We propose an adaptive hybrid control causal (AHCC) design to leverage historical control data to reduce the sample size demanded by standard randomised controlled trials (RCT). Under the causal inference framework, we define the causal... more
We propose an adaptive hybrid control causal (AHCC) design to leverage historical control data to reduce the sample size demanded by standard randomised controlled trials (RCT). Under the causal inference framework, we define the causal estimand of the average treatment effect and derive the corresponding estimator based on the trial data and historical control data. The AHCC design takes a multistage or group sequential approach. The number of patients randomised to the concurrent control is adaptively adjusted based on the amount of information borrowed from the historical control data. At each stage, based on the interim data, the contribution of the historical control data, quantified by the effective sample size, is updated and used to determine the randomisation ratio between the treatment and control arms for the next stage, with the goal to resemble a standard RCT upon the completion of the trial. Simulation studies show that the AHCC design has desirable operating character...
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Existing phase II clinical trial designs focus on a single scalar endpoint, such as a binary, continuous, or survival endpoint. In some clinical trials, such as pain management studies, the efficacy endpoint of interest is measured... more
Existing phase II clinical trial designs focus on a single scalar endpoint, such as a binary, continuous, or survival endpoint. In some clinical trials, such as pain management studies, the efficacy endpoint of interest is measured longitudinally. We propose a Bayesian phase II design for such clinical trials. We model the longitudinal measurement process using Bayesian hierarchical model, where subject‐specific trajectory shrinks toward the population trajectory to borrow information across subjects. The Bayesian penalized spline is used to model subject‐specific and population trajectories without making strong parametric assumption on their shapes. We use the area under the curve of the trajectory as the summary of the treatment effect over time. The design takes a group sequential approach and takes into account both statistical significance and clinical relevance. Bayesian criteria is proposed to make interim and final decisions based on the evidence of statistical significance...
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Abstract Traditional vaccine clinical development is an undertaking involving meticulous, multiple studies in multiple populations at risk of infection and disease over multiple years. SARS-CoV-2 and COVID-19 vaccine development is... more
Abstract Traditional vaccine clinical development is an undertaking involving meticulous, multiple studies in multiple populations at risk of infection and disease over multiple years. SARS-CoV-2 and COVID-19 vaccine development is following this traditional development pathway, and accelerated Phase I-II-III clinical programs are being applied. This is not the first time vaccines have been manufactured and tested quickly to meet a public health crisis. Selected statistical concepts pertaining to vaccine efficacy and safety, relevant during the design and implementation of such clinical development programs, will be discussed.
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Industries such as the manufacturing or logistics industry need algorithms that are flexible to handle novel or unknown objects. Many current solutions in the market are unsuitable for grasping these objects in high-mix and low-volume... more
Industries such as the manufacturing or logistics industry need algorithms that are flexible to handle novel or unknown objects. Many current solutions in the market are unsuitable for grasping these objects in high-mix and low-volume scenarios. Finally, there are still gaps in terms of grasping accuracy and speed that we would like to address in this research. This project aims to improve the robotic grasping capability for novel objects with varying shapes and textures through the use of soft grippers and data-driven learning in a hyper-personalization line. A literature review was conducted to understand the tradeoffs between the deep reinforcement learning (DRL) approach and the deep learning (DL) approach. The DRL approach was found to be data-intensive, complex, and collision-prone. As a result, we opted for a data-driven approach, which to be more specific, is PointNet GPD in this project. In addition, a comprehensive market survey was performed on tactile sensors and soft gr...
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Initial release of the Isabelle/HoTT object logic, coinciding with the submission of my MS thesis. There is still lots of work to be done, and it is quite likely that future versions will not look very much like the current state. In... more
Initial release of the Isabelle/HoTT object logic, coinciding with the submission of my MS thesis. There is still lots of work to be done, and it is quite likely that future versions will not look very much like the current state. In particular, polymorphism is a pain. Also proof methods.
Even when racially diversified, American organizations remain dominated by whites. The color line regularly reasserts itself through racialized structures and social patterns. Many academics therefore argue that racial integration does... more
Even when racially diversified, American organizations remain dominated by whites. The color line regularly reasserts itself through racialized structures and social patterns. Many academics therefore argue that racial integration does not work. However, this argument has two limitations. Theoretically, the argument conflates integration with desegregation. Most diverse institutions are integrated in principle but desegregated in practice. Whereas desegregation dismantles racial barriers to entry, it leaves existing structures unchanged. Integration, by contrast, makes changes that facilitate the structural inclusion of people of color. Empirically, the majority of research is drawn from studies of predominantly white organizations. Theories of colorblind racism show how such organizations can be expected to sustain white hegemony. By contrast, I analyze two years worth of ethnographic, interview, and survey data from two organizations where whites are not dominant: a church in the ...
