Faculty Bibliography

BACKGROUND:Team-based care (TBC), a team of ≥2 healthcare professionals working collaboratively toward a shared clinical goal, is a recommended strategy to manage blood pressure (BP). However, the most effective and cost-effective TBC strategy is unknown. METHODS:A meta-analysis of clinical trials in US adults (aged ≥20 years) with uncontrolled hypertension (≥140/90 mm Hg) was performed to estimate the systolic BP reduction for TBC strategies versus usual care at 12 months. TBC strategies were stratified by the inclusion of a nonphysician team member who could titrate antihypertensive medications. The validated BP Control Model-Cardiovascular Disease Policy Model was used to project the expected BP reductions out to 10 years and simulate cardiovascular disease events, direct healthcare costs, quality-adjusted life years, and cost-effectiveness of TBC with physician and nonphysician titration. RESULTS:Among 19 studies comprising 5993 participants, the 12-month systolic BP change versus usual care was -5.0 (95% CI, -7.9 to -2.2) mm Hg for TBC with physician titration and -10.5 (-16.2 to -4.8) mm Hg for TBC with nonphysician titration. Relative to usual care at 10 years, TBC with nonphysician titration was estimated to cost $95 (95% uncertainty interval, -$563 to $664) more per patient and gain 0.022 (0.003-0.042) quality-adjusted life years, costing $4400/quality-adjusted life year gained. TBC with physician titration was estimated to cost more and gain fewer quality-adjusted life years than TBC with nonphysician titration. CONCLUSIONS:TBC with nonphysician titration yields superior hypertension outcomes compared with other strategies and is a cost-effective way to reduce hypertension-related morbidity and mortality in the United States.

BACKGROUND:There are well-established guidelines for treating hypertension (HTN), yet only half of patients with HTN meet the defined target of < 140/90. Team-based care (TBC) is an evidence-based strategy for improving blood pressure (BP) management and control. TBC is defined as the provision of health services by at least two health professionals "who work collaboratively with patients and their caregivers to accomplish shared goals to achieve coordinated, high-quality care". However, primary care practices experience challenges to implementing TBC principles and care processes; these are more pronounced in small independent practice settings (SIPs). Practice facilitation (PF) is an implementation strategy that may overcome barriers to adopting evidence-based TBC to improve HTN management in SIPs. METHODS:Using a stepped wedge randomized controlled trial design, we will test the effect of PF on the adoption of TBC to improve HTN management in small practices (< 5 FTE clinicians) in New York City, and the impact on BP control compared with usual care. We will enroll 90 SIPs and randomize them into one of three 12-month intervention waves. Practice facilitators will support SIPs to adopt TBC principles to improve implementation of five HTN management strategies (i.e., panel management, population health, measuring BP, supporting medication adherence, self-management). The primary outcome is the adoption of TBC for HTN management measured at baseline and 12 months. Secondary outcomes include the rate of BP control and sustainability of TBC and BP outcomes at 18 months. Aggregated data on BP measures are collected every 6 months in all clusters so that each cluster provides data points in both the control and intervention conditions. Using a mixed methods approach, we will also explore factors that influence the effectiveness of PF at the organization and team level. DISCUSSION/CONCLUSIONS:This study will provide much-needed guidance on how to optimize adoption and sustainability of TBC in independent primary care settings to reduce the burden of disease related to suboptimal BP control and advance understanding of how facilitation works to improve implementation of evidence-based interventions. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov; NCT05413252 .

INTRODUCTION:Culturally validated neurocognitive measures for children in Low- and Middle-Income Countries are important in the timely and correct identification of neurocognitive impairments. Such measures can inform development of interventions for children exposed to additional vulnerabilities like HIV infection. The Battery for Neuropsychological Evaluation of Children (BENCI) is an openly available, computerized neuropsychological battery specifically developed to evaluate neurocognitive impairment. This study adapted the BENCI and evaluated its reliability and validity in Kenya. METHODOLOGY:The BENCI was adapted using translation and back-translation from Spanish to English. The psychometric properties were evaluated in a case-control study of 328 children (aged 6 - 14 years) living with HIV and 260 children not living with HIV in Kenya. We assessed reliability, factor structure, and measurement invariance with respect to HIV. Additionally, we examined convergent validity of the BENCI using tests from the Kilifi Toolkit. RESULTS: = 135.57, DF = 51, N = 604, p < .001, RMSEA = .052, CFI = .944, TLI = .914) and was partially scalar invariant between HIV positive and negative groups. CONCLUSION:The English version of the BENCI formally translated for use in Kenya can be further adapted and integrated in clinical and research settings as a valid and reliable cognitive test battery.

