicating a lack of convincing evidence for biological differences by race in medication response, we suggest removing race from the JNC 8 guidelines to avoid risk of perpetuating or exacerbating health disparities in hypertension.

Solutions From Mexican-Descent Perinatal Women To Pandemic-Related Food, Mental Health, And Health And Safety Stressors.

Latina women in the US were disproportionately affected by the COVID-19 pandemic because of structural racism, including discrimination, reduced care access, and elevated risk for illness and death. Although several US policies were implemented to offset the economic toll of the pandemic, few addressed complex stressors, particularly those among Mexican-descent mothers. This qualitative study with thirty-eight perinatal women and mothers of young children who were of Mexican descent sought to identify pandemic-related stressors and solicit recommendations for addressing them during future large-scale crises. Identified stressors included food access issues, mental health needs, and health and safety concerns. The women's recommendations revealed feasible and actionable strategies, including increased access to behavioral and health care services and accessible information about food-related resources. The findings highlight the critical need for responsive policies and programs to ensure the well-being of Mexican-descent perinatal women and mothers of young children during large-scale crises.

Early Evidence of Chronic Obstructive Pulmonary Disease Obscured by Race-Specific Prediction Equations.

Rationale: The identification of early chronic obstructive pulmonary disease (COPD) is essential to appropriately counsel patients regarding smoking cessation, provide symptomatic treatment, and eventually develop disease-modifying treatments. Disease severity in COPD is defined using race-specific spirometry equations. These may disadvantage non-White individuals in diagnosis and care. Objectives: Determine the impact of race-specific equations on African American (AA) versus non-Hispanic White individuals. Methods: Cross-sectional analyses of the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort were conducted, comparing non-Hispanic White (n = 6,766) and AA (n = 3,366) participants for COPD manifestations. Measurements and Main Results: Spirometric classifications using race-specific, multiethnic, and "race-reversed" prediction equations (NHANES [National Health and Nutrition Examination Survey] and Global Lung Function Initiative "Other" and "Global") were compared, as were respiratory symptoms, 6-minute-walk distance, computed tomography imaging, respiratory exacerbations, and St. George's Respiratory Questionnaire. Application of different prediction equations to the cohort resulted in different classifications by stage, with NHANES and Global Lung Function Initiative race-specific equations being minimally different, but race-reversed equations moving AA participants to more severe stages and especially between the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0 and preserved ratio impaired spirometry groups. Classification using the established NHANES race-specific equations demonstrated that for each of GOLD stages 1-4, AA participants were younger, had fewer pack-years and more current smoking, but had more exacerbations, shorter 6-minute-walk distance, greater dyspnea, and worse BODE (body mass index, airway obstruction, dyspnea, and exercise capacity) scores and St. George's Respiratory Questionnaire scores. Differences were greatest in GOLD stages 1 and 2. Race-reversed equations reclassified 774 AA participants (43%) from GOLD stage 0 to preserved ratio impaired spirometry. Conclusions: Race-specific equations underestimated disease severity among AA participants. These effects were particularly evident in early disease and may result in late detection of COPD.

Considerations, Caveats, and Suggestions for the Use of Polygenic Scores for Social and Behavioral Traits.

Polygenic scores (PGS) are increasingly being used for prediction of social and behavioral traits, but suffer from many methodological, theoretical, and ethical concerns that profoundly limit their value. Primarily, these scores are derived from statistical correlations, carrying no inherent biological meaning, and thus may capture indirect effects. Further, the performance of these scores depends upon the diversity of the reference populations and the genomic panels from which they were derived, which consistently underrepresent minoritized populations, leading to poor fit when applied to diverse groups. There is also inherent danger of eugenic applications for the information gained from these scores, and general risk of misunderstandings that could lead to stigmatization for underrepresented groups. We urge extreme caution in use of PGS particularly for social/behavioral outcomes fraught for misinterpretation, with potential harm for the minoritized groups least likely to benefit from their use.