Supplement_Inconsistency_Examples_26Jun for Lessons Learned From Multi-regional Trials With Signals of Treatment Effect Heterogeneity by Gang Li, Hui Quan, Gordon Lan, Soo Peter Ouyang, Fei Chen, Weining Robieson, William Wang, Bruce... more
Supplement_Inconsistency_Examples_26Jun for Lessons Learned From Multi-regional Trials With Signals of Treatment Effect Heterogeneity by Gang Li, Hui Quan, Gordon Lan, Soo Peter Ouyang, Fei Chen, Weining Robieson, William Wang, Bruce Binkowitz, Shuai Sammy Yuan, Yoko Tanaka, Josh Chen, Nobushige Matsuoka, Lanju Zhang, Song Yang, and Paul Gallo in Therapeutic Innovation & Regulatory Science
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Abstract Traditional vaccine clinical development is an undertaking involving meticulous, multiple studies in multiple populations at risk of infection and disease over multiple years. SARS-CoV-2 and COVID-19 vaccine development is... more
Abstract Traditional vaccine clinical development is an undertaking involving meticulous, multiple studies in multiple populations at risk of infection and disease over multiple years. SARS-CoV-2 and COVID-19 vaccine development is following this traditional development pathway, and accelerated Phase I-II-III clinical programs are being applied. This is not the first time vaccines have been manufactured and tested quickly to meet a public health crisis. Selected statistical concepts pertaining to vaccine efficacy and safety, relevant during the design and implementation of such clinical development programs, will be discussed.
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Drugs that alter ventricular repolarization have been associated with malignant ventricular arrhythmia, which has been shown to increase with increasing QT interval—the time required for ventricular depolarization and repolarization. To... more
Drugs that alter ventricular repolarization have been associated with malignant ventricular arrhythmia, which has been shown to increase with increasing QT interval—the time required for ventricular depolarization and repolarization. To determine whether a new drug, especially a nonanti-arrhythmia drug, can cause an increase in the QT interval is a necessary step in safety evaluation. Since the QT interval is inversely
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Extensive research has been conducted in the Multi-Regional Clinical Trial (MRCT) area. To effectively apply an appropriate approach to a MRCT, we need to synthesize and understand the features of different approaches. In this paper,... more
Extensive research has been conducted in the Multi-Regional Clinical Trial (MRCT) area. To effectively apply an appropriate approach to a MRCT, we need to synthesize and understand the features of different approaches. In this paper, examples are used to illustrate considerations regarding design, conduct, analysis and interpretation of result of MRCTs. We start with a brief discussion of region definitions and the scenarios where different regions have differing requirements for a MRCT. We then compare different designs and models as well as the corresponding interpretation of the results. We highlight the importance of paying special attention to trial monitoring and conduct to prevent potential issues associated with the final trial results. Besides evaluating the overall treatment effect for the entire MRCT, we also consider other key analyses including quantification of regional treatment effects within a MRCT, and assessment of consistency of these regional treatment effects.
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ATM/IP directly over WDM ring with optical layer protection is proposed and demonstrated. Traffics are 1+1 protected ATM OC-48c and a low priority part-time OC-48c IP traffic. When either fiber or cable failure occurs, optical layer... more
ATM/IP directly over WDM ring with optical layer protection is proposed and demonstrated. Traffics are 1+1 protected ATM OC-48c and a low priority part-time OC-48c IP traffic. When either fiber or cable failure occurs, optical layer protection can restore the ATM traffic via optical layer span/ring protection within 13 ms/23 ms while the part-time traffic is dropped. A faster protection time comparing with SONET standard is experimentally verified by both physical layer and ATM layer test results.
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AIII-V Mach-Zehnder (MZ) optical modulator has successfully been employed within a .10 Gb/s optical transmitter1,2 to achieve transmission in excess of 80 km over NDSF without use of external dispersion compensation components.
