Marginal Association Research Articles

Associations between prenatal phthalate exposure and childhood epigenetic age acceleration

Phthalates, a group of pervasive endocrine-disrupting chemicals found in plastics and personal care products, have been associated with a wide range of developmental and health outcomes. However, their impact on biomarkers of aging has not been characterized. We tested associations between prenatal exposure to 11 phthalate metabolites on epigenetic aging in children at birth, 7, 9, and 14 years of age. We hypothesized that prenatal phthalate exposure will be associated with epigenetic age acceleration measures at birth and in early childhood, with patterns dependent on sex and timing of DNAm measurement. Among 385 mother-child pairs from the CHAMACOS cohort, we measured DNAm at birth, 7, 9, and 14 years of age, and utilized adjusted linear regression to assess the association between prenatal phthalate exposure and Bohlin's Gestational Age Acceleration (GAA) at birth and Intrinsic Epigenetic Age Acceleration (IEAA) throughout childhood. Additionally, quantile g-computation was utilized to assess the effect of the phthalate mixture on GAA at birth and IEAA throughout childhood. We found a negative association between prenatal di (2-ethylhexyl) phthalate (DEHP) exposure and IEAA among males at age 7 (-0.62 years; 95% CI:-1.06 to -0.18), and a marginal negative association between the whole phthalate mixture and GAA among males at birth (-1.54 days, 95% CI: -2.79 to -0.28), while most other associations were nonsignificant. Our results suggest that prenatal exposure to certain phthalates is associated with epigenetic aging in children. Additionally, our findings suggest that the influence of prenatal exposures on epigenetic age may only manifest during specific periods of child development, and studies relying on DNAm measurements solely from cord blood or single time points may overlook potential relationships.

Risk of OSA affects reaction time and driving performance more than insomnia in the Canadian Longitudinal Study on Aging

Sleep disorders have been implicated as a cause of motor vehicle crashes in select populations through reduced cognitive function. We investigated the impact of insomnia and obstructive sleep apnea (OSA) on reaction times and driving performance in the population-based cohort of older adults in the Canadian Longitudinal Study on Aging (CLSA). Risk of OSA was classified by the positive responses to the STOP-BA(N)G questionnaire. Time-dependent cognitive function was formally evaluated in all participants with choice reaction times (CRT). Of 30,097 participants, 2657 (8.8 %) met criteria for insomnia and 2092 (7.0 %) were classified as high risk of OSA. Insomnia was equally distributed in all risk categories for OSA. Both self-reported lane position errors and driving safety were more often described as worse in moderate and higher risk groups for OSA although there was also a marginal association with improved driving safety. This is in spite of the fact that daily driving frequency was reported more often with higher risk categories of OSA. Choice reaction times were on average longer in both moderate (845.7 ± 245 msec) and higher (860.2 ± 263 msec) risk groups for OSA compared to participants with low risk of OSA (860.2 ± 266 msec). Insomnia was not associated with driving performance, lane position errors and CRT. Subgroups with categories based upon OSA risk groups with and without insomnia showed no distinct relationship beyond the association with OSA risk categories alone. Too few responses were recorded to assess near miss and motor vehicle crashes. We conclude that objective slower reaction times and poorer self-reported driving performance were associated with the risk of OSA but not insomnia.

Seroprevalence of SARS-CoV-2 in treatment naïve patients of rheumatological diseases

