1 Background: The relationship between germline genetic variation and breast cancer 2 survival is largely unknown, especially in understudied minority populations who often 3 have poorer survival. Genome-wide association studies (GWAS) have interrogated 4 breast cancer survival but often are underpowered due to subtype heterogeneity and 5 many clinical covariates and detect loci in non-coding regions that are difficult to interpret. 6 Transcriptome-wide association studies (TWAS) show increased power in detecting 7 functionally-relevant loci by leveraging expression quantitative trait loci (eQTLs) from 8 external reference panels in relevant tissues. However, ancestry-or race-specific 9 reference panels may be needed to draw correct inference in ancestrally-diverse cohorts. 10 Such panels for breast cancer are lacking. 12Results: We provide a framework for TWAS for breast cancer in diverse populations, 13 using data from the Carolina Breast Cancer Study (CBCS), a North Carolina population-14 based cohort that oversampled black women. We perform eQTL analysis for 406 breast 15 cancer-related genes to train race-stratified predictive models of tumor expression from 16 germline genotypes. Using these models, we impute expression in independent data from 17 CBCS and TCGA, accounting for sampling variability in assessing performance. These 18 models are not applicable across race, and their predictive performance varies across 19 tumor subtype. Within CBCS (ܰ = 3,828), at a false discovery-adjusted significance of 20 0.10 and stratifying for race, we identify associations in black women near AURKA, 21 CAPN13, PIK3CA, and SERPINB5 via TWAS that are underpowered in GWAS. 22Conclusions: We show that carefully implemented and thoroughly validated TWAS is an 24 efficient approach for understanding the genetics underpinning breast cancer outcomes 25 in diverse populations. 26 27 Keywords: transcriptome-wide analysis (TWAS); breast cancer; expression quantitative 28 trait loci (eQTL); survival; polygenic traits 29 4 Background 30 Breast cancer remains the most common cancer among women in the world [1]. Breast 31 cancer tends to be more aggressive in young women and African American women, 32 though underlying germline determinants of poor outcomes are not well-studied. Cohorts 33 that represent understudied minority populations, like the Carolina Breast Cancer Study 34 (CBCS), have identified differences in healthcare access, socioeconomics, and 35 environmental exposures associated with disparities in outcome [2-4], but more targeted 36 genomic studies are necessary to interrogate these disparities from a biologic and genetic 37 perspective. 38 39 Few genome-wide association studies (GWAS) have studied the relationship between 40 germline variation and survival outcomes in breast cancer, with most focusing instead on 41 genetic predictors of risk [5,6]. Recently, GWAS have shown evidence of association 42 between candidate common germline variants and breast cancer survival, but these 43 studies are often underpow...
Objective: To investigate first-year survival of infants born with spina bifida, and examine the association of maternal prepregnancy body mass index (BMI) with infant mortality. Methods: This is a retrospective cohort study of 1,533 liveborn infants with nonsyndromic spina bifida with estimated dates of delivery from 1998 to 2011 whose mothers were eligible for the National Birth Defects Prevention Study (NBDPS). NBDPS data were linked to death records to conduct survival analyses. Kaplan-Meier survival functions estimated mortality risk over the firstyear of life. Cox proportional hazards models estimated hazard ratios (HRs) for maternal prepregnancy BMI categorized as underweight (<18.5), normal (18.5-24.9), overweight (25-29.9), and obese (≥30). Results: Infant mortality risk among infants with spina bifida was (4.4% [3.52, 5.60%]). Infants with multiple co-occurring defects, very preterm delivery, multiple gestation, high-level spina bifida lesions, or non-Hispanic Black mothers had an elevated risk of infant mortality. Maternal prepregnancy underweight and obesity were associated with higher infant mortality (15.7% [7.20, 32.30%] and 5.82% [3.60, 9.35%], respectively). Adjusted HR estimates showed underweight and obese mothers had greater hazard of infant mortality compared to normal weight mothers (HR: 4.5 [1.08, 16.72] and 2.6 [1.36, 8.02], respectively). Conclusion: The overall risk of infant mortality for infants born with spina bifida was lower than most previously reported estimates. Infants born with spina bifida to mothers who were underweight or obese prepregnancy were at higher risk of
