Population-level Differences Research Articles

Genetic Variants of Obesity in Malaysia: A Scoping Review.

Obesity is a pressing public health issue in Malaysia, involving not only excess weight but also complex metabolic and physiological changes. Addressing these complexities requires comprehensive strategies, including understanding the population-level differences in obesity susceptibility. This review aims to compile the genetic variants studied among Malaysians and emphasize their implications for obesity risk. Relevant articles published up to March 2024 were extracted from the Scopus, PubMed, and ScienceDirect databases. The review process was conducted in accordance with the PRISMA-ScR guidelines. From an initial pool of 579 articles, 35 of these were selected for the final review. The identified gene variants, including LEPR (K656N), LEP (G2548A-Indian only), ADIPOQ (rs17366568), UCP2 (45bp-I/D), ADRB3 (rs4994), MC3R (rs3827103), PPARγ (pro12Ala-Malay only), IL1RA (intron 2 VNTR), NFKB1 (rs28362491), and FADS1 (rs174547-Indian only), showed significant associations with obesity as measured by the respective studies. Overall, more intensive genetic research is needed, starting with population-based profiling of genetic data on obesity, including among children. Sociocultural contexts and environmental factors influence variations in genetic elements, highlighting the need for targeted interventions to mitigate the impacts of obesity in the population.

Grade-stratified meningioma risk among individuals who are Non-Hispanic black and interactions with male sex.

Meningioma risk factors include older age, female sex, and African-American race. Limited data explore how meningioma risk in African-Americans varies across the lifespan, interacts with sex, and differs by tumor grade. The Central Brain Tumor Registry of the United States (CBTRUS) is a population-based registry covering the entire U.S. population. Meningioma diagnoses from 2004-2019 were used to calculate incidence rate ratios (IRRs) for non-Hispanic Black individuals (NHB) compared to non-Hispanic white individuals (NHW) across 10-year age intervals, and stratified by sex and by WHO tumor grade in this retrospective study. 53,890 NHB individuals and 322,373 NHW individuals with an intracranial meningioma diagnosis were included in analyses. Beginning in young adulthood, the NHB-to-NHW IRR was elevated for both grade 1 and grade 2/3 tumors. The IRR peaked in the seventh decade of life regardless of grade, and was higher for grade 2/3 tumors (IRR = 1.57; 95% CI: 1.46-1.69) than grade 1 tumors (IRR = 1.27; 95% CI: 1.25-1.30) in this age group. The NHB-to-NHW IRR was elevated in females (IRR = 1.17; 95% CI: 1.16-1.18) and was further elevated in males (IRR = 1.28; 95% CI: 1.26-1.30), revealing synergistic interaction between NHB race/ethnicity and male sex (PInteraction=0.001). Relative to NHW individuals, NHB individuals are at elevated risk of meningioma from young adulthood through old age. NHB race/ethnicity conferred greater risk of meningioma among men than women, and greater risk of grade 2/3 tumors. Population-level differences in meningioma incidence and tumor behavior suggest potential disparities in the geographic, socioeconomic, and racial distribution of meningioma risk factors within the U.S.

Socio-demographic differences in the dietary inflammatory index from National Health and Nutrition Examination Survey 2005-2018: a comparison of multiple imputation versus complete case analysis.