Dear Sir,COVID-19 is of paramount concern in the rheumatology community. As per current consensus, patients of rheumatological diseases (RDs) are at higher risk of SARS-CoV-2 infection than the general population (high agreement but very low grade of evidence); however, contradictory reports are available regarding its seroprevalence and association with severity and mortality. However, these inferences are mainly based on patients who have long-standing RDs and on various therapies. Then what would happen to those who are treatment-naive, mildly symptomatic, or carrying this disease unknowingly in the community during this pandemic? To explore this aspect, we screened blood samples of clinically suspected patients of autoimmune diseases (ADs) for COVID-19 IgG antibody during the pandemic in the pre-vaccination period. Based on clinical profile, antinuclear antibody (ANA), antineutrophilic cytoplasmic antibody (ANCA), and myositis-associated autoantibodies were tested. Out of 268 clinically suspected cases of RDs, 131 samples were positive for autoantibodies: RD group (114 ANA+08 myositis associated antibody+09 ANCA), and the rest 137 were negative (non-RD group). Out of these, three samples each from RD (3/131; 2.29%) and non-RD group (3/137; 2.17%) turned out to be positive for COVID-19 IgG antibody (EUROIMMUN, Germany), suggesting no increased prevalence of COVID19 in patients of the RD group (OR=1.046, 95% CI: 0.145–7.53, P=0.9645). Among the RD group, two patients were finally diagnosed with systemic lupus erythematosus (SLE); however, others did not turn up again to the hospital to comment on the final diagnosis. None of these COVID-19 positive patients had any known comorbidities or RD-related treatment. These positive patients from both groups had almost similar mildto-moderate COVID-19 disease courses with a favorable outcome. A meta-analysis found a marginal association of ADs with increased risk of severity and mortality of COVID-19 disease (Risk of severity: OR=1.21, 95% CI: 0.58–2.5, P=0.79; Risk of mortality: OR=1.31, 95% CI: 0.33–5.2, P=0.95); however, the difference was not significant. Studies have documented COVID-19 frequency of 2.4% (4/165) among SLE patients with severe cases mostly in coexisting comorbidities. Even recent consensus has suggested older age, presence of comorbidities, and use of prednisolone ≥10 as a risk factor for poor outcome in these two coexisting diseases. Unlike the previous reports, the present study highlighted the susceptibility of treatment naïve cases of RDs for COVID-19. The RD group either has an almost similar SARS-CoV-2 prevalence as the non-RD group (2.29% vs. 2.17%) or even lowers than the general population (2.29% vs. 7%). In conclusion, RD itself does not seem to be a risk factor for SARS-CoV2 infection, even in treatment naïve patients; however, disease outcome may depend on various coexisting factors/comorbidities. Inter-talk between SARS-CoV-2 and RDs yet to be explored.

ORTH.Ord: An R package for analyzing correlated ordinal outcomes using alternating logistic regressions with orthogonalized residuals

Background and objectivesMarginal models with generalized estimating equations (GEE) are usually recommended for analyzing correlated ordinal outcomes which are commonly seen in a longitudinal study or clustered randomized trial (CRT). Within-cluster association is often of interest in longitudinal studies or CRTs, and can be estimated with paired estimating equations. However, the estimators for within-cluster association parameters and variances may be subject to finite-sample biases when the number of clusters is small. The objective of this article is to introduce a newly developed R package ORTH.Ord for analyzing correlated ordinal outcomes using GEE models with finite-sample bias corrections. MethodsThe R package ORTH.Ord implements a modified version of alternating logistic regressions with estimation based on orthogonalized residuals (ORTH), which use paired estimating equations to jointly estimate parameters in marginal mean and association models. The within-cluster association between ordinal responses is modeled by global pairwise odds ratios (POR). The R package also provides a finite-sample bias correction to POR parameter estimates based on matrix multiplicative adjusted orthogonalized residuals (MMORTH) for correcting estimating equations, and bias-corrected sandwich estimators with different options for covariance estimation. ResultsA simulation study shows that MMORTH provides less biased global POR estimates and coverage of their 95% confidence intervals closer to the nominal level than uncorrected ORTH. An analysis of patient-reported outcomes from an orthognathic surgery clinical trial illustrates features of ORTH.Ord. ConclusionsThis article provides an overview of the ORTH method with bias-correction on both estimating equations and sandwich estimators for analyzing correlated ordinal data, describes the features of the ORTH.Ord R package, evaluates the performance of the package using a simulation study, and finally illustrates its application in an analysis of a clinical trial.

Associations between the use of insecticide-treated nets in early childhood and educational outcomes, marriage and child-bearing in early adulthood: evidence from a 22-year prospective cohort study in Tanzania

BackgroundThe effectiveness of insecticide-treated nets (ITNs) in preventing malaria in young children is well established. However, the long-term effects of early childhood ITN use on educational outcomes, fertility, and marriage in early adulthood are not well understood.MethodsThis study uses 22 years of longitudinal data from rural Tanzania to investigate the associations between early life ITN use and educational attainment, fertility and marriage in early adulthood. Unadjusted and adjusted logistic regression models were used to estimate the associations between early life ITN use and early adult outcomes (education, childbearing, and marriage), controlling for potential confounders, such as parental education, household asset quintiles, and year of birth. Analyses were conducted separately for men and women.ResultsA total of 6706 participants born between 1998 and 2000 were enrolled in the study between 1998 and 2003. By 2019 a total of 604 had died and a further 723 could not be found, leaving 5379 participants who were interviewed, among whom complete data were available for 5216. Among women, sleeping under a treated net at least half of the time during early childhood [“high ITN use”] was associated with a 13% increase in the odds of completing primary school (adjusted odds ratio (aOR) 1.13 [0.85, 1.50]) and with a 40% increase in the odds of completing secondary school (aOR 1.40 [1.11, 1.76]) compared with women sleeping less frequently under ITNs in early life (< age 5 years). Among men, high ITN use was associated with a 50% increase in the odds of completing primary school (aOR 1.50 [1.18, 1.92]) and a 56% increase in the odds of completing secondary school (aOR 1.56 [1.16, 2.08]) compared to men with low ITN use in early life. Weaker associations were found between ITN use in early life and both adolescent childbearing (aOR 0.91 [0.75, 1.10]) and early marriage (aOR 0.86 [0.69, 1.05]).ConclusionThis study found that early life use of ITNs was strongly associated with increased school completion in both men and women. More marginal associations were found between early-life ITN use and both marriage and child-bearing in early adulthood. ITN use during early childhood may have long-term positive effects on educational attainment in Tanzania. However, further research is needed to understand the mechanisms behind these associations and to explore the broader impacts of ITN use on other aspects of early adult life.

