Faculty Bibliography

Electronic health records (EHRs) contain rich clinical information for millions of patients and are increasingly used for public health research. However, non-random inclusion of subjects in EHRs can result in selection bias, with factors such as demographics, socioeconomic status, healthcare referral patterns, and underlying health status playing a role. While this issue has been well documented, little work has been done to develop or apply bias-correction methods, often due to the fact that most of these factors are unavailable in EHRs. To address this gap, we propose a series of Heckman type bias correction methods by incorporating social determinants of health selection covariates to model the EHR non-random sampling probability. Through simulations under various settings, we demonstrate the effectiveness of our proposed method in correcting biases in both the association coefficient and the outcome mean. Our method augments the utility of EHRs for public health inferences, as we show by estimating the prevalence of cardiovascular disease and its correlation with risk factors in the New York City network of EHRs.

Background: We previously reported a higher incidence of a pathogenic germline variant in the kinase insert domain receptor (KDR) in melanoma patients compared to the general population. Here, we dissect the impact of this genotype on melanoma tumor growth kinetics, tumor phenotype, and response to treatment with immune checkpoint inhibitors (ICIs) or targeted therapy. Methods: The KDR genotype was determined and the associations between the KDR Q472H variant (KDR-Var), angiogenesis, tumor immunophenotype, and response to MAPK inhibition or ICI treatment were examined. Melanoma B16 cell lines were transfected with KDR-Var or KDR wild type (KDR-WT), and the differences in tumor kinetics were evaluated. We also examined the impact of KDR-Var on the response of melanoma cells to a combination of VEGFR inhibition with MAPKi. Results: We identified the KDR-Var genotype in 81/489 (37%) patients, and it was associated with a more angiogenic (p = 0.003) and immune-suppressive tumor phenotype. KDR-Var was also associated with decreased PFS to MAPKi (p = 0.022) and a trend with worse PFS to anti-PD1 therapy (p = 0.06). KDR-Var B16 murine models had increased average tumor volume (p = 0.0027) and decreased CD45 tumor-infiltrating lymphocytes (p = 0.0282). The anti-VEGFR treatment Lenvatinib reduced the tumor size of KDR-Var murine tumors (p = 0.0159), and KDR-Var cells showed synergistic cytotoxicity to the combination of dabrafenib and lenvatinib. Conclusions: Our data demonstrate a role of germline KDR-Var in modulating melanoma behavior, including response to treatment. Our data also suggest that anti-angiogenic therapy might be beneficial in patients harboring this genotype, which needs to be tested in clinical trials.

INTRODUCTION/UNASSIGNED:Quantitative, multiplexed imaging is revealing complex spatial relationships between phenotypically diverse tumor infiltrating leukocyte populations and their prognostic implications. The underlying mechanisms and tissue structures that determine leukocyte distribution within and around tumor nests, however, remain poorly understood. While presumed players in metastatic dissemination, new preclinical data demonstrates that blood and lymphatic vessels (lymphovasculature) also dictate leukocyte trafficking within tumor microenvironments and thereby impact anti-tumor immunity. Here we interrogate these relationships in primary human cutaneous melanoma. METHODS/UNASSIGNED:We established a quantitative, multiplexed imaging platform to simultaneously detect immune infiltrates and tumor-associated vessels in formalin-fixed paraffin embedded patient samples. We performed a discovery, retrospective analysis of 28 treatment-naïve, primary cutaneous melanomas. RESULTS/UNASSIGNED:Here we find that the lymphvasculature and immune infiltrate is heterogenous across patients in treatment naïve, primary melanoma. We categorized five lymphovascular subtypes that differ by functionality and morphology and mapped their localization in and around primary tumors. Interestingly, the localization of specific vessel subtypes, but not overall vessel density, significantly associated with the presence of lymphoid aggregates, regional progression, and intratumoral T cell infiltrates. DISCUSSION/UNASSIGNED:We describe a quantitative platform to enable simultaneous lymphovascular and immune infiltrate analysis and map their spatial relationships in primary melanoma. Our data indicate that tumor-associated vessels exist in different states and that their localization may determine potential for metastasis or immune infiltration. This platform will support future efforts to map tumor-associated lymphovascular evolution across stage, assess its prognostic value, and stratify patients for adjuvant therapy.