Studies using the dietary inflammatory index often perform complete case analyses (CCA) to handle missing data, which may reduce the sample size and increase the risk of bias. Furthermore, population-level socio-economic differences in the energy-adjusted dietary inflammatory index (E-DII) have not been recently studied. Therefore, we aimed to describe socio-demographic differences in E-DII scores among American adults and compare the results using two statistical approaches for handling missing data, i.e. CCA and multiple imputation (MI). Cross-sectional analysis. E-DII scores were computed using a 24-hour dietary recall. Linear regression was used to compare the E-DII scores by age, sex, race/ethnicity, education and income using both CCA and MI. USA. This study included 34 547 non-Hispanic White, non-Hispanic Black and Hispanic adults aged ≥ 20 years from the 2005-2018 National Health and Nutrition Examination Survey. The MI and CCA subpopulations comprised 34 547 and 23 955 participants, respectively. Overall, 57 % of the American adults reported 24-hour dietary intakes associated with inflammation. Both methods showed similar patterns wherein 24-hour dietary intakes associated with high inflammation were commonly reported among males, younger adults, non-Hispanic Black adults and those with lower education or income. Differences in point estimates between CCA and MI were mostly modest at ≤ 20 %. The two approaches for handling missing data produced comparable point estimates and 95 % CI. Differences in the E-DII scores by age, sex, race/ethnicity, education and income suggest that socio-economic disparities in health may be partially explained by the inflammatory potential of diet.

A Multigroup Structural Equation Modeling Approach for Analyzing Differences Among Sexually Diverse Youth

ABSTRACT High rates of negative behavioral health outcomes among sexually diverse (SD) youth are consistently documented, but population-level trends obscure within-group differences. Social dynamics intersect in youths’ lives in ways that cannot be accounted for by summing their independent effects. An intersectional perspective is essential to understanding the behavioral health outcomes of SD youth. We performed multigroup structural equation modeling using an SD subset of New Mexico Youth Risk and Resiliency Survey (N = 10,037) respondents to examine the moderating role of supportive adult relationships for lesbian, gay, and bisexual youth across 12 intersecting (sexual orientation by race/ethnicity by sex) identity categories. Standardized estimates show that supportive relationships are associated with moderate reductions in psychological distress among lesbians (β = –0.459 for Native, β = –0.303 for Hispanic, and β = –0.421 for white) and female bisexual youth (β = –0.352 for Native, β = –0.376 for Hispanic, and β = –0.393 for white). Among male youth, supportive relationships are associated with reduced likelihood of substance use for gay (β = –0.330 for Native, β = –0.464 for Latinx and β = –0.591 for white) and bisexual youth (β = –0.442 for Native, β = –0.306 for Latinx and β = –0.290 for white). This study challenges monolithic characterizations of SD youth, illustrating that the health-promotive benefits of support differ based on sexual orientation, race/ethnicity, and sex.

Supplier-origin gut microbiomes affect host body weight and select autism-related behaviors

ABSTRACT Autism spectrum disorders (ASD) are complex human neurodiversities increasing in prevalence within the human population. In search of therapeutics to improve quality-of-life for ASD patients, the gut microbiome (GM) has become a promising target as a growing body of work supports roles for the complex community of microorganisms in influencing host behavior via the gut-brain-axis. However, whether naturally-occurring microbial diversity within the host GM affects these behaviors is often overlooked. Here, we applied a model of population-level differences in the GM to a classic ASD model – the BTBR T+ Itpr3tf/J mouse – to assess how complex GMs affect host behavior. Leveraging the naturally occurring differences between supplier-origin GMs, our data demonstrate that differing, complex GMs selectively effect host ASD-related behavior – especially neonatal ultrasonic communication – and reveal a male-specific effect on behavior not typically observed in this strain. We then identified that the body weight of BTBR mice is influenced by the postnatal GM which was potentially mediated by microbiome-dependent effects on energy harvest in the gut. These data provide insight into how variability within the GM affects host behavior and growth, thereby emphasizing the need to incorporate microbial diversity within the host GM as an experimental factor in biomedical research.

The unmet mental health needs of U.S. adults living with chronic pain.

