Hong-Bin Fang's research while affiliated with Georgetown University and other places
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Publications (85)
Combinations of drugs are now ubiquitous in treating complex diseases such as cancer and HIV due to their potential for enhanced efficacy and reduced side effects. The traditional combination experiments of drugs focus primarily on the dose effects of the constituent drugs. However, with the doses of drugs remaining unchanged, different sequences o...
The human microbiome has been recently shown to be associated with disease risks and has important implications in risk stratification and precision medicine. Due to abundant taxa in the human body, microbiome data are high-dimensional and compositional. Dirichlet distributions and their generalization are used to characterize the dependence struct...
Functional data analysis has important applications in biomedical, health studies and other areas. In this paper, we develop a general framework for a mean curve estimation for functional data using a reproducing kernel Hilbert space (RKHS) and derive its asymptotic distribution theory. We also propose two statistics for testing the equality of mea...
We investigate a nonparametric, varying coefficient regression approach for modeling and estimating the regression effects caused by two functionally correlated datasets. Due to modern biomedical technology to measure multiple patient features during a time interval or intermittently at several discrete time points to review underlying biological m...
![True coefficient function β(t)\documentclass[12pt]{minimal}...](publication/354176723/figure/fig1/AS:11431281118044090@1675651846340/True-coefficient-function-btdocumentclass12ptminimal-usepackageamsmath_Q320.jpg)
![True coefficient function β(t)\documentclass[12pt]{minimal}...](publication/354176723/figure/fig2/AS:11431281118034980@1675651846430/True-coefficient-function-btdocumentclass12ptminimal-usepackageamsmath_Q320.jpg)
![True coefficient function β(t)\documentclass[12pt]{minimal}...](publication/354176723/figure/fig3/AS:11431281118044093@1675651846572/True-coefficient-function-btdocumentclass12ptminimal-usepackageamsmath_Q320.jpg)
![True coefficient function β(t)\documentclass[12pt]{minimal}...](publication/354176723/figure/fig4/AS:11431281118044094@1675651846609/True-coefficient-function-btdocumentclass12ptminimal-usepackageamsmath_Q320.jpg)
![Box plots of log10(MSE)\documentclass[12pt]{minimal}...](publication/354176723/figure/fig5/AS:11431281118044097@1675651846724/Box-plots-of-log10MSEdocumentclass12ptminimal-usepackageamsmath_Q320.jpg)
In this article, we study stochastic functional linear models (SFLM) driven by an underlying square integrable stochastic process X(t) which is generated by a standard Brownian motion. Utilizing the magnificent Itô integrals and Malliavin calculus, X(t) is expanded into a summation of orthogonal multiple integrals, i.e., Wiener-Itô chaos expansions...
In integrative analysis parametric or nonparametric methods are often used. The former is easier for interpretation but not robust, while the latter is robust but not easy to interpret the relationships among the different types of variables. To combine the advantages of both methods and for flexibility, here a system of semiparametric projection n...
Drug combination has been an important therapeutic development approach for cancer, viral or microbial infections, and other diseases involving complex biological networks. Synergistic drug combinations, which are more effective than predicted from summing effects of individual drugs, often achieve improved therapeutic index. Because drug-effect is...
We develop linear mixed models (LMMs) and functional linear mixed models (FLMMs) for gene-based tests of association between a quantitative trait and genetic variants on pedigrees. The effects of a major gene are modeled as a fixed effect, the contributions of polygenes are modeled as a random effect, and the correlations of pedigree members are mo...
Obesity is associated with cancer risk and its link with liver cancer is particularly strong. Obesity causes non-alcoholic fatty liver disease (NAFLD) that could progress to hepatocellular carcinoma (HCC). Chronic inflammation likely plays a key role. We carried out a bioassay in the high fat diet (HFD) fed C57BL/6J mice to provide insight into the...
The goal of a Phase I trial is to find the maximum tolerated dose (MTD). In a single-agent dose finding Phase I trial, the key underlying assumption is that toxicity probability increases monotonically with the dose level. However, in multi-agent trials, this assumption may not hold because the drug-drug interaction potentially can either decrease...
