Faculty Bibliography

BACKGROUND:Systematic profiling of plasma proteins in population studies offers a complementary approach to discovery of novel risk factors and may provide new insights into the causes of coronary heart disease. METHODS:To explore relationships between the circulating proteome and coronary heart disease (CHD), we evaluated associations of 4780 plasma proteins with incident CHD in the Cardiovascular Health Study (CHS, N=2856, 575 CHD events) and replicated significant associations in the Atherosclerosis Risk in Communities Study (ARIC, N = 10456; 1375 events). RESULTS:We find that 11 proteins significantly associate with incident CHD after adjusting for risk factors; and eight significantly replicated in ARIC. Several proteins correlate with carotid intimal medial thickness and CHD associations are attenuated in participants without subclinical atherosclerosis. Macrophage metalloelastase (MMP12) is the strongest observed association (Hazard Ratio, 1.31; 95% Confidence Interval, 1.19-1.44). Mendelian randomization (MR) identifies a causal relationship between higher MMP12 and lower CHD (Odds Ratio, OR 0.94) and ischemic stroke (OR 0.90) risk, while reverse MR found that genetic propensity to CHD increased MMP12. Taken together, multivariable MR confirms a direct protective effect of higher plasma MMP12 on CHD risk and a genetic effect of atherosclerosis and CHD on elevating MMP12. CONCLUSIONS:Proteomic analyses reveal associations with incident CHD and genomic evidence suggests that therapeutic MMP12 inhibition may confer adverse cardiovascular effects.

BACKGROUND:Latino individuals represent one of the fastest-growing demographic groups in the United States, and the impact of dementia is rising within this population. Despite this growth, most research on healthcare utilization has predominantly focused on non-Hispanic White populations. The limited body of literature that does include Latino populations often treats them as a monolithic racial/ethnic category, which overlooks intra-group heterogeneity. As a result, little is known about how healthcare utilization patterns relate to cognitive impairment status across specific Latino ethnic groups. METHODS:Using data collected from the Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA), we examined the odds of overall healthcare utilization and avoidable healthcare utilization according to cognitive impairment and whether these associations vary by Latino ethnicity. Weighted logistic regressions and two-way interactions were conducted. RESULTS:This study included 4,825 (unweighted) Latino participants (1,664 Mexican, 917 Cuban, 859 Puerto Rican, 437 Dominican, 481 Central American, 345 South American, and 142 More than One/Other). Overall, participants reported high rates of overall healthcare utilization (88%) and avoidable healthcare utilization (42%). Individuals with cognitive impairment had higher odds of both overall (OR = 1.94, p = 0.013) and avoidable healthcare utilization (OR = 1.51, p = 0.004) compared to those without cognitive impairment. Puerto Rican participants were the only ethnic group found to have significant differences in avoidable healthcare utilization and cognitive impairment (OR = 2.61, p = 0.014). DISCUSSION/CONCLUSIONS:Disaggregation of Latino data revealed significant healthcare utilization across Latino ethnic groups. Targeted interventions and resources are needed to promote preventive care that may decrease avoidable healthcare utilization and associated expenditures.

BACKGROUND:Self-reported smoking may not fully capture individualized risk of smoking-related cancer. Circulating proteins may reflect biological consequences of smoking. Thus, we developed a score from smoking-related proteins and evaluated its association with smoking-related cancer. METHODS:This prospective cohort study included 10,563 participants aged 47-70 years in the Atherosclerosis Risk in Communities study. Plasma proteins were measured by SomaScan. The score was constructed from proteins associated with current smoking, packyears, and/or recent quitting identified by linear regression and elastic net regression. Cox regression was used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI). We confirmed the association in a case-cohort study in the European Prospective Investigation into Cancer and Nutrition (EPIC). RESULTS:aHRs comparing score quartiles Q4 to Q1 for total incidence and mortality of 13 smoking-related cancers were 3.89 (95% CI 3.06-4.96) and 5.73 (95% CI 4.08-8.06) before, and 2.28 (95% CI 1.65-3.15) and 2.07 (95% CI 1.74-4.10) after adjusting for self-reported smoking. aHRs for lung cancer were 12.1 (95% CI 7.11-20.6) and 14.2 (95% CI 7.58-26.8) before, 3.04 (95% CI 1.59-5.81) and 4.12 (95% CI 1.99-8.53) after adjusting. In EPIC, aHRs for lung cancer were 9.47 (95% CI 6.82-13.15) before and 2.23 (95% CI 1.48-3.35) after adjusting. CONCLUSION/CONCLUSIONS:The smoking-related protein score provided relative risk information for smoking-associated cancers beyond self-reported smoking, which was confirmed in an independent cohort. Such a score may be considered for use in risk stratification for prevention and cancer screening in settings in which detailed smoking history cannot be obtained.

