Antibodies to Helminth Defense Molecule-1 are associated with inflammation, organomegaly, and decreased nutritional status in schistosomiasis japonica.

Immunomodulation enhances parasite fitness by reducing inflammation-induced morbidity in the mammalian host, as well as by attenuating parasite-targeting immune responses. Using a whole proteome differential screening method, we identified Schistosoma japonicum Helminth Defense Molecule (SjHDM-1) as a target of antibodies expressed by S. japonicum resistant, but not susceptible, individuals. In a longitudinal cohort study (N=644) conducted in a S. japonicum endemic region of the Philippines, antibody levels to SjHDM-1 did not predict resistance to reinfection but were associated with increased measures of inflammation. Individuals with high levels of anti-SjHDM-1 IgG had higher levels of C-reactive protein compared to individuals with low anti-SjHDM-1. High anti-SjHDM-1 IgG responses were also associated with reduced biomarkers of nutritional status (albumin), as well as decreased anthropometric measures of nutritional status (WAZ and HAZ) and increased measures of hepatomegaly. Our results suggest that anti-SjHDM-1 responses inhibit the immunomodulatory function of SjHDM-1, resulting in increased morbidity.

Gestational weight gain and adverse birth outcomes in South African women with HIV on antiretroviral therapy and without HIV: a prospective cohort study.

INTRODUCTION: Outside of pregnancy, evidence shows that persons with HIV initiating or switching to dolutegravir (DTG)-based antiretroviral therapy (ART) experience greater weight gain compared to those on other ART classes. However, there are few data on the impact of DTG-based ART on gestational weight gain (GWG) in sub-Saharan Africa where HIV is most common. According to the National Academy of Medicine (NAM), GWG below and above NAM guidelines is associated with adverse birth outcomes. Therefore, the objective of this study was to describe GWG by HIV status and ART regimen, and examine the associations with adverse birth outcomes. METHODS: We enrolled pregnant women with HIV (WHIV) and without HIV (≥18 years) in a peri-urban primary healthcare facility in Cape Town, South Africa between 2019 and 2022. GWG was study-measured at 24-28 (baseline) and 33-38 weeks gestation and converted to GWG rate (kg/week) in accordance with NAM guidelines. GWG z-scores were generated using the INTEGROWTH-21 and US standards to account for differing lengths of gestation. Birth outcome data were obtained from medical records. Associations of GWG z-score with adverse birth outcomes were assessed using multivariable linear or log-binomial regression. RESULTS: Among 292 participants (48% WHIV), median age was 29 years (IQR, 25-33), median pre-pregnancy body mass index (BMI) was 31 kg/m2 (IQR, 26-36) and 20% were primiparous at baseline. The median weekly rate of GWG was 0.30 kg/week (IQR, 0.12-0.50), 35% had GWG below NAM standards (59% WHIV) and 48% had GWG above NAM standards (36% WHIV). WHIV gained weight more slowly (0.25 vs. 0.37 kg/week, p<0.01) than women without HIV. Weekly rate of GWG did not differ by ART regimen (DTG-based ART 0.25 vs. efavirenz-based ART 0.27 kg/week, p = 0.80). In multivariable analyses, GWG z-score was positively associated with continuous birth weight (mean difference = 68.53 95% CI 8.96, 128.10) and categorical high birth weight of >4000 g (RR = 2.18 95% CI 1.18, 4.01). CONCLUSIONS: Despite slower GWG among WHIV, nearly half of all women gained weight faster than recommended by the NAM. GWG was positively associated with infant birth weight. Interventions to support healthy GWG in sub-Saharan Africa are urgently needed.

Associations between fasting glucose rate-of-change and the missense variant, rs373863828, in an adult Samoan cohort.

