Faculty Bibliography

Previous studies have developed proteomic aging clocks to estimate biological age and predict mortality and age-related diseases. However, these earlier clocks were based on cross-sectional data, capturing only the cumulative aging burden at a single time point but were unable to reflect the dynamic trajectory of biological aging over time. We constructed a longitudinal proteomic aging index (LPAI) using data from 4684 plasma proteins measured by the SomaScan 5K Array across three visits in the Atherosclerosis Risk in Communities (ARIC) study (ages 67-90 at last visit). Our two-step approach applied functional principal component analysis (FPCA) to capture protein-level change patterns over time, followed by elastic net penalized Cox regression for protein selection. LPAI was constructed in a randomly selected training set of ARIC participants (N = 2954), tested among the remaining ARIC participants (N = 1267), and validated externally in Multi-Ethnic Study of Atherosclerosis (MESA) participants (N = 3726, ages 53-94 at last exam). Using Cox proportional hazards model, higher LPAI was associated with increased all-cause mortality (HR = 2.50, 95% CI: [2.15, 2.92] per SD), CVD mortality (HR = 1.79, 95% CI: [1.34, 2.39] per SD), and cancer mortality (HR = 1.96, 95% CI: [1.45, 2.64] per SD) risk in ARIC, with statistically significant and directionally consistent associations also observed in MESA. Additionally, higher LPAI was associated with increased multimorbidity and frailty. This study demonstrates the feasibility of developing biological aging measures from longitudinal proteomics data and supports LPAI as a biomarker for aging-related health risks.

Fatty acids are involved in disease risk and aging processes. In the US National Health and Nutrition Examination Survey (1999-2002), we tested for associations of total, saturated (SFA), monounsaturated (MUFA), polyunsaturated (PUFA), and subtypes of dietary fatty acids with DNA methylation-based aging biomarkers, adjusting for age, BMI, total energy intake, and sociodemographic and behavioral factors (N = 2260). Higher SFA and MUFA were associated with greater GrimAge2, an aging biomarker of mortality; PUFA was associated with lower Horvath1, Hannum, and PhenoAge (p < 0.05). Omega-3 and the PUFA:SFA ratio were negatively associated with Horvath1, Hannum, Vidal-Bralo, and PhenoAge. Notably, a one-unit increase in PUFA:SFA was associated with 1.05 years lower PhenoAge (95% CI = -1.87, -0.22). We found consistent positive associations for SFA subtypes and negative associations for PUFA subtypes with epigenetic aging; associations of MUFA subtypes varied. Future studies, including randomized controlled trials, are needed to investigate causality and downstream clinical outcomes.

PURPOSE/OBJECTIVE:The National Academy of Science Engineering and Medicine (NASEM) developed items to collect sexual orientation and gender identity (SOGI) in healthcare settings to harmonize collection of these data and address disparities often experienced by sexual and gender minorities (SGM) (LGBTQAI+). This study tested wording of SOGI items among the SGM Community. METHODS:Individuals were recruited to participate in an interview about the NASEM SOGI items. Eligible participants identified as SGM, lived within the catchment area of an NYC academic medical center, had a history of cancer, or were caregivers of a person with cancer. Interviews were audio-recorded, transcribed, and qualitatively coded. RESULTS:Thirty-eight SGM individuals participated. The majority disliked the options for sexual orientation (SO) and gender identity (GI) but did find one they would choose. For SO, participants thought options like queer, pansexual, and asexual were missing, and for GI, participants said non-binary and transgender category (transgender man, transgender woman) were needed. Half said they had no concerns about disclosing SOGI information on medical intake forms and others reported preferring knowing why it was needed and who would have access. Several expressed worry about their safety upon disclosure of SOGI. Respondents cited being less likely to disclose SOGI if there was an offensive question on intake form (e.g., spouse instead of partner) or if there were no privacy assurances. Almost all expected reported SOGI to be reflected in their oncology healthcare. CONCLUSIONS:The NASEM questions need improvement. To improve trust and encourage disclosure, clinicians and clinics should improve the options for SOGI data collection and take steps to ensure privacy is addressed.