Longitudinal weight status and academic achievement in elementary schoolchildren in the United States.

Childhood overweight and obesity have a well-established negative impact on children's health. Overweight and obesity might also negatively impact children's academic performance, but existing literature on this association is inconclusive. This study uses a longitudinal design in a large, diverse elementary school sample to rigorously test the association between longitudinal weight status and academic achievement. Analyses also investigate modification by sex, race/ethnicity, and cardiorespiratory fitness (CRF). In a large suburban school district in the United States, 4936 Grade 4 students were recruited. Demographic, course grade, and standardized test data were collected from school records for Grades 3-5, and body mass index and CRF were assessed each year. Students wore accelerometers during the school day for up to 15 days across three semesters (Grade 4 Fall and Spring, Grade 5 Fall) to objectively measure physical activity. Multiple imputation addressed missing data and multilevel analyses controlled for student demographics and clustering within schools. Unadjusted multilevel models found small negative associations between persistent obesity and course grades and standardized test scores, but these associations largely disappeared when controlling for demographic characteristics. Residual associations for math and writing course grades were attenuated when controlling for CRF, though some marginal negative associations for math and writing remained for students who developed obesity during follow-up. There was also evidence of marginal negative associations with course grades for students who developed overweight/obesity. There was no evidence of modification by sex or race/ethnicity. Results suggest very small associations between weight status and academic achievement that were largely explained by sociodemographic factors and CRF. Evidence of an association between weight status and achievement was stronger among students who developed overweight/obesity. Interventions promoting healthy weight and high CRF remain critical for schools given the link between student health and achievement.

DNA methylation epi-signature and biological age in attention deficit hyperactivity disorder patients

ObjectiveAttention Deficit/Hyperactivity Disorder (ADHD) is a common behavioral syndrome that begins in childhood and affects 3.4% of children worldwide. Due to its etiological complexity, there are no consistent biomarkers for ADHD, however the high heritability presented by the disorder indicates a genetic/epigenetic influence. The main epigenetic mechanism is DNA methylation, a process with an important role in gene expression and in many psychiatric disorders. Thus, our study sought to identify epi-signatures biomarkers in 29 children clinically diagnosed with ADHD. MethodsAfter DNA extraction and bisulfite conversion, we performed methylation array experiment for differential methylation, ontological and biological age analysis. ResultsThe biological response in ADHD patients was not sufficient to determine a conclusive epi-signature in our study. However, our results highlighted the interaction of energy metabolism and oxidative stress pathways in ADHD patients detected by differential methylation patterns. Furthermore, we were able to identify a marginal association between the DNAmAge and ADHD. ConclusionOur study present new methylation biomarkers findings associated with energy metabolism and oxidative stress pathways, in addition to DNAmAge in ADHD patients. However, we propose that further multiethnic studies, with larger cohorts and including maternal conditions, are necessary to demonstrate a definitive association between ADHD and these methylation biomarkers.

Abstract 5234: Novel predictive biomarker SNPs and polygenic risk scores of immune-related genes for colorectal cancer survival in Korea