Previous research suggests that individuals with mental health needs and chronic pain may be less likely to use mental health treatment compared with those with mental health needs only. Yet, few studies have investigated the existence of population-level differences in mental health treatment use. We analyzed data from the National Health Interview Survey (n = 31,997) to address this question. We found that chronic pain was associated with end-to-end disparities in the mental health journeys of U.S. adults: (1) Those living with chronic pain are overrepresented among U.S. adults with mental health needs; (2) among U.S. adults with mental health needs, those living with chronic pain had a lower prevalence of mental health treatment use; (3) among U.S. adults who used mental health treatment, those living with chronic pain had a higher prevalence of screening positive for unremitted anxiety or depression; (4) among U.S. adults living with both chronic pain and mental health needs, suboptimal mental health experiences were more common than otherwise-just 44.4% of those living with mental health needs and co-occurring chronic pain reported use of mental health treatment and screened negative for unremitted anxiety and depression, compared with 71.5% among those with mental health needs only. Overall, our results suggest that U.S. adults with chronic pain constitute an underrecognized majority of those living with unremitted anxiety/depression symptoms and that the U.S. healthcare system is not yet adequately equipped to educate, screen, navigate to care, and successfully address their unmet mental health needs.

Progress in Early Detection of HIV in Tajikistan.

HIV early detection (CD4 counts ≥350 cells/μL) is correlated with higher life expectancy among people living with HIV (PLHIV). Several factors, including physical, cultural, structural, and financial barriers, may limit early detection of HIV. This is a first-of-its-kind study on population-level differences in early detection of HIV across time within Tajikistan and any country in the Central Asia region. Utilizing the Tajikistan Ministry of Health's national HIV data (N = 10,700) spanning 2010 to 2023, we developed median regression models with the median CD4 cell count as the outcome and with the following predictors: time (years), region, age, gender, and area (urban/rural status). Individuals younger than 19 years old were detected early for HIV, whereas those older than 39 years were detected late. Females were detected earlier compared to their male counterparts regardless of region of residence. Rural populations were detected earlier in most years compared to their urban counterparts. The COVID-19 pandemic accelerated HIV early detection in 2021 but most regions have returned to near pre-pandemic levels of detection in 2022 and 2023. There were differences identified among different demographic and geographic groups which warrant further attention.

Identifying Population-Level and Within-Hospital Disparities in Surgical Care.

The lack of consensus on equity measurement and its incorporation into quality-assessment programs at the hospital and system levels may be a barrier to addressing disparities in surgical care. This study aimed to identify population-level and within-hospital differences in the quality of surgical care provision. The analysis included 657 NSQIP participating hospitals with more than 4 million patients (2014 to 2018). Multilevel random slope, random intercept modeling was used to examine for population-level and in-hospital disparities. Disparities in surgical care by Area Deprivation Index (ADI), race, and ethnicity were analyzed for 5 measures: all-case inpatient mortality, all-case urgent readmission, all-case postoperative surgical site infection, colectomy mortality, and spine surgery complications. Population-level disparities were identified across all measures by ADI, 2 measures for Black race (all-case readmissions and spine surgery complications), and none for Hispanic ethnicity. Disparities remained significant in the adjusted models. Before risk adjustment, in all measures examined, within-hospital disparities were detected in: 25.8% to 99.8% of hospitals for ADI, 0% to 6.1% of hospitals for Black race, and 0% to 0.8% of hospitals for Hispanic ethnicity. After risk adjustment, in all measures examined, less than 1.1% of hospitals demonstrated disparities by ADI, race, or ethnicity. After risk adjustment, very few hospitals demonstrated significant disparities in care. Disparities were more frequently detected by ADI than by race and ethnicity. The lack of substantial in-hospital disparities may be due to the use of postoperative metrics, small sample sizes, the risk adjustment methodology, and healthcare segregation. Further work should examine surgical access and healthcare segregation.