BACKGROUND:Pregnancy is a crucial period to improve cardiovascular health (CVH) for mothers and their families. The current study emphasizes framework-guided factors that influence the adaptation of an evidence-based intervention (Parents as Teachers and Healthy Eating Active Living Taught at Home [PAT + HEALTH]) to support healthy gestational weight gain and postpartum weight management among pregnant women with obesity and their infants in Nigeria. METHODS:From May to June 2023, 43 in-depth interviews were conducted with 11 parents, 15 community health extension workers (CHEWs)/health educators, and 17 policymakers/ healthcare supervisors in the Federal Capital Territory, Nigeria. Additionally, nine focus groups were conducted with 75 participants. Interviews were recorded, de-identified, and transcribed. The updated Consolidated Framework for Implementation Research (CFIR 2.0) informed the development of the interview guides and the thematic analysis. Transcripts were double-coded using Dedoose. RESULTS:We identified assessing context, tailoring strategies, local attitudes, and sustainability as constructs to consider when adapting and implementing the PAT + HEALTH intervention successfully within the Nigerian primary care context. For example, policymakers and healthcare supervisors emphasized the feasibility of the intervention, including raising community awareness, planning for hard-to-reach areas, and ensuring supportive supervision of CHEWs delivering the intervention. Additional factors included customizing educational content and delivery methods to fit the cultural, socioeconomic, and environmental contexts of Nigerian families. CHEWs highlighted the importance of public education on locally available foods for better nutrition. Potential barriers to the PAT + HEALTH intervention included local attitudes influenced by sociocultural factors, such as food taboos, and structural factors, including limited financial support for the long-term sustainability of some components of the home visiting program. CONCLUSIONS:Building on these formative activities, the ENHANCE CVH trial will advance dissemination and implementation science by adapting, testing, and evaluating the effectiveness and implementation of the PAT + HEALTH intervention among pregnant women with obesity and their infants in Nigeria in a cluster randomized trial. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov/NCT06773299, Registration Date: January 14, 2025.

BACKGROUND/UNASSIGNED:Despite the growing relevance of rural areas in the overdose crisis, research on rural people who inject drugs and their experiences with law enforcement remains limited. This research examines how rural policing and stigma uniquely shape the lives of people who inject drugs. METHODS/UNASSIGNED:Forty-one semi-structured qualitative interviews were conducted with people who inject drugs in southern Illinois. For this analysis, we focused on participants who mentioned police in response to the question, "Have you ever been treated differently because you used drugs?" RESULTS/UNASSIGNED:We identified three interrelated manifestations of stigma in rural people who inject drugs' interactions with police-verbal degradation and discrediting, unwarranted searches, and dehumanization-that align with Earnshaw's (2020) model distinguishing between stigma components (stereotypes, prejudice, discrimination) and health impact pathways. CONCLUSION/UNASSIGNED:This study emphasizes the impact of stigma on people who use drugs, particularly in their interactions with law enforcement.

BACKGROUND:Estimated glomerular filtration rate (eGFR) using creatinine (eGFRcr), cystatin C (eGFRcys), or both (eGFRcr-cys) is not sufficiently accurate in many settings, often due to non-glomerular filtration rate (GFR) determinants of the filtration markers. In principle, using a panel of endogenous markers (panel eGFR) could reduce the impact of non-GFR determinants of each marker, improving the accuracy of eGFR. Using global untargeted metabolomics, we previously identified 33 endogenous metabolites that correlate highly with measured GFR. METHODS:A LC-MS/MS measurement procedure was developed to quantify 11 endogenous metabolites from serum and plasma. The assay was evaluated in 99 participants with measured GFR (mGFR) from 2 research studies, including a subgroup of 51 participants with large errors in eGFRcr and large discordance between eGFRcr and eGFRcys. Performance of eGFR models using single metabolites and all metabolites (panel eGFR-11) compared to mGFR was assessed by leave-one-out cross-validated root mean square error (RMSE). RESULTS:Assay CV for single metabolites ranged from 1.1% to 6.3% over the course of 21 days. RMSE of eGFR in single metabolite models ranged from 0.184 to 0.324. RMSEs for panel eGFR-11, eGFRcr, and eGFRcr-cys were 0.195, 0.251, and 0.201, respectively, and 0.155, 0.290, and 0.203, respectively, in the subgroup with large errors and large discordance. CONCLUSIONS:A precise metabolite (LC-MS/MS) measurement procedure shows promise for more accurate GFR estimation when eGFRcr is unreliable, offering a potential new confirmatory test for GFR evaluation.