BACKGROUND: The A allele of rs373863828 in CREB3 regulatory factor is associated with high Body Mass Index, but lower odds of type 2 diabetes. These associations have been replicated elsewhere, but to date all studies have been cross-sectional. Our aims were (1) to describe the development of type 2 diabetes and change in fasting glucose between 2010 and 2018 among a longitudinal cohort of adult Samoans without type 2 diabetes or who were not using diabetes medications at baseline, and (2) to examine associations between fasting glucose rate-of-change (mmol/L per year) and the A allele of rs373863828. METHODS: We describe and test differences in fasting glucose, the development of type 2 diabetes, body mass index, age, smoking status, physical activity, urbanicity of residence, and household asset scores between 2010 and 2018 among a cohort of n = 401 adult Samoans, selected to have a ~2:2:1 ratio of GG:AG: AA rs373863828 genotypes. Multivariate linear regression was used to test whether fasting glucose rate-of-change was associated with rs373863828 genotype, and other baseline variables. RESULTS: By 2018, fasting glucose and BMI significantly increased among all genotype groups, and a substantial portion of the sample developed type 2 diabetes mellitus. The A allele was associated with a lower fasting glucose rate-of-change (ß = -0.05 mmol/L/year per allele, p = 0.058 among women; ß = -0.004 mmol/L/year per allele, p = 0.863 among men), after accounting for baseline variables. Mean fasting glucose and mean BMI increased over an eight-year period and a substantial number of individuals developed type 2 diabetes by 2018. However, fasting glucose rate-of-change, and type 2 diabetes development was lower among females with AG and AA genotypes. CONCLUSIONS: Further research is needed to understand the effect of the A allele on fasting glucose and type 2 diabetes development. Based on our observations that other risk factors increased over time, we advocate for the continued promotion for diabetes prevention and treatment programming, and the reduction of modifiable risk factors, in this setting.

Child, family and household characteristics associated with physical activity in Samoan children aged 3-8 years: A cross-sectional study.

Physical activity is a key component of many obesity prevention strategies. The aim of this analysis was to identify child, family, and household characteristics associated with parent-reported physical activity in Samoan children aged 3-8 years. Children (n = 445; 51.2% female, mean age 5.4 years) were part of an ongoing, mixed-longitudinal study of child growth, development, and wellbeing (the Ola Tuputupua'e cohort). Bivariate analyses and multivariate generalized linear regressions were conducted to investigate the relationship of child, family, and household characteristics with physical activity level, measured using the Netherlands Physical Activity Questionnaire (NPAQ). Children were classified as being 'highly active' if they had NPAQ scores in the 75th percentile or above. Among the n = 111 children classified as 'highly active', n = 67 (60.4%) were boys. After adjusting for child, family, and household-level characteristics, hours of child sleep per night was the only variable significantly associated with odds of being highly active. Compared to children who slept less than 9 hours at night, those who slept 10-10.99 hours (OR: 5.97, 95% CI: 2.14-18.13) and 11+ hours (OR: 25.75, 95% CI: 8.14-90.12) had higher odds of being 'highly active'. Future research should examine the mechanisms driving the relationship between nighttime sleep and physical activity among Samoan children. Intervening on sleep duration and quality may improve physical activity and, in turn, obesity risk in this setting.

Accelerometer-Based Estimates of Physical Activity and Sedentary Time Among Samoan Adults.

BACKGROUND: The prevalence of obesity-related cardiometabolic disease in Samoa is among the highest globally. While physical activity is a modifiable risk factor for obesity-related disease, little is known about physical activity levels among adult Samoans. Using wrist-worn accelerometer-based devices, this study aimed to characterize physical activity among Samoan adults. METHODS: Samoan adults (n = 385; 55% female, mean [SD] age 52 [10] y) wore Actigraph GT3X+ devices for 7 to 10 days. General linear models were used to examine mean daily minutes of sedentary time, light physical activity, and moderate to vigorous physical activity by various participant characteristics. RESULTS: Time spent in moderate to vigorous physical activity did not differ statistically between men (88 [5] min; 95% confidence interval [CI], 80-97) and women (78 [4] min; 95% CI, 70-86; P = .08). Women, however, spent more time than men in light physical activity: 380 (7) minutes (95% CI, 367-393) versus 344 (7) minutes (95% CI, 329-358; P < .001). While there were no differences in physical activity by census region, education, or occupation among women, men in urban areas spent significantly less time in moderate to vigorous physical activity than those in peri-urban and rural areas (P = .015). Women with class II/III obesity spent more time in sedentary activities than those with healthy weight or overweight/class I obesity (P = .048). CONCLUSIONS: This study characterizes physical activity among Samoan adults and highlights variation by sex, urbanicity, and weight status. In providing initial device-measured estimates of physical activity in Samoa, this analysis establishes a baseline from which the success of future attempts to intervene on physical activity may be assessed.

