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Risk-Adjusted Time-to-Event Modeling: Integrating Absolute Risk and Biomarker-Driven Splitting
Get PDFAlzheimer’s Disease (AD) progression exhibits substantial heterogeneity, complicating
risk stratification using biomarkers and risk factors during the critical preclinical phase.
Standard models often struggle with interactions and confounding. We developed and
evaluated the Personalized Risk-Adjusted Survival Tree (PRAST), using risk-adjusted
recursive partitioning to identify interpretable, biomarker-defined prognostic subgroups
in longitudinal AD data.
PRAST adjusts for risk factors via node-specific Cox models, generating a transformed
outcome Y ∗ to isolate biomarker effects. Tree splits minimize Y ∗ ariance based on
biomarkers, with complexity controlled by pre-stopping rules.
Simulations versus benchmarks (CART, CTree, Cox) confirmed PRAST’s effectiveness.
It excelled at subgroup recovery (high Adjusted Rand Index) and showed good noise
resistance versus CART, validating its risk-adjustment mechanism for capturing
biomarker-driven heterogeneity. Standard metrics like C-index require suitable risk
scores derived from the PRAST structure.
Application to the PAC dataset (n = 1136) yielded four distinct prognostic
subgroups via interpretable splits (hippocampus, SPARE-AD, memory) after risk
adjustment. These biomarker-defined subgroups showed significantly different cognitive
decline trajectories (p < 0.0001), demonstrating PRAST’s utility for revealing
meaningful heterogeneity. This stratification offers insights into diverse AD pathways
and suggests potential for clinical applications like targeted monitoring or trial
enrichment in early AD
EVALUATING IMPLEMENTATION OF ANTENATAL MULTIPLE MICRONUTRIENT VERSUS IRON-FOLIC ACID SUPPLEMENTATION WITHIN THE UNRWA HEALTH CARE SYSTEM IN JORDAN
Get PDFMaternal micronutrient deficiencies are prevalent among pregnant Palestine refugee women across the Middle East. Trials demonstrate that antenatal multiple micronutrient supplementation (MMS) reduces adverse birth outcomes versus iron-folic acid (IFA). WHO recommends antenatal MMS accompanied by rigorous research. Accordingly, the United Nations Relief and Works Agency for Palestine Refugees in the Near East (UNRWA) decided to replace antenatal folic acid (FA) and IFA use with MMS, starting in Jordan, guided by implementation research.
Following an enabling period, including a 6-month pilot, we conducted a systems trial comparing antenatal MMS to FA/IFA delivery. Thirteen clinics (two pilot plus 11 randomized) provided 15-nutrient, UNIMMAP-formulated MMS in 180-count bottles at registration. Twelve clinics continued providing daily FA tablets in the 1st trimester and IFA 2-7-times weekly throughout the 2nd-3rd trimesters, in 10-count blister packs. Outcomes included coverage, adherence, side effects, acceptability expressed at anonymous exit interviews, mid-pregnancy hemoglobin (Hb) and anemia, and costs to recipients and the Agency. Deidentified data were abstracted from UNRWA’s eHealth system. The study was approved by the UNRWA Research Review Board and Johns Hopkins IRB.
Over 10 months, 9754 and 5574 women registered in MMS and FA/IFA clinics. Initial coverage was 94.4% for MMS and 70.4/80.6% FA/IFA. Throughout follow-up visits, adherence ≥90% was 81.7-85.9% and 74.5-82.5%, while adherence <70% was 5.1-6.4% and 10.1-17% among MMS and IFA recipients, respectively (all p<0.04). MMS recipients reported fewer side effects and less constipation, although side effects comparably reduced adherence in both groups. More MMS recipients reported improved appetite, feeling healthier and having more energy (all p<0.001). Running out of tablets was less common with MMS than IFA recipients (3.2% versus 27.2%), as was purchasing vitamins (3.3-5.7% versus 13.5-29.6%).
Among 4212 and 2349 registrants with Hb>10 g/dL, the adjusted relative risk (aRR, 95% CI) of mid-pregnancy moderate-to-severe anemia (Hb<10 g/dL) among MMS versus FA/IFA recipients was 0.66 (0.50-0.86). Among registrants with Hb<10 g/dL, adding MMS to IFA anemia treatment improved mid-pregnancy recovery (Hb≥11 g/dL), per aRR=1.29 (1.04-1.59), and required fewer follow-up Hb tests.
