Faculty Bibliography

Provider profiling has been recognized as a useful tool in monitoring health care quality, facilitating inter-provider care coordination, and improving medical cost-effectiveness. Existing methods often use generalized linear models with fixed provider effects, especially when profiling dialysis facilities. As the number of providers under evaluation escalates, the computational burden becomes formidable even for specially designed workstations. To address this challenge, we introduce a serial blockwise inversion Newton algorithm exploiting the block structure of the information matrix. A shared-memory divide-and-conquer algorithm is proposed to further boost computational efficiency. In addition to the computational challenge, the current literature lacks an appropriate inferential approach to detecting providers with outlying performance especially when small providers with extreme outcomes are present. In this context, traditional score and Wald tests relying on large-sample distributions of the test statistics lead to inaccurate approximations of the small-sample properties. In light of the inferential issue, we develop an exact test of provider effects using exact finite-sample distributions, with the Poisson-binomial distribution as a special case when the outcome is binary. Simulation analyses demonstrate improved estimation and inference over existing methods. The proposed methods are applied to profiling dialysis facilities based on emergency department encounters using a dialysis patient database from the Centers for Medicare & Medicaid Services.

Fetal exposure to bisphenols and phthalates may influence development of the reproductive system. In a population-based, prospective cohort study of 1059 mother-child pairs, we examined the associations of maternal gestational urinary bisphenols and phthalates concentrations with offspring reproductive development from infancy until 13 years. We measured urinary bisphenol and phthalate concentrations in each trimester. We obtained information on cryptorchidism or hypospadias after birth from medical records. At 9.7 years, we measured testicular and ovarian volume by MRI. At 13.5 years, we measured child Tanner stages and menstruation through questionnaire. We performed linear or logistic regression models for boys and girls to assess the associations of maternal urinary average and trimester-specific bisphenols and phthalates with child reproductive outcomes. Next, to further explore potential synergistic or additive effects of exposures together, we performed mixed exposure models using a quantile g computation approach. Models were adjusted for maternal age, ethnicity, body-mass index, education, parity, energy intake, smoking and alcohol use, and child's gestational age at birth, birthweight and body-mass index. In boys, no associations of maternal gestational phthalate or bisphenol with offspring cryptorchidism and hypospadias were found. Higher maternal high-molecular-weight phthalate and total bisphenol, but not phthalic acid or low-molecular-weight phthalate, were associated with larger child testicular volume at 10 years. Higher maternal phthalic acid and total bisphenol were associated with earlier genital and pubic hair development at 13 years, respectively (p-values<0.05). In girls, we found no associations of maternal urinary bisphenol and phthalate with ovarian volume or menstrual age. Only higher maternal urinary high-molecular-weight phthalate was associated with earlier pubic hair development at 13 years (p-values <0.05). Higher mixture exposure was associated with earlier pubic hair development in both sexes. In conclusion, higher maternal gestational urinary bisphenol and phthalate concentrations were associated with alterations in offspring reproductive development, mainly in boys.

INTRODUCTION/BACKGROUND:Coronavirus disease 2019 (COVID-19) has been shown to affect outcomes among surgical patients. We hypothesized that COVID-19 would be linked to higher mortality and longer length of stay of trauma patients regardless of the injury severity score (ISS). METHODS:We performed a retrospective analysis of trauma registries from two level 1 trauma centers (suburban and urban) from March 1, 2019, to June 30, 2019, and March 1, 2020, to June 30, 2020, comparing baseline characteristics and cumulative adverse events. Data collected included ISS, demographics, and comorbidities. The primary outcome was time from hospitalization to in-hospital death. Outcomes during the height of the first New York COVID-19 wave were also compared with the same time frame in the prior year. Kaplan-Meier method with log-rank test and Cox proportional hazard models were used to compare outcomes. RESULTS:There were 1180 trauma patients admitted during the study period from March 2020 to June 2020. Of these, 596 were never tested for COVID-19 and were excluded from the analysis. A total of 148 COVID+ patients and 436 COVID- patients composed the 2020 cohort for analysis. Compared with the 2019 cohort, the 2020 cohort was older with more associated comorbidities, more adverse events, but lower ISS. Higher rates of historical hypertension, diabetes, neurologic events, and coagulopathy were found among COVID+ patients compared with COVID- patients. D-dimer and ferritin were unreliable indicators of COVID-19 severity; however, C-reactive protein levels were higher in COVID+ relative to COVID- patients. Patients who were COVID+ had a lower median ISS compared with COVID- patients, and COVID+ patients had higher rates of mortality and longer length of stay. CONCLUSIONS:COVID+ trauma patients admitted to our two level 1 trauma centers had increased morbidity and mortality compared with admitted COVID- trauma patients despite age and lower ISS. C-reactive protein may play a role in monitoring COVID-19 activity in trauma patients. A better understanding of the physiological impact of COVID-19 on injured patients warrants further investigation.