Cardiometabolic Health in Pregnancy and Postpartum: Findings From a Prospective Cohort Study in South Africa.

Background: The cardiometabolic impact of HIV infection and treatment with antiretroviral therapy (ART) in pregnancy and the postpartum period remains unclear. Methods: We enrolled pregnant persons with (PHIV) and without HIV in Cape Town, South Africa, who were ≥18 years old at 24-28 weeks' gestation and followed them up to 32 months postpartum. We estimated associations between HIV status and cardiometabolic risk including body mass index (BMI), obesity (BMI ≥30 kg/m2), blood pressure (BP; elevated systolic BP ≥130 and/or diastolic ≥85 mmHg), lipid levels, and metabolic syndrome according to the Joint Interim Statement criteria using multivariable log binomial or linear regression models. Subgroup analyses compared PHIV on efavirenz (EFV)- vs dolutegravir (DTG)-based ART. Results: Among 400 participants (n = 200 without HIV, n = 200 PHIV), 52% had prepregnancy obesity and 9% had elevated BP. Postpartum, 57% were classified with obesity, 31% had elevated BP, and 29% had metabolic syndrome. In multivariable analyses, HIV was associated with a lower BMI prepregnancy but not postpartum; however, mean indices were in the obese range regardless of HIV status. Neither BMI nor obesity prepregnancy or postpartum differed by ART regimen. Among PHIV, participants on DTG had higher levels of elevated BP in pregnancy and postpartum, compared with PHIV on EFV. Conclusions: We observed high levels of obesity, elevated BP, and metabolic syndrome in the perinatal period but few differences by HIV status. Participants on DTG may be more likely to have elevated BP in pregnancy and postpartum. Monitoring of cardiometabolic health for pregnant persons on DTG is warranted.

Associations of childhood BMI traits with blood pressure and glycated haemoglobin in 6-9-year-old Samoan children.

INTRODUCTION: Prevalence and risk factors for elevated glycated haemoglobin (HbA1c) and blood pressure (BP) are poorly understood among Pacific children. We examined associations of HbA1c and BP in 6-9 year-olds with body mass index (BMI) at ages 2, 5, and BMI velocity between 2-9 years in Samoa. METHODS: HbA1c (capillary blood) and BP were measured in n = 410 Samoan children who were part of an ongoing cohort study. Multilevel models predicted BMI trajectory characteristics. Generalized linear regressions assessed associations of childhood characteristics and BMI trajectories with HbA1c and BP treated as both continuous and categorical outcomes. Primary caregiver-reported childhood characteristics were used as covariates. RESULTS: Overall, 12.90% (n = 53) of children had high HbA1c (≥5.7%) and 33.17% (n = 136) had elevated BP. BMI at 5-years and BMI velocity were positively associated with high HbA1c prevalence in males. A 1 kg/m2 per year higher velocity was associated with a 1.71 (95% CI: 1.07, 2.75) times higher prevalence of high HbA1c. In females, higher BMI at 5-years and greater BMI velocity were associated with higher BP at 6-9 years (95% CI: 1.12, 1.40, and 1.42, 2.74, respectively). CONCLUSION: Monitoring childhood BMI trajectories may inform cardiometabolic disease screening and prevention efforts in this at-risk population.

When the cold gets under your skin: Evidence for brown adipose tissue activity in Samoan adults.