Combinations of multiple drugs are an important approach to maximize the chance for therapeutic success by inhibiting multiple pathways/targets. Analytic methods for studying drug combinations have received increasing attention because major advances in biomedical research have made available large number of potential agents for testing. The precli...
The basket trial is a recent development in the clinical trial practice. It conducts the test of the same treatment on several different related diseases in a single trial, and has the advantage of reduced cost and enhanced efficiency. A natural question is how to assess the performance of the group sequential basket trial against the classical gro...
Structure-based drug repositioning in addition to random chemical screening is now a viable route to rapid drug development. Proteochemometric computational methods coupled with kinase assays showed that mebendazole (MBZ) binds and inhibits kinases important in cancer, especially both BRAFWT and BRAFV600E. We find that MBZ synergizes with the MEK i...
Temporal gene expression data is of importance in the classifications of gene functions and have been extensively used in biomedical studies, such as cancer diagnostics. However, since temporal gene expressions vary over time, after the initial time periods, many genes exhibit some kind of stability, which means that gene expressions keep constant...
Multidrug combination is an important therapeutic approach for cancer, viral or microbial infections, hypertension and other diseases involving complex biological networks. Synergistic drug combinations, which are more effective than predicted from summing effects of individual drugs, often achieve increased therapeutic index. Because drug-effect i...
Few articles have been written on analyzing three-way interactions between drugs. It may seem to be quite straightforward to extend a statistical method from two-drugs to three-drugs. However, there may exist more complex nonlinear response surface of the interaction index (II) with more complex local synergy and/or local antagonism interspersed in...
Drug combination is a critically important therapeutic approach for complex diseases such as cancer and HIV due to its potential for efficacy at lower, less toxic doses and the need to move new therapies rapidly into clinical trials. One of the key issues is to identify which combinations are additive, synergistic, or antagonistic. While the value...
In tumour xenograft experiments, treatment regimens are ad-
ministered and the tumour volume of each individual is measured repeatedly
over time. Survival data are recorded due to the death of some individuals
during the observation time period. Also, cure data are observed due to a
portion of individuals who are completely cured in the experiments...
Abstract In cancer drug development, demonstrated efficacy in tumor xenograft models is an important step to bring a promising compound to human. A key outcome variable is tumor volume measured over a period of time, while mice are treated with certain treatment regimens. Constrained parametric model has been proposed to account for special feature...
Predictive or prognostic analysis plays an increasingly important role in the era of personalized medicine to identify subsets of patients whom the treatment may benefit the most. Although various time-dependent covariate models are available, such models require that covariates be followed in the whole follow-up period. This article studies a new...
Purpose:
Myeloma-directed cellular immune responses after autologous stem cell transplantation (ASCT) may reduce relapse rates. We studied whether coinjecting the TLR-3 agonist and vaccine adjuvant Poly-ICLC with a MAGE-A3 peptide vaccine was safe and would elicit a high frequency of vaccine-directed immune responses when combined with vaccine-pri...
We retrospectively evaluated the tolerability and efficacy of fractionated total body irradiation (TBI) (1,200 cGy) and melphalan (MEL) (100-110 mg/m(2)) myeloablative conditioning in 48 patients with nonremission AML (n = 14), ALL (n = 10), NHL (n = 18), and other refractory hematologic malignancies (n = 6) who received allogeneic stem cell transp...
Non-surgical bleeding (NSB) is a major complication among heart failure (HF) patients supported by continuous-flow left ventricular assist devices (CF-LVADs). Understanding the hemostatic defects contributing to NSB after CF-LVAD implantation is crucial for prevention of this adverse event. The aim of this study was to examine the link between plat...
BACKGROUND: Non-surgical bleeding (NSB) is a major complication among heart failure (HF) patients supported by CF-LVADs. Understanding the hemostatic defects contributing to NSB after CF-LVAD implantation is crucial for prevention of this adverse event. The aim of this study was to examine the link of platelet glycoprotein Ibα (GPIbα) ectodomain sh...