IMPORTANCE/UNASSIGNED:Millions of children worldwide are experiencing prolonged symptoms after SARS-CoV-2 infection, yet social risk factors for developing long COVID are largely unknown. As child health is influenced by the environment in which they live and interact, adverse social determinants of health (SDOH) may contribute to the development of pediatric long COVID. OBJECTIVE/UNASSIGNED:To identify whether adverse SDOH are associated with increased odds of long COVID in school-aged children and adolescents in the US. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cross-sectional analysis of a multicenter, longitudinal, meta-cohort study encompassed 52 sites (health care and community settings) across the US. School-aged children (6-11 years; n = 903) and adolescents (12-17 years; n = 3681) with SARS-CoV-2 infection history were included. Those with an unknown date of first infection, history of multisystem inflammatory syndrome in children, or symptom surveys with less than 50% of questions completed were excluded. Participants were recruited via health care systems, long COVID clinics, fliers, websites, social media campaigns, radio, health fairs, community-based organizations, community health workers, and existing research cohorts from March 2022 to August 2024, and surveys were completed by caregivers between March 2022 and August 2024. EXPOSURE/UNASSIGNED:Twenty-four individual social determinant of health factors were grouped into 5 Healthy People 2030 domains: economic stability, social and community context, caregiver education access and quality, neighborhood and built environment, and health care access and quality. Latent classes were created within each domain and used in regression models. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Presence of long COVID using caregiver-reported, symptom-based, age-specific research indices. RESULTS/UNASSIGNED:The mean (SD) age among 4584 individuals included in this study was 14 (3) years, and 2330 (51%) of participants were male. The number of latent classes varied by domain; the reference group was the class with the least adversity. In unadjusted analyses, most classes in each domain were associated with higher odds of long COVID. After adjusting for many factors, including age group, sex, timing of infection, referral source, and other social determinant of health domains, economic instability characterized by difficulty covering expenses, poverty, receipt of government assistance, and food insecurity were associated with an increased risk of having long COVID (class 2 adjusted odds ratio [aOR], 1.57; 95% CI, 1.18-2.09; class 4 aOR, 2.39; 95% CI, 1.73-3.30); economic instability without food insecurity (class 3) was not (aOR, 0.93; 95% CI, 0.70-1.23). Poorer social and community context (eg, high levels of discrimination and low social support) was also associated with long COVID (aOR, 2.17; 95% CI, 1.77-2.66). Sensitivity analyses stratified by age group and adjusted for race and ethnicity did not alter or attenuate these results. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this study, economic instability that included food insecurity and poor social and community context were associated with greater odds of pediatric long COVID. Those with food security, despite experiencing other economic challenges, did not have greater odds of long COVID. Further study is needed to determine if addressing SDOH factors can decrease the rate of pediatric long COVID.

BACKGROUND/UNASSIGNED:Effective management of alcohol withdrawal syndrome during hospitalization is paramount to patient safety and quality care. NYC Health + Hospitals initiated a quality improvement project to pilot an electronic health record (EHR) integrated, nurse-driven CIWA-Ar symptom-triggered protocol, including recommendations for medications for alcohol use disorder (MAUD), in medical and surgical units at 3 public hospitals. OBJECTIVE/UNASSIGNED:To describe implementation processes and to report related implementation outcomes (appropriateness, feasibility, and adoption) of the updated CIWA-Ar protocol in a safety net hospital setting. METHODS/UNASSIGNED:NYC Health + Hospitals implemented a standardized CIWA-Ar symptom-triggered, nurse-driven EHR protocol on March 15, 2022. The protocol included order sets, practice advisories, task lists, and reminders for assessments and orders. We measured nursing perspectives on feasibility and appropriateness at 6 months via a survey. We measured provider adoption as the proportion of admissions with a CIWA-Ar protocol ordered among admissions that triggered a recommendation, and MAUD use as the proportion of admissions with a MAUD order during hospitalization among all patients with a protocol ordered. RESULTS/UNASSIGNED:= .249). CONCLUSIONS/UNASSIGNED:The CIWA-Ar protocol was appropriate, feasible, and adopted at NYC public hospitals. Quality improvements to ensure protocol fidelity with benzodiazepine dosing and MAUD prescribing are needed.