Abstract Background: One of the major topics about colorectal cancer (CRC) is the core role of various immune cells against cancer cells. To comprehensively understand genetic basis of immune system underlying CRC progression, association of single-nucleotide polymorphisms (SNPs) and polygenic risk scores (PRS) of immune-related genes were investigated with colorectal cancer survival. Methods: CRC patients enrolled in the Seoul National University Hospital with prospective follow-up were included in the study. From blood-derived DNA from CRC patients, genome-wide SNPs were genotyped by using the Korea Biobank Array (KoreanChip). 2,729 immune-related genes were selected from Ensembl, Gene Ontology (GO), and KEGG database and 37,398 mapped SNPs were extracted. SNP or PRS-based Cox proportional hazard models were fit for events of overall survival (OS) and progression-free survival (PFS) estimating effect sizes with hazard ratios (HRs). PRS was calculated as effect size weighted sum of risk alleles of individual patients and categorized into tertiles. To investigate enriched pathways, protein-protein interaction networks analysis was conducted. Bonferroni-corrected p-value (1.3 × 10−6) was used as statistically significance threshold. Results: Among 960 CRC patients, 154 (16.0%) occurred events of death and 245 (25.5%) of progression during the follow-up (median=1,698 days, range=7-2,563 days). For OS, a statistically significant associations were mapped to ACTR3B, ST6GAL1, COTL1, PRKCZ, and CAMK1D genes with the strongest SNP rs14808985 (HR=3.07, P=1.87 × 10−7). For PFS, marginal association was mapped to MECOM gene with the strongest SNP rs16854234 (HR=1.48, P=6.13 × 10−6). In PRS analysis, the highest tertile group showed the prominently increased risk for OS (HR=25.0, P&amp;lt;2.0 × 10−16 ) and PFS (HR=5.88, P&amp;lt;2.0 × 10−16 ) compared with the lowest group for a reference. In protein-protein interaction networks analysis, the strongest enrichments were shown in Th17 cell differentiation pathway for OS and in adherences junction for PFS. Conclusions: We identified novel predictive biomarker genetic variants in ACTR3B and MECOM genes associated with OS and PFS, respectively, among CRC patients. Additionally, we presented PRS as a useful biomarker for survival outcomes and suggested enriched biological pathways involved in CRC progression. These knowledges can promote the understanding of CRC survival and the development of immune-related therapeutic interventions for CRC patients in the future. Citation Format: Dabin Yun, Nan Song, Jin-Ah Sim, Min Jung Kim, Ji Won Park, Seung Yong Jeong, Aesun Shin. Novel predictive biomarker SNPs and polygenic risk scores of immune-related genes for colorectal cancer survival in Korea. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5234.

Abstract 6451: Dietary medium-chain fatty acids and risk of incident colorectal cancer in a predominantly low-income population: a report from the Southern Community Cohort Study (SCCS)

Abstract Purpose: Previous studies have investigated medium-chain fatty acids (MCFAs) as a part of saturated fat intake and risk of colorectal cancer (CRC). However, unlike long-chain saturated fatty acids, MCFAs possess many unique properties, including inhibition of pro-carcinogenic bacteria, biofilm formation, and induction of apoptosis. Further, C12:0 has been consistently shown in vitro to exhibit the most potent anti-microbial properties in a dose-dependent manner compared to other MCFAs. Black Americans have the highest CRC incidence and mortality across all racial subgroups in the US. In a predominantly low-income population, we aimed to examine whether dietary intake of MCFAs is associated with a reduced risk of CRC overall and among racial subgroups. Methods: The daily intake of total energy and individual nutrients, including MCFAs, was derived from a food frequency questionnaire. Multivariable-adjusted Cox regression was used to assess the associations between dietary intake of MCFAs and the risk of incident CRC during the 13.75-year follow up after adjustment for confounders. Results: Among 71,599 eligible participants, 868 incident CRC cases were identified (622 Blacks, 220 Whites and 26 other racial groups). High intake of C12:0 was significantly associated with a reduced risk of CRC only in White participants in a dose-response manner (for highest VS lowest quartile: HR, 0.37; 95% CI, 0.17 to 0.80; P for trend =0.0068). This protective association primarily appeared in White participants at high risk of CRC, such as those aged 50 years or older, overweight or obese, ever smokers, or living in a neighborhood with greater deprivation. On the other hand, we did not find a significant association in Black participants (HR, 0.87; 95% CI, 0.59 to 1.27); P for trend =0.72). However, there was a marginal linear association in Black participants with the lowest deprivation index while the association disappeared among Black participants with higher deprivation index. Finally, we found from the NHANES 2005-2016, a representative sample of the US general population, that Black Americans had the lowest intake of MCFAs across all racial subgroups and, overall, intakes of MCFAs decreased with reducing poverty-income ratio. No associations were found between intakes of C6:0, C8:0, or C10:0 and the risk of incident CRC overall or within the racial group. Conclusion: In this predominantly low-income population, increasing dietary C12:0 intake was associated with a substantially reduced risk of CRC only among White participants, but not in Black participants. This racial difference in associations may be because Black Americans consumed the lowest levels of MCFAs in all racial groups while a much higher proportion of Black participants had lactose intolerance and a lower proportion of them consumed lactose-free fermented foods. Citation Format: Lei Fan, Xiangzhu Zhu, Qingxia Chen, Xiang Huang, Mark D. Steinwandel, Martha Shrubsole, Qi Dai. Dietary medium-chain fatty acids and risk of incident colorectal cancer in a predominantly low-income population: a report from the Southern Community Cohort Study (SCCS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6451.