OBJECTIVES: Brown adipose tissue (BAT) is a heat-producing organ aiding nonshivering thermogenesis (NST) during cold stress. Due to its potential cold-adaptive role BAT has been predominantly studied in cold and temperate climate populations, but not among warm-climate adults. This work explores if BAT activity can be inferred in Samoans. MATERIALS AND METHODS: We inferred BAT activity by comparing metabolic rate and surface heat dissipation using indirect calorimetry and thermal imaging between room temperature and cold exposure among Samoans (N = 61, females: n = 38) from 'Upolu Island, Samoa. BAT activity was inferred using ANOVA linear regression models with the variables measured at cold exposure as outcomes. T-tests were used to compare changes in surface temperature between room temperature and cold exposure. RESULTS: Metabolic rate significantly increased after cooling. In both the supraclavicular area, a known BAT location, and the sternum, a non-BAT location, temperatures decreased significantly upon cold exposure. Differences in supraclavicular temperatures between room temperature and cold were significantly smaller than differences in sternum temperatures between exposures. These results suggest that BAT thermogenesis occurred in known BAT-locations and thus contributed to NST during cooling. CONCLUSIONS: This study adds to our understanding of BAT activity across different populations and climates. Further study may illuminate whether the cold-adaptive properties of BAT may have played a role in the successful expansion of populations across the globe, including warm-climate groups.

Association between age at menarche and cardiometabolic risk among Samoan adults.

OBJECTIVES: Recent studies suggest that early menarche may increase cardiometabolic morbidity and mortality. Yet few studies have examined this association in the Pacific Islands, where obesity prevalence is among the highest globally. We sought to examine associations between age at menarche and cardiometabolic risk in Samoa. METHODS: Participants were from the Soifua Manuia study (n = 285, age 32-72 years) conducted in Samoa from 2017 to 2019. Logistic regressions were conducted to estimate odds of obesity, hypertension, diabetes, dyslipidemia, and metabolic syndrome per one-year increase in age at menarche. Linear regressions were conducted to examine associations between age at menarche and continuous measures of adiposity, blood pressure, insulin resistance, and serum lipids. RESULTS: Median age at menarche was 14 years (IQR = 2). After controlling for relevant covariates, each one-year increase in age at menarche was associated with a 15% decrease (OR = 0.85, 95% CI: 0.72-1.01, p = .067) in odds of hypertension, but a 21% increase (OR = 1.21, 95% CI: 1.01-1.45, p = .044) in odds of diabetes and 18% increase (OR = 1.18, 95% CI: 0.98-1.42, p = .081) in odds of high total cholesterol. Each additional year in age at menarche was associated with a 1.60 ± 0.52 kg (p = .002) decrease in lean mass and 1.56 ± 0.51 kg (p = .003) decrease in fat-free mass. CONCLUSIONS: Associations between age at menarche and cardiometabolic risk may be population-specific and are likely influenced by both current and historical nutritional and epidemiological contexts. Prospective studies are needed to clarify the role of childhood adiposity and other early life exposures on age at menarche and subsequent cardiometabolic risk.

Improving imputation quality in Samoans through the integration of population-specific sequences into existing reference panels.

Genotype imputation is fundamental to association studies, and yet even gold standard panels like TOPMed are limited in the populations for which they yield good imputation. Specifically, Pacific Islanders are poorly represented in extant panels. To address this, we constructed an imputation reference panel using 1,285 Samoan individuals with whole-genome sequencing, combined with 1000 Genomes (1000G) samples, to create a reference panel that better represents Pacific Islander, specifically Samoan, genetic variation. We compared this panel to 1000G and TOPMed panels based on imputed variants using genotyping array data for 1,834 Samoan participants who were not part of the panels. The 1000G + 1285 Samoan panel yielded up to 2.25-2.76 times more well-imputed (r 2 ≥ 0.80) variants than TOPMed and 1000G. There was improved imputation accuracy across the minor allele frequency (MAF) spectrum, although it was more pronounced for variants with 0.01 ≤ MAF ≤ 0.05. Imputation accuracy (r 2 ) was greater for population-specific variants (high fixation index, F ST ) and those from larger haplotypes (high LD score). The gain in imputation accuracy over TOPMed was largest for small haplotypes (low LD score), reflecting the Samoan panel's ability to capture population-specific variation not well tagged by other panels. We also augmented the 1000G reference panel with varying numbers of Samoan samples and found that panels with 48 or more Samoans included outperformed TOPMed for all variants with MAF ≥ 0.001. This study identifies variants with improved imputation using population-specific reference panels and provides a framework for constructing other population-specific reference panels.