Purpose:
To determine the maximum-tolerated dose (MTD) of the histone deacetylase inhibitor vorinostat combined with fixed doses of cytarabine (ara-C or cytosine arabinoside) and etoposide in patients with poor-risk or advanced acute leukemia, to obtain preliminary efficacy data, describe pharmacokinetics, and in vivo pharmacodynamic effects of vo...
c-Myc has been implicated in a variety of hematologic malignancies including Burkitt's lymphoma. Targeting c-Myc driven growth pathways could be therapeutically useful but might require the identification of critical downstream proteins. Here we show that the serine-threonine kinase PBK/TOPK is frequently overexpressed in high-grade lymphomas and i...
352
Background
Autologous stem cell transplantation (ASCT) for MM leads to complete responses in ∼20–40% of patients but rare cures. Patients with rapid recovery of T cells post ASCT may have improved outcomes suggesting possible immune mediated tumor control. We have shown that adoptive T-cell transfers after ASCT for MM using vaccine-primed and...
Temporal gene expression data are of particular interest to researchers as they contain rich information in characterization of gene function and have been widely used in biomedical studies and early cancer detection. However, the current temporal gene expressions usually have few measuring time series levels; extracting information and identifying...
![Figure 2. A, ponatinib decreases [ 125 I]-IAAP photolabeling of ABCB1...](profile/Zhe-Sheng-Chen/publication/229015533/figure/fig1/AS:459837109739520@1486645118339/A-ponatinib-decreases-125-I-IAAP-photolabeling-of-ABCB1-and-ABCG2-Crude-membranes_Q320.jpg)
Ponatinib is a novel tyrosine kinase inhibitor with potent activity against BCR-ABL with mutations, including T315I, and also against fms-like tyrosine kinase 3. We tested interactions between ponatinib at pharmacologically relevant concentrations of 50 to 200 nmol/L and the MDR-associated ATP-binding cassette (ABC) proteins ABCB1, ABCC1, and ABCG2...
Despite the role of aerobic glycolysis in cancer, recent studies highlight the importance of the mitochondria and biosynthetic pathways as well. PPARγ coactivator 1α (PGC1α) is a key transcriptional regulator of several metabolic pathways including oxidative metabolism and lipogenesis. Initial studies suggested that PGC1α expression is reduced in t...
Qualitative evaluation of open-ended questions for evaluation of web-based palliative care training course—July 1, 2004 thru Dec 13, 2010. N = 318 respondents
Open-ended questions regarding web-based EOLC training course for medical residents. N = 318 respondents
To assist the development and application of blood-contacting medical devices, two novel flow-through Couette-type blood-shearing devices have been developed to study the quantitative relationship between blood damage indexes and flow-dependent parameters. One device is an axial flow-through Couette-type device supported by a pair of pin bearings a...
To graduate internal medicine residents with basic competency in palliative care, we employ a two-pronged strategy targeted at both residents and attending physicians as learners. The first prong provides a knowledge foundation using web-based learning programs designed specifically for residents and clinical faculty members. The second prong is as...
A mark variable is a generalization of measurements such as lifetime medical costs and quality-adjusted lifetimes. Recently, analysis of the mark variable has generated significant interest as an important component in health treatment evaluation. In this paper, a novel approach to estimating the mean of the mark variable under right censoring is p...
In a phase 1/2 two-arm trial, 54 patients with myeloma received autografts followed by ex vivo anti-CD3/anti-CD28 costimulated autologous T cells at day 2 after transplantation. Study patients positive for human leukocyte antigen A2 (arm A, n = 28) also received pneumococcal conjugate vaccine immunizations before and after transplantation and a mul...
Drug combinations are the hallmark of cancer therapy. Preclinical experiments on multi-drug combinations are important steps to bring the therapy to clinic. A statistical approach for evaluating the joint effect of the combination is necessary because even in vitro experiments often demonstrate significant variation in dose-effect. Such variation n...
