Browsing by Author "Liu, Ziyue"
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Item A Multi-Center, Single Arm, Phase Ib study of Pembrolizumab (MK-3475) in Combination with Chemotherapy for Patients with Advanced Colorectal Cancer: HCRN GI14-186(Springer, 2021) Herting, Cameron J.; Farren, Matthew R.; Tong, Yan; Liu, Ziyue; O’Neil, Bert; Bekaii-Saab, Tanios; Noonan, Anne; McQuinn, Christopher; Mace, Thomas A.; Shaib, Walid; Wu, Christina; El-Rayes, Bassel F.; Shahda, Safi; Lesinski, Gregory B.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthModified FOLFOX6 is an established therapy for patients with metastatic colorectal cancer (mCRC). We conducted a single-arm phase Ib study to address the hypothesis that addition of pembrolizumab to this regimen could safely and effectively improve patient outcomes (NCT02375672). The relationship between immune biomarkers and clinical response were assessed in an exploratory manner. Patients with mCRC received concurrent pembrolizumab and modified FOLFOX6. The study included safety run-in for the first six patients. The primary objective was median progression-free survival (mPFS), with secondary objectives including median overall survival, safety, and exploratory assessment of immune changes. To assess immunological impact, peripheral blood was collected at baseline and during treatment. The levels of soluble factors were measured via bioplex, while a panel of checkpoint molecules and phenotypically defined cell populations were assessed with flow cytometry and correlated with RECIST and mPFS. Due to incidences of grade 3 and grade 4 neutropenia in the safety lead-in, the dose of mFOLFOX6 was reduced in the expansion cohort. Median PFS was 8.8 months and median OS was not reached at data cutoff. Best responses of stable disease, partial response, and complete response were observed in 43.3%, 50.0%, and 6.7% of patients, respectively. Several soluble and cellular immune biomarkers were associated with improved RECIST and mPFS. Immunosuppressive myeloid and T cell subsets that were analyzed were not associated with response. Primary endpoint was not superior to historic control. Biomarkers that were associated with improved response may be informative for future regimens combining chemotherapy with immune checkpoint inhibitors.Item A sequential Monte Carlo Gibbs coupled with stochastically approximated expectation-maximization algorithm for functional data(International Press, 2022-01-11) Liu, Ziyue; Biostatistics and Health Data Science, School of MedicineWe develop an algorithm to overcome the curse of dimensionality in sequential Monte Carlo (SMC) for functional data. In the inner iterations of the algorithm for given parameter values, the conditional SMC is extended to obtain draws of the underlying state vectors. These draws in turn are used in the outer iterations to update the parameter values in the framework of stochastically approximated expectation-maximization to obtain maximum likelihood estimates of the parameters. Standard errors of the parameters are calculated using a stochastic approximation of Louis formula. Three numeric examples are used for illustration. They show that although the computational burden remains high, the algorithm produces reasonable results without exponentially increasing the particle numbers.Item Am I big boned? Bone length scaled reference data for HRpQCT measures of the radial and tibial diaphysis in White adults(Elsevier, 2024-01-06) Warden, Stuart J.; Fuchs, Robyn K.; Liu, Ziyue; Toloday, Katelynn R.; Surowiec, Rachel; Moe, Sharon M.; Physical Therapy, School of Health and Human SciencesCross-sectional size of a long bone shaft influences its mechanical properties. We recently used high-resolution peripheral quantitative computed tomography (HRpQCT) to create reference data for size measures of the radial and tibial diaphyses. However, data did not take into account the impact of bone length. Human bone exhibits relatively isometric allometry whereby cross-sectional area increases proportionally with bone length. The consequence is that taller than average individuals will generally have larger z-scores for bone size outcomes when length is not considered. The goal of the current work was to develop a means of determining whether an individual's cross-sectional bone size is suitable for their bone length. HRpQCT scans performed at 30 % of bone length proximal from the distal end of the radius and tibia were acquired from 1034 White females (age = 18.0 to 85.3 y) and 392 White males (age = 18.4 to 83.6 y). Positive relationships were