These findings showed MMS outperformed FA/IFA, prompting UNRWA to scale up MMS in Agency clinics across the Middle East
SUSTAINING PREPAREDNESS: STUDY OF THE FUTURE PANDEMIC CAPACITIES BUILT AMONG FRONTLINE HEALTH WORKERS IN HUMANITARIAN CONTEXTS DURING COVID-19
Get PDFProblem: It is widely agreed future pandemics are imminent, yet, debated whether COVID-19 left the world more prepared. Health workers and systems were strained worldwide. In humanitarian contexts, this strain was exacerbated by concurrent emergencies and weak, fragmented health systems. Frontline health workers received infection prevention and control-related (IPC) training from 2020-2022 by humanitarian organizations. The goal of this study is to assess the pandemic capacities built during COVID-19 amongst primary care level health workers in humanitarian contexts, including factors affecting their retention over time.
This thesis includes a mixed methods retrospective case study approach and three aims: Aim 1 – to understand the relevance of COVID-19 humanitarian health worker training curriculum to global health security (GHS) competencies. Method/data: Systematic content analysis of 165 COVID-19 training documents from 13 humanitarian health programs and purposive interviews (n=35). Aim 2 – to measure the sustainment of pandemic capacities (perceived knowledge, skills, and confidence) and implementation outcomes by health workers in South Sudan, Honduras, and Syria. Method/data: Descriptive and non-parametric analysis for recalled capacities before training, after, and current (n=129). Aim 3 – to assess the factors contributing to sustained pandemic capacities among these health workers. Method/data: Coincidence analysis (CNA) from above health worker survey.
Results: For Aim 1, training programs addressed an average of 69% of GHS framework indicators, with strong emphasis on local public health risks, risk communication, and facility IPC measures. Gaps in the framework identified: Proper PPE use, disinfection, health worker mental health, contact tracing, and safe burials. Aim 2 showed that knowledge, skills, and confidence were significantly improved (p<0.001) post-training, with indication of sustainment years after training. Refreshers and institutional support were low. Aim 3 used CNA to identify predictors affecting sustained confidence, including comprehensive training, health worker education, support structures, and continuity of essential services.
Conclusions: Key findings are relevant to other emerging disease risks from avian influenza to mpox or Ebola. Investments in ongoing health emergency training for frontline health workers are needed. The International Health Regulation’s implementation priorities must extend to subnational level. For a prepared world, GHS strategies must not overlook the most fragile contexts
Investigation of Tissue Remodeling in Chronic Obstructive Pulmonary Disease
Get PDFChronic obstructive pulmonary disease (COPD) is a debilitating chronic disease of the lungs that impacts millions of people worldwide. Cigarette smoking is one of the leading risk factors for developing COPD, but chronic exposure to other ambient air pollutants is also associated with disease development. The lungs of patients with COPD undergo considerable tissue remodeling as the disease progresses leading to airway obstruction and difficulty breathing. Although COPD is a pressing and well described health risk, there are currently no disease modifying treatments that can reverse COPD associated tissue remodeling to restore optimal lung function. Innovative research is necessary to aid in the understanding of the processes driving tissue remodeling in COPD. In this thesis we explore two distinct angles of lung biology and disease to help enhance our understanding of COPD.
First, we used precision-cut lung slices (PCLS) exposed to cigarette smoke ex vivo to effectively model COPD. Our findings revealed that repeated, physiologically relevant doses of cigarette smoke mimic the tissue remodeling seen in COPD, offering a scalable and more time-efficient alternative to traditional in vivo models while maintaining the complex 3D architecture and cell-cell relationships absent in in vitro models. Second, we investigate the role of planar cell polarity in the process of epithelial wound closure using primary bronchial epithelial cells derived from COPD patients. Understanding the mechanisms of planar cell polarity can provide valuable insights into epithelial integrity and repair in the context of lung disease. Using primary bronchial epithelial cells from COPD patients, we identified mislocalization of the core planar cell polarity protein, Vangl1, and a significant reduction in the protein ARFRP1, which is known to target Vangl1 to the cell membrane. We propose that loss of ARFRP1 is a key driver in COPD associated epithelial disruption by limiting epithelial cell’s ability to sense their surroundings and migrate towards a wound
Targeting the Serine Synthesis Pathway to Enhance Venetoclax Efficacy in Acute Myeloid Leukemia
Get PDFAcute myeloid leukemia (AML) presents significant challenges, with high relapse rates and limited survival despite recent therapeutic advancements. The combination of the BCL-2 inhibitor venetoclax (VEN) with azacytidine has recently been approved for elderly AML patients. However, a substantial portion of patients do not respond to this treatment. This study aims to enhance the efficacy of VEN by targeting AML cell metabolism. We found that VEN treatment downregulates key players of the serine synthesis pathway, potentially reducing the flux and limiting total serine availability in the cell, rendering AML cells acutely sensitive to exogenous serine. Our findings demonstrate that depleting exogenous serine potentiates VEN’s anti-leukemic effects, depending on the cell’s reliance on serine. Serine depletion primes AML cells for VEN-induced intrinsic apoptosis and exacerbates VEN-induced mitochondrial dysfunction. This study suggests potential for developing novel diet-based strategies to optimize VEN-based treatments, potentially expanding the number of responsive patients
FUNDING THE GRAY AREA: AN EXPLORATION OF ESSENTIAL SHARED RESEARCH COSTS OUTSIDE OF DIRECT AND INDIRECT COSTS, THEIR RELEVANCE, AND OPTIONS FOR FUNDING THEM
Get PDFFunding the full cost of biomedical research is a challenge for many institutions and researchers throughout the United States. Most grant funding mechanisms do not cover the full cost of a research project due to maximum allowed direct costs and limits on indirect cost recovery. Additionally, there are costs shared across multiple researchers in a divisional disease-specific center that fall into a gray area between direct and indirect costs. The nature of these costs, while neither directly attributable to a specific project nor considered facilities and administrative for indirect cost recovery, causes challenges in capturing the costs in proposal budgets. Allocation of indirect cost recovery varies greatly across institutions, leading some researchers to find ways on their own to cover these gray area costs.