The design and analysis of drug combination studies continue to be an area requiring further methodological developments. Faessel et al. (1998) studied the joint effects of the combinations of trimetrexate (TMQ) and the GARFT inhibitor AG2034 to inhibit the growth of HCT-8 human ileocecal adenocarcinoma cells. Their experiments provide a rich data...
784
BACKGROUND
Previously, we showed that adoptive transfer of in vivo vaccine-primed and ex vivo (anti-CD3/anti-CD28) costimulated autologous T cells (ex-T) at day +12 after transplant increased CD4 & CD8 levels at day +42 and augmented vaccine-specific immune responses in pts with myeloma (MM)[Nat Med 2005; 11: 1230-7].
DESIGN
We conducted a ph...
This paper considers the nonparametric estimation of a failure time distribution function when only doubly censored data are available, which occurs in many situations such as epidemiological studies. In these situations, the failure time of interest is defined as the elapsed time between an initial event and a subsequent event, and the observation...
This paper considers non-parametric estimation of a multivariate failure time distribution function when only doubly censored data are available, which occurs in many situations such as epidemiological studies. In these situations, each of multivariate failure times of interest is defined as the elapsed time between an initial event and a subsequen...
Motivated by experimental designs for drug combination studies, in this paper, we propose a novel approach for generating a uniform distribution on an arbitrary tetragon in two-dimensional Euclidean space . The key idea is to construct a one-to-one transformation between an arbitrary tetragon and the unit square [0,1]2. This transformation then pro...
Preclinical experiment on multi-drug combination has an increasingly important role in (especially cancer) drug development because of the need to reduce development time and costs. Despite recent progress in statistical methods for assessing drug interaction, there is a lack of general methods for determining the doses comprising the combinations...
The study of drug combinations has become important in drug development due to its potential for efficacy at lower, less toxic doses and the need to move new therapies rapidly into clinical trials. The goal is to identify which combinations are additive, synergistic, or antagonistic. Although there exists statistical framework for finding doses and...
Previously, we showed that adoptive transfer of in vivo vaccine-primed and ex vivo (anti-CD3/anti-CD28) costimulated autologous T cells (ex-T) at day +12 after transplant increased CD4 and CD8 T-cell counts at day +42 and augmented vaccine-specific immune responses in patients with myeloma. Here, we investigated the safety and kinetics of T-cell re...
Vorinostat [suberoylanilide hydroxamic acid (SAHA)] is a potent histone deacetylase inhibitor with promising clinical efficacy as an anticancer agent. In this preclinical study, we evaluated combining cytosine arabinoside [1-beta-D-arabinofuranosylcytosine (ara-C)] and/or etoposide with vorinostat for use in the treatment of acute leukemias.
Cell s...
Clustering analysis is a common statistical tool for knowledge discovery. It is mainly conducted when a project still is in the exploratory phase without any priori hypotheses. However, the statistical significance testing between the clusters can be meaningful in helping the researchers to assess if the classification results from implementing a c...
This article considers the nonparametric maximum likelihood estimator (NPMLE) of a joint distribution function when the multivariate failure times of interest are interval-censored. With different types of interval censoring mechanism, the NPMLE's of the multivariate distribution function are studied and the strong consistency for the NPMLEs is obt...
Temporal gene expression data are of particular interest to researchers as they contain rich information in characterization of gene function and have been widely used in biomedical studies. However, extracting information and identifying efficient treatment effects without loss of temporal information are still in problem. In this paper, we propos...
It is well known that the bridge regression (with tuning parameter less or equal to 1) gives asymptotically unbiased estimates of the nonzero regression parameters while shrink-ing smaller regression parameters to zero to achieve variable selection. Despite advances in the last several decades in de-veloping such regularized regression models, issu...
We previously reported that our novel compound 3beta-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (VN/124-1) is a potent 17alpha-hydroxylase/17,20-lyase (CYP17) inhibitor/antiandrogen and strongly inhibits the formation and proliferation of human prostate cancer LAPC4 tumor xenografts in severe combined immunodeficient mice. In this study,...