INTRODUCTION/UNASSIGNED:Membranous nephropathy (MN) is a common cause of nephrotic syndrome usually diagnosed using kidney biopsy. METHODS/UNASSIGNED:= 132). RESULTS/UNASSIGNED:In BKBC, 2 proteins, testican-2 and alpha-1,6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase (MGT5A), were associated with MN when compared with the reference diagnosis (normal or thin basement membrane [TBM] disease) as well as when compared with all other diagnoses among individuals who had undergone kidney biopsy for the indication of proteinuria or nephrotic syndrome. In NEPTUNE, plasma levels of both proteins, as well as glomerular expression of their cognate genes, were increased in MN compared with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). In receiver operating characteristic curve analyses, the addition of plasma testican-2 and MGT5A levels significantly improved discrimination of MN from other diagnoses in BKBC and NEPTUNE compared with models incorporating age, sex, race, estimated glomerular filtration rate (eGFR), and proteinuria. CONCLUSION/UNASSIGNED:Together, these findings motivate interest in testican-2 and MGT5A as markers and potential functional participants in MN. More work is required to understand the biological role of these proteins in the glomerular basement membrane in relation to immune complex deposition as well as to assess their performance as biomarkers alongside circulating autoantibodies in patients with MN.

Despite well-studied benefits of preventive parenting programs for early child development, various real-world barriers may impede families from engaging in those programs. The current study aims to provide new insights into family engagement by examining enrollment, retention, and involvement and their predictors in an evidence-based universal pediatric primary care parenting program for families with young children. Data (n = 204) were from an ongoing longitudinal randomized controlled trial of PlayReadVIP in Flint, MI. Families (66% Black, 35% White, low socioeconomic status) had high enrollment and retention in the program. As exploratory analyses, random forest models, a machine learning method, identified a multitude of sociodemographic, psychosocial, and contextual predictors of retention and involvement in PlayReadVIP across the first 9 months. As confirmatory analyses, multiple regressions showed that COVID-19 significantly hindered retention (odds ratio = .04; b =  - .30) and involvement (b =  - .31) and that higher parenting self-efficacy was associated with lower retention (odds ratio = .76). Furthermore, the association between COVID-19 and family engagement was moderated by household income, suggesting that families with the highest economic risks were less likely to attend and be actively involved in sessions during the pandemic. This study addresses important research gaps by focusing on multiple aspects of family engagement in a pediatric program during infancy, assessing whether experiencing contextual adversity hinders or motivates engagement, and employing a machine learning method. These findings have crucial implications for designing and implementing early childhood prevention parenting programs to more effectively engage families with higher needs.

BACKGROUND:Midkine is a heparin-binding growth factor that is overexpressed in most human malignancies, including breast cancer. While elevated midkine levels have been associated with tumor progression and aging, its role as a predictive biomarker for breast cancer risk in healthy individuals remains unclear. We previously showed that higher midkine expression in estrogen receptor-positive (ER +) breast cancer in younger (< 55) women is associated with shorter disease-free survival. We investigated whether serum midkine levels in premenopausal women are associated with subsequent risk of ER + breast cancer. METHODS:We conducted a prospective, nested case-control study within the New York University Women's Health Study (NYUWHS). Serum midkine levels were measured in baseline blood samples from 249 premenopausal women who developed ER + breast cancer more than 10 years after blood collection and 249 matched controls. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) across quartiles and continuous midkine levels, adjusting for key breast cancer risk factors. RESULTS:Higher circulating midkine levels were associated with a marginally statistically significant lower risk of ER + breast cancer. Compared to the lowest quartile, women in the highest quartile had an OR of 0.55 (95% CI: 0.30-0.99; P for trend = 0.10). A doubling in midkine was associated with a 34% reduction in risk (OR = 0.66; 95% CI: 0.42-1.02). The inverse association was generally consistent across subgroups. CONCLUSION/CONCLUSIONS:These findings suggest that higher baseline serum midkine levels in premenopausal women are associated with a reduced long-term risk of ER + breast cancer. This challenges prior assumptions about midkine's uniformly pro-tumorigenic role and suggests it may be a context-dependent biomarker in breast cancer development.