Improved two-step testing of genome-wide gene-environment interactions.

Two-step tests for gene-environment ( G × E $G\times E$ ) interactions exploit marginal single-nucleotide polymorphism (SNP) effects to improve the power of a genome-wide interaction scan. They combine a screening step based on marginal effects used to "bin" SNPs for weighted hypothesis testing in the second step to deliver greater power over single-step tests while preserving the genome-wide Type I error. However, the presence of many SNPs with detectable marginal effects on the trait of interest can reduce power by "displacing" true interactions with weaker marginal effects and by adding to the number of tests that need to be corrected for multiple testing. We introduce a new significance-based allocation into bins for Step-2 G × E $G\times E$ testing that overcomes the displacement issue and propose a computationally efficient approach to account for multiple testing within bins. Simulation results demonstrate that these simple improvements can provide substantially greater power than current methods under several scenarios. An application to a multistudy collaboration for understanding colorectal cancer reveals a G × Sex interaction located near the SMAD7 gene.

Population-based evaluation of disparities in stomach cancer by nativity among Asian and Hispanic populations in California, 2011-2015.

BACKGROUND: Stomach cancer incidence presents significant racial/ethnic disparities among racial/ethnic minority groups in the United States, particularly among Asian and Hispanic immigrant populations. However, population-based evaluation of disparities by nativity has been scarce because of the lack of nativity-specific population denominators, especially for disaggregated Asian subgroups. Population-based stomach cancer incidence and tumor characteristics by detailed race/ethnicity and nativity were examined. METHODS: Annual age-adjusted incidence rates were calculated by race/ethnicity, sex, and nativity and tumor characteristics, such as stage and anatomic subsite, were evaluated using the 2011-2015 California Cancer Registry data. For Hispanic and Asian populations, nativity-specific population counts were estimated using the US Census and the American Community Survey Public Use Microdata Sample data. RESULTS: During 2011-2015 in California, 14,198 patients were diagnosed with stomach cancer. Annual age-adjusted incidence rates were higher among foreign-born individuals than their US-born counterparts. The difference was modest among Hispanics (∼1.3-fold) but larger (∼2- to 3-fold) among Chinese, Japanese, and Korean Americans. The highest incidence was observed for foreign-born Korean and Japanese Americans (33 and 33 per 100,000 for men; 15 and 12 per 100,000 for women, respectively). The proportion of localized stage disease was highest among foreign-born Korean Americans (44%); a similar proportion was observed among US-born Korean Americans, although numbers were limited. For other Asians and Hispanics, the localized stage proportion was generally lower among foreign-born than US-born individuals and lowest among foreign-born Japanese Americans (23%). CONCLUSIONS: Nativity-specific investigation with disaggregated racial/ethnic groups identified substantial stomach cancer disparities among foreign-born immigrant populations.

Characterization of additive gene-environment interactions for colorectal cancer risk.

BACKGROUND: Colorectal cancer (CRC) is a common, fatal cancer. Identifying subgroups who may benefit more from intervention is of critical public health importance. Previous studies have assessed multiplicative interaction between genetic risk scores and environmental factors, but few have assessed additive interaction, the relevant public health measure. METHODS: Using resources from colorectal cancer consortia including 45,247 CRC cases and 52,671 controls, we assessed multiplicative and additive interaction (relative excess risk due to interaction, RERI) using logistic regression between 13 harmonized environmental factors and genetic risk score including 141 variants associated with CRC risk. RESULTS: There was no evidence of multiplicative interaction between environmental factors and genetic risk score. There was additive interaction where, for individuals with high genetic susceptibility, either heavy drinking [RERI = 0.24, 95% confidence interval, CI, (0.13, 0.36)], ever smoking [0.11 (0.05, 0.16)], high BMI [female 0.09 (0.05, 0.13), male 0.10 (0.05, 0.14)], or high red meat intake [highest versus lowest quartile 0.18 (0.09, 0.27)] was associated with excess CRC risk greater than that for individuals with average genetic susceptibility. Conversely, we estimate those with high genetic susceptibility may benefit more from reducing CRC risk with aspirin/NSAID use [-0.16 (-0.20, -0.11)] or higher intake of fruit, fiber, or calcium [highest quartile versus lowest quartile -0.12 (-0.18, -0.050); -0.16 (-0.23, -0.09); -0.11 (-0.18, -0.05), respectively] than those with average genetic susceptibility. CONCLUSIONS: Additive interaction is important to assess for identifying subgroups who may benefit from intervention. The subgroups identified in this study may help inform precision CRC prevention.