confirmed between bone length and cross-sectional areas and estimated mechanical properties. Scaling factors were calculated and used to scale HRpQCT outcomes to bone length. Centile curves were generated for both raw and bone length scaled HRpQCT data using the LMS approach. Excel-based calculators are provided to facilitate calculation of z-scores for both raw and bone length scaled HRpQCT outcomes. The raw z-scores indicate the magnitude that an individual's HRpQCT outcomes differ relative to expected sex- and age-specific values, with the scaled z-scores also considering bone length. The latter enables it to be determined whether an individual or population of interest has normal sized bones for their length, which may have implications for injury risk. In addition to providing a means of expressing HRpQCT bone size outcomes relative to bone length, the current study also provides centile curves for outcomes previously without reference data, including tissue mineral density and moments of inertia.Item Association between Urinary Phytoestrogens and C-reactive Protein in the Continuous National Health and Nutrition Examination Survey(Taylor & Francis, 2017) Reger, Michael K.; Zollinger, Terrell W.; Liu, Ziyue; Jones, Josette; Zhang, Jianjun; Epidemiology, School of Public HealthObjective: A reduced risk of some cancers and cardiovascular disease associated with phytoestrogen intake may be mediated through its effect on serum C-reactive protein (CRP; an inflammation biomarker). Therefore, this study examined the associations between urinary phytoestrogens and serum CRP. Methods: Urinary phytoestrogen and serum CRP data obtained from 6009 participants aged ≥ 40 years in the continuous National Health and Nutrition Examination Survey during 1999–2010 were analyzed. Results: After adjustment for confounders, urinary concentrations of total and all individual phytoestrogens were inversely associated with serum concentrations of CRP (all p < 0.004). The largest reductions in serum CRP (mg/L) per interquartile range increase in urinary phytoestrogens (ng/mL) were observed for total phytoestrogens (β = −0.18; 95% confidence interval [CI], −0.22, −0.15), total lignan (β = −0.15; 95% CI, −0.18, −0.12), and enterolactone (β = −0.15; 95% CI, −0.19, −0.12). A decreased risk of having high CRP concentrations (≥3.0 mg/L) for quartile 4 vs quartile 1 was also found for total phytoestrogens (OR = 0.63; 95% CI, 0.53, 0.73), total lignan (OR = 0.64; 95% CI, 0.54, 0.75), and enterolactone (OR = 0.59; 95% CI, 0.51, 0.69). Conclusion: Urinary total and individual phytoestrogens were significantly inversely associated with serum CRP in a nationally representative sample of the U.S. population.Item Association of Tryptophan and NAD+ Metabolites with Brain and Skeletal Muscle Function in Critical Care Patients and Survivors(2024-07) Yates, Brandon Alston; Coggan, Andrew; Khan, Babar; Kroenke, Kurt; Liu, Ziyue; Newman, JohnBackground: Patients who survive Intensive Care Unit (ICU) acquired delirium will likely experience new or worsened physical, mental, and/or cognitive impairments (termed Post-Intensive Care Syndrome (PICS)). Although advances in critical care treatments have reduced mortality rates among older adult ICU survivors, roughly 67% suffer PICS. The most vulnerable to long-term physical and cognitive impairments are older adults or those who exhibit accelerated aging because of pre-existing physical frailty or cognitive frailty. Yet, identification of at-risk patients during admittance is likely difficult because of the 1) homogeneity in the clinical presentation of patients with pre-existing age-related physical frailty and critical illness compared to those suffering from only critical illness and 2) many patients arrive severely debilitated making administration of physical function or other volitional assessments difficult. Therefore, it is essential that new biomarkers to guide early diagnosis, prognosis, and disease monitoring are identified. To this point, tryptophan derivatives, particularly kynurenines and nicotinamide family (e.g., NAD+), have been shown to mediate the relationship between chronic inflammation and physical impairment or signal accelerated aging, respectively. However, it remains unknown if similar associations exist in ICU patients and the prognostic utility of elevated neurotoxic tryptophan metabolites relative to neuroprotective tryptophan metabolites to predict adverse health outcomes while in the ICU. Methods: A secondary analysis of pooled data from three randomized control trials was used to investigate