Characterization of sleep apnea among a sample of adults from Samoa.

Sleep apnea is a public health concern around the world, but little research has been dedicated to examining this issue in low- and middle-income countries, including Samoa. Using data collected through the Soifua Manuia ("Good Health") study, which aimed to investigate the impact of the body mass index (BMI)-associated genetic variant rs373863828 in CREB3 Regulatory Factor ( CREBRF ) on metabolic traits in Samoan adults, we examined the sample prevalence and characteristics of sleep apnea using data collected with a validated home sleep apnea device (WatchPAT, Itamar). A total of 330 participants (sampled to overrepresent the obesity-risk allele of interest) had sleep data available. Participants (53.3% female) had a mean (SD) age of 52.0 (9.9) years and BMI of 35.5 (7.5) kg/m 2 and 36.3% of the sample had type 2 diabetes. Based on the 3% and 4% apnea hypopnea indices (AHI) and the 4% oxygen desaturation index (ODI), descriptive analyses revealed that many participants had potentially actionable sleep apnea defined as >5 events/hr (87.9%, 68.5%, and 71.2%, respectively) or clinically actionable sleep apnea defined as ≥15 events/hr (54.9%, 31.5%, and 34.5%, respectively). Sleep apnea was more severe in men; for example, clinically actionable sleep apnea (≥15) based on the AHI 3% definition was observed in 61.7% of men and 48.9% of women. Correction for non-representational sampling related to the CREBRF obesity-risk allele resulted in only slightly lower estimates. Across the AHI 3%, AHI 4%, and ODI 4%, multiple linear regression revealed associations between a greater number of events/hr and higher age, male sex, higher body mass index, higher abdominal-hip circumference ratio, and geographic region of residence. Our study identified a much higher frequency of sleep apnea in Samoa compared with published data from other studies, but similar predictors. Continued research addressing generalizability of these findings, as well as a specific focus on diagnosis and affordable and equitable access to treatment, is needed to alleviate the burden of sleep apnea in Samoa and around the world.

Associations of HIV and antiretroviral therapy with gestational diabetes in South Africa.

OBJECTIVE: To estimate associations of HIV status and antiretroviral (ART) regimen with gestational diabetes (GDM) and postpartum glucose metabolism. DESIGN: Prospective cohort study. METHODS: We enrolled pregnant persons with HIV (PWH) and without HIV in Cape Town, South Africa who were at least 18 years of age at 24-28 weeks' gestation and followed up to 26 months postpartum. Participants were tested for GDM in pregnancy and for diabetes postpartum using a 75 g 2 h oral glucose tolerance test (OGTT) and diagnosed via WHO criteria. We estimated associations of HIV status and ART regime [efavirenz (EFV) versus dolutegravir (DTG)] with GDM and postpartum impaired glucose metabolism using multivariable log binomial or linear regression models. RESULTS: Among 397 participants [median age 30 (interquartile range (IQR) 25-34; n  = 198 without HIV, n  = 199 PWH], the prevalence of GDM was 6% (9 PWH versus 3% without HIV). In multivariable analyses, PWH were at higher risk of GDM [risk ratio (RR) 3.9, 95% confidence interval (CI) 1.4-10.7] after adjustment for prepregnancy BMI and other confounders. GDM risk did not differ by ART regimen (unadjusted prevalence 8.1% DTG versus 5.6% EFV, adjusted RR 1.1, 95% CI 0.2-6.6). Few participants had diabetes, impaired glucose tolerance (IGT), or impaired fasting glucose postpartum ( n  = 13, 6%) with no differences by HIV or ART status. CONCLUSION: In a setting of universal GDM testing, PWH had an increased risk of impaired glucose metabolism during pregnancy but not postpartum. Among PWH, GDM risk was similar regardless of EFV or DTG use. Given concerns about DTG and weight gain, diabetes risk should continue to be monitored.

Urban residence and elevated blood pressure among migrant women in South Africa.