Comparison of waitlist and post-transplant outcomes in patients supported with total artificial heart versus continuous biventricular assist devices.

BACKGROUND: Durable biventricular support may be necessary to bridge patients with end-stage biventricular failure to heart transplantation. This study compares waitlist and post-transplant outcomes between patients supported with continuous flow, durable biventricular assist devices (BiVAD), and total artificial heart (TAH). METHODS: Using the UNOS registry, we analyzed adult (≥18 years old), first-time transplant candidates with TAH or BiVAD at the time of listing or transplantation from 10/1/2010-10/31/2020, with follow-up through 3/31/2022. Multivariable proportional subdistribution hazards models and cause-specific Cox proportional hazards models were used to compare death/deterioration or heart transplantation on the waitlist between cohorts. Kaplan-Meier and multivariable Cox proportional hazards model were used to evaluate one-year post-transplant survival and evaluate difference in outcomes based on annual transplant center volume. RESULTS: The waitlist cohort included a total of 228 patients (25% BiVAD). Waitlist outcomes between device types were similar. The transplanted cohort included a total of 352 patients (25% BiVAD). There was a trend towards worse one-year post-transplant survival in patients bridged with TAH versus BiVAD (log-rank p-value = 0.072) that persisted after adjusting for age, gender, policy, and removing dual-organ recipients (HR 1.94 (0.94, 3.98) p-value = 0.07). There was a difference in one-year post-transplant survival amongst TAH-bridged patients when stratified by annual transplant center volume (log-rank p-value = 0.013). One-year post-transplant survival between TAH-supported patients from high annual transplant volume centers and BiVAD-supported patients was similar (p-value = 0.815). CONCLUSIONS: BiVAD and TAH are reasonable support strategies with TAH implantation at high-volume transplant centers (51+ transplants/year) having similar 1-year post-transplant survival to BiVAD-supported patients.

UNOS policy change benefits high-priority patients without harming those at low priority.

The heart transplantation policy change (PC) has improved outcomes in high-acuity (Old 1A, New 1-3) patients, but the effect on low-priority (Old 1B/2, New 4-6) patients is unknown. We sought to determine if low-priority patient outcomes were compromised by benefits to high-priority patients by evaluating for interaction between PC and priority status (PS). We included adult first-time heart transplant candidates and recipients from the UNOS registry during a 19-month period before and after the PC. We compared clinical characteristics and performed competing risks and survival analyses stratified by PC and PS. There was a dependence of PC and PS on waitlist death/deterioration with an interaction sub-distribution hazard ratio (adjusted sdHR) of 0.59 (0.45-0.78), p-value < .001. There was a trend toward a benefit of PC on waitlist death/deterioration (adjusted sdHR: 0.86 [0.73-1.01]; p = .07) and an increase in heart transplantation (adjusted sdHR: 1.08 [1.02-1.14], p = .007) for low-priority patients. There was no difference in 1-year post-transplant survival (log-rank p = .22) when stratifying by PC and PS. PC did not negatively affect waitlisted or transplanted low-priority patients. High-priority, post-PC patients had a targeted reduction in waitlist death/deterioration and did not come at the expense of worse post-transplant survival.

Two-step hypothesis testing to detect gene-environment interactions in a genome-wide scan with a survival endpoint.

Defined by their genetic profile, individuals may exhibit differential clinical outcomes due to an environmental exposure. Identifying subgroups based on specific exposure-modifying genes can lead to targeted interventions and focused studies. Genome-wide interaction scans (GWIS) can be performed to identify such genes, but these scans typically suffer from low power due to the large multiple testing burden. We provide a novel framework for powerful two-step hypothesis tests for GWIS with a time-to-event endpoint under the Cox proportional hazards model. In the Cox regression setting, we develop an approach that prioritizes genes for Step-2 G×E testing based on a carefully constructed Step-1 screening procedure. Simulation results demonstrate this two-step approach can lead to substantially higher power for identifying gene-environment ( G×E ) interactions compared to the standard GWIS while preserving the family wise error rate over a range of scenarios. In a taxane-anthracycline chemotherapy study for breast cancer patients, the two-step approach identifies several gene expression by treatment interactions that would not be detected using the standard GWIS.

Effect of UNOS policy change and exception status request on outcomes in patients bridged to heart transplant with an intra-aortic balloon pump.