OBJECTIVE:Research with lesbian, gay, and bisexual (LGB) older widows rarely focuses on familial relationships. Studies on heterosexual spousal bereavement indicate older widows face issues influencing identity but show resilience by maintaining close relationships with adult children and extended family. Though research with older LGB widows suggests similarities around loss and resilience, grief and family engagement are markedly different. METHODS:Guided by Relational Cultural Theory, which illuminates how LGB women cope through connection/disconnection, this qualitative descriptive study employed semi-structured, open-ended interviews with 16 LGB women, 60 to 85 years of age from across the United States who had lost a spouse or partner within the past five years. We conducted interviews regarding the perception of self as bereaved LGB women and sustained or altered relationships with biological and chosen families following the loss of their spouses/partners. RESULTS:Findings are illustrated in three themes around acceptance, support, and identity. Participants: 1) experienced differing levels of acceptance, tolerance, and inclusion from biological families; 2) experienced family or friends "disappearing" or providing critical support following a spouse/partner death; 3) negotiated challenges by creating or seeking out families of choice, new communities, and a better understanding of themselves. DISCUSSION/CONCLUSIONS:While LGB widows share some grief experiences with heterosexual widows, they also experience varying biological family acceptance and support as well as the need for friends and families of choice as advocates. It is important to recognize the unique consequences of spousal loss for this population and be cognizant of the differences in normative grief.

BACKGROUND:Myocardial injury is currently defined as a cardiac troponin above the sex-specific 99th percentile of a healthy reference population (upper reference limit [URL]). OBJECTIVES:The purpose of this study was to estimate high-sensitivity (hs) troponin URLs in a representative sample of the U.S. adult population; overall and by sex, race/ethnicity, and age group. METHODS:Among adults participating in the 1999-2004 National Health and Nutrition Examination Survey (NHANES), we measured hs-troponin T using 1 assay (Roche) and hs-troponin I using 3 assays (Abbott, Siemens, and Ortho). In a strictly defined healthy reference subgroup, we estimated 99th percentile URLs for each assay using the recommended nonparametric method. RESULTS:Of 12,545 participants, 2,746 met criteria for the healthy subgroup (mean age 37 years, 50% men). The NHANES 99th percentile URL for hs-troponin T (19 ng/L) matched the manufacturer-reported URL (19 ng/L). NHANES URLs were 13 ng/L (95% CI: 10-15 ng/L) for Abbott hs-troponin I (manufacturer: 28 ng/L), 5 ng/L (95% CI: 4-7 ng/L) for Ortho hs-troponin I (manufacturer: 11 ng/L), and 37 ng/L (95% CI: 27-66 ng/L) for Siemens hs-troponin I (manufacturer: 46.5 ng/L). There were significant differences in URLs by sex, but none by race/ethnicity. Furthermore, the 99th percentile URLs for all 4 hs-troponin assays were statistically significantly lower in healthy adults aged <40 years compared with healthy adults ≥60 years (all P < 0.001 by rank sum testing). CONCLUSIONS:We found URLs for hs-troponin I assays that were substantially lower than currently listed 99th percentile URLs. There were significant differences in hs-troponin T and I URLs by sex and by age group in healthy U.S. adults but none by race/ethnicity.