This capstone project analyzes the definitions of direct and indirect costs, examples of shared costs, and several different options for funding these costs. By examining the most authoritative sources for definitions and guidance, opportunities were sought for including shared costs in either direct or indirect costs. A case study and reviewing journal articles provided insight into examples of and the nature of shared costs, their relevance and application in biomedical research. Options for funding shared costs were identified by examining federal funding agencies, foundations, philanthropic and other funding mechanisms such as commercial partnerships and internal shared funding models. Roles within research administration were studied to determine which might assist research faculty in developing strategies to support shared costs.
Biomedical research centers can better support the full cost of doing research by engaging in long-term strategic planning to build sustainable funding across multiple funding sources. A diversified portfolio of funding is essential, without reliance on one particular sector, to ensure maintenance and
growth of research
Control Pathway Deficits and Time Delay Compensation in Cerebellar Ataxia
No full textDamage to the cerebellum can cause ataxia, a condition associated with impaired movement coordination. While there is currently no cure for ataxia, prior studies showed that visual feedback control can be leveraged to compensate for control deficits, mitigating dysmetria in single-joint reaching tasks. To further develop effective compensation mechanisms, it is critical to understand which control pathways remain intact and how control pathways are impaired in people with ataxia.
Typically, coordinated movement relies on a combination of anticipatory mechanisms (specifically, feedforward control) and corrective mechanisms (feedback control). Here, we used a tracking task in a custom ship-to-home virtual reality system to examine how these anticipatory and corrective mechanisms become impaired with ataxia severity. We found that both the feedforward and feedback control structure remain largely preserved with ataxia, but with significantly different increases in time delay, suggesting that the internal model structure may not be substantially altered in ataxia. Instead, time delay deficits, and their associated mismatch between pathways, may be a primary contributor to movement incoordination.
Building on this understanding, we explored visual interventions that leverage largely intact control pathways to compensate for time delay deficits. We sought to leverage the feedforward control pathway to compensate for time delay deficits through preview, in the form of time lead information about a moving target. We found that preview could potentially be leveraged to enhance the tracking performance of those with ataxia. We also explored the potential of leveraging visual feedback control to improve movement performance in people with ataxia. We manipulated the visual feedback displayed to participants, by adding an acceleration-dependent gain. We found that altering visual feedback can systematically manipulate dysmetria in unconstrained 3D reaches, indicating that altering self-movement visual feedback can enhance movement control performance for individuals with ataxia.
Finally, in addition to these experimental findings, we investigated theoretical approaches to address sensorimotor delays, employing state estimation with Padé approximation and showing its relationship to a Smith predictor, an architecture often used to describe the role of the cerebellum in feedback control. Our analysis of this control structure offers theoretical insights into understanding of cerebellar mechanisms in managing sensorimotor delays
DIFFERENCES IN HEMOGLOBIN A1C 12 MONTHS AFTER DIRECT ACTING ANTIVIRALS TO TREAT HEPATITIS C VIRUS INFECTION IN ADULTS WITH HIV
Get PDFBackground: Previous studies suggested improved glycemic outcomes in hepatitis C virus
(HCV)-infected adults after direct-acting antivirals (DAAs) treatment. However, the impact of DAAs on glycated hemoglobin (HbA1c) levels in people with HIV/HCV coinfection is relatively unknown. This study aimed to determine the 12-month difference in HbA1c level between HIV/HCV coinfected adults on antiretroviral therapy (ART) who received a DAA prescription and those who did not receive a prescription in a large North American cohort of people living with
HIV.