How to Prevent Atopic Dermatitis (Eczema) in 2024: Theory and Evidence

Atopic dermatitis (AD) or eczema is a chronic inflammatory skin disease characterized by dry, itchy, and inflamed skin. We review emerging concepts and clinical evidence addressing the pathogenesis and prevention of atopic dermatitis. We review several interventions ranging from skin barrier enhancement strategies; probiotics, prebiotics, and synbiotics, and conversely, antimicrobial exposure; vitamin D and omega fatty acid supplementation; breastfeeding and hydrolyzed formula; house dust mite avoidance and immunotherapy. We appraise the available evidence base within the context of the GRADE approach. We also contextualize our findings in relation to concepts relating atopic dermatitis and individual-patient allergic life trajectories versus a linear concept of the atopic march and provide insights into future knowledge gaps and clinical trial design considerations that must be addressed in future research. Finally, we provide implementation considerations to detect population-level differences in AD risk. Major international efforts are required to provide definitive evidence regarding what works, and what does not, for preventing AD.

Host–symbiont plasticity in the upside-down jellyfish Cassiopea xamachana: strobilation across symbiont genera

IntroductionIn the upside-down jellyfish, Cassiopea xamachana (Cnidaria: Scyphozoa), the establishment of photosymbiosis with dinoflagellates (family Symbiodiniaceae) is necessary for the sessile polyp to undergo metamorphosis (strobilation) into a free-swimming adult. C. xamachana has the capacity to associate with a wide variety of dinoflagellate species and representatives of divergent genera. While some studies have looked at the successful induction of symbiosis, none to date have examined the lasting effect of diverse symbiont taxa on host survivorship and development, which is needed to assess the fitness costs of such symbioses.MethodsOur study exposes C. xamachana polyps to 22 different cultured Symbiodinaceae strains representing 13 species from 5 genera. We analyzed the time to strobilation, the number of ephyra (juvenile medusa) produced, and the proportion of ephyra that died prematurely.ResultsHere we show that C. xamachana strobilation can be induced by nearly each symbiodinacean strain we tested, with the exception of free-living species (i.e., unknown to establish symbiosis with any other marine host). Additionally, ephyrae did not display morphological variation or survivorship differences with varying symbionts. However, we observed intraspecific variation in time to induce strobilation with different cultured dinoflagellate strains.DiscussionThis work expands the known symbiont species that can form stable mutualisms with C. xamachana, primarily in the genera Symbiodinium and Breviolum. Additionally, we provide evidence of differences in ability of cultured symbiodiniaceans to establish symbiosis with a host, which suggests population-level differences in dinoflagellate cultures impact their symbiosis success. By utilizing an animal like C. xamachana with flexible symbiont uptake, we are able to explore how symbiont diversity can influence the timing and success of symbiosis-driven development.

Evolution and Influencing Factors of Spatial Correlation Network of Construction Carbon Emission in China from the Perspective of Whole Life Cycle

Based on the whole life cycle perspective, the carbon emissions of the provincial construction industry in China from 2011 to 2019 were calculated from the production, construction, operation, and demolition stages of building materials. A spatial correlation network matrix of the carbon emissions in the construction industry was constructed by using the modified gravity model, and the structural characteristics of the correlation network were described by introducing social network analysis. Through the quadratic assignment program, the spatial correlation matrix of carbon emissions in the construction industry and its influencing factors were regressed and analyzed. The conclusions were as follows:① the spatial correlation network of carbon emissions in China's construction industry clearly existed. The network density and network correlation numbers were gradually rising, and the network tightness and stability were gradually improving. ② Shanghai, Tianjin, Beijing, and Jiangsu had a higher degree centrality and closeness centrality, which are the core and dominant positions of the spatial correlation network of carbon emissions in the construction industry. Zhejiang replaced Shanghai in the top four from 2013 to 2018, and the betweenness centrality of each province had unbalanced characteristics. ③ Beijing, Tianjin, Jiangsu, Inner Mongolia, Shanghai, and Shandong were "net beneficiaries" blocks, receiving the carbon emissions from other regions. Four provinces, Guangdong, Chongqing, Fujian, and Shandong, belonged to the "broker" sector, achieving a dynamic balance between the production and consumption sides of building carbon emissions. The remaining 20 provinces played a "net spillovers" role, actively sending carbon emissions from the construction industry to other provinces. The correlation between blocks was much greater than the correlation relationship within the blocks. ④ Industrial structure, urban population, spatial adjacency, consumption level, and construction industry process structure had a significant influence on the spatial correlation of carbon emissions in the construction industry. The greater the inter-provincial differences in industrial structure, urban population, spatial adjacency, and consumption level, the greater the similarity of inter-provincial construction industry process structure, and the stronger the spatial correlation and spatial spillover of the construction industry carbon emissions. Finally, according to the evolution characteristics and influencing factors of the spatial correlation network of building carbon emissions, relevant countermeasures and suggestions were provided for the collaborative carbon reduction development of the construction industry region.