BACKGROUND: Intra-aortic balloon pumps (IABP) are used to bridge select end-stage heart disease patients to heart transplant (HT). IABP use and exception requests both increased dramatically after the UNOS policy change (PC). The purpose of this study was to evaluate the effect of PC and exception status requests on waitlist and post-transplant outcomes in patients bridged to HT with IABP support. METHODS: We analyzed adult, first-time, single-organ HT recipients from the UNOS Registry either on IABP at the time of registration for HT or at the time of HT. We compared waitlist and post-HT outcomes between patients from the PRE (October 18, 2016 to May 30, 2018) and POST (October 18, 2018 to May 30, 2020) eras using Kaplan-Meier curves and time-to-event analyses. RESULTS: A total of 1267 patients underwent HT from IABP (261 pre-policy/1006 post-policy). On multivariate analysis, PC was associated with an increase in HT (sub-distribution hazard ratio (sdHR): 2.15, p < .001) and decrease in death/deterioration (sdHR: 0.55, p = .011) on the waitlist with no effect on 1-year post-HT survival (p = .8). The exception status of patients undergoing HT was predominantly seen in the POST era (29%, 293/1006); only four patients in the PRE era. Exception requests in the POST era did not alter patient outcomes. CONCLUSIONS: In patients bridged to heart transplant with an IABP, policy change is associated with decreased rates of death/deterioration and increased rates of heart transplantation on the waitlist without affecting 1-year post-transplant survival. While exception status use has markedly increased post-PC, it is not associated with patient outcomes.

A surrogate ℓ0 sparse Cox's regression with applications to sparse high-dimensional massive sample size time-to-event data.

Sparse high-dimensional massive sample size (sHDMSS) time-to-event data present multiple challenges to quantitative researchers as most current sparse survival regression methods and software will grind to a halt and become practically inoperable. This paper develops a scalable ℓ0 -based sparse Cox regression tool for right-censored time-to-event data that easily takes advantage of existing high performance implementation of ℓ2 -penalized regression method for sHDMSS time-to-event data. Specifically, we extend the ℓ0 -based broken adaptive ridge (BAR) methodology to the Cox model, which involves repeatedly performing reweighted ℓ2 -penalized regression. We rigorously show that the resulting estimator for the Cox model is selection consistent, oracle for parameter estimation, and has a grouping property for highly correlated covariates. Furthermore, we implement our BAR method in an R package for sHDMSS time-to-event data by leveraging existing efficient algorithms for massive ℓ2 -penalized Cox regression. We evaluate the BAR Cox regression method by extensive simulations and illustrate its application on an sHDMSS time-to-event data from the National Trauma Data Bank with hundreds of thousands of observations and tens of thousands sparsely represented covariates.

Genome-Wide Gene-Environment Interaction Analyses to Understand the Relationship between Red Meat and Processed Meat Intake and Colorectal Cancer Risk.

BACKGROUND: High red meat and/or processed meat consumption are established colorectal cancer risk factors. We conducted a genome-wide gene-environment (GxE) interaction analysis to identify genetic variants that may modify these associations. METHODS: A pooled sample of 29,842 colorectal cancer cases and 39,635 controls of European ancestry from 27 studies were included. Quantiles for red meat and processed meat intake were constructed from harmonized questionnaire data. Genotyping arrays were imputed to the Haplotype Reference Consortium. Two-step EDGE and joint tests of GxE interaction were utilized in our genome-wide scan. RESULTS: Meta-analyses confirmed positive associations between increased consumption of red meat and processed meat with colorectal cancer risk [per quartile red meat OR = 1.30; 95% confidence interval (CI) = 1.21-1.41; processed meat OR = 1.40; 95% CI = 1.20-1.63]. Two significant genome-wide GxE interactions for red meat consumption were found. Joint GxE tests revealed the rs4871179 SNP in chromosome 8 (downstream of HAS2); greater than median of consumption ORs = 1.38 (95% CI = 1.29-1.46), 1.20 (95% CI = 1.12-1.27), and 1.07 (95% CI = 0.95-1.19) for CC, CG, and GG, respectively. The two-step EDGE method identified the rs35352860 SNP in chromosome 18 (SMAD7 intron); greater than median of consumption ORs = 1.18 (95% CI = 1.11-1.24), 1.35 (95% CI = 1.26-1.44), and 1.46 (95% CI = 1.26-1.69) for CC, CT, and TT, respectively. CONCLUSIONS: We propose two novel biomarkers that support the role of meat consumption with an increased risk of colorectal cancer. IMPACT: The reported GxE interactions may explain the increased risk of colorectal cancer in certain population subgroups.