BACKGROUND:Prediabetes affects 26.4 million people aged 65 years or older (48.8%) in the United States. Although older adults respond well to the evidence-based Diabetes Prevention Program, they are a heterogeneous group with differing physiological, biomedical, and psychosocial needs who can benefit from additional support to accommodate age-related changes in sensory and motor function. OBJECTIVE:The purpose of this paper is to describe adaptations of the Centers for Disease Control and Prevention's Diabetes Prevention Program aimed at preventing diabetes among older adults (ages ≥65 years) and findings from a pilot of 2 virtual sessions of the adapted program that evaluated the acceptability of the content. METHODS:The research team adapted the program by incorporating additional resources necessary for older adults. A certified lifestyle coach delivered 2 sessions of the adapted content via videoconference to 189 older adults. RESULTS:The first session had a 34.9% (38/109) response rate to the survey, and the second had a 34% (30/88) response rate. Over three-quarters (50/59, 85%) of respondents agreed that they liked the virtual program, with 82% (45/55) agreeing that they would recommend it to a family member or a friend. CONCLUSIONS:This data will be used to inform intervention delivery in a randomized controlled trial comparing in-person versus virtual delivery of the adapted program.

BACKGROUND:Although studies to date have broadly shown that cardiovascular disease (CVD) increases cognitive and physical impairment risk, there is still limited understanding of the magnitude of this risk among relevant CVD subtypes or age cohorts. METHODS:We analyzed longitudinal data from 16 679 U.S. Health and Retirement Study participants who were aged ≥65 years at study entry. Primary endpoints were physical impairment (activities of daily living impairment) or cognitive impairment (Langa-Weir Classification of dementia). We compared these endpoints among participants who developed incident CVD versus those who were CVD free, both in the short term (<2-year postdiagnosis) and long term (>5 years), controlling for sociodemographic and health characteristics. We then analyzed the effects by CVD subtype (atrial fibrillation, congestive heart failure, ischemic heart disease, and stroke) and age-at-diagnosis (65-74, 75-84, and ≥85). RESULTS:Over a median follow-up of 10 years, 8 750 participants (52%) developed incident CVD. Incident CVD was associated with significantly higher adjusted odds (aOR) of short-term and long-term physical and cognitive impairment. The oldest (≥85) age-at-diagnosis subgroup had the highest risk of short-term physical (aOR 3.01, 95% confidence interval [CI]: 2.40-3.77) and cognitive impairment (aOR 1.96, 95% CI: 1.55-2.48), as well as long-term impairment. All CVD subtypes were associated with higher odds of physical and cognitive impairment, with the highest risk for patients with incident stroke. CONCLUSIONS:Incident CVD was associated with an increased risk of physical and cognitive impairment across CVD subtypes. Impairment risk after CVD was highest among the oldest patients (≥85 years) who should therefore remain a target for prevention efforts.

In data collection for predictive modeling, under-representation of certain groups, based on gender, race/ethnicity, or age, may yield less-accurate predictions for these groups. Recently, this issue of fairness in predictions has attracted significant attention, as data-driven models are increasingly utilized to perform crucial decision-making tasks. Existing methods to achieve fairness in the machine learning literature typically build a single prediction model in a manner that encourages fair prediction performance for all groups. These approaches have two major limitations: i) fairness is often achieved by compromising accuracy for some groups; ii) the underlying relationship between dependent and independent variables may not be the same across groups. We propose a Joint Fairness Model (JFM) approach for logistic regression models for binary outcomes that estimates group-specific classifiers using a joint modeling objective function that incorporates fairness criteria for prediction. We introduce an Accelerated Smoothing Proximal Gradient Algorithm to solve the convex objective function, and present the key asymptotic properties of the JFM estimates. Through simulations, we demonstrate the efficacy of the JFM in achieving good prediction performance and across-group parity, in comparison with the single fairness model, group-separate model, and group-ignorant model, especially when the minority group's sample size is small. Finally, we demonstrate the utility of the JFM method in a real-world example to obtain fair risk predictions for under-represented older patients diagnosed with coronavirus disease 2019 (COVID-19). This article is protected by copyright. All rights reserved.

BACKGROUND:Evading immune surveillance is a hallmark for the development of multiple cancer types. Whether immune evasion contributes to the pathogenesis of high-grade prostate cancer (HGPCa) remains an area of active inquiry. METHODS:Through single-cell RNA sequencing and multicolor flow cytometry of freshly isolated prostatectomy specimens and matched peripheral blood, we aimed to characterize the tumor immune microenvironment (TME) of localized prostate cancer (PCa), including HGPCa and low-grade prostate cancer (LGPCa). RESULTS: TILs. The PCa TME was infiltrated by macrophages but these did not clearly cluster by M1 and M2 markers. CONCLUSIONS:T cell exhaustion in localized PCa, a finding enriched in HGPCa relative to LGPCa. These studies suggest a possible link between the clinical-pathologic risk of PCa and the associated TME. Our results have implications for our understanding of the immunologic mechanisms of PCa pathogenesis and the implementation of immunotherapy for localized PCa.