Projection-based two-sample inference for sparsely observed multivariate functional data.

Modern longitudinal studies collect multiple outcomes as the primary endpoints to understand the complex dynamics of the diseases. Oftentimes, especially in clinical trials, the joint variation among the multidimensional responses plays a significant role in assessing the differential characteristics between two or more groups, rather than drawing inferences based on a single outcome. We develop a projection-based two-sample significance test to identify the population-level difference between the multivariate profiles observed under a sparse longitudinal design. The methodology is built upon widely adopted multivariate functional principal component analysis to reduce the dimension of the infinite-dimensional multi-modal functions while preserving the dynamic correlation between the components. The test applies to a wide class of (non-stationary) covariance structures of the response, and it detects a significant group difference based on a single p-value, thereby overcoming the issue of adjusting for multiple p-values that arise due to comparing the means in each of components separately. Finite-sample numerical studies demonstrate that the test maintains the type-I error, and is powerful to detect significant group differences, compared to the state-of-the-art testing procedures. The test is carried out on two significant longitudinal studies for Alzheimer's disease and Parkinson's disease (PD) patients, namely, TOMMORROW study of individuals at high risk of mild cognitive impairment to detect differences in the cognitive test scores between the pioglitazone and the placebo groups, and Azillect study to assess the efficacy of rasagiline as a potential treatment to slow down the progression of PD.

Educational Attainment and Later-Life Cognitive Function in High- and Middle-Income Countries: Evidence From the Harmonized Cognitive Assessment Protocol.

Identifying social policies that can promote cognitive health is crucial for reducing the global burden of dementia. We evaluated the importance of educational attainment for later-life cognitive function in various social and geographic settings. Using harmonized data for individuals aged ≥65 years from the United States Health and Retirement Study (HRS) and its international partner studies in England, Mexico, China, and India, and each study's respective Harmonized Cognitive Assessment Protocol (HCAP), we conducted a cross-national comparative study to examine the role of educational attainment in later-life cognitive function across countries (n = 14,980, 2016-2019). We used multivariable-adjusted regression to estimate associations between educational attainment and harmonized global cognitive function scores. In Mexico, China, and India, the general cognitive function scores on average are approximately one standard deviation of the HRS-HCAP cognitive function score distribution lower compared to the United States and England, paralleling patterns of educational attainment across countries. In all countries, higher educational attainment was associated with progressively higher later-life cognitive function scores. Population-level differences in educational attainment explained about 50%-90% of the observed differences in cognitive function scores across countries. The relationship between education and later-life cognitive function across social and geographic contexts underscores the crucial role of education to promote cognitive health and reduce dementia risk. Continual improvement of educational attainment in low- and middle-income settings may yield a significant pay-off in later-life cognitive health.

Racial and ethnic disparities in emergency department transfers to public hospitals.