This paper demonstrates that internal migration may be contributing to rising non-communicable disease risk in low- and middle-income countries in gendered and geographically differentiated ways. With 2018 baseline data from the Migrant Health Follow-Up Study, we investigate the relationship between internal migration and elevated blood pressure (BP) among 2163 rural-origin men and women in South Africa, testing for sex differences. To examine the influence of place, we test whether the migration-BP relationship differs by migrants' destination locations, controlling for household composition, social support, prior migration, and housing quality. We find that migration is associated with elevated BP only among women, and that this association is greatest for migrants living in Tembisa township. Our research underscores that gender and migration are important social determinants of noncommunicable disease risk in low-resource, rapidly-urbanizing settings.

A Polynesian-specific missense CETP variant alters the lipid profile.

Identifying population-specific genetic variants associated with disease and disease-predisposing traits is important to provide insights into the genetic determinants of health and disease between populations, as well as furthering genomic justice. Various common pan-population polymorphisms at CETP associate with serum lipid profiles and cardiovascular disease. Here, sequencing of CETP identified a missense variant rs1597000001 (p.Pro177Leu) specific to Maori and Pacific people that associates with higher HDL-C and lower LDL-C levels. Each copy of the minor allele associated with higher HDL-C by 0.236 mmol/L and lower LDL-C by 0.133 mmol/L. The rs1597000001 effect on HDL-C is comparable with CETP Mendelian loss-of-function mutations that result in CETP deficiency, consistent with our data, which shows that rs1597000001 lowers CETP activity by 27.9%. This study highlights the potential of population-specific genetic analyses for improving equity in genomics and health outcomes for population groups underrepresented in genomic studies.

Association of rs9939609 in FTO with BMI among Polynesian peoples living in Aotearoa New Zealand and other Pacific nations.

The fat mass and obesity associated (FTO) locus consistently associates with higher body mass index (BMI) across diverse ancestral groups. However, previous small studies of people of Polynesian ancestries have failed to replicate the association. In this study, we used Bayesian meta-analysis to test rs9939609, the most replicated FTO variant, for association with BMI with a large sample (n = 6095) of Aotearoa New Zealanders of Polynesian (Maori and Pacific) ancestry and of Samoan people living in the Independent State of Samoa and in American Samoa. We did not observe statistically significant association within each separate Polynesian subgroup. Bayesian meta-analysis of the Aotearoa New Zealand Polynesian and Samoan samples resulted in a posterior mean effect size estimate of +0.21 kg/m2, with a 95% credible interval [+0.03 kg/m2, +0.39 kg/m2]. While the Bayes Factor (BF) of 0.77 weakly favors the null, the BF = 1.4 Bayesian support interval is [+0.04, +0.20]. These results suggest that rs9939609 in FTO may have a similar effect on mean BMI in people of Polynesian ancestries as previously observed in other ancestral groups.

Structural variation across 138,134 samples in the TOPMed consortium.

Ever larger Structural Variant (SV) catalogs highlighting the diversity within and between populations help researchers better understand the links between SVs and disease. The identification of SVs from DNA sequence data is non-trivial and requires a balance between comprehensiveness and precision. Here we present a catalog of 355,667 SVs (59.34% novel) across autosomes and the X chromosome (50bp+) from 138,134 individuals in the diverse TOPMed consortium. We describe our methodologies for SV inference resulting in high variant quality and >90% allele concordance compared to long-read de-novo assemblies of well-characterized control samples. We demonstrate utility through significant associations between SVs and important various cardio-metabolic and hemotologic traits. We have identified 690 SV hotspots and deserts and those that potentially impact the regulation of medically relevant genes. This catalog characterizes SVs across multiple populations and will serve as a valuable tool to understand the impact of SV on disease development and progression.

Structural variation across 138,134 samples in the TOPMed consortium.