Drug combination is a major treatment approach in cancer and antiviral therapies. A key issue is to find which combinations are additive, synergistic or antagonistic. In this paper, we develop statistical methods for experimental design and data analysis of combination studies of drugs that have log-linear dose-response curves. This class of dose r...
Fitting logistic regression models is challenging when their parameters are restricted. In this article, we first develop a quadratic lower-bound (QLB) algorithm for optimization with box or linear inequality constraints and derive the fastest QLB algorithm corresponding to the smallest global majorization matrix. The proposed QLB algorithm is part...
A functional genomic approach integrating microarray and proteomic analyses done in our laboratory has identified 14-3-3zeta as a putative oncogene whose activation was common and driven by its genomic amplification in lung adenocarcinomas. 14-3-3zeta is believed to function in cell signaling, cycle control, and apoptotic death. Following our initi...
Convex constraints (CCs), such as box constraints and linear inequality constraints, appear frequently in statistical inference and in applications. The problems of quadratic optimization (QO) subject to CCs occur in isotonic regression, shape-restricted nonparametric regression, variable selection (via the lasso algorithm and bridge regression), l...
Analysis of molecular genetic markers in biological fluids has been proposed as a powerful tool for cancer diagnosis. We have characterized in detail the genetic signatures in primary non-small cell lung cancer, which provided potential diagnostic biomarkers for lung cancer. The aim of this study was to determine whether the genetic changes can be...
Postoperative interferon-α (IFN-α) therapy improved survival in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). The identification of predictive markers of outcome will help to select patients who are most likely to benefit from treatment.
An immunohistochemical study of P48 was performed on specimens that were collect...
In clinical studies, multiple endpoints are often measured for each patient longitudinally. The multivariate random-effects or random coefficient model has been a useful method for analysis. However, medical research problems may impose restrictions on the model parameters of interests. For example, in a paediatric brain tumour study on radiation t...
Immunodeficiency is a barrier to successful vaccination in individuals with cancer and chronic infection. We performed a randomized phase 1/2 study in lymphopenic individuals after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for myeloma. Combination immunotherapy consisting of a single early post-transplant infusio...
We present a unified approach to Laplace approximation of hypergeometric functions with two matrix arguments. The general form of the approximation is designed to exploit the Laplace approximations to hypergeometric functions of a single matrix argument ...
Copulas, as dependence measures of random variables, have wide applications in distribution theory, medical research, multivariate survival analysis, risk management, and other fields. The basic properties of copulas have been studied extensively in the literature. However, their geometric and topological properties, which are very important for pr...
In cancer drug development, demonstrated efficacy in tumor xenograft experiments on severe combined immunodeficient mice who are grafted with human tumor tissues or cells is an important step to bring a promising compound to human. These experiments also demonstrated a good correlation in efficacy with clinical outcomes. A key outcome variable is t...
In longitudinal studies with small samples and incomplete data, multivariate normal-based models continue to be a powerful tool for analysis. This has included a broad scope of biomedical studies. Testing the assumption of multivariate normality (MVN) is critical. Although many methods are available for testing normality in complete data with large...
We consider large sample inference in a semiparametric logistic/proportional-hazards mixture model. This model has been proposed to model survival data where there exists a positive portion of subjects in the population who are not susceptible to the event under consideration. Previous studies of the logistic/proportional-hazards mixture model have...
In cancer drug development, xenograft experiments (models) where mice are grafted with human cancer cells are used to elucidate the mechanism of action and/or to assess efficacy of a promising compound. Demonstrated activity in this model is an important step to bring a promising compound to humans. A key outcome variable in these experiments is tu...
A novel noninformative censoring structure is revealed and the small sample properties of the Kaplan-Meier estimator [E. L. Kaplan and P. Meier, J. Am. Assoc. 53, 457–481 (1958; Zbl 0089.14801)] and the W. Nelson estimator [J. Qual. Technol. 1, 27–52 (1969)] under such noninformative censoring are studied. The exact bias expressions of these estima...