Integrative analysis of individual-level data and high-dimensional summary statistics.

Researchers usually conduct statistical analyses based on models built on raw data collected from individual participants (individual-level data). There is a growing interest in enhancing inference efficiency by incorporating aggregated summary information from other sources, such as summary statistics on genetic markers' marginal associations with a given trait generated from genome-wide association studies. However, combining high-dimensional summary data with individual-level data using existing integrative procedures can be challenging due to various numeric issues in optimizing an objective function over a large number of unknown parameters. We develop a procedure to improve the fitting of a targeted statistical model by leveraging external summary data for more efficient statistical inference (both effect estimation and hypothesis testing). To make this procedure scalable to high-dimensional summary data, we propose a divide-and-conquer strategy by breaking the task into easier parallel jobs, each fitting the targeted model by integrating the individual-level data with a small proportion of summary data. We obtain the final estimates of model parameters by pooling results from multiple fitted models through the minimum distance estimation procedure. We improve the procedure for a general class of additive models commonly encountered in genetic studies. We further expand these two approaches to integrate individual-level and high-dimensional summary data from different study populations. We demonstrate the advantage of the proposed methods through simulations and an application to the study of the effect on pancreatic cancer risk by the polygenic risk score defined by BMI-associated genetic markers. R package is available at https://github.com/fushengstat/MetaGIM.

Causal effects on complex traits are similar for common variants across segments of different continental ancestries within admixed individuals.

Individuals of admixed ancestries (for example, African Americans) inherit a mosaic of ancestry segments (local ancestry) originating from multiple continental ancestral populations. This offers the unique opportunity of investigating the similarity of genetic effects on traits across ancestries within the same population. Here we introduce an approach to estimate correlation of causal genetic effects (radmix) across local ancestries and analyze 38 complex traits in African-European admixed individuals (N = 53,001) to observe very high correlations (meta-analysis radmix = 0.95, 95% credible interval 0.93-0.97), much higher than correlation of causal effects across continental ancestries. We replicate our results using regression-based methods from marginal genome-wide association study summary statistics. We also report realistic scenarios where regression-based methods yield inflated heterogeneity-by-ancestry due to ancestry-specific tagging of causal effects, and/or polygenicity. Our results motivate genetic analyses that assume minimal heterogeneity in causal effects by ancestry, with implications for the inclusion of ancestry-diverse individuals in studies.

On the exploration of regression dependence structures in multidimensional contingency tables with ordinal response variables

In this paper, we propose a new data-driven method to explore complex regression dependence structures in a multi-dimensional contingency table with an ordinal response variable and categorical (ordinal or nominal) explanatory variables. The proposed method is based on a sequential decomposition of the overall regression dependence for the data quantified by the checkerboard copula regression association measure (Wei and Kim, 2021) in an informative and interpretable fashion. It can measure the marginal and conditional contributions of any subset of all available explanatory variables to the overall regression association in a hierarchical manner taking into account the order of the explanatory variables. Thus, the proposed method enables a holistic description of various aspects of regression association in a multivariate contingency table, including marginal and conditional associations between an ordinal response variable and a subset of explanatory variables of interest. We investigate theoretical properties of the proposed decomposition method, and we further illustrate its performance through simulation and two real data examples, one from a randomized controlled trial and the other from a longitudinal epidemiological study.

Lead Exposure Can Affect Early Childhood Development and Could Be Aggravated by Stunted Growth: Perspectives from Mexico.

Lead can affect early childhood development (ECD) differentially due to nutritional deficiencies that lead to stunted growth, defined as being at least two standard deviations below the average height-for-age. These deficiencies are more frequent among children living in rural locations or with lower socioeconomic status (SES); however, studies at a population level are scarce worldwide. Early childhood development plays a crucial role in influencing a child's health and wellbeing throughout life. Therefore, the aim of this study was to analyze how stunted growth can modify the association between lead exposure and ECD in children from disadvantaged communities. Data were analyzed from the 2018 National Health and Nutrition Survey in localities with fewer than 100,000 inhabitants in Mexico (ENSANUT-100K). Capillary blood lead (BPb) levels were measured using a LeadCare II device and dichotomized as detectable (cutoff point ≥ 3.3 µg/dL) and non-detectable. As a measure of ECD, language development was assessed in n = 1394 children, representing 2,415,000 children aged 12-59 months. To assess the association between lead exposure and language z-scores, a linear model was generated adjusted by age, sex, stunted growth, maternal education, socioeconomic status, area, region (north, center, south), and family care characteristics; afterwards, the model was stratified by stunted growth. Fifty percent of children had detectable BPb and 15.3% had stunted growth. BPb showed a marginal inverse association with language z-scores (β: -0.08, 95% CI: -0.53, 0.36). Children with detectable BPb and stunted growth had significantly lower language z-scores (β: -0.40, 95% CI: -0.71, -0.10) than those without stunted growth (β: -0.15, 95% CI: -0.36, 0.06). Children with stunted growth are more vulnerable to the adverse effects of lead exposure. These results add to previous research calling for action to reduce lead exposure, particularly in children with chronic undernutrition.