IMPORTANCE/UNASSIGNED:Estimated glomerular filtration rates (eGFRs) can differ according to whether creatinine or cystatin C is used for the eGFR calculation, but the prevalence and importance of these differences remain unclear. OBJECTIVES/UNASSIGNED:To evaluate the prevalence of a discordance between cystatin C-based eGFR (eGFRcys) and creatinine-based eGFR (eGFRcr), identify characteristics associated with greater discordance, and evaluate associations of discordance with adverse outcomes. DATA SOURCES/UNASSIGNED:Participants in the Chronic Kidney Disease Prognosis Consortium (CKD-PC). STUDY SELECTION/UNASSIGNED:Participants with concurrent cystatin C and creatinine measurements and clinical outcome measurement. DATA EXTRACTION AND SYNTHESIS/UNASSIGNED:Between April 2024 and August 2025, data were synthesized using individual-level meta-analysis. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary independent measurement was a large negative eGFR difference (eGFRdiff), defined as an eGFRcys that was at least 30% lower than eGFRcr. Secondary (dependent) outcomes included all-cause and cardiovascular mortality, atherosclerotic cardiovascular disease, heart failure, and kidney failure with replacement therapy. RESULTS/UNASSIGNED:A total of 821 327 individuals from 23 outpatient cohorts (mean [SD] age, 59 [12] years; 48% female; 13.5% with diabetes; 40% with hypertension) and 39 639 individuals from 2 inpatient cohorts (mean [SD] age, 67 [16] years; 31% female; 30% with diabetes; 72% with hypertension) were included. Among outpatient participants, 11% had a large negative eGFRdiff (range, 3%-50%). Among inpatients, 35% had a large negative eGFRdiff. Among outpatient participants, at a mean (SD) follow-up of 11 (4) years, a large negative eGFRdiff, compared with an eGFRdiff between -30% and 30%, was associated with higher rates of all-cause mortality (28.4 vs 16.8 per 1000 person-years [PY]; hazard ratio [HR], 1.69 [95% CI, 1.57-1.82]), cardiovascular mortality (6.1 vs 3.8 per 1000 PY; HR, 1.61 [95% CI, 1.48-1.76]), atherosclerotic cardiovascular disease (13.3 vs 9.8 per 1000 PY; HR, 1.35 [95% CI, 1.27-1.44]), heart failure (13.2 vs 8.6 per 1000 PY; HR, 1.54 [95% CI, 1.40-1.68]), and kidney failure with replacement therapy (2.7 vs 2.1 per 1000 PY; HR, 1.29 [95% CI, 1.13-1.47]). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In the CKD-PC, 11% of outpatient participants and 35% of hospitalized patients had an eGFRcys that was at least 30% lower than their eGFRcr. In the outpatient setting, presence of eGFRcys at least 30% lower than eGFRcr was associated with significantly higher rates of all-cause mortality, cardiovascular events, and kidney failure.

Long-term exposure to ambient air pollution has been associated with epigenetic age acceleration (EAA) in adults, but its impact on children remains less understood. We analyzed data from 457 children (mean age: 7.9 years) in the Project Viva cohort (2007-2010, eastern Massachusetts, USA). We calculated the following EAAs from leukocytes: Horvath's epigenetic age acceleration (HorvathEAA), intrinsic epigenetic age acceleration (IEAA), and skin and blood epigenetic age acceleration (Skin&BloodEAA). We applied generalized additive models to evaluate associations of prior-365-day average and lifetime average exposure to fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3), as well as the distance to major roadways, with EAA. Results indicated that each IQR increase (1.9 μg m-3) in the prior-365-day average of PM2.5 was associated with 0.26 years (95% CI, -0.49 to -0.03) lower HorvathEAA, although it did not survive multiple testing adjustment. Similar patterns but with wider CIs were observed for IEAA (-0.22; 95% CI, -0.44 to 0.01) and Skin&BloodEAA (-0.04; 95% CI, -0.19 to 0.11). No associations were observed of exposure to lifetime average PM2.5, prior-365-day or lifetime average NO2 or O3, or distance to major roadways with EAA. These findings suggest higher prior-365-day average PM2.5 exposure may relate to lower HorvathEAA in children.