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A novel bi-directional wavelength path switched ring (BWPSR) is proposed and demonstrated. Various optical channel layer protection schemes (1+1 UPSR, Optical BLSR, and BWPSR) are discussed and compared. BWPSR has an advantage of higher... more
A novel bi-directional wavelength path switched ring (BWPSR) is proposed and demonstrated. Various optical channel layer protection schemes (1+1 UPSR, Optical BLSR, and BWPSR) are discussed and compared. BWPSR has an advantage of higher efficiency of wavelength utilization and smaller propagation delay for optical channel layer ring restoration. Both BER and Jitter performances of BWPSR are measured, which comply with Bellcore standard requirement. Optical channel layer span and ring protection time are measured to be 13 ms and 23 ms, respectively, which are faster than SONET standard requirement (50 ms). Interoperability test with other WDM transport equipment are performed, which shows no performance degradation.
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Accelerated Test for Effect of Moisture and Temperature on Glass-encapsulant Interface Shaofu Wu, Josh Chen, Bert Weaver, Bill Sumner, and Victor Juarez New Products R&D, The Dow Chemical Company 2301 Brazosport Blvd., B-1470... more
Accelerated Test for Effect of Moisture and Temperature on Glass-encapsulant Interface Shaofu Wu, Josh Chen, Bert Weaver, Bill Sumner, and Victor Juarez New Products R&D, The Dow Chemical Company 2301 Brazosport Blvd., B-1470 Freeport, Texas 77541 ABSTRACT ...
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Global trial strategy with the participation of all major regions including countries from emerging markets surely increases new drug development efficiency. Nevertheless, there are circumstances in which some countries in emerging... more
Global trial strategy with the participation of all major regions including countries from emerging markets surely increases new drug development efficiency. Nevertheless, there are circumstances in which some countries in emerging markets cannot join the original global trial. To evaluate the extrapolability of the original trial results to a new country, a bridging trial in the country has to be conducted. In this paper, we first evaluate the efficiency loss of the bridging trial strategy compared to that of the global trial strategy as a function of between-study variability from consistency assessment perspective. The provided evidence should encourage countries in emerging markets to make a greater effort to participate in the original global trial. We then discuss sample size requirement for desired assurance probability for consistency assessment based on various approaches for both global and bridging trial strategies. Examples are presented for numerical demonstration and comparisons.
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Raltegravir is the first integrase strand transfer inhibitor approved for the treatment of HIV‐1 infection. As the first agent in this new class of antiretroviral therapies, raltegravir has demonstrated safety and efficacy in... more
Raltegravir is the first integrase strand transfer inhibitor approved for the treatment of HIV‐1 infection. As the first agent in this new class of antiretroviral therapies, raltegravir has demonstrated safety and efficacy in treatment‐naive as well as heavily pretreated HIV‐infected patients failing therapy with multidrug‐resistant virus. Raltegravir has a favorable drug interaction profile that permits both administration to a wide, demographically diverse patient population and coadministration with many other therapeutic agents, including antiretroviral agents and supportive medications, without restrictions or dose adjustment. Data through 96 weeks of follow‐up in three phase III studies, protocol 021 (STARTMRK) in treatment‐naive patients, and protocols 018 (BENCHMRK‐1) and 019 (BENCHMRK‐2) in treatment‐experienced patients, demonstrated the potent and durable antiretroviral and immunologic effects and the favorable long‐term safety profile of raltegravir in both treatment‐nai...
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Background In efficacy trials of a tetravalent dengue vaccine (CYD-TDV), excess hospitalizations for dengue were observed among vaccine recipients 2 to 5 years of age. Precise risk estimates according to observed dengue serostatus could... more
Background In efficacy trials of a tetravalent dengue vaccine (CYD-TDV), excess hospitalizations for dengue were observed among vaccine recipients 2 to 5 years of age. Precise risk estimates according to observed dengue serostatus could not be ascertained because of the limited numbers of samples collected at baseline. We developed a dengue anti-nonstructural protein 1 (NS1) IgG enzyme-linked immunosorbent assay and used samples from month 13 to infer serostatus for a post hoc analysis of safety and efficacy. Methods In a case-cohort study, we reanalyzed data from three efficacy trials. For the principal analyses, we used baseline serostatus determined on the basis of measured (when baseline values were available) or imputed (when baseline values were missing) titers from a 50% plaque-reduction neutralization test (PRNT), with imputation conducted with the use of covariates that included the month 13 anti-NS1 assay results. The risk of hospitalization for virologically confirmed den...