Methods: The study was nested in the NA-ACCORD, a collaboration of observational HIV clinical cohort studies. Adults (>18 years old) with HIV/HCV coinfection who were on ART and prescribed DAAs between January 1, 2014, and December 31, 2022 ("case") were individually matched by year of observation, 10-year age group, sex, and race and ethnicity with one HIV/HCV coinfected participant who was under observation and not prescribed DAAs within one year of the DAA prescription date for the case (baseline). Multivariable linear regression models were used to evaluate the difference in HbA1c levels 12 months post-DAA prescription after
adjusting for baseline demographic and clinical characteristics, including baseline HbA1c.
Results: The 1,149 individuals with HIV/HCV coinfection and DAA prescription were matched to
1,100 similar individuals without DAA prescription (N= 2,249). The median HbA1c values in individuals with DAA prescription and those without DAA prescription at 12 months were 5.7% (interquartile range [IQR]: 5.3%-6.3%) and 5.6% (IQR: 5.2%-6.2%), respectively. There was no difference in the average HbA1c value at 12 months by DAA prescription (adjusted mean difference = 0.01%, 95% confidence interval: -0.09%, 0.08%) after adjusting for age, baseline
CD4 counts, baseline HbA1c, race and ethnicity, HIV risk groups, history of statin use, diabetes, chronic kidney disease > stage 3, and clinical cohorts; further controlling for sex did not change the results.
Conclusions: The study did not find a significant difference in HbA1c 12 months after DAA prescription in HIV/HCV coinfected adults on ART with DAA prescription compared to similar adults without DAA prescription. Studies investigating DAA's long-term (>12 months) effects on diabetes and cardiovascular risk factors are needed and may yield different findings
Association Between Ambient Air Pollution and Heart Failure Biomarkers
No full textBackground and Aims:
Heart failure is a critical and escalating public health problem. With the aging population, heart failure brings a heavy burden to society. Meanwhile, the World Health Organization has determined air pollution to be the most critical environmental health threat globally. There are fewer studies examining the relationship between air pollution and biomarkers of heart failure. This study investigated the associations between air pollution exposure and biomarkers change in treated heart failure patients with chronic stable heart failure and explored preventive therapy and vulnerable populations.
Methods:
We studied 173 heart failure patients from the clinical trial of Study to Evaluate the Effects of Trientine in Patients with Heart Failure and Reduced Ejection Fraction (TRACER-HF). The clinically relevant circulating biomarkers indicative of biological change, including N-terminal prohormone of brain natriuretic peptide (NT-proBNP), soluble growth stimulation expressed gene 2 (sST2), and Troponin T, were measured at multiple follow-up visits. Ambient air pollution data was matched to hospitals' locations, and linear mixed models were used to assess the associations between air pollutants and biomarkers change.
Results:
The study shows increased ozone (O3) levels were significantly associated with higher Troponin T concentrations across multiple lag periods: 10 µg/m³ rise in O3 was associated with a 3.25% increase in Troponin T (95% CI: 1.73, 4.80) over a lag of 0-7 days. In contrast, levels of sST2 and NT-proBNP slightly decreased, respectively. Sodium-glucose Cotransporter-2 inhibitors significantly modified the adverse effect of O3 across all examined periods. Conversely, particulate matter less than 2.5 μm in aerodynamic diameter (PM2.5) exposure demonstrated a significant inverse relationship with Troponin T during short-term periods (lag0 to lag0-3), with reductions ranging from -1.26% to -1.62% per 10 μg/m³ increase. PM2.5 did not cause notable changes in sST2 or NT-proBNP.
Conclusion:
Ambient O3 exposure was associated with increased Troponin T levels, indicating the adverse impact of O3 on heart failure patients, even under optimal guideline-directed medical therapy. Moreover, the study identified the potential treatment with sodium-glucose Cotransporter-2 inhibitors to reduce the adverse effects of O3 exposure. In contrast, PM2.5 exposure showed an unexpected effect on Troponin T, which may be influenced by patient behaviors or treatments. Further studies are required to verify these results and explore the mechanisms behind them
Playing Through the Future: On the Ethics of Advance Research Directives in Collision Sports Athletes
Get PDFChronic traumatic encephalopathy (CTE), a neurodegenerative disease caused by repetitive head injuries, poses significant concern for collision sports athletes. Since CTE and traumatic brain injuries (TBIs) can cause diminished decision-making capacity, researchers studying these conditions cannot always fulfill contemporary informed consent ethical and legal norms. Patient recruitment is challenging, stunting the development of supportive research for CTE and TBI treatment. Advance research directives (ARDs)—documents allowing pre-emptive indication of one’s research preferences in case of diminished decision-making capacity—can foster successful, ethical research. This paper primarily focuses on the meaningful use of ARDs in the U.S., offering a standard practice model to maximize implementation value by targeting collision sports athletes. Subsequently, this paper justifies this ARD model through public health ethics justificatory conditions. Future work could involve comparison of this model with other alternatives to the current surrogacy system