To examine racial/ethnic differences in emergency department (ED) transfers to public hospitals and factors explaining these differences. ED and inpatient data from the Healthcare Cost and Utilization Project for Florida (2010-2019); American Hospital Association Annual Survey (2009-2018). Logistic regression examined race/ethnicity and payer on the likelihood of transfer to a public hospital among transferred ED patients. The base model was controlled for patient and hospital characteristics and year fixed effects. Models II and III added urbanicity and hospital referral region (HRR), respectively. Model IV used hospital fixed effects, which compares patients within the same hospital. Models V and VI stratified Model IV by payer and condition, respectively. Conditions were classified as emergency care sensitive conditions (ECSCs), where transfer is protocolized, and non-ECSCs. We reported marginal effects at the means. We examined 1,265,588 adult ED patients transferred from 187 hospitals. Black patients were more likely to be transferred to public hospitals compared with White patients in all models except ECSC patients within the same initial hospital (except trauma). Black patients were 0.5-1.3 percentage points (pp) more likely to be transferred to public hospitals than White patients in the same hospital with the same payer. In the base model, Hispanic patients were more likely to be transferred to public hospitals compared with White patients, but this difference reversed after controlling for HRR. Hispanic patients were - 0.6 pp to -1.2 pp less likely to be transferred to public hospitals than White patients in the same hospital with the same payer. Large population-level differences in whether ED patients of different races/ethnicities were transferred to public hospitals were largely explained by hospital market and the initial hospital, suggesting that they may play a larger role in explaining differences in transfer to public hospitals, compared with other external factors.

Replication of population-level differences in auditory-motor synchronization ability in a Norwegian-speaking population

The Speech-to-Speech Synchronization test is a powerful tool in assessing individuals’ auditory-motor synchronization ability, namely the ability to synchronize one’s own utterances to the rhythm of an external speech signal. Recent studies using the test have revealed that participants fall into two distinct groups—high synchronizers and low synchronizers—with significant differences in their neural (structural and functional) underpinnings and outcomes on several behavioral tasks. Therefore, it is critical to assess the universality of the population-level distribution (indicating two groups rather than a normal distribution) across populations of speakers. Here we demonstrate that the previous results replicate with a Norwegian-speaking population, indicating that the test is generalizable beyond previously tested populations of native English- and German-speakers.

TARGETING UNDERREPRESENTED POPULATIONS IN PRECISION MEDICINE: A FEDERATED TRANSFER LEARNING APPROACH.

The limited representation of minorities and disadvantaged populations in large-scale clinical and genomics research poses a significant barrier to translating precision medicine research into practice. Prediction models are likely to underperform in underrepresented populations due to heterogeneity across populations, thereby exacerbating known health disparities. To address this issue, we propose FETA, a two-way data integration method that leverages a federated transfer learning approach to integrate heterogeneous data from diverse populations and multiple healthcare institutions, with a focus on a target population of interest having limited sample sizes. We show that FETA achieves performance comparable to the pooled analysis, where individual-level data is shared across institutions, with only a small number of communications across participating sites. Our theoretical analysis and simulation study demonstrate how FETA's estimation accuracy is influenced by communication budgets, privacy restrictions, and heterogeneity across populations. We apply FETA to multisite data from the electronic Medical Records and Genomics (eMERGE) Network to construct genetic risk prediction models for extreme obesity. Compared to models trained using target data only, source data only, and all data without accounting for population-level differences, FETA shows superior predictive performance. FETA has the potential to improve estimation and prediction accuracy in underrepresented populations and reduce the gap in model performance across populations.

Machine learning analysis of the T cell receptor repertoire identifies sequence features of self-reactivity

The Tcell receptor (TCR) determines specificity and affinity for both foreign and self-peptides presented by the major histocompatibility complex (MHC). Although the strength of TCR interactions with self-pMHC impacts Tcell function, it has been challenging to identify TCR sequence features that predict Tcell fate. To discern patterns distinguishing TCRs from naive CD4+ Tcells with low versus high self-reactivity, we used data from 42 mice to train a machine learning (ML) algorithm that identifies population-level differences between TCRβ sequence sets. This approach revealed that weakly self-reactive Tcell populations were enriched for longer CDR3β regions and acidic amino acids. We tested our ML predictions of self-reactivity using retrogenic mice with fixed TCRβ sequences. Extrapolating our analyses to independent datasets, we predicted high self-reactivity for regulatory Tcells and slightly reduced self-reactivity for Tcells responding to chronic infections. Our analyses suggest a potential trade-off between TCR repertoire diversity and self-reactivity. A record of this paper's transparent peer review process is included in the supplemental information.