BACKGROUND/UNASSIGNED:Suicide continues to be one of the leading causes of death in the United States and lesbian, gay, and bisexual (LGB) individuals are disproportionately at risk of suicide in comparison to heterosexuals. METHODS/UNASSIGNED:We examined data from adults participating for five waves (2015-2019) of the National Survey on Drug Use and Health. We first determined whether there is differential risk of suicidal thoughts, suicide plans, and suicide attempts (self-injurious thoughts and behaviors [SITBs]) in the past year according to current sexual orientation. We then estimated linear trends in prevalence of each SITB outcome stratified by each sexual orientation category. RESULTS/UNASSIGNED: < 0.001). CONCLUSIONS/UNASSIGNED:Sexual minority identity is a risk factor for SITBs. Bisexual women in particular are not only at greater risk for SITBs, but estimated prevalence has increased in recent years. More attention needs to be paid to LGB populations regarding future suicide prevention efforts.

BACKGROUND:Epigenetic dysregulation has been proposed as a key mechanism for arsenic-related cardiovascular disease (CVD). We evaluated differentially methylated positions (DMPs) as potential mediators on the association between arsenic and CVD. METHODS:) mouse model of atherosclerosis. RESULTS:A total of 20 and 13 DMPs were potential mediators for CVD incidence and mortality, respectively, several of them annotated to genes related to diabetes. Eleven of these DMPs were similarly associated with incident CVD in 3 diverse prospective cohorts (Framingham Heart Study, Women's Health Initiative, and Multi-Ethnic Study of Atherosclerosis). In the mouse model, differentially methylated regions in 20 of those genes and DMPs in 10 genes were associated with arsenic. CONCLUSIONS:Differential DNA methylation might be part of the biological link between arsenic and CVD. The gene functions suggest that diabetes might represent a relevant mechanism for arsenic-related cardiovascular risk in populations with a high burden of diabetes.

Despite the growing number of genome-wide association studies (GWASs), it remains unclear to what extent gene-by-gene and gene-by-environment interactions influence complex traits in humans. The magnitude of genetic interactions in complex traits has been difficult to quantify because GWASs are generally underpowered to detect individual interactions of small effect. Here, we develop a method to test for genetic interactions that aggregates information across all trait-associated loci. Specifically, we test whether SNPs in regions of European ancestry shared between European American and admixed African American individuals have the same causal effect sizes. We hypothesize that in African Americans, the presence of genetic interactions will drive the causal effect sizes of SNPs in regions of European ancestry to be more similar to those of SNPs in regions of African ancestry. We apply our method to two traits: gene expression in 296 African Americans and 482 European Americans in the Multi-Ethnic Study of Atherosclerosis (MESA) and low-density lipoprotein cholesterol (LDL-C) in 74K African Americans and 296K European Americans in the Million Veteran Program (MVP). We find significant evidence for genetic interactions in our analysis of gene expression; for LDL-C, we observe a similar point estimate, although this is not significant, most likely due to lower statistical power. These results suggest that gene-by-gene or gene-by-environment interactions modify the effect sizes of causal variants in human complex traits.

BACKGROUND:In 2021, Delta became the predominant SARS-CoV-2 variant worldwide. While vaccines have effectively prevented COVID-19 hospitalization and death, vaccine breakthrough infections increasingly occurred. The precise role of clinical and genomic determinants in Delta infections is not known, and whether they contributed to increased rates of breakthrough infections compared to unvaccinated controls. METHODS:We studied SARS-CoV-2 variant distribution, dynamics, and adaptive selection over time in relation to vaccine status, phylogenetic relatedness of viruses, full genome mutation profiles, and associated clinical and demographic parameters. FINDINGS/RESULTS:We show a steep and near-complete replacement of circulating variants with Delta between May and August 2021 in metropolitan New York. We observed an increase of the Delta sublineage AY.25 (14% in vaccinated, 7% in unvaccinated), its spike mutation S112L, and AY.44 (8% in vaccinated, 2% in unvaccinated) with its nsp12 mutation F192V in breakthroughs. Delta infections were associated with younger age and lower hospitalization rates than Alpha. Delta breakthrough infections increased significantly with time since vaccination, and, after adjusting for confounders, they rose at similar rates as in unvaccinated individuals. INTERPRETATION/CONCLUSIONS:We observed a modest adaptation of Delta genomes in breakthrough infections in New York, suggesting an improved genomic framework to support Delta's epidemic growth in times of waning vaccine protection despite limited impact on vaccine escape. FUNDING/BACKGROUND:The study was supported by NYU institutional funds. The NYULH Genome Technology Center is partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center.