COVID-19-Related Risk, Resilience, and Mental Health Among Mexican American Mothers Across the First Year of the Pandemic.

BACKGROUND: Latina mothers have been especially affected by the pandemic and historically exhibit high rates of depression and anxiety. However, few longitudinal studies have assessed the effect of the pandemic on this vulnerable population. We hypothesized that COVID-19-related stressors would associate with psychological distress among Latina mothers across the first year of the pandemic. METHODS: We investigated COVID-19-related impact, stigma, and fears across two critical time points and changes in these measures in relation to changes in maternal anxiety and depression among mothers of Mexican descent living in Southern California (n=152). Surveys were administered within 5-16 weeks of the March 19, 2020 stay-at-home COVID-19 order in California and again between June to December 2021. RESULTS: High proportions of women reported moderate to severe impacts of COVID-19 early in the pandemic, which reduced modestly a year later, e.g., reduced family incomes (55.9% 2020 Lockdown vs 32.7% 1-year follow-up). Anticipatory stigma was high across the first year, e.g., worrying at least some of the time that a family member will be deported (33.1% 2020 Lockdown vs. 14.1% 1-year follow-up), or they would not be able to care for their children (88.5% 2020 lockdown vs 82.2% 1-year follow-up). COVID-19 stigma, impact, and fears were significantly associated with higher levels of anxiety and depressive symptoms at both time points (p<0.003), and changes in COVID-19 impact were associated with changes in depression (p=0.0004). CONCLUSION: Findings emphasize the adverse socioeconomic and psychological effects of the pandemic for Latina mothers.

Changes in mental health symptoms and sociocultural factors across the COVID-19 pandemic in mothers of Mexican descent.

Latinos have been disproportionately affected by the COVID-19 pandemic in the US. Little is known about the lasting effects on mental health, particularly among mothers of young children, who historically report high levels of depression and anxiety. We examined if anxiety and depression symptoms worsened for mothers of Mexican descent across the pandemic and identified the role of sociocultural risk and protective factors on these changes. Mothers of Mexican descent (n = 141) with young children (ages 0-7) were administered surveys on mental health symptoms (anxiety and depression), stress-related sociocultural factors (perceived discrimination) before (pre-pandemic), within 3 months (early pandemic), and 18 months after the COVID-19 stay-at-home order (late pandemic). Another sociocultural factor, acculturative stress, was only measured pre-pandemic while during the later phase of the pandemic mothers reported their levels of loneliness, optimism, and coping styles. Repeated measures (RM) ANOVA demonstrated that depressive and anxiety symptoms as well as perceived discrimination increased from pre to early months of the COVID-19 pandemic and slightly lowered in late-COVID but did not return to pre-COVID levels. Two-way RM ANOVA showed that acculturative stress and perceived discrimination predicted worse mental health trajectories across the pandemic while moderations revealed that optimism buffered against, and avoidant coping increased the adverse effects of sociocultural factors on mental health. The effects of the COVID pandemic on mental health are lingering in mothers of young children; however, optimism may be a protective factor. The results also highlight the damaging effects of external factors, such as discrimination, on maternal mental health during times of crisis.

Race-Specific Spirometry Equations Do Not Improve Models of Dyspnea and Quantitative Chest CT Phenotypes.