Primary congenital glaucoma (PCG) and anterior segment defects (ASDs) are rare ocular malformations diagnosed early in life which can cause blindness. Pathogenic variants in several genes have been linked to these conditions, but little is known about nongenetic risk factors. We investigated the association between maternal nutrition and PCG and ASDs in the National Birth Defects Prevention Study, a large population‐based, multicenter case–control study of major birth defects in the United States. Mothers of cases (n = 152) and control infants without a birth defect (n = 9,178) completed an interview which included a food frequency questionnaire capturing usual dietary intake in the year before pregnancy. Maternal nutrition was assessed through individual nutrient intake, calculating a Diet Quality Index for Pregnancy (DQI‐P) score for each mother, and using latent class analysis to empirically derive four dietary patterns. We calculated adjusted odds ratios (aORs) and 95% confidence intervals (CI) using logistic regression. The results for individual nutrients varied, with some having an inverse or U‐shaped pattern of association with increasing intake. The DQI‐P was not associated with risk of PCG and ASDs (aOR 0.91; CI 0.49–1.66, highest vs. lowest quartile). The dietary pattern analysis suggested lower odds among women with a Prudent and Mexican dietary pattern (aOR 0.82, 95% CI 0.52–1.29; aOR 0.80, 95% CI 0.36–1.78, respectively) compared to those with a Western dietary pattern. We found that higher intake of some nutrients and certain dietary patterns may be inversely associated with PCG and ASDs, though caution is urged due to imprecision of estimates.
Background: Continuous risk of recurrence scores (CRS) based on PAM50 gene expression are vital prognostic tools for breast cancer (BC). Studies have shown that Black women (BW) have higher CRS than White women (WW). Although systemic injustices contribute substantially to BC disparities, evidence for biological and germline contributions is also emerging. We investigated germline genetic associations with CRS and CRS disparity through a Transcriptome-Wide Association Study (TWAS). Methods: In the Carolina Breast Cancer Study, using race-specific predictive models of tumor expression from germline genetics, we performed race-stratified (N=1,043 WW, 1083 BW) linear regressions of three CRS (ROR-S: PAM50 subtype score; Proliferation Score; ROR-P: ROR-S plus Proliferation Score) on imputed Genetically-Regulated tumor eXpression (GReX). Using Bayesian multivariate regression and adaptive shrinkage, we tested TWAS-significant genes for associations with PAM50 tumor expression and subtype to elucidate patterns of germline regulation underlying TWAS-gene and CRS associations. Results: At FDR-adjusted P < 0.10, we detected 7 TWAS-genes among WW and 1 TWAS-gene among BW. Among WW, CRS showed positive associations with MCM10, FAM64A, CCNB2, and MMP1 GReX and negative associations with VAV3, PCSK6, and GNG11 GReX. Among BW, higher MMP1 GReX predicted lower Proliferation score and ROR-P. TWAS-gene and PAM50 tumor expression associations highlighted potential mechanisms for TWAS-gene to CRS associations. Conclusions: Among BC patients, we find differential germline associations with three CRS by race, underscoring the need for larger, more diverse datasets in molecular studies of BC. Our findings also suggest possible germline trans-regulation of PAM50 tumor expression, with potential implications for interpreting CRS in clinical settings.
In 2018, the Society for Epidemiologic Research and its partner journal, the American Journal of Epidemiology, assembled a working group to develop a set of papers devoted to the “future of epidemiology.” These 14 papers covered a wide range of topic areas and perspectives, from thoughts on our profession, teaching, and methods to critical areas of substantive research. The authors of those papers considered current challenges and future opportunities for research and education. In light of past commentaries, 4 papers also include reflections on the discipline at present and in the future.
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