Genome-wide interaction study of dietary intake of fibre, fruits, and vegetables with risk of colorectal cancer.

BACKGROUND: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations. METHODS: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G × E interactions, we used the traditional 1--degree-of-freedom (DF) G × E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G × E interaction simultaneously. FINDINGS: The 3-DF joint test revealed two significant loci with p-value <5 × 10-8. Rs4730274 close to the SLC26A3 gene showed an association with fibre (p-value: 2.4 × 10-3) and G × fibre interaction with CRC (OR per quartile of fibre increase = 0.87, 0.80, and 0.75 for CC, TC, and TT genotype, respectively; G × E p-value: 1.8 × 10-7). Rs1620977 in the NEGR1 gene showed an association with fruit intake (p-value: 1.0 × 10-8) and G × fruit interaction with CRC (OR per quartile of fruit increase = 0.75, 0.65, and 0.56 for AA, AG, and GG genotype, respectively; G × E -p-value: 0.029). INTERPRETATION: We identified 2 loci associated with fibre and fruit intake that also modify the association of these dietary factors with CRC risk. Potential mechanisms include chronic inflammatory intestinal disorders, and gut function. However, further studies are needed for mechanistic validation and replication of findings. FUNDING: National Institutes of Health, National Cancer Institute. Full funding details for the individual consortia are provided in acknowledgments.

A note on p-value multiple-testing adjustment for two-step genome-wide gene-environment interactions scans.

Two-step testing is the state-of-the art approach for performing genome-wide interaction scans (GWIS). It is computationally efficient and yields higher power than standard single-step-based GWIS for virtually all biologically plausible scenarios. However, while two-step tests control the genome-wide type I error rate at the desired level, the lack of associated valid p-values can make it difficult for users to compare with single step-results. We show how multiple-testing adjusted p-values can be defined for two-step test based on standard multiple-testing theory, and how they can be in turn scaled to make valid comparisons with single-step tests possible.

The Differential Experience of COVID-19 on Asian American Subgroups: The Los Angeles Pandemic Surveillance Cohort Study.

Data from Asian Americans (AsA) are commonly aggregated in research studies and reporting, obscuring the significant differences across AsA subgroups. We investigated the differential experience of AsA subgroups in COVID-19 testing, vaccination, engagement in risky and protective behaviors and mental health status against this infectious disease. We surveyed a representative sample of the Los Angeles County population (N = 5500) in April 2021 as part of the Los Angeles Pandemic Surveillance Cohort Study and focused on participants who self-identified as AsA (N = 756). There were significant differences across the AsA subgroups, with Koreans, Asian Indians, and Other Asians living in areas with higher COVID-19 mortality rates, and Asian Indians demonstrating the lowest proportion of COVID-19 vaccination. Vietnamese and Koreans had a higher proportion of becoming unemployed during the pandemic. Although the AsA sample on average demonstrated better outcomes than other racial and ethnic groups, the apparent advantages were heterogenous and due to specific subgroups of AsAs rather than AsAs as a whole. The observed differences in COVID-19 measures across AsA subgroups underscore the need to disaggregate AsA data to identify and reduce existing disparities.

Quantification of Severe Acute Respiratory Syndrome Coronavirus 2 Binding Antibody Levels To Assess Infection and Vaccine-Induced Immunity Using WHO Standards.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binding antibody (Ab) levels following vaccination or natural infection could be used as a surrogate for immune protection if results of serological assays were standardized to yield quantitative results using an international standard. Using a bead-based serological assay (Luminex xMAP), anti-receptor binding domain (anti-RBD) Ab levels were determined for 1,450 participants enrolled in the Los Angeles Pandemic Surveillance Cohort (LAPSC) study. For 123 participants, SARS-CoV-2 binding antibody unit (BAU) levels were also quantified using WHO standards and then compared to the semiquantitative results. Samples were chosen to represent the range of results and time from vaccination. Antibody levels and decay rates were then compared using unadjusted and adjusted linear regression models. The linear range of the assay used in this study was determined to be 300 to 5,000 mean fluorescence intensity units (MFI). Among the fully vaccinated groups (vaccinated only and vaccinated with past infection), 84.8% had anti-RBD MFI values above the linear range of >5,000 MFI, and 33.8% had values of >15,000 MFI. Among vaccinated participants with past infection (hybrid immunity), 97% had anti-RBD values of >5,000 MFI and 70% (120/171) had anti-RBD values of >15,000 MFI. In the subgroup quantified using the WHO control, BAU levels were significantly higher than the semiquantitative MFI results. In vaccinated participants, Ab decay levels were similar between infected and noninfected groups (P = 0.337). These results demonstrate that accurate quantitation is possible if standardized with an international standard. BAU can then be compared over time or between subjects and would be useful in clinical decision making. IMPORTANCE Accurate quantification of SARS-CoV-2-specific antibodies can be achieved using a universal standard with sample dilution within the linear range. With hybrid immunity being now common, it is critical to use protocols adapted to high Ab levels to standardize serological results. We validated this approach with the Los Angeles Pandemic Surveillance Cohort by comparing the antibody decay rates in vaccinated participants and vaccinated infected participants.