BACKGROUND: Race-specific spirometry reference equations are used globally to interpret lung function for clinical, research, and occupational purposes, but inclusion of race is under scrutiny. RESEARCH QUESTION: Does including self-identified race in spirometry reference equation formation improve the ability of predicted FEV1 values to explain quantitative chest CT abnormalities, dyspnea, or Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification? STUDY DESIGN AND METHODS: Using data from healthy adults who have never smoked in both the National Health and Nutrition Survey (2007-2012) and COPDGene study cohorts, race-neutral, race-free, and race-specific prediction equations were generated for FEV1. Using sensitivity/specificity, multivariable logistic regression, and random forest models, these equations were applied in a cross-sectional analysis to populations of individuals who currently smoke and individuals who formerly smoked to determine how they affected GOLD classification and the fit of models predicting quantitative chest CT phenotypes or dyspnea. RESULTS: Race-specific equations showed no advantage relative to race-neutral or race-free equations in models of quantitative chest CT phenotypes or dyspnea. Race-neutral reference equations reclassified up to 19% of Black participants into more severe GOLD classes, while race-neutral/race-free equations may improve model fit for dyspnea symptoms relative to race-specific equations. INTERPRETATION: Race-specific equations offered no advantage over race-neutral/race-free equations in three distinct explanatory models of dyspnea and chest CT scan abnormalities. Race-neutral/race-free reference equations may improve pulmonary disease diagnoses and treatment in populations highly vulnerable to lung disease.

Is it time to end race and ethnicity adjustment for pediatric pulmonary function tests?

The continued inclusion of race in spirometry reference equations is a topic of intense debate for adult lung function, but less discussion has focused on implications for children. Obtaining accurate estimates of children's lung function is an important component of the diagnosis of childhood respiratory illnesses, including asthma, cystic fibrosis, and interstitial lung disease. Given the higher burden among racial/ethnic minorities for many respiratory illnesses, it is critical to avoid racial bias in interpreting lung function. We recommend against the continued use of race-specific reference equations for a number of reasons. The original reference populations used to develop the equations were comprised of children with restricted racial diversity, relatively small sample sizes, and likely included some unhealthy children. Moreover, there is no scientific justification for innate racial differences in lung function, as there is no clear physiological or genetic explanation for the disparities. Alternatively, many environmental factors harm lung development, including allergens from pests, asbestos, lead, prenatal smoking, and air pollution, as well as preterm birth and childhood respiratory illnesses, which are all more common among minority racial groups. Race-neutral equations may provide a temporary solution, but still rely on the racial diversity of the reference populations used to build them. Ultimately researchers must uncover the underlying factors truly driving racial differences in lung function.

Changes in sociocultural stressors, protective factors, and mental health for US Latina mothers in a shifting political climate.

BACKGROUND: To investigate changes in sociocultural stressors and protective factors, and mental health in Latina mothers before and after the 2016 Republican presidential nomination. METHODS: We examined changes in sociocultural stressors, protective factors, and mental health from two prospective cohorts of Latina mothers from interior and border US cities (Nashville, TN, n = 39 and San Diego, CA, ns range = 78-83; 2013-2020). RESULTS: We identified significant longitudinal increases in depression, anxiety, and perceived stress in the border city, and reductions in protective factors (e.g., optimism, social support, and familism) across sites. Discrimination varied by location, and was associated with higher stress only at baseline in the border city, and with higher anxiety in the interior city at follow-up. Acculturative stress was consistently associated with worse mental health across time points in the border city. Various protective factors were associated with reduced stress and anxiety across time points in both cities. DISCUSSION: We identified decreased mental health at the border city, and reduced protective factors in Latina mothers across both study sites in the years following the 2016 presidential nomination, during a time of shifting sociopolitical climate. We also identify increased acculturative stress and discrimination over time, particularly at the border city. Interventions to maintain and enhance psychosocial protective factors amongst Latina mothers are warranted.

Time Domains of Hypoxia Responses and -Omics Insights.

The ability to respond rapidly to changes in oxygen tension is critical for many forms of life. Challenges to oxygen homeostasis, specifically in the contexts of evolutionary biology and biomedicine, provide important insights into mechanisms of hypoxia adaptation and tolerance. Here we synthesize findings across varying time domains of hypoxia in terms of oxygen delivery, ranging from early animal to modern human evolution and examine the potential impacts of environmental and clinical challenges through emerging multi-omics approaches. We discuss how diverse animal species have adapted to hypoxic environments, how humans vary in their responses to hypoxia (i.e., in the context of high-altitude exposure, cardiopulmonary disease, and sleep apnea), and how findings from each of these fields inform the other and lead to promising new directions in basic and clinical hypoxia research.