The SOX9 transcription factor ensures proper tissue development and homeostasis and has been implicated in promoting tumor progression. However, the role of SOX9 as a driver of lung adenocarcinoma (LUAD), or any cancer, remains unclear. Using CRISPR/Cas9 and Cre-LoxP gene knockout approaches in the Kras^G12D-driven mouse LUAD model, we found that loss of Sox9 significantly reduces lung tumor development, burden and progression, contributing to significantly longer overall survival. SOX9 consistently drove organoid growth in vitro, but SOX9-promoted tumor growth was significantly attenuated in immunocompromised mice compared to syngeneic mice. We demonstrate that SOX9 suppresses immune cell infiltration and functionally suppresses tumor associated CD8⁺ T, natural killer and dendritic cells. These data were validated by flow cytometry, gene expression, RT-qPCR, and immunohistochemistry analyses in Kras^G12D-driven murine LUAD, then confirmed by interrogating bulk and single-cell gene expression repertoires and immunohistochemistry in human LUAD. Notably, SOX9 significantly elevates collagen-related gene expression and substantially increases collagen fibers. We propose that SOX9 increases tumor stiffness and inhibits tumor-infiltrating dendritic cells, thereby suppressing CD8⁺ T cell and NK cell infiltration and activity. Thus, SOX9 drives Kras^G12D-driven lung tumor progression and inhibits anti-tumor immunity at least partly by modulating the tumor microenvironment.

Background Psychological well-being is important among individuals with myocardial infarction (MI) given the clear links between stress, depression, and adverse cardiovascular outcomes. Stress and depressive disorders are more prevalent in women than men after MI. Resilience may protect against stress and depressive disorders after a traumatic event. Longitudinal data are lacking in populations post MI. We examined the role of resilience in the psychological recovery of women post MI, over time. Methods and Results We analyzed a sample from a longitudinal observational multicenter study (United States, Canada) of women post MI, between 2016 and 2020. Perceived stress (Perceived Stress Scale-4 [PSS-4]) and depressive symptoms (Patient Health Questionnaire-2 [PHQ-2]) were assessed at baseline (time of MI) and 2 months post MI. Demographics, clinical characteristics, and resilience (Brief Resilience Scale [BRS]) were collected at baseline. Low and normal/high resilience groups were established as per published cutoffs (BRS scores <3 or ≥3). Mixed-effects modeling was used to examine associations between resilience and psychological recovery over 2 months. The sample included 449 women, mean (SD) age, 62.2 (13.2) years, of whom 61.1% identified as non-Hispanic White, 18.5% as non-Hispanic Black, and 15.4% as Hispanic/Latina. Twenty-three percent had low resilience. The low resilience group had significantly higher PSS-4 and PHQ-2 scores than the normal/high resilience group at all time points. In adjusted models, both groups showed a decrease in PSS-4 scores over time. Conclusions In a diverse cohort of women post MI, higher resilience is associated with better psychological recovery over time. Future work should focus on developing strategies to strengthen resilience and improve psychological well-being for women with MI. Registration URL: https://clinicaltrials.gov/ct2/show/NCT02905357; Unique identifier: NCT02905357.

BACKGROUND/UNASSIGNED:There has been a call by both patients and health professionals for the integration of palliative care with nephrology care, yet there is little evidence describing the effect of this approach. The objective of this paper is to report the feasibility and acceptability of a pilot randomized controlled trial testing the efficacy of integrated palliative and nephrology care. METHODS/UNASSIGNED:English speaking patients with CKD stage 5 were randomized to monthly palliative care visits for 3 months in addition to their usual care, as compared with usual nephrology care. Feasibility of recruitment, retention, completion of intervention processes, and feedback on participation was measured. Other outcomes included differences in symptom burden change, measured by the Integrated Palliative Outcome Scale-Renal, and change in quality of life, measured by the Kidney Disease Quality of Life questionnaire and completion of advance care planning documents. RESULTS/UNASSIGNED:Of the 67 patients approached, 45 (67%) provided informed consent. Of these, 27 patients completed the study (60%), and 14 (74%) of those in the intervention group completed all visits. We found small improvements in overall symptom burden (-2.92 versus 1.57) and physical symptom burden scores (-1.92 versus 1.79) in the intervention group. We did not see improvements in the quality-of-life scores, with the exception of the physical component score. The intervention group completed more advance care planning documents than controls (five health care proxy forms completed versus one, nine Medical Orders for Life Sustaining Treatment forms versus none). CONCLUSIONS/UNASSIGNED:We found that pilot testing through a randomized controlled trial of an ambulatory integrated palliative and nephrology care clinical program was feasible and acceptable to participants. This intervention has the potential to improve the disease experience for those with nondialysis CKD and should be tested in other CKD populations with longer follow-up. CLINICAL TRIALS REGISTRY NAME AND REGISTRATION NUMBER/UNASSIGNED:Pilot Randomized-controlled Trial of Integrated Palliative and Nephrology Care Versus Usual Nephrology Care, NCT04520984.