BACKGROUND:Sub-cohort sampling designs such as a case-cohort study play a key role in studying biomarker-disease associations due to their cost effectiveness. Time-to-event outcome is often the focus in cohort studies, and the research goal is to assess the association between the event risk and risk factors. In this paper, we propose a novel goodness-of-fit two-phase sampling design for time-to-event outcomes when some covariates (e.g., biomarkers) can only be measured on a subgroup of study subjects. METHODS:Assuming that an external model, which can be the well-established risk models such as the Gail model for breast cancer, Gleason score for prostate cancer, and Framingham risk models for heart diseases, or built from preliminary data, is available to relate the outcome and complete covariates, we propose to oversample subjects with worse goodness-of-fit (GOF) based on an external survival model and time-to-event. With the cases and controls sampled using the GOF two-phase design, the inverse sampling probability weighting method is used to estimate the log hazard ratio of both incomplete and complete covariates. We conducted extensive simulations to evaluate the efficiency gain of our proposed GOF two-phase sampling designs over case-cohort study designs. RESULTS:Through extensive simulations based on a dataset from the New York University Women's Health Study, we showed that the proposed GOF two-phase sampling designs were unbiased and generally had higher efficiency compared to the standard case-cohort study designs. CONCLUSION:In cohort studies with rare outcomes, an important design question is how to select informative subjects to reduce sampling costs while maintaining statistical efficiency. Our proposed goodness-of-fit two-phase design provides efficient alternatives to standard case-cohort designs for assessing the association between time-to-event outcome and risk factors. This method is conveniently implemented in standard software.

Youth-onset type 2 diabetes (T2D) is a growing public health concern. Its genetic basis and relationship to other forms of diabetes are largely unknown. To gain insight into the genetic architecture and biology of youth-onset T2D, we analyzed exome sequences of 3,005 youth-onset T2D cases and 9,777 ancestry matched adult controls. We identified (a) monogenic diabetes variants in 2.1% of individuals; (b) two exome-wide significant (P < 4.3×10^-7) common coding variant associations (in WFS1 and SLC30A8); (c) three exome-wide significant (P < 2.5×10^-6) rare variant gene-level associations (HNF1A, MC4R, ATX2NL); and (d) rare variant association enrichments within 25 gene sets broadly related to obesity, monogenic diabetes, and β-cell function. Many association signals were shared between youth-onset and adult-onset T2D but had larger effects for youth-onset T2D risk (1.18-fold increase for common variants and 2.86-fold increase for rare variants). Both common and rare variant associations contributed more to youth-onset T2D liability variance than they did to adult-onset T2D, but the relative increase was larger for rare variant associations (5.0-fold) than for common variant associations (3.4-fold). Youth-onset T2D cases showed phenotypic differences depending on whether their genetic risk was driven by common variants (primarily related to insulin resistance) or rare variants (primarily related to β-cell dysfunction). These data paint a picture of youth-onset T2D as a disease genetically similar to both monogenic diabetes and adult-onset T2D, in which genetic heterogeneity might be used to sub-classify patients for different treatment strategies.

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown and to date no genetic mechanisms for AKI have been established. Clonal hematopoiesis of indeterminate potential (CHIP) is a recently recognized biological mechanism conferring risk of several chronic aging diseases including cardiovascular disease, pulmonary disease and liver disease. In CHIP, blood stem cells acquire mutations in myeloid cancer driver genes such as DNMT3A, TET2, ASXL1 and JAK2 and the myeloid progeny of these mutated cells contribute to end-organ damage through inflammatory dysregulation. We sought to establish whether CHIP causes acute kidney injury (AKI). To address this question, we first evaluated associations with incident AKI events in three population-based epidemiology cohorts (N = 442,153). We found that CHIP was associated with a greater risk of AKI (adjusted HR 1.26, 95% CI: 1.19-1.34, p<0.0001), which was more pronounced in patients with AKI requiring dialysis (adjusted HR 1.65, 95% CI: 1.24-2.20, p=0.001). The risk was particularly high in the subset of individuals where CHIP was driven by mutations in genes other than DNMT3A (HR: 1.49, 95% CI: 1.37-1.61, p<0.0001). We then examined the association between CHIP and recovery from AKI in the ASSESS-AKI cohort and identified that non-DNMT3A CHIP was more common among those with a non-resolving pattern of injury (HR 2.3, 95% CI: 1.14-4.64, p = 0.03). To gain mechanistic insight, we evaluated the role of Tet2-CHIP to AKI in ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO) mouse models. In both models, we observed more severe AKI and greater post-AKI kidney fibrosis in Tet2-CHIP mice. Kidney macrophage infiltration was markedly increased in Tet2-CHIP mice and Tet2-CHIP mutant renal macrophages displayed greater proinflammatory responses. In summary, this work establishes CHIP as a genetic mechanism conferring risk of AKI and impaired kidney function recovery following AKI via an aberrant inflammatory response in CHIP derived renal macrophages.