Genomic supremacy: the harm of conflating genetic ancestry and race.

BACKGROUND: Recent studies have reignited the tinderbox of debate surrounding the use of race and ancestry in medicine. These controversial studies have argued for a strong correlation between genetic ancestry and race, justifying continued use of genetic ancestry measures in studies of disease. These studies contend that increased use of continental ancestry estimates can inform clinical risk assessments and management. Further, recent studies of racial corrections used in clinical algorithms, such as those used to estimate 'normal' lung function, also advocate for use of genetic ancestry in place of race for refining risk algorithms. MAIN BODY: These positions are misleading, harmful, and reflect superficial interpretations of population genetics. In this Perspective, we argue that continental genetic ancestry, often proxied by race, serves as a poor indicator of disease risk, and reinforces racialized inequities. CONCLUSION: Instead, we endorse that racial disparities in disease should be investigated by rigorous measures of structural racism alongside careful measures of genetic factors in relevant disease pathways, rather than relying on genetic ancestry or race as a crude proxy for disease-causing alleles.

A Developmental Framework for Embodiment Research: The Next Step Toward Integrating Concepts and Methods.

Embodiment research is at a turning point. There is an increasing amount of data and studies investigating embodiment phenomena and their role in mental processing and functions from across a wide range of disciplines and theoretical schools within the life sciences. However, the integration of behavioral data with data from different biological levels is challenging for the involved research fields such as movement psychology, social and developmental neuroscience, computational psychosomatics, social and behavioral epigenetics, human-centered robotics, and many more. This highlights the need for an interdisciplinary framework of embodiment research. In addition, there is a growing need for a cross-disciplinary consensus on level-specific criteria of embodiment. We propose that a developmental perspective on embodiment is able to provide a framework for overcoming such pressing issues, providing analytical tools to link timescales and levels of embodiment specific to the function under study, uncovering the underlying developmental processes, clarifying level-specific embodiment criteria, and providing a matrix and platform to bridge disciplinary boundaries among the involved research fields.

Epigenetics as a Mechanism of Developmental Embodiment of Stress, Resilience, and Cardiometabolic Risk Across Generations of Latinx Immigrant Families.

Psychosocial stressors can become embodied to alter biology throughout the life course in ways that may have lasting health consequences. Immigrants are particularly vulnerable to high burdens of stress, which have heightened in the current sociopolitical climate. This study is an investigation of how immigration-related stress (IRS) may impact the cardiometabolic risk and epigenetic markers of Latinx immigrant mothers and children in Nashville, TN. We compared stress and resilience factors reported by Latina immigrant mothers and their children (aged 5-13) from two time points spanning the 2016 U.S. presidential election (June 2015-June 2016 baseline, n = 81; March-September 2018 follow-up, n = 39) with cardiometabolic risk markers (BMI, waist circumference, and blood pressure). We also analyzed these factors in relation to DNA methylation in saliva of stress-related candidate genes (SLC6A4 and FKBP5), generated via bisulfite pyrosequencing (complete case n's range from 67-72 baseline and 29-31 follow-up) (n's range from 80 baseline to 36 follow-up). We found various associations with cardiometabolic risk, such as higher social support and greater acculturation were associated with lower BMI in mothers; discrimination and school stress associated with greater waist circumferences in children. Very few exposures associated with FKBP5, but various stressors associated with methylation at many sites in SLC6A4, including immigrant-related stress in both mothers and children, and fear of parent deportation in children. Additionally, in the mothers, total maternal stress, health stress, and subjective social status associated with methylation at multiple sites of SLC6A4. Acculturation associated with methylation in mothers in both genes, though directions of effect varied over time. We also find DNA methylation at SLC6A4 associates with measures of adiposity and blood pressure, suggesting that methylation may be on the pathway linking stress with cardiometabolic risk. More research is needed to determine the role of these epigenetic differences in contributing to embodiment of stress across generations.