New UNOS allocation system associated with no added benefit in waitlist outcomes and worse post-transplant survival in heart-kidney patients.

BACKGROUND: The 2018 United Network for Organ Sharing (UNOS) heart transplant policy change (PC) sought to improve waitlist risk stratification to decrease waitlist mortality and promote geographically broader sharing for high-acuity patients awaiting heart transplantation. Our analysis sought to determine the effect of the UNOS PC on outcomes in patients waiting for, or who have received, a heart-kidney transplantation. METHODS: We analyzed adult (≥18 years old), first-time, heart-only and heart-kidney transplant candidates and recipients from the UNOS Registry. Patients were divided into pre-PC (PRE: October 18, 2016-May 30, 2018) and post-PC (POST: October 18, 2018-May 30, 2020) groups for comparison. Competing risks analysis (subdistribution and cause-specific hazards analyses) was performed to assess for differences in waitlist death/deterioration or heart transplantation. One-year post-transplant survival was assessed with Kaplan-Meier and Cox analyses. We included an interaction term (policy era × heart ± kidney) in our analyses to evaluate the effect of PC on outcomes in heart-kidney patients. RESULTS: One-year post-transplant survival was similar (p = 0.83) for PRE heart-kidney and heart-only recipients, but worse (p < 0.001) for POST heart-kidney vs heart-only recipients. There was a policy-era interaction between heart-kidney and heart-only recipients (HR 1.92[1.04,3.55], p = 0.038) indicating a detrimental effect of policy on 1-year survival in POST vs PRE heart-kidney recipients. No added beneficial effect of PC on waitlist outcomes in heart-kidney vs heart-only candidates was observed. CONCLUSIONS: There was no added policy-era benefit on waitlist outcomes for heart-kidney candidates when compared to heart-only candidates. POST heart-kidney recipients experienced worse 1-year survival compared to PRE heart-kidney recipients with no policy effect on heart-only recipients.

Effect of the UNOS policy change on rates of rejection, infection, and hospital readmission following heart transplantation.

BACKGROUND: The 2018 adult heart allocation policy sought to improve waitlist risk stratification, reduce waitlist mortality, and increase organ access. This system prioritized patients at greatest risk for waitlist mortality, especially individuals requiring temporary mechanical circulatory support (tMCS). Posttransplant complications are significantly higher in patients on tMCS before transplantation, and early posttransplant complications impact long-term mortality. We sought to determine if policy change affected early posttransplant complication rates of rejection, infection, and hospitalization. METHODS: We included all adult, heart-only, single-organ heart transplant recipients from the UNOS registry with pre-policy (PRE) individuals transplanted between November 1, 2016, and October 31, 2017, and post-policy (POST) between November 1, 2018, and October 31, 2019. We used a multivariable logistic regression analysis to assess the effect of policy change on posttransplant rejection, infection, and hospitalization. Two COVID-19 eras (2019-2020, 2020-2021) were included in our analysis. RESULTS: The majority of baseline characteristics were comparable between PRE and POST era recipients. The odds of treated rejection (p = 0.8), hospitalization (p = 0.69), and hospitalization due to rejection (p = 0.76) and infection (p = 0.66) were similar between PRE and POST eras; there was a trend towards reduced odds of rejection (p = 0.08). In both COVID eras, there was a clear reduction in rejection and treated rejection with no effect on hospitalization for rejection or infection. Odds of all-cause hospitalization was increased in both COVID eras. CONCLUSIONS: The UNOS policy change improves access to heart transplantation for higher acuity patients without increasing early posttransplant rates of treated rejection or hospitalization for rejection or infection, factors which portend risk for long-term posttransplant mortality.