Abstract P2-11-09: Association of 21-gene recurrence score with overall survival in phase 3 TAILORx trial

Abstract Background: The 21-gene recurrence score (RS) assay is a prognostic measurement originally established for distant recurrence in estrogen receptor-positive and node-negative breast cancer. Retrospective studies and the Trial Assigning Individualized Options for Treatment (TAILORx; ClinicalTrials.gov NCT00310180) validated its significance besides testing chemotherapy benefit in patients with midrange RS (11-25). However, unclarity remains as to whether RS has comparable prognostic value for overall survival (OS) in the TAILORx trial population. Methods: Association between the recurrence scores (midrange or high-range 26-100 vs. low-range 0-10) and OS was evaluated in all eligible patients with clinicopathological and treatment information by multivariable Cox proportional hazards regression model including RS, tumor size, tumor grades, chemotherapy, endocrine regimens, surgery type, progesterone receptor and demographics. We also evaluated the association between RS and invasive disease-free survival (DFS), recurrence-free interval (RFI) or distant recurrence-free interval (dRFI) by multivariable Cox analysis. Results: Median follow-up was 95.5 (range 0.1 to 138.6) months for OS, 89.6 months (range 0 to 134.8) for DFS, 87.7 (range 0 to 134.8) months for RFI or 87.6 (range 0-134.8) months for dRFI. Compared with low score group, midrange and high-range scores were associated with RFI and dRFI, respectively (P≤0.01 each). However, midrange score was neither associated with OS (adjusted HR 1.15; 95% CI 0.87-1.52; P=0.33) nor associated with DFS (HR 1.16; 95% CI 0.97-1.38; P=0.11). High-range score was associated with DFS (HR 1.58; 95% CI 1.21-2.06; P&amp;lt; 0.01) and had a trend towards association with OS (HR 1.44; 95% CI 0.95-2.19; P=0.08). Conclusions: The data indicate that the recurrence scores provide independent prognosis for breast cancer recurrence at both distant and locoregional sites and for distant recurrence, respectively. High-range score is prognostic of disease-free survival, with the midrange score showing marginal association. Midrange and high-range recurrence scores do not provide independent prognostic information for overall survival in hormone receptor-positive, HER2-negative, node-negative breast cancer in the TAILORx trial population. Citation Format: Sherry X. Yang, John Yu, Molin Wang. Association of 21-gene recurrence score with overall survival in phase 3 TAILORx trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-09.

Disappearance and Re-Emergence of Influenza during the COVID-19 Pandemic: Association with Infection Control Measures.

During the coronavirus disease 2019 (COVID-19) pandemic, the influenza virus had a very low prevalence, and in many areas, outbreaks were almost non-existent. In this study, the associations between infection control measures taken for COVID-19 and the global disappearance of the influenza virus were investigated. The detection rate of influenza from baseline was investigated during four seasons (12 weeks from epidemiological week 49 in 2020 and 2021 and 12 weeks from epidemiological week 23 in 2020 and 2021) in each country participating in the surveillance system of the World Health Organization. Three measures of infection control: mask use ratio, social distancing index (an index of human mobility and physical distance obligations), and an index of stringency of measures taken by authorities were studied. In mid-2020, most countries analyzed had high levels of infection control measures, and in most countries, influenza was drastically reduced compared to previous years. Multiple regression analyses compared the study data with data from other seasons. There was an association between high mask use with low influenza detection in all three remaining seasons, an association between a low social distancing index (low mobility and more social contact obligations) with a low influenza detection rate in two seasons, and a marginal significant association of high stringency index with a low influenza detection rate(in 2020-end-seasons). These results support the notion that seasonal influenza is controllable through effective preventive measures, especially those of mask use and human social contact, and these measures should be recommended during future waves of novel influenza virus infection.