the following aims. To address Aims 1 and 2, blood samples from patients with ICU acquired delirium were analyzed for kynurenine and salvage pathway metabolites. To address Aim 3, blood samples from patients who survived an ICU stay, experienced ICU delirium, and completed both objective and subjective physical function assessments within in month of ICU discharge and before the COVID-19 pandemic. Results: Delirium duration was significantly (p< 0.05) associated with elevated circulating kynurenine and lower NAD+. Delirium severity was significantly associated with elevated circulating lower NAD+ but not kynurenine. Post-ICU physical function performance was significantly associated with elevated circulating kynurenine but not NAD+. Conclusion: Elevated concentration of frailty biomarkers are associated with delirium severity and duration in the ICU and post-ICU physical function.Item Bayesian design and analysis of cluster randomized trials(2017-08-07) Xiao, Shan; Tu, Wanzhu; Liu, ZiyueCluster randomization is frequently used in clinical trials for convenience of inter ventional implementation and for reducing the risk of contamination. The opera tional convenience of cluster randomized trials, however, is gained at the expense of reduced analytical power. Compared to individually randomized studies, cluster randomized trials often have a much-reduced power. In this dissertation, I consider ways of enhancing analytical power with historical trial data. Specifically, I introduce a hierarchical Bayesian model that is designed to incorporate available information from previous trials of the same or similar interventions. Operationally, the amount of information gained from the previous trials is determined by a Kullback-Leibler divergence measure that quantifies the similarity, or lack thereof, between the histor ical and current trial data. More weight is given to the historical data if they more closely resemble the current trial data. Along this line, I examine the Type I error rates and analytical power associated with the proposed method, in comparison with the existing methods without utilizing the ancillary historical information. Similarly, to design a cluster randomized trial, one could estimate the power by simulating trial data and comparing them with the historical data from the published studies. Data analytical and power simulation methods are developed for more general situations of cluster randomized trials, with multiple arms and multiple types of data following the exponential family of distributions. An R package is developed for practical use of the methods in data analysis and trial design.Item Body weight influences musculoskeletal adaptation to long-term voluntary wheel running during aging in female mice(Impact Journals, 2022) Kitase, Yukiko; Vallejo, Julian A.; Dallas, Sarah L.; Xie, Yixia; Dallas, Mark; Tiede-Lewis, LeAnn; Moore, David; Meljanac, Anthony; Kumar, Corrine; Zhao, Carrie; Rosser, Jennifer; Brotto, Marco; Johnson, Mark L.; Liu, Ziyue; Wacker, Michael J.; Bonewald, Lynda; Anatomy, Cell Biology and Physiology, School of MedicineFrailty is the hallmark of aging that can be delayed with exercise. The present studies were initiated based on the hypothesis that long-term voluntary wheel running (VWR) in female mice from 12 to 18 or 22 months of age would have beneficial effects on the musculoskeletal system. Mice were separated into high (HBW) and low (LBW) body weight based on final body weights upon termination of experiments. Bone marrow fat was significantly higher in HBW than LBW under sedentary conditions, but not with VWR. HBW was more protective for soleus size and function than LBW under sedentary conditions, however VWR increased soleus size and function regardless of body weight. VWR plus HBW was more protective against muscle loss with aging. Similar effects of VWR plus HBW were observed with the extensor digitorum longus, EDL, however, LBW with VWR was beneficial in improving EDL fatigue resistance in 18 mo mice and was more beneficial with regards to muscle production of bone protective factors. VWR plus HBW maintained bone in aged animals. In summary, HBW had a more beneficial effect on muscle and bone with aging especially in combination with exercise. These effects were independent of bone marrow fat, suggesting that intrinsic musculoskeletal adaptions were responsible for these beneficial effects.Item Brain network hypersensitivity underlies pain crises in sickle cell disease(Springer Nature, 2024-03-27) Joo, Pangyu; Kim, Minkyung; Kish, Brianna; Nair, Vidhya