In cancer drug development, demonstrated anticancer activity in animal models is an important step to bring a promising compound to clinic. Proper design and analysis of experiments using laboratory animals have received increasing attention recently. These experiments involve informatively censored longitudinal data with small samples. The problem...
There is insufficient information about combination therapy with approved anti-influenza agents. We tested combinations that paired a neuraminidase (NA) inhibitor (zanamivir, oseltamivir carboxylate, or peramivir) with rimantadine against infection of MDCK cells with H1N1 and H3N2 subtypes of influenza A virus and characterized their mode of intera...
DISCLOSURE
ABSTRACT
Purpose/Objective: To determine whether pain relief, medication usage, and development of facial numbness after Gamma Knife surgery (GKS) for the treatment of trigeminal neuralgia (TN) is affected by trigeminal nerve compression, quality of nerve visualization on MRI, or brainstem radiation dose. Materials/Methods: 112 patients...
To review our results with gamma knife surgery (GKS) in the treatment of trigeminal neuralgia (TN), and to determine whether pain relief, medication usage, and the development of facial numbness are affected by trigeminal nerve compression, MRI imaging quality, or brainstem radiation dose.
One hundred twelve patients with TN refractory to medical o...
To evaluate the function and substrate specificity of human breast cancer resistance protein (BCRP, ABCG2) in the absence of cofactors or heterologous partner proteins, Xenopus laevis oocytes were injected with cRNA of wild-type or mutant (R482T) BCRP. High expression of BCRP was observed on the oocyte surface. Accumulation and efflux assays reveal...
To determine whether a unit specific nursing acuity score is useful for assessing patients with cancer admitted to the pediatric intensive care unit.
Prospective, cohort analysis.
The intensive care unit of a tertiary-care pediatric oncology hospital.
A total of 219 patients admitted to the pediatric intensive care unit with a diagnosis of cancer o...
In anticancer drug development, the combined use of two drugs is an important strategy to achieve greater therapeutic success. Often combination studies are performed in animal (mostly mice) models before clinical trials are conducted. These experiments on mice are costly, especially with combination studies. However, experimental designs and sampl...
Restricted parameter problems arise in many applications, for example, in ordinal regression, sample surveys, bioassay, dose-response, variance components models, and factor analysis models. We proposed a unified method to estimate normal means with or without nuisance variance parameters subject to a class of restrictions. This class encompasses t...
The problem of two-sample survival comparisons has been investigated by several authors. Pepe and Fleming (1989) introduced a test for right-censored survival data. Petroni and Wolfe (1994) considered a similar test where the survival times can only take on a finite number of values. We extend their tests to general types of interval-censored data...
In cancer drug development, demonstrating activity in xenograft models, where mice are grafted with human cancer cells, is an important step in bringing a promising compound to humans. A key outcome variable is the tumor volume measured in a given period of time for groups of mice given different doses of a single or combination anticancer regimen....
Square tray distributions have been studied by Johson and Kotz (Statist. Probab. Lett. 42 (1999) 157). As an extension, multiple square tray distributions are considered in this paper. These distributions are simple in the sense that there are only three different levels of the probability density function; they lead, however, to more complicated a...
Based on an analysis of copulas of elliptically contoured distributions, joint densities of continuous variables with given strictly increasing marginal distributions are constructed. A method utilized for this procedure is to embed the spherical distribution quantile transformation of each variable into an elliptically contoured distribution. The...
We study the nonparametric maximum likelihood estimation of a failure time distribution function based on doubly interval-censored data. A self-consistent equation is derived for the estimator. Furthermore, the strong consistency of the estimator is established.
In this paper, a family of copulas with two parameters is proposed and its dependence analysis is performed. The corresponding family of bivariate distributions with specified marginals is constructed. For normal marginals, the new distributions are non-elliptical and can be applied in data analysis. They provide various alternative hypotheses for...