Assessing the potential for healthier consumer food substitutions in Canada: population-level differences in dietary intakes of whole grains, refined grains, red meats, and legumes.

The potential for healthier consumer food substitutions is an important factor in the study of food environments, dietary choices, and population nutrition promotion. The burden of diet-related non-communicable diseases is unevenly distributed across Canada and variation in the food environment sub-nationally may be an important explanation. We used population-based 24 h dietary recall data from the 2015 Canadian Community Health Survey-Nutrition for Canadian adults (n=13 919) to examine dietary intakes of two food group pairings (whole grains/refined grains and legumes/red meats) where consumer substitutions have been recognized to be of importance in promoting healthy and sustainable population diet. We used an ANOVA followed by pairwise comparisons with Bonferroni correction to estimate differences in intakes between provinces for daily weight and proportion of total energy consumed. Based on the Global Burden of Disease Study, Canadians consumed below the average daily requirements of legumes and whole grains and well above the required range of red meat, suggesting room for broad improvements to population diet. Findings also demonstrate that there is potential for targeted shifts in dietary intakes among non-consumers of certain foods (e.g., legumes). This study may inform intervention development for the consumer nutrition environment including food accessibility and affordability to reduce non-communicable disease risk.

Prostate Cancer, Race, and Health Disparity: What We Know.

Prostate cancer (PCa) in African American men is one of the most common cancers with a great disparity in outcomes. The higher incidence and tendency to present with more advanced disease have prompted investigators to postulate that this is a problem of innate biology. However, unequal access to health care and poorer quality of care raise questions about the relative importance of genetics versus social/health injustice. Although race is inconsistent with global human genetic diversity, we need to understand the sociocultural reality that race and racism impact biology. Genetic studies reveal enrichment of PCa risk alleles in populations of West African descent and population-level differences in tumor immunology. Structural racism may explain some of the differences previously reported in PCa clinical outcomes; fortunately, there is high-level evidence that when care is comparable, outcomes are comparable.

Morality beyond the WEIRD: How the nomological network of morality varies across cultures.

Moral foundations theory has been a generative framework in moral psychology in the last 2 decades. Here, we revisit the theory and develop a new measurement tool, the Moral Foundations Questionnaire-2 (MFQ-2), based on data from 25 populations. We demonstrate empirically that equality and proportionality are distinct moral foundations while retaining the other four existing foundations of care, loyalty, authority, and purity. Three studies were conducted to develop the MFQ-2 and to examine how the nomological network of moral foundations varies across 25 populations. Study 1 (N = 3,360, five populations) specified a refined top-down approach for measurement of moral foundations. Study 2 (N = 3,902, 19 populations) used a variety of methods (e.g., factor analysis, exploratory structural equations model, network psychometrics, alignment measurement equivalence) to provide evidence that the MFQ-2 fares well in terms of reliability and validity across cultural contexts. We also examined population-level, religious, ideological, and gender differences using the new measure. Study 3 (N = 1,410, three populations) provided evidence for convergent validity of the MFQ-2 scores, expanded the nomological network of the six moral foundations, and demonstrated the improved predictive power of the measure compared with the original MFQ. Importantly, our results showed how the nomological network of moral foundations varied across cultural contexts: consistent with a pluralistic view of morality, different foundations were influential in the network of moral foundations depending on cultural context. These studies sharpen the theoretical and methodological resolution of moral foundations theory and provide the field of moral psychology a more accurate instrument for investigating the many ways that moral conflicts and divisions are shaping the modern world. (PsycInfo Database Record (c) 2023 APA, all rights reserved).