Ever larger Structural Variant (SV) catalogs highlighting the diversity within and between populations help researchers better understand the links between SVs and disease. The identification of SVs from DNA sequence data is non-trivial and requires a balance between comprehensiveness and precision. Here we present a catalog of 355,667 SVs (59.34% novel) across autosomes and the X chromosome (50bp+) from 138,134 individuals in the diverse TOPMed consortium. We describe our methodologies for SV inference resulting in high variant quality and >90% allele concordance compared to long-read de-novo assemblies of well-characterized control samples. We demonstrate utility through significant associations between SVs and important various cardio-metabolic and hematologic traits. We have identified 690 SV hotspots and deserts and those that potentially impact the regulation of medically relevant genes. This catalog characterizes SVs across multiple populations and will serve as a valuable tool to understand the impact of SV on disease development and progression.

Prediction of fat mass from anthropometry at ages 7 to 9 years in Samoans: a cross-sectional study in the Ola Tuputupua'e cohort.

BACKGROUND/OBJECTIVE: With increasing obesity prevalence in children globally, accurate and practical methods for quantifying body fat are critical for effective monitoring and prevention, particularly in high-risk settings. No population is at higher risk of obesity than Pacific Islanders, including children living in the independent nation of Samoa. We developed and validated sex-specific prediction models for fat mass in Samoan children. SUBJECTS/METHODS: Dual X-ray absorptiometry (DXA) assessments of fat mass and weight, height, circumferences, and skinfolds were obtained from 356 children aged 7-9 years old in the Ola Tuputupua'e "Growing Up" study. Sex-specific models were developed from a randomly selected model development sample (n = 118 females, n = 120 males) using generalized linear regressions. In a validation sample (n = 59 females; n = 59 males), Lin's concordance and Bland-Altman limits-of-agreement (LoA) of DXA-derived and predicted fat mass from this study and other published models were examined to assess precision and accuracy. RESULTS: Models to predict fat mass in kilograms were: e^[(-0.0034355 * Age8 - 0.0059041 * Age9 + 1.660441 * ln (Weight (kg))-0.0087281 * Height (cm) + 0.1393258 * ln[Suprailiac (mm)] - 2.661793)] for females and e^[-0.0409724 * Age8 - 0.0549923 * Age9 + 336.8575 * [Weight (kg)]-2 - 22.34261 * ln (Weight (kg)) [Weight (kg)]-1 + 0.0108696 * Abdominal (cm) + 6.811015 * Subscapular (mm)-2 - 8.642559 * ln (Subscapular (mm)) Subscapular (mm)-2 - 1.663095 * Tricep (mm)-1 + 3.849035]for males, where Age8 = Age9 = 0 for children at age 7 years, Age8 = 1 and Age9 = 0 at 8 years, Age8 = 0 and Age9 = 1 at 9 years. Models showed high predictive ability, with substantial concordance (ρC > 0.96), and agreement between DXA-derived and model-predicted fat mass (LoA female = -0.235, 95% CI:-2.924-2.453; male = -0.202, 95% CI:-1.977-1.572). Only one of four existing models, developed in a non-Samoan sample, accurately predicted fat mass among Samoan children. CONCLUSIONS: We developed models that predicted fat mass in Samoans aged 7-9 years old with greater precision and accuracy than the majority of existing models that were tested. Monitoring adiposity in children with these models may inform future obesity prevention and interventions.

Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies.

Meta-analysis of whole genome sequencing/whole exome sequencing (WGS/WES) studies provides an attractive solution to the problem of collecting large sample sizes for discovering rare variants associated with complex phenotypes. Existing rare variant meta-analysis approaches are not scalable to biobank-scale WGS data. Here we present MetaSTAAR, a powerful and resource-efficient rare variant meta-analysis framework for large-scale WGS/WES studies. MetaSTAAR accounts for relatedness and population structure, can analyze both quantitative and dichotomous traits and boosts the power of rare variant tests by incorporating multiple variant functional annotations. Through meta-analysis of four lipid traits in 30,138 ancestrally diverse samples from 14 studies of the Trans Omics for Precision Medicine (TOPMed) Program, we show that MetaSTAAR performs rare variant meta-analysis at scale and produces results comparable to using pooled data. Additionally, we identified several conditionally significant rare variant associations with lipid traits. We further demonstrate that MetaSTAAR is scalable to biobank-scale cohorts through meta-analysis of TOPMed WGS data and UK Biobank WES data of ~200,000 samples.