BACKGROUND:Greater adherence to plant-based diets is associated with a lower risk of incident chronic kidney disease (CKD). Metabolomics can help identify blood biomarkers of plant-based diets and enhance understanding of underlying mechanisms. OBJECTIVES:Using untargeted metabolomics, we aimed to identify metabolites associated with 4 plant-based diet indices (PDIs) (overall PDI, provegetarian diet, healthful PDI, and unhealthful PDI) and incident CKD in 2 subgroups within the Atherosclerosis Risk in Communities study. METHODS:We calculated 4 PDIs based on participants' responses on an FFQ. We used multivariable linear regression to examine the association between 4 PDIs and 374 individual metabolites, adjusting for confounders. We used Cox proportional hazards regression to evaluate associations between PDI-related metabolites and incident CKD. Estimates were meta-analyzed across 2 subgroups (n1 = 1762; n2 = 1960). We calculated C-statistics to assess whether metabolites improved the prediction of those in the highest quintile compared to the lower 4 quintiles of PDIs, and whether PDI- and CKD-related metabolites predicted incident CKD beyond the CKD prediction model. RESULTS:We identified 82 significant PDI-metabolite associations (overall PDI = 27; provegetarian = 17; healthful PDI = 20; unhealthful PDI = 18); 11 metabolites overlapped across the overall PDI, provegetarian diet, and healthful PDI. The addition of metabolites improved prediction of those in the highest quintile as opposed to the lower 4 quintiles of PDIs compared with participant characteristics alone (range of differences in C-statistics = 0.026-0.104; P value ≤ 0.001 for all tests). Six PDI-related metabolites (glycerate, 1,5-anhydroglucitol, γ-glutamylalanine, γ-glutamylglutamate, γ-glutamylleucine, γ-glutamylvaline), involved in glycolysis, gluconeogenesis, pyruvate metabolism, and γ-glutamyl peptide metabolism, were significantly associated with incident CKD and improved prediction of incident CKD beyond the CKD prediction model (difference in C-statistics for 6 metabolites = 0.005; P value = 0.006). CONCLUSIONS:In a community-based study of US adults, we identified metabolites that were related to plant-based diets and predicted incident CKD. These metabolites highlight pathways through which plant-based diets are associated with incident CKD.

BACKGROUND:More than 80% of adult patients diagnosed with cancer survive long term. Long-term complications of cancer and its therapies may increase the risk of cardiovascular disease (CVD), but prospective studies using adjudicated cancer and CVD events are lacking. OBJECTIVES:The aim of this study was to assess the risk of CVD in cancer survivors in a prospective community-based study. METHODS:We included 12,414 ARIC (Atherosclerosis Risk In Communities) study participants. Cancer diagnoses were ascertained via linkage with state registries supplemented with medical records. Incident CVD outcomes were coronary heart disease (CHD), heart failure (HF), stroke, and a composite of these. We used multivariable Poisson and Cox regressions to estimate the association of cancer with incident CVD. RESULTS:Mean age was 54 years, 55% were female, and 25% were Black. A total of 3,250 participants (25%) had incident cancer over a median 13.6 years of follow-up. Age-adjusted incidence rates of CVD (per 1,000 person-years) were 23.1 (95% CI: 24.7-29.1) for cancer survivors and 12.0 (95% CI: 11.5-12.4) for subjects without cancer. After adjustment for cardiovascular risk factors, cancer survivors had significantly higher risks of CVD (HR: 1.37; 95% CI: 1.26-1.50), HF (HR: 1.52; 95% CI: 1.38-1.68), and stroke (HR: 1.22; 95% CI: 1.03-1.44), but not CHD (HR: 1.11; 95% CI: 0.97-1.28). Breast, lung, colorectal, and hematologic/lymphatic cancers, but not prostate cancer, were significantly associated with CVD risk. CONCLUSIONS:Compared with persons without cancer, adult cancer survivors have significantly higher risk of CVD, especially HF, independent of traditional cardiovascular risk factors. There is an unmet need to define strategies for CVD prevention in this high-risk population.