Association of rurality, type of primary caregiver and place of death with end-of-life medical expenditures among the oldest-old population in China

BackgroundUnderstanding whether the type of primary caregiver and end-of-life (EOL) care location are associated with EOL medical expenditures is crucial to inform global debates on policies for efficient and effective EOL care. This study aims to assess trends in the type of primary caregiver and place of death stratified by rural‒urban status among the oldest-old population from 1998–2018 in China. A secondary objective is to determine the associations between rurality, the type of primary caregiver, place of death and EOL medical expenditures. MethodsA total of 20,149 deaths of people aged 80 years or older were derived from the Chinese Longitudinal Health Longevity Survey (CLHLS). Cochran-Armitage tests and Cuzick’s tests were used to test trends in the type of primary caregiver and place of death over time, respectively. Tobit models were used to estimate the marginal associations of rurality, type of primary caregiver, and place of death with EOL medical expenditures because CLHLS sets 100,000 Chinese yuan (approximately US$15,286) as the upper limit of the outcome variable. ResultsOf the 20,149 oldest-old people, the median age at death was 97 years old, 12,490 (weighted, 58.6%, hereafter) were female, and 8,235 lived in urban areas. From 1998–2018, the prevalence of informal caregivers significantly increased from 94.3% to 96.2%, and home death significantly increased from 86.0% to 89.5%. The proportion of people receiving help from informal caregivers significantly increased in urban decedents (16.5%) but decreased in rural decedents (-4.0%), while home death rates significantly increased among both urban (15.3%) and rural (1.8%) decedents. In the adjusted models, rural decedents spent less than urban decedents did (marginal difference [95% CI]: $-229 [$-378, $-80]). Those who died in hospitals spent more than those who died at home ($798 [$518, $1077]). No difference in medical expenditures by type of primary caregiver was observed.ConclusionsOver the past two decades, the increases in informal caregiver utilization and home deaths were unequal, leading to substantially higher EOL medical expenditures among urban decedents and deceased individuals who died at hospitals than among their counterparts who lived in rural areas and died at home.

Machine-learning diet quality score and risk of cardiovascular disease

&lt;i&gt;Objectives&lt;/i&gt;: Various diet scores have been established to measure overall diet quality, especially for the prevention of cardiovascular disease (CVD). Diet scores constructed by utilizing modern machine learning techniques may contain independent information and can provide better dietary recommendations in combination with the existing diet scores. &lt;i&gt;Methods&lt;/i&gt;: We proposed a novel machine-learning diet quality score (DQS) and examined the performance of DQS in combination with the Healthy Eating Index-2015 (HEI2015), Mediterranean Diet Score (MED), Alternative Healthy Eating Index-2010 (AHEI) and Dietary Approaches to Stop Hypertension score (DASH score). The data used in this study were from the 2011–2012 to 2017–2018 cycles of the US National Health and Nutrition Examination Survey (NHANES). Participants aged above 20 self-reported their food intake and information on relevant covariates. We used an elastic-net penalty regression model to select important food features and used a generalized linear regression model to estimate odds ratios (ORs) and 95% CIs after controlling for age, sex, and other relevant covariates. &lt;i&gt;Results&lt;/i&gt;: A total of 16756 participants were included in the analysis. DQS was significantly associated with coronary artery disease (CAD) risk after adjusting for one of the other common diet scores. The ORs for DQS combined with the HEI2015, MED, AHEI, and DASH scores were all approximately 0.900, with &lt;i&gt;p&lt;/i&gt; values smaller than 0.05. The OR for DQS in the full score model including all other scores was 0.905 (95% CI, 0.828–0.989, &lt;i&gt;p&lt;/i&gt;=0.028). Only marginal associations were found between DQS and other CVDs after adjusting for other diet scores. &lt;i&gt;Conclusions&lt;/i&gt;: Based on data from four continuous cycles of the NHANES, higher DQS was found to be consistently associated with a lower risk of CAD. The DQS captured unique predictive information independent of the existing diet scores and thus can be used as a complementary scoring system to further improve dietary recommendations for CAD patients.

Association Between Transforming Growth Factor-β1 Polymorphisms and Ischemic Stroke Susceptibility: A Meta-Analysis.