Genome-wide interaction analysis of folate for colorectal cancer risk.

BACKGROUND: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC. OBJECTIVES: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. METHODS: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). RESULTS: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. CONCLUSIONS: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.

A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk.

Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.

Hierarchical Ridge Regression for Incorporating Prior Information in Genomic Studies.

There is a great deal of prior knowledge about gene function and regulation in the form of annotations or prior results that, if directly integrated into individual prognostic or diagnostic studies, could improve predictive performance. For example, in a study to develop a predictive model for cancer survival based on gene expression, effect sizes from previous studies or the grouping of genes based on pathways constitute such prior knowledge. However, this external information is typically only used post-analysis to aid in the interpretation of any findings. We propose a new hierarchical two-level ridge regression model that can integrate external information in the form of "meta features" to predict an outcome. We show that the model can be fit efficiently using cyclic coordinate descent by recasting the problem as a single-level regression model. In a simulation-based evaluation we show that the proposed method outperforms standard ridge regression and competing methods that integrate prior information, in terms of prediction performance when the meta features are informative on the mean of the features, and that there is no loss in performance when the meta features are uninformative. We demonstrate our approach with applications to the prediction of chronological age based on methylation features and breast cancer mortality based on gene expression features.

COVID-19 booster vaccine attitudes and behaviors among university students and staff in the United States: The USC Trojan pandemic research Initiative.

Although authorized mRNA COVID-19 vaccines (BNT162b2 by BioNTech/Pfizer and mRNA-1273 by Moderna) significantly reduce morbidity and mortality, recent evidence suggests that immunity wanes over time, and that a booster dose could further reduce COVID-19 transmission and severe illness. However, research examining attitudes on booster willingness in diverse populations is needed. This study examined COVID-19 booster vaccine attitudes and behaviors among university students and staff in the fall of 2021. In our sample, 96.2% of respondents indicated willingness to get a COVID-19 booster shot at least once per year. In both bivariate and multivariate analyses higher trust in science was associated with having higher odds of booster willingness. Those who identify as Black, on average, reported trusting science less than other racial/ethnic groups. Our findings demonstrate high willingness to receive a COVID-19 booster shot and highlight the importance of educational messages and initiatives that focus on building trust in science to increase willingness to get the COVID-19 booster. More research is needed to better understand the impact of cultural beliefs on booster willingness and vaccine hesitancy. This understanding will help determine what messages and populations to target to increase booster willingness in the future.

Bariatric surgery in patients with breast and endometrial cancer in California: population-based prevalence and survival.

BACKGROUND: The number of bariatric surgeries performed in the United States has increased substantially since the 1990's. However, the prevalence and prognostic impact of bariatric surgery, or weight loss surgery (WLS), among patients with cancer are not known. OBJECTIVES: We investigated the population-based prevalence of WLS in women with breast or endometrial cancer and conducted exploratory analysis to examine whether postdiagnosis WLS is associated with survival. SETTING: Administrative statewide database. METHODS: WLS records for women with nonmetastasized breast (n = 395,146) or endometrial (n = 69,859) cancer were identified from the 1991-2014 California Cancer Registry data linked with the California Office of Statewide Health Planning and Development database. Characteristics of the patients were examined according to history of WLS. Using body mass index data available since 2011, a retrospective cohort of patients with breast or endometrial cancer and obesity (n = 12,540) was established and followed until 2017 (5% lost to follow-up). Multivariable cause-specific Cox proportional hazards models were used to examine the associations between postdiagnostic WLS and time to death. RESULTS: WLS records were identified for 2844 (.7%) patients with breast cancer and 1140 (1.6%) patients with endometrial cancer; about half of the surgeries were performed after cancer diagnosis. Postdiagnosis WLS was performed in ∼1% of patients with obesity and was associated with a decreased hazard for death (cause-specific hazard ratio = .37; 95% confidence interval = .014-.99; P = .049), adjusting for age, stage, co-morbidity, race/ethnicity, and socioeconomic status. CONCLUSION: About 2000 patients with breast or endometrial cancer in California underwent post-diagnosis WLS between 1991 and 2014. Our data support survival benefits of WLS after breast and endometrial cancer diagnosis.