Vijayakrishnan; Tong, Yunjie; Liu, Ziyue; O’Brien, Andrew R. W.; Harte, Steven E.; Harris, Richard E.; Lee, UnCheol; Wang, Ying; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthSickle cell disease (SCD) is a genetic disorder causing painful and unpredictable Vaso-occlusive crises (VOCs) through blood vessel blockages. In this study, we propose explosive synchronization (ES) as a novel approach to comprehend the hypersensitivity and occurrence of VOCs in the SCD brain network. We hypothesized that the accumulated disruptions in the brain network induced by SCD might lead to strengthened ES and hypersensitivity. We explored ES's relationship with patient reported outcome measures (PROMs) as well as VOCs by analyzing EEG data from 25 SCD patients and 18 matched controls. SCD patients exhibited lower alpha frequency than controls. SCD patients showed correlation between frequency disassortativity (FDA), an ES condition, and three important PROMs. Furthermore, stronger FDA was observed in SCD patients with a higher frequency of VOCs and EEG recording near VOC. We also conducted computational modeling on SCD brain network to study FDA's role in network sensitivity. Our model demonstrated that a stronger FDA could be linked to increased sensitivity and frequency of VOCs. This study establishes connections between SCD pain and the universal network mechanism, ES, offering a strong theoretical foundation. This understanding will aid predicting VOCs and refining pain management for SCD patients.Item Brief report: Endothelial colony-forming cells and inflammatory monocytes in HIV(Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2015-04-15) Hays, Travis R.; Mund, Julie A.; Liu, Ziyue; Case, Jamie; Ingram, David A.; Gupta, Samir K.; Department of Medicine, IU School of MedicineThe relationships between HIV infection, monocyte activation, and endothelial colony-forming cells (ECFCs) are unknown. We compared ECFC, intermediate monocytes (CD14 CD16), and nonclassical monocytes (CD14 CD16) levels in HIV-infected participants virologically suppressed on antiretroviral therapy, HIV-infected treatment-naive participants, and HIV-uninfected healthy controls. ECFC levels were significantly higher in the HIV-infected virologically suppressed group compared with the uninfected controls. CD14 CD16 percentages (but not CD14 CD16 cells) were significantly higher in both HIV-infected groups vs. uninfected controls. In the HIV-infected groups, ECFCs and CD14 CD16 intermediate monocytes were significantly and inversely correlated. Lower availability of ECFCs may partly explain the relationship between greater intermediate monocytes and atherosclerosis in HIV.Item Casual analysis using two-part models : a general framework for specification, estimation and inference(2018-06-22) Hao, Zhuang; Terza, Joseph V.; Devaraj, Srikant; Liu, Ziyue; Mak, Henry; Ottoni-Wilhelm, MarkThe two-part model (2PM) is the most widely applied modeling and estimation framework in empirical health economics. By design, the two-part model allows the process governing observation at zero to systematically differ from that which determines non-zero observations. The former is commonly referred to as the extensive margin (EM) and the latter is called the intensive margin (IM). The analytic focus of my dissertation is on the development of a general framework for specifying, estimating and drawing inference regarding causally interpretable (CI) effect parameters in the 2PM context. Our proposed fully parametric 2PM (FP2PM) framework comprises very flexible versions of the EM and IM for both continuous and count-valued outcome models and encompasses all implementations of the 2PM found in the literature. Because our modeling approach is potential outcomes (PO) based, it provides a context for clear definition of targeted counterfactual CI parameters of interest. This PO basis also provides a context for identifying the conditions under which such parameters can be consistently estimated using the observable data (via the appropriately specified data generating process). These conditions also ensure that the estimation results are CI. There is substantial literature on statistical testing for model selection in the 2PM context, yet there has been virtually no attention paid to testing the “one-part” null hypothesis. Within our general modeling and estimation framework, we devise a relatively simple test of that null for both continuous and count-valued outcomes. We illustrate our proposed model, method and testing protocol in the context of estimating price effects on the demand for alcohol.