Epidemiological studies have suggested a potential relationship between the transforming growth factor-β1 (TGF-β1) gene and ischemic stroke (IS) risk; however, the current results are inconsistent. Therefore, we performed this meta-analysis to assess the precise association between TGF-β1 polymorphisms and IS risk. Online databases were searched for themes related to TGF-β1 polymorphisms and ARE risk. Quantitative calculations of odds ratios (ORs) and confidence intervals (CIs) were performed using 5 genetic models of each variant locus. Heterogeneity tests, cumulative analyses, sensitivity analyses, and publication bias were conducted to examine statistical power. Moreover, changes in the secondary structure and minimum free energy (MFE) were explored using in silico analysis. Nineteen case-control studies were included in our meta-analysis on rs1800468 G>A, rs1800469 C>T, and rs1800470 T>C polymorphisms and IS risk. Overall, only a marginal association was found between the rs1800469 C>T polymorphism and IS risk (T vs C: OR = 1.12, 95%CI = 1.00-1.46, P = .05, I2 = 77.0%). Otherwise, no significant association was observed between the rs1800468 G>A and rs1800470 T>C polymorphisms and IS risk in general and stratified analyses. Moreover, no significant changes in secondary structure and MFE were found in any of the 3 polymorphic loci. Current evidence cautiously suggests that TGF-β1 polymorphisms are not associated with IS susceptibility.

Prevalence and associated factors of enamel developmental defects among Nigerian children with perinatal HIV exposure.

To evaluate the prevalence and pattern of developmental defects of the enamel (DDE) and their risk factors among children born infected with Human Immunodeficiency Virus (HIV) and those born to HIV-infected mothers compared with their unexposed counterparts (i.e., children born to uninfected mothers). This was an analytic cross-sectional study evaluating the presence and pattern of distribution of DDE in three groups of school-aged children (age, 4-11 years) receiving care and treatment at a Nigerian tertiary hospital, comprising: (1) HIV-infected (HI) on antiretroviral therapy (ART) (n = 184), (2) HIV-exposed but uninfected (HEU) (n = 186) and (3) HIV-unexposed and uninfected (HUU) (n = 184). Data capture forms and questionnaires were used to record the children's medical and dental history based on clinical chart review and recall from their parents/guardians. Dental examinations were performed by calibrated dentists blinded to the study grouping. CD4+ (Cluster of Differentiation) T-cell counts were assayed for all participants. The diagnosis of DDE corresponded with the codes enumerated in the World Dental Federation's modified DDE Index. Analyses relied on comparative statistics to determine risk factors associated with DDE. A total of 103 participants distributed among the three groups presented with at least one form of DDE, which indicated a prevalence of 18.59%. The HI group had the highest frequency of DDE-affected teeth (4.36%), while that of the HEU and HUU groups were 2.73% and 2.05%, respectively. Overall, the most encountered DDE was code 1 (Demarcated Opacity), accounting for 30.93% of all codes. DDE codes 1, 4 and 6 showed significant associations with the HI and HEU groups in both dentitions (p < 0.05). We found no significant association DDE and either very low birth weight or preterm births. A marginal association with CD4+ lymphocyte count was observed in HI participants. DDE is prevalent in school-aged children, and HIV infection is a significant risk factor for hypoplasia, a common form of DDE. Our results were consistent with other research linking controlled HIV (with ART) to oral diseases and reinforce advocacies for public policies targeted at infants exposed/infected perinatally with HIV.

Biomarkers Predictive of Distant Disease-free Survival Derived from Diffusion-weighted Imaging of Breast Cancer.

To investigate whether intravoxel incoherent motion (IVIM) and/or non-Gaussian diffusion parameters are associated with distant disease-free survival (DDFS) in patients with invasive breast cancer. From May 2013 to March 2015, 101 patients (mean age 60.0, range 28-88) with invasive breast cancer were evaluated prospectively. IVIM parameters (flowing blood volume fraction [fIVIM] and pseudodiffusion coefficient [D*]) and non-Gaussian diffusion parameters (theoretical apparent diffusion coefficient [ADC] at a b value of 0 s/mm2 [ADC0] and kurtosis [K]) were estimated using a diffusion-weighted imaging series of 16 b values up to 2500 s/mm2. Shifted ADC values (sADC200-1500) and standard ADC values (ADC0-800) were also calculated. The Kaplan-Meier method was used to generate survival analyses for DDFS, which were compared using the log-rank test. Univariable Cox proportional hazards models were used to assess any associations between each parameter and distant metastasis-free survival. The median observation period was 80 months (range, 35-92 months). Among the 101 patients, 12 (11.9%) developed distant metastasis, with a median time to metastasis of 79 months (range, 10-92 months). Kaplan-Meier analysis showed that DDFS was significantly shorter in patients with K > 0.98 than in those with K ≤ 0.98 (P = 0.04). Cox regression analysis showed a marginal statistical association between K and distant metastasis-free survival (P = 0.05). Non-Gaussian diffusion may be associated with prognosis in invasive breast cancer. A higher K may be a marker to help identify patients at an elevated risk of distant metastasis, which could guide subsequent treatment.